good clinical practices
TRANSCRIPT
Dr Dhruva Kumar Sharma
Department of Pharmacology
SMUSMIMS
Saturday the 19th Of July 2014
Evolution of Good Clinical
Practices
An overview
2
PROTOCOL
bull Nazi war crimes
bull Tuskegee syphilis trial
bull Thalidomide disaster
bull Jews chronic disease trial
bull Neuremberg trial code
bull Declaration of helsinki
bull Belmonte report
bull ICHGCP Guidelines
3
Good Clinical Practice (GCP) Meaning
4
Good Clinical Practice (GCP) is an international
ethical and scientific quality standard for designing
conducting recording and reporting trials that involve the
participation of human subjects
Compliance with this standard provides public
assurance that the rights safety and well-being of trial
subjects are protected consistent with the principles that
have their origin in the Declaration of Helsinki and that
the clinical trial data are credible
bull The objective of this ICH GCP Guideline is to provide a unified standard for the European Union (EU) Japan and the United States to facilitate the mutual acceptance of clinical data by the regulatory authorities in these jurisdictions
5
History
Why Do We Need Guidelines
Why Are We Regulated
Nazi Medical War Crimesduring World War II
bull Experiments conducted by Nazi physicians during World War II were unprecedented in their scope and the degree of harm and suffering to which human beings were subjected
bull Typically the experiments resulted in death disfigurement or permanent disability and as such are considered as examples of medical torture
Nazi Medical War Crimes
Medical experiments were performed onthousands of concentration campprisoners and included deadly studies andtortures such as-
Injecting people with gasoline and liveviruses
Immersing people in ice water
Forcing people to ingest poisons
9
Incisions made by
medical personnel
that were purposely
infected with bacteria
dirt and slivers of
glass
Victim of a tuberculosis medical experiment
10
Prisoner in a compression chamber
11
An experiment to
determine
altitudes at which
aircraft crews
could survive
without oxygen
Immersing people in ice water
bull With the intent of discovering means to prevent and treat hypothermia
bull 280 to 300 victims
bull One study forced subjects to endure a tank of ice water for up to five hours
12
bull In 1946 an American military tribunal opened criminal proceedings against 23 leading German physicians Doctors Trial
bull Sixteen of the doctors were found guilty
bull Seven were sentenced to death
bull Development of the Nuremberg Code of medical ethics
13
THE DOCTORS TRIAL
The Tuskegee Syphilis Study
bull Research participants was the long-term study of black males conducted at Tuskegee Alabama by the United States Public Health Service
bull (1930s-1970) - examination of the natural history of untreated syphilis
bull More than 400 African-American men with syphilis participated
bull The men were recruited without informed consent and in fact were misinformed that some of the procedures done in the interest of the research (eg spinal taps) were actually special free treatment
The Tuskegee Syphilis Study
bull In the 1940s penicillin was found to be effective in the treatment of syphilis
bull The study continued however and the men were neither informed of nor treated with the antibiotic
bull The first accounts of this study appeared in the national press in 1972
bull Belmont report 1978 (Ethical Principles and guidelines for the protection of human subjects of research)-Tuskegee syphilis study
The Jewish Chronic Disease Hospital Study
bull In 1963 studies were undertaken at New Yorks Jewish Chronic Disease Hospital to understand whether the bodys inability to reject cancer cells was due to cancer or debilitation
bull Previous studies had indicated that healthy persons reject cancer cells promptly and the researchers allegedly believed that the debilitated patients would also reject the cancers but at a substantially slower rate compared to healthy participants
The Jewish Chronic Disease Hospital Study
bull Further patients were not told that they would receive cancer cells because the researchers felt it would unnecessarily frighten them
bull It was found that the study had not been presented to the hospitals research committee and that the physicians responsible for the patients care had not been consulted
bull The researchers were found guilty of fraud deceit and unprofessional conduct
The Willowbrook Study
bull Institutionalized children as participants in research is demonstrated in a series of studies conducted from 1963 through 1966 at the Willowbrook State School a New York institution for mentally defective children
bull In order to gain an understanding of the natural history of infectious hepatitis under controlled circumstances newly admitted children were deliberately infected with the hepatitis virus
bull In some cases parents found they were unable to admit their children to Willowbrook unless they agreed to their childrsquos participation in the studies
The Willowbrook Study
This controversial case raised important questions about the adequacy and freedom of consent inadequate disclosure of the childs risk of later developing chronic liver disease
The Milgram Study
bull The lsquoteachersrsquo were instructed to give the lsquolearnersrsquo electrical shocks in response to incorrect answers on verbally given lsquotestsrsquo
bull Participants were deceived as to the nature of the study being told it was to test new teaching-learning techniques
Thalidomide tragedy
bull Thalidomide was a widely used drug in the late 1950s and early 1960s for the treatment of nausea in pregnant women
bull It became apparent in the 1960s that thalidomide treatment resulted in severe birth defects in thousands of children
21
bull Within a few years of the widespread use of thalidomide in Europe Australia and Japan approximately 10000 children were born with phocomelia leading to the ban of thalidomide in most countries in 1961
22
bull The thalidomide tragedy marked a turning point in toxicity testing as it prompted United States and international regulatory agencies to develop systematic toxicity testing protocols
bull The thalidomide tragedy also brought into sharp focus the importance of rigorous and relevant testing of pharmaceuticals prior to their introduction into the market place (Kelsey 1988)
23
Thalidomide tragedy
Nuremberg Code-1947
bull On April 17 1947 United States Counsel for War Crimescame out with six points defining ldquolegitimate researchrdquo
bull The verdict of August 19 reiterated almost all of thesepoints in a section entitled Permissible MedicalExperiments and revised the original six points into ten
bull Subsequently the ten points became known as theNuremberg Code
24
Codes and Guidelines
Nuremberg Code (1947)
WMArsquos Declaration of Helsinki (1964)
bull Belmont Report (USA) (1979)-Tuskegee syphilis study
Council for International Organizations of Medical Sciences (CIOMS) 1993
International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) in 1996 Guideline on Good Clinical PracticeE6 (GCP)
Nuremberg Code (1947)
Voluntary and Informed consent-absolutely essential
Anticipate scientific benefits Useful
Animal experimentation first
Avoid physical and mental suffering
Benefits outweigh risks
No intentional death or disability
Protection from harm
Subject free to withdraw
Qualified investigators
Investigator will stop if harm occurs
THE DECLARATION OF HELSINKI-1964
Is an international standard for the conduct of clinicalresearch adopted by International Conference onHarmonization(ICH) Good Clinical Practice standards
A global ethical standard for medical research and wasapproved at the WMA General Assembly by a majority voteof 75
It is the mission of the clinical research professionals tosafeguard the health of the people
THE DECLARATION OF HELSINKI-1964
Historical Overview-
Its origin has been found in the Nazi Disaster and hasundergone several modifications
Prior to 1947 Nuremberg Code there was noaccepted code of conduct governing the ethicalaspects of human research
World Medical Association
It is an international organization of physicians
established on September 17 1947
First general Assembly of WMA was held in Paris
France
Mission- Serve humanity by endeavoring to achieve the
highest international standards in medical education
science ethics and health care for all peoples of the world
Declaration of Helsinki 1964
Adapted from Nuremberg
Code by the World Medical Association (WMA)
First adopted in Helsinki Finland 1964
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI- 2008
Ethical Principles for Medical Research Involving Human Subjects
Adopted by the 18th WMA General Assembly Helsinki Finland June 1964 and amended by the
29th WMA General Assembly Tokyo Japan October 1975
35th WMA General Assembly Venice Italy October 1983
41st WMA General Assembly Hong Kong September 1989
53th WMA General Assembly Washington 2002 (Note of Clarification on paragraph 29 added)
55th WMA General Assembly Tokyo 2004 (Note of Clarification on Paragraph 30 added)
59th WMA General Assembly Seoul October 2008
Seven Ethical Pillars of Clinical Research
AUTONOMY
BENEFICENCE
NON ndash MALFEASANCE
FIDELITY
TRUTHFULNESS
CONFIDENTIALITY
JUSTICE
Declaration of Helsinki
Autonomy
Consent
Para 20 The subjects must be volunteers andinformed participants in the research project
Para 22 freely-given informed consent
preferably in writing
Declaration of Helsinki
Para 5 well-being of the human subject shouldtake precedence over the interests of scienceand society
Beneficence
Declaration of Helsinki
Para 16
bull Preceded by careful assessment ofpredictable risks and burdens
bull Attempt to avoid any act or treatmentplan that would harm the patient
Non Malfeasance
Declaration of Helsinki
Para 11
Medical research involving human subjects must be basedon generally accepted scientific principles thoroughknowledge of the scientific literature and on adequatelaboratory and where appropriate animalexperimentation
Para 15
Conducted only by clinically competent medical person
Fidelity ndash duty of care
Declaration of Helsinki
Para 27
Both authors amp investigators are obliged topreserve the accuracy of the results Negativeas well as positive results should be published
Truthfulness - Honesty
Declaration of Helsinki
Para 21
Every precaution should be taken torespect the privacy of the subject theconfidentiality of the patients information
Confidentiality
Declaration of Helsinki
Para 30
Every patient entered into the study should be assured ofaccess to the best proven prophylactic diagnostic andtherapeutic methods identified by the study
Para 9
Research Investigators should be aware of the ethicallegal and regulatory requirements for research on humansubjects
Para 17
Physicians should cease any investigation if the risksoutweigh the potential benefits
Justice
DECLARATION OF HELSINKI -Basic Principles
1 Conform to accepted scientific principles
2 Design formulated in experimental protocol reviewed by IEC
3 Conducted by qualified and trained persons
4 Importance in proportion to inherent risk
5 Assessment of risks vs benefits
6 Safeguard subjectrsquos integrity (privacy)
7 Abstain unless hazards are predictable
8 Preserve accuracy when publishing
9 Adequately inform or right to withdraw
10 Obtain true informed consent in writing
11 Reliance on legal guardian
12 State compliance with Declaration
Ethical Principles and Guidelines for the Protection of Human Subjects of Research
bull Tuskegee Syphilis Study (1932ndash1972)
bull Named the Belmont Report for the Belmont Conference Center where the National Commission met when first drafting the report
42
Belmont Report 1979
Belmont Report 1979
Three ethical principles related to research on human subjects
1 Respect for Persons
2 Beneficence Do no harm while maximizing benefits for research project and minimizing risks to the research subjects
3 Justice ensuring reasonable non-exploitative and well-considered procedures are administered
Overview of
ICH GCP
What is ICH
bull The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)- is unique in bringing together the regulatory authorities and pharmaceutical industry of Europe Japan and the US to discuss scientific and technical aspects of drug registration
45
What is ICH
bull Since its inception in 1990 ICH has
gradually evolved
bull ICHs mission is to ensure that safe
effective and high quality medicines are
developed and registered in the most
resource-efficient manner
How did it evolve
The need to harmonize
bull Public disasters serious fraud and abuse of human rights
bull Trials of War criminals-Nuremberg code 1949
bull Thalidomide- Declaration of Helsinki 1964
bull Belmont report 1978 (Ethical Principles and guidelines for the protection of human subjects of research)-Tuskegee syphilis study
History
1962 US FDA IND Guidelines
1964 Declaration of Helsinki
1968 Committee on Safety of Medicines uk
1978 GCP US FDA
1991 GCP Europe
1996 ICH GCP
1997 ICH GCP Guideline
When did it begin
bull Ist conf in 1990 in Brussels
3 regions participated
bull Representatives from
Industry
Academia
Ministry of
health
ICH parties
6 parties
bull EU bull EFPIA European federation of pharmaceutical industriesrsquo associations
bull MHLW Ministry of health Labor and welfare Japan
bull JPMA Japan Pharmaceuticals manufacturers Association
bull US FDA
bull PhRMA
bull Observers WHO TPP(canada)
bull International federation of Pharmaceutical manufacturerrsquos association
Key objective
bull To discuss and define the minimum standards for the development and registration of investigational products
The result
Many guidelines made
bull Most important- ICH GCP guidelines
bull Evolved in several steps
bull Consolidated guideline ICH E6 Sept 1997
ICH Guidelines examples
bull Efficacy ndash clinical trials etc
bull Safety ndash pharmacovigilance adverse drug reaction
reporting
bull Quality ndash raw materials impurities residual solvents etc
bull Multidisciplinary ndash common technical document electronic
submission coding systems
What is GCP
A standard for the design conduct performance monitoring auditing recording analyses and reporting of clinical trials that provide assurance that the data and the reported results are credible accurate and that the rights integrity and confidentiality of trial subjects are protected
Why is it needed
bull To ensure the rights safety and well being of the trial subjects are protected
bull Ensure the credibility of clinical trial data
The ICH GCP guideline
bull Provide a unified standard for the EU Japan and USA regions to facilitate mutual acceptance of clinical trial data by the regulatory authorities in
these regions
bull 8 sections
ICH GCP guideline
1 Glossary
Common language for investigatorssponsorsethics committees
2Principles of Good Clinical Practice
13 tenets of ICH GCP
3Requirements for IRBIEC
Roles responsibilities and composition
ICH GCP guideline
4Responsibilities of the investigator
5Responsibilities of the sponsor
6Requirements for clinical trial protocol and protocol amendments
7Responsibility of the sponsor in the development of investigatorrsquos brochure
8Essential documents
Principles of ICH GCP
bull Ethical conduct as per
Declaration of Helsinki
GCP
Regulatory Requirements
Risk- Benefit
Primary concern- Subject
Principles of ICH GCP
bull Supportive data
bull Protocol
Scientifically sound clear detailed
bull Ethical Clearance
Study to be conducted in compliance to the protocol which has received EC approval
Principles of ICH GCP
bull Subject Care
Medical decisions responsibility of qualified physician
bull Qualified staff
By education training experience in their area of responsibility
bull Informed Consent
Principles of ICH GCP
bull Clinical Trial data
Recorded handled and stored to enable accurate reporting interpretation and verification
bull Confidentiality
Principles of ICH GCP
bull Investigational Product
Manufactured handled and stored as per GMP
Principles of ICH GCP
bull Quality Assurance
Systems and procedures to ensure the Quality of every aspect of the trial
Indian GCP guidelines
bull Released in Dec 2001(Developed by CDCSO and endorsed by DCGI)
bull In general in line with ICH GCP
bull Has Revised Schedule Y (Jan 2005) addressed discrepancies
bull SAFEGUARD PUBLIC HEALTH
bull ASSURE CONSUMER PROTECTION STANDARDS
bull FACILITATE AVAILABILITY OF SAFE AND EFFECTIVE PRODUCTS
bull ELIMINATE INCONSISTENT STANDARDS INTERNATIONALLY
bull FACILITATE MUTUAL ACCEPTANCE OF DATA FROM CLINICAL TRIALS
GOALS OF INTERNATIONAL HARMONIZATION OF
REGULATORY REQUIREMENTS
Study DocumentationDuring the study
The investigator must keepndash Source documents
bull Medical records (including access to computer records)
bull Laboratory reports
bull ECGs X-rays etc
bull Any other medical records reports or notes (hospital admissions and discharges)
ndash A subject identification list
ndash Copies of all study related documentation
Medical Records
bull In particular they should contain notes on
ndash Sufficient information to support subject eligibility
ndash This should be well documented (signed and dated)
ndash Subjectrsquos participation in the study
ndash Dates of visits
ndash Procedures investigations done
ndash Observations diagnoses
ndash Medications taken (including study medication)
ndash Adverse events
ndash Completion or withdrawal (reason) from the study
Study DocumentationAfter the study
The sponsor needs from the investigator
ndash Final drug accountability records
ndash All used and unused supplies and medication
ndash All required documents completed
Conclusion
70
Thanks
ldquoWhen a doctor [goes] wrong he is
the first of criminals He has nerve
and he has knowledgerdquo
- Sherlock Holmes
References
httpwwwwmanetepolicyb3htm
wwwhhsgovohrphumansubjectsguidancebelmonthtml
wwwhhsgovohrpreferencesnurcodehtml
wwwicmrnicinguidelinesGCLP
wwwcdsconicin
wwwubedurecercaBioeticadocDeclaracio_Helsinki_2013
wwwjewishvirtuallibraryorgjsourceHolocaustnazi_experiments
wwwichorgfileadminPublic_WebICHE6_R1__Guideline
Evolution of Good Clinical
Practices
An overview
2
PROTOCOL
bull Nazi war crimes
bull Tuskegee syphilis trial
bull Thalidomide disaster
bull Jews chronic disease trial
bull Neuremberg trial code
bull Declaration of helsinki
bull Belmonte report
bull ICHGCP Guidelines
3
Good Clinical Practice (GCP) Meaning
4
Good Clinical Practice (GCP) is an international
ethical and scientific quality standard for designing
conducting recording and reporting trials that involve the
participation of human subjects
Compliance with this standard provides public
assurance that the rights safety and well-being of trial
subjects are protected consistent with the principles that
have their origin in the Declaration of Helsinki and that
the clinical trial data are credible
bull The objective of this ICH GCP Guideline is to provide a unified standard for the European Union (EU) Japan and the United States to facilitate the mutual acceptance of clinical data by the regulatory authorities in these jurisdictions
5
History
Why Do We Need Guidelines
Why Are We Regulated
Nazi Medical War Crimesduring World War II
bull Experiments conducted by Nazi physicians during World War II were unprecedented in their scope and the degree of harm and suffering to which human beings were subjected
bull Typically the experiments resulted in death disfigurement or permanent disability and as such are considered as examples of medical torture
Nazi Medical War Crimes
Medical experiments were performed onthousands of concentration campprisoners and included deadly studies andtortures such as-
Injecting people with gasoline and liveviruses
Immersing people in ice water
Forcing people to ingest poisons
9
Incisions made by
medical personnel
that were purposely
infected with bacteria
dirt and slivers of
glass
Victim of a tuberculosis medical experiment
10
Prisoner in a compression chamber
11
An experiment to
determine
altitudes at which
aircraft crews
could survive
without oxygen
Immersing people in ice water
bull With the intent of discovering means to prevent and treat hypothermia
bull 280 to 300 victims
bull One study forced subjects to endure a tank of ice water for up to five hours
12
bull In 1946 an American military tribunal opened criminal proceedings against 23 leading German physicians Doctors Trial
bull Sixteen of the doctors were found guilty
bull Seven were sentenced to death
bull Development of the Nuremberg Code of medical ethics
13
THE DOCTORS TRIAL
The Tuskegee Syphilis Study
bull Research participants was the long-term study of black males conducted at Tuskegee Alabama by the United States Public Health Service
bull (1930s-1970) - examination of the natural history of untreated syphilis
bull More than 400 African-American men with syphilis participated
bull The men were recruited without informed consent and in fact were misinformed that some of the procedures done in the interest of the research (eg spinal taps) were actually special free treatment
The Tuskegee Syphilis Study
bull In the 1940s penicillin was found to be effective in the treatment of syphilis
bull The study continued however and the men were neither informed of nor treated with the antibiotic
bull The first accounts of this study appeared in the national press in 1972
bull Belmont report 1978 (Ethical Principles and guidelines for the protection of human subjects of research)-Tuskegee syphilis study
The Jewish Chronic Disease Hospital Study
bull In 1963 studies were undertaken at New Yorks Jewish Chronic Disease Hospital to understand whether the bodys inability to reject cancer cells was due to cancer or debilitation
bull Previous studies had indicated that healthy persons reject cancer cells promptly and the researchers allegedly believed that the debilitated patients would also reject the cancers but at a substantially slower rate compared to healthy participants
The Jewish Chronic Disease Hospital Study
bull Further patients were not told that they would receive cancer cells because the researchers felt it would unnecessarily frighten them
bull It was found that the study had not been presented to the hospitals research committee and that the physicians responsible for the patients care had not been consulted
bull The researchers were found guilty of fraud deceit and unprofessional conduct
The Willowbrook Study
bull Institutionalized children as participants in research is demonstrated in a series of studies conducted from 1963 through 1966 at the Willowbrook State School a New York institution for mentally defective children
bull In order to gain an understanding of the natural history of infectious hepatitis under controlled circumstances newly admitted children were deliberately infected with the hepatitis virus
bull In some cases parents found they were unable to admit their children to Willowbrook unless they agreed to their childrsquos participation in the studies
The Willowbrook Study
This controversial case raised important questions about the adequacy and freedom of consent inadequate disclosure of the childs risk of later developing chronic liver disease
The Milgram Study
bull The lsquoteachersrsquo were instructed to give the lsquolearnersrsquo electrical shocks in response to incorrect answers on verbally given lsquotestsrsquo
bull Participants were deceived as to the nature of the study being told it was to test new teaching-learning techniques
Thalidomide tragedy
bull Thalidomide was a widely used drug in the late 1950s and early 1960s for the treatment of nausea in pregnant women
bull It became apparent in the 1960s that thalidomide treatment resulted in severe birth defects in thousands of children
21
bull Within a few years of the widespread use of thalidomide in Europe Australia and Japan approximately 10000 children were born with phocomelia leading to the ban of thalidomide in most countries in 1961
22
bull The thalidomide tragedy marked a turning point in toxicity testing as it prompted United States and international regulatory agencies to develop systematic toxicity testing protocols
bull The thalidomide tragedy also brought into sharp focus the importance of rigorous and relevant testing of pharmaceuticals prior to their introduction into the market place (Kelsey 1988)
23
Thalidomide tragedy
Nuremberg Code-1947
bull On April 17 1947 United States Counsel for War Crimescame out with six points defining ldquolegitimate researchrdquo
bull The verdict of August 19 reiterated almost all of thesepoints in a section entitled Permissible MedicalExperiments and revised the original six points into ten
bull Subsequently the ten points became known as theNuremberg Code
24
Codes and Guidelines
Nuremberg Code (1947)
WMArsquos Declaration of Helsinki (1964)
bull Belmont Report (USA) (1979)-Tuskegee syphilis study
Council for International Organizations of Medical Sciences (CIOMS) 1993
International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) in 1996 Guideline on Good Clinical PracticeE6 (GCP)
Nuremberg Code (1947)
Voluntary and Informed consent-absolutely essential
Anticipate scientific benefits Useful
Animal experimentation first
Avoid physical and mental suffering
Benefits outweigh risks
No intentional death or disability
Protection from harm
Subject free to withdraw
Qualified investigators
Investigator will stop if harm occurs
THE DECLARATION OF HELSINKI-1964
Is an international standard for the conduct of clinicalresearch adopted by International Conference onHarmonization(ICH) Good Clinical Practice standards
A global ethical standard for medical research and wasapproved at the WMA General Assembly by a majority voteof 75
It is the mission of the clinical research professionals tosafeguard the health of the people
THE DECLARATION OF HELSINKI-1964
Historical Overview-
Its origin has been found in the Nazi Disaster and hasundergone several modifications
Prior to 1947 Nuremberg Code there was noaccepted code of conduct governing the ethicalaspects of human research
World Medical Association
It is an international organization of physicians
established on September 17 1947
First general Assembly of WMA was held in Paris
France
Mission- Serve humanity by endeavoring to achieve the
highest international standards in medical education
science ethics and health care for all peoples of the world
Declaration of Helsinki 1964
Adapted from Nuremberg
Code by the World Medical Association (WMA)
First adopted in Helsinki Finland 1964
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI- 2008
Ethical Principles for Medical Research Involving Human Subjects
Adopted by the 18th WMA General Assembly Helsinki Finland June 1964 and amended by the
29th WMA General Assembly Tokyo Japan October 1975
35th WMA General Assembly Venice Italy October 1983
41st WMA General Assembly Hong Kong September 1989
53th WMA General Assembly Washington 2002 (Note of Clarification on paragraph 29 added)
55th WMA General Assembly Tokyo 2004 (Note of Clarification on Paragraph 30 added)
59th WMA General Assembly Seoul October 2008
Seven Ethical Pillars of Clinical Research
AUTONOMY
BENEFICENCE
NON ndash MALFEASANCE
FIDELITY
TRUTHFULNESS
CONFIDENTIALITY
JUSTICE
Declaration of Helsinki
Autonomy
Consent
Para 20 The subjects must be volunteers andinformed participants in the research project
Para 22 freely-given informed consent
preferably in writing
Declaration of Helsinki
Para 5 well-being of the human subject shouldtake precedence over the interests of scienceand society
Beneficence
Declaration of Helsinki
Para 16
bull Preceded by careful assessment ofpredictable risks and burdens
bull Attempt to avoid any act or treatmentplan that would harm the patient
Non Malfeasance
Declaration of Helsinki
Para 11
Medical research involving human subjects must be basedon generally accepted scientific principles thoroughknowledge of the scientific literature and on adequatelaboratory and where appropriate animalexperimentation
Para 15
Conducted only by clinically competent medical person
Fidelity ndash duty of care
Declaration of Helsinki
Para 27
Both authors amp investigators are obliged topreserve the accuracy of the results Negativeas well as positive results should be published
Truthfulness - Honesty
Declaration of Helsinki
Para 21
Every precaution should be taken torespect the privacy of the subject theconfidentiality of the patients information
Confidentiality
Declaration of Helsinki
Para 30
Every patient entered into the study should be assured ofaccess to the best proven prophylactic diagnostic andtherapeutic methods identified by the study
Para 9
Research Investigators should be aware of the ethicallegal and regulatory requirements for research on humansubjects
Para 17
Physicians should cease any investigation if the risksoutweigh the potential benefits
Justice
DECLARATION OF HELSINKI -Basic Principles
1 Conform to accepted scientific principles
2 Design formulated in experimental protocol reviewed by IEC
3 Conducted by qualified and trained persons
4 Importance in proportion to inherent risk
5 Assessment of risks vs benefits
6 Safeguard subjectrsquos integrity (privacy)
7 Abstain unless hazards are predictable
8 Preserve accuracy when publishing
9 Adequately inform or right to withdraw
10 Obtain true informed consent in writing
11 Reliance on legal guardian
12 State compliance with Declaration
Ethical Principles and Guidelines for the Protection of Human Subjects of Research
bull Tuskegee Syphilis Study (1932ndash1972)
bull Named the Belmont Report for the Belmont Conference Center where the National Commission met when first drafting the report
42
Belmont Report 1979
Belmont Report 1979
Three ethical principles related to research on human subjects
1 Respect for Persons
2 Beneficence Do no harm while maximizing benefits for research project and minimizing risks to the research subjects
3 Justice ensuring reasonable non-exploitative and well-considered procedures are administered
Overview of
ICH GCP
What is ICH
bull The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)- is unique in bringing together the regulatory authorities and pharmaceutical industry of Europe Japan and the US to discuss scientific and technical aspects of drug registration
45
What is ICH
bull Since its inception in 1990 ICH has
gradually evolved
bull ICHs mission is to ensure that safe
effective and high quality medicines are
developed and registered in the most
resource-efficient manner
How did it evolve
The need to harmonize
bull Public disasters serious fraud and abuse of human rights
bull Trials of War criminals-Nuremberg code 1949
bull Thalidomide- Declaration of Helsinki 1964
bull Belmont report 1978 (Ethical Principles and guidelines for the protection of human subjects of research)-Tuskegee syphilis study
History
1962 US FDA IND Guidelines
1964 Declaration of Helsinki
1968 Committee on Safety of Medicines uk
1978 GCP US FDA
1991 GCP Europe
1996 ICH GCP
1997 ICH GCP Guideline
When did it begin
bull Ist conf in 1990 in Brussels
3 regions participated
bull Representatives from
Industry
Academia
Ministry of
health
ICH parties
6 parties
bull EU bull EFPIA European federation of pharmaceutical industriesrsquo associations
bull MHLW Ministry of health Labor and welfare Japan
bull JPMA Japan Pharmaceuticals manufacturers Association
bull US FDA
bull PhRMA
bull Observers WHO TPP(canada)
bull International federation of Pharmaceutical manufacturerrsquos association
Key objective
bull To discuss and define the minimum standards for the development and registration of investigational products
The result
Many guidelines made
bull Most important- ICH GCP guidelines
bull Evolved in several steps
bull Consolidated guideline ICH E6 Sept 1997
ICH Guidelines examples
bull Efficacy ndash clinical trials etc
bull Safety ndash pharmacovigilance adverse drug reaction
reporting
bull Quality ndash raw materials impurities residual solvents etc
bull Multidisciplinary ndash common technical document electronic
submission coding systems
What is GCP
A standard for the design conduct performance monitoring auditing recording analyses and reporting of clinical trials that provide assurance that the data and the reported results are credible accurate and that the rights integrity and confidentiality of trial subjects are protected
Why is it needed
bull To ensure the rights safety and well being of the trial subjects are protected
bull Ensure the credibility of clinical trial data
The ICH GCP guideline
bull Provide a unified standard for the EU Japan and USA regions to facilitate mutual acceptance of clinical trial data by the regulatory authorities in
these regions
bull 8 sections
ICH GCP guideline
1 Glossary
Common language for investigatorssponsorsethics committees
2Principles of Good Clinical Practice
13 tenets of ICH GCP
3Requirements for IRBIEC
Roles responsibilities and composition
ICH GCP guideline
4Responsibilities of the investigator
5Responsibilities of the sponsor
6Requirements for clinical trial protocol and protocol amendments
7Responsibility of the sponsor in the development of investigatorrsquos brochure
8Essential documents
Principles of ICH GCP
bull Ethical conduct as per
Declaration of Helsinki
GCP
Regulatory Requirements
Risk- Benefit
Primary concern- Subject
Principles of ICH GCP
bull Supportive data
bull Protocol
Scientifically sound clear detailed
bull Ethical Clearance
Study to be conducted in compliance to the protocol which has received EC approval
Principles of ICH GCP
bull Subject Care
Medical decisions responsibility of qualified physician
bull Qualified staff
By education training experience in their area of responsibility
bull Informed Consent
Principles of ICH GCP
bull Clinical Trial data
Recorded handled and stored to enable accurate reporting interpretation and verification
bull Confidentiality
Principles of ICH GCP
bull Investigational Product
Manufactured handled and stored as per GMP
Principles of ICH GCP
bull Quality Assurance
Systems and procedures to ensure the Quality of every aspect of the trial
Indian GCP guidelines
bull Released in Dec 2001(Developed by CDCSO and endorsed by DCGI)
bull In general in line with ICH GCP
bull Has Revised Schedule Y (Jan 2005) addressed discrepancies
bull SAFEGUARD PUBLIC HEALTH
bull ASSURE CONSUMER PROTECTION STANDARDS
bull FACILITATE AVAILABILITY OF SAFE AND EFFECTIVE PRODUCTS
bull ELIMINATE INCONSISTENT STANDARDS INTERNATIONALLY
bull FACILITATE MUTUAL ACCEPTANCE OF DATA FROM CLINICAL TRIALS
GOALS OF INTERNATIONAL HARMONIZATION OF
REGULATORY REQUIREMENTS
Study DocumentationDuring the study
The investigator must keepndash Source documents
bull Medical records (including access to computer records)
bull Laboratory reports
bull ECGs X-rays etc
bull Any other medical records reports or notes (hospital admissions and discharges)
ndash A subject identification list
ndash Copies of all study related documentation
Medical Records
bull In particular they should contain notes on
ndash Sufficient information to support subject eligibility
ndash This should be well documented (signed and dated)
ndash Subjectrsquos participation in the study
ndash Dates of visits
ndash Procedures investigations done
ndash Observations diagnoses
ndash Medications taken (including study medication)
ndash Adverse events
ndash Completion or withdrawal (reason) from the study
Study DocumentationAfter the study
The sponsor needs from the investigator
ndash Final drug accountability records
ndash All used and unused supplies and medication
ndash All required documents completed
Conclusion
70
Thanks
ldquoWhen a doctor [goes] wrong he is
the first of criminals He has nerve
and he has knowledgerdquo
- Sherlock Holmes
References
httpwwwwmanetepolicyb3htm
wwwhhsgovohrphumansubjectsguidancebelmonthtml
wwwhhsgovohrpreferencesnurcodehtml
wwwicmrnicinguidelinesGCLP
wwwcdsconicin
wwwubedurecercaBioeticadocDeclaracio_Helsinki_2013
wwwjewishvirtuallibraryorgjsourceHolocaustnazi_experiments
wwwichorgfileadminPublic_WebICHE6_R1__Guideline
PROTOCOL
bull Nazi war crimes
bull Tuskegee syphilis trial
bull Thalidomide disaster
bull Jews chronic disease trial
bull Neuremberg trial code
bull Declaration of helsinki
bull Belmonte report
bull ICHGCP Guidelines
3
Good Clinical Practice (GCP) Meaning
4
Good Clinical Practice (GCP) is an international
ethical and scientific quality standard for designing
conducting recording and reporting trials that involve the
participation of human subjects
Compliance with this standard provides public
assurance that the rights safety and well-being of trial
subjects are protected consistent with the principles that
have their origin in the Declaration of Helsinki and that
the clinical trial data are credible
bull The objective of this ICH GCP Guideline is to provide a unified standard for the European Union (EU) Japan and the United States to facilitate the mutual acceptance of clinical data by the regulatory authorities in these jurisdictions
5
History
Why Do We Need Guidelines
Why Are We Regulated
Nazi Medical War Crimesduring World War II
bull Experiments conducted by Nazi physicians during World War II were unprecedented in their scope and the degree of harm and suffering to which human beings were subjected
bull Typically the experiments resulted in death disfigurement or permanent disability and as such are considered as examples of medical torture
Nazi Medical War Crimes
Medical experiments were performed onthousands of concentration campprisoners and included deadly studies andtortures such as-
Injecting people with gasoline and liveviruses
Immersing people in ice water
Forcing people to ingest poisons
9
Incisions made by
medical personnel
that were purposely
infected with bacteria
dirt and slivers of
glass
Victim of a tuberculosis medical experiment
10
Prisoner in a compression chamber
11
An experiment to
determine
altitudes at which
aircraft crews
could survive
without oxygen
Immersing people in ice water
bull With the intent of discovering means to prevent and treat hypothermia
bull 280 to 300 victims
bull One study forced subjects to endure a tank of ice water for up to five hours
12
bull In 1946 an American military tribunal opened criminal proceedings against 23 leading German physicians Doctors Trial
bull Sixteen of the doctors were found guilty
bull Seven were sentenced to death
bull Development of the Nuremberg Code of medical ethics
13
THE DOCTORS TRIAL
The Tuskegee Syphilis Study
bull Research participants was the long-term study of black males conducted at Tuskegee Alabama by the United States Public Health Service
bull (1930s-1970) - examination of the natural history of untreated syphilis
bull More than 400 African-American men with syphilis participated
bull The men were recruited without informed consent and in fact were misinformed that some of the procedures done in the interest of the research (eg spinal taps) were actually special free treatment
The Tuskegee Syphilis Study
bull In the 1940s penicillin was found to be effective in the treatment of syphilis
bull The study continued however and the men were neither informed of nor treated with the antibiotic
bull The first accounts of this study appeared in the national press in 1972
bull Belmont report 1978 (Ethical Principles and guidelines for the protection of human subjects of research)-Tuskegee syphilis study
The Jewish Chronic Disease Hospital Study
bull In 1963 studies were undertaken at New Yorks Jewish Chronic Disease Hospital to understand whether the bodys inability to reject cancer cells was due to cancer or debilitation
bull Previous studies had indicated that healthy persons reject cancer cells promptly and the researchers allegedly believed that the debilitated patients would also reject the cancers but at a substantially slower rate compared to healthy participants
The Jewish Chronic Disease Hospital Study
bull Further patients were not told that they would receive cancer cells because the researchers felt it would unnecessarily frighten them
bull It was found that the study had not been presented to the hospitals research committee and that the physicians responsible for the patients care had not been consulted
bull The researchers were found guilty of fraud deceit and unprofessional conduct
The Willowbrook Study
bull Institutionalized children as participants in research is demonstrated in a series of studies conducted from 1963 through 1966 at the Willowbrook State School a New York institution for mentally defective children
bull In order to gain an understanding of the natural history of infectious hepatitis under controlled circumstances newly admitted children were deliberately infected with the hepatitis virus
bull In some cases parents found they were unable to admit their children to Willowbrook unless they agreed to their childrsquos participation in the studies
The Willowbrook Study
This controversial case raised important questions about the adequacy and freedom of consent inadequate disclosure of the childs risk of later developing chronic liver disease
The Milgram Study
bull The lsquoteachersrsquo were instructed to give the lsquolearnersrsquo electrical shocks in response to incorrect answers on verbally given lsquotestsrsquo
bull Participants were deceived as to the nature of the study being told it was to test new teaching-learning techniques
Thalidomide tragedy
bull Thalidomide was a widely used drug in the late 1950s and early 1960s for the treatment of nausea in pregnant women
bull It became apparent in the 1960s that thalidomide treatment resulted in severe birth defects in thousands of children
21
bull Within a few years of the widespread use of thalidomide in Europe Australia and Japan approximately 10000 children were born with phocomelia leading to the ban of thalidomide in most countries in 1961
22
bull The thalidomide tragedy marked a turning point in toxicity testing as it prompted United States and international regulatory agencies to develop systematic toxicity testing protocols
bull The thalidomide tragedy also brought into sharp focus the importance of rigorous and relevant testing of pharmaceuticals prior to their introduction into the market place (Kelsey 1988)
23
Thalidomide tragedy
Nuremberg Code-1947
bull On April 17 1947 United States Counsel for War Crimescame out with six points defining ldquolegitimate researchrdquo
bull The verdict of August 19 reiterated almost all of thesepoints in a section entitled Permissible MedicalExperiments and revised the original six points into ten
bull Subsequently the ten points became known as theNuremberg Code
24
Codes and Guidelines
Nuremberg Code (1947)
WMArsquos Declaration of Helsinki (1964)
bull Belmont Report (USA) (1979)-Tuskegee syphilis study
Council for International Organizations of Medical Sciences (CIOMS) 1993
International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) in 1996 Guideline on Good Clinical PracticeE6 (GCP)
Nuremberg Code (1947)
Voluntary and Informed consent-absolutely essential
Anticipate scientific benefits Useful
Animal experimentation first
Avoid physical and mental suffering
Benefits outweigh risks
No intentional death or disability
Protection from harm
Subject free to withdraw
Qualified investigators
Investigator will stop if harm occurs
THE DECLARATION OF HELSINKI-1964
Is an international standard for the conduct of clinicalresearch adopted by International Conference onHarmonization(ICH) Good Clinical Practice standards
A global ethical standard for medical research and wasapproved at the WMA General Assembly by a majority voteof 75
It is the mission of the clinical research professionals tosafeguard the health of the people
THE DECLARATION OF HELSINKI-1964
Historical Overview-
Its origin has been found in the Nazi Disaster and hasundergone several modifications
Prior to 1947 Nuremberg Code there was noaccepted code of conduct governing the ethicalaspects of human research
World Medical Association
It is an international organization of physicians
established on September 17 1947
First general Assembly of WMA was held in Paris
France
Mission- Serve humanity by endeavoring to achieve the
highest international standards in medical education
science ethics and health care for all peoples of the world
Declaration of Helsinki 1964
Adapted from Nuremberg
Code by the World Medical Association (WMA)
First adopted in Helsinki Finland 1964
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI- 2008
Ethical Principles for Medical Research Involving Human Subjects
Adopted by the 18th WMA General Assembly Helsinki Finland June 1964 and amended by the
29th WMA General Assembly Tokyo Japan October 1975
35th WMA General Assembly Venice Italy October 1983
41st WMA General Assembly Hong Kong September 1989
53th WMA General Assembly Washington 2002 (Note of Clarification on paragraph 29 added)
55th WMA General Assembly Tokyo 2004 (Note of Clarification on Paragraph 30 added)
59th WMA General Assembly Seoul October 2008
Seven Ethical Pillars of Clinical Research
AUTONOMY
BENEFICENCE
NON ndash MALFEASANCE
FIDELITY
TRUTHFULNESS
CONFIDENTIALITY
JUSTICE
Declaration of Helsinki
Autonomy
Consent
Para 20 The subjects must be volunteers andinformed participants in the research project
Para 22 freely-given informed consent
preferably in writing
Declaration of Helsinki
Para 5 well-being of the human subject shouldtake precedence over the interests of scienceand society
Beneficence
Declaration of Helsinki
Para 16
bull Preceded by careful assessment ofpredictable risks and burdens
bull Attempt to avoid any act or treatmentplan that would harm the patient
Non Malfeasance
Declaration of Helsinki
Para 11
Medical research involving human subjects must be basedon generally accepted scientific principles thoroughknowledge of the scientific literature and on adequatelaboratory and where appropriate animalexperimentation
Para 15
Conducted only by clinically competent medical person
Fidelity ndash duty of care
Declaration of Helsinki
Para 27
Both authors amp investigators are obliged topreserve the accuracy of the results Negativeas well as positive results should be published
Truthfulness - Honesty
Declaration of Helsinki
Para 21
Every precaution should be taken torespect the privacy of the subject theconfidentiality of the patients information
Confidentiality
Declaration of Helsinki
Para 30
Every patient entered into the study should be assured ofaccess to the best proven prophylactic diagnostic andtherapeutic methods identified by the study
Para 9
Research Investigators should be aware of the ethicallegal and regulatory requirements for research on humansubjects
Para 17
Physicians should cease any investigation if the risksoutweigh the potential benefits
Justice
DECLARATION OF HELSINKI -Basic Principles
1 Conform to accepted scientific principles
2 Design formulated in experimental protocol reviewed by IEC
3 Conducted by qualified and trained persons
4 Importance in proportion to inherent risk
5 Assessment of risks vs benefits
6 Safeguard subjectrsquos integrity (privacy)
7 Abstain unless hazards are predictable
8 Preserve accuracy when publishing
9 Adequately inform or right to withdraw
10 Obtain true informed consent in writing
11 Reliance on legal guardian
12 State compliance with Declaration
Ethical Principles and Guidelines for the Protection of Human Subjects of Research
bull Tuskegee Syphilis Study (1932ndash1972)
bull Named the Belmont Report for the Belmont Conference Center where the National Commission met when first drafting the report
42
Belmont Report 1979
Belmont Report 1979
Three ethical principles related to research on human subjects
1 Respect for Persons
2 Beneficence Do no harm while maximizing benefits for research project and minimizing risks to the research subjects
3 Justice ensuring reasonable non-exploitative and well-considered procedures are administered
Overview of
ICH GCP
What is ICH
bull The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)- is unique in bringing together the regulatory authorities and pharmaceutical industry of Europe Japan and the US to discuss scientific and technical aspects of drug registration
45
What is ICH
bull Since its inception in 1990 ICH has
gradually evolved
bull ICHs mission is to ensure that safe
effective and high quality medicines are
developed and registered in the most
resource-efficient manner
How did it evolve
The need to harmonize
bull Public disasters serious fraud and abuse of human rights
bull Trials of War criminals-Nuremberg code 1949
bull Thalidomide- Declaration of Helsinki 1964
bull Belmont report 1978 (Ethical Principles and guidelines for the protection of human subjects of research)-Tuskegee syphilis study
History
1962 US FDA IND Guidelines
1964 Declaration of Helsinki
1968 Committee on Safety of Medicines uk
1978 GCP US FDA
1991 GCP Europe
1996 ICH GCP
1997 ICH GCP Guideline
When did it begin
bull Ist conf in 1990 in Brussels
3 regions participated
bull Representatives from
Industry
Academia
Ministry of
health
ICH parties
6 parties
bull EU bull EFPIA European federation of pharmaceutical industriesrsquo associations
bull MHLW Ministry of health Labor and welfare Japan
bull JPMA Japan Pharmaceuticals manufacturers Association
bull US FDA
bull PhRMA
bull Observers WHO TPP(canada)
bull International federation of Pharmaceutical manufacturerrsquos association
Key objective
bull To discuss and define the minimum standards for the development and registration of investigational products
The result
Many guidelines made
bull Most important- ICH GCP guidelines
bull Evolved in several steps
bull Consolidated guideline ICH E6 Sept 1997
ICH Guidelines examples
bull Efficacy ndash clinical trials etc
bull Safety ndash pharmacovigilance adverse drug reaction
reporting
bull Quality ndash raw materials impurities residual solvents etc
bull Multidisciplinary ndash common technical document electronic
submission coding systems
What is GCP
A standard for the design conduct performance monitoring auditing recording analyses and reporting of clinical trials that provide assurance that the data and the reported results are credible accurate and that the rights integrity and confidentiality of trial subjects are protected
Why is it needed
bull To ensure the rights safety and well being of the trial subjects are protected
bull Ensure the credibility of clinical trial data
The ICH GCP guideline
bull Provide a unified standard for the EU Japan and USA regions to facilitate mutual acceptance of clinical trial data by the regulatory authorities in
these regions
bull 8 sections
ICH GCP guideline
1 Glossary
Common language for investigatorssponsorsethics committees
2Principles of Good Clinical Practice
13 tenets of ICH GCP
3Requirements for IRBIEC
Roles responsibilities and composition
ICH GCP guideline
4Responsibilities of the investigator
5Responsibilities of the sponsor
6Requirements for clinical trial protocol and protocol amendments
7Responsibility of the sponsor in the development of investigatorrsquos brochure
8Essential documents
Principles of ICH GCP
bull Ethical conduct as per
Declaration of Helsinki
GCP
Regulatory Requirements
Risk- Benefit
Primary concern- Subject
Principles of ICH GCP
bull Supportive data
bull Protocol
Scientifically sound clear detailed
bull Ethical Clearance
Study to be conducted in compliance to the protocol which has received EC approval
Principles of ICH GCP
bull Subject Care
Medical decisions responsibility of qualified physician
bull Qualified staff
By education training experience in their area of responsibility
bull Informed Consent
Principles of ICH GCP
bull Clinical Trial data
Recorded handled and stored to enable accurate reporting interpretation and verification
bull Confidentiality
Principles of ICH GCP
bull Investigational Product
Manufactured handled and stored as per GMP
Principles of ICH GCP
bull Quality Assurance
Systems and procedures to ensure the Quality of every aspect of the trial
Indian GCP guidelines
bull Released in Dec 2001(Developed by CDCSO and endorsed by DCGI)
bull In general in line with ICH GCP
bull Has Revised Schedule Y (Jan 2005) addressed discrepancies
bull SAFEGUARD PUBLIC HEALTH
bull ASSURE CONSUMER PROTECTION STANDARDS
bull FACILITATE AVAILABILITY OF SAFE AND EFFECTIVE PRODUCTS
bull ELIMINATE INCONSISTENT STANDARDS INTERNATIONALLY
bull FACILITATE MUTUAL ACCEPTANCE OF DATA FROM CLINICAL TRIALS
GOALS OF INTERNATIONAL HARMONIZATION OF
REGULATORY REQUIREMENTS
Study DocumentationDuring the study
The investigator must keepndash Source documents
bull Medical records (including access to computer records)
bull Laboratory reports
bull ECGs X-rays etc
bull Any other medical records reports or notes (hospital admissions and discharges)
ndash A subject identification list
ndash Copies of all study related documentation
Medical Records
bull In particular they should contain notes on
ndash Sufficient information to support subject eligibility
ndash This should be well documented (signed and dated)
ndash Subjectrsquos participation in the study
ndash Dates of visits
ndash Procedures investigations done
ndash Observations diagnoses
ndash Medications taken (including study medication)
ndash Adverse events
ndash Completion or withdrawal (reason) from the study
Study DocumentationAfter the study
The sponsor needs from the investigator
ndash Final drug accountability records
ndash All used and unused supplies and medication
ndash All required documents completed
Conclusion
70
Thanks
ldquoWhen a doctor [goes] wrong he is
the first of criminals He has nerve
and he has knowledgerdquo
- Sherlock Holmes
References
httpwwwwmanetepolicyb3htm
wwwhhsgovohrphumansubjectsguidancebelmonthtml
wwwhhsgovohrpreferencesnurcodehtml
wwwicmrnicinguidelinesGCLP
wwwcdsconicin
wwwubedurecercaBioeticadocDeclaracio_Helsinki_2013
wwwjewishvirtuallibraryorgjsourceHolocaustnazi_experiments
wwwichorgfileadminPublic_WebICHE6_R1__Guideline
Good Clinical Practice (GCP) Meaning
4
Good Clinical Practice (GCP) is an international
ethical and scientific quality standard for designing
conducting recording and reporting trials that involve the
participation of human subjects
Compliance with this standard provides public
assurance that the rights safety and well-being of trial
subjects are protected consistent with the principles that
have their origin in the Declaration of Helsinki and that
the clinical trial data are credible
bull The objective of this ICH GCP Guideline is to provide a unified standard for the European Union (EU) Japan and the United States to facilitate the mutual acceptance of clinical data by the regulatory authorities in these jurisdictions
5
History
Why Do We Need Guidelines
Why Are We Regulated
Nazi Medical War Crimesduring World War II
bull Experiments conducted by Nazi physicians during World War II were unprecedented in their scope and the degree of harm and suffering to which human beings were subjected
bull Typically the experiments resulted in death disfigurement or permanent disability and as such are considered as examples of medical torture
Nazi Medical War Crimes
Medical experiments were performed onthousands of concentration campprisoners and included deadly studies andtortures such as-
Injecting people with gasoline and liveviruses
Immersing people in ice water
Forcing people to ingest poisons
9
Incisions made by
medical personnel
that were purposely
infected with bacteria
dirt and slivers of
glass
Victim of a tuberculosis medical experiment
10
Prisoner in a compression chamber
11
An experiment to
determine
altitudes at which
aircraft crews
could survive
without oxygen
Immersing people in ice water
bull With the intent of discovering means to prevent and treat hypothermia
bull 280 to 300 victims
bull One study forced subjects to endure a tank of ice water for up to five hours
12
bull In 1946 an American military tribunal opened criminal proceedings against 23 leading German physicians Doctors Trial
bull Sixteen of the doctors were found guilty
bull Seven were sentenced to death
bull Development of the Nuremberg Code of medical ethics
13
THE DOCTORS TRIAL
The Tuskegee Syphilis Study
bull Research participants was the long-term study of black males conducted at Tuskegee Alabama by the United States Public Health Service
bull (1930s-1970) - examination of the natural history of untreated syphilis
bull More than 400 African-American men with syphilis participated
bull The men were recruited without informed consent and in fact were misinformed that some of the procedures done in the interest of the research (eg spinal taps) were actually special free treatment
The Tuskegee Syphilis Study
bull In the 1940s penicillin was found to be effective in the treatment of syphilis
bull The study continued however and the men were neither informed of nor treated with the antibiotic
bull The first accounts of this study appeared in the national press in 1972
bull Belmont report 1978 (Ethical Principles and guidelines for the protection of human subjects of research)-Tuskegee syphilis study
The Jewish Chronic Disease Hospital Study
bull In 1963 studies were undertaken at New Yorks Jewish Chronic Disease Hospital to understand whether the bodys inability to reject cancer cells was due to cancer or debilitation
bull Previous studies had indicated that healthy persons reject cancer cells promptly and the researchers allegedly believed that the debilitated patients would also reject the cancers but at a substantially slower rate compared to healthy participants
The Jewish Chronic Disease Hospital Study
bull Further patients were not told that they would receive cancer cells because the researchers felt it would unnecessarily frighten them
bull It was found that the study had not been presented to the hospitals research committee and that the physicians responsible for the patients care had not been consulted
bull The researchers were found guilty of fraud deceit and unprofessional conduct
The Willowbrook Study
bull Institutionalized children as participants in research is demonstrated in a series of studies conducted from 1963 through 1966 at the Willowbrook State School a New York institution for mentally defective children
bull In order to gain an understanding of the natural history of infectious hepatitis under controlled circumstances newly admitted children were deliberately infected with the hepatitis virus
bull In some cases parents found they were unable to admit their children to Willowbrook unless they agreed to their childrsquos participation in the studies
The Willowbrook Study
This controversial case raised important questions about the adequacy and freedom of consent inadequate disclosure of the childs risk of later developing chronic liver disease
The Milgram Study
bull The lsquoteachersrsquo were instructed to give the lsquolearnersrsquo electrical shocks in response to incorrect answers on verbally given lsquotestsrsquo
bull Participants were deceived as to the nature of the study being told it was to test new teaching-learning techniques
Thalidomide tragedy
bull Thalidomide was a widely used drug in the late 1950s and early 1960s for the treatment of nausea in pregnant women
bull It became apparent in the 1960s that thalidomide treatment resulted in severe birth defects in thousands of children
21
bull Within a few years of the widespread use of thalidomide in Europe Australia and Japan approximately 10000 children were born with phocomelia leading to the ban of thalidomide in most countries in 1961
22
bull The thalidomide tragedy marked a turning point in toxicity testing as it prompted United States and international regulatory agencies to develop systematic toxicity testing protocols
bull The thalidomide tragedy also brought into sharp focus the importance of rigorous and relevant testing of pharmaceuticals prior to their introduction into the market place (Kelsey 1988)
23
Thalidomide tragedy
Nuremberg Code-1947
bull On April 17 1947 United States Counsel for War Crimescame out with six points defining ldquolegitimate researchrdquo
bull The verdict of August 19 reiterated almost all of thesepoints in a section entitled Permissible MedicalExperiments and revised the original six points into ten
bull Subsequently the ten points became known as theNuremberg Code
24
Codes and Guidelines
Nuremberg Code (1947)
WMArsquos Declaration of Helsinki (1964)
bull Belmont Report (USA) (1979)-Tuskegee syphilis study
Council for International Organizations of Medical Sciences (CIOMS) 1993
International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) in 1996 Guideline on Good Clinical PracticeE6 (GCP)
Nuremberg Code (1947)
Voluntary and Informed consent-absolutely essential
Anticipate scientific benefits Useful
Animal experimentation first
Avoid physical and mental suffering
Benefits outweigh risks
No intentional death or disability
Protection from harm
Subject free to withdraw
Qualified investigators
Investigator will stop if harm occurs
THE DECLARATION OF HELSINKI-1964
Is an international standard for the conduct of clinicalresearch adopted by International Conference onHarmonization(ICH) Good Clinical Practice standards
A global ethical standard for medical research and wasapproved at the WMA General Assembly by a majority voteof 75
It is the mission of the clinical research professionals tosafeguard the health of the people
THE DECLARATION OF HELSINKI-1964
Historical Overview-
Its origin has been found in the Nazi Disaster and hasundergone several modifications
Prior to 1947 Nuremberg Code there was noaccepted code of conduct governing the ethicalaspects of human research
World Medical Association
It is an international organization of physicians
established on September 17 1947
First general Assembly of WMA was held in Paris
France
Mission- Serve humanity by endeavoring to achieve the
highest international standards in medical education
science ethics and health care for all peoples of the world
Declaration of Helsinki 1964
Adapted from Nuremberg
Code by the World Medical Association (WMA)
First adopted in Helsinki Finland 1964
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI- 2008
Ethical Principles for Medical Research Involving Human Subjects
Adopted by the 18th WMA General Assembly Helsinki Finland June 1964 and amended by the
29th WMA General Assembly Tokyo Japan October 1975
35th WMA General Assembly Venice Italy October 1983
41st WMA General Assembly Hong Kong September 1989
53th WMA General Assembly Washington 2002 (Note of Clarification on paragraph 29 added)
55th WMA General Assembly Tokyo 2004 (Note of Clarification on Paragraph 30 added)
59th WMA General Assembly Seoul October 2008
Seven Ethical Pillars of Clinical Research
AUTONOMY
BENEFICENCE
NON ndash MALFEASANCE
FIDELITY
TRUTHFULNESS
CONFIDENTIALITY
JUSTICE
Declaration of Helsinki
Autonomy
Consent
Para 20 The subjects must be volunteers andinformed participants in the research project
Para 22 freely-given informed consent
preferably in writing
Declaration of Helsinki
Para 5 well-being of the human subject shouldtake precedence over the interests of scienceand society
Beneficence
Declaration of Helsinki
Para 16
bull Preceded by careful assessment ofpredictable risks and burdens
bull Attempt to avoid any act or treatmentplan that would harm the patient
Non Malfeasance
Declaration of Helsinki
Para 11
Medical research involving human subjects must be basedon generally accepted scientific principles thoroughknowledge of the scientific literature and on adequatelaboratory and where appropriate animalexperimentation
Para 15
Conducted only by clinically competent medical person
Fidelity ndash duty of care
Declaration of Helsinki
Para 27
Both authors amp investigators are obliged topreserve the accuracy of the results Negativeas well as positive results should be published
Truthfulness - Honesty
Declaration of Helsinki
Para 21
Every precaution should be taken torespect the privacy of the subject theconfidentiality of the patients information
Confidentiality
Declaration of Helsinki
Para 30
Every patient entered into the study should be assured ofaccess to the best proven prophylactic diagnostic andtherapeutic methods identified by the study
Para 9
Research Investigators should be aware of the ethicallegal and regulatory requirements for research on humansubjects
Para 17
Physicians should cease any investigation if the risksoutweigh the potential benefits
Justice
DECLARATION OF HELSINKI -Basic Principles
1 Conform to accepted scientific principles
2 Design formulated in experimental protocol reviewed by IEC
3 Conducted by qualified and trained persons
4 Importance in proportion to inherent risk
5 Assessment of risks vs benefits
6 Safeguard subjectrsquos integrity (privacy)
7 Abstain unless hazards are predictable
8 Preserve accuracy when publishing
9 Adequately inform or right to withdraw
10 Obtain true informed consent in writing
11 Reliance on legal guardian
12 State compliance with Declaration
Ethical Principles and Guidelines for the Protection of Human Subjects of Research
bull Tuskegee Syphilis Study (1932ndash1972)
bull Named the Belmont Report for the Belmont Conference Center where the National Commission met when first drafting the report
42
Belmont Report 1979
Belmont Report 1979
Three ethical principles related to research on human subjects
1 Respect for Persons
2 Beneficence Do no harm while maximizing benefits for research project and minimizing risks to the research subjects
3 Justice ensuring reasonable non-exploitative and well-considered procedures are administered
Overview of
ICH GCP
What is ICH
bull The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)- is unique in bringing together the regulatory authorities and pharmaceutical industry of Europe Japan and the US to discuss scientific and technical aspects of drug registration
45
What is ICH
bull Since its inception in 1990 ICH has
gradually evolved
bull ICHs mission is to ensure that safe
effective and high quality medicines are
developed and registered in the most
resource-efficient manner
How did it evolve
The need to harmonize
bull Public disasters serious fraud and abuse of human rights
bull Trials of War criminals-Nuremberg code 1949
bull Thalidomide- Declaration of Helsinki 1964
bull Belmont report 1978 (Ethical Principles and guidelines for the protection of human subjects of research)-Tuskegee syphilis study
History
1962 US FDA IND Guidelines
1964 Declaration of Helsinki
1968 Committee on Safety of Medicines uk
1978 GCP US FDA
1991 GCP Europe
1996 ICH GCP
1997 ICH GCP Guideline
When did it begin
bull Ist conf in 1990 in Brussels
3 regions participated
bull Representatives from
Industry
Academia
Ministry of
health
ICH parties
6 parties
bull EU bull EFPIA European federation of pharmaceutical industriesrsquo associations
bull MHLW Ministry of health Labor and welfare Japan
bull JPMA Japan Pharmaceuticals manufacturers Association
bull US FDA
bull PhRMA
bull Observers WHO TPP(canada)
bull International federation of Pharmaceutical manufacturerrsquos association
Key objective
bull To discuss and define the minimum standards for the development and registration of investigational products
The result
Many guidelines made
bull Most important- ICH GCP guidelines
bull Evolved in several steps
bull Consolidated guideline ICH E6 Sept 1997
ICH Guidelines examples
bull Efficacy ndash clinical trials etc
bull Safety ndash pharmacovigilance adverse drug reaction
reporting
bull Quality ndash raw materials impurities residual solvents etc
bull Multidisciplinary ndash common technical document electronic
submission coding systems
What is GCP
A standard for the design conduct performance monitoring auditing recording analyses and reporting of clinical trials that provide assurance that the data and the reported results are credible accurate and that the rights integrity and confidentiality of trial subjects are protected
Why is it needed
bull To ensure the rights safety and well being of the trial subjects are protected
bull Ensure the credibility of clinical trial data
The ICH GCP guideline
bull Provide a unified standard for the EU Japan and USA regions to facilitate mutual acceptance of clinical trial data by the regulatory authorities in
these regions
bull 8 sections
ICH GCP guideline
1 Glossary
Common language for investigatorssponsorsethics committees
2Principles of Good Clinical Practice
13 tenets of ICH GCP
3Requirements for IRBIEC
Roles responsibilities and composition
ICH GCP guideline
4Responsibilities of the investigator
5Responsibilities of the sponsor
6Requirements for clinical trial protocol and protocol amendments
7Responsibility of the sponsor in the development of investigatorrsquos brochure
8Essential documents
Principles of ICH GCP
bull Ethical conduct as per
Declaration of Helsinki
GCP
Regulatory Requirements
Risk- Benefit
Primary concern- Subject
Principles of ICH GCP
bull Supportive data
bull Protocol
Scientifically sound clear detailed
bull Ethical Clearance
Study to be conducted in compliance to the protocol which has received EC approval
Principles of ICH GCP
bull Subject Care
Medical decisions responsibility of qualified physician
bull Qualified staff
By education training experience in their area of responsibility
bull Informed Consent
Principles of ICH GCP
bull Clinical Trial data
Recorded handled and stored to enable accurate reporting interpretation and verification
bull Confidentiality
Principles of ICH GCP
bull Investigational Product
Manufactured handled and stored as per GMP
Principles of ICH GCP
bull Quality Assurance
Systems and procedures to ensure the Quality of every aspect of the trial
Indian GCP guidelines
bull Released in Dec 2001(Developed by CDCSO and endorsed by DCGI)
bull In general in line with ICH GCP
bull Has Revised Schedule Y (Jan 2005) addressed discrepancies
bull SAFEGUARD PUBLIC HEALTH
bull ASSURE CONSUMER PROTECTION STANDARDS
bull FACILITATE AVAILABILITY OF SAFE AND EFFECTIVE PRODUCTS
bull ELIMINATE INCONSISTENT STANDARDS INTERNATIONALLY
bull FACILITATE MUTUAL ACCEPTANCE OF DATA FROM CLINICAL TRIALS
GOALS OF INTERNATIONAL HARMONIZATION OF
REGULATORY REQUIREMENTS
Study DocumentationDuring the study
The investigator must keepndash Source documents
bull Medical records (including access to computer records)
bull Laboratory reports
bull ECGs X-rays etc
bull Any other medical records reports or notes (hospital admissions and discharges)
ndash A subject identification list
ndash Copies of all study related documentation
Medical Records
bull In particular they should contain notes on
ndash Sufficient information to support subject eligibility
ndash This should be well documented (signed and dated)
ndash Subjectrsquos participation in the study
ndash Dates of visits
ndash Procedures investigations done
ndash Observations diagnoses
ndash Medications taken (including study medication)
ndash Adverse events
ndash Completion or withdrawal (reason) from the study
Study DocumentationAfter the study
The sponsor needs from the investigator
ndash Final drug accountability records
ndash All used and unused supplies and medication
ndash All required documents completed
Conclusion
70
Thanks
ldquoWhen a doctor [goes] wrong he is
the first of criminals He has nerve
and he has knowledgerdquo
- Sherlock Holmes
References
httpwwwwmanetepolicyb3htm
wwwhhsgovohrphumansubjectsguidancebelmonthtml
wwwhhsgovohrpreferencesnurcodehtml
wwwicmrnicinguidelinesGCLP
wwwcdsconicin
wwwubedurecercaBioeticadocDeclaracio_Helsinki_2013
wwwjewishvirtuallibraryorgjsourceHolocaustnazi_experiments
wwwichorgfileadminPublic_WebICHE6_R1__Guideline
bull The objective of this ICH GCP Guideline is to provide a unified standard for the European Union (EU) Japan and the United States to facilitate the mutual acceptance of clinical data by the regulatory authorities in these jurisdictions
5
History
Why Do We Need Guidelines
Why Are We Regulated
Nazi Medical War Crimesduring World War II
bull Experiments conducted by Nazi physicians during World War II were unprecedented in their scope and the degree of harm and suffering to which human beings were subjected
bull Typically the experiments resulted in death disfigurement or permanent disability and as such are considered as examples of medical torture
Nazi Medical War Crimes
Medical experiments were performed onthousands of concentration campprisoners and included deadly studies andtortures such as-
Injecting people with gasoline and liveviruses
Immersing people in ice water
Forcing people to ingest poisons
9
Incisions made by
medical personnel
that were purposely
infected with bacteria
dirt and slivers of
glass
Victim of a tuberculosis medical experiment
10
Prisoner in a compression chamber
11
An experiment to
determine
altitudes at which
aircraft crews
could survive
without oxygen
Immersing people in ice water
bull With the intent of discovering means to prevent and treat hypothermia
bull 280 to 300 victims
bull One study forced subjects to endure a tank of ice water for up to five hours
12
bull In 1946 an American military tribunal opened criminal proceedings against 23 leading German physicians Doctors Trial
bull Sixteen of the doctors were found guilty
bull Seven were sentenced to death
bull Development of the Nuremberg Code of medical ethics
13
THE DOCTORS TRIAL
The Tuskegee Syphilis Study
bull Research participants was the long-term study of black males conducted at Tuskegee Alabama by the United States Public Health Service
bull (1930s-1970) - examination of the natural history of untreated syphilis
bull More than 400 African-American men with syphilis participated
bull The men were recruited without informed consent and in fact were misinformed that some of the procedures done in the interest of the research (eg spinal taps) were actually special free treatment
The Tuskegee Syphilis Study
bull In the 1940s penicillin was found to be effective in the treatment of syphilis
bull The study continued however and the men were neither informed of nor treated with the antibiotic
bull The first accounts of this study appeared in the national press in 1972
bull Belmont report 1978 (Ethical Principles and guidelines for the protection of human subjects of research)-Tuskegee syphilis study
The Jewish Chronic Disease Hospital Study
bull In 1963 studies were undertaken at New Yorks Jewish Chronic Disease Hospital to understand whether the bodys inability to reject cancer cells was due to cancer or debilitation
bull Previous studies had indicated that healthy persons reject cancer cells promptly and the researchers allegedly believed that the debilitated patients would also reject the cancers but at a substantially slower rate compared to healthy participants
The Jewish Chronic Disease Hospital Study
bull Further patients were not told that they would receive cancer cells because the researchers felt it would unnecessarily frighten them
bull It was found that the study had not been presented to the hospitals research committee and that the physicians responsible for the patients care had not been consulted
bull The researchers were found guilty of fraud deceit and unprofessional conduct
The Willowbrook Study
bull Institutionalized children as participants in research is demonstrated in a series of studies conducted from 1963 through 1966 at the Willowbrook State School a New York institution for mentally defective children
bull In order to gain an understanding of the natural history of infectious hepatitis under controlled circumstances newly admitted children were deliberately infected with the hepatitis virus
bull In some cases parents found they were unable to admit their children to Willowbrook unless they agreed to their childrsquos participation in the studies
The Willowbrook Study
This controversial case raised important questions about the adequacy and freedom of consent inadequate disclosure of the childs risk of later developing chronic liver disease
The Milgram Study
bull The lsquoteachersrsquo were instructed to give the lsquolearnersrsquo electrical shocks in response to incorrect answers on verbally given lsquotestsrsquo
bull Participants were deceived as to the nature of the study being told it was to test new teaching-learning techniques
Thalidomide tragedy
bull Thalidomide was a widely used drug in the late 1950s and early 1960s for the treatment of nausea in pregnant women
bull It became apparent in the 1960s that thalidomide treatment resulted in severe birth defects in thousands of children
21
bull Within a few years of the widespread use of thalidomide in Europe Australia and Japan approximately 10000 children were born with phocomelia leading to the ban of thalidomide in most countries in 1961
22
bull The thalidomide tragedy marked a turning point in toxicity testing as it prompted United States and international regulatory agencies to develop systematic toxicity testing protocols
bull The thalidomide tragedy also brought into sharp focus the importance of rigorous and relevant testing of pharmaceuticals prior to their introduction into the market place (Kelsey 1988)
23
Thalidomide tragedy
Nuremberg Code-1947
bull On April 17 1947 United States Counsel for War Crimescame out with six points defining ldquolegitimate researchrdquo
bull The verdict of August 19 reiterated almost all of thesepoints in a section entitled Permissible MedicalExperiments and revised the original six points into ten
bull Subsequently the ten points became known as theNuremberg Code
24
Codes and Guidelines
Nuremberg Code (1947)
WMArsquos Declaration of Helsinki (1964)
bull Belmont Report (USA) (1979)-Tuskegee syphilis study
Council for International Organizations of Medical Sciences (CIOMS) 1993
International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) in 1996 Guideline on Good Clinical PracticeE6 (GCP)
Nuremberg Code (1947)
Voluntary and Informed consent-absolutely essential
Anticipate scientific benefits Useful
Animal experimentation first
Avoid physical and mental suffering
Benefits outweigh risks
No intentional death or disability
Protection from harm
Subject free to withdraw
Qualified investigators
Investigator will stop if harm occurs
THE DECLARATION OF HELSINKI-1964
Is an international standard for the conduct of clinicalresearch adopted by International Conference onHarmonization(ICH) Good Clinical Practice standards
A global ethical standard for medical research and wasapproved at the WMA General Assembly by a majority voteof 75
It is the mission of the clinical research professionals tosafeguard the health of the people
THE DECLARATION OF HELSINKI-1964
Historical Overview-
Its origin has been found in the Nazi Disaster and hasundergone several modifications
Prior to 1947 Nuremberg Code there was noaccepted code of conduct governing the ethicalaspects of human research
World Medical Association
It is an international organization of physicians
established on September 17 1947
First general Assembly of WMA was held in Paris
France
Mission- Serve humanity by endeavoring to achieve the
highest international standards in medical education
science ethics and health care for all peoples of the world
Declaration of Helsinki 1964
Adapted from Nuremberg
Code by the World Medical Association (WMA)
First adopted in Helsinki Finland 1964
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI- 2008
Ethical Principles for Medical Research Involving Human Subjects
Adopted by the 18th WMA General Assembly Helsinki Finland June 1964 and amended by the
29th WMA General Assembly Tokyo Japan October 1975
35th WMA General Assembly Venice Italy October 1983
41st WMA General Assembly Hong Kong September 1989
53th WMA General Assembly Washington 2002 (Note of Clarification on paragraph 29 added)
55th WMA General Assembly Tokyo 2004 (Note of Clarification on Paragraph 30 added)
59th WMA General Assembly Seoul October 2008
Seven Ethical Pillars of Clinical Research
AUTONOMY
BENEFICENCE
NON ndash MALFEASANCE
FIDELITY
TRUTHFULNESS
CONFIDENTIALITY
JUSTICE
Declaration of Helsinki
Autonomy
Consent
Para 20 The subjects must be volunteers andinformed participants in the research project
Para 22 freely-given informed consent
preferably in writing
Declaration of Helsinki
Para 5 well-being of the human subject shouldtake precedence over the interests of scienceand society
Beneficence
Declaration of Helsinki
Para 16
bull Preceded by careful assessment ofpredictable risks and burdens
bull Attempt to avoid any act or treatmentplan that would harm the patient
Non Malfeasance
Declaration of Helsinki
Para 11
Medical research involving human subjects must be basedon generally accepted scientific principles thoroughknowledge of the scientific literature and on adequatelaboratory and where appropriate animalexperimentation
Para 15
Conducted only by clinically competent medical person
Fidelity ndash duty of care
Declaration of Helsinki
Para 27
Both authors amp investigators are obliged topreserve the accuracy of the results Negativeas well as positive results should be published
Truthfulness - Honesty
Declaration of Helsinki
Para 21
Every precaution should be taken torespect the privacy of the subject theconfidentiality of the patients information
Confidentiality
Declaration of Helsinki
Para 30
Every patient entered into the study should be assured ofaccess to the best proven prophylactic diagnostic andtherapeutic methods identified by the study
Para 9
Research Investigators should be aware of the ethicallegal and regulatory requirements for research on humansubjects
Para 17
Physicians should cease any investigation if the risksoutweigh the potential benefits
Justice
DECLARATION OF HELSINKI -Basic Principles
1 Conform to accepted scientific principles
2 Design formulated in experimental protocol reviewed by IEC
3 Conducted by qualified and trained persons
4 Importance in proportion to inherent risk
5 Assessment of risks vs benefits
6 Safeguard subjectrsquos integrity (privacy)
7 Abstain unless hazards are predictable
8 Preserve accuracy when publishing
9 Adequately inform or right to withdraw
10 Obtain true informed consent in writing
11 Reliance on legal guardian
12 State compliance with Declaration
Ethical Principles and Guidelines for the Protection of Human Subjects of Research
bull Tuskegee Syphilis Study (1932ndash1972)
bull Named the Belmont Report for the Belmont Conference Center where the National Commission met when first drafting the report
42
Belmont Report 1979
Belmont Report 1979
Three ethical principles related to research on human subjects
1 Respect for Persons
2 Beneficence Do no harm while maximizing benefits for research project and minimizing risks to the research subjects
3 Justice ensuring reasonable non-exploitative and well-considered procedures are administered
Overview of
ICH GCP
What is ICH
bull The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)- is unique in bringing together the regulatory authorities and pharmaceutical industry of Europe Japan and the US to discuss scientific and technical aspects of drug registration
45
What is ICH
bull Since its inception in 1990 ICH has
gradually evolved
bull ICHs mission is to ensure that safe
effective and high quality medicines are
developed and registered in the most
resource-efficient manner
How did it evolve
The need to harmonize
bull Public disasters serious fraud and abuse of human rights
bull Trials of War criminals-Nuremberg code 1949
bull Thalidomide- Declaration of Helsinki 1964
bull Belmont report 1978 (Ethical Principles and guidelines for the protection of human subjects of research)-Tuskegee syphilis study
History
1962 US FDA IND Guidelines
1964 Declaration of Helsinki
1968 Committee on Safety of Medicines uk
1978 GCP US FDA
1991 GCP Europe
1996 ICH GCP
1997 ICH GCP Guideline
When did it begin
bull Ist conf in 1990 in Brussels
3 regions participated
bull Representatives from
Industry
Academia
Ministry of
health
ICH parties
6 parties
bull EU bull EFPIA European federation of pharmaceutical industriesrsquo associations
bull MHLW Ministry of health Labor and welfare Japan
bull JPMA Japan Pharmaceuticals manufacturers Association
bull US FDA
bull PhRMA
bull Observers WHO TPP(canada)
bull International federation of Pharmaceutical manufacturerrsquos association
Key objective
bull To discuss and define the minimum standards for the development and registration of investigational products
The result
Many guidelines made
bull Most important- ICH GCP guidelines
bull Evolved in several steps
bull Consolidated guideline ICH E6 Sept 1997
ICH Guidelines examples
bull Efficacy ndash clinical trials etc
bull Safety ndash pharmacovigilance adverse drug reaction
reporting
bull Quality ndash raw materials impurities residual solvents etc
bull Multidisciplinary ndash common technical document electronic
submission coding systems
What is GCP
A standard for the design conduct performance monitoring auditing recording analyses and reporting of clinical trials that provide assurance that the data and the reported results are credible accurate and that the rights integrity and confidentiality of trial subjects are protected
Why is it needed
bull To ensure the rights safety and well being of the trial subjects are protected
bull Ensure the credibility of clinical trial data
The ICH GCP guideline
bull Provide a unified standard for the EU Japan and USA regions to facilitate mutual acceptance of clinical trial data by the regulatory authorities in
these regions
bull 8 sections
ICH GCP guideline
1 Glossary
Common language for investigatorssponsorsethics committees
2Principles of Good Clinical Practice
13 tenets of ICH GCP
3Requirements for IRBIEC
Roles responsibilities and composition
ICH GCP guideline
4Responsibilities of the investigator
5Responsibilities of the sponsor
6Requirements for clinical trial protocol and protocol amendments
7Responsibility of the sponsor in the development of investigatorrsquos brochure
8Essential documents
Principles of ICH GCP
bull Ethical conduct as per
Declaration of Helsinki
GCP
Regulatory Requirements
Risk- Benefit
Primary concern- Subject
Principles of ICH GCP
bull Supportive data
bull Protocol
Scientifically sound clear detailed
bull Ethical Clearance
Study to be conducted in compliance to the protocol which has received EC approval
Principles of ICH GCP
bull Subject Care
Medical decisions responsibility of qualified physician
bull Qualified staff
By education training experience in their area of responsibility
bull Informed Consent
Principles of ICH GCP
bull Clinical Trial data
Recorded handled and stored to enable accurate reporting interpretation and verification
bull Confidentiality
Principles of ICH GCP
bull Investigational Product
Manufactured handled and stored as per GMP
Principles of ICH GCP
bull Quality Assurance
Systems and procedures to ensure the Quality of every aspect of the trial
Indian GCP guidelines
bull Released in Dec 2001(Developed by CDCSO and endorsed by DCGI)
bull In general in line with ICH GCP
bull Has Revised Schedule Y (Jan 2005) addressed discrepancies
bull SAFEGUARD PUBLIC HEALTH
bull ASSURE CONSUMER PROTECTION STANDARDS
bull FACILITATE AVAILABILITY OF SAFE AND EFFECTIVE PRODUCTS
bull ELIMINATE INCONSISTENT STANDARDS INTERNATIONALLY
bull FACILITATE MUTUAL ACCEPTANCE OF DATA FROM CLINICAL TRIALS
GOALS OF INTERNATIONAL HARMONIZATION OF
REGULATORY REQUIREMENTS
Study DocumentationDuring the study
The investigator must keepndash Source documents
bull Medical records (including access to computer records)
bull Laboratory reports
bull ECGs X-rays etc
bull Any other medical records reports or notes (hospital admissions and discharges)
ndash A subject identification list
ndash Copies of all study related documentation
Medical Records
bull In particular they should contain notes on
ndash Sufficient information to support subject eligibility
ndash This should be well documented (signed and dated)
ndash Subjectrsquos participation in the study
ndash Dates of visits
ndash Procedures investigations done
ndash Observations diagnoses
ndash Medications taken (including study medication)
ndash Adverse events
ndash Completion or withdrawal (reason) from the study
Study DocumentationAfter the study
The sponsor needs from the investigator
ndash Final drug accountability records
ndash All used and unused supplies and medication
ndash All required documents completed
Conclusion
70
Thanks
ldquoWhen a doctor [goes] wrong he is
the first of criminals He has nerve
and he has knowledgerdquo
- Sherlock Holmes
References
httpwwwwmanetepolicyb3htm
wwwhhsgovohrphumansubjectsguidancebelmonthtml
wwwhhsgovohrpreferencesnurcodehtml
wwwicmrnicinguidelinesGCLP
wwwcdsconicin
wwwubedurecercaBioeticadocDeclaracio_Helsinki_2013
wwwjewishvirtuallibraryorgjsourceHolocaustnazi_experiments
wwwichorgfileadminPublic_WebICHE6_R1__Guideline
History
Why Do We Need Guidelines
Why Are We Regulated
Nazi Medical War Crimesduring World War II
bull Experiments conducted by Nazi physicians during World War II were unprecedented in their scope and the degree of harm and suffering to which human beings were subjected
bull Typically the experiments resulted in death disfigurement or permanent disability and as such are considered as examples of medical torture
Nazi Medical War Crimes
Medical experiments were performed onthousands of concentration campprisoners and included deadly studies andtortures such as-
Injecting people with gasoline and liveviruses
Immersing people in ice water
Forcing people to ingest poisons
9
Incisions made by
medical personnel
that were purposely
infected with bacteria
dirt and slivers of
glass
Victim of a tuberculosis medical experiment
10
Prisoner in a compression chamber
11
An experiment to
determine
altitudes at which
aircraft crews
could survive
without oxygen
Immersing people in ice water
bull With the intent of discovering means to prevent and treat hypothermia
bull 280 to 300 victims
bull One study forced subjects to endure a tank of ice water for up to five hours
12
bull In 1946 an American military tribunal opened criminal proceedings against 23 leading German physicians Doctors Trial
bull Sixteen of the doctors were found guilty
bull Seven were sentenced to death
bull Development of the Nuremberg Code of medical ethics
13
THE DOCTORS TRIAL
The Tuskegee Syphilis Study
bull Research participants was the long-term study of black males conducted at Tuskegee Alabama by the United States Public Health Service
bull (1930s-1970) - examination of the natural history of untreated syphilis
bull More than 400 African-American men with syphilis participated
bull The men were recruited without informed consent and in fact were misinformed that some of the procedures done in the interest of the research (eg spinal taps) were actually special free treatment
The Tuskegee Syphilis Study
bull In the 1940s penicillin was found to be effective in the treatment of syphilis
bull The study continued however and the men were neither informed of nor treated with the antibiotic
bull The first accounts of this study appeared in the national press in 1972
bull Belmont report 1978 (Ethical Principles and guidelines for the protection of human subjects of research)-Tuskegee syphilis study
The Jewish Chronic Disease Hospital Study
bull In 1963 studies were undertaken at New Yorks Jewish Chronic Disease Hospital to understand whether the bodys inability to reject cancer cells was due to cancer or debilitation
bull Previous studies had indicated that healthy persons reject cancer cells promptly and the researchers allegedly believed that the debilitated patients would also reject the cancers but at a substantially slower rate compared to healthy participants
The Jewish Chronic Disease Hospital Study
bull Further patients were not told that they would receive cancer cells because the researchers felt it would unnecessarily frighten them
bull It was found that the study had not been presented to the hospitals research committee and that the physicians responsible for the patients care had not been consulted
bull The researchers were found guilty of fraud deceit and unprofessional conduct
The Willowbrook Study
bull Institutionalized children as participants in research is demonstrated in a series of studies conducted from 1963 through 1966 at the Willowbrook State School a New York institution for mentally defective children
bull In order to gain an understanding of the natural history of infectious hepatitis under controlled circumstances newly admitted children were deliberately infected with the hepatitis virus
bull In some cases parents found they were unable to admit their children to Willowbrook unless they agreed to their childrsquos participation in the studies
The Willowbrook Study
This controversial case raised important questions about the adequacy and freedom of consent inadequate disclosure of the childs risk of later developing chronic liver disease
The Milgram Study
bull The lsquoteachersrsquo were instructed to give the lsquolearnersrsquo electrical shocks in response to incorrect answers on verbally given lsquotestsrsquo
bull Participants were deceived as to the nature of the study being told it was to test new teaching-learning techniques
Thalidomide tragedy
bull Thalidomide was a widely used drug in the late 1950s and early 1960s for the treatment of nausea in pregnant women
bull It became apparent in the 1960s that thalidomide treatment resulted in severe birth defects in thousands of children
21
bull Within a few years of the widespread use of thalidomide in Europe Australia and Japan approximately 10000 children were born with phocomelia leading to the ban of thalidomide in most countries in 1961
22
bull The thalidomide tragedy marked a turning point in toxicity testing as it prompted United States and international regulatory agencies to develop systematic toxicity testing protocols
bull The thalidomide tragedy also brought into sharp focus the importance of rigorous and relevant testing of pharmaceuticals prior to their introduction into the market place (Kelsey 1988)
23
Thalidomide tragedy
Nuremberg Code-1947
bull On April 17 1947 United States Counsel for War Crimescame out with six points defining ldquolegitimate researchrdquo
bull The verdict of August 19 reiterated almost all of thesepoints in a section entitled Permissible MedicalExperiments and revised the original six points into ten
bull Subsequently the ten points became known as theNuremberg Code
24
Codes and Guidelines
Nuremberg Code (1947)
WMArsquos Declaration of Helsinki (1964)
bull Belmont Report (USA) (1979)-Tuskegee syphilis study
Council for International Organizations of Medical Sciences (CIOMS) 1993
International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) in 1996 Guideline on Good Clinical PracticeE6 (GCP)
Nuremberg Code (1947)
Voluntary and Informed consent-absolutely essential
Anticipate scientific benefits Useful
Animal experimentation first
Avoid physical and mental suffering
Benefits outweigh risks
No intentional death or disability
Protection from harm
Subject free to withdraw
Qualified investigators
Investigator will stop if harm occurs
THE DECLARATION OF HELSINKI-1964
Is an international standard for the conduct of clinicalresearch adopted by International Conference onHarmonization(ICH) Good Clinical Practice standards
A global ethical standard for medical research and wasapproved at the WMA General Assembly by a majority voteof 75
It is the mission of the clinical research professionals tosafeguard the health of the people
THE DECLARATION OF HELSINKI-1964
Historical Overview-
Its origin has been found in the Nazi Disaster and hasundergone several modifications
Prior to 1947 Nuremberg Code there was noaccepted code of conduct governing the ethicalaspects of human research
World Medical Association
It is an international organization of physicians
established on September 17 1947
First general Assembly of WMA was held in Paris
France
Mission- Serve humanity by endeavoring to achieve the
highest international standards in medical education
science ethics and health care for all peoples of the world
Declaration of Helsinki 1964
Adapted from Nuremberg
Code by the World Medical Association (WMA)
First adopted in Helsinki Finland 1964
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI- 2008
Ethical Principles for Medical Research Involving Human Subjects
Adopted by the 18th WMA General Assembly Helsinki Finland June 1964 and amended by the
29th WMA General Assembly Tokyo Japan October 1975
35th WMA General Assembly Venice Italy October 1983
41st WMA General Assembly Hong Kong September 1989
53th WMA General Assembly Washington 2002 (Note of Clarification on paragraph 29 added)
55th WMA General Assembly Tokyo 2004 (Note of Clarification on Paragraph 30 added)
59th WMA General Assembly Seoul October 2008
Seven Ethical Pillars of Clinical Research
AUTONOMY
BENEFICENCE
NON ndash MALFEASANCE
FIDELITY
TRUTHFULNESS
CONFIDENTIALITY
JUSTICE
Declaration of Helsinki
Autonomy
Consent
Para 20 The subjects must be volunteers andinformed participants in the research project
Para 22 freely-given informed consent
preferably in writing
Declaration of Helsinki
Para 5 well-being of the human subject shouldtake precedence over the interests of scienceand society
Beneficence
Declaration of Helsinki
Para 16
bull Preceded by careful assessment ofpredictable risks and burdens
bull Attempt to avoid any act or treatmentplan that would harm the patient
Non Malfeasance
Declaration of Helsinki
Para 11
Medical research involving human subjects must be basedon generally accepted scientific principles thoroughknowledge of the scientific literature and on adequatelaboratory and where appropriate animalexperimentation
Para 15
Conducted only by clinically competent medical person
Fidelity ndash duty of care
Declaration of Helsinki
Para 27
Both authors amp investigators are obliged topreserve the accuracy of the results Negativeas well as positive results should be published
Truthfulness - Honesty
Declaration of Helsinki
Para 21
Every precaution should be taken torespect the privacy of the subject theconfidentiality of the patients information
Confidentiality
Declaration of Helsinki
Para 30
Every patient entered into the study should be assured ofaccess to the best proven prophylactic diagnostic andtherapeutic methods identified by the study
Para 9
Research Investigators should be aware of the ethicallegal and regulatory requirements for research on humansubjects
Para 17
Physicians should cease any investigation if the risksoutweigh the potential benefits
Justice
DECLARATION OF HELSINKI -Basic Principles
1 Conform to accepted scientific principles
2 Design formulated in experimental protocol reviewed by IEC
3 Conducted by qualified and trained persons
4 Importance in proportion to inherent risk
5 Assessment of risks vs benefits
6 Safeguard subjectrsquos integrity (privacy)
7 Abstain unless hazards are predictable
8 Preserve accuracy when publishing
9 Adequately inform or right to withdraw
10 Obtain true informed consent in writing
11 Reliance on legal guardian
12 State compliance with Declaration
Ethical Principles and Guidelines for the Protection of Human Subjects of Research
bull Tuskegee Syphilis Study (1932ndash1972)
bull Named the Belmont Report for the Belmont Conference Center where the National Commission met when first drafting the report
42
Belmont Report 1979
Belmont Report 1979
Three ethical principles related to research on human subjects
1 Respect for Persons
2 Beneficence Do no harm while maximizing benefits for research project and minimizing risks to the research subjects
3 Justice ensuring reasonable non-exploitative and well-considered procedures are administered
Overview of
ICH GCP
What is ICH
bull The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)- is unique in bringing together the regulatory authorities and pharmaceutical industry of Europe Japan and the US to discuss scientific and technical aspects of drug registration
45
What is ICH
bull Since its inception in 1990 ICH has
gradually evolved
bull ICHs mission is to ensure that safe
effective and high quality medicines are
developed and registered in the most
resource-efficient manner
How did it evolve
The need to harmonize
bull Public disasters serious fraud and abuse of human rights
bull Trials of War criminals-Nuremberg code 1949
bull Thalidomide- Declaration of Helsinki 1964
bull Belmont report 1978 (Ethical Principles and guidelines for the protection of human subjects of research)-Tuskegee syphilis study
History
1962 US FDA IND Guidelines
1964 Declaration of Helsinki
1968 Committee on Safety of Medicines uk
1978 GCP US FDA
1991 GCP Europe
1996 ICH GCP
1997 ICH GCP Guideline
When did it begin
bull Ist conf in 1990 in Brussels
3 regions participated
bull Representatives from
Industry
Academia
Ministry of
health
ICH parties
6 parties
bull EU bull EFPIA European federation of pharmaceutical industriesrsquo associations
bull MHLW Ministry of health Labor and welfare Japan
bull JPMA Japan Pharmaceuticals manufacturers Association
bull US FDA
bull PhRMA
bull Observers WHO TPP(canada)
bull International federation of Pharmaceutical manufacturerrsquos association
Key objective
bull To discuss and define the minimum standards for the development and registration of investigational products
The result
Many guidelines made
bull Most important- ICH GCP guidelines
bull Evolved in several steps
bull Consolidated guideline ICH E6 Sept 1997
ICH Guidelines examples
bull Efficacy ndash clinical trials etc
bull Safety ndash pharmacovigilance adverse drug reaction
reporting
bull Quality ndash raw materials impurities residual solvents etc
bull Multidisciplinary ndash common technical document electronic
submission coding systems
What is GCP
A standard for the design conduct performance monitoring auditing recording analyses and reporting of clinical trials that provide assurance that the data and the reported results are credible accurate and that the rights integrity and confidentiality of trial subjects are protected
Why is it needed
bull To ensure the rights safety and well being of the trial subjects are protected
bull Ensure the credibility of clinical trial data
The ICH GCP guideline
bull Provide a unified standard for the EU Japan and USA regions to facilitate mutual acceptance of clinical trial data by the regulatory authorities in
these regions
bull 8 sections
ICH GCP guideline
1 Glossary
Common language for investigatorssponsorsethics committees
2Principles of Good Clinical Practice
13 tenets of ICH GCP
3Requirements for IRBIEC
Roles responsibilities and composition
ICH GCP guideline
4Responsibilities of the investigator
5Responsibilities of the sponsor
6Requirements for clinical trial protocol and protocol amendments
7Responsibility of the sponsor in the development of investigatorrsquos brochure
8Essential documents
Principles of ICH GCP
bull Ethical conduct as per
Declaration of Helsinki
GCP
Regulatory Requirements
Risk- Benefit
Primary concern- Subject
Principles of ICH GCP
bull Supportive data
bull Protocol
Scientifically sound clear detailed
bull Ethical Clearance
Study to be conducted in compliance to the protocol which has received EC approval
Principles of ICH GCP
bull Subject Care
Medical decisions responsibility of qualified physician
bull Qualified staff
By education training experience in their area of responsibility
bull Informed Consent
Principles of ICH GCP
bull Clinical Trial data
Recorded handled and stored to enable accurate reporting interpretation and verification
bull Confidentiality
Principles of ICH GCP
bull Investigational Product
Manufactured handled and stored as per GMP
Principles of ICH GCP
bull Quality Assurance
Systems and procedures to ensure the Quality of every aspect of the trial
Indian GCP guidelines
bull Released in Dec 2001(Developed by CDCSO and endorsed by DCGI)
bull In general in line with ICH GCP
bull Has Revised Schedule Y (Jan 2005) addressed discrepancies
bull SAFEGUARD PUBLIC HEALTH
bull ASSURE CONSUMER PROTECTION STANDARDS
bull FACILITATE AVAILABILITY OF SAFE AND EFFECTIVE PRODUCTS
bull ELIMINATE INCONSISTENT STANDARDS INTERNATIONALLY
bull FACILITATE MUTUAL ACCEPTANCE OF DATA FROM CLINICAL TRIALS
GOALS OF INTERNATIONAL HARMONIZATION OF
REGULATORY REQUIREMENTS
Study DocumentationDuring the study
The investigator must keepndash Source documents
bull Medical records (including access to computer records)
bull Laboratory reports
bull ECGs X-rays etc
bull Any other medical records reports or notes (hospital admissions and discharges)
ndash A subject identification list
ndash Copies of all study related documentation
Medical Records
bull In particular they should contain notes on
ndash Sufficient information to support subject eligibility
ndash This should be well documented (signed and dated)
ndash Subjectrsquos participation in the study
ndash Dates of visits
ndash Procedures investigations done
ndash Observations diagnoses
ndash Medications taken (including study medication)
ndash Adverse events
ndash Completion or withdrawal (reason) from the study
Study DocumentationAfter the study
The sponsor needs from the investigator
ndash Final drug accountability records
ndash All used and unused supplies and medication
ndash All required documents completed
Conclusion
70
Thanks
ldquoWhen a doctor [goes] wrong he is
the first of criminals He has nerve
and he has knowledgerdquo
- Sherlock Holmes
References
httpwwwwmanetepolicyb3htm
wwwhhsgovohrphumansubjectsguidancebelmonthtml
wwwhhsgovohrpreferencesnurcodehtml
wwwicmrnicinguidelinesGCLP
wwwcdsconicin
wwwubedurecercaBioeticadocDeclaracio_Helsinki_2013
wwwjewishvirtuallibraryorgjsourceHolocaustnazi_experiments
wwwichorgfileadminPublic_WebICHE6_R1__Guideline
Nazi Medical War Crimesduring World War II
bull Experiments conducted by Nazi physicians during World War II were unprecedented in their scope and the degree of harm and suffering to which human beings were subjected
bull Typically the experiments resulted in death disfigurement or permanent disability and as such are considered as examples of medical torture
Nazi Medical War Crimes
Medical experiments were performed onthousands of concentration campprisoners and included deadly studies andtortures such as-
Injecting people with gasoline and liveviruses
Immersing people in ice water
Forcing people to ingest poisons
9
Incisions made by
medical personnel
that were purposely
infected with bacteria
dirt and slivers of
glass
Victim of a tuberculosis medical experiment
10
Prisoner in a compression chamber
11
An experiment to
determine
altitudes at which
aircraft crews
could survive
without oxygen
Immersing people in ice water
bull With the intent of discovering means to prevent and treat hypothermia
bull 280 to 300 victims
bull One study forced subjects to endure a tank of ice water for up to five hours
12
bull In 1946 an American military tribunal opened criminal proceedings against 23 leading German physicians Doctors Trial
bull Sixteen of the doctors were found guilty
bull Seven were sentenced to death
bull Development of the Nuremberg Code of medical ethics
13
THE DOCTORS TRIAL
The Tuskegee Syphilis Study
bull Research participants was the long-term study of black males conducted at Tuskegee Alabama by the United States Public Health Service
bull (1930s-1970) - examination of the natural history of untreated syphilis
bull More than 400 African-American men with syphilis participated
bull The men were recruited without informed consent and in fact were misinformed that some of the procedures done in the interest of the research (eg spinal taps) were actually special free treatment
The Tuskegee Syphilis Study
bull In the 1940s penicillin was found to be effective in the treatment of syphilis
bull The study continued however and the men were neither informed of nor treated with the antibiotic
bull The first accounts of this study appeared in the national press in 1972
bull Belmont report 1978 (Ethical Principles and guidelines for the protection of human subjects of research)-Tuskegee syphilis study
The Jewish Chronic Disease Hospital Study
bull In 1963 studies were undertaken at New Yorks Jewish Chronic Disease Hospital to understand whether the bodys inability to reject cancer cells was due to cancer or debilitation
bull Previous studies had indicated that healthy persons reject cancer cells promptly and the researchers allegedly believed that the debilitated patients would also reject the cancers but at a substantially slower rate compared to healthy participants
The Jewish Chronic Disease Hospital Study
bull Further patients were not told that they would receive cancer cells because the researchers felt it would unnecessarily frighten them
bull It was found that the study had not been presented to the hospitals research committee and that the physicians responsible for the patients care had not been consulted
bull The researchers were found guilty of fraud deceit and unprofessional conduct
The Willowbrook Study
bull Institutionalized children as participants in research is demonstrated in a series of studies conducted from 1963 through 1966 at the Willowbrook State School a New York institution for mentally defective children
bull In order to gain an understanding of the natural history of infectious hepatitis under controlled circumstances newly admitted children were deliberately infected with the hepatitis virus
bull In some cases parents found they were unable to admit their children to Willowbrook unless they agreed to their childrsquos participation in the studies
The Willowbrook Study
This controversial case raised important questions about the adequacy and freedom of consent inadequate disclosure of the childs risk of later developing chronic liver disease
The Milgram Study
bull The lsquoteachersrsquo were instructed to give the lsquolearnersrsquo electrical shocks in response to incorrect answers on verbally given lsquotestsrsquo
bull Participants were deceived as to the nature of the study being told it was to test new teaching-learning techniques
Thalidomide tragedy
bull Thalidomide was a widely used drug in the late 1950s and early 1960s for the treatment of nausea in pregnant women
bull It became apparent in the 1960s that thalidomide treatment resulted in severe birth defects in thousands of children
21
bull Within a few years of the widespread use of thalidomide in Europe Australia and Japan approximately 10000 children were born with phocomelia leading to the ban of thalidomide in most countries in 1961
22
bull The thalidomide tragedy marked a turning point in toxicity testing as it prompted United States and international regulatory agencies to develop systematic toxicity testing protocols
bull The thalidomide tragedy also brought into sharp focus the importance of rigorous and relevant testing of pharmaceuticals prior to their introduction into the market place (Kelsey 1988)
23
Thalidomide tragedy
Nuremberg Code-1947
bull On April 17 1947 United States Counsel for War Crimescame out with six points defining ldquolegitimate researchrdquo
bull The verdict of August 19 reiterated almost all of thesepoints in a section entitled Permissible MedicalExperiments and revised the original six points into ten
bull Subsequently the ten points became known as theNuremberg Code
24
Codes and Guidelines
Nuremberg Code (1947)
WMArsquos Declaration of Helsinki (1964)
bull Belmont Report (USA) (1979)-Tuskegee syphilis study
Council for International Organizations of Medical Sciences (CIOMS) 1993
International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) in 1996 Guideline on Good Clinical PracticeE6 (GCP)
Nuremberg Code (1947)
Voluntary and Informed consent-absolutely essential
Anticipate scientific benefits Useful
Animal experimentation first
Avoid physical and mental suffering
Benefits outweigh risks
No intentional death or disability
Protection from harm
Subject free to withdraw
Qualified investigators
Investigator will stop if harm occurs
THE DECLARATION OF HELSINKI-1964
Is an international standard for the conduct of clinicalresearch adopted by International Conference onHarmonization(ICH) Good Clinical Practice standards
A global ethical standard for medical research and wasapproved at the WMA General Assembly by a majority voteof 75
It is the mission of the clinical research professionals tosafeguard the health of the people
THE DECLARATION OF HELSINKI-1964
Historical Overview-
Its origin has been found in the Nazi Disaster and hasundergone several modifications
Prior to 1947 Nuremberg Code there was noaccepted code of conduct governing the ethicalaspects of human research
World Medical Association
It is an international organization of physicians
established on September 17 1947
First general Assembly of WMA was held in Paris
France
Mission- Serve humanity by endeavoring to achieve the
highest international standards in medical education
science ethics and health care for all peoples of the world
Declaration of Helsinki 1964
Adapted from Nuremberg
Code by the World Medical Association (WMA)
First adopted in Helsinki Finland 1964
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI- 2008
Ethical Principles for Medical Research Involving Human Subjects
Adopted by the 18th WMA General Assembly Helsinki Finland June 1964 and amended by the
29th WMA General Assembly Tokyo Japan October 1975
35th WMA General Assembly Venice Italy October 1983
41st WMA General Assembly Hong Kong September 1989
53th WMA General Assembly Washington 2002 (Note of Clarification on paragraph 29 added)
55th WMA General Assembly Tokyo 2004 (Note of Clarification on Paragraph 30 added)
59th WMA General Assembly Seoul October 2008
Seven Ethical Pillars of Clinical Research
AUTONOMY
BENEFICENCE
NON ndash MALFEASANCE
FIDELITY
TRUTHFULNESS
CONFIDENTIALITY
JUSTICE
Declaration of Helsinki
Autonomy
Consent
Para 20 The subjects must be volunteers andinformed participants in the research project
Para 22 freely-given informed consent
preferably in writing
Declaration of Helsinki
Para 5 well-being of the human subject shouldtake precedence over the interests of scienceand society
Beneficence
Declaration of Helsinki
Para 16
bull Preceded by careful assessment ofpredictable risks and burdens
bull Attempt to avoid any act or treatmentplan that would harm the patient
Non Malfeasance
Declaration of Helsinki
Para 11
Medical research involving human subjects must be basedon generally accepted scientific principles thoroughknowledge of the scientific literature and on adequatelaboratory and where appropriate animalexperimentation
Para 15
Conducted only by clinically competent medical person
Fidelity ndash duty of care
Declaration of Helsinki
Para 27
Both authors amp investigators are obliged topreserve the accuracy of the results Negativeas well as positive results should be published
Truthfulness - Honesty
Declaration of Helsinki
Para 21
Every precaution should be taken torespect the privacy of the subject theconfidentiality of the patients information
Confidentiality
Declaration of Helsinki
Para 30
Every patient entered into the study should be assured ofaccess to the best proven prophylactic diagnostic andtherapeutic methods identified by the study
Para 9
Research Investigators should be aware of the ethicallegal and regulatory requirements for research on humansubjects
Para 17
Physicians should cease any investigation if the risksoutweigh the potential benefits
Justice
DECLARATION OF HELSINKI -Basic Principles
1 Conform to accepted scientific principles
2 Design formulated in experimental protocol reviewed by IEC
3 Conducted by qualified and trained persons
4 Importance in proportion to inherent risk
5 Assessment of risks vs benefits
6 Safeguard subjectrsquos integrity (privacy)
7 Abstain unless hazards are predictable
8 Preserve accuracy when publishing
9 Adequately inform or right to withdraw
10 Obtain true informed consent in writing
11 Reliance on legal guardian
12 State compliance with Declaration
Ethical Principles and Guidelines for the Protection of Human Subjects of Research
bull Tuskegee Syphilis Study (1932ndash1972)
bull Named the Belmont Report for the Belmont Conference Center where the National Commission met when first drafting the report
42
Belmont Report 1979
Belmont Report 1979
Three ethical principles related to research on human subjects
1 Respect for Persons
2 Beneficence Do no harm while maximizing benefits for research project and minimizing risks to the research subjects
3 Justice ensuring reasonable non-exploitative and well-considered procedures are administered
Overview of
ICH GCP
What is ICH
bull The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)- is unique in bringing together the regulatory authorities and pharmaceutical industry of Europe Japan and the US to discuss scientific and technical aspects of drug registration
45
What is ICH
bull Since its inception in 1990 ICH has
gradually evolved
bull ICHs mission is to ensure that safe
effective and high quality medicines are
developed and registered in the most
resource-efficient manner
How did it evolve
The need to harmonize
bull Public disasters serious fraud and abuse of human rights
bull Trials of War criminals-Nuremberg code 1949
bull Thalidomide- Declaration of Helsinki 1964
bull Belmont report 1978 (Ethical Principles and guidelines for the protection of human subjects of research)-Tuskegee syphilis study
History
1962 US FDA IND Guidelines
1964 Declaration of Helsinki
1968 Committee on Safety of Medicines uk
1978 GCP US FDA
1991 GCP Europe
1996 ICH GCP
1997 ICH GCP Guideline
When did it begin
bull Ist conf in 1990 in Brussels
3 regions participated
bull Representatives from
Industry
Academia
Ministry of
health
ICH parties
6 parties
bull EU bull EFPIA European federation of pharmaceutical industriesrsquo associations
bull MHLW Ministry of health Labor and welfare Japan
bull JPMA Japan Pharmaceuticals manufacturers Association
bull US FDA
bull PhRMA
bull Observers WHO TPP(canada)
bull International federation of Pharmaceutical manufacturerrsquos association
Key objective
bull To discuss and define the minimum standards for the development and registration of investigational products
The result
Many guidelines made
bull Most important- ICH GCP guidelines
bull Evolved in several steps
bull Consolidated guideline ICH E6 Sept 1997
ICH Guidelines examples
bull Efficacy ndash clinical trials etc
bull Safety ndash pharmacovigilance adverse drug reaction
reporting
bull Quality ndash raw materials impurities residual solvents etc
bull Multidisciplinary ndash common technical document electronic
submission coding systems
What is GCP
A standard for the design conduct performance monitoring auditing recording analyses and reporting of clinical trials that provide assurance that the data and the reported results are credible accurate and that the rights integrity and confidentiality of trial subjects are protected
Why is it needed
bull To ensure the rights safety and well being of the trial subjects are protected
bull Ensure the credibility of clinical trial data
The ICH GCP guideline
bull Provide a unified standard for the EU Japan and USA regions to facilitate mutual acceptance of clinical trial data by the regulatory authorities in
these regions
bull 8 sections
ICH GCP guideline
1 Glossary
Common language for investigatorssponsorsethics committees
2Principles of Good Clinical Practice
13 tenets of ICH GCP
3Requirements for IRBIEC
Roles responsibilities and composition
ICH GCP guideline
4Responsibilities of the investigator
5Responsibilities of the sponsor
6Requirements for clinical trial protocol and protocol amendments
7Responsibility of the sponsor in the development of investigatorrsquos brochure
8Essential documents
Principles of ICH GCP
bull Ethical conduct as per
Declaration of Helsinki
GCP
Regulatory Requirements
Risk- Benefit
Primary concern- Subject
Principles of ICH GCP
bull Supportive data
bull Protocol
Scientifically sound clear detailed
bull Ethical Clearance
Study to be conducted in compliance to the protocol which has received EC approval
Principles of ICH GCP
bull Subject Care
Medical decisions responsibility of qualified physician
bull Qualified staff
By education training experience in their area of responsibility
bull Informed Consent
Principles of ICH GCP
bull Clinical Trial data
Recorded handled and stored to enable accurate reporting interpretation and verification
bull Confidentiality
Principles of ICH GCP
bull Investigational Product
Manufactured handled and stored as per GMP
Principles of ICH GCP
bull Quality Assurance
Systems and procedures to ensure the Quality of every aspect of the trial
Indian GCP guidelines
bull Released in Dec 2001(Developed by CDCSO and endorsed by DCGI)
bull In general in line with ICH GCP
bull Has Revised Schedule Y (Jan 2005) addressed discrepancies
bull SAFEGUARD PUBLIC HEALTH
bull ASSURE CONSUMER PROTECTION STANDARDS
bull FACILITATE AVAILABILITY OF SAFE AND EFFECTIVE PRODUCTS
bull ELIMINATE INCONSISTENT STANDARDS INTERNATIONALLY
bull FACILITATE MUTUAL ACCEPTANCE OF DATA FROM CLINICAL TRIALS
GOALS OF INTERNATIONAL HARMONIZATION OF
REGULATORY REQUIREMENTS
Study DocumentationDuring the study
The investigator must keepndash Source documents
bull Medical records (including access to computer records)
bull Laboratory reports
bull ECGs X-rays etc
bull Any other medical records reports or notes (hospital admissions and discharges)
ndash A subject identification list
ndash Copies of all study related documentation
Medical Records
bull In particular they should contain notes on
ndash Sufficient information to support subject eligibility
ndash This should be well documented (signed and dated)
ndash Subjectrsquos participation in the study
ndash Dates of visits
ndash Procedures investigations done
ndash Observations diagnoses
ndash Medications taken (including study medication)
ndash Adverse events
ndash Completion or withdrawal (reason) from the study
Study DocumentationAfter the study
The sponsor needs from the investigator
ndash Final drug accountability records
ndash All used and unused supplies and medication
ndash All required documents completed
Conclusion
70
Thanks
ldquoWhen a doctor [goes] wrong he is
the first of criminals He has nerve
and he has knowledgerdquo
- Sherlock Holmes
References
httpwwwwmanetepolicyb3htm
wwwhhsgovohrphumansubjectsguidancebelmonthtml
wwwhhsgovohrpreferencesnurcodehtml
wwwicmrnicinguidelinesGCLP
wwwcdsconicin
wwwubedurecercaBioeticadocDeclaracio_Helsinki_2013
wwwjewishvirtuallibraryorgjsourceHolocaustnazi_experiments
wwwichorgfileadminPublic_WebICHE6_R1__Guideline
Nazi Medical War Crimes
Medical experiments were performed onthousands of concentration campprisoners and included deadly studies andtortures such as-
Injecting people with gasoline and liveviruses
Immersing people in ice water
Forcing people to ingest poisons
9
Incisions made by
medical personnel
that were purposely
infected with bacteria
dirt and slivers of
glass
Victim of a tuberculosis medical experiment
10
Prisoner in a compression chamber
11
An experiment to
determine
altitudes at which
aircraft crews
could survive
without oxygen
Immersing people in ice water
bull With the intent of discovering means to prevent and treat hypothermia
bull 280 to 300 victims
bull One study forced subjects to endure a tank of ice water for up to five hours
12
bull In 1946 an American military tribunal opened criminal proceedings against 23 leading German physicians Doctors Trial
bull Sixteen of the doctors were found guilty
bull Seven were sentenced to death
bull Development of the Nuremberg Code of medical ethics
13
THE DOCTORS TRIAL
The Tuskegee Syphilis Study
bull Research participants was the long-term study of black males conducted at Tuskegee Alabama by the United States Public Health Service
bull (1930s-1970) - examination of the natural history of untreated syphilis
bull More than 400 African-American men with syphilis participated
bull The men were recruited without informed consent and in fact were misinformed that some of the procedures done in the interest of the research (eg spinal taps) were actually special free treatment
The Tuskegee Syphilis Study
bull In the 1940s penicillin was found to be effective in the treatment of syphilis
bull The study continued however and the men were neither informed of nor treated with the antibiotic
bull The first accounts of this study appeared in the national press in 1972
bull Belmont report 1978 (Ethical Principles and guidelines for the protection of human subjects of research)-Tuskegee syphilis study
The Jewish Chronic Disease Hospital Study
bull In 1963 studies were undertaken at New Yorks Jewish Chronic Disease Hospital to understand whether the bodys inability to reject cancer cells was due to cancer or debilitation
bull Previous studies had indicated that healthy persons reject cancer cells promptly and the researchers allegedly believed that the debilitated patients would also reject the cancers but at a substantially slower rate compared to healthy participants
The Jewish Chronic Disease Hospital Study
bull Further patients were not told that they would receive cancer cells because the researchers felt it would unnecessarily frighten them
bull It was found that the study had not been presented to the hospitals research committee and that the physicians responsible for the patients care had not been consulted
bull The researchers were found guilty of fraud deceit and unprofessional conduct
The Willowbrook Study
bull Institutionalized children as participants in research is demonstrated in a series of studies conducted from 1963 through 1966 at the Willowbrook State School a New York institution for mentally defective children
bull In order to gain an understanding of the natural history of infectious hepatitis under controlled circumstances newly admitted children were deliberately infected with the hepatitis virus
bull In some cases parents found they were unable to admit their children to Willowbrook unless they agreed to their childrsquos participation in the studies
The Willowbrook Study
This controversial case raised important questions about the adequacy and freedom of consent inadequate disclosure of the childs risk of later developing chronic liver disease
The Milgram Study
bull The lsquoteachersrsquo were instructed to give the lsquolearnersrsquo electrical shocks in response to incorrect answers on verbally given lsquotestsrsquo
bull Participants were deceived as to the nature of the study being told it was to test new teaching-learning techniques
Thalidomide tragedy
bull Thalidomide was a widely used drug in the late 1950s and early 1960s for the treatment of nausea in pregnant women
bull It became apparent in the 1960s that thalidomide treatment resulted in severe birth defects in thousands of children
21
bull Within a few years of the widespread use of thalidomide in Europe Australia and Japan approximately 10000 children were born with phocomelia leading to the ban of thalidomide in most countries in 1961
22
bull The thalidomide tragedy marked a turning point in toxicity testing as it prompted United States and international regulatory agencies to develop systematic toxicity testing protocols
bull The thalidomide tragedy also brought into sharp focus the importance of rigorous and relevant testing of pharmaceuticals prior to their introduction into the market place (Kelsey 1988)
23
Thalidomide tragedy
Nuremberg Code-1947
bull On April 17 1947 United States Counsel for War Crimescame out with six points defining ldquolegitimate researchrdquo
bull The verdict of August 19 reiterated almost all of thesepoints in a section entitled Permissible MedicalExperiments and revised the original six points into ten
bull Subsequently the ten points became known as theNuremberg Code
24
Codes and Guidelines
Nuremberg Code (1947)
WMArsquos Declaration of Helsinki (1964)
bull Belmont Report (USA) (1979)-Tuskegee syphilis study
Council for International Organizations of Medical Sciences (CIOMS) 1993
International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) in 1996 Guideline on Good Clinical PracticeE6 (GCP)
Nuremberg Code (1947)
Voluntary and Informed consent-absolutely essential
Anticipate scientific benefits Useful
Animal experimentation first
Avoid physical and mental suffering
Benefits outweigh risks
No intentional death or disability
Protection from harm
Subject free to withdraw
Qualified investigators
Investigator will stop if harm occurs
THE DECLARATION OF HELSINKI-1964
Is an international standard for the conduct of clinicalresearch adopted by International Conference onHarmonization(ICH) Good Clinical Practice standards
A global ethical standard for medical research and wasapproved at the WMA General Assembly by a majority voteof 75
It is the mission of the clinical research professionals tosafeguard the health of the people
THE DECLARATION OF HELSINKI-1964
Historical Overview-
Its origin has been found in the Nazi Disaster and hasundergone several modifications
Prior to 1947 Nuremberg Code there was noaccepted code of conduct governing the ethicalaspects of human research
World Medical Association
It is an international organization of physicians
established on September 17 1947
First general Assembly of WMA was held in Paris
France
Mission- Serve humanity by endeavoring to achieve the
highest international standards in medical education
science ethics and health care for all peoples of the world
Declaration of Helsinki 1964
Adapted from Nuremberg
Code by the World Medical Association (WMA)
First adopted in Helsinki Finland 1964
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI- 2008
Ethical Principles for Medical Research Involving Human Subjects
Adopted by the 18th WMA General Assembly Helsinki Finland June 1964 and amended by the
29th WMA General Assembly Tokyo Japan October 1975
35th WMA General Assembly Venice Italy October 1983
41st WMA General Assembly Hong Kong September 1989
53th WMA General Assembly Washington 2002 (Note of Clarification on paragraph 29 added)
55th WMA General Assembly Tokyo 2004 (Note of Clarification on Paragraph 30 added)
59th WMA General Assembly Seoul October 2008
Seven Ethical Pillars of Clinical Research
AUTONOMY
BENEFICENCE
NON ndash MALFEASANCE
FIDELITY
TRUTHFULNESS
CONFIDENTIALITY
JUSTICE
Declaration of Helsinki
Autonomy
Consent
Para 20 The subjects must be volunteers andinformed participants in the research project
Para 22 freely-given informed consent
preferably in writing
Declaration of Helsinki
Para 5 well-being of the human subject shouldtake precedence over the interests of scienceand society
Beneficence
Declaration of Helsinki
Para 16
bull Preceded by careful assessment ofpredictable risks and burdens
bull Attempt to avoid any act or treatmentplan that would harm the patient
Non Malfeasance
Declaration of Helsinki
Para 11
Medical research involving human subjects must be basedon generally accepted scientific principles thoroughknowledge of the scientific literature and on adequatelaboratory and where appropriate animalexperimentation
Para 15
Conducted only by clinically competent medical person
Fidelity ndash duty of care
Declaration of Helsinki
Para 27
Both authors amp investigators are obliged topreserve the accuracy of the results Negativeas well as positive results should be published
Truthfulness - Honesty
Declaration of Helsinki
Para 21
Every precaution should be taken torespect the privacy of the subject theconfidentiality of the patients information
Confidentiality
Declaration of Helsinki
Para 30
Every patient entered into the study should be assured ofaccess to the best proven prophylactic diagnostic andtherapeutic methods identified by the study
Para 9
Research Investigators should be aware of the ethicallegal and regulatory requirements for research on humansubjects
Para 17
Physicians should cease any investigation if the risksoutweigh the potential benefits
Justice
DECLARATION OF HELSINKI -Basic Principles
1 Conform to accepted scientific principles
2 Design formulated in experimental protocol reviewed by IEC
3 Conducted by qualified and trained persons
4 Importance in proportion to inherent risk
5 Assessment of risks vs benefits
6 Safeguard subjectrsquos integrity (privacy)
7 Abstain unless hazards are predictable
8 Preserve accuracy when publishing
9 Adequately inform or right to withdraw
10 Obtain true informed consent in writing
11 Reliance on legal guardian
12 State compliance with Declaration
Ethical Principles and Guidelines for the Protection of Human Subjects of Research
bull Tuskegee Syphilis Study (1932ndash1972)
bull Named the Belmont Report for the Belmont Conference Center where the National Commission met when first drafting the report
42
Belmont Report 1979
Belmont Report 1979
Three ethical principles related to research on human subjects
1 Respect for Persons
2 Beneficence Do no harm while maximizing benefits for research project and minimizing risks to the research subjects
3 Justice ensuring reasonable non-exploitative and well-considered procedures are administered
Overview of
ICH GCP
What is ICH
bull The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)- is unique in bringing together the regulatory authorities and pharmaceutical industry of Europe Japan and the US to discuss scientific and technical aspects of drug registration
45
What is ICH
bull Since its inception in 1990 ICH has
gradually evolved
bull ICHs mission is to ensure that safe
effective and high quality medicines are
developed and registered in the most
resource-efficient manner
How did it evolve
The need to harmonize
bull Public disasters serious fraud and abuse of human rights
bull Trials of War criminals-Nuremberg code 1949
bull Thalidomide- Declaration of Helsinki 1964
bull Belmont report 1978 (Ethical Principles and guidelines for the protection of human subjects of research)-Tuskegee syphilis study
History
1962 US FDA IND Guidelines
1964 Declaration of Helsinki
1968 Committee on Safety of Medicines uk
1978 GCP US FDA
1991 GCP Europe
1996 ICH GCP
1997 ICH GCP Guideline
When did it begin
bull Ist conf in 1990 in Brussels
3 regions participated
bull Representatives from
Industry
Academia
Ministry of
health
ICH parties
6 parties
bull EU bull EFPIA European federation of pharmaceutical industriesrsquo associations
bull MHLW Ministry of health Labor and welfare Japan
bull JPMA Japan Pharmaceuticals manufacturers Association
bull US FDA
bull PhRMA
bull Observers WHO TPP(canada)
bull International federation of Pharmaceutical manufacturerrsquos association
Key objective
bull To discuss and define the minimum standards for the development and registration of investigational products
The result
Many guidelines made
bull Most important- ICH GCP guidelines
bull Evolved in several steps
bull Consolidated guideline ICH E6 Sept 1997
ICH Guidelines examples
bull Efficacy ndash clinical trials etc
bull Safety ndash pharmacovigilance adverse drug reaction
reporting
bull Quality ndash raw materials impurities residual solvents etc
bull Multidisciplinary ndash common technical document electronic
submission coding systems
What is GCP
A standard for the design conduct performance monitoring auditing recording analyses and reporting of clinical trials that provide assurance that the data and the reported results are credible accurate and that the rights integrity and confidentiality of trial subjects are protected
Why is it needed
bull To ensure the rights safety and well being of the trial subjects are protected
bull Ensure the credibility of clinical trial data
The ICH GCP guideline
bull Provide a unified standard for the EU Japan and USA regions to facilitate mutual acceptance of clinical trial data by the regulatory authorities in
these regions
bull 8 sections
ICH GCP guideline
1 Glossary
Common language for investigatorssponsorsethics committees
2Principles of Good Clinical Practice
13 tenets of ICH GCP
3Requirements for IRBIEC
Roles responsibilities and composition
ICH GCP guideline
4Responsibilities of the investigator
5Responsibilities of the sponsor
6Requirements for clinical trial protocol and protocol amendments
7Responsibility of the sponsor in the development of investigatorrsquos brochure
8Essential documents
Principles of ICH GCP
bull Ethical conduct as per
Declaration of Helsinki
GCP
Regulatory Requirements
Risk- Benefit
Primary concern- Subject
Principles of ICH GCP
bull Supportive data
bull Protocol
Scientifically sound clear detailed
bull Ethical Clearance
Study to be conducted in compliance to the protocol which has received EC approval
Principles of ICH GCP
bull Subject Care
Medical decisions responsibility of qualified physician
bull Qualified staff
By education training experience in their area of responsibility
bull Informed Consent
Principles of ICH GCP
bull Clinical Trial data
Recorded handled and stored to enable accurate reporting interpretation and verification
bull Confidentiality
Principles of ICH GCP
bull Investigational Product
Manufactured handled and stored as per GMP
Principles of ICH GCP
bull Quality Assurance
Systems and procedures to ensure the Quality of every aspect of the trial
Indian GCP guidelines
bull Released in Dec 2001(Developed by CDCSO and endorsed by DCGI)
bull In general in line with ICH GCP
bull Has Revised Schedule Y (Jan 2005) addressed discrepancies
bull SAFEGUARD PUBLIC HEALTH
bull ASSURE CONSUMER PROTECTION STANDARDS
bull FACILITATE AVAILABILITY OF SAFE AND EFFECTIVE PRODUCTS
bull ELIMINATE INCONSISTENT STANDARDS INTERNATIONALLY
bull FACILITATE MUTUAL ACCEPTANCE OF DATA FROM CLINICAL TRIALS
GOALS OF INTERNATIONAL HARMONIZATION OF
REGULATORY REQUIREMENTS
Study DocumentationDuring the study
The investigator must keepndash Source documents
bull Medical records (including access to computer records)
bull Laboratory reports
bull ECGs X-rays etc
bull Any other medical records reports or notes (hospital admissions and discharges)
ndash A subject identification list
ndash Copies of all study related documentation
Medical Records
bull In particular they should contain notes on
ndash Sufficient information to support subject eligibility
ndash This should be well documented (signed and dated)
ndash Subjectrsquos participation in the study
ndash Dates of visits
ndash Procedures investigations done
ndash Observations diagnoses
ndash Medications taken (including study medication)
ndash Adverse events
ndash Completion or withdrawal (reason) from the study
Study DocumentationAfter the study
The sponsor needs from the investigator
ndash Final drug accountability records
ndash All used and unused supplies and medication
ndash All required documents completed
Conclusion
70
Thanks
ldquoWhen a doctor [goes] wrong he is
the first of criminals He has nerve
and he has knowledgerdquo
- Sherlock Holmes
References
httpwwwwmanetepolicyb3htm
wwwhhsgovohrphumansubjectsguidancebelmonthtml
wwwhhsgovohrpreferencesnurcodehtml
wwwicmrnicinguidelinesGCLP
wwwcdsconicin
wwwubedurecercaBioeticadocDeclaracio_Helsinki_2013
wwwjewishvirtuallibraryorgjsourceHolocaustnazi_experiments
wwwichorgfileadminPublic_WebICHE6_R1__Guideline
9
Incisions made by
medical personnel
that were purposely
infected with bacteria
dirt and slivers of
glass
Victim of a tuberculosis medical experiment
10
Prisoner in a compression chamber
11
An experiment to
determine
altitudes at which
aircraft crews
could survive
without oxygen
Immersing people in ice water
bull With the intent of discovering means to prevent and treat hypothermia
bull 280 to 300 victims
bull One study forced subjects to endure a tank of ice water for up to five hours
12
bull In 1946 an American military tribunal opened criminal proceedings against 23 leading German physicians Doctors Trial
bull Sixteen of the doctors were found guilty
bull Seven were sentenced to death
bull Development of the Nuremberg Code of medical ethics
13
THE DOCTORS TRIAL
The Tuskegee Syphilis Study
bull Research participants was the long-term study of black males conducted at Tuskegee Alabama by the United States Public Health Service
bull (1930s-1970) - examination of the natural history of untreated syphilis
bull More than 400 African-American men with syphilis participated
bull The men were recruited without informed consent and in fact were misinformed that some of the procedures done in the interest of the research (eg spinal taps) were actually special free treatment
The Tuskegee Syphilis Study
bull In the 1940s penicillin was found to be effective in the treatment of syphilis
bull The study continued however and the men were neither informed of nor treated with the antibiotic
bull The first accounts of this study appeared in the national press in 1972
bull Belmont report 1978 (Ethical Principles and guidelines for the protection of human subjects of research)-Tuskegee syphilis study
The Jewish Chronic Disease Hospital Study
bull In 1963 studies were undertaken at New Yorks Jewish Chronic Disease Hospital to understand whether the bodys inability to reject cancer cells was due to cancer or debilitation
bull Previous studies had indicated that healthy persons reject cancer cells promptly and the researchers allegedly believed that the debilitated patients would also reject the cancers but at a substantially slower rate compared to healthy participants
The Jewish Chronic Disease Hospital Study
bull Further patients were not told that they would receive cancer cells because the researchers felt it would unnecessarily frighten them
bull It was found that the study had not been presented to the hospitals research committee and that the physicians responsible for the patients care had not been consulted
bull The researchers were found guilty of fraud deceit and unprofessional conduct
The Willowbrook Study
bull Institutionalized children as participants in research is demonstrated in a series of studies conducted from 1963 through 1966 at the Willowbrook State School a New York institution for mentally defective children
bull In order to gain an understanding of the natural history of infectious hepatitis under controlled circumstances newly admitted children were deliberately infected with the hepatitis virus
bull In some cases parents found they were unable to admit their children to Willowbrook unless they agreed to their childrsquos participation in the studies
The Willowbrook Study
This controversial case raised important questions about the adequacy and freedom of consent inadequate disclosure of the childs risk of later developing chronic liver disease
The Milgram Study
bull The lsquoteachersrsquo were instructed to give the lsquolearnersrsquo electrical shocks in response to incorrect answers on verbally given lsquotestsrsquo
bull Participants were deceived as to the nature of the study being told it was to test new teaching-learning techniques
Thalidomide tragedy
bull Thalidomide was a widely used drug in the late 1950s and early 1960s for the treatment of nausea in pregnant women
bull It became apparent in the 1960s that thalidomide treatment resulted in severe birth defects in thousands of children
21
bull Within a few years of the widespread use of thalidomide in Europe Australia and Japan approximately 10000 children were born with phocomelia leading to the ban of thalidomide in most countries in 1961
22
bull The thalidomide tragedy marked a turning point in toxicity testing as it prompted United States and international regulatory agencies to develop systematic toxicity testing protocols
bull The thalidomide tragedy also brought into sharp focus the importance of rigorous and relevant testing of pharmaceuticals prior to their introduction into the market place (Kelsey 1988)
23
Thalidomide tragedy
Nuremberg Code-1947
bull On April 17 1947 United States Counsel for War Crimescame out with six points defining ldquolegitimate researchrdquo
bull The verdict of August 19 reiterated almost all of thesepoints in a section entitled Permissible MedicalExperiments and revised the original six points into ten
bull Subsequently the ten points became known as theNuremberg Code
24
Codes and Guidelines
Nuremberg Code (1947)
WMArsquos Declaration of Helsinki (1964)
bull Belmont Report (USA) (1979)-Tuskegee syphilis study
Council for International Organizations of Medical Sciences (CIOMS) 1993
International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) in 1996 Guideline on Good Clinical PracticeE6 (GCP)
Nuremberg Code (1947)
Voluntary and Informed consent-absolutely essential
Anticipate scientific benefits Useful
Animal experimentation first
Avoid physical and mental suffering
Benefits outweigh risks
No intentional death or disability
Protection from harm
Subject free to withdraw
Qualified investigators
Investigator will stop if harm occurs
THE DECLARATION OF HELSINKI-1964
Is an international standard for the conduct of clinicalresearch adopted by International Conference onHarmonization(ICH) Good Clinical Practice standards
A global ethical standard for medical research and wasapproved at the WMA General Assembly by a majority voteof 75
It is the mission of the clinical research professionals tosafeguard the health of the people
THE DECLARATION OF HELSINKI-1964
Historical Overview-
Its origin has been found in the Nazi Disaster and hasundergone several modifications
Prior to 1947 Nuremberg Code there was noaccepted code of conduct governing the ethicalaspects of human research
World Medical Association
It is an international organization of physicians
established on September 17 1947
First general Assembly of WMA was held in Paris
France
Mission- Serve humanity by endeavoring to achieve the
highest international standards in medical education
science ethics and health care for all peoples of the world
Declaration of Helsinki 1964
Adapted from Nuremberg
Code by the World Medical Association (WMA)
First adopted in Helsinki Finland 1964
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI- 2008
Ethical Principles for Medical Research Involving Human Subjects
Adopted by the 18th WMA General Assembly Helsinki Finland June 1964 and amended by the
29th WMA General Assembly Tokyo Japan October 1975
35th WMA General Assembly Venice Italy October 1983
41st WMA General Assembly Hong Kong September 1989
53th WMA General Assembly Washington 2002 (Note of Clarification on paragraph 29 added)
55th WMA General Assembly Tokyo 2004 (Note of Clarification on Paragraph 30 added)
59th WMA General Assembly Seoul October 2008
Seven Ethical Pillars of Clinical Research
AUTONOMY
BENEFICENCE
NON ndash MALFEASANCE
FIDELITY
TRUTHFULNESS
CONFIDENTIALITY
JUSTICE
Declaration of Helsinki
Autonomy
Consent
Para 20 The subjects must be volunteers andinformed participants in the research project
Para 22 freely-given informed consent
preferably in writing
Declaration of Helsinki
Para 5 well-being of the human subject shouldtake precedence over the interests of scienceand society
Beneficence
Declaration of Helsinki
Para 16
bull Preceded by careful assessment ofpredictable risks and burdens
bull Attempt to avoid any act or treatmentplan that would harm the patient
Non Malfeasance
Declaration of Helsinki
Para 11
Medical research involving human subjects must be basedon generally accepted scientific principles thoroughknowledge of the scientific literature and on adequatelaboratory and where appropriate animalexperimentation
Para 15
Conducted only by clinically competent medical person
Fidelity ndash duty of care
Declaration of Helsinki
Para 27
Both authors amp investigators are obliged topreserve the accuracy of the results Negativeas well as positive results should be published
Truthfulness - Honesty
Declaration of Helsinki
Para 21
Every precaution should be taken torespect the privacy of the subject theconfidentiality of the patients information
Confidentiality
Declaration of Helsinki
Para 30
Every patient entered into the study should be assured ofaccess to the best proven prophylactic diagnostic andtherapeutic methods identified by the study
Para 9
Research Investigators should be aware of the ethicallegal and regulatory requirements for research on humansubjects
Para 17
Physicians should cease any investigation if the risksoutweigh the potential benefits
Justice
DECLARATION OF HELSINKI -Basic Principles
1 Conform to accepted scientific principles
2 Design formulated in experimental protocol reviewed by IEC
3 Conducted by qualified and trained persons
4 Importance in proportion to inherent risk
5 Assessment of risks vs benefits
6 Safeguard subjectrsquos integrity (privacy)
7 Abstain unless hazards are predictable
8 Preserve accuracy when publishing
9 Adequately inform or right to withdraw
10 Obtain true informed consent in writing
11 Reliance on legal guardian
12 State compliance with Declaration
Ethical Principles and Guidelines for the Protection of Human Subjects of Research
bull Tuskegee Syphilis Study (1932ndash1972)
bull Named the Belmont Report for the Belmont Conference Center where the National Commission met when first drafting the report
42
Belmont Report 1979
Belmont Report 1979
Three ethical principles related to research on human subjects
1 Respect for Persons
2 Beneficence Do no harm while maximizing benefits for research project and minimizing risks to the research subjects
3 Justice ensuring reasonable non-exploitative and well-considered procedures are administered
Overview of
ICH GCP
What is ICH
bull The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)- is unique in bringing together the regulatory authorities and pharmaceutical industry of Europe Japan and the US to discuss scientific and technical aspects of drug registration
45
What is ICH
bull Since its inception in 1990 ICH has
gradually evolved
bull ICHs mission is to ensure that safe
effective and high quality medicines are
developed and registered in the most
resource-efficient manner
How did it evolve
The need to harmonize
bull Public disasters serious fraud and abuse of human rights
bull Trials of War criminals-Nuremberg code 1949
bull Thalidomide- Declaration of Helsinki 1964
bull Belmont report 1978 (Ethical Principles and guidelines for the protection of human subjects of research)-Tuskegee syphilis study
History
1962 US FDA IND Guidelines
1964 Declaration of Helsinki
1968 Committee on Safety of Medicines uk
1978 GCP US FDA
1991 GCP Europe
1996 ICH GCP
1997 ICH GCP Guideline
When did it begin
bull Ist conf in 1990 in Brussels
3 regions participated
bull Representatives from
Industry
Academia
Ministry of
health
ICH parties
6 parties
bull EU bull EFPIA European federation of pharmaceutical industriesrsquo associations
bull MHLW Ministry of health Labor and welfare Japan
bull JPMA Japan Pharmaceuticals manufacturers Association
bull US FDA
bull PhRMA
bull Observers WHO TPP(canada)
bull International federation of Pharmaceutical manufacturerrsquos association
Key objective
bull To discuss and define the minimum standards for the development and registration of investigational products
The result
Many guidelines made
bull Most important- ICH GCP guidelines
bull Evolved in several steps
bull Consolidated guideline ICH E6 Sept 1997
ICH Guidelines examples
bull Efficacy ndash clinical trials etc
bull Safety ndash pharmacovigilance adverse drug reaction
reporting
bull Quality ndash raw materials impurities residual solvents etc
bull Multidisciplinary ndash common technical document electronic
submission coding systems
What is GCP
A standard for the design conduct performance monitoring auditing recording analyses and reporting of clinical trials that provide assurance that the data and the reported results are credible accurate and that the rights integrity and confidentiality of trial subjects are protected
Why is it needed
bull To ensure the rights safety and well being of the trial subjects are protected
bull Ensure the credibility of clinical trial data
The ICH GCP guideline
bull Provide a unified standard for the EU Japan and USA regions to facilitate mutual acceptance of clinical trial data by the regulatory authorities in
these regions
bull 8 sections
ICH GCP guideline
1 Glossary
Common language for investigatorssponsorsethics committees
2Principles of Good Clinical Practice
13 tenets of ICH GCP
3Requirements for IRBIEC
Roles responsibilities and composition
ICH GCP guideline
4Responsibilities of the investigator
5Responsibilities of the sponsor
6Requirements for clinical trial protocol and protocol amendments
7Responsibility of the sponsor in the development of investigatorrsquos brochure
8Essential documents
Principles of ICH GCP
bull Ethical conduct as per
Declaration of Helsinki
GCP
Regulatory Requirements
Risk- Benefit
Primary concern- Subject
Principles of ICH GCP
bull Supportive data
bull Protocol
Scientifically sound clear detailed
bull Ethical Clearance
Study to be conducted in compliance to the protocol which has received EC approval
Principles of ICH GCP
bull Subject Care
Medical decisions responsibility of qualified physician
bull Qualified staff
By education training experience in their area of responsibility
bull Informed Consent
Principles of ICH GCP
bull Clinical Trial data
Recorded handled and stored to enable accurate reporting interpretation and verification
bull Confidentiality
Principles of ICH GCP
bull Investigational Product
Manufactured handled and stored as per GMP
Principles of ICH GCP
bull Quality Assurance
Systems and procedures to ensure the Quality of every aspect of the trial
Indian GCP guidelines
bull Released in Dec 2001(Developed by CDCSO and endorsed by DCGI)
bull In general in line with ICH GCP
bull Has Revised Schedule Y (Jan 2005) addressed discrepancies
bull SAFEGUARD PUBLIC HEALTH
bull ASSURE CONSUMER PROTECTION STANDARDS
bull FACILITATE AVAILABILITY OF SAFE AND EFFECTIVE PRODUCTS
bull ELIMINATE INCONSISTENT STANDARDS INTERNATIONALLY
bull FACILITATE MUTUAL ACCEPTANCE OF DATA FROM CLINICAL TRIALS
GOALS OF INTERNATIONAL HARMONIZATION OF
REGULATORY REQUIREMENTS
Study DocumentationDuring the study
The investigator must keepndash Source documents
bull Medical records (including access to computer records)
bull Laboratory reports
bull ECGs X-rays etc
bull Any other medical records reports or notes (hospital admissions and discharges)
ndash A subject identification list
ndash Copies of all study related documentation
Medical Records
bull In particular they should contain notes on
ndash Sufficient information to support subject eligibility
ndash This should be well documented (signed and dated)
ndash Subjectrsquos participation in the study
ndash Dates of visits
ndash Procedures investigations done
ndash Observations diagnoses
ndash Medications taken (including study medication)
ndash Adverse events
ndash Completion or withdrawal (reason) from the study
Study DocumentationAfter the study
The sponsor needs from the investigator
ndash Final drug accountability records
ndash All used and unused supplies and medication
ndash All required documents completed
Conclusion
70
Thanks
ldquoWhen a doctor [goes] wrong he is
the first of criminals He has nerve
and he has knowledgerdquo
- Sherlock Holmes
References
httpwwwwmanetepolicyb3htm
wwwhhsgovohrphumansubjectsguidancebelmonthtml
wwwhhsgovohrpreferencesnurcodehtml
wwwicmrnicinguidelinesGCLP
wwwcdsconicin
wwwubedurecercaBioeticadocDeclaracio_Helsinki_2013
wwwjewishvirtuallibraryorgjsourceHolocaustnazi_experiments
wwwichorgfileadminPublic_WebICHE6_R1__Guideline
Victim of a tuberculosis medical experiment
10
Prisoner in a compression chamber
11
An experiment to
determine
altitudes at which
aircraft crews
could survive
without oxygen
Immersing people in ice water
bull With the intent of discovering means to prevent and treat hypothermia
bull 280 to 300 victims
bull One study forced subjects to endure a tank of ice water for up to five hours
12
bull In 1946 an American military tribunal opened criminal proceedings against 23 leading German physicians Doctors Trial
bull Sixteen of the doctors were found guilty
bull Seven were sentenced to death
bull Development of the Nuremberg Code of medical ethics
13
THE DOCTORS TRIAL
The Tuskegee Syphilis Study
bull Research participants was the long-term study of black males conducted at Tuskegee Alabama by the United States Public Health Service
bull (1930s-1970) - examination of the natural history of untreated syphilis
bull More than 400 African-American men with syphilis participated
bull The men were recruited without informed consent and in fact were misinformed that some of the procedures done in the interest of the research (eg spinal taps) were actually special free treatment
The Tuskegee Syphilis Study
bull In the 1940s penicillin was found to be effective in the treatment of syphilis
bull The study continued however and the men were neither informed of nor treated with the antibiotic
bull The first accounts of this study appeared in the national press in 1972
bull Belmont report 1978 (Ethical Principles and guidelines for the protection of human subjects of research)-Tuskegee syphilis study
The Jewish Chronic Disease Hospital Study
bull In 1963 studies were undertaken at New Yorks Jewish Chronic Disease Hospital to understand whether the bodys inability to reject cancer cells was due to cancer or debilitation
bull Previous studies had indicated that healthy persons reject cancer cells promptly and the researchers allegedly believed that the debilitated patients would also reject the cancers but at a substantially slower rate compared to healthy participants
The Jewish Chronic Disease Hospital Study
bull Further patients were not told that they would receive cancer cells because the researchers felt it would unnecessarily frighten them
bull It was found that the study had not been presented to the hospitals research committee and that the physicians responsible for the patients care had not been consulted
bull The researchers were found guilty of fraud deceit and unprofessional conduct
The Willowbrook Study
bull Institutionalized children as participants in research is demonstrated in a series of studies conducted from 1963 through 1966 at the Willowbrook State School a New York institution for mentally defective children
bull In order to gain an understanding of the natural history of infectious hepatitis under controlled circumstances newly admitted children were deliberately infected with the hepatitis virus
bull In some cases parents found they were unable to admit their children to Willowbrook unless they agreed to their childrsquos participation in the studies
The Willowbrook Study
This controversial case raised important questions about the adequacy and freedom of consent inadequate disclosure of the childs risk of later developing chronic liver disease
The Milgram Study
bull The lsquoteachersrsquo were instructed to give the lsquolearnersrsquo electrical shocks in response to incorrect answers on verbally given lsquotestsrsquo
bull Participants were deceived as to the nature of the study being told it was to test new teaching-learning techniques
Thalidomide tragedy
bull Thalidomide was a widely used drug in the late 1950s and early 1960s for the treatment of nausea in pregnant women
bull It became apparent in the 1960s that thalidomide treatment resulted in severe birth defects in thousands of children
21
bull Within a few years of the widespread use of thalidomide in Europe Australia and Japan approximately 10000 children were born with phocomelia leading to the ban of thalidomide in most countries in 1961
22
bull The thalidomide tragedy marked a turning point in toxicity testing as it prompted United States and international regulatory agencies to develop systematic toxicity testing protocols
bull The thalidomide tragedy also brought into sharp focus the importance of rigorous and relevant testing of pharmaceuticals prior to their introduction into the market place (Kelsey 1988)
23
Thalidomide tragedy
Nuremberg Code-1947
bull On April 17 1947 United States Counsel for War Crimescame out with six points defining ldquolegitimate researchrdquo
bull The verdict of August 19 reiterated almost all of thesepoints in a section entitled Permissible MedicalExperiments and revised the original six points into ten
bull Subsequently the ten points became known as theNuremberg Code
24
Codes and Guidelines
Nuremberg Code (1947)
WMArsquos Declaration of Helsinki (1964)
bull Belmont Report (USA) (1979)-Tuskegee syphilis study
Council for International Organizations of Medical Sciences (CIOMS) 1993
International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) in 1996 Guideline on Good Clinical PracticeE6 (GCP)
Nuremberg Code (1947)
Voluntary and Informed consent-absolutely essential
Anticipate scientific benefits Useful
Animal experimentation first
Avoid physical and mental suffering
Benefits outweigh risks
No intentional death or disability
Protection from harm
Subject free to withdraw
Qualified investigators
Investigator will stop if harm occurs
THE DECLARATION OF HELSINKI-1964
Is an international standard for the conduct of clinicalresearch adopted by International Conference onHarmonization(ICH) Good Clinical Practice standards
A global ethical standard for medical research and wasapproved at the WMA General Assembly by a majority voteof 75
It is the mission of the clinical research professionals tosafeguard the health of the people
THE DECLARATION OF HELSINKI-1964
Historical Overview-
Its origin has been found in the Nazi Disaster and hasundergone several modifications
Prior to 1947 Nuremberg Code there was noaccepted code of conduct governing the ethicalaspects of human research
World Medical Association
It is an international organization of physicians
established on September 17 1947
First general Assembly of WMA was held in Paris
France
Mission- Serve humanity by endeavoring to achieve the
highest international standards in medical education
science ethics and health care for all peoples of the world
Declaration of Helsinki 1964
Adapted from Nuremberg
Code by the World Medical Association (WMA)
First adopted in Helsinki Finland 1964
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI- 2008
Ethical Principles for Medical Research Involving Human Subjects
Adopted by the 18th WMA General Assembly Helsinki Finland June 1964 and amended by the
29th WMA General Assembly Tokyo Japan October 1975
35th WMA General Assembly Venice Italy October 1983
41st WMA General Assembly Hong Kong September 1989
53th WMA General Assembly Washington 2002 (Note of Clarification on paragraph 29 added)
55th WMA General Assembly Tokyo 2004 (Note of Clarification on Paragraph 30 added)
59th WMA General Assembly Seoul October 2008
Seven Ethical Pillars of Clinical Research
AUTONOMY
BENEFICENCE
NON ndash MALFEASANCE
FIDELITY
TRUTHFULNESS
CONFIDENTIALITY
JUSTICE
Declaration of Helsinki
Autonomy
Consent
Para 20 The subjects must be volunteers andinformed participants in the research project
Para 22 freely-given informed consent
preferably in writing
Declaration of Helsinki
Para 5 well-being of the human subject shouldtake precedence over the interests of scienceand society
Beneficence
Declaration of Helsinki
Para 16
bull Preceded by careful assessment ofpredictable risks and burdens
bull Attempt to avoid any act or treatmentplan that would harm the patient
Non Malfeasance
Declaration of Helsinki
Para 11
Medical research involving human subjects must be basedon generally accepted scientific principles thoroughknowledge of the scientific literature and on adequatelaboratory and where appropriate animalexperimentation
Para 15
Conducted only by clinically competent medical person
Fidelity ndash duty of care
Declaration of Helsinki
Para 27
Both authors amp investigators are obliged topreserve the accuracy of the results Negativeas well as positive results should be published
Truthfulness - Honesty
Declaration of Helsinki
Para 21
Every precaution should be taken torespect the privacy of the subject theconfidentiality of the patients information
Confidentiality
Declaration of Helsinki
Para 30
Every patient entered into the study should be assured ofaccess to the best proven prophylactic diagnostic andtherapeutic methods identified by the study
Para 9
Research Investigators should be aware of the ethicallegal and regulatory requirements for research on humansubjects
Para 17
Physicians should cease any investigation if the risksoutweigh the potential benefits
Justice
DECLARATION OF HELSINKI -Basic Principles
1 Conform to accepted scientific principles
2 Design formulated in experimental protocol reviewed by IEC
3 Conducted by qualified and trained persons
4 Importance in proportion to inherent risk
5 Assessment of risks vs benefits
6 Safeguard subjectrsquos integrity (privacy)
7 Abstain unless hazards are predictable
8 Preserve accuracy when publishing
9 Adequately inform or right to withdraw
10 Obtain true informed consent in writing
11 Reliance on legal guardian
12 State compliance with Declaration
Ethical Principles and Guidelines for the Protection of Human Subjects of Research
bull Tuskegee Syphilis Study (1932ndash1972)
bull Named the Belmont Report for the Belmont Conference Center where the National Commission met when first drafting the report
42
Belmont Report 1979
Belmont Report 1979
Three ethical principles related to research on human subjects
1 Respect for Persons
2 Beneficence Do no harm while maximizing benefits for research project and minimizing risks to the research subjects
3 Justice ensuring reasonable non-exploitative and well-considered procedures are administered
Overview of
ICH GCP
What is ICH
bull The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)- is unique in bringing together the regulatory authorities and pharmaceutical industry of Europe Japan and the US to discuss scientific and technical aspects of drug registration
45
What is ICH
bull Since its inception in 1990 ICH has
gradually evolved
bull ICHs mission is to ensure that safe
effective and high quality medicines are
developed and registered in the most
resource-efficient manner
How did it evolve
The need to harmonize
bull Public disasters serious fraud and abuse of human rights
bull Trials of War criminals-Nuremberg code 1949
bull Thalidomide- Declaration of Helsinki 1964
bull Belmont report 1978 (Ethical Principles and guidelines for the protection of human subjects of research)-Tuskegee syphilis study
History
1962 US FDA IND Guidelines
1964 Declaration of Helsinki
1968 Committee on Safety of Medicines uk
1978 GCP US FDA
1991 GCP Europe
1996 ICH GCP
1997 ICH GCP Guideline
When did it begin
bull Ist conf in 1990 in Brussels
3 regions participated
bull Representatives from
Industry
Academia
Ministry of
health
ICH parties
6 parties
bull EU bull EFPIA European federation of pharmaceutical industriesrsquo associations
bull MHLW Ministry of health Labor and welfare Japan
bull JPMA Japan Pharmaceuticals manufacturers Association
bull US FDA
bull PhRMA
bull Observers WHO TPP(canada)
bull International federation of Pharmaceutical manufacturerrsquos association
Key objective
bull To discuss and define the minimum standards for the development and registration of investigational products
The result
Many guidelines made
bull Most important- ICH GCP guidelines
bull Evolved in several steps
bull Consolidated guideline ICH E6 Sept 1997
ICH Guidelines examples
bull Efficacy ndash clinical trials etc
bull Safety ndash pharmacovigilance adverse drug reaction
reporting
bull Quality ndash raw materials impurities residual solvents etc
bull Multidisciplinary ndash common technical document electronic
submission coding systems
What is GCP
A standard for the design conduct performance monitoring auditing recording analyses and reporting of clinical trials that provide assurance that the data and the reported results are credible accurate and that the rights integrity and confidentiality of trial subjects are protected
Why is it needed
bull To ensure the rights safety and well being of the trial subjects are protected
bull Ensure the credibility of clinical trial data
The ICH GCP guideline
bull Provide a unified standard for the EU Japan and USA regions to facilitate mutual acceptance of clinical trial data by the regulatory authorities in
these regions
bull 8 sections
ICH GCP guideline
1 Glossary
Common language for investigatorssponsorsethics committees
2Principles of Good Clinical Practice
13 tenets of ICH GCP
3Requirements for IRBIEC
Roles responsibilities and composition
ICH GCP guideline
4Responsibilities of the investigator
5Responsibilities of the sponsor
6Requirements for clinical trial protocol and protocol amendments
7Responsibility of the sponsor in the development of investigatorrsquos brochure
8Essential documents
Principles of ICH GCP
bull Ethical conduct as per
Declaration of Helsinki
GCP
Regulatory Requirements
Risk- Benefit
Primary concern- Subject
Principles of ICH GCP
bull Supportive data
bull Protocol
Scientifically sound clear detailed
bull Ethical Clearance
Study to be conducted in compliance to the protocol which has received EC approval
Principles of ICH GCP
bull Subject Care
Medical decisions responsibility of qualified physician
bull Qualified staff
By education training experience in their area of responsibility
bull Informed Consent
Principles of ICH GCP
bull Clinical Trial data
Recorded handled and stored to enable accurate reporting interpretation and verification
bull Confidentiality
Principles of ICH GCP
bull Investigational Product
Manufactured handled and stored as per GMP
Principles of ICH GCP
bull Quality Assurance
Systems and procedures to ensure the Quality of every aspect of the trial
Indian GCP guidelines
bull Released in Dec 2001(Developed by CDCSO and endorsed by DCGI)
bull In general in line with ICH GCP
bull Has Revised Schedule Y (Jan 2005) addressed discrepancies
bull SAFEGUARD PUBLIC HEALTH
bull ASSURE CONSUMER PROTECTION STANDARDS
bull FACILITATE AVAILABILITY OF SAFE AND EFFECTIVE PRODUCTS
bull ELIMINATE INCONSISTENT STANDARDS INTERNATIONALLY
bull FACILITATE MUTUAL ACCEPTANCE OF DATA FROM CLINICAL TRIALS
GOALS OF INTERNATIONAL HARMONIZATION OF
REGULATORY REQUIREMENTS
Study DocumentationDuring the study
The investigator must keepndash Source documents
bull Medical records (including access to computer records)
bull Laboratory reports
bull ECGs X-rays etc
bull Any other medical records reports or notes (hospital admissions and discharges)
ndash A subject identification list
ndash Copies of all study related documentation
Medical Records
bull In particular they should contain notes on
ndash Sufficient information to support subject eligibility
ndash This should be well documented (signed and dated)
ndash Subjectrsquos participation in the study
ndash Dates of visits
ndash Procedures investigations done
ndash Observations diagnoses
ndash Medications taken (including study medication)
ndash Adverse events
ndash Completion or withdrawal (reason) from the study
Study DocumentationAfter the study
The sponsor needs from the investigator
ndash Final drug accountability records
ndash All used and unused supplies and medication
ndash All required documents completed
Conclusion
70
Thanks
ldquoWhen a doctor [goes] wrong he is
the first of criminals He has nerve
and he has knowledgerdquo
- Sherlock Holmes
References
httpwwwwmanetepolicyb3htm
wwwhhsgovohrphumansubjectsguidancebelmonthtml
wwwhhsgovohrpreferencesnurcodehtml
wwwicmrnicinguidelinesGCLP
wwwcdsconicin
wwwubedurecercaBioeticadocDeclaracio_Helsinki_2013
wwwjewishvirtuallibraryorgjsourceHolocaustnazi_experiments
wwwichorgfileadminPublic_WebICHE6_R1__Guideline
Prisoner in a compression chamber
11
An experiment to
determine
altitudes at which
aircraft crews
could survive
without oxygen
Immersing people in ice water
bull With the intent of discovering means to prevent and treat hypothermia
bull 280 to 300 victims
bull One study forced subjects to endure a tank of ice water for up to five hours
12
bull In 1946 an American military tribunal opened criminal proceedings against 23 leading German physicians Doctors Trial
bull Sixteen of the doctors were found guilty
bull Seven were sentenced to death
bull Development of the Nuremberg Code of medical ethics
13
THE DOCTORS TRIAL
The Tuskegee Syphilis Study
bull Research participants was the long-term study of black males conducted at Tuskegee Alabama by the United States Public Health Service
bull (1930s-1970) - examination of the natural history of untreated syphilis
bull More than 400 African-American men with syphilis participated
bull The men were recruited without informed consent and in fact were misinformed that some of the procedures done in the interest of the research (eg spinal taps) were actually special free treatment
The Tuskegee Syphilis Study
bull In the 1940s penicillin was found to be effective in the treatment of syphilis
bull The study continued however and the men were neither informed of nor treated with the antibiotic
bull The first accounts of this study appeared in the national press in 1972
bull Belmont report 1978 (Ethical Principles and guidelines for the protection of human subjects of research)-Tuskegee syphilis study
The Jewish Chronic Disease Hospital Study
bull In 1963 studies were undertaken at New Yorks Jewish Chronic Disease Hospital to understand whether the bodys inability to reject cancer cells was due to cancer or debilitation
bull Previous studies had indicated that healthy persons reject cancer cells promptly and the researchers allegedly believed that the debilitated patients would also reject the cancers but at a substantially slower rate compared to healthy participants
The Jewish Chronic Disease Hospital Study
bull Further patients were not told that they would receive cancer cells because the researchers felt it would unnecessarily frighten them
bull It was found that the study had not been presented to the hospitals research committee and that the physicians responsible for the patients care had not been consulted
bull The researchers were found guilty of fraud deceit and unprofessional conduct
The Willowbrook Study
bull Institutionalized children as participants in research is demonstrated in a series of studies conducted from 1963 through 1966 at the Willowbrook State School a New York institution for mentally defective children
bull In order to gain an understanding of the natural history of infectious hepatitis under controlled circumstances newly admitted children were deliberately infected with the hepatitis virus
bull In some cases parents found they were unable to admit their children to Willowbrook unless they agreed to their childrsquos participation in the studies
The Willowbrook Study
This controversial case raised important questions about the adequacy and freedom of consent inadequate disclosure of the childs risk of later developing chronic liver disease
The Milgram Study
bull The lsquoteachersrsquo were instructed to give the lsquolearnersrsquo electrical shocks in response to incorrect answers on verbally given lsquotestsrsquo
bull Participants were deceived as to the nature of the study being told it was to test new teaching-learning techniques
Thalidomide tragedy
bull Thalidomide was a widely used drug in the late 1950s and early 1960s for the treatment of nausea in pregnant women
bull It became apparent in the 1960s that thalidomide treatment resulted in severe birth defects in thousands of children
21
bull Within a few years of the widespread use of thalidomide in Europe Australia and Japan approximately 10000 children were born with phocomelia leading to the ban of thalidomide in most countries in 1961
22
bull The thalidomide tragedy marked a turning point in toxicity testing as it prompted United States and international regulatory agencies to develop systematic toxicity testing protocols
bull The thalidomide tragedy also brought into sharp focus the importance of rigorous and relevant testing of pharmaceuticals prior to their introduction into the market place (Kelsey 1988)
23
Thalidomide tragedy
Nuremberg Code-1947
bull On April 17 1947 United States Counsel for War Crimescame out with six points defining ldquolegitimate researchrdquo
bull The verdict of August 19 reiterated almost all of thesepoints in a section entitled Permissible MedicalExperiments and revised the original six points into ten
bull Subsequently the ten points became known as theNuremberg Code
24
Codes and Guidelines
Nuremberg Code (1947)
WMArsquos Declaration of Helsinki (1964)
bull Belmont Report (USA) (1979)-Tuskegee syphilis study
Council for International Organizations of Medical Sciences (CIOMS) 1993
International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) in 1996 Guideline on Good Clinical PracticeE6 (GCP)
Nuremberg Code (1947)
Voluntary and Informed consent-absolutely essential
Anticipate scientific benefits Useful
Animal experimentation first
Avoid physical and mental suffering
Benefits outweigh risks
No intentional death or disability
Protection from harm
Subject free to withdraw
Qualified investigators
Investigator will stop if harm occurs
THE DECLARATION OF HELSINKI-1964
Is an international standard for the conduct of clinicalresearch adopted by International Conference onHarmonization(ICH) Good Clinical Practice standards
A global ethical standard for medical research and wasapproved at the WMA General Assembly by a majority voteof 75
It is the mission of the clinical research professionals tosafeguard the health of the people
THE DECLARATION OF HELSINKI-1964
Historical Overview-
Its origin has been found in the Nazi Disaster and hasundergone several modifications
Prior to 1947 Nuremberg Code there was noaccepted code of conduct governing the ethicalaspects of human research
World Medical Association
It is an international organization of physicians
established on September 17 1947
First general Assembly of WMA was held in Paris
France
Mission- Serve humanity by endeavoring to achieve the
highest international standards in medical education
science ethics and health care for all peoples of the world
Declaration of Helsinki 1964
Adapted from Nuremberg
Code by the World Medical Association (WMA)
First adopted in Helsinki Finland 1964
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI- 2008
Ethical Principles for Medical Research Involving Human Subjects
Adopted by the 18th WMA General Assembly Helsinki Finland June 1964 and amended by the
29th WMA General Assembly Tokyo Japan October 1975
35th WMA General Assembly Venice Italy October 1983
41st WMA General Assembly Hong Kong September 1989
53th WMA General Assembly Washington 2002 (Note of Clarification on paragraph 29 added)
55th WMA General Assembly Tokyo 2004 (Note of Clarification on Paragraph 30 added)
59th WMA General Assembly Seoul October 2008
Seven Ethical Pillars of Clinical Research
AUTONOMY
BENEFICENCE
NON ndash MALFEASANCE
FIDELITY
TRUTHFULNESS
CONFIDENTIALITY
JUSTICE
Declaration of Helsinki
Autonomy
Consent
Para 20 The subjects must be volunteers andinformed participants in the research project
Para 22 freely-given informed consent
preferably in writing
Declaration of Helsinki
Para 5 well-being of the human subject shouldtake precedence over the interests of scienceand society
Beneficence
Declaration of Helsinki
Para 16
bull Preceded by careful assessment ofpredictable risks and burdens
bull Attempt to avoid any act or treatmentplan that would harm the patient
Non Malfeasance
Declaration of Helsinki
Para 11
Medical research involving human subjects must be basedon generally accepted scientific principles thoroughknowledge of the scientific literature and on adequatelaboratory and where appropriate animalexperimentation
Para 15
Conducted only by clinically competent medical person
Fidelity ndash duty of care
Declaration of Helsinki
Para 27
Both authors amp investigators are obliged topreserve the accuracy of the results Negativeas well as positive results should be published
Truthfulness - Honesty
Declaration of Helsinki
Para 21
Every precaution should be taken torespect the privacy of the subject theconfidentiality of the patients information
Confidentiality
Declaration of Helsinki
Para 30
Every patient entered into the study should be assured ofaccess to the best proven prophylactic diagnostic andtherapeutic methods identified by the study
Para 9
Research Investigators should be aware of the ethicallegal and regulatory requirements for research on humansubjects
Para 17
Physicians should cease any investigation if the risksoutweigh the potential benefits
Justice
DECLARATION OF HELSINKI -Basic Principles
1 Conform to accepted scientific principles
2 Design formulated in experimental protocol reviewed by IEC
3 Conducted by qualified and trained persons
4 Importance in proportion to inherent risk
5 Assessment of risks vs benefits
6 Safeguard subjectrsquos integrity (privacy)
7 Abstain unless hazards are predictable
8 Preserve accuracy when publishing
9 Adequately inform or right to withdraw
10 Obtain true informed consent in writing
11 Reliance on legal guardian
12 State compliance with Declaration
Ethical Principles and Guidelines for the Protection of Human Subjects of Research
bull Tuskegee Syphilis Study (1932ndash1972)
bull Named the Belmont Report for the Belmont Conference Center where the National Commission met when first drafting the report
42
Belmont Report 1979
Belmont Report 1979
Three ethical principles related to research on human subjects
1 Respect for Persons
2 Beneficence Do no harm while maximizing benefits for research project and minimizing risks to the research subjects
3 Justice ensuring reasonable non-exploitative and well-considered procedures are administered
Overview of
ICH GCP
What is ICH
bull The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)- is unique in bringing together the regulatory authorities and pharmaceutical industry of Europe Japan and the US to discuss scientific and technical aspects of drug registration
45
What is ICH
bull Since its inception in 1990 ICH has
gradually evolved
bull ICHs mission is to ensure that safe
effective and high quality medicines are
developed and registered in the most
resource-efficient manner
How did it evolve
The need to harmonize
bull Public disasters serious fraud and abuse of human rights
bull Trials of War criminals-Nuremberg code 1949
bull Thalidomide- Declaration of Helsinki 1964
bull Belmont report 1978 (Ethical Principles and guidelines for the protection of human subjects of research)-Tuskegee syphilis study
History
1962 US FDA IND Guidelines
1964 Declaration of Helsinki
1968 Committee on Safety of Medicines uk
1978 GCP US FDA
1991 GCP Europe
1996 ICH GCP
1997 ICH GCP Guideline
When did it begin
bull Ist conf in 1990 in Brussels
3 regions participated
bull Representatives from
Industry
Academia
Ministry of
health
ICH parties
6 parties
bull EU bull EFPIA European federation of pharmaceutical industriesrsquo associations
bull MHLW Ministry of health Labor and welfare Japan
bull JPMA Japan Pharmaceuticals manufacturers Association
bull US FDA
bull PhRMA
bull Observers WHO TPP(canada)
bull International federation of Pharmaceutical manufacturerrsquos association
Key objective
bull To discuss and define the minimum standards for the development and registration of investigational products
The result
Many guidelines made
bull Most important- ICH GCP guidelines
bull Evolved in several steps
bull Consolidated guideline ICH E6 Sept 1997
ICH Guidelines examples
bull Efficacy ndash clinical trials etc
bull Safety ndash pharmacovigilance adverse drug reaction
reporting
bull Quality ndash raw materials impurities residual solvents etc
bull Multidisciplinary ndash common technical document electronic
submission coding systems
What is GCP
A standard for the design conduct performance monitoring auditing recording analyses and reporting of clinical trials that provide assurance that the data and the reported results are credible accurate and that the rights integrity and confidentiality of trial subjects are protected
Why is it needed
bull To ensure the rights safety and well being of the trial subjects are protected
bull Ensure the credibility of clinical trial data
The ICH GCP guideline
bull Provide a unified standard for the EU Japan and USA regions to facilitate mutual acceptance of clinical trial data by the regulatory authorities in
these regions
bull 8 sections
ICH GCP guideline
1 Glossary
Common language for investigatorssponsorsethics committees
2Principles of Good Clinical Practice
13 tenets of ICH GCP
3Requirements for IRBIEC
Roles responsibilities and composition
ICH GCP guideline
4Responsibilities of the investigator
5Responsibilities of the sponsor
6Requirements for clinical trial protocol and protocol amendments
7Responsibility of the sponsor in the development of investigatorrsquos brochure
8Essential documents
Principles of ICH GCP
bull Ethical conduct as per
Declaration of Helsinki
GCP
Regulatory Requirements
Risk- Benefit
Primary concern- Subject
Principles of ICH GCP
bull Supportive data
bull Protocol
Scientifically sound clear detailed
bull Ethical Clearance
Study to be conducted in compliance to the protocol which has received EC approval
Principles of ICH GCP
bull Subject Care
Medical decisions responsibility of qualified physician
bull Qualified staff
By education training experience in their area of responsibility
bull Informed Consent
Principles of ICH GCP
bull Clinical Trial data
Recorded handled and stored to enable accurate reporting interpretation and verification
bull Confidentiality
Principles of ICH GCP
bull Investigational Product
Manufactured handled and stored as per GMP
Principles of ICH GCP
bull Quality Assurance
Systems and procedures to ensure the Quality of every aspect of the trial
Indian GCP guidelines
bull Released in Dec 2001(Developed by CDCSO and endorsed by DCGI)
bull In general in line with ICH GCP
bull Has Revised Schedule Y (Jan 2005) addressed discrepancies
bull SAFEGUARD PUBLIC HEALTH
bull ASSURE CONSUMER PROTECTION STANDARDS
bull FACILITATE AVAILABILITY OF SAFE AND EFFECTIVE PRODUCTS
bull ELIMINATE INCONSISTENT STANDARDS INTERNATIONALLY
bull FACILITATE MUTUAL ACCEPTANCE OF DATA FROM CLINICAL TRIALS
GOALS OF INTERNATIONAL HARMONIZATION OF
REGULATORY REQUIREMENTS
Study DocumentationDuring the study
The investigator must keepndash Source documents
bull Medical records (including access to computer records)
bull Laboratory reports
bull ECGs X-rays etc
bull Any other medical records reports or notes (hospital admissions and discharges)
ndash A subject identification list
ndash Copies of all study related documentation
Medical Records
bull In particular they should contain notes on
ndash Sufficient information to support subject eligibility
ndash This should be well documented (signed and dated)
ndash Subjectrsquos participation in the study
ndash Dates of visits
ndash Procedures investigations done
ndash Observations diagnoses
ndash Medications taken (including study medication)
ndash Adverse events
ndash Completion or withdrawal (reason) from the study
Study DocumentationAfter the study
The sponsor needs from the investigator
ndash Final drug accountability records
ndash All used and unused supplies and medication
ndash All required documents completed
Conclusion
70
Thanks
ldquoWhen a doctor [goes] wrong he is
the first of criminals He has nerve
and he has knowledgerdquo
- Sherlock Holmes
References
httpwwwwmanetepolicyb3htm
wwwhhsgovohrphumansubjectsguidancebelmonthtml
wwwhhsgovohrpreferencesnurcodehtml
wwwicmrnicinguidelinesGCLP
wwwcdsconicin
wwwubedurecercaBioeticadocDeclaracio_Helsinki_2013
wwwjewishvirtuallibraryorgjsourceHolocaustnazi_experiments
wwwichorgfileadminPublic_WebICHE6_R1__Guideline
Immersing people in ice water
bull With the intent of discovering means to prevent and treat hypothermia
bull 280 to 300 victims
bull One study forced subjects to endure a tank of ice water for up to five hours
12
bull In 1946 an American military tribunal opened criminal proceedings against 23 leading German physicians Doctors Trial
bull Sixteen of the doctors were found guilty
bull Seven were sentenced to death
bull Development of the Nuremberg Code of medical ethics
13
THE DOCTORS TRIAL
The Tuskegee Syphilis Study
bull Research participants was the long-term study of black males conducted at Tuskegee Alabama by the United States Public Health Service
bull (1930s-1970) - examination of the natural history of untreated syphilis
bull More than 400 African-American men with syphilis participated
bull The men were recruited without informed consent and in fact were misinformed that some of the procedures done in the interest of the research (eg spinal taps) were actually special free treatment
The Tuskegee Syphilis Study
bull In the 1940s penicillin was found to be effective in the treatment of syphilis
bull The study continued however and the men were neither informed of nor treated with the antibiotic
bull The first accounts of this study appeared in the national press in 1972
bull Belmont report 1978 (Ethical Principles and guidelines for the protection of human subjects of research)-Tuskegee syphilis study
The Jewish Chronic Disease Hospital Study
bull In 1963 studies were undertaken at New Yorks Jewish Chronic Disease Hospital to understand whether the bodys inability to reject cancer cells was due to cancer or debilitation
bull Previous studies had indicated that healthy persons reject cancer cells promptly and the researchers allegedly believed that the debilitated patients would also reject the cancers but at a substantially slower rate compared to healthy participants
The Jewish Chronic Disease Hospital Study
bull Further patients were not told that they would receive cancer cells because the researchers felt it would unnecessarily frighten them
bull It was found that the study had not been presented to the hospitals research committee and that the physicians responsible for the patients care had not been consulted
bull The researchers were found guilty of fraud deceit and unprofessional conduct
The Willowbrook Study
bull Institutionalized children as participants in research is demonstrated in a series of studies conducted from 1963 through 1966 at the Willowbrook State School a New York institution for mentally defective children
bull In order to gain an understanding of the natural history of infectious hepatitis under controlled circumstances newly admitted children were deliberately infected with the hepatitis virus
bull In some cases parents found they were unable to admit their children to Willowbrook unless they agreed to their childrsquos participation in the studies
The Willowbrook Study
This controversial case raised important questions about the adequacy and freedom of consent inadequate disclosure of the childs risk of later developing chronic liver disease
The Milgram Study
bull The lsquoteachersrsquo were instructed to give the lsquolearnersrsquo electrical shocks in response to incorrect answers on verbally given lsquotestsrsquo
bull Participants were deceived as to the nature of the study being told it was to test new teaching-learning techniques
Thalidomide tragedy
bull Thalidomide was a widely used drug in the late 1950s and early 1960s for the treatment of nausea in pregnant women
bull It became apparent in the 1960s that thalidomide treatment resulted in severe birth defects in thousands of children
21
bull Within a few years of the widespread use of thalidomide in Europe Australia and Japan approximately 10000 children were born with phocomelia leading to the ban of thalidomide in most countries in 1961
22
bull The thalidomide tragedy marked a turning point in toxicity testing as it prompted United States and international regulatory agencies to develop systematic toxicity testing protocols
bull The thalidomide tragedy also brought into sharp focus the importance of rigorous and relevant testing of pharmaceuticals prior to their introduction into the market place (Kelsey 1988)
23
Thalidomide tragedy
Nuremberg Code-1947
bull On April 17 1947 United States Counsel for War Crimescame out with six points defining ldquolegitimate researchrdquo
bull The verdict of August 19 reiterated almost all of thesepoints in a section entitled Permissible MedicalExperiments and revised the original six points into ten
bull Subsequently the ten points became known as theNuremberg Code
24
Codes and Guidelines
Nuremberg Code (1947)
WMArsquos Declaration of Helsinki (1964)
bull Belmont Report (USA) (1979)-Tuskegee syphilis study
Council for International Organizations of Medical Sciences (CIOMS) 1993
International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) in 1996 Guideline on Good Clinical PracticeE6 (GCP)
Nuremberg Code (1947)
Voluntary and Informed consent-absolutely essential
Anticipate scientific benefits Useful
Animal experimentation first
Avoid physical and mental suffering
Benefits outweigh risks
No intentional death or disability
Protection from harm
Subject free to withdraw
Qualified investigators
Investigator will stop if harm occurs
THE DECLARATION OF HELSINKI-1964
Is an international standard for the conduct of clinicalresearch adopted by International Conference onHarmonization(ICH) Good Clinical Practice standards
A global ethical standard for medical research and wasapproved at the WMA General Assembly by a majority voteof 75
It is the mission of the clinical research professionals tosafeguard the health of the people
THE DECLARATION OF HELSINKI-1964
Historical Overview-
Its origin has been found in the Nazi Disaster and hasundergone several modifications
Prior to 1947 Nuremberg Code there was noaccepted code of conduct governing the ethicalaspects of human research
World Medical Association
It is an international organization of physicians
established on September 17 1947
First general Assembly of WMA was held in Paris
France
Mission- Serve humanity by endeavoring to achieve the
highest international standards in medical education
science ethics and health care for all peoples of the world
Declaration of Helsinki 1964
Adapted from Nuremberg
Code by the World Medical Association (WMA)
First adopted in Helsinki Finland 1964
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI- 2008
Ethical Principles for Medical Research Involving Human Subjects
Adopted by the 18th WMA General Assembly Helsinki Finland June 1964 and amended by the
29th WMA General Assembly Tokyo Japan October 1975
35th WMA General Assembly Venice Italy October 1983
41st WMA General Assembly Hong Kong September 1989
53th WMA General Assembly Washington 2002 (Note of Clarification on paragraph 29 added)
55th WMA General Assembly Tokyo 2004 (Note of Clarification on Paragraph 30 added)
59th WMA General Assembly Seoul October 2008
Seven Ethical Pillars of Clinical Research
AUTONOMY
BENEFICENCE
NON ndash MALFEASANCE
FIDELITY
TRUTHFULNESS
CONFIDENTIALITY
JUSTICE
Declaration of Helsinki
Autonomy
Consent
Para 20 The subjects must be volunteers andinformed participants in the research project
Para 22 freely-given informed consent
preferably in writing
Declaration of Helsinki
Para 5 well-being of the human subject shouldtake precedence over the interests of scienceand society
Beneficence
Declaration of Helsinki
Para 16
bull Preceded by careful assessment ofpredictable risks and burdens
bull Attempt to avoid any act or treatmentplan that would harm the patient
Non Malfeasance
Declaration of Helsinki
Para 11
Medical research involving human subjects must be basedon generally accepted scientific principles thoroughknowledge of the scientific literature and on adequatelaboratory and where appropriate animalexperimentation
Para 15
Conducted only by clinically competent medical person
Fidelity ndash duty of care
Declaration of Helsinki
Para 27
Both authors amp investigators are obliged topreserve the accuracy of the results Negativeas well as positive results should be published
Truthfulness - Honesty
Declaration of Helsinki
Para 21
Every precaution should be taken torespect the privacy of the subject theconfidentiality of the patients information
Confidentiality
Declaration of Helsinki
Para 30
Every patient entered into the study should be assured ofaccess to the best proven prophylactic diagnostic andtherapeutic methods identified by the study
Para 9
Research Investigators should be aware of the ethicallegal and regulatory requirements for research on humansubjects
Para 17
Physicians should cease any investigation if the risksoutweigh the potential benefits
Justice
DECLARATION OF HELSINKI -Basic Principles
1 Conform to accepted scientific principles
2 Design formulated in experimental protocol reviewed by IEC
3 Conducted by qualified and trained persons
4 Importance in proportion to inherent risk
5 Assessment of risks vs benefits
6 Safeguard subjectrsquos integrity (privacy)
7 Abstain unless hazards are predictable
8 Preserve accuracy when publishing
9 Adequately inform or right to withdraw
10 Obtain true informed consent in writing
11 Reliance on legal guardian
12 State compliance with Declaration
Ethical Principles and Guidelines for the Protection of Human Subjects of Research
bull Tuskegee Syphilis Study (1932ndash1972)
bull Named the Belmont Report for the Belmont Conference Center where the National Commission met when first drafting the report
42
Belmont Report 1979
Belmont Report 1979
Three ethical principles related to research on human subjects
1 Respect for Persons
2 Beneficence Do no harm while maximizing benefits for research project and minimizing risks to the research subjects
3 Justice ensuring reasonable non-exploitative and well-considered procedures are administered
Overview of
ICH GCP
What is ICH
bull The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)- is unique in bringing together the regulatory authorities and pharmaceutical industry of Europe Japan and the US to discuss scientific and technical aspects of drug registration
45
What is ICH
bull Since its inception in 1990 ICH has
gradually evolved
bull ICHs mission is to ensure that safe
effective and high quality medicines are
developed and registered in the most
resource-efficient manner
How did it evolve
The need to harmonize
bull Public disasters serious fraud and abuse of human rights
bull Trials of War criminals-Nuremberg code 1949
bull Thalidomide- Declaration of Helsinki 1964
bull Belmont report 1978 (Ethical Principles and guidelines for the protection of human subjects of research)-Tuskegee syphilis study
History
1962 US FDA IND Guidelines
1964 Declaration of Helsinki
1968 Committee on Safety of Medicines uk
1978 GCP US FDA
1991 GCP Europe
1996 ICH GCP
1997 ICH GCP Guideline
When did it begin
bull Ist conf in 1990 in Brussels
3 regions participated
bull Representatives from
Industry
Academia
Ministry of
health
ICH parties
6 parties
bull EU bull EFPIA European federation of pharmaceutical industriesrsquo associations
bull MHLW Ministry of health Labor and welfare Japan
bull JPMA Japan Pharmaceuticals manufacturers Association
bull US FDA
bull PhRMA
bull Observers WHO TPP(canada)
bull International federation of Pharmaceutical manufacturerrsquos association
Key objective
bull To discuss and define the minimum standards for the development and registration of investigational products
The result
Many guidelines made
bull Most important- ICH GCP guidelines
bull Evolved in several steps
bull Consolidated guideline ICH E6 Sept 1997
ICH Guidelines examples
bull Efficacy ndash clinical trials etc
bull Safety ndash pharmacovigilance adverse drug reaction
reporting
bull Quality ndash raw materials impurities residual solvents etc
bull Multidisciplinary ndash common technical document electronic
submission coding systems
What is GCP
A standard for the design conduct performance monitoring auditing recording analyses and reporting of clinical trials that provide assurance that the data and the reported results are credible accurate and that the rights integrity and confidentiality of trial subjects are protected
Why is it needed
bull To ensure the rights safety and well being of the trial subjects are protected
bull Ensure the credibility of clinical trial data
The ICH GCP guideline
bull Provide a unified standard for the EU Japan and USA regions to facilitate mutual acceptance of clinical trial data by the regulatory authorities in
these regions
bull 8 sections
ICH GCP guideline
1 Glossary
Common language for investigatorssponsorsethics committees
2Principles of Good Clinical Practice
13 tenets of ICH GCP
3Requirements for IRBIEC
Roles responsibilities and composition
ICH GCP guideline
4Responsibilities of the investigator
5Responsibilities of the sponsor
6Requirements for clinical trial protocol and protocol amendments
7Responsibility of the sponsor in the development of investigatorrsquos brochure
8Essential documents
Principles of ICH GCP
bull Ethical conduct as per
Declaration of Helsinki
GCP
Regulatory Requirements
Risk- Benefit
Primary concern- Subject
Principles of ICH GCP
bull Supportive data
bull Protocol
Scientifically sound clear detailed
bull Ethical Clearance
Study to be conducted in compliance to the protocol which has received EC approval
Principles of ICH GCP
bull Subject Care
Medical decisions responsibility of qualified physician
bull Qualified staff
By education training experience in their area of responsibility
bull Informed Consent
Principles of ICH GCP
bull Clinical Trial data
Recorded handled and stored to enable accurate reporting interpretation and verification
bull Confidentiality
Principles of ICH GCP
bull Investigational Product
Manufactured handled and stored as per GMP
Principles of ICH GCP
bull Quality Assurance
Systems and procedures to ensure the Quality of every aspect of the trial
Indian GCP guidelines
bull Released in Dec 2001(Developed by CDCSO and endorsed by DCGI)
bull In general in line with ICH GCP
bull Has Revised Schedule Y (Jan 2005) addressed discrepancies
bull SAFEGUARD PUBLIC HEALTH
bull ASSURE CONSUMER PROTECTION STANDARDS
bull FACILITATE AVAILABILITY OF SAFE AND EFFECTIVE PRODUCTS
bull ELIMINATE INCONSISTENT STANDARDS INTERNATIONALLY
bull FACILITATE MUTUAL ACCEPTANCE OF DATA FROM CLINICAL TRIALS
GOALS OF INTERNATIONAL HARMONIZATION OF
REGULATORY REQUIREMENTS
Study DocumentationDuring the study
The investigator must keepndash Source documents
bull Medical records (including access to computer records)
bull Laboratory reports
bull ECGs X-rays etc
bull Any other medical records reports or notes (hospital admissions and discharges)
ndash A subject identification list
ndash Copies of all study related documentation
Medical Records
bull In particular they should contain notes on
ndash Sufficient information to support subject eligibility
ndash This should be well documented (signed and dated)
ndash Subjectrsquos participation in the study
ndash Dates of visits
ndash Procedures investigations done
ndash Observations diagnoses
ndash Medications taken (including study medication)
ndash Adverse events
ndash Completion or withdrawal (reason) from the study
Study DocumentationAfter the study
The sponsor needs from the investigator
ndash Final drug accountability records
ndash All used and unused supplies and medication
ndash All required documents completed
Conclusion
70
Thanks
ldquoWhen a doctor [goes] wrong he is
the first of criminals He has nerve
and he has knowledgerdquo
- Sherlock Holmes
References
httpwwwwmanetepolicyb3htm
wwwhhsgovohrphumansubjectsguidancebelmonthtml
wwwhhsgovohrpreferencesnurcodehtml
wwwicmrnicinguidelinesGCLP
wwwcdsconicin
wwwubedurecercaBioeticadocDeclaracio_Helsinki_2013
wwwjewishvirtuallibraryorgjsourceHolocaustnazi_experiments
wwwichorgfileadminPublic_WebICHE6_R1__Guideline
bull In 1946 an American military tribunal opened criminal proceedings against 23 leading German physicians Doctors Trial
bull Sixteen of the doctors were found guilty
bull Seven were sentenced to death
bull Development of the Nuremberg Code of medical ethics
13
THE DOCTORS TRIAL
The Tuskegee Syphilis Study
bull Research participants was the long-term study of black males conducted at Tuskegee Alabama by the United States Public Health Service
bull (1930s-1970) - examination of the natural history of untreated syphilis
bull More than 400 African-American men with syphilis participated
bull The men were recruited without informed consent and in fact were misinformed that some of the procedures done in the interest of the research (eg spinal taps) were actually special free treatment
The Tuskegee Syphilis Study
bull In the 1940s penicillin was found to be effective in the treatment of syphilis
bull The study continued however and the men were neither informed of nor treated with the antibiotic
bull The first accounts of this study appeared in the national press in 1972
bull Belmont report 1978 (Ethical Principles and guidelines for the protection of human subjects of research)-Tuskegee syphilis study
The Jewish Chronic Disease Hospital Study
bull In 1963 studies were undertaken at New Yorks Jewish Chronic Disease Hospital to understand whether the bodys inability to reject cancer cells was due to cancer or debilitation
bull Previous studies had indicated that healthy persons reject cancer cells promptly and the researchers allegedly believed that the debilitated patients would also reject the cancers but at a substantially slower rate compared to healthy participants
The Jewish Chronic Disease Hospital Study
bull Further patients were not told that they would receive cancer cells because the researchers felt it would unnecessarily frighten them
bull It was found that the study had not been presented to the hospitals research committee and that the physicians responsible for the patients care had not been consulted
bull The researchers were found guilty of fraud deceit and unprofessional conduct
The Willowbrook Study
bull Institutionalized children as participants in research is demonstrated in a series of studies conducted from 1963 through 1966 at the Willowbrook State School a New York institution for mentally defective children
bull In order to gain an understanding of the natural history of infectious hepatitis under controlled circumstances newly admitted children were deliberately infected with the hepatitis virus
bull In some cases parents found they were unable to admit their children to Willowbrook unless they agreed to their childrsquos participation in the studies
The Willowbrook Study
This controversial case raised important questions about the adequacy and freedom of consent inadequate disclosure of the childs risk of later developing chronic liver disease
The Milgram Study
bull The lsquoteachersrsquo were instructed to give the lsquolearnersrsquo electrical shocks in response to incorrect answers on verbally given lsquotestsrsquo
bull Participants were deceived as to the nature of the study being told it was to test new teaching-learning techniques
Thalidomide tragedy
bull Thalidomide was a widely used drug in the late 1950s and early 1960s for the treatment of nausea in pregnant women
bull It became apparent in the 1960s that thalidomide treatment resulted in severe birth defects in thousands of children
21
bull Within a few years of the widespread use of thalidomide in Europe Australia and Japan approximately 10000 children were born with phocomelia leading to the ban of thalidomide in most countries in 1961
22
bull The thalidomide tragedy marked a turning point in toxicity testing as it prompted United States and international regulatory agencies to develop systematic toxicity testing protocols
bull The thalidomide tragedy also brought into sharp focus the importance of rigorous and relevant testing of pharmaceuticals prior to their introduction into the market place (Kelsey 1988)
23
Thalidomide tragedy
Nuremberg Code-1947
bull On April 17 1947 United States Counsel for War Crimescame out with six points defining ldquolegitimate researchrdquo
bull The verdict of August 19 reiterated almost all of thesepoints in a section entitled Permissible MedicalExperiments and revised the original six points into ten
bull Subsequently the ten points became known as theNuremberg Code
24
Codes and Guidelines
Nuremberg Code (1947)
WMArsquos Declaration of Helsinki (1964)
bull Belmont Report (USA) (1979)-Tuskegee syphilis study
Council for International Organizations of Medical Sciences (CIOMS) 1993
International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) in 1996 Guideline on Good Clinical PracticeE6 (GCP)
Nuremberg Code (1947)
Voluntary and Informed consent-absolutely essential
Anticipate scientific benefits Useful
Animal experimentation first
Avoid physical and mental suffering
Benefits outweigh risks
No intentional death or disability
Protection from harm
Subject free to withdraw
Qualified investigators
Investigator will stop if harm occurs
THE DECLARATION OF HELSINKI-1964
Is an international standard for the conduct of clinicalresearch adopted by International Conference onHarmonization(ICH) Good Clinical Practice standards
A global ethical standard for medical research and wasapproved at the WMA General Assembly by a majority voteof 75
It is the mission of the clinical research professionals tosafeguard the health of the people
THE DECLARATION OF HELSINKI-1964
Historical Overview-
Its origin has been found in the Nazi Disaster and hasundergone several modifications
Prior to 1947 Nuremberg Code there was noaccepted code of conduct governing the ethicalaspects of human research
World Medical Association
It is an international organization of physicians
established on September 17 1947
First general Assembly of WMA was held in Paris
France
Mission- Serve humanity by endeavoring to achieve the
highest international standards in medical education
science ethics and health care for all peoples of the world
Declaration of Helsinki 1964
Adapted from Nuremberg
Code by the World Medical Association (WMA)
First adopted in Helsinki Finland 1964
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI- 2008
Ethical Principles for Medical Research Involving Human Subjects
Adopted by the 18th WMA General Assembly Helsinki Finland June 1964 and amended by the
29th WMA General Assembly Tokyo Japan October 1975
35th WMA General Assembly Venice Italy October 1983
41st WMA General Assembly Hong Kong September 1989
53th WMA General Assembly Washington 2002 (Note of Clarification on paragraph 29 added)
55th WMA General Assembly Tokyo 2004 (Note of Clarification on Paragraph 30 added)
59th WMA General Assembly Seoul October 2008
Seven Ethical Pillars of Clinical Research
AUTONOMY
BENEFICENCE
NON ndash MALFEASANCE
FIDELITY
TRUTHFULNESS
CONFIDENTIALITY
JUSTICE
Declaration of Helsinki
Autonomy
Consent
Para 20 The subjects must be volunteers andinformed participants in the research project
Para 22 freely-given informed consent
preferably in writing
Declaration of Helsinki
Para 5 well-being of the human subject shouldtake precedence over the interests of scienceand society
Beneficence
Declaration of Helsinki
Para 16
bull Preceded by careful assessment ofpredictable risks and burdens
bull Attempt to avoid any act or treatmentplan that would harm the patient
Non Malfeasance
Declaration of Helsinki
Para 11
Medical research involving human subjects must be basedon generally accepted scientific principles thoroughknowledge of the scientific literature and on adequatelaboratory and where appropriate animalexperimentation
Para 15
Conducted only by clinically competent medical person
Fidelity ndash duty of care
Declaration of Helsinki
Para 27
Both authors amp investigators are obliged topreserve the accuracy of the results Negativeas well as positive results should be published
Truthfulness - Honesty
Declaration of Helsinki
Para 21
Every precaution should be taken torespect the privacy of the subject theconfidentiality of the patients information
Confidentiality
Declaration of Helsinki
Para 30
Every patient entered into the study should be assured ofaccess to the best proven prophylactic diagnostic andtherapeutic methods identified by the study
Para 9
Research Investigators should be aware of the ethicallegal and regulatory requirements for research on humansubjects
Para 17
Physicians should cease any investigation if the risksoutweigh the potential benefits
Justice
DECLARATION OF HELSINKI -Basic Principles
1 Conform to accepted scientific principles
2 Design formulated in experimental protocol reviewed by IEC
3 Conducted by qualified and trained persons
4 Importance in proportion to inherent risk
5 Assessment of risks vs benefits
6 Safeguard subjectrsquos integrity (privacy)
7 Abstain unless hazards are predictable
8 Preserve accuracy when publishing
9 Adequately inform or right to withdraw
10 Obtain true informed consent in writing
11 Reliance on legal guardian
12 State compliance with Declaration
Ethical Principles and Guidelines for the Protection of Human Subjects of Research
bull Tuskegee Syphilis Study (1932ndash1972)
bull Named the Belmont Report for the Belmont Conference Center where the National Commission met when first drafting the report
42
Belmont Report 1979
Belmont Report 1979
Three ethical principles related to research on human subjects
1 Respect for Persons
2 Beneficence Do no harm while maximizing benefits for research project and minimizing risks to the research subjects
3 Justice ensuring reasonable non-exploitative and well-considered procedures are administered
Overview of
ICH GCP
What is ICH
bull The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)- is unique in bringing together the regulatory authorities and pharmaceutical industry of Europe Japan and the US to discuss scientific and technical aspects of drug registration
45
What is ICH
bull Since its inception in 1990 ICH has
gradually evolved
bull ICHs mission is to ensure that safe
effective and high quality medicines are
developed and registered in the most
resource-efficient manner
How did it evolve
The need to harmonize
bull Public disasters serious fraud and abuse of human rights
bull Trials of War criminals-Nuremberg code 1949
bull Thalidomide- Declaration of Helsinki 1964
bull Belmont report 1978 (Ethical Principles and guidelines for the protection of human subjects of research)-Tuskegee syphilis study
History
1962 US FDA IND Guidelines
1964 Declaration of Helsinki
1968 Committee on Safety of Medicines uk
1978 GCP US FDA
1991 GCP Europe
1996 ICH GCP
1997 ICH GCP Guideline
When did it begin
bull Ist conf in 1990 in Brussels
3 regions participated
bull Representatives from
Industry
Academia
Ministry of
health
ICH parties
6 parties
bull EU bull EFPIA European federation of pharmaceutical industriesrsquo associations
bull MHLW Ministry of health Labor and welfare Japan
bull JPMA Japan Pharmaceuticals manufacturers Association
bull US FDA
bull PhRMA
bull Observers WHO TPP(canada)
bull International federation of Pharmaceutical manufacturerrsquos association
Key objective
bull To discuss and define the minimum standards for the development and registration of investigational products
The result
Many guidelines made
bull Most important- ICH GCP guidelines
bull Evolved in several steps
bull Consolidated guideline ICH E6 Sept 1997
ICH Guidelines examples
bull Efficacy ndash clinical trials etc
bull Safety ndash pharmacovigilance adverse drug reaction
reporting
bull Quality ndash raw materials impurities residual solvents etc
bull Multidisciplinary ndash common technical document electronic
submission coding systems
What is GCP
A standard for the design conduct performance monitoring auditing recording analyses and reporting of clinical trials that provide assurance that the data and the reported results are credible accurate and that the rights integrity and confidentiality of trial subjects are protected
Why is it needed
bull To ensure the rights safety and well being of the trial subjects are protected
bull Ensure the credibility of clinical trial data
The ICH GCP guideline
bull Provide a unified standard for the EU Japan and USA regions to facilitate mutual acceptance of clinical trial data by the regulatory authorities in
these regions
bull 8 sections
ICH GCP guideline
1 Glossary
Common language for investigatorssponsorsethics committees
2Principles of Good Clinical Practice
13 tenets of ICH GCP
3Requirements for IRBIEC
Roles responsibilities and composition
ICH GCP guideline
4Responsibilities of the investigator
5Responsibilities of the sponsor
6Requirements for clinical trial protocol and protocol amendments
7Responsibility of the sponsor in the development of investigatorrsquos brochure
8Essential documents
Principles of ICH GCP
bull Ethical conduct as per
Declaration of Helsinki
GCP
Regulatory Requirements
Risk- Benefit
Primary concern- Subject
Principles of ICH GCP
bull Supportive data
bull Protocol
Scientifically sound clear detailed
bull Ethical Clearance
Study to be conducted in compliance to the protocol which has received EC approval
Principles of ICH GCP
bull Subject Care
Medical decisions responsibility of qualified physician
bull Qualified staff
By education training experience in their area of responsibility
bull Informed Consent
Principles of ICH GCP
bull Clinical Trial data
Recorded handled and stored to enable accurate reporting interpretation and verification
bull Confidentiality
Principles of ICH GCP
bull Investigational Product
Manufactured handled and stored as per GMP
Principles of ICH GCP
bull Quality Assurance
Systems and procedures to ensure the Quality of every aspect of the trial
Indian GCP guidelines
bull Released in Dec 2001(Developed by CDCSO and endorsed by DCGI)
bull In general in line with ICH GCP
bull Has Revised Schedule Y (Jan 2005) addressed discrepancies
bull SAFEGUARD PUBLIC HEALTH
bull ASSURE CONSUMER PROTECTION STANDARDS
bull FACILITATE AVAILABILITY OF SAFE AND EFFECTIVE PRODUCTS
bull ELIMINATE INCONSISTENT STANDARDS INTERNATIONALLY
bull FACILITATE MUTUAL ACCEPTANCE OF DATA FROM CLINICAL TRIALS
GOALS OF INTERNATIONAL HARMONIZATION OF
REGULATORY REQUIREMENTS
Study DocumentationDuring the study
The investigator must keepndash Source documents
bull Medical records (including access to computer records)
bull Laboratory reports
bull ECGs X-rays etc
bull Any other medical records reports or notes (hospital admissions and discharges)
ndash A subject identification list
ndash Copies of all study related documentation
Medical Records
bull In particular they should contain notes on
ndash Sufficient information to support subject eligibility
ndash This should be well documented (signed and dated)
ndash Subjectrsquos participation in the study
ndash Dates of visits
ndash Procedures investigations done
ndash Observations diagnoses
ndash Medications taken (including study medication)
ndash Adverse events
ndash Completion or withdrawal (reason) from the study
Study DocumentationAfter the study
The sponsor needs from the investigator
ndash Final drug accountability records
ndash All used and unused supplies and medication
ndash All required documents completed
Conclusion
70
Thanks
ldquoWhen a doctor [goes] wrong he is
the first of criminals He has nerve
and he has knowledgerdquo
- Sherlock Holmes
References
httpwwwwmanetepolicyb3htm
wwwhhsgovohrphumansubjectsguidancebelmonthtml
wwwhhsgovohrpreferencesnurcodehtml
wwwicmrnicinguidelinesGCLP
wwwcdsconicin
wwwubedurecercaBioeticadocDeclaracio_Helsinki_2013
wwwjewishvirtuallibraryorgjsourceHolocaustnazi_experiments
wwwichorgfileadminPublic_WebICHE6_R1__Guideline
The Tuskegee Syphilis Study
bull Research participants was the long-term study of black males conducted at Tuskegee Alabama by the United States Public Health Service
bull (1930s-1970) - examination of the natural history of untreated syphilis
bull More than 400 African-American men with syphilis participated
bull The men were recruited without informed consent and in fact were misinformed that some of the procedures done in the interest of the research (eg spinal taps) were actually special free treatment
The Tuskegee Syphilis Study
bull In the 1940s penicillin was found to be effective in the treatment of syphilis
bull The study continued however and the men were neither informed of nor treated with the antibiotic
bull The first accounts of this study appeared in the national press in 1972
bull Belmont report 1978 (Ethical Principles and guidelines for the protection of human subjects of research)-Tuskegee syphilis study
The Jewish Chronic Disease Hospital Study
bull In 1963 studies were undertaken at New Yorks Jewish Chronic Disease Hospital to understand whether the bodys inability to reject cancer cells was due to cancer or debilitation
bull Previous studies had indicated that healthy persons reject cancer cells promptly and the researchers allegedly believed that the debilitated patients would also reject the cancers but at a substantially slower rate compared to healthy participants
The Jewish Chronic Disease Hospital Study
bull Further patients were not told that they would receive cancer cells because the researchers felt it would unnecessarily frighten them
bull It was found that the study had not been presented to the hospitals research committee and that the physicians responsible for the patients care had not been consulted
bull The researchers were found guilty of fraud deceit and unprofessional conduct
The Willowbrook Study
bull Institutionalized children as participants in research is demonstrated in a series of studies conducted from 1963 through 1966 at the Willowbrook State School a New York institution for mentally defective children
bull In order to gain an understanding of the natural history of infectious hepatitis under controlled circumstances newly admitted children were deliberately infected with the hepatitis virus
bull In some cases parents found they were unable to admit their children to Willowbrook unless they agreed to their childrsquos participation in the studies
The Willowbrook Study
This controversial case raised important questions about the adequacy and freedom of consent inadequate disclosure of the childs risk of later developing chronic liver disease
The Milgram Study
bull The lsquoteachersrsquo were instructed to give the lsquolearnersrsquo electrical shocks in response to incorrect answers on verbally given lsquotestsrsquo
bull Participants were deceived as to the nature of the study being told it was to test new teaching-learning techniques
Thalidomide tragedy
bull Thalidomide was a widely used drug in the late 1950s and early 1960s for the treatment of nausea in pregnant women
bull It became apparent in the 1960s that thalidomide treatment resulted in severe birth defects in thousands of children
21
bull Within a few years of the widespread use of thalidomide in Europe Australia and Japan approximately 10000 children were born with phocomelia leading to the ban of thalidomide in most countries in 1961
22
bull The thalidomide tragedy marked a turning point in toxicity testing as it prompted United States and international regulatory agencies to develop systematic toxicity testing protocols
bull The thalidomide tragedy also brought into sharp focus the importance of rigorous and relevant testing of pharmaceuticals prior to their introduction into the market place (Kelsey 1988)
23
Thalidomide tragedy
Nuremberg Code-1947
bull On April 17 1947 United States Counsel for War Crimescame out with six points defining ldquolegitimate researchrdquo
bull The verdict of August 19 reiterated almost all of thesepoints in a section entitled Permissible MedicalExperiments and revised the original six points into ten
bull Subsequently the ten points became known as theNuremberg Code
24
Codes and Guidelines
Nuremberg Code (1947)
WMArsquos Declaration of Helsinki (1964)
bull Belmont Report (USA) (1979)-Tuskegee syphilis study
Council for International Organizations of Medical Sciences (CIOMS) 1993
International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) in 1996 Guideline on Good Clinical PracticeE6 (GCP)
Nuremberg Code (1947)
Voluntary and Informed consent-absolutely essential
Anticipate scientific benefits Useful
Animal experimentation first
Avoid physical and mental suffering
Benefits outweigh risks
No intentional death or disability
Protection from harm
Subject free to withdraw
Qualified investigators
Investigator will stop if harm occurs
THE DECLARATION OF HELSINKI-1964
Is an international standard for the conduct of clinicalresearch adopted by International Conference onHarmonization(ICH) Good Clinical Practice standards
A global ethical standard for medical research and wasapproved at the WMA General Assembly by a majority voteof 75
It is the mission of the clinical research professionals tosafeguard the health of the people
THE DECLARATION OF HELSINKI-1964
Historical Overview-
Its origin has been found in the Nazi Disaster and hasundergone several modifications
Prior to 1947 Nuremberg Code there was noaccepted code of conduct governing the ethicalaspects of human research
World Medical Association
It is an international organization of physicians
established on September 17 1947
First general Assembly of WMA was held in Paris
France
Mission- Serve humanity by endeavoring to achieve the
highest international standards in medical education
science ethics and health care for all peoples of the world
Declaration of Helsinki 1964
Adapted from Nuremberg
Code by the World Medical Association (WMA)
First adopted in Helsinki Finland 1964
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI- 2008
Ethical Principles for Medical Research Involving Human Subjects
Adopted by the 18th WMA General Assembly Helsinki Finland June 1964 and amended by the
29th WMA General Assembly Tokyo Japan October 1975
35th WMA General Assembly Venice Italy October 1983
41st WMA General Assembly Hong Kong September 1989
53th WMA General Assembly Washington 2002 (Note of Clarification on paragraph 29 added)
55th WMA General Assembly Tokyo 2004 (Note of Clarification on Paragraph 30 added)
59th WMA General Assembly Seoul October 2008
Seven Ethical Pillars of Clinical Research
AUTONOMY
BENEFICENCE
NON ndash MALFEASANCE
FIDELITY
TRUTHFULNESS
CONFIDENTIALITY
JUSTICE
Declaration of Helsinki
Autonomy
Consent
Para 20 The subjects must be volunteers andinformed participants in the research project
Para 22 freely-given informed consent
preferably in writing
Declaration of Helsinki
Para 5 well-being of the human subject shouldtake precedence over the interests of scienceand society
Beneficence
Declaration of Helsinki
Para 16
bull Preceded by careful assessment ofpredictable risks and burdens
bull Attempt to avoid any act or treatmentplan that would harm the patient
Non Malfeasance
Declaration of Helsinki
Para 11
Medical research involving human subjects must be basedon generally accepted scientific principles thoroughknowledge of the scientific literature and on adequatelaboratory and where appropriate animalexperimentation
Para 15
Conducted only by clinically competent medical person
Fidelity ndash duty of care
Declaration of Helsinki
Para 27
Both authors amp investigators are obliged topreserve the accuracy of the results Negativeas well as positive results should be published
Truthfulness - Honesty
Declaration of Helsinki
Para 21
Every precaution should be taken torespect the privacy of the subject theconfidentiality of the patients information
Confidentiality
Declaration of Helsinki
Para 30
Every patient entered into the study should be assured ofaccess to the best proven prophylactic diagnostic andtherapeutic methods identified by the study
Para 9
Research Investigators should be aware of the ethicallegal and regulatory requirements for research on humansubjects
Para 17
Physicians should cease any investigation if the risksoutweigh the potential benefits
Justice
DECLARATION OF HELSINKI -Basic Principles
1 Conform to accepted scientific principles
2 Design formulated in experimental protocol reviewed by IEC
3 Conducted by qualified and trained persons
4 Importance in proportion to inherent risk
5 Assessment of risks vs benefits
6 Safeguard subjectrsquos integrity (privacy)
7 Abstain unless hazards are predictable
8 Preserve accuracy when publishing
9 Adequately inform or right to withdraw
10 Obtain true informed consent in writing
11 Reliance on legal guardian
12 State compliance with Declaration
Ethical Principles and Guidelines for the Protection of Human Subjects of Research
bull Tuskegee Syphilis Study (1932ndash1972)
bull Named the Belmont Report for the Belmont Conference Center where the National Commission met when first drafting the report
42
Belmont Report 1979
Belmont Report 1979
Three ethical principles related to research on human subjects
1 Respect for Persons
2 Beneficence Do no harm while maximizing benefits for research project and minimizing risks to the research subjects
3 Justice ensuring reasonable non-exploitative and well-considered procedures are administered
Overview of
ICH GCP
What is ICH
bull The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)- is unique in bringing together the regulatory authorities and pharmaceutical industry of Europe Japan and the US to discuss scientific and technical aspects of drug registration
45
What is ICH
bull Since its inception in 1990 ICH has
gradually evolved
bull ICHs mission is to ensure that safe
effective and high quality medicines are
developed and registered in the most
resource-efficient manner
How did it evolve
The need to harmonize
bull Public disasters serious fraud and abuse of human rights
bull Trials of War criminals-Nuremberg code 1949
bull Thalidomide- Declaration of Helsinki 1964
bull Belmont report 1978 (Ethical Principles and guidelines for the protection of human subjects of research)-Tuskegee syphilis study
History
1962 US FDA IND Guidelines
1964 Declaration of Helsinki
1968 Committee on Safety of Medicines uk
1978 GCP US FDA
1991 GCP Europe
1996 ICH GCP
1997 ICH GCP Guideline
When did it begin
bull Ist conf in 1990 in Brussels
3 regions participated
bull Representatives from
Industry
Academia
Ministry of
health
ICH parties
6 parties
bull EU bull EFPIA European federation of pharmaceutical industriesrsquo associations
bull MHLW Ministry of health Labor and welfare Japan
bull JPMA Japan Pharmaceuticals manufacturers Association
bull US FDA
bull PhRMA
bull Observers WHO TPP(canada)
bull International federation of Pharmaceutical manufacturerrsquos association
Key objective
bull To discuss and define the minimum standards for the development and registration of investigational products
The result
Many guidelines made
bull Most important- ICH GCP guidelines
bull Evolved in several steps
bull Consolidated guideline ICH E6 Sept 1997
ICH Guidelines examples
bull Efficacy ndash clinical trials etc
bull Safety ndash pharmacovigilance adverse drug reaction
reporting
bull Quality ndash raw materials impurities residual solvents etc
bull Multidisciplinary ndash common technical document electronic
submission coding systems
What is GCP
A standard for the design conduct performance monitoring auditing recording analyses and reporting of clinical trials that provide assurance that the data and the reported results are credible accurate and that the rights integrity and confidentiality of trial subjects are protected
Why is it needed
bull To ensure the rights safety and well being of the trial subjects are protected
bull Ensure the credibility of clinical trial data
The ICH GCP guideline
bull Provide a unified standard for the EU Japan and USA regions to facilitate mutual acceptance of clinical trial data by the regulatory authorities in
these regions
bull 8 sections
ICH GCP guideline
1 Glossary
Common language for investigatorssponsorsethics committees
2Principles of Good Clinical Practice
13 tenets of ICH GCP
3Requirements for IRBIEC
Roles responsibilities and composition
ICH GCP guideline
4Responsibilities of the investigator
5Responsibilities of the sponsor
6Requirements for clinical trial protocol and protocol amendments
7Responsibility of the sponsor in the development of investigatorrsquos brochure
8Essential documents
Principles of ICH GCP
bull Ethical conduct as per
Declaration of Helsinki
GCP
Regulatory Requirements
Risk- Benefit
Primary concern- Subject
Principles of ICH GCP
bull Supportive data
bull Protocol
Scientifically sound clear detailed
bull Ethical Clearance
Study to be conducted in compliance to the protocol which has received EC approval
Principles of ICH GCP
bull Subject Care
Medical decisions responsibility of qualified physician
bull Qualified staff
By education training experience in their area of responsibility
bull Informed Consent
Principles of ICH GCP
bull Clinical Trial data
Recorded handled and stored to enable accurate reporting interpretation and verification
bull Confidentiality
Principles of ICH GCP
bull Investigational Product
Manufactured handled and stored as per GMP
Principles of ICH GCP
bull Quality Assurance
Systems and procedures to ensure the Quality of every aspect of the trial
Indian GCP guidelines
bull Released in Dec 2001(Developed by CDCSO and endorsed by DCGI)
bull In general in line with ICH GCP
bull Has Revised Schedule Y (Jan 2005) addressed discrepancies
bull SAFEGUARD PUBLIC HEALTH
bull ASSURE CONSUMER PROTECTION STANDARDS
bull FACILITATE AVAILABILITY OF SAFE AND EFFECTIVE PRODUCTS
bull ELIMINATE INCONSISTENT STANDARDS INTERNATIONALLY
bull FACILITATE MUTUAL ACCEPTANCE OF DATA FROM CLINICAL TRIALS
GOALS OF INTERNATIONAL HARMONIZATION OF
REGULATORY REQUIREMENTS
Study DocumentationDuring the study
The investigator must keepndash Source documents
bull Medical records (including access to computer records)
bull Laboratory reports
bull ECGs X-rays etc
bull Any other medical records reports or notes (hospital admissions and discharges)
ndash A subject identification list
ndash Copies of all study related documentation
Medical Records
bull In particular they should contain notes on
ndash Sufficient information to support subject eligibility
ndash This should be well documented (signed and dated)
ndash Subjectrsquos participation in the study
ndash Dates of visits
ndash Procedures investigations done
ndash Observations diagnoses
ndash Medications taken (including study medication)
ndash Adverse events
ndash Completion or withdrawal (reason) from the study
Study DocumentationAfter the study
The sponsor needs from the investigator
ndash Final drug accountability records
ndash All used and unused supplies and medication
ndash All required documents completed
Conclusion
70
Thanks
ldquoWhen a doctor [goes] wrong he is
the first of criminals He has nerve
and he has knowledgerdquo
- Sherlock Holmes
References
httpwwwwmanetepolicyb3htm
wwwhhsgovohrphumansubjectsguidancebelmonthtml
wwwhhsgovohrpreferencesnurcodehtml
wwwicmrnicinguidelinesGCLP
wwwcdsconicin
wwwubedurecercaBioeticadocDeclaracio_Helsinki_2013
wwwjewishvirtuallibraryorgjsourceHolocaustnazi_experiments
wwwichorgfileadminPublic_WebICHE6_R1__Guideline
The Tuskegee Syphilis Study
bull In the 1940s penicillin was found to be effective in the treatment of syphilis
bull The study continued however and the men were neither informed of nor treated with the antibiotic
bull The first accounts of this study appeared in the national press in 1972
bull Belmont report 1978 (Ethical Principles and guidelines for the protection of human subjects of research)-Tuskegee syphilis study
The Jewish Chronic Disease Hospital Study
bull In 1963 studies were undertaken at New Yorks Jewish Chronic Disease Hospital to understand whether the bodys inability to reject cancer cells was due to cancer or debilitation
bull Previous studies had indicated that healthy persons reject cancer cells promptly and the researchers allegedly believed that the debilitated patients would also reject the cancers but at a substantially slower rate compared to healthy participants
The Jewish Chronic Disease Hospital Study
bull Further patients were not told that they would receive cancer cells because the researchers felt it would unnecessarily frighten them
bull It was found that the study had not been presented to the hospitals research committee and that the physicians responsible for the patients care had not been consulted
bull The researchers were found guilty of fraud deceit and unprofessional conduct
The Willowbrook Study
bull Institutionalized children as participants in research is demonstrated in a series of studies conducted from 1963 through 1966 at the Willowbrook State School a New York institution for mentally defective children
bull In order to gain an understanding of the natural history of infectious hepatitis under controlled circumstances newly admitted children were deliberately infected with the hepatitis virus
bull In some cases parents found they were unable to admit their children to Willowbrook unless they agreed to their childrsquos participation in the studies
The Willowbrook Study
This controversial case raised important questions about the adequacy and freedom of consent inadequate disclosure of the childs risk of later developing chronic liver disease
The Milgram Study
bull The lsquoteachersrsquo were instructed to give the lsquolearnersrsquo electrical shocks in response to incorrect answers on verbally given lsquotestsrsquo
bull Participants were deceived as to the nature of the study being told it was to test new teaching-learning techniques
Thalidomide tragedy
bull Thalidomide was a widely used drug in the late 1950s and early 1960s for the treatment of nausea in pregnant women
bull It became apparent in the 1960s that thalidomide treatment resulted in severe birth defects in thousands of children
21
bull Within a few years of the widespread use of thalidomide in Europe Australia and Japan approximately 10000 children were born with phocomelia leading to the ban of thalidomide in most countries in 1961
22
bull The thalidomide tragedy marked a turning point in toxicity testing as it prompted United States and international regulatory agencies to develop systematic toxicity testing protocols
bull The thalidomide tragedy also brought into sharp focus the importance of rigorous and relevant testing of pharmaceuticals prior to their introduction into the market place (Kelsey 1988)
23
Thalidomide tragedy
Nuremberg Code-1947
bull On April 17 1947 United States Counsel for War Crimescame out with six points defining ldquolegitimate researchrdquo
bull The verdict of August 19 reiterated almost all of thesepoints in a section entitled Permissible MedicalExperiments and revised the original six points into ten
bull Subsequently the ten points became known as theNuremberg Code
24
Codes and Guidelines
Nuremberg Code (1947)
WMArsquos Declaration of Helsinki (1964)
bull Belmont Report (USA) (1979)-Tuskegee syphilis study
Council for International Organizations of Medical Sciences (CIOMS) 1993
International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) in 1996 Guideline on Good Clinical PracticeE6 (GCP)
Nuremberg Code (1947)
Voluntary and Informed consent-absolutely essential
Anticipate scientific benefits Useful
Animal experimentation first
Avoid physical and mental suffering
Benefits outweigh risks
No intentional death or disability
Protection from harm
Subject free to withdraw
Qualified investigators
Investigator will stop if harm occurs
THE DECLARATION OF HELSINKI-1964
Is an international standard for the conduct of clinicalresearch adopted by International Conference onHarmonization(ICH) Good Clinical Practice standards
A global ethical standard for medical research and wasapproved at the WMA General Assembly by a majority voteof 75
It is the mission of the clinical research professionals tosafeguard the health of the people
THE DECLARATION OF HELSINKI-1964
Historical Overview-
Its origin has been found in the Nazi Disaster and hasundergone several modifications
Prior to 1947 Nuremberg Code there was noaccepted code of conduct governing the ethicalaspects of human research
World Medical Association
It is an international organization of physicians
established on September 17 1947
First general Assembly of WMA was held in Paris
France
Mission- Serve humanity by endeavoring to achieve the
highest international standards in medical education
science ethics and health care for all peoples of the world
Declaration of Helsinki 1964
Adapted from Nuremberg
Code by the World Medical Association (WMA)
First adopted in Helsinki Finland 1964
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI- 2008
Ethical Principles for Medical Research Involving Human Subjects
Adopted by the 18th WMA General Assembly Helsinki Finland June 1964 and amended by the
29th WMA General Assembly Tokyo Japan October 1975
35th WMA General Assembly Venice Italy October 1983
41st WMA General Assembly Hong Kong September 1989
53th WMA General Assembly Washington 2002 (Note of Clarification on paragraph 29 added)
55th WMA General Assembly Tokyo 2004 (Note of Clarification on Paragraph 30 added)
59th WMA General Assembly Seoul October 2008
Seven Ethical Pillars of Clinical Research
AUTONOMY
BENEFICENCE
NON ndash MALFEASANCE
FIDELITY
TRUTHFULNESS
CONFIDENTIALITY
JUSTICE
Declaration of Helsinki
Autonomy
Consent
Para 20 The subjects must be volunteers andinformed participants in the research project
Para 22 freely-given informed consent
preferably in writing
Declaration of Helsinki
Para 5 well-being of the human subject shouldtake precedence over the interests of scienceand society
Beneficence
Declaration of Helsinki
Para 16
bull Preceded by careful assessment ofpredictable risks and burdens
bull Attempt to avoid any act or treatmentplan that would harm the patient
Non Malfeasance
Declaration of Helsinki
Para 11
Medical research involving human subjects must be basedon generally accepted scientific principles thoroughknowledge of the scientific literature and on adequatelaboratory and where appropriate animalexperimentation
Para 15
Conducted only by clinically competent medical person
Fidelity ndash duty of care
Declaration of Helsinki
Para 27
Both authors amp investigators are obliged topreserve the accuracy of the results Negativeas well as positive results should be published
Truthfulness - Honesty
Declaration of Helsinki
Para 21
Every precaution should be taken torespect the privacy of the subject theconfidentiality of the patients information
Confidentiality
Declaration of Helsinki
Para 30
Every patient entered into the study should be assured ofaccess to the best proven prophylactic diagnostic andtherapeutic methods identified by the study
Para 9
Research Investigators should be aware of the ethicallegal and regulatory requirements for research on humansubjects
Para 17
Physicians should cease any investigation if the risksoutweigh the potential benefits
Justice
DECLARATION OF HELSINKI -Basic Principles
1 Conform to accepted scientific principles
2 Design formulated in experimental protocol reviewed by IEC
3 Conducted by qualified and trained persons
4 Importance in proportion to inherent risk
5 Assessment of risks vs benefits
6 Safeguard subjectrsquos integrity (privacy)
7 Abstain unless hazards are predictable
8 Preserve accuracy when publishing
9 Adequately inform or right to withdraw
10 Obtain true informed consent in writing
11 Reliance on legal guardian
12 State compliance with Declaration
Ethical Principles and Guidelines for the Protection of Human Subjects of Research
bull Tuskegee Syphilis Study (1932ndash1972)
bull Named the Belmont Report for the Belmont Conference Center where the National Commission met when first drafting the report
42
Belmont Report 1979
Belmont Report 1979
Three ethical principles related to research on human subjects
1 Respect for Persons
2 Beneficence Do no harm while maximizing benefits for research project and minimizing risks to the research subjects
3 Justice ensuring reasonable non-exploitative and well-considered procedures are administered
Overview of
ICH GCP
What is ICH
bull The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)- is unique in bringing together the regulatory authorities and pharmaceutical industry of Europe Japan and the US to discuss scientific and technical aspects of drug registration
45
What is ICH
bull Since its inception in 1990 ICH has
gradually evolved
bull ICHs mission is to ensure that safe
effective and high quality medicines are
developed and registered in the most
resource-efficient manner
How did it evolve
The need to harmonize
bull Public disasters serious fraud and abuse of human rights
bull Trials of War criminals-Nuremberg code 1949
bull Thalidomide- Declaration of Helsinki 1964
bull Belmont report 1978 (Ethical Principles and guidelines for the protection of human subjects of research)-Tuskegee syphilis study
History
1962 US FDA IND Guidelines
1964 Declaration of Helsinki
1968 Committee on Safety of Medicines uk
1978 GCP US FDA
1991 GCP Europe
1996 ICH GCP
1997 ICH GCP Guideline
When did it begin
bull Ist conf in 1990 in Brussels
3 regions participated
bull Representatives from
Industry
Academia
Ministry of
health
ICH parties
6 parties
bull EU bull EFPIA European federation of pharmaceutical industriesrsquo associations
bull MHLW Ministry of health Labor and welfare Japan
bull JPMA Japan Pharmaceuticals manufacturers Association
bull US FDA
bull PhRMA
bull Observers WHO TPP(canada)
bull International federation of Pharmaceutical manufacturerrsquos association
Key objective
bull To discuss and define the minimum standards for the development and registration of investigational products
The result
Many guidelines made
bull Most important- ICH GCP guidelines
bull Evolved in several steps
bull Consolidated guideline ICH E6 Sept 1997
ICH Guidelines examples
bull Efficacy ndash clinical trials etc
bull Safety ndash pharmacovigilance adverse drug reaction
reporting
bull Quality ndash raw materials impurities residual solvents etc
bull Multidisciplinary ndash common technical document electronic
submission coding systems
What is GCP
A standard for the design conduct performance monitoring auditing recording analyses and reporting of clinical trials that provide assurance that the data and the reported results are credible accurate and that the rights integrity and confidentiality of trial subjects are protected
Why is it needed
bull To ensure the rights safety and well being of the trial subjects are protected
bull Ensure the credibility of clinical trial data
The ICH GCP guideline
bull Provide a unified standard for the EU Japan and USA regions to facilitate mutual acceptance of clinical trial data by the regulatory authorities in
these regions
bull 8 sections
ICH GCP guideline
1 Glossary
Common language for investigatorssponsorsethics committees
2Principles of Good Clinical Practice
13 tenets of ICH GCP
3Requirements for IRBIEC
Roles responsibilities and composition
ICH GCP guideline
4Responsibilities of the investigator
5Responsibilities of the sponsor
6Requirements for clinical trial protocol and protocol amendments
7Responsibility of the sponsor in the development of investigatorrsquos brochure
8Essential documents
Principles of ICH GCP
bull Ethical conduct as per
Declaration of Helsinki
GCP
Regulatory Requirements
Risk- Benefit
Primary concern- Subject
Principles of ICH GCP
bull Supportive data
bull Protocol
Scientifically sound clear detailed
bull Ethical Clearance
Study to be conducted in compliance to the protocol which has received EC approval
Principles of ICH GCP
bull Subject Care
Medical decisions responsibility of qualified physician
bull Qualified staff
By education training experience in their area of responsibility
bull Informed Consent
Principles of ICH GCP
bull Clinical Trial data
Recorded handled and stored to enable accurate reporting interpretation and verification
bull Confidentiality
Principles of ICH GCP
bull Investigational Product
Manufactured handled and stored as per GMP
Principles of ICH GCP
bull Quality Assurance
Systems and procedures to ensure the Quality of every aspect of the trial
Indian GCP guidelines
bull Released in Dec 2001(Developed by CDCSO and endorsed by DCGI)
bull In general in line with ICH GCP
bull Has Revised Schedule Y (Jan 2005) addressed discrepancies
bull SAFEGUARD PUBLIC HEALTH
bull ASSURE CONSUMER PROTECTION STANDARDS
bull FACILITATE AVAILABILITY OF SAFE AND EFFECTIVE PRODUCTS
bull ELIMINATE INCONSISTENT STANDARDS INTERNATIONALLY
bull FACILITATE MUTUAL ACCEPTANCE OF DATA FROM CLINICAL TRIALS
GOALS OF INTERNATIONAL HARMONIZATION OF
REGULATORY REQUIREMENTS
Study DocumentationDuring the study
The investigator must keepndash Source documents
bull Medical records (including access to computer records)
bull Laboratory reports
bull ECGs X-rays etc
bull Any other medical records reports or notes (hospital admissions and discharges)
ndash A subject identification list
ndash Copies of all study related documentation
Medical Records
bull In particular they should contain notes on
ndash Sufficient information to support subject eligibility
ndash This should be well documented (signed and dated)
ndash Subjectrsquos participation in the study
ndash Dates of visits
ndash Procedures investigations done
ndash Observations diagnoses
ndash Medications taken (including study medication)
ndash Adverse events
ndash Completion or withdrawal (reason) from the study
Study DocumentationAfter the study
The sponsor needs from the investigator
ndash Final drug accountability records
ndash All used and unused supplies and medication
ndash All required documents completed
Conclusion
70
Thanks
ldquoWhen a doctor [goes] wrong he is
the first of criminals He has nerve
and he has knowledgerdquo
- Sherlock Holmes
References
httpwwwwmanetepolicyb3htm
wwwhhsgovohrphumansubjectsguidancebelmonthtml
wwwhhsgovohrpreferencesnurcodehtml
wwwicmrnicinguidelinesGCLP
wwwcdsconicin
wwwubedurecercaBioeticadocDeclaracio_Helsinki_2013
wwwjewishvirtuallibraryorgjsourceHolocaustnazi_experiments
wwwichorgfileadminPublic_WebICHE6_R1__Guideline
The Jewish Chronic Disease Hospital Study
bull In 1963 studies were undertaken at New Yorks Jewish Chronic Disease Hospital to understand whether the bodys inability to reject cancer cells was due to cancer or debilitation
bull Previous studies had indicated that healthy persons reject cancer cells promptly and the researchers allegedly believed that the debilitated patients would also reject the cancers but at a substantially slower rate compared to healthy participants
The Jewish Chronic Disease Hospital Study
bull Further patients were not told that they would receive cancer cells because the researchers felt it would unnecessarily frighten them
bull It was found that the study had not been presented to the hospitals research committee and that the physicians responsible for the patients care had not been consulted
bull The researchers were found guilty of fraud deceit and unprofessional conduct
The Willowbrook Study
bull Institutionalized children as participants in research is demonstrated in a series of studies conducted from 1963 through 1966 at the Willowbrook State School a New York institution for mentally defective children
bull In order to gain an understanding of the natural history of infectious hepatitis under controlled circumstances newly admitted children were deliberately infected with the hepatitis virus
bull In some cases parents found they were unable to admit their children to Willowbrook unless they agreed to their childrsquos participation in the studies
The Willowbrook Study
This controversial case raised important questions about the adequacy and freedom of consent inadequate disclosure of the childs risk of later developing chronic liver disease
The Milgram Study
bull The lsquoteachersrsquo were instructed to give the lsquolearnersrsquo electrical shocks in response to incorrect answers on verbally given lsquotestsrsquo
bull Participants were deceived as to the nature of the study being told it was to test new teaching-learning techniques
Thalidomide tragedy
bull Thalidomide was a widely used drug in the late 1950s and early 1960s for the treatment of nausea in pregnant women
bull It became apparent in the 1960s that thalidomide treatment resulted in severe birth defects in thousands of children
21
bull Within a few years of the widespread use of thalidomide in Europe Australia and Japan approximately 10000 children were born with phocomelia leading to the ban of thalidomide in most countries in 1961
22
bull The thalidomide tragedy marked a turning point in toxicity testing as it prompted United States and international regulatory agencies to develop systematic toxicity testing protocols
bull The thalidomide tragedy also brought into sharp focus the importance of rigorous and relevant testing of pharmaceuticals prior to their introduction into the market place (Kelsey 1988)
23
Thalidomide tragedy
Nuremberg Code-1947
bull On April 17 1947 United States Counsel for War Crimescame out with six points defining ldquolegitimate researchrdquo
bull The verdict of August 19 reiterated almost all of thesepoints in a section entitled Permissible MedicalExperiments and revised the original six points into ten
bull Subsequently the ten points became known as theNuremberg Code
24
Codes and Guidelines
Nuremberg Code (1947)
WMArsquos Declaration of Helsinki (1964)
bull Belmont Report (USA) (1979)-Tuskegee syphilis study
Council for International Organizations of Medical Sciences (CIOMS) 1993
International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) in 1996 Guideline on Good Clinical PracticeE6 (GCP)
Nuremberg Code (1947)
Voluntary and Informed consent-absolutely essential
Anticipate scientific benefits Useful
Animal experimentation first
Avoid physical and mental suffering
Benefits outweigh risks
No intentional death or disability
Protection from harm
Subject free to withdraw
Qualified investigators
Investigator will stop if harm occurs
THE DECLARATION OF HELSINKI-1964
Is an international standard for the conduct of clinicalresearch adopted by International Conference onHarmonization(ICH) Good Clinical Practice standards
A global ethical standard for medical research and wasapproved at the WMA General Assembly by a majority voteof 75
It is the mission of the clinical research professionals tosafeguard the health of the people
THE DECLARATION OF HELSINKI-1964
Historical Overview-
Its origin has been found in the Nazi Disaster and hasundergone several modifications
Prior to 1947 Nuremberg Code there was noaccepted code of conduct governing the ethicalaspects of human research
World Medical Association
It is an international organization of physicians
established on September 17 1947
First general Assembly of WMA was held in Paris
France
Mission- Serve humanity by endeavoring to achieve the
highest international standards in medical education
science ethics and health care for all peoples of the world
Declaration of Helsinki 1964
Adapted from Nuremberg
Code by the World Medical Association (WMA)
First adopted in Helsinki Finland 1964
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI- 2008
Ethical Principles for Medical Research Involving Human Subjects
Adopted by the 18th WMA General Assembly Helsinki Finland June 1964 and amended by the
29th WMA General Assembly Tokyo Japan October 1975
35th WMA General Assembly Venice Italy October 1983
41st WMA General Assembly Hong Kong September 1989
53th WMA General Assembly Washington 2002 (Note of Clarification on paragraph 29 added)
55th WMA General Assembly Tokyo 2004 (Note of Clarification on Paragraph 30 added)
59th WMA General Assembly Seoul October 2008
Seven Ethical Pillars of Clinical Research
AUTONOMY
BENEFICENCE
NON ndash MALFEASANCE
FIDELITY
TRUTHFULNESS
CONFIDENTIALITY
JUSTICE
Declaration of Helsinki
Autonomy
Consent
Para 20 The subjects must be volunteers andinformed participants in the research project
Para 22 freely-given informed consent
preferably in writing
Declaration of Helsinki
Para 5 well-being of the human subject shouldtake precedence over the interests of scienceand society
Beneficence
Declaration of Helsinki
Para 16
bull Preceded by careful assessment ofpredictable risks and burdens
bull Attempt to avoid any act or treatmentplan that would harm the patient
Non Malfeasance
Declaration of Helsinki
Para 11
Medical research involving human subjects must be basedon generally accepted scientific principles thoroughknowledge of the scientific literature and on adequatelaboratory and where appropriate animalexperimentation
Para 15
Conducted only by clinically competent medical person
Fidelity ndash duty of care
Declaration of Helsinki
Para 27
Both authors amp investigators are obliged topreserve the accuracy of the results Negativeas well as positive results should be published
Truthfulness - Honesty
Declaration of Helsinki
Para 21
Every precaution should be taken torespect the privacy of the subject theconfidentiality of the patients information
Confidentiality
Declaration of Helsinki
Para 30
Every patient entered into the study should be assured ofaccess to the best proven prophylactic diagnostic andtherapeutic methods identified by the study
Para 9
Research Investigators should be aware of the ethicallegal and regulatory requirements for research on humansubjects
Para 17
Physicians should cease any investigation if the risksoutweigh the potential benefits
Justice
DECLARATION OF HELSINKI -Basic Principles
1 Conform to accepted scientific principles
2 Design formulated in experimental protocol reviewed by IEC
3 Conducted by qualified and trained persons
4 Importance in proportion to inherent risk
5 Assessment of risks vs benefits
6 Safeguard subjectrsquos integrity (privacy)
7 Abstain unless hazards are predictable
8 Preserve accuracy when publishing
9 Adequately inform or right to withdraw
10 Obtain true informed consent in writing
11 Reliance on legal guardian
12 State compliance with Declaration
Ethical Principles and Guidelines for the Protection of Human Subjects of Research
bull Tuskegee Syphilis Study (1932ndash1972)
bull Named the Belmont Report for the Belmont Conference Center where the National Commission met when first drafting the report
42
Belmont Report 1979
Belmont Report 1979
Three ethical principles related to research on human subjects
1 Respect for Persons
2 Beneficence Do no harm while maximizing benefits for research project and minimizing risks to the research subjects
3 Justice ensuring reasonable non-exploitative and well-considered procedures are administered
Overview of
ICH GCP
What is ICH
bull The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)- is unique in bringing together the regulatory authorities and pharmaceutical industry of Europe Japan and the US to discuss scientific and technical aspects of drug registration
45
What is ICH
bull Since its inception in 1990 ICH has
gradually evolved
bull ICHs mission is to ensure that safe
effective and high quality medicines are
developed and registered in the most
resource-efficient manner
How did it evolve
The need to harmonize
bull Public disasters serious fraud and abuse of human rights
bull Trials of War criminals-Nuremberg code 1949
bull Thalidomide- Declaration of Helsinki 1964
bull Belmont report 1978 (Ethical Principles and guidelines for the protection of human subjects of research)-Tuskegee syphilis study
History
1962 US FDA IND Guidelines
1964 Declaration of Helsinki
1968 Committee on Safety of Medicines uk
1978 GCP US FDA
1991 GCP Europe
1996 ICH GCP
1997 ICH GCP Guideline
When did it begin
bull Ist conf in 1990 in Brussels
3 regions participated
bull Representatives from
Industry
Academia
Ministry of
health
ICH parties
6 parties
bull EU bull EFPIA European federation of pharmaceutical industriesrsquo associations
bull MHLW Ministry of health Labor and welfare Japan
bull JPMA Japan Pharmaceuticals manufacturers Association
bull US FDA
bull PhRMA
bull Observers WHO TPP(canada)
bull International federation of Pharmaceutical manufacturerrsquos association
Key objective
bull To discuss and define the minimum standards for the development and registration of investigational products
The result
Many guidelines made
bull Most important- ICH GCP guidelines
bull Evolved in several steps
bull Consolidated guideline ICH E6 Sept 1997
ICH Guidelines examples
bull Efficacy ndash clinical trials etc
bull Safety ndash pharmacovigilance adverse drug reaction
reporting
bull Quality ndash raw materials impurities residual solvents etc
bull Multidisciplinary ndash common technical document electronic
submission coding systems
What is GCP
A standard for the design conduct performance monitoring auditing recording analyses and reporting of clinical trials that provide assurance that the data and the reported results are credible accurate and that the rights integrity and confidentiality of trial subjects are protected
Why is it needed
bull To ensure the rights safety and well being of the trial subjects are protected
bull Ensure the credibility of clinical trial data
The ICH GCP guideline
bull Provide a unified standard for the EU Japan and USA regions to facilitate mutual acceptance of clinical trial data by the regulatory authorities in
these regions
bull 8 sections
ICH GCP guideline
1 Glossary
Common language for investigatorssponsorsethics committees
2Principles of Good Clinical Practice
13 tenets of ICH GCP
3Requirements for IRBIEC
Roles responsibilities and composition
ICH GCP guideline
4Responsibilities of the investigator
5Responsibilities of the sponsor
6Requirements for clinical trial protocol and protocol amendments
7Responsibility of the sponsor in the development of investigatorrsquos brochure
8Essential documents
Principles of ICH GCP
bull Ethical conduct as per
Declaration of Helsinki
GCP
Regulatory Requirements
Risk- Benefit
Primary concern- Subject
Principles of ICH GCP
bull Supportive data
bull Protocol
Scientifically sound clear detailed
bull Ethical Clearance
Study to be conducted in compliance to the protocol which has received EC approval
Principles of ICH GCP
bull Subject Care
Medical decisions responsibility of qualified physician
bull Qualified staff
By education training experience in their area of responsibility
bull Informed Consent
Principles of ICH GCP
bull Clinical Trial data
Recorded handled and stored to enable accurate reporting interpretation and verification
bull Confidentiality
Principles of ICH GCP
bull Investigational Product
Manufactured handled and stored as per GMP
Principles of ICH GCP
bull Quality Assurance
Systems and procedures to ensure the Quality of every aspect of the trial
Indian GCP guidelines
bull Released in Dec 2001(Developed by CDCSO and endorsed by DCGI)
bull In general in line with ICH GCP
bull Has Revised Schedule Y (Jan 2005) addressed discrepancies
bull SAFEGUARD PUBLIC HEALTH
bull ASSURE CONSUMER PROTECTION STANDARDS
bull FACILITATE AVAILABILITY OF SAFE AND EFFECTIVE PRODUCTS
bull ELIMINATE INCONSISTENT STANDARDS INTERNATIONALLY
bull FACILITATE MUTUAL ACCEPTANCE OF DATA FROM CLINICAL TRIALS
GOALS OF INTERNATIONAL HARMONIZATION OF
REGULATORY REQUIREMENTS
Study DocumentationDuring the study
The investigator must keepndash Source documents
bull Medical records (including access to computer records)
bull Laboratory reports
bull ECGs X-rays etc
bull Any other medical records reports or notes (hospital admissions and discharges)
ndash A subject identification list
ndash Copies of all study related documentation
Medical Records
bull In particular they should contain notes on
ndash Sufficient information to support subject eligibility
ndash This should be well documented (signed and dated)
ndash Subjectrsquos participation in the study
ndash Dates of visits
ndash Procedures investigations done
ndash Observations diagnoses
ndash Medications taken (including study medication)
ndash Adverse events
ndash Completion or withdrawal (reason) from the study
Study DocumentationAfter the study
The sponsor needs from the investigator
ndash Final drug accountability records
ndash All used and unused supplies and medication
ndash All required documents completed
Conclusion
70
Thanks
ldquoWhen a doctor [goes] wrong he is
the first of criminals He has nerve
and he has knowledgerdquo
- Sherlock Holmes
References
httpwwwwmanetepolicyb3htm
wwwhhsgovohrphumansubjectsguidancebelmonthtml
wwwhhsgovohrpreferencesnurcodehtml
wwwicmrnicinguidelinesGCLP
wwwcdsconicin
wwwubedurecercaBioeticadocDeclaracio_Helsinki_2013
wwwjewishvirtuallibraryorgjsourceHolocaustnazi_experiments
wwwichorgfileadminPublic_WebICHE6_R1__Guideline
The Jewish Chronic Disease Hospital Study
bull Further patients were not told that they would receive cancer cells because the researchers felt it would unnecessarily frighten them
bull It was found that the study had not been presented to the hospitals research committee and that the physicians responsible for the patients care had not been consulted
bull The researchers were found guilty of fraud deceit and unprofessional conduct
The Willowbrook Study
bull Institutionalized children as participants in research is demonstrated in a series of studies conducted from 1963 through 1966 at the Willowbrook State School a New York institution for mentally defective children
bull In order to gain an understanding of the natural history of infectious hepatitis under controlled circumstances newly admitted children were deliberately infected with the hepatitis virus
bull In some cases parents found they were unable to admit their children to Willowbrook unless they agreed to their childrsquos participation in the studies
The Willowbrook Study
This controversial case raised important questions about the adequacy and freedom of consent inadequate disclosure of the childs risk of later developing chronic liver disease
The Milgram Study
bull The lsquoteachersrsquo were instructed to give the lsquolearnersrsquo electrical shocks in response to incorrect answers on verbally given lsquotestsrsquo
bull Participants were deceived as to the nature of the study being told it was to test new teaching-learning techniques
Thalidomide tragedy
bull Thalidomide was a widely used drug in the late 1950s and early 1960s for the treatment of nausea in pregnant women
bull It became apparent in the 1960s that thalidomide treatment resulted in severe birth defects in thousands of children
21
bull Within a few years of the widespread use of thalidomide in Europe Australia and Japan approximately 10000 children were born with phocomelia leading to the ban of thalidomide in most countries in 1961
22
bull The thalidomide tragedy marked a turning point in toxicity testing as it prompted United States and international regulatory agencies to develop systematic toxicity testing protocols
bull The thalidomide tragedy also brought into sharp focus the importance of rigorous and relevant testing of pharmaceuticals prior to their introduction into the market place (Kelsey 1988)
23
Thalidomide tragedy
Nuremberg Code-1947
bull On April 17 1947 United States Counsel for War Crimescame out with six points defining ldquolegitimate researchrdquo
bull The verdict of August 19 reiterated almost all of thesepoints in a section entitled Permissible MedicalExperiments and revised the original six points into ten
bull Subsequently the ten points became known as theNuremberg Code
24
Codes and Guidelines
Nuremberg Code (1947)
WMArsquos Declaration of Helsinki (1964)
bull Belmont Report (USA) (1979)-Tuskegee syphilis study
Council for International Organizations of Medical Sciences (CIOMS) 1993
International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) in 1996 Guideline on Good Clinical PracticeE6 (GCP)
Nuremberg Code (1947)
Voluntary and Informed consent-absolutely essential
Anticipate scientific benefits Useful
Animal experimentation first
Avoid physical and mental suffering
Benefits outweigh risks
No intentional death or disability
Protection from harm
Subject free to withdraw
Qualified investigators
Investigator will stop if harm occurs
THE DECLARATION OF HELSINKI-1964
Is an international standard for the conduct of clinicalresearch adopted by International Conference onHarmonization(ICH) Good Clinical Practice standards
A global ethical standard for medical research and wasapproved at the WMA General Assembly by a majority voteof 75
It is the mission of the clinical research professionals tosafeguard the health of the people
THE DECLARATION OF HELSINKI-1964
Historical Overview-
Its origin has been found in the Nazi Disaster and hasundergone several modifications
Prior to 1947 Nuremberg Code there was noaccepted code of conduct governing the ethicalaspects of human research
World Medical Association
It is an international organization of physicians
established on September 17 1947
First general Assembly of WMA was held in Paris
France
Mission- Serve humanity by endeavoring to achieve the
highest international standards in medical education
science ethics and health care for all peoples of the world
Declaration of Helsinki 1964
Adapted from Nuremberg
Code by the World Medical Association (WMA)
First adopted in Helsinki Finland 1964
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI- 2008
Ethical Principles for Medical Research Involving Human Subjects
Adopted by the 18th WMA General Assembly Helsinki Finland June 1964 and amended by the
29th WMA General Assembly Tokyo Japan October 1975
35th WMA General Assembly Venice Italy October 1983
41st WMA General Assembly Hong Kong September 1989
53th WMA General Assembly Washington 2002 (Note of Clarification on paragraph 29 added)
55th WMA General Assembly Tokyo 2004 (Note of Clarification on Paragraph 30 added)
59th WMA General Assembly Seoul October 2008
Seven Ethical Pillars of Clinical Research
AUTONOMY
BENEFICENCE
NON ndash MALFEASANCE
FIDELITY
TRUTHFULNESS
CONFIDENTIALITY
JUSTICE
Declaration of Helsinki
Autonomy
Consent
Para 20 The subjects must be volunteers andinformed participants in the research project
Para 22 freely-given informed consent
preferably in writing
Declaration of Helsinki
Para 5 well-being of the human subject shouldtake precedence over the interests of scienceand society
Beneficence
Declaration of Helsinki
Para 16
bull Preceded by careful assessment ofpredictable risks and burdens
bull Attempt to avoid any act or treatmentplan that would harm the patient
Non Malfeasance
Declaration of Helsinki
Para 11
Medical research involving human subjects must be basedon generally accepted scientific principles thoroughknowledge of the scientific literature and on adequatelaboratory and where appropriate animalexperimentation
Para 15
Conducted only by clinically competent medical person
Fidelity ndash duty of care
Declaration of Helsinki
Para 27
Both authors amp investigators are obliged topreserve the accuracy of the results Negativeas well as positive results should be published
Truthfulness - Honesty
Declaration of Helsinki
Para 21
Every precaution should be taken torespect the privacy of the subject theconfidentiality of the patients information
Confidentiality
Declaration of Helsinki
Para 30
Every patient entered into the study should be assured ofaccess to the best proven prophylactic diagnostic andtherapeutic methods identified by the study
Para 9
Research Investigators should be aware of the ethicallegal and regulatory requirements for research on humansubjects
Para 17
Physicians should cease any investigation if the risksoutweigh the potential benefits
Justice
DECLARATION OF HELSINKI -Basic Principles
1 Conform to accepted scientific principles
2 Design formulated in experimental protocol reviewed by IEC
3 Conducted by qualified and trained persons
4 Importance in proportion to inherent risk
5 Assessment of risks vs benefits
6 Safeguard subjectrsquos integrity (privacy)
7 Abstain unless hazards are predictable
8 Preserve accuracy when publishing
9 Adequately inform or right to withdraw
10 Obtain true informed consent in writing
11 Reliance on legal guardian
12 State compliance with Declaration
Ethical Principles and Guidelines for the Protection of Human Subjects of Research
bull Tuskegee Syphilis Study (1932ndash1972)
bull Named the Belmont Report for the Belmont Conference Center where the National Commission met when first drafting the report
42
Belmont Report 1979
Belmont Report 1979
Three ethical principles related to research on human subjects
1 Respect for Persons
2 Beneficence Do no harm while maximizing benefits for research project and minimizing risks to the research subjects
3 Justice ensuring reasonable non-exploitative and well-considered procedures are administered
Overview of
ICH GCP
What is ICH
bull The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)- is unique in bringing together the regulatory authorities and pharmaceutical industry of Europe Japan and the US to discuss scientific and technical aspects of drug registration
45
What is ICH
bull Since its inception in 1990 ICH has
gradually evolved
bull ICHs mission is to ensure that safe
effective and high quality medicines are
developed and registered in the most
resource-efficient manner
How did it evolve
The need to harmonize
bull Public disasters serious fraud and abuse of human rights
bull Trials of War criminals-Nuremberg code 1949
bull Thalidomide- Declaration of Helsinki 1964
bull Belmont report 1978 (Ethical Principles and guidelines for the protection of human subjects of research)-Tuskegee syphilis study
History
1962 US FDA IND Guidelines
1964 Declaration of Helsinki
1968 Committee on Safety of Medicines uk
1978 GCP US FDA
1991 GCP Europe
1996 ICH GCP
1997 ICH GCP Guideline
When did it begin
bull Ist conf in 1990 in Brussels
3 regions participated
bull Representatives from
Industry
Academia
Ministry of
health
ICH parties
6 parties
bull EU bull EFPIA European federation of pharmaceutical industriesrsquo associations
bull MHLW Ministry of health Labor and welfare Japan
bull JPMA Japan Pharmaceuticals manufacturers Association
bull US FDA
bull PhRMA
bull Observers WHO TPP(canada)
bull International federation of Pharmaceutical manufacturerrsquos association
Key objective
bull To discuss and define the minimum standards for the development and registration of investigational products
The result
Many guidelines made
bull Most important- ICH GCP guidelines
bull Evolved in several steps
bull Consolidated guideline ICH E6 Sept 1997
ICH Guidelines examples
bull Efficacy ndash clinical trials etc
bull Safety ndash pharmacovigilance adverse drug reaction
reporting
bull Quality ndash raw materials impurities residual solvents etc
bull Multidisciplinary ndash common technical document electronic
submission coding systems
What is GCP
A standard for the design conduct performance monitoring auditing recording analyses and reporting of clinical trials that provide assurance that the data and the reported results are credible accurate and that the rights integrity and confidentiality of trial subjects are protected
Why is it needed
bull To ensure the rights safety and well being of the trial subjects are protected
bull Ensure the credibility of clinical trial data
The ICH GCP guideline
bull Provide a unified standard for the EU Japan and USA regions to facilitate mutual acceptance of clinical trial data by the regulatory authorities in
these regions
bull 8 sections
ICH GCP guideline
1 Glossary
Common language for investigatorssponsorsethics committees
2Principles of Good Clinical Practice
13 tenets of ICH GCP
3Requirements for IRBIEC
Roles responsibilities and composition
ICH GCP guideline
4Responsibilities of the investigator
5Responsibilities of the sponsor
6Requirements for clinical trial protocol and protocol amendments
7Responsibility of the sponsor in the development of investigatorrsquos brochure
8Essential documents
Principles of ICH GCP
bull Ethical conduct as per
Declaration of Helsinki
GCP
Regulatory Requirements
Risk- Benefit
Primary concern- Subject
Principles of ICH GCP
bull Supportive data
bull Protocol
Scientifically sound clear detailed
bull Ethical Clearance
Study to be conducted in compliance to the protocol which has received EC approval
Principles of ICH GCP
bull Subject Care
Medical decisions responsibility of qualified physician
bull Qualified staff
By education training experience in their area of responsibility
bull Informed Consent
Principles of ICH GCP
bull Clinical Trial data
Recorded handled and stored to enable accurate reporting interpretation and verification
bull Confidentiality
Principles of ICH GCP
bull Investigational Product
Manufactured handled and stored as per GMP
Principles of ICH GCP
bull Quality Assurance
Systems and procedures to ensure the Quality of every aspect of the trial
Indian GCP guidelines
bull Released in Dec 2001(Developed by CDCSO and endorsed by DCGI)
bull In general in line with ICH GCP
bull Has Revised Schedule Y (Jan 2005) addressed discrepancies
bull SAFEGUARD PUBLIC HEALTH
bull ASSURE CONSUMER PROTECTION STANDARDS
bull FACILITATE AVAILABILITY OF SAFE AND EFFECTIVE PRODUCTS
bull ELIMINATE INCONSISTENT STANDARDS INTERNATIONALLY
bull FACILITATE MUTUAL ACCEPTANCE OF DATA FROM CLINICAL TRIALS
GOALS OF INTERNATIONAL HARMONIZATION OF
REGULATORY REQUIREMENTS
Study DocumentationDuring the study
The investigator must keepndash Source documents
bull Medical records (including access to computer records)
bull Laboratory reports
bull ECGs X-rays etc
bull Any other medical records reports or notes (hospital admissions and discharges)
ndash A subject identification list
ndash Copies of all study related documentation
Medical Records
bull In particular they should contain notes on
ndash Sufficient information to support subject eligibility
ndash This should be well documented (signed and dated)
ndash Subjectrsquos participation in the study
ndash Dates of visits
ndash Procedures investigations done
ndash Observations diagnoses
ndash Medications taken (including study medication)
ndash Adverse events
ndash Completion or withdrawal (reason) from the study
Study DocumentationAfter the study
The sponsor needs from the investigator
ndash Final drug accountability records
ndash All used and unused supplies and medication
ndash All required documents completed
Conclusion
70
Thanks
ldquoWhen a doctor [goes] wrong he is
the first of criminals He has nerve
and he has knowledgerdquo
- Sherlock Holmes
References
httpwwwwmanetepolicyb3htm
wwwhhsgovohrphumansubjectsguidancebelmonthtml
wwwhhsgovohrpreferencesnurcodehtml
wwwicmrnicinguidelinesGCLP
wwwcdsconicin
wwwubedurecercaBioeticadocDeclaracio_Helsinki_2013
wwwjewishvirtuallibraryorgjsourceHolocaustnazi_experiments
wwwichorgfileadminPublic_WebICHE6_R1__Guideline
The Willowbrook Study
bull Institutionalized children as participants in research is demonstrated in a series of studies conducted from 1963 through 1966 at the Willowbrook State School a New York institution for mentally defective children
bull In order to gain an understanding of the natural history of infectious hepatitis under controlled circumstances newly admitted children were deliberately infected with the hepatitis virus
bull In some cases parents found they were unable to admit their children to Willowbrook unless they agreed to their childrsquos participation in the studies
The Willowbrook Study
This controversial case raised important questions about the adequacy and freedom of consent inadequate disclosure of the childs risk of later developing chronic liver disease
The Milgram Study
bull The lsquoteachersrsquo were instructed to give the lsquolearnersrsquo electrical shocks in response to incorrect answers on verbally given lsquotestsrsquo
bull Participants were deceived as to the nature of the study being told it was to test new teaching-learning techniques
Thalidomide tragedy
bull Thalidomide was a widely used drug in the late 1950s and early 1960s for the treatment of nausea in pregnant women
bull It became apparent in the 1960s that thalidomide treatment resulted in severe birth defects in thousands of children
21
bull Within a few years of the widespread use of thalidomide in Europe Australia and Japan approximately 10000 children were born with phocomelia leading to the ban of thalidomide in most countries in 1961
22
bull The thalidomide tragedy marked a turning point in toxicity testing as it prompted United States and international regulatory agencies to develop systematic toxicity testing protocols
bull The thalidomide tragedy also brought into sharp focus the importance of rigorous and relevant testing of pharmaceuticals prior to their introduction into the market place (Kelsey 1988)
23
Thalidomide tragedy
Nuremberg Code-1947
bull On April 17 1947 United States Counsel for War Crimescame out with six points defining ldquolegitimate researchrdquo
bull The verdict of August 19 reiterated almost all of thesepoints in a section entitled Permissible MedicalExperiments and revised the original six points into ten
bull Subsequently the ten points became known as theNuremberg Code
24
Codes and Guidelines
Nuremberg Code (1947)
WMArsquos Declaration of Helsinki (1964)
bull Belmont Report (USA) (1979)-Tuskegee syphilis study
Council for International Organizations of Medical Sciences (CIOMS) 1993
International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) in 1996 Guideline on Good Clinical PracticeE6 (GCP)
Nuremberg Code (1947)
Voluntary and Informed consent-absolutely essential
Anticipate scientific benefits Useful
Animal experimentation first
Avoid physical and mental suffering
Benefits outweigh risks
No intentional death or disability
Protection from harm
Subject free to withdraw
Qualified investigators
Investigator will stop if harm occurs
THE DECLARATION OF HELSINKI-1964
Is an international standard for the conduct of clinicalresearch adopted by International Conference onHarmonization(ICH) Good Clinical Practice standards
A global ethical standard for medical research and wasapproved at the WMA General Assembly by a majority voteof 75
It is the mission of the clinical research professionals tosafeguard the health of the people
THE DECLARATION OF HELSINKI-1964
Historical Overview-
Its origin has been found in the Nazi Disaster and hasundergone several modifications
Prior to 1947 Nuremberg Code there was noaccepted code of conduct governing the ethicalaspects of human research
World Medical Association
It is an international organization of physicians
established on September 17 1947
First general Assembly of WMA was held in Paris
France
Mission- Serve humanity by endeavoring to achieve the
highest international standards in medical education
science ethics and health care for all peoples of the world
Declaration of Helsinki 1964
Adapted from Nuremberg
Code by the World Medical Association (WMA)
First adopted in Helsinki Finland 1964
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI- 2008
Ethical Principles for Medical Research Involving Human Subjects
Adopted by the 18th WMA General Assembly Helsinki Finland June 1964 and amended by the
29th WMA General Assembly Tokyo Japan October 1975
35th WMA General Assembly Venice Italy October 1983
41st WMA General Assembly Hong Kong September 1989
53th WMA General Assembly Washington 2002 (Note of Clarification on paragraph 29 added)
55th WMA General Assembly Tokyo 2004 (Note of Clarification on Paragraph 30 added)
59th WMA General Assembly Seoul October 2008
Seven Ethical Pillars of Clinical Research
AUTONOMY
BENEFICENCE
NON ndash MALFEASANCE
FIDELITY
TRUTHFULNESS
CONFIDENTIALITY
JUSTICE
Declaration of Helsinki
Autonomy
Consent
Para 20 The subjects must be volunteers andinformed participants in the research project
Para 22 freely-given informed consent
preferably in writing
Declaration of Helsinki
Para 5 well-being of the human subject shouldtake precedence over the interests of scienceand society
Beneficence
Declaration of Helsinki
Para 16
bull Preceded by careful assessment ofpredictable risks and burdens
bull Attempt to avoid any act or treatmentplan that would harm the patient
Non Malfeasance
Declaration of Helsinki
Para 11
Medical research involving human subjects must be basedon generally accepted scientific principles thoroughknowledge of the scientific literature and on adequatelaboratory and where appropriate animalexperimentation
Para 15
Conducted only by clinically competent medical person
Fidelity ndash duty of care
Declaration of Helsinki
Para 27
Both authors amp investigators are obliged topreserve the accuracy of the results Negativeas well as positive results should be published
Truthfulness - Honesty
Declaration of Helsinki
Para 21
Every precaution should be taken torespect the privacy of the subject theconfidentiality of the patients information
Confidentiality
Declaration of Helsinki
Para 30
Every patient entered into the study should be assured ofaccess to the best proven prophylactic diagnostic andtherapeutic methods identified by the study
Para 9
Research Investigators should be aware of the ethicallegal and regulatory requirements for research on humansubjects
Para 17
Physicians should cease any investigation if the risksoutweigh the potential benefits
Justice
DECLARATION OF HELSINKI -Basic Principles
1 Conform to accepted scientific principles
2 Design formulated in experimental protocol reviewed by IEC
3 Conducted by qualified and trained persons
4 Importance in proportion to inherent risk
5 Assessment of risks vs benefits
6 Safeguard subjectrsquos integrity (privacy)
7 Abstain unless hazards are predictable
8 Preserve accuracy when publishing
9 Adequately inform or right to withdraw
10 Obtain true informed consent in writing
11 Reliance on legal guardian
12 State compliance with Declaration
Ethical Principles and Guidelines for the Protection of Human Subjects of Research
bull Tuskegee Syphilis Study (1932ndash1972)
bull Named the Belmont Report for the Belmont Conference Center where the National Commission met when first drafting the report
42
Belmont Report 1979
Belmont Report 1979
Three ethical principles related to research on human subjects
1 Respect for Persons
2 Beneficence Do no harm while maximizing benefits for research project and minimizing risks to the research subjects
3 Justice ensuring reasonable non-exploitative and well-considered procedures are administered
Overview of
ICH GCP
What is ICH
bull The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)- is unique in bringing together the regulatory authorities and pharmaceutical industry of Europe Japan and the US to discuss scientific and technical aspects of drug registration
45
What is ICH
bull Since its inception in 1990 ICH has
gradually evolved
bull ICHs mission is to ensure that safe
effective and high quality medicines are
developed and registered in the most
resource-efficient manner
How did it evolve
The need to harmonize
bull Public disasters serious fraud and abuse of human rights
bull Trials of War criminals-Nuremberg code 1949
bull Thalidomide- Declaration of Helsinki 1964
bull Belmont report 1978 (Ethical Principles and guidelines for the protection of human subjects of research)-Tuskegee syphilis study
History
1962 US FDA IND Guidelines
1964 Declaration of Helsinki
1968 Committee on Safety of Medicines uk
1978 GCP US FDA
1991 GCP Europe
1996 ICH GCP
1997 ICH GCP Guideline
When did it begin
bull Ist conf in 1990 in Brussels
3 regions participated
bull Representatives from
Industry
Academia
Ministry of
health
ICH parties
6 parties
bull EU bull EFPIA European federation of pharmaceutical industriesrsquo associations
bull MHLW Ministry of health Labor and welfare Japan
bull JPMA Japan Pharmaceuticals manufacturers Association
bull US FDA
bull PhRMA
bull Observers WHO TPP(canada)
bull International federation of Pharmaceutical manufacturerrsquos association
Key objective
bull To discuss and define the minimum standards for the development and registration of investigational products
The result
Many guidelines made
bull Most important- ICH GCP guidelines
bull Evolved in several steps
bull Consolidated guideline ICH E6 Sept 1997
ICH Guidelines examples
bull Efficacy ndash clinical trials etc
bull Safety ndash pharmacovigilance adverse drug reaction
reporting
bull Quality ndash raw materials impurities residual solvents etc
bull Multidisciplinary ndash common technical document electronic
submission coding systems
What is GCP
A standard for the design conduct performance monitoring auditing recording analyses and reporting of clinical trials that provide assurance that the data and the reported results are credible accurate and that the rights integrity and confidentiality of trial subjects are protected
Why is it needed
bull To ensure the rights safety and well being of the trial subjects are protected
bull Ensure the credibility of clinical trial data
The ICH GCP guideline
bull Provide a unified standard for the EU Japan and USA regions to facilitate mutual acceptance of clinical trial data by the regulatory authorities in
these regions
bull 8 sections
ICH GCP guideline
1 Glossary
Common language for investigatorssponsorsethics committees
2Principles of Good Clinical Practice
13 tenets of ICH GCP
3Requirements for IRBIEC
Roles responsibilities and composition
ICH GCP guideline
4Responsibilities of the investigator
5Responsibilities of the sponsor
6Requirements for clinical trial protocol and protocol amendments
7Responsibility of the sponsor in the development of investigatorrsquos brochure
8Essential documents
Principles of ICH GCP
bull Ethical conduct as per
Declaration of Helsinki
GCP
Regulatory Requirements
Risk- Benefit
Primary concern- Subject
Principles of ICH GCP
bull Supportive data
bull Protocol
Scientifically sound clear detailed
bull Ethical Clearance
Study to be conducted in compliance to the protocol which has received EC approval
Principles of ICH GCP
bull Subject Care
Medical decisions responsibility of qualified physician
bull Qualified staff
By education training experience in their area of responsibility
bull Informed Consent
Principles of ICH GCP
bull Clinical Trial data
Recorded handled and stored to enable accurate reporting interpretation and verification
bull Confidentiality
Principles of ICH GCP
bull Investigational Product
Manufactured handled and stored as per GMP
Principles of ICH GCP
bull Quality Assurance
Systems and procedures to ensure the Quality of every aspect of the trial
Indian GCP guidelines
bull Released in Dec 2001(Developed by CDCSO and endorsed by DCGI)
bull In general in line with ICH GCP
bull Has Revised Schedule Y (Jan 2005) addressed discrepancies
bull SAFEGUARD PUBLIC HEALTH
bull ASSURE CONSUMER PROTECTION STANDARDS
bull FACILITATE AVAILABILITY OF SAFE AND EFFECTIVE PRODUCTS
bull ELIMINATE INCONSISTENT STANDARDS INTERNATIONALLY
bull FACILITATE MUTUAL ACCEPTANCE OF DATA FROM CLINICAL TRIALS
GOALS OF INTERNATIONAL HARMONIZATION OF
REGULATORY REQUIREMENTS
Study DocumentationDuring the study
The investigator must keepndash Source documents
bull Medical records (including access to computer records)
bull Laboratory reports
bull ECGs X-rays etc
bull Any other medical records reports or notes (hospital admissions and discharges)
ndash A subject identification list
ndash Copies of all study related documentation
Medical Records
bull In particular they should contain notes on
ndash Sufficient information to support subject eligibility
ndash This should be well documented (signed and dated)
ndash Subjectrsquos participation in the study
ndash Dates of visits
ndash Procedures investigations done
ndash Observations diagnoses
ndash Medications taken (including study medication)
ndash Adverse events
ndash Completion or withdrawal (reason) from the study
Study DocumentationAfter the study
The sponsor needs from the investigator
ndash Final drug accountability records
ndash All used and unused supplies and medication
ndash All required documents completed
Conclusion
70
Thanks
ldquoWhen a doctor [goes] wrong he is
the first of criminals He has nerve
and he has knowledgerdquo
- Sherlock Holmes
References
httpwwwwmanetepolicyb3htm
wwwhhsgovohrphumansubjectsguidancebelmonthtml
wwwhhsgovohrpreferencesnurcodehtml
wwwicmrnicinguidelinesGCLP
wwwcdsconicin
wwwubedurecercaBioeticadocDeclaracio_Helsinki_2013
wwwjewishvirtuallibraryorgjsourceHolocaustnazi_experiments
wwwichorgfileadminPublic_WebICHE6_R1__Guideline
The Willowbrook Study
This controversial case raised important questions about the adequacy and freedom of consent inadequate disclosure of the childs risk of later developing chronic liver disease
The Milgram Study
bull The lsquoteachersrsquo were instructed to give the lsquolearnersrsquo electrical shocks in response to incorrect answers on verbally given lsquotestsrsquo
bull Participants were deceived as to the nature of the study being told it was to test new teaching-learning techniques
Thalidomide tragedy
bull Thalidomide was a widely used drug in the late 1950s and early 1960s for the treatment of nausea in pregnant women
bull It became apparent in the 1960s that thalidomide treatment resulted in severe birth defects in thousands of children
21
bull Within a few years of the widespread use of thalidomide in Europe Australia and Japan approximately 10000 children were born with phocomelia leading to the ban of thalidomide in most countries in 1961
22
bull The thalidomide tragedy marked a turning point in toxicity testing as it prompted United States and international regulatory agencies to develop systematic toxicity testing protocols
bull The thalidomide tragedy also brought into sharp focus the importance of rigorous and relevant testing of pharmaceuticals prior to their introduction into the market place (Kelsey 1988)
23
Thalidomide tragedy
Nuremberg Code-1947
bull On April 17 1947 United States Counsel for War Crimescame out with six points defining ldquolegitimate researchrdquo
bull The verdict of August 19 reiterated almost all of thesepoints in a section entitled Permissible MedicalExperiments and revised the original six points into ten
bull Subsequently the ten points became known as theNuremberg Code
24
Codes and Guidelines
Nuremberg Code (1947)
WMArsquos Declaration of Helsinki (1964)
bull Belmont Report (USA) (1979)-Tuskegee syphilis study
Council for International Organizations of Medical Sciences (CIOMS) 1993
International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) in 1996 Guideline on Good Clinical PracticeE6 (GCP)
Nuremberg Code (1947)
Voluntary and Informed consent-absolutely essential
Anticipate scientific benefits Useful
Animal experimentation first
Avoid physical and mental suffering
Benefits outweigh risks
No intentional death or disability
Protection from harm
Subject free to withdraw
Qualified investigators
Investigator will stop if harm occurs
THE DECLARATION OF HELSINKI-1964
Is an international standard for the conduct of clinicalresearch adopted by International Conference onHarmonization(ICH) Good Clinical Practice standards
A global ethical standard for medical research and wasapproved at the WMA General Assembly by a majority voteof 75
It is the mission of the clinical research professionals tosafeguard the health of the people
THE DECLARATION OF HELSINKI-1964
Historical Overview-
Its origin has been found in the Nazi Disaster and hasundergone several modifications
Prior to 1947 Nuremberg Code there was noaccepted code of conduct governing the ethicalaspects of human research
World Medical Association
It is an international organization of physicians
established on September 17 1947
First general Assembly of WMA was held in Paris
France
Mission- Serve humanity by endeavoring to achieve the
highest international standards in medical education
science ethics and health care for all peoples of the world
Declaration of Helsinki 1964
Adapted from Nuremberg
Code by the World Medical Association (WMA)
First adopted in Helsinki Finland 1964
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI- 2008
Ethical Principles for Medical Research Involving Human Subjects
Adopted by the 18th WMA General Assembly Helsinki Finland June 1964 and amended by the
29th WMA General Assembly Tokyo Japan October 1975
35th WMA General Assembly Venice Italy October 1983
41st WMA General Assembly Hong Kong September 1989
53th WMA General Assembly Washington 2002 (Note of Clarification on paragraph 29 added)
55th WMA General Assembly Tokyo 2004 (Note of Clarification on Paragraph 30 added)
59th WMA General Assembly Seoul October 2008
Seven Ethical Pillars of Clinical Research
AUTONOMY
BENEFICENCE
NON ndash MALFEASANCE
FIDELITY
TRUTHFULNESS
CONFIDENTIALITY
JUSTICE
Declaration of Helsinki
Autonomy
Consent
Para 20 The subjects must be volunteers andinformed participants in the research project
Para 22 freely-given informed consent
preferably in writing
Declaration of Helsinki
Para 5 well-being of the human subject shouldtake precedence over the interests of scienceand society
Beneficence
Declaration of Helsinki
Para 16
bull Preceded by careful assessment ofpredictable risks and burdens
bull Attempt to avoid any act or treatmentplan that would harm the patient
Non Malfeasance
Declaration of Helsinki
Para 11
Medical research involving human subjects must be basedon generally accepted scientific principles thoroughknowledge of the scientific literature and on adequatelaboratory and where appropriate animalexperimentation
Para 15
Conducted only by clinically competent medical person
Fidelity ndash duty of care
Declaration of Helsinki
Para 27
Both authors amp investigators are obliged topreserve the accuracy of the results Negativeas well as positive results should be published
Truthfulness - Honesty
Declaration of Helsinki
Para 21
Every precaution should be taken torespect the privacy of the subject theconfidentiality of the patients information
Confidentiality
Declaration of Helsinki
Para 30
Every patient entered into the study should be assured ofaccess to the best proven prophylactic diagnostic andtherapeutic methods identified by the study
Para 9
Research Investigators should be aware of the ethicallegal and regulatory requirements for research on humansubjects
Para 17
Physicians should cease any investigation if the risksoutweigh the potential benefits
Justice
DECLARATION OF HELSINKI -Basic Principles
1 Conform to accepted scientific principles
2 Design formulated in experimental protocol reviewed by IEC
3 Conducted by qualified and trained persons
4 Importance in proportion to inherent risk
5 Assessment of risks vs benefits
6 Safeguard subjectrsquos integrity (privacy)
7 Abstain unless hazards are predictable
8 Preserve accuracy when publishing
9 Adequately inform or right to withdraw
10 Obtain true informed consent in writing
11 Reliance on legal guardian
12 State compliance with Declaration
Ethical Principles and Guidelines for the Protection of Human Subjects of Research
bull Tuskegee Syphilis Study (1932ndash1972)
bull Named the Belmont Report for the Belmont Conference Center where the National Commission met when first drafting the report
42
Belmont Report 1979
Belmont Report 1979
Three ethical principles related to research on human subjects
1 Respect for Persons
2 Beneficence Do no harm while maximizing benefits for research project and minimizing risks to the research subjects
3 Justice ensuring reasonable non-exploitative and well-considered procedures are administered
Overview of
ICH GCP
What is ICH
bull The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)- is unique in bringing together the regulatory authorities and pharmaceutical industry of Europe Japan and the US to discuss scientific and technical aspects of drug registration
45
What is ICH
bull Since its inception in 1990 ICH has
gradually evolved
bull ICHs mission is to ensure that safe
effective and high quality medicines are
developed and registered in the most
resource-efficient manner
How did it evolve
The need to harmonize
bull Public disasters serious fraud and abuse of human rights
bull Trials of War criminals-Nuremberg code 1949
bull Thalidomide- Declaration of Helsinki 1964
bull Belmont report 1978 (Ethical Principles and guidelines for the protection of human subjects of research)-Tuskegee syphilis study
History
1962 US FDA IND Guidelines
1964 Declaration of Helsinki
1968 Committee on Safety of Medicines uk
1978 GCP US FDA
1991 GCP Europe
1996 ICH GCP
1997 ICH GCP Guideline
When did it begin
bull Ist conf in 1990 in Brussels
3 regions participated
bull Representatives from
Industry
Academia
Ministry of
health
ICH parties
6 parties
bull EU bull EFPIA European federation of pharmaceutical industriesrsquo associations
bull MHLW Ministry of health Labor and welfare Japan
bull JPMA Japan Pharmaceuticals manufacturers Association
bull US FDA
bull PhRMA
bull Observers WHO TPP(canada)
bull International federation of Pharmaceutical manufacturerrsquos association
Key objective
bull To discuss and define the minimum standards for the development and registration of investigational products
The result
Many guidelines made
bull Most important- ICH GCP guidelines
bull Evolved in several steps
bull Consolidated guideline ICH E6 Sept 1997
ICH Guidelines examples
bull Efficacy ndash clinical trials etc
bull Safety ndash pharmacovigilance adverse drug reaction
reporting
bull Quality ndash raw materials impurities residual solvents etc
bull Multidisciplinary ndash common technical document electronic
submission coding systems
What is GCP
A standard for the design conduct performance monitoring auditing recording analyses and reporting of clinical trials that provide assurance that the data and the reported results are credible accurate and that the rights integrity and confidentiality of trial subjects are protected
Why is it needed
bull To ensure the rights safety and well being of the trial subjects are protected
bull Ensure the credibility of clinical trial data
The ICH GCP guideline
bull Provide a unified standard for the EU Japan and USA regions to facilitate mutual acceptance of clinical trial data by the regulatory authorities in
these regions
bull 8 sections
ICH GCP guideline
1 Glossary
Common language for investigatorssponsorsethics committees
2Principles of Good Clinical Practice
13 tenets of ICH GCP
3Requirements for IRBIEC
Roles responsibilities and composition
ICH GCP guideline
4Responsibilities of the investigator
5Responsibilities of the sponsor
6Requirements for clinical trial protocol and protocol amendments
7Responsibility of the sponsor in the development of investigatorrsquos brochure
8Essential documents
Principles of ICH GCP
bull Ethical conduct as per
Declaration of Helsinki
GCP
Regulatory Requirements
Risk- Benefit
Primary concern- Subject
Principles of ICH GCP
bull Supportive data
bull Protocol
Scientifically sound clear detailed
bull Ethical Clearance
Study to be conducted in compliance to the protocol which has received EC approval
Principles of ICH GCP
bull Subject Care
Medical decisions responsibility of qualified physician
bull Qualified staff
By education training experience in their area of responsibility
bull Informed Consent
Principles of ICH GCP
bull Clinical Trial data
Recorded handled and stored to enable accurate reporting interpretation and verification
bull Confidentiality
Principles of ICH GCP
bull Investigational Product
Manufactured handled and stored as per GMP
Principles of ICH GCP
bull Quality Assurance
Systems and procedures to ensure the Quality of every aspect of the trial
Indian GCP guidelines
bull Released in Dec 2001(Developed by CDCSO and endorsed by DCGI)
bull In general in line with ICH GCP
bull Has Revised Schedule Y (Jan 2005) addressed discrepancies
bull SAFEGUARD PUBLIC HEALTH
bull ASSURE CONSUMER PROTECTION STANDARDS
bull FACILITATE AVAILABILITY OF SAFE AND EFFECTIVE PRODUCTS
bull ELIMINATE INCONSISTENT STANDARDS INTERNATIONALLY
bull FACILITATE MUTUAL ACCEPTANCE OF DATA FROM CLINICAL TRIALS
GOALS OF INTERNATIONAL HARMONIZATION OF
REGULATORY REQUIREMENTS
Study DocumentationDuring the study
The investigator must keepndash Source documents
bull Medical records (including access to computer records)
bull Laboratory reports
bull ECGs X-rays etc
bull Any other medical records reports or notes (hospital admissions and discharges)
ndash A subject identification list
ndash Copies of all study related documentation
Medical Records
bull In particular they should contain notes on
ndash Sufficient information to support subject eligibility
ndash This should be well documented (signed and dated)
ndash Subjectrsquos participation in the study
ndash Dates of visits
ndash Procedures investigations done
ndash Observations diagnoses
ndash Medications taken (including study medication)
ndash Adverse events
ndash Completion or withdrawal (reason) from the study
Study DocumentationAfter the study
The sponsor needs from the investigator
ndash Final drug accountability records
ndash All used and unused supplies and medication
ndash All required documents completed
Conclusion
70
Thanks
ldquoWhen a doctor [goes] wrong he is
the first of criminals He has nerve
and he has knowledgerdquo
- Sherlock Holmes
References
httpwwwwmanetepolicyb3htm
wwwhhsgovohrphumansubjectsguidancebelmonthtml
wwwhhsgovohrpreferencesnurcodehtml
wwwicmrnicinguidelinesGCLP
wwwcdsconicin
wwwubedurecercaBioeticadocDeclaracio_Helsinki_2013
wwwjewishvirtuallibraryorgjsourceHolocaustnazi_experiments
wwwichorgfileadminPublic_WebICHE6_R1__Guideline
The Milgram Study
bull The lsquoteachersrsquo were instructed to give the lsquolearnersrsquo electrical shocks in response to incorrect answers on verbally given lsquotestsrsquo
bull Participants were deceived as to the nature of the study being told it was to test new teaching-learning techniques
Thalidomide tragedy
bull Thalidomide was a widely used drug in the late 1950s and early 1960s for the treatment of nausea in pregnant women
bull It became apparent in the 1960s that thalidomide treatment resulted in severe birth defects in thousands of children
21
bull Within a few years of the widespread use of thalidomide in Europe Australia and Japan approximately 10000 children were born with phocomelia leading to the ban of thalidomide in most countries in 1961
22
bull The thalidomide tragedy marked a turning point in toxicity testing as it prompted United States and international regulatory agencies to develop systematic toxicity testing protocols
bull The thalidomide tragedy also brought into sharp focus the importance of rigorous and relevant testing of pharmaceuticals prior to their introduction into the market place (Kelsey 1988)
23
Thalidomide tragedy
Nuremberg Code-1947
bull On April 17 1947 United States Counsel for War Crimescame out with six points defining ldquolegitimate researchrdquo
bull The verdict of August 19 reiterated almost all of thesepoints in a section entitled Permissible MedicalExperiments and revised the original six points into ten
bull Subsequently the ten points became known as theNuremberg Code
24
Codes and Guidelines
Nuremberg Code (1947)
WMArsquos Declaration of Helsinki (1964)
bull Belmont Report (USA) (1979)-Tuskegee syphilis study
Council for International Organizations of Medical Sciences (CIOMS) 1993
International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) in 1996 Guideline on Good Clinical PracticeE6 (GCP)
Nuremberg Code (1947)
Voluntary and Informed consent-absolutely essential
Anticipate scientific benefits Useful
Animal experimentation first
Avoid physical and mental suffering
Benefits outweigh risks
No intentional death or disability
Protection from harm
Subject free to withdraw
Qualified investigators
Investigator will stop if harm occurs
THE DECLARATION OF HELSINKI-1964
Is an international standard for the conduct of clinicalresearch adopted by International Conference onHarmonization(ICH) Good Clinical Practice standards
A global ethical standard for medical research and wasapproved at the WMA General Assembly by a majority voteof 75
It is the mission of the clinical research professionals tosafeguard the health of the people
THE DECLARATION OF HELSINKI-1964
Historical Overview-
Its origin has been found in the Nazi Disaster and hasundergone several modifications
Prior to 1947 Nuremberg Code there was noaccepted code of conduct governing the ethicalaspects of human research
World Medical Association
It is an international organization of physicians
established on September 17 1947
First general Assembly of WMA was held in Paris
France
Mission- Serve humanity by endeavoring to achieve the
highest international standards in medical education
science ethics and health care for all peoples of the world
Declaration of Helsinki 1964
Adapted from Nuremberg
Code by the World Medical Association (WMA)
First adopted in Helsinki Finland 1964
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI- 2008
Ethical Principles for Medical Research Involving Human Subjects
Adopted by the 18th WMA General Assembly Helsinki Finland June 1964 and amended by the
29th WMA General Assembly Tokyo Japan October 1975
35th WMA General Assembly Venice Italy October 1983
41st WMA General Assembly Hong Kong September 1989
53th WMA General Assembly Washington 2002 (Note of Clarification on paragraph 29 added)
55th WMA General Assembly Tokyo 2004 (Note of Clarification on Paragraph 30 added)
59th WMA General Assembly Seoul October 2008
Seven Ethical Pillars of Clinical Research
AUTONOMY
BENEFICENCE
NON ndash MALFEASANCE
FIDELITY
TRUTHFULNESS
CONFIDENTIALITY
JUSTICE
Declaration of Helsinki
Autonomy
Consent
Para 20 The subjects must be volunteers andinformed participants in the research project
Para 22 freely-given informed consent
preferably in writing
Declaration of Helsinki
Para 5 well-being of the human subject shouldtake precedence over the interests of scienceand society
Beneficence
Declaration of Helsinki
Para 16
bull Preceded by careful assessment ofpredictable risks and burdens
bull Attempt to avoid any act or treatmentplan that would harm the patient
Non Malfeasance
Declaration of Helsinki
Para 11
Medical research involving human subjects must be basedon generally accepted scientific principles thoroughknowledge of the scientific literature and on adequatelaboratory and where appropriate animalexperimentation
Para 15
Conducted only by clinically competent medical person
Fidelity ndash duty of care
Declaration of Helsinki
Para 27
Both authors amp investigators are obliged topreserve the accuracy of the results Negativeas well as positive results should be published
Truthfulness - Honesty
Declaration of Helsinki
Para 21
Every precaution should be taken torespect the privacy of the subject theconfidentiality of the patients information
Confidentiality
Declaration of Helsinki
Para 30
Every patient entered into the study should be assured ofaccess to the best proven prophylactic diagnostic andtherapeutic methods identified by the study
Para 9
Research Investigators should be aware of the ethicallegal and regulatory requirements for research on humansubjects
Para 17
Physicians should cease any investigation if the risksoutweigh the potential benefits
Justice
DECLARATION OF HELSINKI -Basic Principles
1 Conform to accepted scientific principles
2 Design formulated in experimental protocol reviewed by IEC
3 Conducted by qualified and trained persons
4 Importance in proportion to inherent risk
5 Assessment of risks vs benefits
6 Safeguard subjectrsquos integrity (privacy)
7 Abstain unless hazards are predictable
8 Preserve accuracy when publishing
9 Adequately inform or right to withdraw
10 Obtain true informed consent in writing
11 Reliance on legal guardian
12 State compliance with Declaration
Ethical Principles and Guidelines for the Protection of Human Subjects of Research
bull Tuskegee Syphilis Study (1932ndash1972)
bull Named the Belmont Report for the Belmont Conference Center where the National Commission met when first drafting the report
42
Belmont Report 1979
Belmont Report 1979
Three ethical principles related to research on human subjects
1 Respect for Persons
2 Beneficence Do no harm while maximizing benefits for research project and minimizing risks to the research subjects
3 Justice ensuring reasonable non-exploitative and well-considered procedures are administered
Overview of
ICH GCP
What is ICH
bull The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)- is unique in bringing together the regulatory authorities and pharmaceutical industry of Europe Japan and the US to discuss scientific and technical aspects of drug registration
45
What is ICH
bull Since its inception in 1990 ICH has
gradually evolved
bull ICHs mission is to ensure that safe
effective and high quality medicines are
developed and registered in the most
resource-efficient manner
How did it evolve
The need to harmonize
bull Public disasters serious fraud and abuse of human rights
bull Trials of War criminals-Nuremberg code 1949
bull Thalidomide- Declaration of Helsinki 1964
bull Belmont report 1978 (Ethical Principles and guidelines for the protection of human subjects of research)-Tuskegee syphilis study
History
1962 US FDA IND Guidelines
1964 Declaration of Helsinki
1968 Committee on Safety of Medicines uk
1978 GCP US FDA
1991 GCP Europe
1996 ICH GCP
1997 ICH GCP Guideline
When did it begin
bull Ist conf in 1990 in Brussels
3 regions participated
bull Representatives from
Industry
Academia
Ministry of
health
ICH parties
6 parties
bull EU bull EFPIA European federation of pharmaceutical industriesrsquo associations
bull MHLW Ministry of health Labor and welfare Japan
bull JPMA Japan Pharmaceuticals manufacturers Association
bull US FDA
bull PhRMA
bull Observers WHO TPP(canada)
bull International federation of Pharmaceutical manufacturerrsquos association
Key objective
bull To discuss and define the minimum standards for the development and registration of investigational products
The result
Many guidelines made
bull Most important- ICH GCP guidelines
bull Evolved in several steps
bull Consolidated guideline ICH E6 Sept 1997
ICH Guidelines examples
bull Efficacy ndash clinical trials etc
bull Safety ndash pharmacovigilance adverse drug reaction
reporting
bull Quality ndash raw materials impurities residual solvents etc
bull Multidisciplinary ndash common technical document electronic
submission coding systems
What is GCP
A standard for the design conduct performance monitoring auditing recording analyses and reporting of clinical trials that provide assurance that the data and the reported results are credible accurate and that the rights integrity and confidentiality of trial subjects are protected
Why is it needed
bull To ensure the rights safety and well being of the trial subjects are protected
bull Ensure the credibility of clinical trial data
The ICH GCP guideline
bull Provide a unified standard for the EU Japan and USA regions to facilitate mutual acceptance of clinical trial data by the regulatory authorities in
these regions
bull 8 sections
ICH GCP guideline
1 Glossary
Common language for investigatorssponsorsethics committees
2Principles of Good Clinical Practice
13 tenets of ICH GCP
3Requirements for IRBIEC
Roles responsibilities and composition
ICH GCP guideline
4Responsibilities of the investigator
5Responsibilities of the sponsor
6Requirements for clinical trial protocol and protocol amendments
7Responsibility of the sponsor in the development of investigatorrsquos brochure
8Essential documents
Principles of ICH GCP
bull Ethical conduct as per
Declaration of Helsinki
GCP
Regulatory Requirements
Risk- Benefit
Primary concern- Subject
Principles of ICH GCP
bull Supportive data
bull Protocol
Scientifically sound clear detailed
bull Ethical Clearance
Study to be conducted in compliance to the protocol which has received EC approval
Principles of ICH GCP
bull Subject Care
Medical decisions responsibility of qualified physician
bull Qualified staff
By education training experience in their area of responsibility
bull Informed Consent
Principles of ICH GCP
bull Clinical Trial data
Recorded handled and stored to enable accurate reporting interpretation and verification
bull Confidentiality
Principles of ICH GCP
bull Investigational Product
Manufactured handled and stored as per GMP
Principles of ICH GCP
bull Quality Assurance
Systems and procedures to ensure the Quality of every aspect of the trial
Indian GCP guidelines
bull Released in Dec 2001(Developed by CDCSO and endorsed by DCGI)
bull In general in line with ICH GCP
bull Has Revised Schedule Y (Jan 2005) addressed discrepancies
bull SAFEGUARD PUBLIC HEALTH
bull ASSURE CONSUMER PROTECTION STANDARDS
bull FACILITATE AVAILABILITY OF SAFE AND EFFECTIVE PRODUCTS
bull ELIMINATE INCONSISTENT STANDARDS INTERNATIONALLY
bull FACILITATE MUTUAL ACCEPTANCE OF DATA FROM CLINICAL TRIALS
GOALS OF INTERNATIONAL HARMONIZATION OF
REGULATORY REQUIREMENTS
Study DocumentationDuring the study
The investigator must keepndash Source documents
bull Medical records (including access to computer records)
bull Laboratory reports
bull ECGs X-rays etc
bull Any other medical records reports or notes (hospital admissions and discharges)
ndash A subject identification list
ndash Copies of all study related documentation
Medical Records
bull In particular they should contain notes on
ndash Sufficient information to support subject eligibility
ndash This should be well documented (signed and dated)
ndash Subjectrsquos participation in the study
ndash Dates of visits
ndash Procedures investigations done
ndash Observations diagnoses
ndash Medications taken (including study medication)
ndash Adverse events
ndash Completion or withdrawal (reason) from the study
Study DocumentationAfter the study
The sponsor needs from the investigator
ndash Final drug accountability records
ndash All used and unused supplies and medication
ndash All required documents completed
Conclusion
70
Thanks
ldquoWhen a doctor [goes] wrong he is
the first of criminals He has nerve
and he has knowledgerdquo
- Sherlock Holmes
References
httpwwwwmanetepolicyb3htm
wwwhhsgovohrphumansubjectsguidancebelmonthtml
wwwhhsgovohrpreferencesnurcodehtml
wwwicmrnicinguidelinesGCLP
wwwcdsconicin
wwwubedurecercaBioeticadocDeclaracio_Helsinki_2013
wwwjewishvirtuallibraryorgjsourceHolocaustnazi_experiments
wwwichorgfileadminPublic_WebICHE6_R1__Guideline
Thalidomide tragedy
bull Thalidomide was a widely used drug in the late 1950s and early 1960s for the treatment of nausea in pregnant women
bull It became apparent in the 1960s that thalidomide treatment resulted in severe birth defects in thousands of children
21
bull Within a few years of the widespread use of thalidomide in Europe Australia and Japan approximately 10000 children were born with phocomelia leading to the ban of thalidomide in most countries in 1961
22
bull The thalidomide tragedy marked a turning point in toxicity testing as it prompted United States and international regulatory agencies to develop systematic toxicity testing protocols
bull The thalidomide tragedy also brought into sharp focus the importance of rigorous and relevant testing of pharmaceuticals prior to their introduction into the market place (Kelsey 1988)
23
Thalidomide tragedy
Nuremberg Code-1947
bull On April 17 1947 United States Counsel for War Crimescame out with six points defining ldquolegitimate researchrdquo
bull The verdict of August 19 reiterated almost all of thesepoints in a section entitled Permissible MedicalExperiments and revised the original six points into ten
bull Subsequently the ten points became known as theNuremberg Code
24
Codes and Guidelines
Nuremberg Code (1947)
WMArsquos Declaration of Helsinki (1964)
bull Belmont Report (USA) (1979)-Tuskegee syphilis study
Council for International Organizations of Medical Sciences (CIOMS) 1993
International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) in 1996 Guideline on Good Clinical PracticeE6 (GCP)
Nuremberg Code (1947)
Voluntary and Informed consent-absolutely essential
Anticipate scientific benefits Useful
Animal experimentation first
Avoid physical and mental suffering
Benefits outweigh risks
No intentional death or disability
Protection from harm
Subject free to withdraw
Qualified investigators
Investigator will stop if harm occurs
THE DECLARATION OF HELSINKI-1964
Is an international standard for the conduct of clinicalresearch adopted by International Conference onHarmonization(ICH) Good Clinical Practice standards
A global ethical standard for medical research and wasapproved at the WMA General Assembly by a majority voteof 75
It is the mission of the clinical research professionals tosafeguard the health of the people
THE DECLARATION OF HELSINKI-1964
Historical Overview-
Its origin has been found in the Nazi Disaster and hasundergone several modifications
Prior to 1947 Nuremberg Code there was noaccepted code of conduct governing the ethicalaspects of human research
World Medical Association
It is an international organization of physicians
established on September 17 1947
First general Assembly of WMA was held in Paris
France
Mission- Serve humanity by endeavoring to achieve the
highest international standards in medical education
science ethics and health care for all peoples of the world
Declaration of Helsinki 1964
Adapted from Nuremberg
Code by the World Medical Association (WMA)
First adopted in Helsinki Finland 1964
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI- 2008
Ethical Principles for Medical Research Involving Human Subjects
Adopted by the 18th WMA General Assembly Helsinki Finland June 1964 and amended by the
29th WMA General Assembly Tokyo Japan October 1975
35th WMA General Assembly Venice Italy October 1983
41st WMA General Assembly Hong Kong September 1989
53th WMA General Assembly Washington 2002 (Note of Clarification on paragraph 29 added)
55th WMA General Assembly Tokyo 2004 (Note of Clarification on Paragraph 30 added)
59th WMA General Assembly Seoul October 2008
Seven Ethical Pillars of Clinical Research
AUTONOMY
BENEFICENCE
NON ndash MALFEASANCE
FIDELITY
TRUTHFULNESS
CONFIDENTIALITY
JUSTICE
Declaration of Helsinki
Autonomy
Consent
Para 20 The subjects must be volunteers andinformed participants in the research project
Para 22 freely-given informed consent
preferably in writing
Declaration of Helsinki
Para 5 well-being of the human subject shouldtake precedence over the interests of scienceand society
Beneficence
Declaration of Helsinki
Para 16
bull Preceded by careful assessment ofpredictable risks and burdens
bull Attempt to avoid any act or treatmentplan that would harm the patient
Non Malfeasance
Declaration of Helsinki
Para 11
Medical research involving human subjects must be basedon generally accepted scientific principles thoroughknowledge of the scientific literature and on adequatelaboratory and where appropriate animalexperimentation
Para 15
Conducted only by clinically competent medical person
Fidelity ndash duty of care
Declaration of Helsinki
Para 27
Both authors amp investigators are obliged topreserve the accuracy of the results Negativeas well as positive results should be published
Truthfulness - Honesty
Declaration of Helsinki
Para 21
Every precaution should be taken torespect the privacy of the subject theconfidentiality of the patients information
Confidentiality
Declaration of Helsinki
Para 30
Every patient entered into the study should be assured ofaccess to the best proven prophylactic diagnostic andtherapeutic methods identified by the study
Para 9
Research Investigators should be aware of the ethicallegal and regulatory requirements for research on humansubjects
Para 17
Physicians should cease any investigation if the risksoutweigh the potential benefits
Justice
DECLARATION OF HELSINKI -Basic Principles
1 Conform to accepted scientific principles
2 Design formulated in experimental protocol reviewed by IEC
3 Conducted by qualified and trained persons
4 Importance in proportion to inherent risk
5 Assessment of risks vs benefits
6 Safeguard subjectrsquos integrity (privacy)
7 Abstain unless hazards are predictable
8 Preserve accuracy when publishing
9 Adequately inform or right to withdraw
10 Obtain true informed consent in writing
11 Reliance on legal guardian
12 State compliance with Declaration
Ethical Principles and Guidelines for the Protection of Human Subjects of Research
bull Tuskegee Syphilis Study (1932ndash1972)
bull Named the Belmont Report for the Belmont Conference Center where the National Commission met when first drafting the report
42
Belmont Report 1979
Belmont Report 1979
Three ethical principles related to research on human subjects
1 Respect for Persons
2 Beneficence Do no harm while maximizing benefits for research project and minimizing risks to the research subjects
3 Justice ensuring reasonable non-exploitative and well-considered procedures are administered
Overview of
ICH GCP
What is ICH
bull The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)- is unique in bringing together the regulatory authorities and pharmaceutical industry of Europe Japan and the US to discuss scientific and technical aspects of drug registration
45
What is ICH
bull Since its inception in 1990 ICH has
gradually evolved
bull ICHs mission is to ensure that safe
effective and high quality medicines are
developed and registered in the most
resource-efficient manner
How did it evolve
The need to harmonize
bull Public disasters serious fraud and abuse of human rights
bull Trials of War criminals-Nuremberg code 1949
bull Thalidomide- Declaration of Helsinki 1964
bull Belmont report 1978 (Ethical Principles and guidelines for the protection of human subjects of research)-Tuskegee syphilis study
History
1962 US FDA IND Guidelines
1964 Declaration of Helsinki
1968 Committee on Safety of Medicines uk
1978 GCP US FDA
1991 GCP Europe
1996 ICH GCP
1997 ICH GCP Guideline
When did it begin
bull Ist conf in 1990 in Brussels
3 regions participated
bull Representatives from
Industry
Academia
Ministry of
health
ICH parties
6 parties
bull EU bull EFPIA European federation of pharmaceutical industriesrsquo associations
bull MHLW Ministry of health Labor and welfare Japan
bull JPMA Japan Pharmaceuticals manufacturers Association
bull US FDA
bull PhRMA
bull Observers WHO TPP(canada)
bull International federation of Pharmaceutical manufacturerrsquos association
Key objective
bull To discuss and define the minimum standards for the development and registration of investigational products
The result
Many guidelines made
bull Most important- ICH GCP guidelines
bull Evolved in several steps
bull Consolidated guideline ICH E6 Sept 1997
ICH Guidelines examples
bull Efficacy ndash clinical trials etc
bull Safety ndash pharmacovigilance adverse drug reaction
reporting
bull Quality ndash raw materials impurities residual solvents etc
bull Multidisciplinary ndash common technical document electronic
submission coding systems
What is GCP
A standard for the design conduct performance monitoring auditing recording analyses and reporting of clinical trials that provide assurance that the data and the reported results are credible accurate and that the rights integrity and confidentiality of trial subjects are protected
Why is it needed
bull To ensure the rights safety and well being of the trial subjects are protected
bull Ensure the credibility of clinical trial data
The ICH GCP guideline
bull Provide a unified standard for the EU Japan and USA regions to facilitate mutual acceptance of clinical trial data by the regulatory authorities in
these regions
bull 8 sections
ICH GCP guideline
1 Glossary
Common language for investigatorssponsorsethics committees
2Principles of Good Clinical Practice
13 tenets of ICH GCP
3Requirements for IRBIEC
Roles responsibilities and composition
ICH GCP guideline
4Responsibilities of the investigator
5Responsibilities of the sponsor
6Requirements for clinical trial protocol and protocol amendments
7Responsibility of the sponsor in the development of investigatorrsquos brochure
8Essential documents
Principles of ICH GCP
bull Ethical conduct as per
Declaration of Helsinki
GCP
Regulatory Requirements
Risk- Benefit
Primary concern- Subject
Principles of ICH GCP
bull Supportive data
bull Protocol
Scientifically sound clear detailed
bull Ethical Clearance
Study to be conducted in compliance to the protocol which has received EC approval
Principles of ICH GCP
bull Subject Care
Medical decisions responsibility of qualified physician
bull Qualified staff
By education training experience in their area of responsibility
bull Informed Consent
Principles of ICH GCP
bull Clinical Trial data
Recorded handled and stored to enable accurate reporting interpretation and verification
bull Confidentiality
Principles of ICH GCP
bull Investigational Product
Manufactured handled and stored as per GMP
Principles of ICH GCP
bull Quality Assurance
Systems and procedures to ensure the Quality of every aspect of the trial
Indian GCP guidelines
bull Released in Dec 2001(Developed by CDCSO and endorsed by DCGI)
bull In general in line with ICH GCP
bull Has Revised Schedule Y (Jan 2005) addressed discrepancies
bull SAFEGUARD PUBLIC HEALTH
bull ASSURE CONSUMER PROTECTION STANDARDS
bull FACILITATE AVAILABILITY OF SAFE AND EFFECTIVE PRODUCTS
bull ELIMINATE INCONSISTENT STANDARDS INTERNATIONALLY
bull FACILITATE MUTUAL ACCEPTANCE OF DATA FROM CLINICAL TRIALS
GOALS OF INTERNATIONAL HARMONIZATION OF
REGULATORY REQUIREMENTS
Study DocumentationDuring the study
The investigator must keepndash Source documents
bull Medical records (including access to computer records)
bull Laboratory reports
bull ECGs X-rays etc
bull Any other medical records reports or notes (hospital admissions and discharges)
ndash A subject identification list
ndash Copies of all study related documentation
Medical Records
bull In particular they should contain notes on
ndash Sufficient information to support subject eligibility
ndash This should be well documented (signed and dated)
ndash Subjectrsquos participation in the study
ndash Dates of visits
ndash Procedures investigations done
ndash Observations diagnoses
ndash Medications taken (including study medication)
ndash Adverse events
ndash Completion or withdrawal (reason) from the study
Study DocumentationAfter the study
The sponsor needs from the investigator
ndash Final drug accountability records
ndash All used and unused supplies and medication
ndash All required documents completed
Conclusion
70
Thanks
ldquoWhen a doctor [goes] wrong he is
the first of criminals He has nerve
and he has knowledgerdquo
- Sherlock Holmes
References
httpwwwwmanetepolicyb3htm
wwwhhsgovohrphumansubjectsguidancebelmonthtml
wwwhhsgovohrpreferencesnurcodehtml
wwwicmrnicinguidelinesGCLP
wwwcdsconicin
wwwubedurecercaBioeticadocDeclaracio_Helsinki_2013
wwwjewishvirtuallibraryorgjsourceHolocaustnazi_experiments
wwwichorgfileadminPublic_WebICHE6_R1__Guideline
bull Within a few years of the widespread use of thalidomide in Europe Australia and Japan approximately 10000 children were born with phocomelia leading to the ban of thalidomide in most countries in 1961
22
bull The thalidomide tragedy marked a turning point in toxicity testing as it prompted United States and international regulatory agencies to develop systematic toxicity testing protocols
bull The thalidomide tragedy also brought into sharp focus the importance of rigorous and relevant testing of pharmaceuticals prior to their introduction into the market place (Kelsey 1988)
23
Thalidomide tragedy
Nuremberg Code-1947
bull On April 17 1947 United States Counsel for War Crimescame out with six points defining ldquolegitimate researchrdquo
bull The verdict of August 19 reiterated almost all of thesepoints in a section entitled Permissible MedicalExperiments and revised the original six points into ten
bull Subsequently the ten points became known as theNuremberg Code
24
Codes and Guidelines
Nuremberg Code (1947)
WMArsquos Declaration of Helsinki (1964)
bull Belmont Report (USA) (1979)-Tuskegee syphilis study
Council for International Organizations of Medical Sciences (CIOMS) 1993
International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) in 1996 Guideline on Good Clinical PracticeE6 (GCP)
Nuremberg Code (1947)
Voluntary and Informed consent-absolutely essential
Anticipate scientific benefits Useful
Animal experimentation first
Avoid physical and mental suffering
Benefits outweigh risks
No intentional death or disability
Protection from harm
Subject free to withdraw
Qualified investigators
Investigator will stop if harm occurs
THE DECLARATION OF HELSINKI-1964
Is an international standard for the conduct of clinicalresearch adopted by International Conference onHarmonization(ICH) Good Clinical Practice standards
A global ethical standard for medical research and wasapproved at the WMA General Assembly by a majority voteof 75
It is the mission of the clinical research professionals tosafeguard the health of the people
THE DECLARATION OF HELSINKI-1964
Historical Overview-
Its origin has been found in the Nazi Disaster and hasundergone several modifications
Prior to 1947 Nuremberg Code there was noaccepted code of conduct governing the ethicalaspects of human research
World Medical Association
It is an international organization of physicians
established on September 17 1947
First general Assembly of WMA was held in Paris
France
Mission- Serve humanity by endeavoring to achieve the
highest international standards in medical education
science ethics and health care for all peoples of the world
Declaration of Helsinki 1964
Adapted from Nuremberg
Code by the World Medical Association (WMA)
First adopted in Helsinki Finland 1964
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI- 2008
Ethical Principles for Medical Research Involving Human Subjects
Adopted by the 18th WMA General Assembly Helsinki Finland June 1964 and amended by the
29th WMA General Assembly Tokyo Japan October 1975
35th WMA General Assembly Venice Italy October 1983
41st WMA General Assembly Hong Kong September 1989
53th WMA General Assembly Washington 2002 (Note of Clarification on paragraph 29 added)
55th WMA General Assembly Tokyo 2004 (Note of Clarification on Paragraph 30 added)
59th WMA General Assembly Seoul October 2008
Seven Ethical Pillars of Clinical Research
AUTONOMY
BENEFICENCE
NON ndash MALFEASANCE
FIDELITY
TRUTHFULNESS
CONFIDENTIALITY
JUSTICE
Declaration of Helsinki
Autonomy
Consent
Para 20 The subjects must be volunteers andinformed participants in the research project
Para 22 freely-given informed consent
preferably in writing
Declaration of Helsinki
Para 5 well-being of the human subject shouldtake precedence over the interests of scienceand society
Beneficence
Declaration of Helsinki
Para 16
bull Preceded by careful assessment ofpredictable risks and burdens
bull Attempt to avoid any act or treatmentplan that would harm the patient
Non Malfeasance
Declaration of Helsinki
Para 11
Medical research involving human subjects must be basedon generally accepted scientific principles thoroughknowledge of the scientific literature and on adequatelaboratory and where appropriate animalexperimentation
Para 15
Conducted only by clinically competent medical person
Fidelity ndash duty of care
Declaration of Helsinki
Para 27
Both authors amp investigators are obliged topreserve the accuracy of the results Negativeas well as positive results should be published
Truthfulness - Honesty
Declaration of Helsinki
Para 21
Every precaution should be taken torespect the privacy of the subject theconfidentiality of the patients information
Confidentiality
Declaration of Helsinki
Para 30
Every patient entered into the study should be assured ofaccess to the best proven prophylactic diagnostic andtherapeutic methods identified by the study
Para 9
Research Investigators should be aware of the ethicallegal and regulatory requirements for research on humansubjects
Para 17
Physicians should cease any investigation if the risksoutweigh the potential benefits
Justice
DECLARATION OF HELSINKI -Basic Principles
1 Conform to accepted scientific principles
2 Design formulated in experimental protocol reviewed by IEC
3 Conducted by qualified and trained persons
4 Importance in proportion to inherent risk
5 Assessment of risks vs benefits
6 Safeguard subjectrsquos integrity (privacy)
7 Abstain unless hazards are predictable
8 Preserve accuracy when publishing
9 Adequately inform or right to withdraw
10 Obtain true informed consent in writing
11 Reliance on legal guardian
12 State compliance with Declaration
Ethical Principles and Guidelines for the Protection of Human Subjects of Research
bull Tuskegee Syphilis Study (1932ndash1972)
bull Named the Belmont Report for the Belmont Conference Center where the National Commission met when first drafting the report
42
Belmont Report 1979
Belmont Report 1979
Three ethical principles related to research on human subjects
1 Respect for Persons
2 Beneficence Do no harm while maximizing benefits for research project and minimizing risks to the research subjects
3 Justice ensuring reasonable non-exploitative and well-considered procedures are administered
Overview of
ICH GCP
What is ICH
bull The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)- is unique in bringing together the regulatory authorities and pharmaceutical industry of Europe Japan and the US to discuss scientific and technical aspects of drug registration
45
What is ICH
bull Since its inception in 1990 ICH has
gradually evolved
bull ICHs mission is to ensure that safe
effective and high quality medicines are
developed and registered in the most
resource-efficient manner
How did it evolve
The need to harmonize
bull Public disasters serious fraud and abuse of human rights
bull Trials of War criminals-Nuremberg code 1949
bull Thalidomide- Declaration of Helsinki 1964
bull Belmont report 1978 (Ethical Principles and guidelines for the protection of human subjects of research)-Tuskegee syphilis study
History
1962 US FDA IND Guidelines
1964 Declaration of Helsinki
1968 Committee on Safety of Medicines uk
1978 GCP US FDA
1991 GCP Europe
1996 ICH GCP
1997 ICH GCP Guideline
When did it begin
bull Ist conf in 1990 in Brussels
3 regions participated
bull Representatives from
Industry
Academia
Ministry of
health
ICH parties
6 parties
bull EU bull EFPIA European federation of pharmaceutical industriesrsquo associations
bull MHLW Ministry of health Labor and welfare Japan
bull JPMA Japan Pharmaceuticals manufacturers Association
bull US FDA
bull PhRMA
bull Observers WHO TPP(canada)
bull International federation of Pharmaceutical manufacturerrsquos association
Key objective
bull To discuss and define the minimum standards for the development and registration of investigational products
The result
Many guidelines made
bull Most important- ICH GCP guidelines
bull Evolved in several steps
bull Consolidated guideline ICH E6 Sept 1997
ICH Guidelines examples
bull Efficacy ndash clinical trials etc
bull Safety ndash pharmacovigilance adverse drug reaction
reporting
bull Quality ndash raw materials impurities residual solvents etc
bull Multidisciplinary ndash common technical document electronic
submission coding systems
What is GCP
A standard for the design conduct performance monitoring auditing recording analyses and reporting of clinical trials that provide assurance that the data and the reported results are credible accurate and that the rights integrity and confidentiality of trial subjects are protected
Why is it needed
bull To ensure the rights safety and well being of the trial subjects are protected
bull Ensure the credibility of clinical trial data
The ICH GCP guideline
bull Provide a unified standard for the EU Japan and USA regions to facilitate mutual acceptance of clinical trial data by the regulatory authorities in
these regions
bull 8 sections
ICH GCP guideline
1 Glossary
Common language for investigatorssponsorsethics committees
2Principles of Good Clinical Practice
13 tenets of ICH GCP
3Requirements for IRBIEC
Roles responsibilities and composition
ICH GCP guideline
4Responsibilities of the investigator
5Responsibilities of the sponsor
6Requirements for clinical trial protocol and protocol amendments
7Responsibility of the sponsor in the development of investigatorrsquos brochure
8Essential documents
Principles of ICH GCP
bull Ethical conduct as per
Declaration of Helsinki
GCP
Regulatory Requirements
Risk- Benefit
Primary concern- Subject
Principles of ICH GCP
bull Supportive data
bull Protocol
Scientifically sound clear detailed
bull Ethical Clearance
Study to be conducted in compliance to the protocol which has received EC approval
Principles of ICH GCP
bull Subject Care
Medical decisions responsibility of qualified physician
bull Qualified staff
By education training experience in their area of responsibility
bull Informed Consent
Principles of ICH GCP
bull Clinical Trial data
Recorded handled and stored to enable accurate reporting interpretation and verification
bull Confidentiality
Principles of ICH GCP
bull Investigational Product
Manufactured handled and stored as per GMP
Principles of ICH GCP
bull Quality Assurance
Systems and procedures to ensure the Quality of every aspect of the trial
Indian GCP guidelines
bull Released in Dec 2001(Developed by CDCSO and endorsed by DCGI)
bull In general in line with ICH GCP
bull Has Revised Schedule Y (Jan 2005) addressed discrepancies
bull SAFEGUARD PUBLIC HEALTH
bull ASSURE CONSUMER PROTECTION STANDARDS
bull FACILITATE AVAILABILITY OF SAFE AND EFFECTIVE PRODUCTS
bull ELIMINATE INCONSISTENT STANDARDS INTERNATIONALLY
bull FACILITATE MUTUAL ACCEPTANCE OF DATA FROM CLINICAL TRIALS
GOALS OF INTERNATIONAL HARMONIZATION OF
REGULATORY REQUIREMENTS
Study DocumentationDuring the study
The investigator must keepndash Source documents
bull Medical records (including access to computer records)
bull Laboratory reports
bull ECGs X-rays etc
bull Any other medical records reports or notes (hospital admissions and discharges)
ndash A subject identification list
ndash Copies of all study related documentation
Medical Records
bull In particular they should contain notes on
ndash Sufficient information to support subject eligibility
ndash This should be well documented (signed and dated)
ndash Subjectrsquos participation in the study
ndash Dates of visits
ndash Procedures investigations done
ndash Observations diagnoses
ndash Medications taken (including study medication)
ndash Adverse events
ndash Completion or withdrawal (reason) from the study
Study DocumentationAfter the study
The sponsor needs from the investigator
ndash Final drug accountability records
ndash All used and unused supplies and medication
ndash All required documents completed
Conclusion
70
Thanks
ldquoWhen a doctor [goes] wrong he is
the first of criminals He has nerve
and he has knowledgerdquo
- Sherlock Holmes
References
httpwwwwmanetepolicyb3htm
wwwhhsgovohrphumansubjectsguidancebelmonthtml
wwwhhsgovohrpreferencesnurcodehtml
wwwicmrnicinguidelinesGCLP
wwwcdsconicin
wwwubedurecercaBioeticadocDeclaracio_Helsinki_2013
wwwjewishvirtuallibraryorgjsourceHolocaustnazi_experiments
wwwichorgfileadminPublic_WebICHE6_R1__Guideline
bull The thalidomide tragedy marked a turning point in toxicity testing as it prompted United States and international regulatory agencies to develop systematic toxicity testing protocols
bull The thalidomide tragedy also brought into sharp focus the importance of rigorous and relevant testing of pharmaceuticals prior to their introduction into the market place (Kelsey 1988)
23
Thalidomide tragedy
Nuremberg Code-1947
bull On April 17 1947 United States Counsel for War Crimescame out with six points defining ldquolegitimate researchrdquo
bull The verdict of August 19 reiterated almost all of thesepoints in a section entitled Permissible MedicalExperiments and revised the original six points into ten
bull Subsequently the ten points became known as theNuremberg Code
24
Codes and Guidelines
Nuremberg Code (1947)
WMArsquos Declaration of Helsinki (1964)
bull Belmont Report (USA) (1979)-Tuskegee syphilis study
Council for International Organizations of Medical Sciences (CIOMS) 1993
International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) in 1996 Guideline on Good Clinical PracticeE6 (GCP)
Nuremberg Code (1947)
Voluntary and Informed consent-absolutely essential
Anticipate scientific benefits Useful
Animal experimentation first
Avoid physical and mental suffering
Benefits outweigh risks
No intentional death or disability
Protection from harm
Subject free to withdraw
Qualified investigators
Investigator will stop if harm occurs
THE DECLARATION OF HELSINKI-1964
Is an international standard for the conduct of clinicalresearch adopted by International Conference onHarmonization(ICH) Good Clinical Practice standards
A global ethical standard for medical research and wasapproved at the WMA General Assembly by a majority voteof 75
It is the mission of the clinical research professionals tosafeguard the health of the people
THE DECLARATION OF HELSINKI-1964
Historical Overview-
Its origin has been found in the Nazi Disaster and hasundergone several modifications
Prior to 1947 Nuremberg Code there was noaccepted code of conduct governing the ethicalaspects of human research
World Medical Association
It is an international organization of physicians
established on September 17 1947
First general Assembly of WMA was held in Paris
France
Mission- Serve humanity by endeavoring to achieve the
highest international standards in medical education
science ethics and health care for all peoples of the world
Declaration of Helsinki 1964
Adapted from Nuremberg
Code by the World Medical Association (WMA)
First adopted in Helsinki Finland 1964
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI- 2008
Ethical Principles for Medical Research Involving Human Subjects
Adopted by the 18th WMA General Assembly Helsinki Finland June 1964 and amended by the
29th WMA General Assembly Tokyo Japan October 1975
35th WMA General Assembly Venice Italy October 1983
41st WMA General Assembly Hong Kong September 1989
53th WMA General Assembly Washington 2002 (Note of Clarification on paragraph 29 added)
55th WMA General Assembly Tokyo 2004 (Note of Clarification on Paragraph 30 added)
59th WMA General Assembly Seoul October 2008
Seven Ethical Pillars of Clinical Research
AUTONOMY
BENEFICENCE
NON ndash MALFEASANCE
FIDELITY
TRUTHFULNESS
CONFIDENTIALITY
JUSTICE
Declaration of Helsinki
Autonomy
Consent
Para 20 The subjects must be volunteers andinformed participants in the research project
Para 22 freely-given informed consent
preferably in writing
Declaration of Helsinki
Para 5 well-being of the human subject shouldtake precedence over the interests of scienceand society
Beneficence
Declaration of Helsinki
Para 16
bull Preceded by careful assessment ofpredictable risks and burdens
bull Attempt to avoid any act or treatmentplan that would harm the patient
Non Malfeasance
Declaration of Helsinki
Para 11
Medical research involving human subjects must be basedon generally accepted scientific principles thoroughknowledge of the scientific literature and on adequatelaboratory and where appropriate animalexperimentation
Para 15
Conducted only by clinically competent medical person
Fidelity ndash duty of care
Declaration of Helsinki
Para 27
Both authors amp investigators are obliged topreserve the accuracy of the results Negativeas well as positive results should be published
Truthfulness - Honesty
Declaration of Helsinki
Para 21
Every precaution should be taken torespect the privacy of the subject theconfidentiality of the patients information
Confidentiality
Declaration of Helsinki
Para 30
Every patient entered into the study should be assured ofaccess to the best proven prophylactic diagnostic andtherapeutic methods identified by the study
Para 9
Research Investigators should be aware of the ethicallegal and regulatory requirements for research on humansubjects
Para 17
Physicians should cease any investigation if the risksoutweigh the potential benefits
Justice
DECLARATION OF HELSINKI -Basic Principles
1 Conform to accepted scientific principles
2 Design formulated in experimental protocol reviewed by IEC
3 Conducted by qualified and trained persons
4 Importance in proportion to inherent risk
5 Assessment of risks vs benefits
6 Safeguard subjectrsquos integrity (privacy)
7 Abstain unless hazards are predictable
8 Preserve accuracy when publishing
9 Adequately inform or right to withdraw
10 Obtain true informed consent in writing
11 Reliance on legal guardian
12 State compliance with Declaration
Ethical Principles and Guidelines for the Protection of Human Subjects of Research
bull Tuskegee Syphilis Study (1932ndash1972)
bull Named the Belmont Report for the Belmont Conference Center where the National Commission met when first drafting the report
42
Belmont Report 1979
Belmont Report 1979
Three ethical principles related to research on human subjects
1 Respect for Persons
2 Beneficence Do no harm while maximizing benefits for research project and minimizing risks to the research subjects
3 Justice ensuring reasonable non-exploitative and well-considered procedures are administered
Overview of
ICH GCP
What is ICH
bull The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)- is unique in bringing together the regulatory authorities and pharmaceutical industry of Europe Japan and the US to discuss scientific and technical aspects of drug registration
45
What is ICH
bull Since its inception in 1990 ICH has
gradually evolved
bull ICHs mission is to ensure that safe
effective and high quality medicines are
developed and registered in the most
resource-efficient manner
How did it evolve
The need to harmonize
bull Public disasters serious fraud and abuse of human rights
bull Trials of War criminals-Nuremberg code 1949
bull Thalidomide- Declaration of Helsinki 1964
bull Belmont report 1978 (Ethical Principles and guidelines for the protection of human subjects of research)-Tuskegee syphilis study
History
1962 US FDA IND Guidelines
1964 Declaration of Helsinki
1968 Committee on Safety of Medicines uk
1978 GCP US FDA
1991 GCP Europe
1996 ICH GCP
1997 ICH GCP Guideline
When did it begin
bull Ist conf in 1990 in Brussels
3 regions participated
bull Representatives from
Industry
Academia
Ministry of
health
ICH parties
6 parties
bull EU bull EFPIA European federation of pharmaceutical industriesrsquo associations
bull MHLW Ministry of health Labor and welfare Japan
bull JPMA Japan Pharmaceuticals manufacturers Association
bull US FDA
bull PhRMA
bull Observers WHO TPP(canada)
bull International federation of Pharmaceutical manufacturerrsquos association
Key objective
bull To discuss and define the minimum standards for the development and registration of investigational products
The result
Many guidelines made
bull Most important- ICH GCP guidelines
bull Evolved in several steps
bull Consolidated guideline ICH E6 Sept 1997
ICH Guidelines examples
bull Efficacy ndash clinical trials etc
bull Safety ndash pharmacovigilance adverse drug reaction
reporting
bull Quality ndash raw materials impurities residual solvents etc
bull Multidisciplinary ndash common technical document electronic
submission coding systems
What is GCP
A standard for the design conduct performance monitoring auditing recording analyses and reporting of clinical trials that provide assurance that the data and the reported results are credible accurate and that the rights integrity and confidentiality of trial subjects are protected
Why is it needed
bull To ensure the rights safety and well being of the trial subjects are protected
bull Ensure the credibility of clinical trial data
The ICH GCP guideline
bull Provide a unified standard for the EU Japan and USA regions to facilitate mutual acceptance of clinical trial data by the regulatory authorities in
these regions
bull 8 sections
ICH GCP guideline
1 Glossary
Common language for investigatorssponsorsethics committees
2Principles of Good Clinical Practice
13 tenets of ICH GCP
3Requirements for IRBIEC
Roles responsibilities and composition
ICH GCP guideline
4Responsibilities of the investigator
5Responsibilities of the sponsor
6Requirements for clinical trial protocol and protocol amendments
7Responsibility of the sponsor in the development of investigatorrsquos brochure
8Essential documents
Principles of ICH GCP
bull Ethical conduct as per
Declaration of Helsinki
GCP
Regulatory Requirements
Risk- Benefit
Primary concern- Subject
Principles of ICH GCP
bull Supportive data
bull Protocol
Scientifically sound clear detailed
bull Ethical Clearance
Study to be conducted in compliance to the protocol which has received EC approval
Principles of ICH GCP
bull Subject Care
Medical decisions responsibility of qualified physician
bull Qualified staff
By education training experience in their area of responsibility
bull Informed Consent
Principles of ICH GCP
bull Clinical Trial data
Recorded handled and stored to enable accurate reporting interpretation and verification
bull Confidentiality
Principles of ICH GCP
bull Investigational Product
Manufactured handled and stored as per GMP
Principles of ICH GCP
bull Quality Assurance
Systems and procedures to ensure the Quality of every aspect of the trial
Indian GCP guidelines
bull Released in Dec 2001(Developed by CDCSO and endorsed by DCGI)
bull In general in line with ICH GCP
bull Has Revised Schedule Y (Jan 2005) addressed discrepancies
bull SAFEGUARD PUBLIC HEALTH
bull ASSURE CONSUMER PROTECTION STANDARDS
bull FACILITATE AVAILABILITY OF SAFE AND EFFECTIVE PRODUCTS
bull ELIMINATE INCONSISTENT STANDARDS INTERNATIONALLY
bull FACILITATE MUTUAL ACCEPTANCE OF DATA FROM CLINICAL TRIALS
GOALS OF INTERNATIONAL HARMONIZATION OF
REGULATORY REQUIREMENTS
Study DocumentationDuring the study
The investigator must keepndash Source documents
bull Medical records (including access to computer records)
bull Laboratory reports
bull ECGs X-rays etc
bull Any other medical records reports or notes (hospital admissions and discharges)
ndash A subject identification list
ndash Copies of all study related documentation
Medical Records
bull In particular they should contain notes on
ndash Sufficient information to support subject eligibility
ndash This should be well documented (signed and dated)
ndash Subjectrsquos participation in the study
ndash Dates of visits
ndash Procedures investigations done
ndash Observations diagnoses
ndash Medications taken (including study medication)
ndash Adverse events
ndash Completion or withdrawal (reason) from the study
Study DocumentationAfter the study
The sponsor needs from the investigator
ndash Final drug accountability records
ndash All used and unused supplies and medication
ndash All required documents completed
Conclusion
70
Thanks
ldquoWhen a doctor [goes] wrong he is
the first of criminals He has nerve
and he has knowledgerdquo
- Sherlock Holmes
References
httpwwwwmanetepolicyb3htm
wwwhhsgovohrphumansubjectsguidancebelmonthtml
wwwhhsgovohrpreferencesnurcodehtml
wwwicmrnicinguidelinesGCLP
wwwcdsconicin
wwwubedurecercaBioeticadocDeclaracio_Helsinki_2013
wwwjewishvirtuallibraryorgjsourceHolocaustnazi_experiments
wwwichorgfileadminPublic_WebICHE6_R1__Guideline
Nuremberg Code-1947
bull On April 17 1947 United States Counsel for War Crimescame out with six points defining ldquolegitimate researchrdquo
bull The verdict of August 19 reiterated almost all of thesepoints in a section entitled Permissible MedicalExperiments and revised the original six points into ten
bull Subsequently the ten points became known as theNuremberg Code
24
Codes and Guidelines
Nuremberg Code (1947)
WMArsquos Declaration of Helsinki (1964)
bull Belmont Report (USA) (1979)-Tuskegee syphilis study
Council for International Organizations of Medical Sciences (CIOMS) 1993
International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) in 1996 Guideline on Good Clinical PracticeE6 (GCP)
Nuremberg Code (1947)
Voluntary and Informed consent-absolutely essential
Anticipate scientific benefits Useful
Animal experimentation first
Avoid physical and mental suffering
Benefits outweigh risks
No intentional death or disability
Protection from harm
Subject free to withdraw
Qualified investigators
Investigator will stop if harm occurs
THE DECLARATION OF HELSINKI-1964
Is an international standard for the conduct of clinicalresearch adopted by International Conference onHarmonization(ICH) Good Clinical Practice standards
A global ethical standard for medical research and wasapproved at the WMA General Assembly by a majority voteof 75
It is the mission of the clinical research professionals tosafeguard the health of the people
THE DECLARATION OF HELSINKI-1964
Historical Overview-
Its origin has been found in the Nazi Disaster and hasundergone several modifications
Prior to 1947 Nuremberg Code there was noaccepted code of conduct governing the ethicalaspects of human research
World Medical Association
It is an international organization of physicians
established on September 17 1947
First general Assembly of WMA was held in Paris
France
Mission- Serve humanity by endeavoring to achieve the
highest international standards in medical education
science ethics and health care for all peoples of the world
Declaration of Helsinki 1964
Adapted from Nuremberg
Code by the World Medical Association (WMA)
First adopted in Helsinki Finland 1964
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI- 2008
Ethical Principles for Medical Research Involving Human Subjects
Adopted by the 18th WMA General Assembly Helsinki Finland June 1964 and amended by the
29th WMA General Assembly Tokyo Japan October 1975
35th WMA General Assembly Venice Italy October 1983
41st WMA General Assembly Hong Kong September 1989
53th WMA General Assembly Washington 2002 (Note of Clarification on paragraph 29 added)
55th WMA General Assembly Tokyo 2004 (Note of Clarification on Paragraph 30 added)
59th WMA General Assembly Seoul October 2008
Seven Ethical Pillars of Clinical Research
AUTONOMY
BENEFICENCE
NON ndash MALFEASANCE
FIDELITY
TRUTHFULNESS
CONFIDENTIALITY
JUSTICE
Declaration of Helsinki
Autonomy
Consent
Para 20 The subjects must be volunteers andinformed participants in the research project
Para 22 freely-given informed consent
preferably in writing
Declaration of Helsinki
Para 5 well-being of the human subject shouldtake precedence over the interests of scienceand society
Beneficence
Declaration of Helsinki
Para 16
bull Preceded by careful assessment ofpredictable risks and burdens
bull Attempt to avoid any act or treatmentplan that would harm the patient
Non Malfeasance
Declaration of Helsinki
Para 11
Medical research involving human subjects must be basedon generally accepted scientific principles thoroughknowledge of the scientific literature and on adequatelaboratory and where appropriate animalexperimentation
Para 15
Conducted only by clinically competent medical person
Fidelity ndash duty of care
Declaration of Helsinki
Para 27
Both authors amp investigators are obliged topreserve the accuracy of the results Negativeas well as positive results should be published
Truthfulness - Honesty
Declaration of Helsinki
Para 21
Every precaution should be taken torespect the privacy of the subject theconfidentiality of the patients information
Confidentiality
Declaration of Helsinki
Para 30
Every patient entered into the study should be assured ofaccess to the best proven prophylactic diagnostic andtherapeutic methods identified by the study
Para 9
Research Investigators should be aware of the ethicallegal and regulatory requirements for research on humansubjects
Para 17
Physicians should cease any investigation if the risksoutweigh the potential benefits
Justice
DECLARATION OF HELSINKI -Basic Principles
1 Conform to accepted scientific principles
2 Design formulated in experimental protocol reviewed by IEC
3 Conducted by qualified and trained persons
4 Importance in proportion to inherent risk
5 Assessment of risks vs benefits
6 Safeguard subjectrsquos integrity (privacy)
7 Abstain unless hazards are predictable
8 Preserve accuracy when publishing
9 Adequately inform or right to withdraw
10 Obtain true informed consent in writing
11 Reliance on legal guardian
12 State compliance with Declaration
Ethical Principles and Guidelines for the Protection of Human Subjects of Research
bull Tuskegee Syphilis Study (1932ndash1972)
bull Named the Belmont Report for the Belmont Conference Center where the National Commission met when first drafting the report
42
Belmont Report 1979
Belmont Report 1979
Three ethical principles related to research on human subjects
1 Respect for Persons
2 Beneficence Do no harm while maximizing benefits for research project and minimizing risks to the research subjects
3 Justice ensuring reasonable non-exploitative and well-considered procedures are administered
Overview of
ICH GCP
What is ICH
bull The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)- is unique in bringing together the regulatory authorities and pharmaceutical industry of Europe Japan and the US to discuss scientific and technical aspects of drug registration
45
What is ICH
bull Since its inception in 1990 ICH has
gradually evolved
bull ICHs mission is to ensure that safe
effective and high quality medicines are
developed and registered in the most
resource-efficient manner
How did it evolve
The need to harmonize
bull Public disasters serious fraud and abuse of human rights
bull Trials of War criminals-Nuremberg code 1949
bull Thalidomide- Declaration of Helsinki 1964
bull Belmont report 1978 (Ethical Principles and guidelines for the protection of human subjects of research)-Tuskegee syphilis study
History
1962 US FDA IND Guidelines
1964 Declaration of Helsinki
1968 Committee on Safety of Medicines uk
1978 GCP US FDA
1991 GCP Europe
1996 ICH GCP
1997 ICH GCP Guideline
When did it begin
bull Ist conf in 1990 in Brussels
3 regions participated
bull Representatives from
Industry
Academia
Ministry of
health
ICH parties
6 parties
bull EU bull EFPIA European federation of pharmaceutical industriesrsquo associations
bull MHLW Ministry of health Labor and welfare Japan
bull JPMA Japan Pharmaceuticals manufacturers Association
bull US FDA
bull PhRMA
bull Observers WHO TPP(canada)
bull International federation of Pharmaceutical manufacturerrsquos association
Key objective
bull To discuss and define the minimum standards for the development and registration of investigational products
The result
Many guidelines made
bull Most important- ICH GCP guidelines
bull Evolved in several steps
bull Consolidated guideline ICH E6 Sept 1997
ICH Guidelines examples
bull Efficacy ndash clinical trials etc
bull Safety ndash pharmacovigilance adverse drug reaction
reporting
bull Quality ndash raw materials impurities residual solvents etc
bull Multidisciplinary ndash common technical document electronic
submission coding systems
What is GCP
A standard for the design conduct performance monitoring auditing recording analyses and reporting of clinical trials that provide assurance that the data and the reported results are credible accurate and that the rights integrity and confidentiality of trial subjects are protected
Why is it needed
bull To ensure the rights safety and well being of the trial subjects are protected
bull Ensure the credibility of clinical trial data
The ICH GCP guideline
bull Provide a unified standard for the EU Japan and USA regions to facilitate mutual acceptance of clinical trial data by the regulatory authorities in
these regions
bull 8 sections
ICH GCP guideline
1 Glossary
Common language for investigatorssponsorsethics committees
2Principles of Good Clinical Practice
13 tenets of ICH GCP
3Requirements for IRBIEC
Roles responsibilities and composition
ICH GCP guideline
4Responsibilities of the investigator
5Responsibilities of the sponsor
6Requirements for clinical trial protocol and protocol amendments
7Responsibility of the sponsor in the development of investigatorrsquos brochure
8Essential documents
Principles of ICH GCP
bull Ethical conduct as per
Declaration of Helsinki
GCP
Regulatory Requirements
Risk- Benefit
Primary concern- Subject
Principles of ICH GCP
bull Supportive data
bull Protocol
Scientifically sound clear detailed
bull Ethical Clearance
Study to be conducted in compliance to the protocol which has received EC approval
Principles of ICH GCP
bull Subject Care
Medical decisions responsibility of qualified physician
bull Qualified staff
By education training experience in their area of responsibility
bull Informed Consent
Principles of ICH GCP
bull Clinical Trial data
Recorded handled and stored to enable accurate reporting interpretation and verification
bull Confidentiality
Principles of ICH GCP
bull Investigational Product
Manufactured handled and stored as per GMP
Principles of ICH GCP
bull Quality Assurance
Systems and procedures to ensure the Quality of every aspect of the trial
Indian GCP guidelines
bull Released in Dec 2001(Developed by CDCSO and endorsed by DCGI)
bull In general in line with ICH GCP
bull Has Revised Schedule Y (Jan 2005) addressed discrepancies
bull SAFEGUARD PUBLIC HEALTH
bull ASSURE CONSUMER PROTECTION STANDARDS
bull FACILITATE AVAILABILITY OF SAFE AND EFFECTIVE PRODUCTS
bull ELIMINATE INCONSISTENT STANDARDS INTERNATIONALLY
bull FACILITATE MUTUAL ACCEPTANCE OF DATA FROM CLINICAL TRIALS
GOALS OF INTERNATIONAL HARMONIZATION OF
REGULATORY REQUIREMENTS
Study DocumentationDuring the study
The investigator must keepndash Source documents
bull Medical records (including access to computer records)
bull Laboratory reports
bull ECGs X-rays etc
bull Any other medical records reports or notes (hospital admissions and discharges)
ndash A subject identification list
ndash Copies of all study related documentation
Medical Records
bull In particular they should contain notes on
ndash Sufficient information to support subject eligibility
ndash This should be well documented (signed and dated)
ndash Subjectrsquos participation in the study
ndash Dates of visits
ndash Procedures investigations done
ndash Observations diagnoses
ndash Medications taken (including study medication)
ndash Adverse events
ndash Completion or withdrawal (reason) from the study
Study DocumentationAfter the study
The sponsor needs from the investigator
ndash Final drug accountability records
ndash All used and unused supplies and medication
ndash All required documents completed
Conclusion
70
Thanks
ldquoWhen a doctor [goes] wrong he is
the first of criminals He has nerve
and he has knowledgerdquo
- Sherlock Holmes
References
httpwwwwmanetepolicyb3htm
wwwhhsgovohrphumansubjectsguidancebelmonthtml
wwwhhsgovohrpreferencesnurcodehtml
wwwicmrnicinguidelinesGCLP
wwwcdsconicin
wwwubedurecercaBioeticadocDeclaracio_Helsinki_2013
wwwjewishvirtuallibraryorgjsourceHolocaustnazi_experiments
wwwichorgfileadminPublic_WebICHE6_R1__Guideline
Codes and Guidelines
Nuremberg Code (1947)
WMArsquos Declaration of Helsinki (1964)
bull Belmont Report (USA) (1979)-Tuskegee syphilis study
Council for International Organizations of Medical Sciences (CIOMS) 1993
International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) in 1996 Guideline on Good Clinical PracticeE6 (GCP)
Nuremberg Code (1947)
Voluntary and Informed consent-absolutely essential
Anticipate scientific benefits Useful
Animal experimentation first
Avoid physical and mental suffering
Benefits outweigh risks
No intentional death or disability
Protection from harm
Subject free to withdraw
Qualified investigators
Investigator will stop if harm occurs
THE DECLARATION OF HELSINKI-1964
Is an international standard for the conduct of clinicalresearch adopted by International Conference onHarmonization(ICH) Good Clinical Practice standards
A global ethical standard for medical research and wasapproved at the WMA General Assembly by a majority voteof 75
It is the mission of the clinical research professionals tosafeguard the health of the people
THE DECLARATION OF HELSINKI-1964
Historical Overview-
Its origin has been found in the Nazi Disaster and hasundergone several modifications
Prior to 1947 Nuremberg Code there was noaccepted code of conduct governing the ethicalaspects of human research
World Medical Association
It is an international organization of physicians
established on September 17 1947
First general Assembly of WMA was held in Paris
France
Mission- Serve humanity by endeavoring to achieve the
highest international standards in medical education
science ethics and health care for all peoples of the world
Declaration of Helsinki 1964
Adapted from Nuremberg
Code by the World Medical Association (WMA)
First adopted in Helsinki Finland 1964
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI- 2008
Ethical Principles for Medical Research Involving Human Subjects
Adopted by the 18th WMA General Assembly Helsinki Finland June 1964 and amended by the
29th WMA General Assembly Tokyo Japan October 1975
35th WMA General Assembly Venice Italy October 1983
41st WMA General Assembly Hong Kong September 1989
53th WMA General Assembly Washington 2002 (Note of Clarification on paragraph 29 added)
55th WMA General Assembly Tokyo 2004 (Note of Clarification on Paragraph 30 added)
59th WMA General Assembly Seoul October 2008
Seven Ethical Pillars of Clinical Research
AUTONOMY
BENEFICENCE
NON ndash MALFEASANCE
FIDELITY
TRUTHFULNESS
CONFIDENTIALITY
JUSTICE
Declaration of Helsinki
Autonomy
Consent
Para 20 The subjects must be volunteers andinformed participants in the research project
Para 22 freely-given informed consent
preferably in writing
Declaration of Helsinki
Para 5 well-being of the human subject shouldtake precedence over the interests of scienceand society
Beneficence
Declaration of Helsinki
Para 16
bull Preceded by careful assessment ofpredictable risks and burdens
bull Attempt to avoid any act or treatmentplan that would harm the patient
Non Malfeasance
Declaration of Helsinki
Para 11
Medical research involving human subjects must be basedon generally accepted scientific principles thoroughknowledge of the scientific literature and on adequatelaboratory and where appropriate animalexperimentation
Para 15
Conducted only by clinically competent medical person
Fidelity ndash duty of care
Declaration of Helsinki
Para 27
Both authors amp investigators are obliged topreserve the accuracy of the results Negativeas well as positive results should be published
Truthfulness - Honesty
Declaration of Helsinki
Para 21
Every precaution should be taken torespect the privacy of the subject theconfidentiality of the patients information
Confidentiality
Declaration of Helsinki
Para 30
Every patient entered into the study should be assured ofaccess to the best proven prophylactic diagnostic andtherapeutic methods identified by the study
Para 9
Research Investigators should be aware of the ethicallegal and regulatory requirements for research on humansubjects
Para 17
Physicians should cease any investigation if the risksoutweigh the potential benefits
Justice
DECLARATION OF HELSINKI -Basic Principles
1 Conform to accepted scientific principles
2 Design formulated in experimental protocol reviewed by IEC
3 Conducted by qualified and trained persons
4 Importance in proportion to inherent risk
5 Assessment of risks vs benefits
6 Safeguard subjectrsquos integrity (privacy)
7 Abstain unless hazards are predictable
8 Preserve accuracy when publishing
9 Adequately inform or right to withdraw
10 Obtain true informed consent in writing
11 Reliance on legal guardian
12 State compliance with Declaration
Ethical Principles and Guidelines for the Protection of Human Subjects of Research
bull Tuskegee Syphilis Study (1932ndash1972)
bull Named the Belmont Report for the Belmont Conference Center where the National Commission met when first drafting the report
42
Belmont Report 1979
Belmont Report 1979
Three ethical principles related to research on human subjects
1 Respect for Persons
2 Beneficence Do no harm while maximizing benefits for research project and minimizing risks to the research subjects
3 Justice ensuring reasonable non-exploitative and well-considered procedures are administered
Overview of
ICH GCP
What is ICH
bull The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)- is unique in bringing together the regulatory authorities and pharmaceutical industry of Europe Japan and the US to discuss scientific and technical aspects of drug registration
45
What is ICH
bull Since its inception in 1990 ICH has
gradually evolved
bull ICHs mission is to ensure that safe
effective and high quality medicines are
developed and registered in the most
resource-efficient manner
How did it evolve
The need to harmonize
bull Public disasters serious fraud and abuse of human rights
bull Trials of War criminals-Nuremberg code 1949
bull Thalidomide- Declaration of Helsinki 1964
bull Belmont report 1978 (Ethical Principles and guidelines for the protection of human subjects of research)-Tuskegee syphilis study
History
1962 US FDA IND Guidelines
1964 Declaration of Helsinki
1968 Committee on Safety of Medicines uk
1978 GCP US FDA
1991 GCP Europe
1996 ICH GCP
1997 ICH GCP Guideline
When did it begin
bull Ist conf in 1990 in Brussels
3 regions participated
bull Representatives from
Industry
Academia
Ministry of
health
ICH parties
6 parties
bull EU bull EFPIA European federation of pharmaceutical industriesrsquo associations
bull MHLW Ministry of health Labor and welfare Japan
bull JPMA Japan Pharmaceuticals manufacturers Association
bull US FDA
bull PhRMA
bull Observers WHO TPP(canada)
bull International federation of Pharmaceutical manufacturerrsquos association
Key objective
bull To discuss and define the minimum standards for the development and registration of investigational products
The result
Many guidelines made
bull Most important- ICH GCP guidelines
bull Evolved in several steps
bull Consolidated guideline ICH E6 Sept 1997
ICH Guidelines examples
bull Efficacy ndash clinical trials etc
bull Safety ndash pharmacovigilance adverse drug reaction
reporting
bull Quality ndash raw materials impurities residual solvents etc
bull Multidisciplinary ndash common technical document electronic
submission coding systems
What is GCP
A standard for the design conduct performance monitoring auditing recording analyses and reporting of clinical trials that provide assurance that the data and the reported results are credible accurate and that the rights integrity and confidentiality of trial subjects are protected
Why is it needed
bull To ensure the rights safety and well being of the trial subjects are protected
bull Ensure the credibility of clinical trial data
The ICH GCP guideline
bull Provide a unified standard for the EU Japan and USA regions to facilitate mutual acceptance of clinical trial data by the regulatory authorities in
these regions
bull 8 sections
ICH GCP guideline
1 Glossary
Common language for investigatorssponsorsethics committees
2Principles of Good Clinical Practice
13 tenets of ICH GCP
3Requirements for IRBIEC
Roles responsibilities and composition
ICH GCP guideline
4Responsibilities of the investigator
5Responsibilities of the sponsor
6Requirements for clinical trial protocol and protocol amendments
7Responsibility of the sponsor in the development of investigatorrsquos brochure
8Essential documents
Principles of ICH GCP
bull Ethical conduct as per
Declaration of Helsinki
GCP
Regulatory Requirements
Risk- Benefit
Primary concern- Subject
Principles of ICH GCP
bull Supportive data
bull Protocol
Scientifically sound clear detailed
bull Ethical Clearance
Study to be conducted in compliance to the protocol which has received EC approval
Principles of ICH GCP
bull Subject Care
Medical decisions responsibility of qualified physician
bull Qualified staff
By education training experience in their area of responsibility
bull Informed Consent
Principles of ICH GCP
bull Clinical Trial data
Recorded handled and stored to enable accurate reporting interpretation and verification
bull Confidentiality
Principles of ICH GCP
bull Investigational Product
Manufactured handled and stored as per GMP
Principles of ICH GCP
bull Quality Assurance
Systems and procedures to ensure the Quality of every aspect of the trial
Indian GCP guidelines
bull Released in Dec 2001(Developed by CDCSO and endorsed by DCGI)
bull In general in line with ICH GCP
bull Has Revised Schedule Y (Jan 2005) addressed discrepancies
bull SAFEGUARD PUBLIC HEALTH
bull ASSURE CONSUMER PROTECTION STANDARDS
bull FACILITATE AVAILABILITY OF SAFE AND EFFECTIVE PRODUCTS
bull ELIMINATE INCONSISTENT STANDARDS INTERNATIONALLY
bull FACILITATE MUTUAL ACCEPTANCE OF DATA FROM CLINICAL TRIALS
GOALS OF INTERNATIONAL HARMONIZATION OF
REGULATORY REQUIREMENTS
Study DocumentationDuring the study
The investigator must keepndash Source documents
bull Medical records (including access to computer records)
bull Laboratory reports
bull ECGs X-rays etc
bull Any other medical records reports or notes (hospital admissions and discharges)
ndash A subject identification list
ndash Copies of all study related documentation
Medical Records
bull In particular they should contain notes on
ndash Sufficient information to support subject eligibility
ndash This should be well documented (signed and dated)
ndash Subjectrsquos participation in the study
ndash Dates of visits
ndash Procedures investigations done
ndash Observations diagnoses
ndash Medications taken (including study medication)
ndash Adverse events
ndash Completion or withdrawal (reason) from the study
Study DocumentationAfter the study
The sponsor needs from the investigator
ndash Final drug accountability records
ndash All used and unused supplies and medication
ndash All required documents completed
Conclusion
70
Thanks
ldquoWhen a doctor [goes] wrong he is
the first of criminals He has nerve
and he has knowledgerdquo
- Sherlock Holmes
References
httpwwwwmanetepolicyb3htm
wwwhhsgovohrphumansubjectsguidancebelmonthtml
wwwhhsgovohrpreferencesnurcodehtml
wwwicmrnicinguidelinesGCLP
wwwcdsconicin
wwwubedurecercaBioeticadocDeclaracio_Helsinki_2013
wwwjewishvirtuallibraryorgjsourceHolocaustnazi_experiments
wwwichorgfileadminPublic_WebICHE6_R1__Guideline
Nuremberg Code (1947)
Voluntary and Informed consent-absolutely essential
Anticipate scientific benefits Useful
Animal experimentation first
Avoid physical and mental suffering
Benefits outweigh risks
No intentional death or disability
Protection from harm
Subject free to withdraw
Qualified investigators
Investigator will stop if harm occurs
THE DECLARATION OF HELSINKI-1964
Is an international standard for the conduct of clinicalresearch adopted by International Conference onHarmonization(ICH) Good Clinical Practice standards
A global ethical standard for medical research and wasapproved at the WMA General Assembly by a majority voteof 75
It is the mission of the clinical research professionals tosafeguard the health of the people
THE DECLARATION OF HELSINKI-1964
Historical Overview-
Its origin has been found in the Nazi Disaster and hasundergone several modifications
Prior to 1947 Nuremberg Code there was noaccepted code of conduct governing the ethicalaspects of human research
World Medical Association
It is an international organization of physicians
established on September 17 1947
First general Assembly of WMA was held in Paris
France
Mission- Serve humanity by endeavoring to achieve the
highest international standards in medical education
science ethics and health care for all peoples of the world
Declaration of Helsinki 1964
Adapted from Nuremberg
Code by the World Medical Association (WMA)
First adopted in Helsinki Finland 1964
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI- 2008
Ethical Principles for Medical Research Involving Human Subjects
Adopted by the 18th WMA General Assembly Helsinki Finland June 1964 and amended by the
29th WMA General Assembly Tokyo Japan October 1975
35th WMA General Assembly Venice Italy October 1983
41st WMA General Assembly Hong Kong September 1989
53th WMA General Assembly Washington 2002 (Note of Clarification on paragraph 29 added)
55th WMA General Assembly Tokyo 2004 (Note of Clarification on Paragraph 30 added)
59th WMA General Assembly Seoul October 2008
Seven Ethical Pillars of Clinical Research
AUTONOMY
BENEFICENCE
NON ndash MALFEASANCE
FIDELITY
TRUTHFULNESS
CONFIDENTIALITY
JUSTICE
Declaration of Helsinki
Autonomy
Consent
Para 20 The subjects must be volunteers andinformed participants in the research project
Para 22 freely-given informed consent
preferably in writing
Declaration of Helsinki
Para 5 well-being of the human subject shouldtake precedence over the interests of scienceand society
Beneficence
Declaration of Helsinki
Para 16
bull Preceded by careful assessment ofpredictable risks and burdens
bull Attempt to avoid any act or treatmentplan that would harm the patient
Non Malfeasance
Declaration of Helsinki
Para 11
Medical research involving human subjects must be basedon generally accepted scientific principles thoroughknowledge of the scientific literature and on adequatelaboratory and where appropriate animalexperimentation
Para 15
Conducted only by clinically competent medical person
Fidelity ndash duty of care
Declaration of Helsinki
Para 27
Both authors amp investigators are obliged topreserve the accuracy of the results Negativeas well as positive results should be published
Truthfulness - Honesty
Declaration of Helsinki
Para 21
Every precaution should be taken torespect the privacy of the subject theconfidentiality of the patients information
Confidentiality
Declaration of Helsinki
Para 30
Every patient entered into the study should be assured ofaccess to the best proven prophylactic diagnostic andtherapeutic methods identified by the study
Para 9
Research Investigators should be aware of the ethicallegal and regulatory requirements for research on humansubjects
Para 17
Physicians should cease any investigation if the risksoutweigh the potential benefits
Justice
DECLARATION OF HELSINKI -Basic Principles
1 Conform to accepted scientific principles
2 Design formulated in experimental protocol reviewed by IEC
3 Conducted by qualified and trained persons
4 Importance in proportion to inherent risk
5 Assessment of risks vs benefits
6 Safeguard subjectrsquos integrity (privacy)
7 Abstain unless hazards are predictable
8 Preserve accuracy when publishing
9 Adequately inform or right to withdraw
10 Obtain true informed consent in writing
11 Reliance on legal guardian
12 State compliance with Declaration
Ethical Principles and Guidelines for the Protection of Human Subjects of Research
bull Tuskegee Syphilis Study (1932ndash1972)
bull Named the Belmont Report for the Belmont Conference Center where the National Commission met when first drafting the report
42
Belmont Report 1979
Belmont Report 1979
Three ethical principles related to research on human subjects
1 Respect for Persons
2 Beneficence Do no harm while maximizing benefits for research project and minimizing risks to the research subjects
3 Justice ensuring reasonable non-exploitative and well-considered procedures are administered
Overview of
ICH GCP
What is ICH
bull The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)- is unique in bringing together the regulatory authorities and pharmaceutical industry of Europe Japan and the US to discuss scientific and technical aspects of drug registration
45
What is ICH
bull Since its inception in 1990 ICH has
gradually evolved
bull ICHs mission is to ensure that safe
effective and high quality medicines are
developed and registered in the most
resource-efficient manner
How did it evolve
The need to harmonize
bull Public disasters serious fraud and abuse of human rights
bull Trials of War criminals-Nuremberg code 1949
bull Thalidomide- Declaration of Helsinki 1964
bull Belmont report 1978 (Ethical Principles and guidelines for the protection of human subjects of research)-Tuskegee syphilis study
History
1962 US FDA IND Guidelines
1964 Declaration of Helsinki
1968 Committee on Safety of Medicines uk
1978 GCP US FDA
1991 GCP Europe
1996 ICH GCP
1997 ICH GCP Guideline
When did it begin
bull Ist conf in 1990 in Brussels
3 regions participated
bull Representatives from
Industry
Academia
Ministry of
health
ICH parties
6 parties
bull EU bull EFPIA European federation of pharmaceutical industriesrsquo associations
bull MHLW Ministry of health Labor and welfare Japan
bull JPMA Japan Pharmaceuticals manufacturers Association
bull US FDA
bull PhRMA
bull Observers WHO TPP(canada)
bull International federation of Pharmaceutical manufacturerrsquos association
Key objective
bull To discuss and define the minimum standards for the development and registration of investigational products
The result
Many guidelines made
bull Most important- ICH GCP guidelines
bull Evolved in several steps
bull Consolidated guideline ICH E6 Sept 1997
ICH Guidelines examples
bull Efficacy ndash clinical trials etc
bull Safety ndash pharmacovigilance adverse drug reaction
reporting
bull Quality ndash raw materials impurities residual solvents etc
bull Multidisciplinary ndash common technical document electronic
submission coding systems
What is GCP
A standard for the design conduct performance monitoring auditing recording analyses and reporting of clinical trials that provide assurance that the data and the reported results are credible accurate and that the rights integrity and confidentiality of trial subjects are protected
Why is it needed
bull To ensure the rights safety and well being of the trial subjects are protected
bull Ensure the credibility of clinical trial data
The ICH GCP guideline
bull Provide a unified standard for the EU Japan and USA regions to facilitate mutual acceptance of clinical trial data by the regulatory authorities in
these regions
bull 8 sections
ICH GCP guideline
1 Glossary
Common language for investigatorssponsorsethics committees
2Principles of Good Clinical Practice
13 tenets of ICH GCP
3Requirements for IRBIEC
Roles responsibilities and composition
ICH GCP guideline
4Responsibilities of the investigator
5Responsibilities of the sponsor
6Requirements for clinical trial protocol and protocol amendments
7Responsibility of the sponsor in the development of investigatorrsquos brochure
8Essential documents
Principles of ICH GCP
bull Ethical conduct as per
Declaration of Helsinki
GCP
Regulatory Requirements
Risk- Benefit
Primary concern- Subject
Principles of ICH GCP
bull Supportive data
bull Protocol
Scientifically sound clear detailed
bull Ethical Clearance
Study to be conducted in compliance to the protocol which has received EC approval
Principles of ICH GCP
bull Subject Care
Medical decisions responsibility of qualified physician
bull Qualified staff
By education training experience in their area of responsibility
bull Informed Consent
Principles of ICH GCP
bull Clinical Trial data
Recorded handled and stored to enable accurate reporting interpretation and verification
bull Confidentiality
Principles of ICH GCP
bull Investigational Product
Manufactured handled and stored as per GMP
Principles of ICH GCP
bull Quality Assurance
Systems and procedures to ensure the Quality of every aspect of the trial
Indian GCP guidelines
bull Released in Dec 2001(Developed by CDCSO and endorsed by DCGI)
bull In general in line with ICH GCP
bull Has Revised Schedule Y (Jan 2005) addressed discrepancies
bull SAFEGUARD PUBLIC HEALTH
bull ASSURE CONSUMER PROTECTION STANDARDS
bull FACILITATE AVAILABILITY OF SAFE AND EFFECTIVE PRODUCTS
bull ELIMINATE INCONSISTENT STANDARDS INTERNATIONALLY
bull FACILITATE MUTUAL ACCEPTANCE OF DATA FROM CLINICAL TRIALS
GOALS OF INTERNATIONAL HARMONIZATION OF
REGULATORY REQUIREMENTS
Study DocumentationDuring the study
The investigator must keepndash Source documents
bull Medical records (including access to computer records)
bull Laboratory reports
bull ECGs X-rays etc
bull Any other medical records reports or notes (hospital admissions and discharges)
ndash A subject identification list
ndash Copies of all study related documentation
Medical Records
bull In particular they should contain notes on
ndash Sufficient information to support subject eligibility
ndash This should be well documented (signed and dated)
ndash Subjectrsquos participation in the study
ndash Dates of visits
ndash Procedures investigations done
ndash Observations diagnoses
ndash Medications taken (including study medication)
ndash Adverse events
ndash Completion or withdrawal (reason) from the study
Study DocumentationAfter the study
The sponsor needs from the investigator
ndash Final drug accountability records
ndash All used and unused supplies and medication
ndash All required documents completed
Conclusion
70
Thanks
ldquoWhen a doctor [goes] wrong he is
the first of criminals He has nerve
and he has knowledgerdquo
- Sherlock Holmes
References
httpwwwwmanetepolicyb3htm
wwwhhsgovohrphumansubjectsguidancebelmonthtml
wwwhhsgovohrpreferencesnurcodehtml
wwwicmrnicinguidelinesGCLP
wwwcdsconicin
wwwubedurecercaBioeticadocDeclaracio_Helsinki_2013
wwwjewishvirtuallibraryorgjsourceHolocaustnazi_experiments
wwwichorgfileadminPublic_WebICHE6_R1__Guideline
THE DECLARATION OF HELSINKI-1964
Is an international standard for the conduct of clinicalresearch adopted by International Conference onHarmonization(ICH) Good Clinical Practice standards
A global ethical standard for medical research and wasapproved at the WMA General Assembly by a majority voteof 75
It is the mission of the clinical research professionals tosafeguard the health of the people
THE DECLARATION OF HELSINKI-1964
Historical Overview-
Its origin has been found in the Nazi Disaster and hasundergone several modifications
Prior to 1947 Nuremberg Code there was noaccepted code of conduct governing the ethicalaspects of human research
World Medical Association
It is an international organization of physicians
established on September 17 1947
First general Assembly of WMA was held in Paris
France
Mission- Serve humanity by endeavoring to achieve the
highest international standards in medical education
science ethics and health care for all peoples of the world
Declaration of Helsinki 1964
Adapted from Nuremberg
Code by the World Medical Association (WMA)
First adopted in Helsinki Finland 1964
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI- 2008
Ethical Principles for Medical Research Involving Human Subjects
Adopted by the 18th WMA General Assembly Helsinki Finland June 1964 and amended by the
29th WMA General Assembly Tokyo Japan October 1975
35th WMA General Assembly Venice Italy October 1983
41st WMA General Assembly Hong Kong September 1989
53th WMA General Assembly Washington 2002 (Note of Clarification on paragraph 29 added)
55th WMA General Assembly Tokyo 2004 (Note of Clarification on Paragraph 30 added)
59th WMA General Assembly Seoul October 2008
Seven Ethical Pillars of Clinical Research
AUTONOMY
BENEFICENCE
NON ndash MALFEASANCE
FIDELITY
TRUTHFULNESS
CONFIDENTIALITY
JUSTICE
Declaration of Helsinki
Autonomy
Consent
Para 20 The subjects must be volunteers andinformed participants in the research project
Para 22 freely-given informed consent
preferably in writing
Declaration of Helsinki
Para 5 well-being of the human subject shouldtake precedence over the interests of scienceand society
Beneficence
Declaration of Helsinki
Para 16
bull Preceded by careful assessment ofpredictable risks and burdens
bull Attempt to avoid any act or treatmentplan that would harm the patient
Non Malfeasance
Declaration of Helsinki
Para 11
Medical research involving human subjects must be basedon generally accepted scientific principles thoroughknowledge of the scientific literature and on adequatelaboratory and where appropriate animalexperimentation
Para 15
Conducted only by clinically competent medical person
Fidelity ndash duty of care
Declaration of Helsinki
Para 27
Both authors amp investigators are obliged topreserve the accuracy of the results Negativeas well as positive results should be published
Truthfulness - Honesty
Declaration of Helsinki
Para 21
Every precaution should be taken torespect the privacy of the subject theconfidentiality of the patients information
Confidentiality
Declaration of Helsinki
Para 30
Every patient entered into the study should be assured ofaccess to the best proven prophylactic diagnostic andtherapeutic methods identified by the study
Para 9
Research Investigators should be aware of the ethicallegal and regulatory requirements for research on humansubjects
Para 17
Physicians should cease any investigation if the risksoutweigh the potential benefits
Justice
DECLARATION OF HELSINKI -Basic Principles
1 Conform to accepted scientific principles
2 Design formulated in experimental protocol reviewed by IEC
3 Conducted by qualified and trained persons
4 Importance in proportion to inherent risk
5 Assessment of risks vs benefits
6 Safeguard subjectrsquos integrity (privacy)
7 Abstain unless hazards are predictable
8 Preserve accuracy when publishing
9 Adequately inform or right to withdraw
10 Obtain true informed consent in writing
11 Reliance on legal guardian
12 State compliance with Declaration
Ethical Principles and Guidelines for the Protection of Human Subjects of Research
bull Tuskegee Syphilis Study (1932ndash1972)
bull Named the Belmont Report for the Belmont Conference Center where the National Commission met when first drafting the report
42
Belmont Report 1979
Belmont Report 1979
Three ethical principles related to research on human subjects
1 Respect for Persons
2 Beneficence Do no harm while maximizing benefits for research project and minimizing risks to the research subjects
3 Justice ensuring reasonable non-exploitative and well-considered procedures are administered
Overview of
ICH GCP
What is ICH
bull The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)- is unique in bringing together the regulatory authorities and pharmaceutical industry of Europe Japan and the US to discuss scientific and technical aspects of drug registration
45
What is ICH
bull Since its inception in 1990 ICH has
gradually evolved
bull ICHs mission is to ensure that safe
effective and high quality medicines are
developed and registered in the most
resource-efficient manner
How did it evolve
The need to harmonize
bull Public disasters serious fraud and abuse of human rights
bull Trials of War criminals-Nuremberg code 1949
bull Thalidomide- Declaration of Helsinki 1964
bull Belmont report 1978 (Ethical Principles and guidelines for the protection of human subjects of research)-Tuskegee syphilis study
History
1962 US FDA IND Guidelines
1964 Declaration of Helsinki
1968 Committee on Safety of Medicines uk
1978 GCP US FDA
1991 GCP Europe
1996 ICH GCP
1997 ICH GCP Guideline
When did it begin
bull Ist conf in 1990 in Brussels
3 regions participated
bull Representatives from
Industry
Academia
Ministry of
health
ICH parties
6 parties
bull EU bull EFPIA European federation of pharmaceutical industriesrsquo associations
bull MHLW Ministry of health Labor and welfare Japan
bull JPMA Japan Pharmaceuticals manufacturers Association
bull US FDA
bull PhRMA
bull Observers WHO TPP(canada)
bull International federation of Pharmaceutical manufacturerrsquos association
Key objective
bull To discuss and define the minimum standards for the development and registration of investigational products
The result
Many guidelines made
bull Most important- ICH GCP guidelines
bull Evolved in several steps
bull Consolidated guideline ICH E6 Sept 1997
ICH Guidelines examples
bull Efficacy ndash clinical trials etc
bull Safety ndash pharmacovigilance adverse drug reaction
reporting
bull Quality ndash raw materials impurities residual solvents etc
bull Multidisciplinary ndash common technical document electronic
submission coding systems
What is GCP
A standard for the design conduct performance monitoring auditing recording analyses and reporting of clinical trials that provide assurance that the data and the reported results are credible accurate and that the rights integrity and confidentiality of trial subjects are protected
Why is it needed
bull To ensure the rights safety and well being of the trial subjects are protected
bull Ensure the credibility of clinical trial data
The ICH GCP guideline
bull Provide a unified standard for the EU Japan and USA regions to facilitate mutual acceptance of clinical trial data by the regulatory authorities in
these regions
bull 8 sections
ICH GCP guideline
1 Glossary
Common language for investigatorssponsorsethics committees
2Principles of Good Clinical Practice
13 tenets of ICH GCP
3Requirements for IRBIEC
Roles responsibilities and composition
ICH GCP guideline
4Responsibilities of the investigator
5Responsibilities of the sponsor
6Requirements for clinical trial protocol and protocol amendments
7Responsibility of the sponsor in the development of investigatorrsquos brochure
8Essential documents
Principles of ICH GCP
bull Ethical conduct as per
Declaration of Helsinki
GCP
Regulatory Requirements
Risk- Benefit
Primary concern- Subject
Principles of ICH GCP
bull Supportive data
bull Protocol
Scientifically sound clear detailed
bull Ethical Clearance
Study to be conducted in compliance to the protocol which has received EC approval
Principles of ICH GCP
bull Subject Care
Medical decisions responsibility of qualified physician
bull Qualified staff
By education training experience in their area of responsibility
bull Informed Consent
Principles of ICH GCP
bull Clinical Trial data
Recorded handled and stored to enable accurate reporting interpretation and verification
bull Confidentiality
Principles of ICH GCP
bull Investigational Product
Manufactured handled and stored as per GMP
Principles of ICH GCP
bull Quality Assurance
Systems and procedures to ensure the Quality of every aspect of the trial
Indian GCP guidelines
bull Released in Dec 2001(Developed by CDCSO and endorsed by DCGI)
bull In general in line with ICH GCP
bull Has Revised Schedule Y (Jan 2005) addressed discrepancies
bull SAFEGUARD PUBLIC HEALTH
bull ASSURE CONSUMER PROTECTION STANDARDS
bull FACILITATE AVAILABILITY OF SAFE AND EFFECTIVE PRODUCTS
bull ELIMINATE INCONSISTENT STANDARDS INTERNATIONALLY
bull FACILITATE MUTUAL ACCEPTANCE OF DATA FROM CLINICAL TRIALS
GOALS OF INTERNATIONAL HARMONIZATION OF
REGULATORY REQUIREMENTS
Study DocumentationDuring the study
The investigator must keepndash Source documents
bull Medical records (including access to computer records)
bull Laboratory reports
bull ECGs X-rays etc
bull Any other medical records reports or notes (hospital admissions and discharges)
ndash A subject identification list
ndash Copies of all study related documentation
Medical Records
bull In particular they should contain notes on
ndash Sufficient information to support subject eligibility
ndash This should be well documented (signed and dated)
ndash Subjectrsquos participation in the study
ndash Dates of visits
ndash Procedures investigations done
ndash Observations diagnoses
ndash Medications taken (including study medication)
ndash Adverse events
ndash Completion or withdrawal (reason) from the study
Study DocumentationAfter the study
The sponsor needs from the investigator
ndash Final drug accountability records
ndash All used and unused supplies and medication
ndash All required documents completed
Conclusion
70
Thanks
ldquoWhen a doctor [goes] wrong he is
the first of criminals He has nerve
and he has knowledgerdquo
- Sherlock Holmes
References
httpwwwwmanetepolicyb3htm
wwwhhsgovohrphumansubjectsguidancebelmonthtml
wwwhhsgovohrpreferencesnurcodehtml
wwwicmrnicinguidelinesGCLP
wwwcdsconicin
wwwubedurecercaBioeticadocDeclaracio_Helsinki_2013
wwwjewishvirtuallibraryorgjsourceHolocaustnazi_experiments
wwwichorgfileadminPublic_WebICHE6_R1__Guideline
Is an international standard for the conduct of clinicalresearch adopted by International Conference onHarmonization(ICH) Good Clinical Practice standards
A global ethical standard for medical research and wasapproved at the WMA General Assembly by a majority voteof 75
It is the mission of the clinical research professionals tosafeguard the health of the people
THE DECLARATION OF HELSINKI-1964
Historical Overview-
Its origin has been found in the Nazi Disaster and hasundergone several modifications
Prior to 1947 Nuremberg Code there was noaccepted code of conduct governing the ethicalaspects of human research
World Medical Association
It is an international organization of physicians
established on September 17 1947
First general Assembly of WMA was held in Paris
France
Mission- Serve humanity by endeavoring to achieve the
highest international standards in medical education
science ethics and health care for all peoples of the world
Declaration of Helsinki 1964
Adapted from Nuremberg
Code by the World Medical Association (WMA)
First adopted in Helsinki Finland 1964
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI- 2008
Ethical Principles for Medical Research Involving Human Subjects
Adopted by the 18th WMA General Assembly Helsinki Finland June 1964 and amended by the
29th WMA General Assembly Tokyo Japan October 1975
35th WMA General Assembly Venice Italy October 1983
41st WMA General Assembly Hong Kong September 1989
53th WMA General Assembly Washington 2002 (Note of Clarification on paragraph 29 added)
55th WMA General Assembly Tokyo 2004 (Note of Clarification on Paragraph 30 added)
59th WMA General Assembly Seoul October 2008
Seven Ethical Pillars of Clinical Research
AUTONOMY
BENEFICENCE
NON ndash MALFEASANCE
FIDELITY
TRUTHFULNESS
CONFIDENTIALITY
JUSTICE
Declaration of Helsinki
Autonomy
Consent
Para 20 The subjects must be volunteers andinformed participants in the research project
Para 22 freely-given informed consent
preferably in writing
Declaration of Helsinki
Para 5 well-being of the human subject shouldtake precedence over the interests of scienceand society
Beneficence
Declaration of Helsinki
Para 16
bull Preceded by careful assessment ofpredictable risks and burdens
bull Attempt to avoid any act or treatmentplan that would harm the patient
Non Malfeasance
Declaration of Helsinki
Para 11
Medical research involving human subjects must be basedon generally accepted scientific principles thoroughknowledge of the scientific literature and on adequatelaboratory and where appropriate animalexperimentation
Para 15
Conducted only by clinically competent medical person
Fidelity ndash duty of care
Declaration of Helsinki
Para 27
Both authors amp investigators are obliged topreserve the accuracy of the results Negativeas well as positive results should be published
Truthfulness - Honesty
Declaration of Helsinki
Para 21
Every precaution should be taken torespect the privacy of the subject theconfidentiality of the patients information
Confidentiality
Declaration of Helsinki
Para 30
Every patient entered into the study should be assured ofaccess to the best proven prophylactic diagnostic andtherapeutic methods identified by the study
Para 9
Research Investigators should be aware of the ethicallegal and regulatory requirements for research on humansubjects
Para 17
Physicians should cease any investigation if the risksoutweigh the potential benefits
Justice
DECLARATION OF HELSINKI -Basic Principles
1 Conform to accepted scientific principles
2 Design formulated in experimental protocol reviewed by IEC
3 Conducted by qualified and trained persons
4 Importance in proportion to inherent risk
5 Assessment of risks vs benefits
6 Safeguard subjectrsquos integrity (privacy)
7 Abstain unless hazards are predictable
8 Preserve accuracy when publishing
9 Adequately inform or right to withdraw
10 Obtain true informed consent in writing
11 Reliance on legal guardian
12 State compliance with Declaration
Ethical Principles and Guidelines for the Protection of Human Subjects of Research
bull Tuskegee Syphilis Study (1932ndash1972)
bull Named the Belmont Report for the Belmont Conference Center where the National Commission met when first drafting the report
42
Belmont Report 1979
Belmont Report 1979
Three ethical principles related to research on human subjects
1 Respect for Persons
2 Beneficence Do no harm while maximizing benefits for research project and minimizing risks to the research subjects
3 Justice ensuring reasonable non-exploitative and well-considered procedures are administered
Overview of
ICH GCP
What is ICH
bull The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)- is unique in bringing together the regulatory authorities and pharmaceutical industry of Europe Japan and the US to discuss scientific and technical aspects of drug registration
45
What is ICH
bull Since its inception in 1990 ICH has
gradually evolved
bull ICHs mission is to ensure that safe
effective and high quality medicines are
developed and registered in the most
resource-efficient manner
How did it evolve
The need to harmonize
bull Public disasters serious fraud and abuse of human rights
bull Trials of War criminals-Nuremberg code 1949
bull Thalidomide- Declaration of Helsinki 1964
bull Belmont report 1978 (Ethical Principles and guidelines for the protection of human subjects of research)-Tuskegee syphilis study
History
1962 US FDA IND Guidelines
1964 Declaration of Helsinki
1968 Committee on Safety of Medicines uk
1978 GCP US FDA
1991 GCP Europe
1996 ICH GCP
1997 ICH GCP Guideline
When did it begin
bull Ist conf in 1990 in Brussels
3 regions participated
bull Representatives from
Industry
Academia
Ministry of
health
ICH parties
6 parties
bull EU bull EFPIA European federation of pharmaceutical industriesrsquo associations
bull MHLW Ministry of health Labor and welfare Japan
bull JPMA Japan Pharmaceuticals manufacturers Association
bull US FDA
bull PhRMA
bull Observers WHO TPP(canada)
bull International federation of Pharmaceutical manufacturerrsquos association
Key objective
bull To discuss and define the minimum standards for the development and registration of investigational products
The result
Many guidelines made
bull Most important- ICH GCP guidelines
bull Evolved in several steps
bull Consolidated guideline ICH E6 Sept 1997
ICH Guidelines examples
bull Efficacy ndash clinical trials etc
bull Safety ndash pharmacovigilance adverse drug reaction
reporting
bull Quality ndash raw materials impurities residual solvents etc
bull Multidisciplinary ndash common technical document electronic
submission coding systems
What is GCP
A standard for the design conduct performance monitoring auditing recording analyses and reporting of clinical trials that provide assurance that the data and the reported results are credible accurate and that the rights integrity and confidentiality of trial subjects are protected
Why is it needed
bull To ensure the rights safety and well being of the trial subjects are protected
bull Ensure the credibility of clinical trial data
The ICH GCP guideline
bull Provide a unified standard for the EU Japan and USA regions to facilitate mutual acceptance of clinical trial data by the regulatory authorities in
these regions
bull 8 sections
ICH GCP guideline
1 Glossary
Common language for investigatorssponsorsethics committees
2Principles of Good Clinical Practice
13 tenets of ICH GCP
3Requirements for IRBIEC
Roles responsibilities and composition
ICH GCP guideline
4Responsibilities of the investigator
5Responsibilities of the sponsor
6Requirements for clinical trial protocol and protocol amendments
7Responsibility of the sponsor in the development of investigatorrsquos brochure
8Essential documents
Principles of ICH GCP
bull Ethical conduct as per
Declaration of Helsinki
GCP
Regulatory Requirements
Risk- Benefit
Primary concern- Subject
Principles of ICH GCP
bull Supportive data
bull Protocol
Scientifically sound clear detailed
bull Ethical Clearance
Study to be conducted in compliance to the protocol which has received EC approval
Principles of ICH GCP
bull Subject Care
Medical decisions responsibility of qualified physician
bull Qualified staff
By education training experience in their area of responsibility
bull Informed Consent
Principles of ICH GCP
bull Clinical Trial data
Recorded handled and stored to enable accurate reporting interpretation and verification
bull Confidentiality
Principles of ICH GCP
bull Investigational Product
Manufactured handled and stored as per GMP
Principles of ICH GCP
bull Quality Assurance
Systems and procedures to ensure the Quality of every aspect of the trial
Indian GCP guidelines
bull Released in Dec 2001(Developed by CDCSO and endorsed by DCGI)
bull In general in line with ICH GCP
bull Has Revised Schedule Y (Jan 2005) addressed discrepancies
bull SAFEGUARD PUBLIC HEALTH
bull ASSURE CONSUMER PROTECTION STANDARDS
bull FACILITATE AVAILABILITY OF SAFE AND EFFECTIVE PRODUCTS
bull ELIMINATE INCONSISTENT STANDARDS INTERNATIONALLY
bull FACILITATE MUTUAL ACCEPTANCE OF DATA FROM CLINICAL TRIALS
GOALS OF INTERNATIONAL HARMONIZATION OF
REGULATORY REQUIREMENTS
Study DocumentationDuring the study
The investigator must keepndash Source documents
bull Medical records (including access to computer records)
bull Laboratory reports
bull ECGs X-rays etc
bull Any other medical records reports or notes (hospital admissions and discharges)
ndash A subject identification list
ndash Copies of all study related documentation
Medical Records
bull In particular they should contain notes on
ndash Sufficient information to support subject eligibility
ndash This should be well documented (signed and dated)
ndash Subjectrsquos participation in the study
ndash Dates of visits
ndash Procedures investigations done
ndash Observations diagnoses
ndash Medications taken (including study medication)
ndash Adverse events
ndash Completion or withdrawal (reason) from the study
Study DocumentationAfter the study
The sponsor needs from the investigator
ndash Final drug accountability records
ndash All used and unused supplies and medication
ndash All required documents completed
Conclusion
70
Thanks
ldquoWhen a doctor [goes] wrong he is
the first of criminals He has nerve
and he has knowledgerdquo
- Sherlock Holmes
References
httpwwwwmanetepolicyb3htm
wwwhhsgovohrphumansubjectsguidancebelmonthtml
wwwhhsgovohrpreferencesnurcodehtml
wwwicmrnicinguidelinesGCLP
wwwcdsconicin
wwwubedurecercaBioeticadocDeclaracio_Helsinki_2013
wwwjewishvirtuallibraryorgjsourceHolocaustnazi_experiments
wwwichorgfileadminPublic_WebICHE6_R1__Guideline
Historical Overview-
Its origin has been found in the Nazi Disaster and hasundergone several modifications
Prior to 1947 Nuremberg Code there was noaccepted code of conduct governing the ethicalaspects of human research
World Medical Association
It is an international organization of physicians
established on September 17 1947
First general Assembly of WMA was held in Paris
France
Mission- Serve humanity by endeavoring to achieve the
highest international standards in medical education
science ethics and health care for all peoples of the world
Declaration of Helsinki 1964
Adapted from Nuremberg
Code by the World Medical Association (WMA)
First adopted in Helsinki Finland 1964
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI- 2008
Ethical Principles for Medical Research Involving Human Subjects
Adopted by the 18th WMA General Assembly Helsinki Finland June 1964 and amended by the
29th WMA General Assembly Tokyo Japan October 1975
35th WMA General Assembly Venice Italy October 1983
41st WMA General Assembly Hong Kong September 1989
53th WMA General Assembly Washington 2002 (Note of Clarification on paragraph 29 added)
55th WMA General Assembly Tokyo 2004 (Note of Clarification on Paragraph 30 added)
59th WMA General Assembly Seoul October 2008
Seven Ethical Pillars of Clinical Research
AUTONOMY
BENEFICENCE
NON ndash MALFEASANCE
FIDELITY
TRUTHFULNESS
CONFIDENTIALITY
JUSTICE
Declaration of Helsinki
Autonomy
Consent
Para 20 The subjects must be volunteers andinformed participants in the research project
Para 22 freely-given informed consent
preferably in writing
Declaration of Helsinki
Para 5 well-being of the human subject shouldtake precedence over the interests of scienceand society
Beneficence
Declaration of Helsinki
Para 16
bull Preceded by careful assessment ofpredictable risks and burdens
bull Attempt to avoid any act or treatmentplan that would harm the patient
Non Malfeasance
Declaration of Helsinki
Para 11
Medical research involving human subjects must be basedon generally accepted scientific principles thoroughknowledge of the scientific literature and on adequatelaboratory and where appropriate animalexperimentation
Para 15
Conducted only by clinically competent medical person
Fidelity ndash duty of care
Declaration of Helsinki
Para 27
Both authors amp investigators are obliged topreserve the accuracy of the results Negativeas well as positive results should be published
Truthfulness - Honesty
Declaration of Helsinki
Para 21
Every precaution should be taken torespect the privacy of the subject theconfidentiality of the patients information
Confidentiality
Declaration of Helsinki
Para 30
Every patient entered into the study should be assured ofaccess to the best proven prophylactic diagnostic andtherapeutic methods identified by the study
Para 9
Research Investigators should be aware of the ethicallegal and regulatory requirements for research on humansubjects
Para 17
Physicians should cease any investigation if the risksoutweigh the potential benefits
Justice
DECLARATION OF HELSINKI -Basic Principles
1 Conform to accepted scientific principles
2 Design formulated in experimental protocol reviewed by IEC
3 Conducted by qualified and trained persons
4 Importance in proportion to inherent risk
5 Assessment of risks vs benefits
6 Safeguard subjectrsquos integrity (privacy)
7 Abstain unless hazards are predictable
8 Preserve accuracy when publishing
9 Adequately inform or right to withdraw
10 Obtain true informed consent in writing
11 Reliance on legal guardian
12 State compliance with Declaration
Ethical Principles and Guidelines for the Protection of Human Subjects of Research
bull Tuskegee Syphilis Study (1932ndash1972)
bull Named the Belmont Report for the Belmont Conference Center where the National Commission met when first drafting the report
42
Belmont Report 1979
Belmont Report 1979
Three ethical principles related to research on human subjects
1 Respect for Persons
2 Beneficence Do no harm while maximizing benefits for research project and minimizing risks to the research subjects
3 Justice ensuring reasonable non-exploitative and well-considered procedures are administered
Overview of
ICH GCP
What is ICH
bull The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)- is unique in bringing together the regulatory authorities and pharmaceutical industry of Europe Japan and the US to discuss scientific and technical aspects of drug registration
45
What is ICH
bull Since its inception in 1990 ICH has
gradually evolved
bull ICHs mission is to ensure that safe
effective and high quality medicines are
developed and registered in the most
resource-efficient manner
How did it evolve
The need to harmonize
bull Public disasters serious fraud and abuse of human rights
bull Trials of War criminals-Nuremberg code 1949
bull Thalidomide- Declaration of Helsinki 1964
bull Belmont report 1978 (Ethical Principles and guidelines for the protection of human subjects of research)-Tuskegee syphilis study
History
1962 US FDA IND Guidelines
1964 Declaration of Helsinki
1968 Committee on Safety of Medicines uk
1978 GCP US FDA
1991 GCP Europe
1996 ICH GCP
1997 ICH GCP Guideline
When did it begin
bull Ist conf in 1990 in Brussels
3 regions participated
bull Representatives from
Industry
Academia
Ministry of
health
ICH parties
6 parties
bull EU bull EFPIA European federation of pharmaceutical industriesrsquo associations
bull MHLW Ministry of health Labor and welfare Japan
bull JPMA Japan Pharmaceuticals manufacturers Association
bull US FDA
bull PhRMA
bull Observers WHO TPP(canada)
bull International federation of Pharmaceutical manufacturerrsquos association
Key objective
bull To discuss and define the minimum standards for the development and registration of investigational products
The result
Many guidelines made
bull Most important- ICH GCP guidelines
bull Evolved in several steps
bull Consolidated guideline ICH E6 Sept 1997
ICH Guidelines examples
bull Efficacy ndash clinical trials etc
bull Safety ndash pharmacovigilance adverse drug reaction
reporting
bull Quality ndash raw materials impurities residual solvents etc
bull Multidisciplinary ndash common technical document electronic
submission coding systems
What is GCP
A standard for the design conduct performance monitoring auditing recording analyses and reporting of clinical trials that provide assurance that the data and the reported results are credible accurate and that the rights integrity and confidentiality of trial subjects are protected
Why is it needed
bull To ensure the rights safety and well being of the trial subjects are protected
bull Ensure the credibility of clinical trial data
The ICH GCP guideline
bull Provide a unified standard for the EU Japan and USA regions to facilitate mutual acceptance of clinical trial data by the regulatory authorities in
these regions
bull 8 sections
ICH GCP guideline
1 Glossary
Common language for investigatorssponsorsethics committees
2Principles of Good Clinical Practice
13 tenets of ICH GCP
3Requirements for IRBIEC
Roles responsibilities and composition
ICH GCP guideline
4Responsibilities of the investigator
5Responsibilities of the sponsor
6Requirements for clinical trial protocol and protocol amendments
7Responsibility of the sponsor in the development of investigatorrsquos brochure
8Essential documents
Principles of ICH GCP
bull Ethical conduct as per
Declaration of Helsinki
GCP
Regulatory Requirements
Risk- Benefit
Primary concern- Subject
Principles of ICH GCP
bull Supportive data
bull Protocol
Scientifically sound clear detailed
bull Ethical Clearance
Study to be conducted in compliance to the protocol which has received EC approval
Principles of ICH GCP
bull Subject Care
Medical decisions responsibility of qualified physician
bull Qualified staff
By education training experience in their area of responsibility
bull Informed Consent
Principles of ICH GCP
bull Clinical Trial data
Recorded handled and stored to enable accurate reporting interpretation and verification
bull Confidentiality
Principles of ICH GCP
bull Investigational Product
Manufactured handled and stored as per GMP
Principles of ICH GCP
bull Quality Assurance
Systems and procedures to ensure the Quality of every aspect of the trial
Indian GCP guidelines
bull Released in Dec 2001(Developed by CDCSO and endorsed by DCGI)
bull In general in line with ICH GCP
bull Has Revised Schedule Y (Jan 2005) addressed discrepancies
bull SAFEGUARD PUBLIC HEALTH
bull ASSURE CONSUMER PROTECTION STANDARDS
bull FACILITATE AVAILABILITY OF SAFE AND EFFECTIVE PRODUCTS
bull ELIMINATE INCONSISTENT STANDARDS INTERNATIONALLY
bull FACILITATE MUTUAL ACCEPTANCE OF DATA FROM CLINICAL TRIALS
GOALS OF INTERNATIONAL HARMONIZATION OF
REGULATORY REQUIREMENTS
Study DocumentationDuring the study
The investigator must keepndash Source documents
bull Medical records (including access to computer records)
bull Laboratory reports
bull ECGs X-rays etc
bull Any other medical records reports or notes (hospital admissions and discharges)
ndash A subject identification list
ndash Copies of all study related documentation
Medical Records
bull In particular they should contain notes on
ndash Sufficient information to support subject eligibility
ndash This should be well documented (signed and dated)
ndash Subjectrsquos participation in the study
ndash Dates of visits
ndash Procedures investigations done
ndash Observations diagnoses
ndash Medications taken (including study medication)
ndash Adverse events
ndash Completion or withdrawal (reason) from the study
Study DocumentationAfter the study
The sponsor needs from the investigator
ndash Final drug accountability records
ndash All used and unused supplies and medication
ndash All required documents completed
Conclusion
70
Thanks
ldquoWhen a doctor [goes] wrong he is
the first of criminals He has nerve
and he has knowledgerdquo
- Sherlock Holmes
References
httpwwwwmanetepolicyb3htm
wwwhhsgovohrphumansubjectsguidancebelmonthtml
wwwhhsgovohrpreferencesnurcodehtml
wwwicmrnicinguidelinesGCLP
wwwcdsconicin
wwwubedurecercaBioeticadocDeclaracio_Helsinki_2013
wwwjewishvirtuallibraryorgjsourceHolocaustnazi_experiments
wwwichorgfileadminPublic_WebICHE6_R1__Guideline
World Medical Association
It is an international organization of physicians
established on September 17 1947
First general Assembly of WMA was held in Paris
France
Mission- Serve humanity by endeavoring to achieve the
highest international standards in medical education
science ethics and health care for all peoples of the world
Declaration of Helsinki 1964
Adapted from Nuremberg
Code by the World Medical Association (WMA)
First adopted in Helsinki Finland 1964
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI- 2008
Ethical Principles for Medical Research Involving Human Subjects
Adopted by the 18th WMA General Assembly Helsinki Finland June 1964 and amended by the
29th WMA General Assembly Tokyo Japan October 1975
35th WMA General Assembly Venice Italy October 1983
41st WMA General Assembly Hong Kong September 1989
53th WMA General Assembly Washington 2002 (Note of Clarification on paragraph 29 added)
55th WMA General Assembly Tokyo 2004 (Note of Clarification on Paragraph 30 added)
59th WMA General Assembly Seoul October 2008
Seven Ethical Pillars of Clinical Research
AUTONOMY
BENEFICENCE
NON ndash MALFEASANCE
FIDELITY
TRUTHFULNESS
CONFIDENTIALITY
JUSTICE
Declaration of Helsinki
Autonomy
Consent
Para 20 The subjects must be volunteers andinformed participants in the research project
Para 22 freely-given informed consent
preferably in writing
Declaration of Helsinki
Para 5 well-being of the human subject shouldtake precedence over the interests of scienceand society
Beneficence
Declaration of Helsinki
Para 16
bull Preceded by careful assessment ofpredictable risks and burdens
bull Attempt to avoid any act or treatmentplan that would harm the patient
Non Malfeasance
Declaration of Helsinki
Para 11
Medical research involving human subjects must be basedon generally accepted scientific principles thoroughknowledge of the scientific literature and on adequatelaboratory and where appropriate animalexperimentation
Para 15
Conducted only by clinically competent medical person
Fidelity ndash duty of care
Declaration of Helsinki
Para 27
Both authors amp investigators are obliged topreserve the accuracy of the results Negativeas well as positive results should be published
Truthfulness - Honesty
Declaration of Helsinki
Para 21
Every precaution should be taken torespect the privacy of the subject theconfidentiality of the patients information
Confidentiality
Declaration of Helsinki
Para 30
Every patient entered into the study should be assured ofaccess to the best proven prophylactic diagnostic andtherapeutic methods identified by the study
Para 9
Research Investigators should be aware of the ethicallegal and regulatory requirements for research on humansubjects
Para 17
Physicians should cease any investigation if the risksoutweigh the potential benefits
Justice
DECLARATION OF HELSINKI -Basic Principles
1 Conform to accepted scientific principles
2 Design formulated in experimental protocol reviewed by IEC
3 Conducted by qualified and trained persons
4 Importance in proportion to inherent risk
5 Assessment of risks vs benefits
6 Safeguard subjectrsquos integrity (privacy)
7 Abstain unless hazards are predictable
8 Preserve accuracy when publishing
9 Adequately inform or right to withdraw
10 Obtain true informed consent in writing
11 Reliance on legal guardian
12 State compliance with Declaration
Ethical Principles and Guidelines for the Protection of Human Subjects of Research
bull Tuskegee Syphilis Study (1932ndash1972)
bull Named the Belmont Report for the Belmont Conference Center where the National Commission met when first drafting the report
42
Belmont Report 1979
Belmont Report 1979
Three ethical principles related to research on human subjects
1 Respect for Persons
2 Beneficence Do no harm while maximizing benefits for research project and minimizing risks to the research subjects
3 Justice ensuring reasonable non-exploitative and well-considered procedures are administered
Overview of
ICH GCP
What is ICH
bull The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)- is unique in bringing together the regulatory authorities and pharmaceutical industry of Europe Japan and the US to discuss scientific and technical aspects of drug registration
45
What is ICH
bull Since its inception in 1990 ICH has
gradually evolved
bull ICHs mission is to ensure that safe
effective and high quality medicines are
developed and registered in the most
resource-efficient manner
How did it evolve
The need to harmonize
bull Public disasters serious fraud and abuse of human rights
bull Trials of War criminals-Nuremberg code 1949
bull Thalidomide- Declaration of Helsinki 1964
bull Belmont report 1978 (Ethical Principles and guidelines for the protection of human subjects of research)-Tuskegee syphilis study
History
1962 US FDA IND Guidelines
1964 Declaration of Helsinki
1968 Committee on Safety of Medicines uk
1978 GCP US FDA
1991 GCP Europe
1996 ICH GCP
1997 ICH GCP Guideline
When did it begin
bull Ist conf in 1990 in Brussels
3 regions participated
bull Representatives from
Industry
Academia
Ministry of
health
ICH parties
6 parties
bull EU bull EFPIA European federation of pharmaceutical industriesrsquo associations
bull MHLW Ministry of health Labor and welfare Japan
bull JPMA Japan Pharmaceuticals manufacturers Association
bull US FDA
bull PhRMA
bull Observers WHO TPP(canada)
bull International federation of Pharmaceutical manufacturerrsquos association
Key objective
bull To discuss and define the minimum standards for the development and registration of investigational products
The result
Many guidelines made
bull Most important- ICH GCP guidelines
bull Evolved in several steps
bull Consolidated guideline ICH E6 Sept 1997
ICH Guidelines examples
bull Efficacy ndash clinical trials etc
bull Safety ndash pharmacovigilance adverse drug reaction
reporting
bull Quality ndash raw materials impurities residual solvents etc
bull Multidisciplinary ndash common technical document electronic
submission coding systems
What is GCP
A standard for the design conduct performance monitoring auditing recording analyses and reporting of clinical trials that provide assurance that the data and the reported results are credible accurate and that the rights integrity and confidentiality of trial subjects are protected
Why is it needed
bull To ensure the rights safety and well being of the trial subjects are protected
bull Ensure the credibility of clinical trial data
The ICH GCP guideline
bull Provide a unified standard for the EU Japan and USA regions to facilitate mutual acceptance of clinical trial data by the regulatory authorities in
these regions
bull 8 sections
ICH GCP guideline
1 Glossary
Common language for investigatorssponsorsethics committees
2Principles of Good Clinical Practice
13 tenets of ICH GCP
3Requirements for IRBIEC
Roles responsibilities and composition
ICH GCP guideline
4Responsibilities of the investigator
5Responsibilities of the sponsor
6Requirements for clinical trial protocol and protocol amendments
7Responsibility of the sponsor in the development of investigatorrsquos brochure
8Essential documents
Principles of ICH GCP
bull Ethical conduct as per
Declaration of Helsinki
GCP
Regulatory Requirements
Risk- Benefit
Primary concern- Subject
Principles of ICH GCP
bull Supportive data
bull Protocol
Scientifically sound clear detailed
bull Ethical Clearance
Study to be conducted in compliance to the protocol which has received EC approval
Principles of ICH GCP
bull Subject Care
Medical decisions responsibility of qualified physician
bull Qualified staff
By education training experience in their area of responsibility
bull Informed Consent
Principles of ICH GCP
bull Clinical Trial data
Recorded handled and stored to enable accurate reporting interpretation and verification
bull Confidentiality
Principles of ICH GCP
bull Investigational Product
Manufactured handled and stored as per GMP
Principles of ICH GCP
bull Quality Assurance
Systems and procedures to ensure the Quality of every aspect of the trial
Indian GCP guidelines
bull Released in Dec 2001(Developed by CDCSO and endorsed by DCGI)
bull In general in line with ICH GCP
bull Has Revised Schedule Y (Jan 2005) addressed discrepancies
bull SAFEGUARD PUBLIC HEALTH
bull ASSURE CONSUMER PROTECTION STANDARDS
bull FACILITATE AVAILABILITY OF SAFE AND EFFECTIVE PRODUCTS
bull ELIMINATE INCONSISTENT STANDARDS INTERNATIONALLY
bull FACILITATE MUTUAL ACCEPTANCE OF DATA FROM CLINICAL TRIALS
GOALS OF INTERNATIONAL HARMONIZATION OF
REGULATORY REQUIREMENTS
Study DocumentationDuring the study
The investigator must keepndash Source documents
bull Medical records (including access to computer records)
bull Laboratory reports
bull ECGs X-rays etc
bull Any other medical records reports or notes (hospital admissions and discharges)
ndash A subject identification list
ndash Copies of all study related documentation
Medical Records
bull In particular they should contain notes on
ndash Sufficient information to support subject eligibility
ndash This should be well documented (signed and dated)
ndash Subjectrsquos participation in the study
ndash Dates of visits
ndash Procedures investigations done
ndash Observations diagnoses
ndash Medications taken (including study medication)
ndash Adverse events
ndash Completion or withdrawal (reason) from the study
Study DocumentationAfter the study
The sponsor needs from the investigator
ndash Final drug accountability records
ndash All used and unused supplies and medication
ndash All required documents completed
Conclusion
70
Thanks
ldquoWhen a doctor [goes] wrong he is
the first of criminals He has nerve
and he has knowledgerdquo
- Sherlock Holmes
References
httpwwwwmanetepolicyb3htm
wwwhhsgovohrphumansubjectsguidancebelmonthtml
wwwhhsgovohrpreferencesnurcodehtml
wwwicmrnicinguidelinesGCLP
wwwcdsconicin
wwwubedurecercaBioeticadocDeclaracio_Helsinki_2013
wwwjewishvirtuallibraryorgjsourceHolocaustnazi_experiments
wwwichorgfileadminPublic_WebICHE6_R1__Guideline
Declaration of Helsinki 1964
Adapted from Nuremberg
Code by the World Medical Association (WMA)
First adopted in Helsinki Finland 1964
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI- 2008
Ethical Principles for Medical Research Involving Human Subjects
Adopted by the 18th WMA General Assembly Helsinki Finland June 1964 and amended by the
29th WMA General Assembly Tokyo Japan October 1975
35th WMA General Assembly Venice Italy October 1983
41st WMA General Assembly Hong Kong September 1989
53th WMA General Assembly Washington 2002 (Note of Clarification on paragraph 29 added)
55th WMA General Assembly Tokyo 2004 (Note of Clarification on Paragraph 30 added)
59th WMA General Assembly Seoul October 2008
Seven Ethical Pillars of Clinical Research
AUTONOMY
BENEFICENCE
NON ndash MALFEASANCE
FIDELITY
TRUTHFULNESS
CONFIDENTIALITY
JUSTICE
Declaration of Helsinki
Autonomy
Consent
Para 20 The subjects must be volunteers andinformed participants in the research project
Para 22 freely-given informed consent
preferably in writing
Declaration of Helsinki
Para 5 well-being of the human subject shouldtake precedence over the interests of scienceand society
Beneficence
Declaration of Helsinki
Para 16
bull Preceded by careful assessment ofpredictable risks and burdens
bull Attempt to avoid any act or treatmentplan that would harm the patient
Non Malfeasance
Declaration of Helsinki
Para 11
Medical research involving human subjects must be basedon generally accepted scientific principles thoroughknowledge of the scientific literature and on adequatelaboratory and where appropriate animalexperimentation
Para 15
Conducted only by clinically competent medical person
Fidelity ndash duty of care
Declaration of Helsinki
Para 27
Both authors amp investigators are obliged topreserve the accuracy of the results Negativeas well as positive results should be published
Truthfulness - Honesty
Declaration of Helsinki
Para 21
Every precaution should be taken torespect the privacy of the subject theconfidentiality of the patients information
Confidentiality
Declaration of Helsinki
Para 30
Every patient entered into the study should be assured ofaccess to the best proven prophylactic diagnostic andtherapeutic methods identified by the study
Para 9
Research Investigators should be aware of the ethicallegal and regulatory requirements for research on humansubjects
Para 17
Physicians should cease any investigation if the risksoutweigh the potential benefits
Justice
DECLARATION OF HELSINKI -Basic Principles
1 Conform to accepted scientific principles
2 Design formulated in experimental protocol reviewed by IEC
3 Conducted by qualified and trained persons
4 Importance in proportion to inherent risk
5 Assessment of risks vs benefits
6 Safeguard subjectrsquos integrity (privacy)
7 Abstain unless hazards are predictable
8 Preserve accuracy when publishing
9 Adequately inform or right to withdraw
10 Obtain true informed consent in writing
11 Reliance on legal guardian
12 State compliance with Declaration
Ethical Principles and Guidelines for the Protection of Human Subjects of Research
bull Tuskegee Syphilis Study (1932ndash1972)
bull Named the Belmont Report for the Belmont Conference Center where the National Commission met when first drafting the report
42
Belmont Report 1979
Belmont Report 1979
Three ethical principles related to research on human subjects
1 Respect for Persons
2 Beneficence Do no harm while maximizing benefits for research project and minimizing risks to the research subjects
3 Justice ensuring reasonable non-exploitative and well-considered procedures are administered
Overview of
ICH GCP
What is ICH
bull The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)- is unique in bringing together the regulatory authorities and pharmaceutical industry of Europe Japan and the US to discuss scientific and technical aspects of drug registration
45
What is ICH
bull Since its inception in 1990 ICH has
gradually evolved
bull ICHs mission is to ensure that safe
effective and high quality medicines are
developed and registered in the most
resource-efficient manner
How did it evolve
The need to harmonize
bull Public disasters serious fraud and abuse of human rights
bull Trials of War criminals-Nuremberg code 1949
bull Thalidomide- Declaration of Helsinki 1964
bull Belmont report 1978 (Ethical Principles and guidelines for the protection of human subjects of research)-Tuskegee syphilis study
History
1962 US FDA IND Guidelines
1964 Declaration of Helsinki
1968 Committee on Safety of Medicines uk
1978 GCP US FDA
1991 GCP Europe
1996 ICH GCP
1997 ICH GCP Guideline
When did it begin
bull Ist conf in 1990 in Brussels
3 regions participated
bull Representatives from
Industry
Academia
Ministry of
health
ICH parties
6 parties
bull EU bull EFPIA European federation of pharmaceutical industriesrsquo associations
bull MHLW Ministry of health Labor and welfare Japan
bull JPMA Japan Pharmaceuticals manufacturers Association
bull US FDA
bull PhRMA
bull Observers WHO TPP(canada)
bull International federation of Pharmaceutical manufacturerrsquos association
Key objective
bull To discuss and define the minimum standards for the development and registration of investigational products
The result
Many guidelines made
bull Most important- ICH GCP guidelines
bull Evolved in several steps
bull Consolidated guideline ICH E6 Sept 1997
ICH Guidelines examples
bull Efficacy ndash clinical trials etc
bull Safety ndash pharmacovigilance adverse drug reaction
reporting
bull Quality ndash raw materials impurities residual solvents etc
bull Multidisciplinary ndash common technical document electronic
submission coding systems
What is GCP
A standard for the design conduct performance monitoring auditing recording analyses and reporting of clinical trials that provide assurance that the data and the reported results are credible accurate and that the rights integrity and confidentiality of trial subjects are protected
Why is it needed
bull To ensure the rights safety and well being of the trial subjects are protected
bull Ensure the credibility of clinical trial data
The ICH GCP guideline
bull Provide a unified standard for the EU Japan and USA regions to facilitate mutual acceptance of clinical trial data by the regulatory authorities in
these regions
bull 8 sections
ICH GCP guideline
1 Glossary
Common language for investigatorssponsorsethics committees
2Principles of Good Clinical Practice
13 tenets of ICH GCP
3Requirements for IRBIEC
Roles responsibilities and composition
ICH GCP guideline
4Responsibilities of the investigator
5Responsibilities of the sponsor
6Requirements for clinical trial protocol and protocol amendments
7Responsibility of the sponsor in the development of investigatorrsquos brochure
8Essential documents
Principles of ICH GCP
bull Ethical conduct as per
Declaration of Helsinki
GCP
Regulatory Requirements
Risk- Benefit
Primary concern- Subject
Principles of ICH GCP
bull Supportive data
bull Protocol
Scientifically sound clear detailed
bull Ethical Clearance
Study to be conducted in compliance to the protocol which has received EC approval
Principles of ICH GCP
bull Subject Care
Medical decisions responsibility of qualified physician
bull Qualified staff
By education training experience in their area of responsibility
bull Informed Consent
Principles of ICH GCP
bull Clinical Trial data
Recorded handled and stored to enable accurate reporting interpretation and verification
bull Confidentiality
Principles of ICH GCP
bull Investigational Product
Manufactured handled and stored as per GMP
Principles of ICH GCP
bull Quality Assurance
Systems and procedures to ensure the Quality of every aspect of the trial
Indian GCP guidelines
bull Released in Dec 2001(Developed by CDCSO and endorsed by DCGI)
bull In general in line with ICH GCP
bull Has Revised Schedule Y (Jan 2005) addressed discrepancies
bull SAFEGUARD PUBLIC HEALTH
bull ASSURE CONSUMER PROTECTION STANDARDS
bull FACILITATE AVAILABILITY OF SAFE AND EFFECTIVE PRODUCTS
bull ELIMINATE INCONSISTENT STANDARDS INTERNATIONALLY
bull FACILITATE MUTUAL ACCEPTANCE OF DATA FROM CLINICAL TRIALS
GOALS OF INTERNATIONAL HARMONIZATION OF
REGULATORY REQUIREMENTS
Study DocumentationDuring the study
The investigator must keepndash Source documents
bull Medical records (including access to computer records)
bull Laboratory reports
bull ECGs X-rays etc
bull Any other medical records reports or notes (hospital admissions and discharges)
ndash A subject identification list
ndash Copies of all study related documentation
Medical Records
bull In particular they should contain notes on
ndash Sufficient information to support subject eligibility
ndash This should be well documented (signed and dated)
ndash Subjectrsquos participation in the study
ndash Dates of visits
ndash Procedures investigations done
ndash Observations diagnoses
ndash Medications taken (including study medication)
ndash Adverse events
ndash Completion or withdrawal (reason) from the study
Study DocumentationAfter the study
The sponsor needs from the investigator
ndash Final drug accountability records
ndash All used and unused supplies and medication
ndash All required documents completed
Conclusion
70
Thanks
ldquoWhen a doctor [goes] wrong he is
the first of criminals He has nerve
and he has knowledgerdquo
- Sherlock Holmes
References
httpwwwwmanetepolicyb3htm
wwwhhsgovohrphumansubjectsguidancebelmonthtml
wwwhhsgovohrpreferencesnurcodehtml
wwwicmrnicinguidelinesGCLP
wwwcdsconicin
wwwubedurecercaBioeticadocDeclaracio_Helsinki_2013
wwwjewishvirtuallibraryorgjsourceHolocaustnazi_experiments
wwwichorgfileadminPublic_WebICHE6_R1__Guideline
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI- 2008
Ethical Principles for Medical Research Involving Human Subjects
Adopted by the 18th WMA General Assembly Helsinki Finland June 1964 and amended by the
29th WMA General Assembly Tokyo Japan October 1975
35th WMA General Assembly Venice Italy October 1983
41st WMA General Assembly Hong Kong September 1989
53th WMA General Assembly Washington 2002 (Note of Clarification on paragraph 29 added)
55th WMA General Assembly Tokyo 2004 (Note of Clarification on Paragraph 30 added)
59th WMA General Assembly Seoul October 2008
Seven Ethical Pillars of Clinical Research
AUTONOMY
BENEFICENCE
NON ndash MALFEASANCE
FIDELITY
TRUTHFULNESS
CONFIDENTIALITY
JUSTICE
Declaration of Helsinki
Autonomy
Consent
Para 20 The subjects must be volunteers andinformed participants in the research project
Para 22 freely-given informed consent
preferably in writing
Declaration of Helsinki
Para 5 well-being of the human subject shouldtake precedence over the interests of scienceand society
Beneficence
Declaration of Helsinki
Para 16
bull Preceded by careful assessment ofpredictable risks and burdens
bull Attempt to avoid any act or treatmentplan that would harm the patient
Non Malfeasance
Declaration of Helsinki
Para 11
Medical research involving human subjects must be basedon generally accepted scientific principles thoroughknowledge of the scientific literature and on adequatelaboratory and where appropriate animalexperimentation
Para 15
Conducted only by clinically competent medical person
Fidelity ndash duty of care
Declaration of Helsinki
Para 27
Both authors amp investigators are obliged topreserve the accuracy of the results Negativeas well as positive results should be published
Truthfulness - Honesty
Declaration of Helsinki
Para 21
Every precaution should be taken torespect the privacy of the subject theconfidentiality of the patients information
Confidentiality
Declaration of Helsinki
Para 30
Every patient entered into the study should be assured ofaccess to the best proven prophylactic diagnostic andtherapeutic methods identified by the study
Para 9
Research Investigators should be aware of the ethicallegal and regulatory requirements for research on humansubjects
Para 17
Physicians should cease any investigation if the risksoutweigh the potential benefits
Justice
DECLARATION OF HELSINKI -Basic Principles
1 Conform to accepted scientific principles
2 Design formulated in experimental protocol reviewed by IEC
3 Conducted by qualified and trained persons
4 Importance in proportion to inherent risk
5 Assessment of risks vs benefits
6 Safeguard subjectrsquos integrity (privacy)
7 Abstain unless hazards are predictable
8 Preserve accuracy when publishing
9 Adequately inform or right to withdraw
10 Obtain true informed consent in writing
11 Reliance on legal guardian
12 State compliance with Declaration
Ethical Principles and Guidelines for the Protection of Human Subjects of Research
bull Tuskegee Syphilis Study (1932ndash1972)
bull Named the Belmont Report for the Belmont Conference Center where the National Commission met when first drafting the report
42
Belmont Report 1979
Belmont Report 1979
Three ethical principles related to research on human subjects
1 Respect for Persons
2 Beneficence Do no harm while maximizing benefits for research project and minimizing risks to the research subjects
3 Justice ensuring reasonable non-exploitative and well-considered procedures are administered
Overview of
ICH GCP
What is ICH
bull The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)- is unique in bringing together the regulatory authorities and pharmaceutical industry of Europe Japan and the US to discuss scientific and technical aspects of drug registration
45
What is ICH
bull Since its inception in 1990 ICH has
gradually evolved
bull ICHs mission is to ensure that safe
effective and high quality medicines are
developed and registered in the most
resource-efficient manner
How did it evolve
The need to harmonize
bull Public disasters serious fraud and abuse of human rights
bull Trials of War criminals-Nuremberg code 1949
bull Thalidomide- Declaration of Helsinki 1964
bull Belmont report 1978 (Ethical Principles and guidelines for the protection of human subjects of research)-Tuskegee syphilis study
History
1962 US FDA IND Guidelines
1964 Declaration of Helsinki
1968 Committee on Safety of Medicines uk
1978 GCP US FDA
1991 GCP Europe
1996 ICH GCP
1997 ICH GCP Guideline
When did it begin
bull Ist conf in 1990 in Brussels
3 regions participated
bull Representatives from
Industry
Academia
Ministry of
health
ICH parties
6 parties
bull EU bull EFPIA European federation of pharmaceutical industriesrsquo associations
bull MHLW Ministry of health Labor and welfare Japan
bull JPMA Japan Pharmaceuticals manufacturers Association
bull US FDA
bull PhRMA
bull Observers WHO TPP(canada)
bull International federation of Pharmaceutical manufacturerrsquos association
Key objective
bull To discuss and define the minimum standards for the development and registration of investigational products
The result
Many guidelines made
bull Most important- ICH GCP guidelines
bull Evolved in several steps
bull Consolidated guideline ICH E6 Sept 1997
ICH Guidelines examples
bull Efficacy ndash clinical trials etc
bull Safety ndash pharmacovigilance adverse drug reaction
reporting
bull Quality ndash raw materials impurities residual solvents etc
bull Multidisciplinary ndash common technical document electronic
submission coding systems
What is GCP
A standard for the design conduct performance monitoring auditing recording analyses and reporting of clinical trials that provide assurance that the data and the reported results are credible accurate and that the rights integrity and confidentiality of trial subjects are protected
Why is it needed
bull To ensure the rights safety and well being of the trial subjects are protected
bull Ensure the credibility of clinical trial data
The ICH GCP guideline
bull Provide a unified standard for the EU Japan and USA regions to facilitate mutual acceptance of clinical trial data by the regulatory authorities in
these regions
bull 8 sections
ICH GCP guideline
1 Glossary
Common language for investigatorssponsorsethics committees
2Principles of Good Clinical Practice
13 tenets of ICH GCP
3Requirements for IRBIEC
Roles responsibilities and composition
ICH GCP guideline
4Responsibilities of the investigator
5Responsibilities of the sponsor
6Requirements for clinical trial protocol and protocol amendments
7Responsibility of the sponsor in the development of investigatorrsquos brochure
8Essential documents
Principles of ICH GCP
bull Ethical conduct as per
Declaration of Helsinki
GCP
Regulatory Requirements
Risk- Benefit
Primary concern- Subject
Principles of ICH GCP
bull Supportive data
bull Protocol
Scientifically sound clear detailed
bull Ethical Clearance
Study to be conducted in compliance to the protocol which has received EC approval
Principles of ICH GCP
bull Subject Care
Medical decisions responsibility of qualified physician
bull Qualified staff
By education training experience in their area of responsibility
bull Informed Consent
Principles of ICH GCP
bull Clinical Trial data
Recorded handled and stored to enable accurate reporting interpretation and verification
bull Confidentiality
Principles of ICH GCP
bull Investigational Product
Manufactured handled and stored as per GMP
Principles of ICH GCP
bull Quality Assurance
Systems and procedures to ensure the Quality of every aspect of the trial
Indian GCP guidelines
bull Released in Dec 2001(Developed by CDCSO and endorsed by DCGI)
bull In general in line with ICH GCP
bull Has Revised Schedule Y (Jan 2005) addressed discrepancies
bull SAFEGUARD PUBLIC HEALTH
bull ASSURE CONSUMER PROTECTION STANDARDS
bull FACILITATE AVAILABILITY OF SAFE AND EFFECTIVE PRODUCTS
bull ELIMINATE INCONSISTENT STANDARDS INTERNATIONALLY
bull FACILITATE MUTUAL ACCEPTANCE OF DATA FROM CLINICAL TRIALS
GOALS OF INTERNATIONAL HARMONIZATION OF
REGULATORY REQUIREMENTS
Study DocumentationDuring the study
The investigator must keepndash Source documents
bull Medical records (including access to computer records)
bull Laboratory reports
bull ECGs X-rays etc
bull Any other medical records reports or notes (hospital admissions and discharges)
ndash A subject identification list
ndash Copies of all study related documentation
Medical Records
bull In particular they should contain notes on
ndash Sufficient information to support subject eligibility
ndash This should be well documented (signed and dated)
ndash Subjectrsquos participation in the study
ndash Dates of visits
ndash Procedures investigations done
ndash Observations diagnoses
ndash Medications taken (including study medication)
ndash Adverse events
ndash Completion or withdrawal (reason) from the study
Study DocumentationAfter the study
The sponsor needs from the investigator
ndash Final drug accountability records
ndash All used and unused supplies and medication
ndash All required documents completed
Conclusion
70
Thanks
ldquoWhen a doctor [goes] wrong he is
the first of criminals He has nerve
and he has knowledgerdquo
- Sherlock Holmes
References
httpwwwwmanetepolicyb3htm
wwwhhsgovohrphumansubjectsguidancebelmonthtml
wwwhhsgovohrpreferencesnurcodehtml
wwwicmrnicinguidelinesGCLP
wwwcdsconicin
wwwubedurecercaBioeticadocDeclaracio_Helsinki_2013
wwwjewishvirtuallibraryorgjsourceHolocaustnazi_experiments
wwwichorgfileadminPublic_WebICHE6_R1__Guideline
Seven Ethical Pillars of Clinical Research
AUTONOMY
BENEFICENCE
NON ndash MALFEASANCE
FIDELITY
TRUTHFULNESS
CONFIDENTIALITY
JUSTICE
Declaration of Helsinki
Autonomy
Consent
Para 20 The subjects must be volunteers andinformed participants in the research project
Para 22 freely-given informed consent
preferably in writing
Declaration of Helsinki
Para 5 well-being of the human subject shouldtake precedence over the interests of scienceand society
Beneficence
Declaration of Helsinki
Para 16
bull Preceded by careful assessment ofpredictable risks and burdens
bull Attempt to avoid any act or treatmentplan that would harm the patient
Non Malfeasance
Declaration of Helsinki
Para 11
Medical research involving human subjects must be basedon generally accepted scientific principles thoroughknowledge of the scientific literature and on adequatelaboratory and where appropriate animalexperimentation
Para 15
Conducted only by clinically competent medical person
Fidelity ndash duty of care
Declaration of Helsinki
Para 27
Both authors amp investigators are obliged topreserve the accuracy of the results Negativeas well as positive results should be published
Truthfulness - Honesty
Declaration of Helsinki
Para 21
Every precaution should be taken torespect the privacy of the subject theconfidentiality of the patients information
Confidentiality
Declaration of Helsinki
Para 30
Every patient entered into the study should be assured ofaccess to the best proven prophylactic diagnostic andtherapeutic methods identified by the study
Para 9
Research Investigators should be aware of the ethicallegal and regulatory requirements for research on humansubjects
Para 17
Physicians should cease any investigation if the risksoutweigh the potential benefits
Justice
DECLARATION OF HELSINKI -Basic Principles
1 Conform to accepted scientific principles
2 Design formulated in experimental protocol reviewed by IEC
3 Conducted by qualified and trained persons
4 Importance in proportion to inherent risk
5 Assessment of risks vs benefits
6 Safeguard subjectrsquos integrity (privacy)
7 Abstain unless hazards are predictable
8 Preserve accuracy when publishing
9 Adequately inform or right to withdraw
10 Obtain true informed consent in writing
11 Reliance on legal guardian
12 State compliance with Declaration
Ethical Principles and Guidelines for the Protection of Human Subjects of Research
bull Tuskegee Syphilis Study (1932ndash1972)
bull Named the Belmont Report for the Belmont Conference Center where the National Commission met when first drafting the report
42
Belmont Report 1979
Belmont Report 1979
Three ethical principles related to research on human subjects
1 Respect for Persons
2 Beneficence Do no harm while maximizing benefits for research project and minimizing risks to the research subjects
3 Justice ensuring reasonable non-exploitative and well-considered procedures are administered
Overview of
ICH GCP
What is ICH
bull The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)- is unique in bringing together the regulatory authorities and pharmaceutical industry of Europe Japan and the US to discuss scientific and technical aspects of drug registration
45
What is ICH
bull Since its inception in 1990 ICH has
gradually evolved
bull ICHs mission is to ensure that safe
effective and high quality medicines are
developed and registered in the most
resource-efficient manner
How did it evolve
The need to harmonize
bull Public disasters serious fraud and abuse of human rights
bull Trials of War criminals-Nuremberg code 1949
bull Thalidomide- Declaration of Helsinki 1964
bull Belmont report 1978 (Ethical Principles and guidelines for the protection of human subjects of research)-Tuskegee syphilis study
History
1962 US FDA IND Guidelines
1964 Declaration of Helsinki
1968 Committee on Safety of Medicines uk
1978 GCP US FDA
1991 GCP Europe
1996 ICH GCP
1997 ICH GCP Guideline
When did it begin
bull Ist conf in 1990 in Brussels
3 regions participated
bull Representatives from
Industry
Academia
Ministry of
health
ICH parties
6 parties
bull EU bull EFPIA European federation of pharmaceutical industriesrsquo associations
bull MHLW Ministry of health Labor and welfare Japan
bull JPMA Japan Pharmaceuticals manufacturers Association
bull US FDA
bull PhRMA
bull Observers WHO TPP(canada)
bull International federation of Pharmaceutical manufacturerrsquos association
Key objective
bull To discuss and define the minimum standards for the development and registration of investigational products
The result
Many guidelines made
bull Most important- ICH GCP guidelines
bull Evolved in several steps
bull Consolidated guideline ICH E6 Sept 1997
ICH Guidelines examples
bull Efficacy ndash clinical trials etc
bull Safety ndash pharmacovigilance adverse drug reaction
reporting
bull Quality ndash raw materials impurities residual solvents etc
bull Multidisciplinary ndash common technical document electronic
submission coding systems
What is GCP
A standard for the design conduct performance monitoring auditing recording analyses and reporting of clinical trials that provide assurance that the data and the reported results are credible accurate and that the rights integrity and confidentiality of trial subjects are protected
Why is it needed
bull To ensure the rights safety and well being of the trial subjects are protected
bull Ensure the credibility of clinical trial data
The ICH GCP guideline
bull Provide a unified standard for the EU Japan and USA regions to facilitate mutual acceptance of clinical trial data by the regulatory authorities in
these regions
bull 8 sections
ICH GCP guideline
1 Glossary
Common language for investigatorssponsorsethics committees
2Principles of Good Clinical Practice
13 tenets of ICH GCP
3Requirements for IRBIEC
Roles responsibilities and composition
ICH GCP guideline
4Responsibilities of the investigator
5Responsibilities of the sponsor
6Requirements for clinical trial protocol and protocol amendments
7Responsibility of the sponsor in the development of investigatorrsquos brochure
8Essential documents
Principles of ICH GCP
bull Ethical conduct as per
Declaration of Helsinki
GCP
Regulatory Requirements
Risk- Benefit
Primary concern- Subject
Principles of ICH GCP
bull Supportive data
bull Protocol
Scientifically sound clear detailed
bull Ethical Clearance
Study to be conducted in compliance to the protocol which has received EC approval
Principles of ICH GCP
bull Subject Care
Medical decisions responsibility of qualified physician
bull Qualified staff
By education training experience in their area of responsibility
bull Informed Consent
Principles of ICH GCP
bull Clinical Trial data
Recorded handled and stored to enable accurate reporting interpretation and verification
bull Confidentiality
Principles of ICH GCP
bull Investigational Product
Manufactured handled and stored as per GMP
Principles of ICH GCP
bull Quality Assurance
Systems and procedures to ensure the Quality of every aspect of the trial
Indian GCP guidelines
bull Released in Dec 2001(Developed by CDCSO and endorsed by DCGI)
bull In general in line with ICH GCP
bull Has Revised Schedule Y (Jan 2005) addressed discrepancies
bull SAFEGUARD PUBLIC HEALTH
bull ASSURE CONSUMER PROTECTION STANDARDS
bull FACILITATE AVAILABILITY OF SAFE AND EFFECTIVE PRODUCTS
bull ELIMINATE INCONSISTENT STANDARDS INTERNATIONALLY
bull FACILITATE MUTUAL ACCEPTANCE OF DATA FROM CLINICAL TRIALS
GOALS OF INTERNATIONAL HARMONIZATION OF
REGULATORY REQUIREMENTS
Study DocumentationDuring the study
The investigator must keepndash Source documents
bull Medical records (including access to computer records)
bull Laboratory reports
bull ECGs X-rays etc
bull Any other medical records reports or notes (hospital admissions and discharges)
ndash A subject identification list
ndash Copies of all study related documentation
Medical Records
bull In particular they should contain notes on
ndash Sufficient information to support subject eligibility
ndash This should be well documented (signed and dated)
ndash Subjectrsquos participation in the study
ndash Dates of visits
ndash Procedures investigations done
ndash Observations diagnoses
ndash Medications taken (including study medication)
ndash Adverse events
ndash Completion or withdrawal (reason) from the study
Study DocumentationAfter the study
The sponsor needs from the investigator
ndash Final drug accountability records
ndash All used and unused supplies and medication
ndash All required documents completed
Conclusion
70
Thanks
ldquoWhen a doctor [goes] wrong he is
the first of criminals He has nerve
and he has knowledgerdquo
- Sherlock Holmes
References
httpwwwwmanetepolicyb3htm
wwwhhsgovohrphumansubjectsguidancebelmonthtml
wwwhhsgovohrpreferencesnurcodehtml
wwwicmrnicinguidelinesGCLP
wwwcdsconicin
wwwubedurecercaBioeticadocDeclaracio_Helsinki_2013
wwwjewishvirtuallibraryorgjsourceHolocaustnazi_experiments
wwwichorgfileadminPublic_WebICHE6_R1__Guideline
Declaration of Helsinki
Autonomy
Consent
Para 20 The subjects must be volunteers andinformed participants in the research project
Para 22 freely-given informed consent
preferably in writing
Declaration of Helsinki
Para 5 well-being of the human subject shouldtake precedence over the interests of scienceand society
Beneficence
Declaration of Helsinki
Para 16
bull Preceded by careful assessment ofpredictable risks and burdens
bull Attempt to avoid any act or treatmentplan that would harm the patient
Non Malfeasance
Declaration of Helsinki
Para 11
Medical research involving human subjects must be basedon generally accepted scientific principles thoroughknowledge of the scientific literature and on adequatelaboratory and where appropriate animalexperimentation
Para 15
Conducted only by clinically competent medical person
Fidelity ndash duty of care
Declaration of Helsinki
Para 27
Both authors amp investigators are obliged topreserve the accuracy of the results Negativeas well as positive results should be published
Truthfulness - Honesty
Declaration of Helsinki
Para 21
Every precaution should be taken torespect the privacy of the subject theconfidentiality of the patients information
Confidentiality
Declaration of Helsinki
Para 30
Every patient entered into the study should be assured ofaccess to the best proven prophylactic diagnostic andtherapeutic methods identified by the study
Para 9
Research Investigators should be aware of the ethicallegal and regulatory requirements for research on humansubjects
Para 17
Physicians should cease any investigation if the risksoutweigh the potential benefits
Justice
DECLARATION OF HELSINKI -Basic Principles
1 Conform to accepted scientific principles
2 Design formulated in experimental protocol reviewed by IEC
3 Conducted by qualified and trained persons
4 Importance in proportion to inherent risk
5 Assessment of risks vs benefits
6 Safeguard subjectrsquos integrity (privacy)
7 Abstain unless hazards are predictable
8 Preserve accuracy when publishing
9 Adequately inform or right to withdraw
10 Obtain true informed consent in writing
11 Reliance on legal guardian
12 State compliance with Declaration
Ethical Principles and Guidelines for the Protection of Human Subjects of Research
bull Tuskegee Syphilis Study (1932ndash1972)
bull Named the Belmont Report for the Belmont Conference Center where the National Commission met when first drafting the report
42
Belmont Report 1979
Belmont Report 1979
Three ethical principles related to research on human subjects
1 Respect for Persons
2 Beneficence Do no harm while maximizing benefits for research project and minimizing risks to the research subjects
3 Justice ensuring reasonable non-exploitative and well-considered procedures are administered
Overview of
ICH GCP
What is ICH
bull The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)- is unique in bringing together the regulatory authorities and pharmaceutical industry of Europe Japan and the US to discuss scientific and technical aspects of drug registration
45
What is ICH
bull Since its inception in 1990 ICH has
gradually evolved
bull ICHs mission is to ensure that safe
effective and high quality medicines are
developed and registered in the most
resource-efficient manner
How did it evolve
The need to harmonize
bull Public disasters serious fraud and abuse of human rights
bull Trials of War criminals-Nuremberg code 1949
bull Thalidomide- Declaration of Helsinki 1964
bull Belmont report 1978 (Ethical Principles and guidelines for the protection of human subjects of research)-Tuskegee syphilis study
History
1962 US FDA IND Guidelines
1964 Declaration of Helsinki
1968 Committee on Safety of Medicines uk
1978 GCP US FDA
1991 GCP Europe
1996 ICH GCP
1997 ICH GCP Guideline
When did it begin
bull Ist conf in 1990 in Brussels
3 regions participated
bull Representatives from
Industry
Academia
Ministry of
health
ICH parties
6 parties
bull EU bull EFPIA European federation of pharmaceutical industriesrsquo associations
bull MHLW Ministry of health Labor and welfare Japan
bull JPMA Japan Pharmaceuticals manufacturers Association
bull US FDA
bull PhRMA
bull Observers WHO TPP(canada)
bull International federation of Pharmaceutical manufacturerrsquos association
Key objective
bull To discuss and define the minimum standards for the development and registration of investigational products
The result
Many guidelines made
bull Most important- ICH GCP guidelines
bull Evolved in several steps
bull Consolidated guideline ICH E6 Sept 1997
ICH Guidelines examples
bull Efficacy ndash clinical trials etc
bull Safety ndash pharmacovigilance adverse drug reaction
reporting
bull Quality ndash raw materials impurities residual solvents etc
bull Multidisciplinary ndash common technical document electronic
submission coding systems
What is GCP
A standard for the design conduct performance monitoring auditing recording analyses and reporting of clinical trials that provide assurance that the data and the reported results are credible accurate and that the rights integrity and confidentiality of trial subjects are protected
Why is it needed
bull To ensure the rights safety and well being of the trial subjects are protected
bull Ensure the credibility of clinical trial data
The ICH GCP guideline
bull Provide a unified standard for the EU Japan and USA regions to facilitate mutual acceptance of clinical trial data by the regulatory authorities in
these regions
bull 8 sections
ICH GCP guideline
1 Glossary
Common language for investigatorssponsorsethics committees
2Principles of Good Clinical Practice
13 tenets of ICH GCP
3Requirements for IRBIEC
Roles responsibilities and composition
ICH GCP guideline
4Responsibilities of the investigator
5Responsibilities of the sponsor
6Requirements for clinical trial protocol and protocol amendments
7Responsibility of the sponsor in the development of investigatorrsquos brochure
8Essential documents
Principles of ICH GCP
bull Ethical conduct as per
Declaration of Helsinki
GCP
Regulatory Requirements
Risk- Benefit
Primary concern- Subject
Principles of ICH GCP
bull Supportive data
bull Protocol
Scientifically sound clear detailed
bull Ethical Clearance
Study to be conducted in compliance to the protocol which has received EC approval
Principles of ICH GCP
bull Subject Care
Medical decisions responsibility of qualified physician
bull Qualified staff
By education training experience in their area of responsibility
bull Informed Consent
Principles of ICH GCP
bull Clinical Trial data
Recorded handled and stored to enable accurate reporting interpretation and verification
bull Confidentiality
Principles of ICH GCP
bull Investigational Product
Manufactured handled and stored as per GMP
Principles of ICH GCP
bull Quality Assurance
Systems and procedures to ensure the Quality of every aspect of the trial
Indian GCP guidelines
bull Released in Dec 2001(Developed by CDCSO and endorsed by DCGI)
bull In general in line with ICH GCP
bull Has Revised Schedule Y (Jan 2005) addressed discrepancies
bull SAFEGUARD PUBLIC HEALTH
bull ASSURE CONSUMER PROTECTION STANDARDS
bull FACILITATE AVAILABILITY OF SAFE AND EFFECTIVE PRODUCTS
bull ELIMINATE INCONSISTENT STANDARDS INTERNATIONALLY
bull FACILITATE MUTUAL ACCEPTANCE OF DATA FROM CLINICAL TRIALS
GOALS OF INTERNATIONAL HARMONIZATION OF
REGULATORY REQUIREMENTS
Study DocumentationDuring the study
The investigator must keepndash Source documents
bull Medical records (including access to computer records)
bull Laboratory reports
bull ECGs X-rays etc
bull Any other medical records reports or notes (hospital admissions and discharges)
ndash A subject identification list
ndash Copies of all study related documentation
Medical Records
bull In particular they should contain notes on
ndash Sufficient information to support subject eligibility
ndash This should be well documented (signed and dated)
ndash Subjectrsquos participation in the study
ndash Dates of visits
ndash Procedures investigations done
ndash Observations diagnoses
ndash Medications taken (including study medication)
ndash Adverse events
ndash Completion or withdrawal (reason) from the study
Study DocumentationAfter the study
The sponsor needs from the investigator
ndash Final drug accountability records
ndash All used and unused supplies and medication
ndash All required documents completed
Conclusion
70
Thanks
ldquoWhen a doctor [goes] wrong he is
the first of criminals He has nerve
and he has knowledgerdquo
- Sherlock Holmes
References
httpwwwwmanetepolicyb3htm
wwwhhsgovohrphumansubjectsguidancebelmonthtml
wwwhhsgovohrpreferencesnurcodehtml
wwwicmrnicinguidelinesGCLP
wwwcdsconicin
wwwubedurecercaBioeticadocDeclaracio_Helsinki_2013
wwwjewishvirtuallibraryorgjsourceHolocaustnazi_experiments
wwwichorgfileadminPublic_WebICHE6_R1__Guideline
Declaration of Helsinki
Para 5 well-being of the human subject shouldtake precedence over the interests of scienceand society
Beneficence
Declaration of Helsinki
Para 16
bull Preceded by careful assessment ofpredictable risks and burdens
bull Attempt to avoid any act or treatmentplan that would harm the patient
Non Malfeasance
Declaration of Helsinki
Para 11
Medical research involving human subjects must be basedon generally accepted scientific principles thoroughknowledge of the scientific literature and on adequatelaboratory and where appropriate animalexperimentation
Para 15
Conducted only by clinically competent medical person
Fidelity ndash duty of care
Declaration of Helsinki
Para 27
Both authors amp investigators are obliged topreserve the accuracy of the results Negativeas well as positive results should be published
Truthfulness - Honesty
Declaration of Helsinki
Para 21
Every precaution should be taken torespect the privacy of the subject theconfidentiality of the patients information
Confidentiality
Declaration of Helsinki
Para 30
Every patient entered into the study should be assured ofaccess to the best proven prophylactic diagnostic andtherapeutic methods identified by the study
Para 9
Research Investigators should be aware of the ethicallegal and regulatory requirements for research on humansubjects
Para 17
Physicians should cease any investigation if the risksoutweigh the potential benefits
Justice
DECLARATION OF HELSINKI -Basic Principles
1 Conform to accepted scientific principles
2 Design formulated in experimental protocol reviewed by IEC
3 Conducted by qualified and trained persons
4 Importance in proportion to inherent risk
5 Assessment of risks vs benefits
6 Safeguard subjectrsquos integrity (privacy)
7 Abstain unless hazards are predictable
8 Preserve accuracy when publishing
9 Adequately inform or right to withdraw
10 Obtain true informed consent in writing
11 Reliance on legal guardian
12 State compliance with Declaration
Ethical Principles and Guidelines for the Protection of Human Subjects of Research
bull Tuskegee Syphilis Study (1932ndash1972)
bull Named the Belmont Report for the Belmont Conference Center where the National Commission met when first drafting the report
42
Belmont Report 1979
Belmont Report 1979
Three ethical principles related to research on human subjects
1 Respect for Persons
2 Beneficence Do no harm while maximizing benefits for research project and minimizing risks to the research subjects
3 Justice ensuring reasonable non-exploitative and well-considered procedures are administered
Overview of
ICH GCP
What is ICH
bull The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)- is unique in bringing together the regulatory authorities and pharmaceutical industry of Europe Japan and the US to discuss scientific and technical aspects of drug registration
45
What is ICH
bull Since its inception in 1990 ICH has
gradually evolved
bull ICHs mission is to ensure that safe
effective and high quality medicines are
developed and registered in the most
resource-efficient manner
How did it evolve
The need to harmonize
bull Public disasters serious fraud and abuse of human rights
bull Trials of War criminals-Nuremberg code 1949
bull Thalidomide- Declaration of Helsinki 1964
bull Belmont report 1978 (Ethical Principles and guidelines for the protection of human subjects of research)-Tuskegee syphilis study
History
1962 US FDA IND Guidelines
1964 Declaration of Helsinki
1968 Committee on Safety of Medicines uk
1978 GCP US FDA
1991 GCP Europe
1996 ICH GCP
1997 ICH GCP Guideline
When did it begin
bull Ist conf in 1990 in Brussels
3 regions participated
bull Representatives from
Industry
Academia
Ministry of
health
ICH parties
6 parties
bull EU bull EFPIA European federation of pharmaceutical industriesrsquo associations
bull MHLW Ministry of health Labor and welfare Japan
bull JPMA Japan Pharmaceuticals manufacturers Association
bull US FDA
bull PhRMA
bull Observers WHO TPP(canada)
bull International federation of Pharmaceutical manufacturerrsquos association
Key objective
bull To discuss and define the minimum standards for the development and registration of investigational products
The result
Many guidelines made
bull Most important- ICH GCP guidelines
bull Evolved in several steps
bull Consolidated guideline ICH E6 Sept 1997
ICH Guidelines examples
bull Efficacy ndash clinical trials etc
bull Safety ndash pharmacovigilance adverse drug reaction
reporting
bull Quality ndash raw materials impurities residual solvents etc
bull Multidisciplinary ndash common technical document electronic
submission coding systems
What is GCP
A standard for the design conduct performance monitoring auditing recording analyses and reporting of clinical trials that provide assurance that the data and the reported results are credible accurate and that the rights integrity and confidentiality of trial subjects are protected
Why is it needed
bull To ensure the rights safety and well being of the trial subjects are protected
bull Ensure the credibility of clinical trial data
The ICH GCP guideline
bull Provide a unified standard for the EU Japan and USA regions to facilitate mutual acceptance of clinical trial data by the regulatory authorities in
these regions
bull 8 sections
ICH GCP guideline
1 Glossary
Common language for investigatorssponsorsethics committees
2Principles of Good Clinical Practice
13 tenets of ICH GCP
3Requirements for IRBIEC
Roles responsibilities and composition
ICH GCP guideline
4Responsibilities of the investigator
5Responsibilities of the sponsor
6Requirements for clinical trial protocol and protocol amendments
7Responsibility of the sponsor in the development of investigatorrsquos brochure
8Essential documents
Principles of ICH GCP
bull Ethical conduct as per
Declaration of Helsinki
GCP
Regulatory Requirements
Risk- Benefit
Primary concern- Subject
Principles of ICH GCP
bull Supportive data
bull Protocol
Scientifically sound clear detailed
bull Ethical Clearance
Study to be conducted in compliance to the protocol which has received EC approval
Principles of ICH GCP
bull Subject Care
Medical decisions responsibility of qualified physician
bull Qualified staff
By education training experience in their area of responsibility
bull Informed Consent
Principles of ICH GCP
bull Clinical Trial data
Recorded handled and stored to enable accurate reporting interpretation and verification
bull Confidentiality
Principles of ICH GCP
bull Investigational Product
Manufactured handled and stored as per GMP
Principles of ICH GCP
bull Quality Assurance
Systems and procedures to ensure the Quality of every aspect of the trial
Indian GCP guidelines
bull Released in Dec 2001(Developed by CDCSO and endorsed by DCGI)
bull In general in line with ICH GCP
bull Has Revised Schedule Y (Jan 2005) addressed discrepancies
bull SAFEGUARD PUBLIC HEALTH
bull ASSURE CONSUMER PROTECTION STANDARDS
bull FACILITATE AVAILABILITY OF SAFE AND EFFECTIVE PRODUCTS
bull ELIMINATE INCONSISTENT STANDARDS INTERNATIONALLY
bull FACILITATE MUTUAL ACCEPTANCE OF DATA FROM CLINICAL TRIALS
GOALS OF INTERNATIONAL HARMONIZATION OF
REGULATORY REQUIREMENTS
Study DocumentationDuring the study
The investigator must keepndash Source documents
bull Medical records (including access to computer records)
bull Laboratory reports
bull ECGs X-rays etc
bull Any other medical records reports or notes (hospital admissions and discharges)
ndash A subject identification list
ndash Copies of all study related documentation
Medical Records
bull In particular they should contain notes on
ndash Sufficient information to support subject eligibility
ndash This should be well documented (signed and dated)
ndash Subjectrsquos participation in the study
ndash Dates of visits
ndash Procedures investigations done
ndash Observations diagnoses
ndash Medications taken (including study medication)
ndash Adverse events
ndash Completion or withdrawal (reason) from the study
Study DocumentationAfter the study
The sponsor needs from the investigator
ndash Final drug accountability records
ndash All used and unused supplies and medication
ndash All required documents completed
Conclusion
70
Thanks
ldquoWhen a doctor [goes] wrong he is
the first of criminals He has nerve
and he has knowledgerdquo
- Sherlock Holmes
References
httpwwwwmanetepolicyb3htm
wwwhhsgovohrphumansubjectsguidancebelmonthtml
wwwhhsgovohrpreferencesnurcodehtml
wwwicmrnicinguidelinesGCLP
wwwcdsconicin
wwwubedurecercaBioeticadocDeclaracio_Helsinki_2013
wwwjewishvirtuallibraryorgjsourceHolocaustnazi_experiments
wwwichorgfileadminPublic_WebICHE6_R1__Guideline
Declaration of Helsinki
Para 16
bull Preceded by careful assessment ofpredictable risks and burdens
bull Attempt to avoid any act or treatmentplan that would harm the patient
Non Malfeasance
Declaration of Helsinki
Para 11
Medical research involving human subjects must be basedon generally accepted scientific principles thoroughknowledge of the scientific literature and on adequatelaboratory and where appropriate animalexperimentation
Para 15
Conducted only by clinically competent medical person
Fidelity ndash duty of care
Declaration of Helsinki
Para 27
Both authors amp investigators are obliged topreserve the accuracy of the results Negativeas well as positive results should be published
Truthfulness - Honesty
Declaration of Helsinki
Para 21
Every precaution should be taken torespect the privacy of the subject theconfidentiality of the patients information
Confidentiality
Declaration of Helsinki
Para 30
Every patient entered into the study should be assured ofaccess to the best proven prophylactic diagnostic andtherapeutic methods identified by the study
Para 9
Research Investigators should be aware of the ethicallegal and regulatory requirements for research on humansubjects
Para 17
Physicians should cease any investigation if the risksoutweigh the potential benefits
Justice
DECLARATION OF HELSINKI -Basic Principles
1 Conform to accepted scientific principles
2 Design formulated in experimental protocol reviewed by IEC
3 Conducted by qualified and trained persons
4 Importance in proportion to inherent risk
5 Assessment of risks vs benefits
6 Safeguard subjectrsquos integrity (privacy)
7 Abstain unless hazards are predictable
8 Preserve accuracy when publishing
9 Adequately inform or right to withdraw
10 Obtain true informed consent in writing
11 Reliance on legal guardian
12 State compliance with Declaration
Ethical Principles and Guidelines for the Protection of Human Subjects of Research
bull Tuskegee Syphilis Study (1932ndash1972)
bull Named the Belmont Report for the Belmont Conference Center where the National Commission met when first drafting the report
42
Belmont Report 1979
Belmont Report 1979
Three ethical principles related to research on human subjects
1 Respect for Persons
2 Beneficence Do no harm while maximizing benefits for research project and minimizing risks to the research subjects
3 Justice ensuring reasonable non-exploitative and well-considered procedures are administered
Overview of
ICH GCP
What is ICH
bull The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)- is unique in bringing together the regulatory authorities and pharmaceutical industry of Europe Japan and the US to discuss scientific and technical aspects of drug registration
45
What is ICH
bull Since its inception in 1990 ICH has
gradually evolved
bull ICHs mission is to ensure that safe
effective and high quality medicines are
developed and registered in the most
resource-efficient manner
How did it evolve
The need to harmonize
bull Public disasters serious fraud and abuse of human rights
bull Trials of War criminals-Nuremberg code 1949
bull Thalidomide- Declaration of Helsinki 1964
bull Belmont report 1978 (Ethical Principles and guidelines for the protection of human subjects of research)-Tuskegee syphilis study
History
1962 US FDA IND Guidelines
1964 Declaration of Helsinki
1968 Committee on Safety of Medicines uk
1978 GCP US FDA
1991 GCP Europe
1996 ICH GCP
1997 ICH GCP Guideline
When did it begin
bull Ist conf in 1990 in Brussels
3 regions participated
bull Representatives from
Industry
Academia
Ministry of
health
ICH parties
6 parties
bull EU bull EFPIA European federation of pharmaceutical industriesrsquo associations
bull MHLW Ministry of health Labor and welfare Japan
bull JPMA Japan Pharmaceuticals manufacturers Association
bull US FDA
bull PhRMA
bull Observers WHO TPP(canada)
bull International federation of Pharmaceutical manufacturerrsquos association
Key objective
bull To discuss and define the minimum standards for the development and registration of investigational products
The result
Many guidelines made
bull Most important- ICH GCP guidelines
bull Evolved in several steps
bull Consolidated guideline ICH E6 Sept 1997
ICH Guidelines examples
bull Efficacy ndash clinical trials etc
bull Safety ndash pharmacovigilance adverse drug reaction
reporting
bull Quality ndash raw materials impurities residual solvents etc
bull Multidisciplinary ndash common technical document electronic
submission coding systems
What is GCP
A standard for the design conduct performance monitoring auditing recording analyses and reporting of clinical trials that provide assurance that the data and the reported results are credible accurate and that the rights integrity and confidentiality of trial subjects are protected
Why is it needed
bull To ensure the rights safety and well being of the trial subjects are protected
bull Ensure the credibility of clinical trial data
The ICH GCP guideline
bull Provide a unified standard for the EU Japan and USA regions to facilitate mutual acceptance of clinical trial data by the regulatory authorities in
these regions
bull 8 sections
ICH GCP guideline
1 Glossary
Common language for investigatorssponsorsethics committees
2Principles of Good Clinical Practice
13 tenets of ICH GCP
3Requirements for IRBIEC
Roles responsibilities and composition
ICH GCP guideline
4Responsibilities of the investigator
5Responsibilities of the sponsor
6Requirements for clinical trial protocol and protocol amendments
7Responsibility of the sponsor in the development of investigatorrsquos brochure
8Essential documents
Principles of ICH GCP
bull Ethical conduct as per
Declaration of Helsinki
GCP
Regulatory Requirements
Risk- Benefit
Primary concern- Subject
Principles of ICH GCP
bull Supportive data
bull Protocol
Scientifically sound clear detailed
bull Ethical Clearance
Study to be conducted in compliance to the protocol which has received EC approval
Principles of ICH GCP
bull Subject Care
Medical decisions responsibility of qualified physician
bull Qualified staff
By education training experience in their area of responsibility
bull Informed Consent
Principles of ICH GCP
bull Clinical Trial data
Recorded handled and stored to enable accurate reporting interpretation and verification
bull Confidentiality
Principles of ICH GCP
bull Investigational Product
Manufactured handled and stored as per GMP
Principles of ICH GCP
bull Quality Assurance
Systems and procedures to ensure the Quality of every aspect of the trial
Indian GCP guidelines
bull Released in Dec 2001(Developed by CDCSO and endorsed by DCGI)
bull In general in line with ICH GCP
bull Has Revised Schedule Y (Jan 2005) addressed discrepancies
bull SAFEGUARD PUBLIC HEALTH
bull ASSURE CONSUMER PROTECTION STANDARDS
bull FACILITATE AVAILABILITY OF SAFE AND EFFECTIVE PRODUCTS
bull ELIMINATE INCONSISTENT STANDARDS INTERNATIONALLY
bull FACILITATE MUTUAL ACCEPTANCE OF DATA FROM CLINICAL TRIALS
GOALS OF INTERNATIONAL HARMONIZATION OF
REGULATORY REQUIREMENTS
Study DocumentationDuring the study
The investigator must keepndash Source documents
bull Medical records (including access to computer records)
bull Laboratory reports
bull ECGs X-rays etc
bull Any other medical records reports or notes (hospital admissions and discharges)
ndash A subject identification list
ndash Copies of all study related documentation
Medical Records
bull In particular they should contain notes on
ndash Sufficient information to support subject eligibility
ndash This should be well documented (signed and dated)
ndash Subjectrsquos participation in the study
ndash Dates of visits
ndash Procedures investigations done
ndash Observations diagnoses
ndash Medications taken (including study medication)
ndash Adverse events
ndash Completion or withdrawal (reason) from the study
Study DocumentationAfter the study
The sponsor needs from the investigator
ndash Final drug accountability records
ndash All used and unused supplies and medication
ndash All required documents completed
Conclusion
70
Thanks
ldquoWhen a doctor [goes] wrong he is
the first of criminals He has nerve
and he has knowledgerdquo
- Sherlock Holmes
References
httpwwwwmanetepolicyb3htm
wwwhhsgovohrphumansubjectsguidancebelmonthtml
wwwhhsgovohrpreferencesnurcodehtml
wwwicmrnicinguidelinesGCLP
wwwcdsconicin
wwwubedurecercaBioeticadocDeclaracio_Helsinki_2013
wwwjewishvirtuallibraryorgjsourceHolocaustnazi_experiments
wwwichorgfileadminPublic_WebICHE6_R1__Guideline
Declaration of Helsinki
Para 11
Medical research involving human subjects must be basedon generally accepted scientific principles thoroughknowledge of the scientific literature and on adequatelaboratory and where appropriate animalexperimentation
Para 15
Conducted only by clinically competent medical person
Fidelity ndash duty of care
Declaration of Helsinki
Para 27
Both authors amp investigators are obliged topreserve the accuracy of the results Negativeas well as positive results should be published
Truthfulness - Honesty
Declaration of Helsinki
Para 21
Every precaution should be taken torespect the privacy of the subject theconfidentiality of the patients information
Confidentiality
Declaration of Helsinki
Para 30
Every patient entered into the study should be assured ofaccess to the best proven prophylactic diagnostic andtherapeutic methods identified by the study
Para 9
Research Investigators should be aware of the ethicallegal and regulatory requirements for research on humansubjects
Para 17
Physicians should cease any investigation if the risksoutweigh the potential benefits
Justice
DECLARATION OF HELSINKI -Basic Principles
1 Conform to accepted scientific principles
2 Design formulated in experimental protocol reviewed by IEC
3 Conducted by qualified and trained persons
4 Importance in proportion to inherent risk
5 Assessment of risks vs benefits
6 Safeguard subjectrsquos integrity (privacy)
7 Abstain unless hazards are predictable
8 Preserve accuracy when publishing
9 Adequately inform or right to withdraw
10 Obtain true informed consent in writing
11 Reliance on legal guardian
12 State compliance with Declaration
Ethical Principles and Guidelines for the Protection of Human Subjects of Research
bull Tuskegee Syphilis Study (1932ndash1972)
bull Named the Belmont Report for the Belmont Conference Center where the National Commission met when first drafting the report
42
Belmont Report 1979
Belmont Report 1979
Three ethical principles related to research on human subjects
1 Respect for Persons
2 Beneficence Do no harm while maximizing benefits for research project and minimizing risks to the research subjects
3 Justice ensuring reasonable non-exploitative and well-considered procedures are administered
Overview of
ICH GCP
What is ICH
bull The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)- is unique in bringing together the regulatory authorities and pharmaceutical industry of Europe Japan and the US to discuss scientific and technical aspects of drug registration
45
What is ICH
bull Since its inception in 1990 ICH has
gradually evolved
bull ICHs mission is to ensure that safe
effective and high quality medicines are
developed and registered in the most
resource-efficient manner
How did it evolve
The need to harmonize
bull Public disasters serious fraud and abuse of human rights
bull Trials of War criminals-Nuremberg code 1949
bull Thalidomide- Declaration of Helsinki 1964
bull Belmont report 1978 (Ethical Principles and guidelines for the protection of human subjects of research)-Tuskegee syphilis study
History
1962 US FDA IND Guidelines
1964 Declaration of Helsinki
1968 Committee on Safety of Medicines uk
1978 GCP US FDA
1991 GCP Europe
1996 ICH GCP
1997 ICH GCP Guideline
When did it begin
bull Ist conf in 1990 in Brussels
3 regions participated
bull Representatives from
Industry
Academia
Ministry of
health
ICH parties
6 parties
bull EU bull EFPIA European federation of pharmaceutical industriesrsquo associations
bull MHLW Ministry of health Labor and welfare Japan
bull JPMA Japan Pharmaceuticals manufacturers Association
bull US FDA
bull PhRMA
bull Observers WHO TPP(canada)
bull International federation of Pharmaceutical manufacturerrsquos association
Key objective
bull To discuss and define the minimum standards for the development and registration of investigational products
The result
Many guidelines made
bull Most important- ICH GCP guidelines
bull Evolved in several steps
bull Consolidated guideline ICH E6 Sept 1997
ICH Guidelines examples
bull Efficacy ndash clinical trials etc
bull Safety ndash pharmacovigilance adverse drug reaction
reporting
bull Quality ndash raw materials impurities residual solvents etc
bull Multidisciplinary ndash common technical document electronic
submission coding systems
What is GCP
A standard for the design conduct performance monitoring auditing recording analyses and reporting of clinical trials that provide assurance that the data and the reported results are credible accurate and that the rights integrity and confidentiality of trial subjects are protected
Why is it needed
bull To ensure the rights safety and well being of the trial subjects are protected
bull Ensure the credibility of clinical trial data
The ICH GCP guideline
bull Provide a unified standard for the EU Japan and USA regions to facilitate mutual acceptance of clinical trial data by the regulatory authorities in
these regions
bull 8 sections
ICH GCP guideline
1 Glossary
Common language for investigatorssponsorsethics committees
2Principles of Good Clinical Practice
13 tenets of ICH GCP
3Requirements for IRBIEC
Roles responsibilities and composition
ICH GCP guideline
4Responsibilities of the investigator
5Responsibilities of the sponsor
6Requirements for clinical trial protocol and protocol amendments
7Responsibility of the sponsor in the development of investigatorrsquos brochure
8Essential documents
Principles of ICH GCP
bull Ethical conduct as per
Declaration of Helsinki
GCP
Regulatory Requirements
Risk- Benefit
Primary concern- Subject
Principles of ICH GCP
bull Supportive data
bull Protocol
Scientifically sound clear detailed
bull Ethical Clearance
Study to be conducted in compliance to the protocol which has received EC approval
Principles of ICH GCP
bull Subject Care
Medical decisions responsibility of qualified physician
bull Qualified staff
By education training experience in their area of responsibility
bull Informed Consent
Principles of ICH GCP
bull Clinical Trial data
Recorded handled and stored to enable accurate reporting interpretation and verification
bull Confidentiality
Principles of ICH GCP
bull Investigational Product
Manufactured handled and stored as per GMP
Principles of ICH GCP
bull Quality Assurance
Systems and procedures to ensure the Quality of every aspect of the trial
Indian GCP guidelines
bull Released in Dec 2001(Developed by CDCSO and endorsed by DCGI)
bull In general in line with ICH GCP
bull Has Revised Schedule Y (Jan 2005) addressed discrepancies
bull SAFEGUARD PUBLIC HEALTH
bull ASSURE CONSUMER PROTECTION STANDARDS
bull FACILITATE AVAILABILITY OF SAFE AND EFFECTIVE PRODUCTS
bull ELIMINATE INCONSISTENT STANDARDS INTERNATIONALLY
bull FACILITATE MUTUAL ACCEPTANCE OF DATA FROM CLINICAL TRIALS
GOALS OF INTERNATIONAL HARMONIZATION OF
REGULATORY REQUIREMENTS
Study DocumentationDuring the study
The investigator must keepndash Source documents
bull Medical records (including access to computer records)
bull Laboratory reports
bull ECGs X-rays etc
bull Any other medical records reports or notes (hospital admissions and discharges)
ndash A subject identification list
ndash Copies of all study related documentation
Medical Records
bull In particular they should contain notes on
ndash Sufficient information to support subject eligibility
ndash This should be well documented (signed and dated)
ndash Subjectrsquos participation in the study
ndash Dates of visits
ndash Procedures investigations done
ndash Observations diagnoses
ndash Medications taken (including study medication)
ndash Adverse events
ndash Completion or withdrawal (reason) from the study
Study DocumentationAfter the study
The sponsor needs from the investigator
ndash Final drug accountability records
ndash All used and unused supplies and medication
ndash All required documents completed
Conclusion
70
Thanks
ldquoWhen a doctor [goes] wrong he is
the first of criminals He has nerve
and he has knowledgerdquo
- Sherlock Holmes
References
httpwwwwmanetepolicyb3htm
wwwhhsgovohrphumansubjectsguidancebelmonthtml
wwwhhsgovohrpreferencesnurcodehtml
wwwicmrnicinguidelinesGCLP
wwwcdsconicin
wwwubedurecercaBioeticadocDeclaracio_Helsinki_2013
wwwjewishvirtuallibraryorgjsourceHolocaustnazi_experiments
wwwichorgfileadminPublic_WebICHE6_R1__Guideline
Declaration of Helsinki
Para 27
Both authors amp investigators are obliged topreserve the accuracy of the results Negativeas well as positive results should be published
Truthfulness - Honesty
Declaration of Helsinki
Para 21
Every precaution should be taken torespect the privacy of the subject theconfidentiality of the patients information
Confidentiality
Declaration of Helsinki
Para 30
Every patient entered into the study should be assured ofaccess to the best proven prophylactic diagnostic andtherapeutic methods identified by the study
Para 9
Research Investigators should be aware of the ethicallegal and regulatory requirements for research on humansubjects
Para 17
Physicians should cease any investigation if the risksoutweigh the potential benefits
Justice
DECLARATION OF HELSINKI -Basic Principles
1 Conform to accepted scientific principles
2 Design formulated in experimental protocol reviewed by IEC
3 Conducted by qualified and trained persons
4 Importance in proportion to inherent risk
5 Assessment of risks vs benefits
6 Safeguard subjectrsquos integrity (privacy)
7 Abstain unless hazards are predictable
8 Preserve accuracy when publishing
9 Adequately inform or right to withdraw
10 Obtain true informed consent in writing
11 Reliance on legal guardian
12 State compliance with Declaration
Ethical Principles and Guidelines for the Protection of Human Subjects of Research
bull Tuskegee Syphilis Study (1932ndash1972)
bull Named the Belmont Report for the Belmont Conference Center where the National Commission met when first drafting the report
42
Belmont Report 1979
Belmont Report 1979
Three ethical principles related to research on human subjects
1 Respect for Persons
2 Beneficence Do no harm while maximizing benefits for research project and minimizing risks to the research subjects
3 Justice ensuring reasonable non-exploitative and well-considered procedures are administered
Overview of
ICH GCP
What is ICH
bull The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)- is unique in bringing together the regulatory authorities and pharmaceutical industry of Europe Japan and the US to discuss scientific and technical aspects of drug registration
45
What is ICH
bull Since its inception in 1990 ICH has
gradually evolved
bull ICHs mission is to ensure that safe
effective and high quality medicines are
developed and registered in the most
resource-efficient manner
How did it evolve
The need to harmonize
bull Public disasters serious fraud and abuse of human rights
bull Trials of War criminals-Nuremberg code 1949
bull Thalidomide- Declaration of Helsinki 1964
bull Belmont report 1978 (Ethical Principles and guidelines for the protection of human subjects of research)-Tuskegee syphilis study
History
1962 US FDA IND Guidelines
1964 Declaration of Helsinki
1968 Committee on Safety of Medicines uk
1978 GCP US FDA
1991 GCP Europe
1996 ICH GCP
1997 ICH GCP Guideline
When did it begin
bull Ist conf in 1990 in Brussels
3 regions participated
bull Representatives from
Industry
Academia
Ministry of
health
ICH parties
6 parties
bull EU bull EFPIA European federation of pharmaceutical industriesrsquo associations
bull MHLW Ministry of health Labor and welfare Japan
bull JPMA Japan Pharmaceuticals manufacturers Association
bull US FDA
bull PhRMA
bull Observers WHO TPP(canada)
bull International federation of Pharmaceutical manufacturerrsquos association
Key objective
bull To discuss and define the minimum standards for the development and registration of investigational products
The result
Many guidelines made
bull Most important- ICH GCP guidelines
bull Evolved in several steps
bull Consolidated guideline ICH E6 Sept 1997
ICH Guidelines examples
bull Efficacy ndash clinical trials etc
bull Safety ndash pharmacovigilance adverse drug reaction
reporting
bull Quality ndash raw materials impurities residual solvents etc
bull Multidisciplinary ndash common technical document electronic
submission coding systems
What is GCP
A standard for the design conduct performance monitoring auditing recording analyses and reporting of clinical trials that provide assurance that the data and the reported results are credible accurate and that the rights integrity and confidentiality of trial subjects are protected
Why is it needed
bull To ensure the rights safety and well being of the trial subjects are protected
bull Ensure the credibility of clinical trial data
The ICH GCP guideline
bull Provide a unified standard for the EU Japan and USA regions to facilitate mutual acceptance of clinical trial data by the regulatory authorities in
these regions
bull 8 sections
ICH GCP guideline
1 Glossary
Common language for investigatorssponsorsethics committees
2Principles of Good Clinical Practice
13 tenets of ICH GCP
3Requirements for IRBIEC
Roles responsibilities and composition
ICH GCP guideline
4Responsibilities of the investigator
5Responsibilities of the sponsor
6Requirements for clinical trial protocol and protocol amendments
7Responsibility of the sponsor in the development of investigatorrsquos brochure
8Essential documents
Principles of ICH GCP
bull Ethical conduct as per
Declaration of Helsinki
GCP
Regulatory Requirements
Risk- Benefit
Primary concern- Subject
Principles of ICH GCP
bull Supportive data
bull Protocol
Scientifically sound clear detailed
bull Ethical Clearance
Study to be conducted in compliance to the protocol which has received EC approval
Principles of ICH GCP
bull Subject Care
Medical decisions responsibility of qualified physician
bull Qualified staff
By education training experience in their area of responsibility
bull Informed Consent
Principles of ICH GCP
bull Clinical Trial data
Recorded handled and stored to enable accurate reporting interpretation and verification
bull Confidentiality
Principles of ICH GCP
bull Investigational Product
Manufactured handled and stored as per GMP
Principles of ICH GCP
bull Quality Assurance
Systems and procedures to ensure the Quality of every aspect of the trial
Indian GCP guidelines
bull Released in Dec 2001(Developed by CDCSO and endorsed by DCGI)
bull In general in line with ICH GCP
bull Has Revised Schedule Y (Jan 2005) addressed discrepancies
bull SAFEGUARD PUBLIC HEALTH
bull ASSURE CONSUMER PROTECTION STANDARDS
bull FACILITATE AVAILABILITY OF SAFE AND EFFECTIVE PRODUCTS
bull ELIMINATE INCONSISTENT STANDARDS INTERNATIONALLY
bull FACILITATE MUTUAL ACCEPTANCE OF DATA FROM CLINICAL TRIALS
GOALS OF INTERNATIONAL HARMONIZATION OF
REGULATORY REQUIREMENTS
Study DocumentationDuring the study
The investigator must keepndash Source documents
bull Medical records (including access to computer records)
bull Laboratory reports
bull ECGs X-rays etc
bull Any other medical records reports or notes (hospital admissions and discharges)
ndash A subject identification list
ndash Copies of all study related documentation
Medical Records
bull In particular they should contain notes on
ndash Sufficient information to support subject eligibility
ndash This should be well documented (signed and dated)
ndash Subjectrsquos participation in the study
ndash Dates of visits
ndash Procedures investigations done
ndash Observations diagnoses
ndash Medications taken (including study medication)
ndash Adverse events
ndash Completion or withdrawal (reason) from the study
Study DocumentationAfter the study
The sponsor needs from the investigator
ndash Final drug accountability records
ndash All used and unused supplies and medication
ndash All required documents completed
Conclusion
70
Thanks
ldquoWhen a doctor [goes] wrong he is
the first of criminals He has nerve
and he has knowledgerdquo
- Sherlock Holmes
References
httpwwwwmanetepolicyb3htm
wwwhhsgovohrphumansubjectsguidancebelmonthtml
wwwhhsgovohrpreferencesnurcodehtml
wwwicmrnicinguidelinesGCLP
wwwcdsconicin
wwwubedurecercaBioeticadocDeclaracio_Helsinki_2013
wwwjewishvirtuallibraryorgjsourceHolocaustnazi_experiments
wwwichorgfileadminPublic_WebICHE6_R1__Guideline
Declaration of Helsinki
Para 21
Every precaution should be taken torespect the privacy of the subject theconfidentiality of the patients information
Confidentiality
Declaration of Helsinki
Para 30
Every patient entered into the study should be assured ofaccess to the best proven prophylactic diagnostic andtherapeutic methods identified by the study
Para 9
Research Investigators should be aware of the ethicallegal and regulatory requirements for research on humansubjects
Para 17
Physicians should cease any investigation if the risksoutweigh the potential benefits
Justice
DECLARATION OF HELSINKI -Basic Principles
1 Conform to accepted scientific principles
2 Design formulated in experimental protocol reviewed by IEC
3 Conducted by qualified and trained persons
4 Importance in proportion to inherent risk
5 Assessment of risks vs benefits
6 Safeguard subjectrsquos integrity (privacy)
7 Abstain unless hazards are predictable
8 Preserve accuracy when publishing
9 Adequately inform or right to withdraw
10 Obtain true informed consent in writing
11 Reliance on legal guardian
12 State compliance with Declaration
Ethical Principles and Guidelines for the Protection of Human Subjects of Research
bull Tuskegee Syphilis Study (1932ndash1972)
bull Named the Belmont Report for the Belmont Conference Center where the National Commission met when first drafting the report
42
Belmont Report 1979
Belmont Report 1979
Three ethical principles related to research on human subjects
1 Respect for Persons
2 Beneficence Do no harm while maximizing benefits for research project and minimizing risks to the research subjects
3 Justice ensuring reasonable non-exploitative and well-considered procedures are administered
Overview of
ICH GCP
What is ICH
bull The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)- is unique in bringing together the regulatory authorities and pharmaceutical industry of Europe Japan and the US to discuss scientific and technical aspects of drug registration
45
What is ICH
bull Since its inception in 1990 ICH has
gradually evolved
bull ICHs mission is to ensure that safe
effective and high quality medicines are
developed and registered in the most
resource-efficient manner
How did it evolve
The need to harmonize
bull Public disasters serious fraud and abuse of human rights
bull Trials of War criminals-Nuremberg code 1949
bull Thalidomide- Declaration of Helsinki 1964
bull Belmont report 1978 (Ethical Principles and guidelines for the protection of human subjects of research)-Tuskegee syphilis study
History
1962 US FDA IND Guidelines
1964 Declaration of Helsinki
1968 Committee on Safety of Medicines uk
1978 GCP US FDA
1991 GCP Europe
1996 ICH GCP
1997 ICH GCP Guideline
When did it begin
bull Ist conf in 1990 in Brussels
3 regions participated
bull Representatives from
Industry
Academia
Ministry of
health
ICH parties
6 parties
bull EU bull EFPIA European federation of pharmaceutical industriesrsquo associations
bull MHLW Ministry of health Labor and welfare Japan
bull JPMA Japan Pharmaceuticals manufacturers Association
bull US FDA
bull PhRMA
bull Observers WHO TPP(canada)
bull International federation of Pharmaceutical manufacturerrsquos association
Key objective
bull To discuss and define the minimum standards for the development and registration of investigational products
The result
Many guidelines made
bull Most important- ICH GCP guidelines
bull Evolved in several steps
bull Consolidated guideline ICH E6 Sept 1997
ICH Guidelines examples
bull Efficacy ndash clinical trials etc
bull Safety ndash pharmacovigilance adverse drug reaction
reporting
bull Quality ndash raw materials impurities residual solvents etc
bull Multidisciplinary ndash common technical document electronic
submission coding systems
What is GCP
A standard for the design conduct performance monitoring auditing recording analyses and reporting of clinical trials that provide assurance that the data and the reported results are credible accurate and that the rights integrity and confidentiality of trial subjects are protected
Why is it needed
bull To ensure the rights safety and well being of the trial subjects are protected
bull Ensure the credibility of clinical trial data
The ICH GCP guideline
bull Provide a unified standard for the EU Japan and USA regions to facilitate mutual acceptance of clinical trial data by the regulatory authorities in
these regions
bull 8 sections
ICH GCP guideline
1 Glossary
Common language for investigatorssponsorsethics committees
2Principles of Good Clinical Practice
13 tenets of ICH GCP
3Requirements for IRBIEC
Roles responsibilities and composition
ICH GCP guideline
4Responsibilities of the investigator
5Responsibilities of the sponsor
6Requirements for clinical trial protocol and protocol amendments
7Responsibility of the sponsor in the development of investigatorrsquos brochure
8Essential documents
Principles of ICH GCP
bull Ethical conduct as per
Declaration of Helsinki
GCP
Regulatory Requirements
Risk- Benefit
Primary concern- Subject
Principles of ICH GCP
bull Supportive data
bull Protocol
Scientifically sound clear detailed
bull Ethical Clearance
Study to be conducted in compliance to the protocol which has received EC approval
Principles of ICH GCP
bull Subject Care
Medical decisions responsibility of qualified physician
bull Qualified staff
By education training experience in their area of responsibility
bull Informed Consent
Principles of ICH GCP
bull Clinical Trial data
Recorded handled and stored to enable accurate reporting interpretation and verification
bull Confidentiality
Principles of ICH GCP
bull Investigational Product
Manufactured handled and stored as per GMP
Principles of ICH GCP
bull Quality Assurance
Systems and procedures to ensure the Quality of every aspect of the trial
Indian GCP guidelines
bull Released in Dec 2001(Developed by CDCSO and endorsed by DCGI)
bull In general in line with ICH GCP
bull Has Revised Schedule Y (Jan 2005) addressed discrepancies
bull SAFEGUARD PUBLIC HEALTH
bull ASSURE CONSUMER PROTECTION STANDARDS
bull FACILITATE AVAILABILITY OF SAFE AND EFFECTIVE PRODUCTS
bull ELIMINATE INCONSISTENT STANDARDS INTERNATIONALLY
bull FACILITATE MUTUAL ACCEPTANCE OF DATA FROM CLINICAL TRIALS
GOALS OF INTERNATIONAL HARMONIZATION OF
REGULATORY REQUIREMENTS
Study DocumentationDuring the study
The investigator must keepndash Source documents
bull Medical records (including access to computer records)
bull Laboratory reports
bull ECGs X-rays etc
bull Any other medical records reports or notes (hospital admissions and discharges)
ndash A subject identification list
ndash Copies of all study related documentation
Medical Records
bull In particular they should contain notes on
ndash Sufficient information to support subject eligibility
ndash This should be well documented (signed and dated)
ndash Subjectrsquos participation in the study
ndash Dates of visits
ndash Procedures investigations done
ndash Observations diagnoses
ndash Medications taken (including study medication)
ndash Adverse events
ndash Completion or withdrawal (reason) from the study
Study DocumentationAfter the study
The sponsor needs from the investigator
ndash Final drug accountability records
ndash All used and unused supplies and medication
ndash All required documents completed
Conclusion
70
Thanks
ldquoWhen a doctor [goes] wrong he is
the first of criminals He has nerve
and he has knowledgerdquo
- Sherlock Holmes
References
httpwwwwmanetepolicyb3htm
wwwhhsgovohrphumansubjectsguidancebelmonthtml
wwwhhsgovohrpreferencesnurcodehtml
wwwicmrnicinguidelinesGCLP
wwwcdsconicin
wwwubedurecercaBioeticadocDeclaracio_Helsinki_2013
wwwjewishvirtuallibraryorgjsourceHolocaustnazi_experiments
wwwichorgfileadminPublic_WebICHE6_R1__Guideline
Declaration of Helsinki
Para 30
Every patient entered into the study should be assured ofaccess to the best proven prophylactic diagnostic andtherapeutic methods identified by the study
Para 9
Research Investigators should be aware of the ethicallegal and regulatory requirements for research on humansubjects
Para 17
Physicians should cease any investigation if the risksoutweigh the potential benefits
Justice
DECLARATION OF HELSINKI -Basic Principles
1 Conform to accepted scientific principles
2 Design formulated in experimental protocol reviewed by IEC
3 Conducted by qualified and trained persons
4 Importance in proportion to inherent risk
5 Assessment of risks vs benefits
6 Safeguard subjectrsquos integrity (privacy)
7 Abstain unless hazards are predictable
8 Preserve accuracy when publishing
9 Adequately inform or right to withdraw
10 Obtain true informed consent in writing
11 Reliance on legal guardian
12 State compliance with Declaration
Ethical Principles and Guidelines for the Protection of Human Subjects of Research
bull Tuskegee Syphilis Study (1932ndash1972)
bull Named the Belmont Report for the Belmont Conference Center where the National Commission met when first drafting the report
42
Belmont Report 1979
Belmont Report 1979
Three ethical principles related to research on human subjects
1 Respect for Persons
2 Beneficence Do no harm while maximizing benefits for research project and minimizing risks to the research subjects
3 Justice ensuring reasonable non-exploitative and well-considered procedures are administered
Overview of
ICH GCP
What is ICH
bull The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)- is unique in bringing together the regulatory authorities and pharmaceutical industry of Europe Japan and the US to discuss scientific and technical aspects of drug registration
45
What is ICH
bull Since its inception in 1990 ICH has
gradually evolved
bull ICHs mission is to ensure that safe
effective and high quality medicines are
developed and registered in the most
resource-efficient manner
How did it evolve
The need to harmonize
bull Public disasters serious fraud and abuse of human rights
bull Trials of War criminals-Nuremberg code 1949
bull Thalidomide- Declaration of Helsinki 1964
bull Belmont report 1978 (Ethical Principles and guidelines for the protection of human subjects of research)-Tuskegee syphilis study
History
1962 US FDA IND Guidelines
1964 Declaration of Helsinki
1968 Committee on Safety of Medicines uk
1978 GCP US FDA
1991 GCP Europe
1996 ICH GCP
1997 ICH GCP Guideline
When did it begin
bull Ist conf in 1990 in Brussels
3 regions participated
bull Representatives from
Industry
Academia
Ministry of
health
ICH parties
6 parties
bull EU bull EFPIA European federation of pharmaceutical industriesrsquo associations
bull MHLW Ministry of health Labor and welfare Japan
bull JPMA Japan Pharmaceuticals manufacturers Association
bull US FDA
bull PhRMA
bull Observers WHO TPP(canada)
bull International federation of Pharmaceutical manufacturerrsquos association
Key objective
bull To discuss and define the minimum standards for the development and registration of investigational products
The result
Many guidelines made
bull Most important- ICH GCP guidelines
bull Evolved in several steps
bull Consolidated guideline ICH E6 Sept 1997
ICH Guidelines examples
bull Efficacy ndash clinical trials etc
bull Safety ndash pharmacovigilance adverse drug reaction
reporting
bull Quality ndash raw materials impurities residual solvents etc
bull Multidisciplinary ndash common technical document electronic
submission coding systems
What is GCP
A standard for the design conduct performance monitoring auditing recording analyses and reporting of clinical trials that provide assurance that the data and the reported results are credible accurate and that the rights integrity and confidentiality of trial subjects are protected
Why is it needed
bull To ensure the rights safety and well being of the trial subjects are protected
bull Ensure the credibility of clinical trial data
The ICH GCP guideline
bull Provide a unified standard for the EU Japan and USA regions to facilitate mutual acceptance of clinical trial data by the regulatory authorities in
these regions
bull 8 sections
ICH GCP guideline
1 Glossary
Common language for investigatorssponsorsethics committees
2Principles of Good Clinical Practice
13 tenets of ICH GCP
3Requirements for IRBIEC
Roles responsibilities and composition
ICH GCP guideline
4Responsibilities of the investigator
5Responsibilities of the sponsor
6Requirements for clinical trial protocol and protocol amendments
7Responsibility of the sponsor in the development of investigatorrsquos brochure
8Essential documents
Principles of ICH GCP
bull Ethical conduct as per
Declaration of Helsinki
GCP
Regulatory Requirements
Risk- Benefit
Primary concern- Subject
Principles of ICH GCP
bull Supportive data
bull Protocol
Scientifically sound clear detailed
bull Ethical Clearance
Study to be conducted in compliance to the protocol which has received EC approval
Principles of ICH GCP
bull Subject Care
Medical decisions responsibility of qualified physician
bull Qualified staff
By education training experience in their area of responsibility
bull Informed Consent
Principles of ICH GCP
bull Clinical Trial data
Recorded handled and stored to enable accurate reporting interpretation and verification
bull Confidentiality
Principles of ICH GCP
bull Investigational Product
Manufactured handled and stored as per GMP
Principles of ICH GCP
bull Quality Assurance
Systems and procedures to ensure the Quality of every aspect of the trial
Indian GCP guidelines
bull Released in Dec 2001(Developed by CDCSO and endorsed by DCGI)
bull In general in line with ICH GCP
bull Has Revised Schedule Y (Jan 2005) addressed discrepancies
bull SAFEGUARD PUBLIC HEALTH
bull ASSURE CONSUMER PROTECTION STANDARDS
bull FACILITATE AVAILABILITY OF SAFE AND EFFECTIVE PRODUCTS
bull ELIMINATE INCONSISTENT STANDARDS INTERNATIONALLY
bull FACILITATE MUTUAL ACCEPTANCE OF DATA FROM CLINICAL TRIALS
GOALS OF INTERNATIONAL HARMONIZATION OF
REGULATORY REQUIREMENTS
Study DocumentationDuring the study
The investigator must keepndash Source documents
bull Medical records (including access to computer records)
bull Laboratory reports
bull ECGs X-rays etc
bull Any other medical records reports or notes (hospital admissions and discharges)
ndash A subject identification list
ndash Copies of all study related documentation
Medical Records
bull In particular they should contain notes on
ndash Sufficient information to support subject eligibility
ndash This should be well documented (signed and dated)
ndash Subjectrsquos participation in the study
ndash Dates of visits
ndash Procedures investigations done
ndash Observations diagnoses
ndash Medications taken (including study medication)
ndash Adverse events
ndash Completion or withdrawal (reason) from the study
Study DocumentationAfter the study
The sponsor needs from the investigator
ndash Final drug accountability records
ndash All used and unused supplies and medication
ndash All required documents completed
Conclusion
70
Thanks
ldquoWhen a doctor [goes] wrong he is
the first of criminals He has nerve
and he has knowledgerdquo
- Sherlock Holmes
References
httpwwwwmanetepolicyb3htm
wwwhhsgovohrphumansubjectsguidancebelmonthtml
wwwhhsgovohrpreferencesnurcodehtml
wwwicmrnicinguidelinesGCLP
wwwcdsconicin
wwwubedurecercaBioeticadocDeclaracio_Helsinki_2013
wwwjewishvirtuallibraryorgjsourceHolocaustnazi_experiments
wwwichorgfileadminPublic_WebICHE6_R1__Guideline
DECLARATION OF HELSINKI -Basic Principles
1 Conform to accepted scientific principles
2 Design formulated in experimental protocol reviewed by IEC
3 Conducted by qualified and trained persons
4 Importance in proportion to inherent risk
5 Assessment of risks vs benefits
6 Safeguard subjectrsquos integrity (privacy)
7 Abstain unless hazards are predictable
8 Preserve accuracy when publishing
9 Adequately inform or right to withdraw
10 Obtain true informed consent in writing
11 Reliance on legal guardian
12 State compliance with Declaration
Ethical Principles and Guidelines for the Protection of Human Subjects of Research
bull Tuskegee Syphilis Study (1932ndash1972)
bull Named the Belmont Report for the Belmont Conference Center where the National Commission met when first drafting the report
42
Belmont Report 1979
Belmont Report 1979
Three ethical principles related to research on human subjects
1 Respect for Persons
2 Beneficence Do no harm while maximizing benefits for research project and minimizing risks to the research subjects
3 Justice ensuring reasonable non-exploitative and well-considered procedures are administered
Overview of
ICH GCP
What is ICH
bull The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)- is unique in bringing together the regulatory authorities and pharmaceutical industry of Europe Japan and the US to discuss scientific and technical aspects of drug registration
45
What is ICH
bull Since its inception in 1990 ICH has
gradually evolved
bull ICHs mission is to ensure that safe
effective and high quality medicines are
developed and registered in the most
resource-efficient manner
How did it evolve
The need to harmonize
bull Public disasters serious fraud and abuse of human rights
bull Trials of War criminals-Nuremberg code 1949
bull Thalidomide- Declaration of Helsinki 1964
bull Belmont report 1978 (Ethical Principles and guidelines for the protection of human subjects of research)-Tuskegee syphilis study
History
1962 US FDA IND Guidelines
1964 Declaration of Helsinki
1968 Committee on Safety of Medicines uk
1978 GCP US FDA
1991 GCP Europe
1996 ICH GCP
1997 ICH GCP Guideline
When did it begin
bull Ist conf in 1990 in Brussels
3 regions participated
bull Representatives from
Industry
Academia
Ministry of
health
ICH parties
6 parties
bull EU bull EFPIA European federation of pharmaceutical industriesrsquo associations
bull MHLW Ministry of health Labor and welfare Japan
bull JPMA Japan Pharmaceuticals manufacturers Association
bull US FDA
bull PhRMA
bull Observers WHO TPP(canada)
bull International federation of Pharmaceutical manufacturerrsquos association
Key objective
bull To discuss and define the minimum standards for the development and registration of investigational products
The result
Many guidelines made
bull Most important- ICH GCP guidelines
bull Evolved in several steps
bull Consolidated guideline ICH E6 Sept 1997
ICH Guidelines examples
bull Efficacy ndash clinical trials etc
bull Safety ndash pharmacovigilance adverse drug reaction
reporting
bull Quality ndash raw materials impurities residual solvents etc
bull Multidisciplinary ndash common technical document electronic
submission coding systems
What is GCP
A standard for the design conduct performance monitoring auditing recording analyses and reporting of clinical trials that provide assurance that the data and the reported results are credible accurate and that the rights integrity and confidentiality of trial subjects are protected
Why is it needed
bull To ensure the rights safety and well being of the trial subjects are protected
bull Ensure the credibility of clinical trial data
The ICH GCP guideline
bull Provide a unified standard for the EU Japan and USA regions to facilitate mutual acceptance of clinical trial data by the regulatory authorities in
these regions
bull 8 sections
ICH GCP guideline
1 Glossary
Common language for investigatorssponsorsethics committees
2Principles of Good Clinical Practice
13 tenets of ICH GCP
3Requirements for IRBIEC
Roles responsibilities and composition
ICH GCP guideline
4Responsibilities of the investigator
5Responsibilities of the sponsor
6Requirements for clinical trial protocol and protocol amendments
7Responsibility of the sponsor in the development of investigatorrsquos brochure
8Essential documents
Principles of ICH GCP
bull Ethical conduct as per
Declaration of Helsinki
GCP
Regulatory Requirements
Risk- Benefit
Primary concern- Subject
Principles of ICH GCP
bull Supportive data
bull Protocol
Scientifically sound clear detailed
bull Ethical Clearance
Study to be conducted in compliance to the protocol which has received EC approval
Principles of ICH GCP
bull Subject Care
Medical decisions responsibility of qualified physician
bull Qualified staff
By education training experience in their area of responsibility
bull Informed Consent
Principles of ICH GCP
bull Clinical Trial data
Recorded handled and stored to enable accurate reporting interpretation and verification
bull Confidentiality
Principles of ICH GCP
bull Investigational Product
Manufactured handled and stored as per GMP
Principles of ICH GCP
bull Quality Assurance
Systems and procedures to ensure the Quality of every aspect of the trial
Indian GCP guidelines
bull Released in Dec 2001(Developed by CDCSO and endorsed by DCGI)
bull In general in line with ICH GCP
bull Has Revised Schedule Y (Jan 2005) addressed discrepancies
bull SAFEGUARD PUBLIC HEALTH
bull ASSURE CONSUMER PROTECTION STANDARDS
bull FACILITATE AVAILABILITY OF SAFE AND EFFECTIVE PRODUCTS
bull ELIMINATE INCONSISTENT STANDARDS INTERNATIONALLY
bull FACILITATE MUTUAL ACCEPTANCE OF DATA FROM CLINICAL TRIALS
GOALS OF INTERNATIONAL HARMONIZATION OF
REGULATORY REQUIREMENTS
Study DocumentationDuring the study
The investigator must keepndash Source documents
bull Medical records (including access to computer records)
bull Laboratory reports
bull ECGs X-rays etc
bull Any other medical records reports or notes (hospital admissions and discharges)
ndash A subject identification list
ndash Copies of all study related documentation
Medical Records
bull In particular they should contain notes on
ndash Sufficient information to support subject eligibility
ndash This should be well documented (signed and dated)
ndash Subjectrsquos participation in the study
ndash Dates of visits
ndash Procedures investigations done
ndash Observations diagnoses
ndash Medications taken (including study medication)
ndash Adverse events
ndash Completion or withdrawal (reason) from the study
Study DocumentationAfter the study
The sponsor needs from the investigator
ndash Final drug accountability records
ndash All used and unused supplies and medication
ndash All required documents completed
Conclusion
70
Thanks
ldquoWhen a doctor [goes] wrong he is
the first of criminals He has nerve
and he has knowledgerdquo
- Sherlock Holmes
References
httpwwwwmanetepolicyb3htm
wwwhhsgovohrphumansubjectsguidancebelmonthtml
wwwhhsgovohrpreferencesnurcodehtml
wwwicmrnicinguidelinesGCLP
wwwcdsconicin
wwwubedurecercaBioeticadocDeclaracio_Helsinki_2013
wwwjewishvirtuallibraryorgjsourceHolocaustnazi_experiments
wwwichorgfileadminPublic_WebICHE6_R1__Guideline
Ethical Principles and Guidelines for the Protection of Human Subjects of Research
bull Tuskegee Syphilis Study (1932ndash1972)
bull Named the Belmont Report for the Belmont Conference Center where the National Commission met when first drafting the report
42
Belmont Report 1979
Belmont Report 1979
Three ethical principles related to research on human subjects
1 Respect for Persons
2 Beneficence Do no harm while maximizing benefits for research project and minimizing risks to the research subjects
3 Justice ensuring reasonable non-exploitative and well-considered procedures are administered
Overview of
ICH GCP
What is ICH
bull The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)- is unique in bringing together the regulatory authorities and pharmaceutical industry of Europe Japan and the US to discuss scientific and technical aspects of drug registration
45
What is ICH
bull Since its inception in 1990 ICH has
gradually evolved
bull ICHs mission is to ensure that safe
effective and high quality medicines are
developed and registered in the most
resource-efficient manner
How did it evolve
The need to harmonize
bull Public disasters serious fraud and abuse of human rights
bull Trials of War criminals-Nuremberg code 1949
bull Thalidomide- Declaration of Helsinki 1964
bull Belmont report 1978 (Ethical Principles and guidelines for the protection of human subjects of research)-Tuskegee syphilis study
History
1962 US FDA IND Guidelines
1964 Declaration of Helsinki
1968 Committee on Safety of Medicines uk
1978 GCP US FDA
1991 GCP Europe
1996 ICH GCP
1997 ICH GCP Guideline
When did it begin
bull Ist conf in 1990 in Brussels
3 regions participated
bull Representatives from
Industry
Academia
Ministry of
health
ICH parties
6 parties
bull EU bull EFPIA European federation of pharmaceutical industriesrsquo associations
bull MHLW Ministry of health Labor and welfare Japan
bull JPMA Japan Pharmaceuticals manufacturers Association
bull US FDA
bull PhRMA
bull Observers WHO TPP(canada)
bull International federation of Pharmaceutical manufacturerrsquos association
Key objective
bull To discuss and define the minimum standards for the development and registration of investigational products
The result
Many guidelines made
bull Most important- ICH GCP guidelines
bull Evolved in several steps
bull Consolidated guideline ICH E6 Sept 1997
ICH Guidelines examples
bull Efficacy ndash clinical trials etc
bull Safety ndash pharmacovigilance adverse drug reaction
reporting
bull Quality ndash raw materials impurities residual solvents etc
bull Multidisciplinary ndash common technical document electronic
submission coding systems
What is GCP
A standard for the design conduct performance monitoring auditing recording analyses and reporting of clinical trials that provide assurance that the data and the reported results are credible accurate and that the rights integrity and confidentiality of trial subjects are protected
Why is it needed
bull To ensure the rights safety and well being of the trial subjects are protected
bull Ensure the credibility of clinical trial data
The ICH GCP guideline
bull Provide a unified standard for the EU Japan and USA regions to facilitate mutual acceptance of clinical trial data by the regulatory authorities in
these regions
bull 8 sections
ICH GCP guideline
1 Glossary
Common language for investigatorssponsorsethics committees
2Principles of Good Clinical Practice
13 tenets of ICH GCP
3Requirements for IRBIEC
Roles responsibilities and composition
ICH GCP guideline
4Responsibilities of the investigator
5Responsibilities of the sponsor
6Requirements for clinical trial protocol and protocol amendments
7Responsibility of the sponsor in the development of investigatorrsquos brochure
8Essential documents
Principles of ICH GCP
bull Ethical conduct as per
Declaration of Helsinki
GCP
Regulatory Requirements
Risk- Benefit
Primary concern- Subject
Principles of ICH GCP
bull Supportive data
bull Protocol
Scientifically sound clear detailed
bull Ethical Clearance
Study to be conducted in compliance to the protocol which has received EC approval
Principles of ICH GCP
bull Subject Care
Medical decisions responsibility of qualified physician
bull Qualified staff
By education training experience in their area of responsibility
bull Informed Consent
Principles of ICH GCP
bull Clinical Trial data
Recorded handled and stored to enable accurate reporting interpretation and verification
bull Confidentiality
Principles of ICH GCP
bull Investigational Product
Manufactured handled and stored as per GMP
Principles of ICH GCP
bull Quality Assurance
Systems and procedures to ensure the Quality of every aspect of the trial
Indian GCP guidelines
bull Released in Dec 2001(Developed by CDCSO and endorsed by DCGI)
bull In general in line with ICH GCP
bull Has Revised Schedule Y (Jan 2005) addressed discrepancies
bull SAFEGUARD PUBLIC HEALTH
bull ASSURE CONSUMER PROTECTION STANDARDS
bull FACILITATE AVAILABILITY OF SAFE AND EFFECTIVE PRODUCTS
bull ELIMINATE INCONSISTENT STANDARDS INTERNATIONALLY
bull FACILITATE MUTUAL ACCEPTANCE OF DATA FROM CLINICAL TRIALS
GOALS OF INTERNATIONAL HARMONIZATION OF
REGULATORY REQUIREMENTS
Study DocumentationDuring the study
The investigator must keepndash Source documents
bull Medical records (including access to computer records)
bull Laboratory reports
bull ECGs X-rays etc
bull Any other medical records reports or notes (hospital admissions and discharges)
ndash A subject identification list
ndash Copies of all study related documentation
Medical Records
bull In particular they should contain notes on
ndash Sufficient information to support subject eligibility
ndash This should be well documented (signed and dated)
ndash Subjectrsquos participation in the study
ndash Dates of visits
ndash Procedures investigations done
ndash Observations diagnoses
ndash Medications taken (including study medication)
ndash Adverse events
ndash Completion or withdrawal (reason) from the study
Study DocumentationAfter the study
The sponsor needs from the investigator
ndash Final drug accountability records
ndash All used and unused supplies and medication
ndash All required documents completed
Conclusion
70
Thanks
ldquoWhen a doctor [goes] wrong he is
the first of criminals He has nerve
and he has knowledgerdquo
- Sherlock Holmes
References
httpwwwwmanetepolicyb3htm
wwwhhsgovohrphumansubjectsguidancebelmonthtml
wwwhhsgovohrpreferencesnurcodehtml
wwwicmrnicinguidelinesGCLP
wwwcdsconicin
wwwubedurecercaBioeticadocDeclaracio_Helsinki_2013
wwwjewishvirtuallibraryorgjsourceHolocaustnazi_experiments
wwwichorgfileadminPublic_WebICHE6_R1__Guideline
Belmont Report 1979
Three ethical principles related to research on human subjects
1 Respect for Persons
2 Beneficence Do no harm while maximizing benefits for research project and minimizing risks to the research subjects
3 Justice ensuring reasonable non-exploitative and well-considered procedures are administered
Overview of
ICH GCP
What is ICH
bull The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)- is unique in bringing together the regulatory authorities and pharmaceutical industry of Europe Japan and the US to discuss scientific and technical aspects of drug registration
45
What is ICH
bull Since its inception in 1990 ICH has
gradually evolved
bull ICHs mission is to ensure that safe
effective and high quality medicines are
developed and registered in the most
resource-efficient manner
How did it evolve
The need to harmonize
bull Public disasters serious fraud and abuse of human rights
bull Trials of War criminals-Nuremberg code 1949
bull Thalidomide- Declaration of Helsinki 1964
bull Belmont report 1978 (Ethical Principles and guidelines for the protection of human subjects of research)-Tuskegee syphilis study
History
1962 US FDA IND Guidelines
1964 Declaration of Helsinki
1968 Committee on Safety of Medicines uk
1978 GCP US FDA
1991 GCP Europe
1996 ICH GCP
1997 ICH GCP Guideline
When did it begin
bull Ist conf in 1990 in Brussels
3 regions participated
bull Representatives from
Industry
Academia
Ministry of
health
ICH parties
6 parties
bull EU bull EFPIA European federation of pharmaceutical industriesrsquo associations
bull MHLW Ministry of health Labor and welfare Japan
bull JPMA Japan Pharmaceuticals manufacturers Association
bull US FDA
bull PhRMA
bull Observers WHO TPP(canada)
bull International federation of Pharmaceutical manufacturerrsquos association
Key objective
bull To discuss and define the minimum standards for the development and registration of investigational products
The result
Many guidelines made
bull Most important- ICH GCP guidelines
bull Evolved in several steps
bull Consolidated guideline ICH E6 Sept 1997
ICH Guidelines examples
bull Efficacy ndash clinical trials etc
bull Safety ndash pharmacovigilance adverse drug reaction
reporting
bull Quality ndash raw materials impurities residual solvents etc
bull Multidisciplinary ndash common technical document electronic
submission coding systems
What is GCP
A standard for the design conduct performance monitoring auditing recording analyses and reporting of clinical trials that provide assurance that the data and the reported results are credible accurate and that the rights integrity and confidentiality of trial subjects are protected
Why is it needed
bull To ensure the rights safety and well being of the trial subjects are protected
bull Ensure the credibility of clinical trial data
The ICH GCP guideline
bull Provide a unified standard for the EU Japan and USA regions to facilitate mutual acceptance of clinical trial data by the regulatory authorities in
these regions
bull 8 sections
ICH GCP guideline
1 Glossary
Common language for investigatorssponsorsethics committees
2Principles of Good Clinical Practice
13 tenets of ICH GCP
3Requirements for IRBIEC
Roles responsibilities and composition
ICH GCP guideline
4Responsibilities of the investigator
5Responsibilities of the sponsor
6Requirements for clinical trial protocol and protocol amendments
7Responsibility of the sponsor in the development of investigatorrsquos brochure
8Essential documents
Principles of ICH GCP
bull Ethical conduct as per
Declaration of Helsinki
GCP
Regulatory Requirements
Risk- Benefit
Primary concern- Subject
Principles of ICH GCP
bull Supportive data
bull Protocol
Scientifically sound clear detailed
bull Ethical Clearance
Study to be conducted in compliance to the protocol which has received EC approval
Principles of ICH GCP
bull Subject Care
Medical decisions responsibility of qualified physician
bull Qualified staff
By education training experience in their area of responsibility
bull Informed Consent
Principles of ICH GCP
bull Clinical Trial data
Recorded handled and stored to enable accurate reporting interpretation and verification
bull Confidentiality
Principles of ICH GCP
bull Investigational Product
Manufactured handled and stored as per GMP
Principles of ICH GCP
bull Quality Assurance
Systems and procedures to ensure the Quality of every aspect of the trial
Indian GCP guidelines
bull Released in Dec 2001(Developed by CDCSO and endorsed by DCGI)
bull In general in line with ICH GCP
bull Has Revised Schedule Y (Jan 2005) addressed discrepancies
bull SAFEGUARD PUBLIC HEALTH
bull ASSURE CONSUMER PROTECTION STANDARDS
bull FACILITATE AVAILABILITY OF SAFE AND EFFECTIVE PRODUCTS
bull ELIMINATE INCONSISTENT STANDARDS INTERNATIONALLY
bull FACILITATE MUTUAL ACCEPTANCE OF DATA FROM CLINICAL TRIALS
GOALS OF INTERNATIONAL HARMONIZATION OF
REGULATORY REQUIREMENTS
Study DocumentationDuring the study
The investigator must keepndash Source documents
bull Medical records (including access to computer records)
bull Laboratory reports
bull ECGs X-rays etc
bull Any other medical records reports or notes (hospital admissions and discharges)
ndash A subject identification list
ndash Copies of all study related documentation
Medical Records
bull In particular they should contain notes on
ndash Sufficient information to support subject eligibility
ndash This should be well documented (signed and dated)
ndash Subjectrsquos participation in the study
ndash Dates of visits
ndash Procedures investigations done
ndash Observations diagnoses
ndash Medications taken (including study medication)
ndash Adverse events
ndash Completion or withdrawal (reason) from the study
Study DocumentationAfter the study
The sponsor needs from the investigator
ndash Final drug accountability records
ndash All used and unused supplies and medication
ndash All required documents completed
Conclusion
70
Thanks
ldquoWhen a doctor [goes] wrong he is
the first of criminals He has nerve
and he has knowledgerdquo
- Sherlock Holmes
References
httpwwwwmanetepolicyb3htm
wwwhhsgovohrphumansubjectsguidancebelmonthtml
wwwhhsgovohrpreferencesnurcodehtml
wwwicmrnicinguidelinesGCLP
wwwcdsconicin
wwwubedurecercaBioeticadocDeclaracio_Helsinki_2013
wwwjewishvirtuallibraryorgjsourceHolocaustnazi_experiments
wwwichorgfileadminPublic_WebICHE6_R1__Guideline
Overview of
ICH GCP
What is ICH
bull The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)- is unique in bringing together the regulatory authorities and pharmaceutical industry of Europe Japan and the US to discuss scientific and technical aspects of drug registration
45
What is ICH
bull Since its inception in 1990 ICH has
gradually evolved
bull ICHs mission is to ensure that safe
effective and high quality medicines are
developed and registered in the most
resource-efficient manner
How did it evolve
The need to harmonize
bull Public disasters serious fraud and abuse of human rights
bull Trials of War criminals-Nuremberg code 1949
bull Thalidomide- Declaration of Helsinki 1964
bull Belmont report 1978 (Ethical Principles and guidelines for the protection of human subjects of research)-Tuskegee syphilis study
History
1962 US FDA IND Guidelines
1964 Declaration of Helsinki
1968 Committee on Safety of Medicines uk
1978 GCP US FDA
1991 GCP Europe
1996 ICH GCP
1997 ICH GCP Guideline
When did it begin
bull Ist conf in 1990 in Brussels
3 regions participated
bull Representatives from
Industry
Academia
Ministry of
health
ICH parties
6 parties
bull EU bull EFPIA European federation of pharmaceutical industriesrsquo associations
bull MHLW Ministry of health Labor and welfare Japan
bull JPMA Japan Pharmaceuticals manufacturers Association
bull US FDA
bull PhRMA
bull Observers WHO TPP(canada)
bull International federation of Pharmaceutical manufacturerrsquos association
Key objective
bull To discuss and define the minimum standards for the development and registration of investigational products
The result
Many guidelines made
bull Most important- ICH GCP guidelines
bull Evolved in several steps
bull Consolidated guideline ICH E6 Sept 1997
ICH Guidelines examples
bull Efficacy ndash clinical trials etc
bull Safety ndash pharmacovigilance adverse drug reaction
reporting
bull Quality ndash raw materials impurities residual solvents etc
bull Multidisciplinary ndash common technical document electronic
submission coding systems
What is GCP
A standard for the design conduct performance monitoring auditing recording analyses and reporting of clinical trials that provide assurance that the data and the reported results are credible accurate and that the rights integrity and confidentiality of trial subjects are protected
Why is it needed
bull To ensure the rights safety and well being of the trial subjects are protected
bull Ensure the credibility of clinical trial data
The ICH GCP guideline
bull Provide a unified standard for the EU Japan and USA regions to facilitate mutual acceptance of clinical trial data by the regulatory authorities in
these regions
bull 8 sections
ICH GCP guideline
1 Glossary
Common language for investigatorssponsorsethics committees
2Principles of Good Clinical Practice
13 tenets of ICH GCP
3Requirements for IRBIEC
Roles responsibilities and composition
ICH GCP guideline
4Responsibilities of the investigator
5Responsibilities of the sponsor
6Requirements for clinical trial protocol and protocol amendments
7Responsibility of the sponsor in the development of investigatorrsquos brochure
8Essential documents
Principles of ICH GCP
bull Ethical conduct as per
Declaration of Helsinki
GCP
Regulatory Requirements
Risk- Benefit
Primary concern- Subject
Principles of ICH GCP
bull Supportive data
bull Protocol
Scientifically sound clear detailed
bull Ethical Clearance
Study to be conducted in compliance to the protocol which has received EC approval
Principles of ICH GCP
bull Subject Care
Medical decisions responsibility of qualified physician
bull Qualified staff
By education training experience in their area of responsibility
bull Informed Consent
Principles of ICH GCP
bull Clinical Trial data
Recorded handled and stored to enable accurate reporting interpretation and verification
bull Confidentiality
Principles of ICH GCP
bull Investigational Product
Manufactured handled and stored as per GMP
Principles of ICH GCP
bull Quality Assurance
Systems and procedures to ensure the Quality of every aspect of the trial
Indian GCP guidelines
bull Released in Dec 2001(Developed by CDCSO and endorsed by DCGI)
bull In general in line with ICH GCP
bull Has Revised Schedule Y (Jan 2005) addressed discrepancies
bull SAFEGUARD PUBLIC HEALTH
bull ASSURE CONSUMER PROTECTION STANDARDS
bull FACILITATE AVAILABILITY OF SAFE AND EFFECTIVE PRODUCTS
bull ELIMINATE INCONSISTENT STANDARDS INTERNATIONALLY
bull FACILITATE MUTUAL ACCEPTANCE OF DATA FROM CLINICAL TRIALS
GOALS OF INTERNATIONAL HARMONIZATION OF
REGULATORY REQUIREMENTS
Study DocumentationDuring the study
The investigator must keepndash Source documents
bull Medical records (including access to computer records)
bull Laboratory reports
bull ECGs X-rays etc
bull Any other medical records reports or notes (hospital admissions and discharges)
ndash A subject identification list
ndash Copies of all study related documentation
Medical Records
bull In particular they should contain notes on
ndash Sufficient information to support subject eligibility
ndash This should be well documented (signed and dated)
ndash Subjectrsquos participation in the study
ndash Dates of visits
ndash Procedures investigations done
ndash Observations diagnoses
ndash Medications taken (including study medication)
ndash Adverse events
ndash Completion or withdrawal (reason) from the study
Study DocumentationAfter the study
The sponsor needs from the investigator
ndash Final drug accountability records
ndash All used and unused supplies and medication
ndash All required documents completed
Conclusion
70
Thanks
ldquoWhen a doctor [goes] wrong he is
the first of criminals He has nerve
and he has knowledgerdquo
- Sherlock Holmes
References
httpwwwwmanetepolicyb3htm
wwwhhsgovohrphumansubjectsguidancebelmonthtml
wwwhhsgovohrpreferencesnurcodehtml
wwwicmrnicinguidelinesGCLP
wwwcdsconicin
wwwubedurecercaBioeticadocDeclaracio_Helsinki_2013
wwwjewishvirtuallibraryorgjsourceHolocaustnazi_experiments
wwwichorgfileadminPublic_WebICHE6_R1__Guideline
What is ICH
bull The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)- is unique in bringing together the regulatory authorities and pharmaceutical industry of Europe Japan and the US to discuss scientific and technical aspects of drug registration
45
What is ICH
bull Since its inception in 1990 ICH has
gradually evolved
bull ICHs mission is to ensure that safe
effective and high quality medicines are
developed and registered in the most
resource-efficient manner
How did it evolve
The need to harmonize
bull Public disasters serious fraud and abuse of human rights
bull Trials of War criminals-Nuremberg code 1949
bull Thalidomide- Declaration of Helsinki 1964
bull Belmont report 1978 (Ethical Principles and guidelines for the protection of human subjects of research)-Tuskegee syphilis study
History
1962 US FDA IND Guidelines
1964 Declaration of Helsinki
1968 Committee on Safety of Medicines uk
1978 GCP US FDA
1991 GCP Europe
1996 ICH GCP
1997 ICH GCP Guideline
When did it begin
bull Ist conf in 1990 in Brussels
3 regions participated
bull Representatives from
Industry
Academia
Ministry of
health
ICH parties
6 parties
bull EU bull EFPIA European federation of pharmaceutical industriesrsquo associations
bull MHLW Ministry of health Labor and welfare Japan
bull JPMA Japan Pharmaceuticals manufacturers Association
bull US FDA
bull PhRMA
bull Observers WHO TPP(canada)
bull International federation of Pharmaceutical manufacturerrsquos association
Key objective
bull To discuss and define the minimum standards for the development and registration of investigational products
The result
Many guidelines made
bull Most important- ICH GCP guidelines
bull Evolved in several steps
bull Consolidated guideline ICH E6 Sept 1997
ICH Guidelines examples
bull Efficacy ndash clinical trials etc
bull Safety ndash pharmacovigilance adverse drug reaction
reporting
bull Quality ndash raw materials impurities residual solvents etc
bull Multidisciplinary ndash common technical document electronic
submission coding systems
What is GCP
A standard for the design conduct performance monitoring auditing recording analyses and reporting of clinical trials that provide assurance that the data and the reported results are credible accurate and that the rights integrity and confidentiality of trial subjects are protected
Why is it needed
bull To ensure the rights safety and well being of the trial subjects are protected
bull Ensure the credibility of clinical trial data
The ICH GCP guideline
bull Provide a unified standard for the EU Japan and USA regions to facilitate mutual acceptance of clinical trial data by the regulatory authorities in
these regions
bull 8 sections
ICH GCP guideline
1 Glossary
Common language for investigatorssponsorsethics committees
2Principles of Good Clinical Practice
13 tenets of ICH GCP
3Requirements for IRBIEC
Roles responsibilities and composition
ICH GCP guideline
4Responsibilities of the investigator
5Responsibilities of the sponsor
6Requirements for clinical trial protocol and protocol amendments
7Responsibility of the sponsor in the development of investigatorrsquos brochure
8Essential documents
Principles of ICH GCP
bull Ethical conduct as per
Declaration of Helsinki
GCP
Regulatory Requirements
Risk- Benefit
Primary concern- Subject
Principles of ICH GCP
bull Supportive data
bull Protocol
Scientifically sound clear detailed
bull Ethical Clearance
Study to be conducted in compliance to the protocol which has received EC approval
Principles of ICH GCP
bull Subject Care
Medical decisions responsibility of qualified physician
bull Qualified staff
By education training experience in their area of responsibility
bull Informed Consent
Principles of ICH GCP
bull Clinical Trial data
Recorded handled and stored to enable accurate reporting interpretation and verification
bull Confidentiality
Principles of ICH GCP
bull Investigational Product
Manufactured handled and stored as per GMP
Principles of ICH GCP
bull Quality Assurance
Systems and procedures to ensure the Quality of every aspect of the trial
Indian GCP guidelines
bull Released in Dec 2001(Developed by CDCSO and endorsed by DCGI)
bull In general in line with ICH GCP
bull Has Revised Schedule Y (Jan 2005) addressed discrepancies
bull SAFEGUARD PUBLIC HEALTH
bull ASSURE CONSUMER PROTECTION STANDARDS
bull FACILITATE AVAILABILITY OF SAFE AND EFFECTIVE PRODUCTS
bull ELIMINATE INCONSISTENT STANDARDS INTERNATIONALLY
bull FACILITATE MUTUAL ACCEPTANCE OF DATA FROM CLINICAL TRIALS
GOALS OF INTERNATIONAL HARMONIZATION OF
REGULATORY REQUIREMENTS
Study DocumentationDuring the study
The investigator must keepndash Source documents
bull Medical records (including access to computer records)
bull Laboratory reports
bull ECGs X-rays etc
bull Any other medical records reports or notes (hospital admissions and discharges)
ndash A subject identification list
ndash Copies of all study related documentation
Medical Records
bull In particular they should contain notes on
ndash Sufficient information to support subject eligibility
ndash This should be well documented (signed and dated)
ndash Subjectrsquos participation in the study
ndash Dates of visits
ndash Procedures investigations done
ndash Observations diagnoses
ndash Medications taken (including study medication)
ndash Adverse events
ndash Completion or withdrawal (reason) from the study
Study DocumentationAfter the study
The sponsor needs from the investigator
ndash Final drug accountability records
ndash All used and unused supplies and medication
ndash All required documents completed
Conclusion
70
Thanks
ldquoWhen a doctor [goes] wrong he is
the first of criminals He has nerve
and he has knowledgerdquo
- Sherlock Holmes
References
httpwwwwmanetepolicyb3htm
wwwhhsgovohrphumansubjectsguidancebelmonthtml
wwwhhsgovohrpreferencesnurcodehtml
wwwicmrnicinguidelinesGCLP
wwwcdsconicin
wwwubedurecercaBioeticadocDeclaracio_Helsinki_2013
wwwjewishvirtuallibraryorgjsourceHolocaustnazi_experiments
wwwichorgfileadminPublic_WebICHE6_R1__Guideline
What is ICH
bull Since its inception in 1990 ICH has
gradually evolved
bull ICHs mission is to ensure that safe
effective and high quality medicines are
developed and registered in the most
resource-efficient manner
How did it evolve
The need to harmonize
bull Public disasters serious fraud and abuse of human rights
bull Trials of War criminals-Nuremberg code 1949
bull Thalidomide- Declaration of Helsinki 1964
bull Belmont report 1978 (Ethical Principles and guidelines for the protection of human subjects of research)-Tuskegee syphilis study
History
1962 US FDA IND Guidelines
1964 Declaration of Helsinki
1968 Committee on Safety of Medicines uk
1978 GCP US FDA
1991 GCP Europe
1996 ICH GCP
1997 ICH GCP Guideline
When did it begin
bull Ist conf in 1990 in Brussels
3 regions participated
bull Representatives from
Industry
Academia
Ministry of
health
ICH parties
6 parties
bull EU bull EFPIA European federation of pharmaceutical industriesrsquo associations
bull MHLW Ministry of health Labor and welfare Japan
bull JPMA Japan Pharmaceuticals manufacturers Association
bull US FDA
bull PhRMA
bull Observers WHO TPP(canada)
bull International federation of Pharmaceutical manufacturerrsquos association
Key objective
bull To discuss and define the minimum standards for the development and registration of investigational products
The result
Many guidelines made
bull Most important- ICH GCP guidelines
bull Evolved in several steps
bull Consolidated guideline ICH E6 Sept 1997
ICH Guidelines examples
bull Efficacy ndash clinical trials etc
bull Safety ndash pharmacovigilance adverse drug reaction
reporting
bull Quality ndash raw materials impurities residual solvents etc
bull Multidisciplinary ndash common technical document electronic
submission coding systems
What is GCP
A standard for the design conduct performance monitoring auditing recording analyses and reporting of clinical trials that provide assurance that the data and the reported results are credible accurate and that the rights integrity and confidentiality of trial subjects are protected
Why is it needed
bull To ensure the rights safety and well being of the trial subjects are protected
bull Ensure the credibility of clinical trial data
The ICH GCP guideline
bull Provide a unified standard for the EU Japan and USA regions to facilitate mutual acceptance of clinical trial data by the regulatory authorities in
these regions
bull 8 sections
ICH GCP guideline
1 Glossary
Common language for investigatorssponsorsethics committees
2Principles of Good Clinical Practice
13 tenets of ICH GCP
3Requirements for IRBIEC
Roles responsibilities and composition
ICH GCP guideline
4Responsibilities of the investigator
5Responsibilities of the sponsor
6Requirements for clinical trial protocol and protocol amendments
7Responsibility of the sponsor in the development of investigatorrsquos brochure
8Essential documents
Principles of ICH GCP
bull Ethical conduct as per
Declaration of Helsinki
GCP
Regulatory Requirements
Risk- Benefit
Primary concern- Subject
Principles of ICH GCP
bull Supportive data
bull Protocol
Scientifically sound clear detailed
bull Ethical Clearance
Study to be conducted in compliance to the protocol which has received EC approval
Principles of ICH GCP
bull Subject Care
Medical decisions responsibility of qualified physician
bull Qualified staff
By education training experience in their area of responsibility
bull Informed Consent
Principles of ICH GCP
bull Clinical Trial data
Recorded handled and stored to enable accurate reporting interpretation and verification
bull Confidentiality
Principles of ICH GCP
bull Investigational Product
Manufactured handled and stored as per GMP
Principles of ICH GCP
bull Quality Assurance
Systems and procedures to ensure the Quality of every aspect of the trial
Indian GCP guidelines
bull Released in Dec 2001(Developed by CDCSO and endorsed by DCGI)
bull In general in line with ICH GCP
bull Has Revised Schedule Y (Jan 2005) addressed discrepancies
bull SAFEGUARD PUBLIC HEALTH
bull ASSURE CONSUMER PROTECTION STANDARDS
bull FACILITATE AVAILABILITY OF SAFE AND EFFECTIVE PRODUCTS
bull ELIMINATE INCONSISTENT STANDARDS INTERNATIONALLY
bull FACILITATE MUTUAL ACCEPTANCE OF DATA FROM CLINICAL TRIALS
GOALS OF INTERNATIONAL HARMONIZATION OF
REGULATORY REQUIREMENTS
Study DocumentationDuring the study
The investigator must keepndash Source documents
bull Medical records (including access to computer records)
bull Laboratory reports
bull ECGs X-rays etc
bull Any other medical records reports or notes (hospital admissions and discharges)
ndash A subject identification list
ndash Copies of all study related documentation
Medical Records
bull In particular they should contain notes on
ndash Sufficient information to support subject eligibility
ndash This should be well documented (signed and dated)
ndash Subjectrsquos participation in the study
ndash Dates of visits
ndash Procedures investigations done
ndash Observations diagnoses
ndash Medications taken (including study medication)
ndash Adverse events
ndash Completion or withdrawal (reason) from the study
Study DocumentationAfter the study
The sponsor needs from the investigator
ndash Final drug accountability records
ndash All used and unused supplies and medication
ndash All required documents completed
Conclusion
70
Thanks
ldquoWhen a doctor [goes] wrong he is
the first of criminals He has nerve
and he has knowledgerdquo
- Sherlock Holmes
References
httpwwwwmanetepolicyb3htm
wwwhhsgovohrphumansubjectsguidancebelmonthtml
wwwhhsgovohrpreferencesnurcodehtml
wwwicmrnicinguidelinesGCLP
wwwcdsconicin
wwwubedurecercaBioeticadocDeclaracio_Helsinki_2013
wwwjewishvirtuallibraryorgjsourceHolocaustnazi_experiments
wwwichorgfileadminPublic_WebICHE6_R1__Guideline
How did it evolve
The need to harmonize
bull Public disasters serious fraud and abuse of human rights
bull Trials of War criminals-Nuremberg code 1949
bull Thalidomide- Declaration of Helsinki 1964
bull Belmont report 1978 (Ethical Principles and guidelines for the protection of human subjects of research)-Tuskegee syphilis study
History
1962 US FDA IND Guidelines
1964 Declaration of Helsinki
1968 Committee on Safety of Medicines uk
1978 GCP US FDA
1991 GCP Europe
1996 ICH GCP
1997 ICH GCP Guideline
When did it begin
bull Ist conf in 1990 in Brussels
3 regions participated
bull Representatives from
Industry
Academia
Ministry of
health
ICH parties
6 parties
bull EU bull EFPIA European federation of pharmaceutical industriesrsquo associations
bull MHLW Ministry of health Labor and welfare Japan
bull JPMA Japan Pharmaceuticals manufacturers Association
bull US FDA
bull PhRMA
bull Observers WHO TPP(canada)
bull International federation of Pharmaceutical manufacturerrsquos association
Key objective
bull To discuss and define the minimum standards for the development and registration of investigational products
The result
Many guidelines made
bull Most important- ICH GCP guidelines
bull Evolved in several steps
bull Consolidated guideline ICH E6 Sept 1997
ICH Guidelines examples
bull Efficacy ndash clinical trials etc
bull Safety ndash pharmacovigilance adverse drug reaction
reporting
bull Quality ndash raw materials impurities residual solvents etc
bull Multidisciplinary ndash common technical document electronic
submission coding systems
What is GCP
A standard for the design conduct performance monitoring auditing recording analyses and reporting of clinical trials that provide assurance that the data and the reported results are credible accurate and that the rights integrity and confidentiality of trial subjects are protected
Why is it needed
bull To ensure the rights safety and well being of the trial subjects are protected
bull Ensure the credibility of clinical trial data
The ICH GCP guideline
bull Provide a unified standard for the EU Japan and USA regions to facilitate mutual acceptance of clinical trial data by the regulatory authorities in
these regions
bull 8 sections
ICH GCP guideline
1 Glossary
Common language for investigatorssponsorsethics committees
2Principles of Good Clinical Practice
13 tenets of ICH GCP
3Requirements for IRBIEC
Roles responsibilities and composition
ICH GCP guideline
4Responsibilities of the investigator
5Responsibilities of the sponsor
6Requirements for clinical trial protocol and protocol amendments
7Responsibility of the sponsor in the development of investigatorrsquos brochure
8Essential documents
Principles of ICH GCP
bull Ethical conduct as per
Declaration of Helsinki
GCP
Regulatory Requirements
Risk- Benefit
Primary concern- Subject
Principles of ICH GCP
bull Supportive data
bull Protocol
Scientifically sound clear detailed
bull Ethical Clearance
Study to be conducted in compliance to the protocol which has received EC approval
Principles of ICH GCP
bull Subject Care
Medical decisions responsibility of qualified physician
bull Qualified staff
By education training experience in their area of responsibility
bull Informed Consent
Principles of ICH GCP
bull Clinical Trial data
Recorded handled and stored to enable accurate reporting interpretation and verification
bull Confidentiality
Principles of ICH GCP
bull Investigational Product
Manufactured handled and stored as per GMP
Principles of ICH GCP
bull Quality Assurance
Systems and procedures to ensure the Quality of every aspect of the trial
Indian GCP guidelines
bull Released in Dec 2001(Developed by CDCSO and endorsed by DCGI)
bull In general in line with ICH GCP
bull Has Revised Schedule Y (Jan 2005) addressed discrepancies
bull SAFEGUARD PUBLIC HEALTH
bull ASSURE CONSUMER PROTECTION STANDARDS
bull FACILITATE AVAILABILITY OF SAFE AND EFFECTIVE PRODUCTS
bull ELIMINATE INCONSISTENT STANDARDS INTERNATIONALLY
bull FACILITATE MUTUAL ACCEPTANCE OF DATA FROM CLINICAL TRIALS
GOALS OF INTERNATIONAL HARMONIZATION OF
REGULATORY REQUIREMENTS
Study DocumentationDuring the study
The investigator must keepndash Source documents
bull Medical records (including access to computer records)
bull Laboratory reports
bull ECGs X-rays etc
bull Any other medical records reports or notes (hospital admissions and discharges)
ndash A subject identification list
ndash Copies of all study related documentation
Medical Records
bull In particular they should contain notes on
ndash Sufficient information to support subject eligibility
ndash This should be well documented (signed and dated)
ndash Subjectrsquos participation in the study
ndash Dates of visits
ndash Procedures investigations done
ndash Observations diagnoses
ndash Medications taken (including study medication)
ndash Adverse events
ndash Completion or withdrawal (reason) from the study
Study DocumentationAfter the study
The sponsor needs from the investigator
ndash Final drug accountability records
ndash All used and unused supplies and medication
ndash All required documents completed
Conclusion
70
Thanks
ldquoWhen a doctor [goes] wrong he is
the first of criminals He has nerve
and he has knowledgerdquo
- Sherlock Holmes
References
httpwwwwmanetepolicyb3htm
wwwhhsgovohrphumansubjectsguidancebelmonthtml
wwwhhsgovohrpreferencesnurcodehtml
wwwicmrnicinguidelinesGCLP
wwwcdsconicin
wwwubedurecercaBioeticadocDeclaracio_Helsinki_2013
wwwjewishvirtuallibraryorgjsourceHolocaustnazi_experiments
wwwichorgfileadminPublic_WebICHE6_R1__Guideline
History
1962 US FDA IND Guidelines
1964 Declaration of Helsinki
1968 Committee on Safety of Medicines uk
1978 GCP US FDA
1991 GCP Europe
1996 ICH GCP
1997 ICH GCP Guideline
When did it begin
bull Ist conf in 1990 in Brussels
3 regions participated
bull Representatives from
Industry
Academia
Ministry of
health
ICH parties
6 parties
bull EU bull EFPIA European federation of pharmaceutical industriesrsquo associations
bull MHLW Ministry of health Labor and welfare Japan
bull JPMA Japan Pharmaceuticals manufacturers Association
bull US FDA
bull PhRMA
bull Observers WHO TPP(canada)
bull International federation of Pharmaceutical manufacturerrsquos association
Key objective
bull To discuss and define the minimum standards for the development and registration of investigational products
The result
Many guidelines made
bull Most important- ICH GCP guidelines
bull Evolved in several steps
bull Consolidated guideline ICH E6 Sept 1997
ICH Guidelines examples
bull Efficacy ndash clinical trials etc
bull Safety ndash pharmacovigilance adverse drug reaction
reporting
bull Quality ndash raw materials impurities residual solvents etc
bull Multidisciplinary ndash common technical document electronic
submission coding systems
What is GCP
A standard for the design conduct performance monitoring auditing recording analyses and reporting of clinical trials that provide assurance that the data and the reported results are credible accurate and that the rights integrity and confidentiality of trial subjects are protected
Why is it needed
bull To ensure the rights safety and well being of the trial subjects are protected
bull Ensure the credibility of clinical trial data
The ICH GCP guideline
bull Provide a unified standard for the EU Japan and USA regions to facilitate mutual acceptance of clinical trial data by the regulatory authorities in
these regions
bull 8 sections
ICH GCP guideline
1 Glossary
Common language for investigatorssponsorsethics committees
2Principles of Good Clinical Practice
13 tenets of ICH GCP
3Requirements for IRBIEC
Roles responsibilities and composition
ICH GCP guideline
4Responsibilities of the investigator
5Responsibilities of the sponsor
6Requirements for clinical trial protocol and protocol amendments
7Responsibility of the sponsor in the development of investigatorrsquos brochure
8Essential documents
Principles of ICH GCP
bull Ethical conduct as per
Declaration of Helsinki
GCP
Regulatory Requirements
Risk- Benefit
Primary concern- Subject
Principles of ICH GCP
bull Supportive data
bull Protocol
Scientifically sound clear detailed
bull Ethical Clearance
Study to be conducted in compliance to the protocol which has received EC approval
Principles of ICH GCP
bull Subject Care
Medical decisions responsibility of qualified physician
bull Qualified staff
By education training experience in their area of responsibility
bull Informed Consent
Principles of ICH GCP
bull Clinical Trial data
Recorded handled and stored to enable accurate reporting interpretation and verification
bull Confidentiality
Principles of ICH GCP
bull Investigational Product
Manufactured handled and stored as per GMP
Principles of ICH GCP
bull Quality Assurance
Systems and procedures to ensure the Quality of every aspect of the trial
Indian GCP guidelines
bull Released in Dec 2001(Developed by CDCSO and endorsed by DCGI)
bull In general in line with ICH GCP
bull Has Revised Schedule Y (Jan 2005) addressed discrepancies
bull SAFEGUARD PUBLIC HEALTH
bull ASSURE CONSUMER PROTECTION STANDARDS
bull FACILITATE AVAILABILITY OF SAFE AND EFFECTIVE PRODUCTS
bull ELIMINATE INCONSISTENT STANDARDS INTERNATIONALLY
bull FACILITATE MUTUAL ACCEPTANCE OF DATA FROM CLINICAL TRIALS
GOALS OF INTERNATIONAL HARMONIZATION OF
REGULATORY REQUIREMENTS
Study DocumentationDuring the study
The investigator must keepndash Source documents
bull Medical records (including access to computer records)
bull Laboratory reports
bull ECGs X-rays etc
bull Any other medical records reports or notes (hospital admissions and discharges)
ndash A subject identification list
ndash Copies of all study related documentation
Medical Records
bull In particular they should contain notes on
ndash Sufficient information to support subject eligibility
ndash This should be well documented (signed and dated)
ndash Subjectrsquos participation in the study
ndash Dates of visits
ndash Procedures investigations done
ndash Observations diagnoses
ndash Medications taken (including study medication)
ndash Adverse events
ndash Completion or withdrawal (reason) from the study
Study DocumentationAfter the study
The sponsor needs from the investigator
ndash Final drug accountability records
ndash All used and unused supplies and medication
ndash All required documents completed
Conclusion
70
Thanks
ldquoWhen a doctor [goes] wrong he is
the first of criminals He has nerve
and he has knowledgerdquo
- Sherlock Holmes
References
httpwwwwmanetepolicyb3htm
wwwhhsgovohrphumansubjectsguidancebelmonthtml
wwwhhsgovohrpreferencesnurcodehtml
wwwicmrnicinguidelinesGCLP
wwwcdsconicin
wwwubedurecercaBioeticadocDeclaracio_Helsinki_2013
wwwjewishvirtuallibraryorgjsourceHolocaustnazi_experiments
wwwichorgfileadminPublic_WebICHE6_R1__Guideline
When did it begin
bull Ist conf in 1990 in Brussels
3 regions participated
bull Representatives from
Industry
Academia
Ministry of
health
ICH parties
6 parties
bull EU bull EFPIA European federation of pharmaceutical industriesrsquo associations
bull MHLW Ministry of health Labor and welfare Japan
bull JPMA Japan Pharmaceuticals manufacturers Association
bull US FDA
bull PhRMA
bull Observers WHO TPP(canada)
bull International federation of Pharmaceutical manufacturerrsquos association
Key objective
bull To discuss and define the minimum standards for the development and registration of investigational products
The result
Many guidelines made
bull Most important- ICH GCP guidelines
bull Evolved in several steps
bull Consolidated guideline ICH E6 Sept 1997
ICH Guidelines examples
bull Efficacy ndash clinical trials etc
bull Safety ndash pharmacovigilance adverse drug reaction
reporting
bull Quality ndash raw materials impurities residual solvents etc
bull Multidisciplinary ndash common technical document electronic
submission coding systems
What is GCP
A standard for the design conduct performance monitoring auditing recording analyses and reporting of clinical trials that provide assurance that the data and the reported results are credible accurate and that the rights integrity and confidentiality of trial subjects are protected
Why is it needed
bull To ensure the rights safety and well being of the trial subjects are protected
bull Ensure the credibility of clinical trial data
The ICH GCP guideline
bull Provide a unified standard for the EU Japan and USA regions to facilitate mutual acceptance of clinical trial data by the regulatory authorities in
these regions
bull 8 sections
ICH GCP guideline
1 Glossary
Common language for investigatorssponsorsethics committees
2Principles of Good Clinical Practice
13 tenets of ICH GCP
3Requirements for IRBIEC
Roles responsibilities and composition
ICH GCP guideline
4Responsibilities of the investigator
5Responsibilities of the sponsor
6Requirements for clinical trial protocol and protocol amendments
7Responsibility of the sponsor in the development of investigatorrsquos brochure
8Essential documents
Principles of ICH GCP
bull Ethical conduct as per
Declaration of Helsinki
GCP
Regulatory Requirements
Risk- Benefit
Primary concern- Subject
Principles of ICH GCP
bull Supportive data
bull Protocol
Scientifically sound clear detailed
bull Ethical Clearance
Study to be conducted in compliance to the protocol which has received EC approval
Principles of ICH GCP
bull Subject Care
Medical decisions responsibility of qualified physician
bull Qualified staff
By education training experience in their area of responsibility
bull Informed Consent
Principles of ICH GCP
bull Clinical Trial data
Recorded handled and stored to enable accurate reporting interpretation and verification
bull Confidentiality
Principles of ICH GCP
bull Investigational Product
Manufactured handled and stored as per GMP
Principles of ICH GCP
bull Quality Assurance
Systems and procedures to ensure the Quality of every aspect of the trial
Indian GCP guidelines
bull Released in Dec 2001(Developed by CDCSO and endorsed by DCGI)
bull In general in line with ICH GCP
bull Has Revised Schedule Y (Jan 2005) addressed discrepancies
bull SAFEGUARD PUBLIC HEALTH
bull ASSURE CONSUMER PROTECTION STANDARDS
bull FACILITATE AVAILABILITY OF SAFE AND EFFECTIVE PRODUCTS
bull ELIMINATE INCONSISTENT STANDARDS INTERNATIONALLY
bull FACILITATE MUTUAL ACCEPTANCE OF DATA FROM CLINICAL TRIALS
GOALS OF INTERNATIONAL HARMONIZATION OF
REGULATORY REQUIREMENTS
Study DocumentationDuring the study
The investigator must keepndash Source documents
bull Medical records (including access to computer records)
bull Laboratory reports
bull ECGs X-rays etc
bull Any other medical records reports or notes (hospital admissions and discharges)
ndash A subject identification list
ndash Copies of all study related documentation
Medical Records
bull In particular they should contain notes on
ndash Sufficient information to support subject eligibility
ndash This should be well documented (signed and dated)
ndash Subjectrsquos participation in the study
ndash Dates of visits
ndash Procedures investigations done
ndash Observations diagnoses
ndash Medications taken (including study medication)
ndash Adverse events
ndash Completion or withdrawal (reason) from the study
Study DocumentationAfter the study
The sponsor needs from the investigator
ndash Final drug accountability records
ndash All used and unused supplies and medication
ndash All required documents completed
Conclusion
70
Thanks
ldquoWhen a doctor [goes] wrong he is
the first of criminals He has nerve
and he has knowledgerdquo
- Sherlock Holmes
References
httpwwwwmanetepolicyb3htm
wwwhhsgovohrphumansubjectsguidancebelmonthtml
wwwhhsgovohrpreferencesnurcodehtml
wwwicmrnicinguidelinesGCLP
wwwcdsconicin
wwwubedurecercaBioeticadocDeclaracio_Helsinki_2013
wwwjewishvirtuallibraryorgjsourceHolocaustnazi_experiments
wwwichorgfileadminPublic_WebICHE6_R1__Guideline
ICH parties
6 parties
bull EU bull EFPIA European federation of pharmaceutical industriesrsquo associations
bull MHLW Ministry of health Labor and welfare Japan
bull JPMA Japan Pharmaceuticals manufacturers Association
bull US FDA
bull PhRMA
bull Observers WHO TPP(canada)
bull International federation of Pharmaceutical manufacturerrsquos association
Key objective
bull To discuss and define the minimum standards for the development and registration of investigational products
The result
Many guidelines made
bull Most important- ICH GCP guidelines
bull Evolved in several steps
bull Consolidated guideline ICH E6 Sept 1997
ICH Guidelines examples
bull Efficacy ndash clinical trials etc
bull Safety ndash pharmacovigilance adverse drug reaction
reporting
bull Quality ndash raw materials impurities residual solvents etc
bull Multidisciplinary ndash common technical document electronic
submission coding systems
What is GCP
A standard for the design conduct performance monitoring auditing recording analyses and reporting of clinical trials that provide assurance that the data and the reported results are credible accurate and that the rights integrity and confidentiality of trial subjects are protected
Why is it needed
bull To ensure the rights safety and well being of the trial subjects are protected
bull Ensure the credibility of clinical trial data
The ICH GCP guideline
bull Provide a unified standard for the EU Japan and USA regions to facilitate mutual acceptance of clinical trial data by the regulatory authorities in
these regions
bull 8 sections
ICH GCP guideline
1 Glossary
Common language for investigatorssponsorsethics committees
2Principles of Good Clinical Practice
13 tenets of ICH GCP
3Requirements for IRBIEC
Roles responsibilities and composition
ICH GCP guideline
4Responsibilities of the investigator
5Responsibilities of the sponsor
6Requirements for clinical trial protocol and protocol amendments
7Responsibility of the sponsor in the development of investigatorrsquos brochure
8Essential documents
Principles of ICH GCP
bull Ethical conduct as per
Declaration of Helsinki
GCP
Regulatory Requirements
Risk- Benefit
Primary concern- Subject
Principles of ICH GCP
bull Supportive data
bull Protocol
Scientifically sound clear detailed
bull Ethical Clearance
Study to be conducted in compliance to the protocol which has received EC approval
Principles of ICH GCP
bull Subject Care
Medical decisions responsibility of qualified physician
bull Qualified staff
By education training experience in their area of responsibility
bull Informed Consent
Principles of ICH GCP
bull Clinical Trial data
Recorded handled and stored to enable accurate reporting interpretation and verification
bull Confidentiality
Principles of ICH GCP
bull Investigational Product
Manufactured handled and stored as per GMP
Principles of ICH GCP
bull Quality Assurance
Systems and procedures to ensure the Quality of every aspect of the trial
Indian GCP guidelines
bull Released in Dec 2001(Developed by CDCSO and endorsed by DCGI)
bull In general in line with ICH GCP
bull Has Revised Schedule Y (Jan 2005) addressed discrepancies
bull SAFEGUARD PUBLIC HEALTH
bull ASSURE CONSUMER PROTECTION STANDARDS
bull FACILITATE AVAILABILITY OF SAFE AND EFFECTIVE PRODUCTS
bull ELIMINATE INCONSISTENT STANDARDS INTERNATIONALLY
bull FACILITATE MUTUAL ACCEPTANCE OF DATA FROM CLINICAL TRIALS
GOALS OF INTERNATIONAL HARMONIZATION OF
REGULATORY REQUIREMENTS
Study DocumentationDuring the study
The investigator must keepndash Source documents
bull Medical records (including access to computer records)
bull Laboratory reports
bull ECGs X-rays etc
bull Any other medical records reports or notes (hospital admissions and discharges)
ndash A subject identification list
ndash Copies of all study related documentation
Medical Records
bull In particular they should contain notes on
ndash Sufficient information to support subject eligibility
ndash This should be well documented (signed and dated)
ndash Subjectrsquos participation in the study
ndash Dates of visits
ndash Procedures investigations done
ndash Observations diagnoses
ndash Medications taken (including study medication)
ndash Adverse events
ndash Completion or withdrawal (reason) from the study
Study DocumentationAfter the study
The sponsor needs from the investigator
ndash Final drug accountability records
ndash All used and unused supplies and medication
ndash All required documents completed
Conclusion
70
Thanks
ldquoWhen a doctor [goes] wrong he is
the first of criminals He has nerve
and he has knowledgerdquo
- Sherlock Holmes
References
httpwwwwmanetepolicyb3htm
wwwhhsgovohrphumansubjectsguidancebelmonthtml
wwwhhsgovohrpreferencesnurcodehtml
wwwicmrnicinguidelinesGCLP
wwwcdsconicin
wwwubedurecercaBioeticadocDeclaracio_Helsinki_2013
wwwjewishvirtuallibraryorgjsourceHolocaustnazi_experiments
wwwichorgfileadminPublic_WebICHE6_R1__Guideline
Key objective
bull To discuss and define the minimum standards for the development and registration of investigational products
The result
Many guidelines made
bull Most important- ICH GCP guidelines
bull Evolved in several steps
bull Consolidated guideline ICH E6 Sept 1997
ICH Guidelines examples
bull Efficacy ndash clinical trials etc
bull Safety ndash pharmacovigilance adverse drug reaction
reporting
bull Quality ndash raw materials impurities residual solvents etc
bull Multidisciplinary ndash common technical document electronic
submission coding systems
What is GCP
A standard for the design conduct performance monitoring auditing recording analyses and reporting of clinical trials that provide assurance that the data and the reported results are credible accurate and that the rights integrity and confidentiality of trial subjects are protected
Why is it needed
bull To ensure the rights safety and well being of the trial subjects are protected
bull Ensure the credibility of clinical trial data
The ICH GCP guideline
bull Provide a unified standard for the EU Japan and USA regions to facilitate mutual acceptance of clinical trial data by the regulatory authorities in
these regions
bull 8 sections
ICH GCP guideline
1 Glossary
Common language for investigatorssponsorsethics committees
2Principles of Good Clinical Practice
13 tenets of ICH GCP
3Requirements for IRBIEC
Roles responsibilities and composition
ICH GCP guideline
4Responsibilities of the investigator
5Responsibilities of the sponsor
6Requirements for clinical trial protocol and protocol amendments
7Responsibility of the sponsor in the development of investigatorrsquos brochure
8Essential documents
Principles of ICH GCP
bull Ethical conduct as per
Declaration of Helsinki
GCP
Regulatory Requirements
Risk- Benefit
Primary concern- Subject
Principles of ICH GCP
bull Supportive data
bull Protocol
Scientifically sound clear detailed
bull Ethical Clearance
Study to be conducted in compliance to the protocol which has received EC approval
Principles of ICH GCP
bull Subject Care
Medical decisions responsibility of qualified physician
bull Qualified staff
By education training experience in their area of responsibility
bull Informed Consent
Principles of ICH GCP
bull Clinical Trial data
Recorded handled and stored to enable accurate reporting interpretation and verification
bull Confidentiality
Principles of ICH GCP
bull Investigational Product
Manufactured handled and stored as per GMP
Principles of ICH GCP
bull Quality Assurance
Systems and procedures to ensure the Quality of every aspect of the trial
Indian GCP guidelines
bull Released in Dec 2001(Developed by CDCSO and endorsed by DCGI)
bull In general in line with ICH GCP
bull Has Revised Schedule Y (Jan 2005) addressed discrepancies
bull SAFEGUARD PUBLIC HEALTH
bull ASSURE CONSUMER PROTECTION STANDARDS
bull FACILITATE AVAILABILITY OF SAFE AND EFFECTIVE PRODUCTS
bull ELIMINATE INCONSISTENT STANDARDS INTERNATIONALLY
bull FACILITATE MUTUAL ACCEPTANCE OF DATA FROM CLINICAL TRIALS
GOALS OF INTERNATIONAL HARMONIZATION OF
REGULATORY REQUIREMENTS
Study DocumentationDuring the study
The investigator must keepndash Source documents
bull Medical records (including access to computer records)
bull Laboratory reports
bull ECGs X-rays etc
bull Any other medical records reports or notes (hospital admissions and discharges)
ndash A subject identification list
ndash Copies of all study related documentation
Medical Records
bull In particular they should contain notes on
ndash Sufficient information to support subject eligibility
ndash This should be well documented (signed and dated)
ndash Subjectrsquos participation in the study
ndash Dates of visits
ndash Procedures investigations done
ndash Observations diagnoses
ndash Medications taken (including study medication)
ndash Adverse events
ndash Completion or withdrawal (reason) from the study
Study DocumentationAfter the study
The sponsor needs from the investigator
ndash Final drug accountability records
ndash All used and unused supplies and medication
ndash All required documents completed
Conclusion
70
Thanks
ldquoWhen a doctor [goes] wrong he is
the first of criminals He has nerve
and he has knowledgerdquo
- Sherlock Holmes
References
httpwwwwmanetepolicyb3htm
wwwhhsgovohrphumansubjectsguidancebelmonthtml
wwwhhsgovohrpreferencesnurcodehtml
wwwicmrnicinguidelinesGCLP
wwwcdsconicin
wwwubedurecercaBioeticadocDeclaracio_Helsinki_2013
wwwjewishvirtuallibraryorgjsourceHolocaustnazi_experiments
wwwichorgfileadminPublic_WebICHE6_R1__Guideline
The result
Many guidelines made
bull Most important- ICH GCP guidelines
bull Evolved in several steps
bull Consolidated guideline ICH E6 Sept 1997
ICH Guidelines examples
bull Efficacy ndash clinical trials etc
bull Safety ndash pharmacovigilance adverse drug reaction
reporting
bull Quality ndash raw materials impurities residual solvents etc
bull Multidisciplinary ndash common technical document electronic
submission coding systems
What is GCP
A standard for the design conduct performance monitoring auditing recording analyses and reporting of clinical trials that provide assurance that the data and the reported results are credible accurate and that the rights integrity and confidentiality of trial subjects are protected
Why is it needed
bull To ensure the rights safety and well being of the trial subjects are protected
bull Ensure the credibility of clinical trial data
The ICH GCP guideline
bull Provide a unified standard for the EU Japan and USA regions to facilitate mutual acceptance of clinical trial data by the regulatory authorities in
these regions
bull 8 sections
ICH GCP guideline
1 Glossary
Common language for investigatorssponsorsethics committees
2Principles of Good Clinical Practice
13 tenets of ICH GCP
3Requirements for IRBIEC
Roles responsibilities and composition
ICH GCP guideline
4Responsibilities of the investigator
5Responsibilities of the sponsor
6Requirements for clinical trial protocol and protocol amendments
7Responsibility of the sponsor in the development of investigatorrsquos brochure
8Essential documents
Principles of ICH GCP
bull Ethical conduct as per
Declaration of Helsinki
GCP
Regulatory Requirements
Risk- Benefit
Primary concern- Subject
Principles of ICH GCP
bull Supportive data
bull Protocol
Scientifically sound clear detailed
bull Ethical Clearance
Study to be conducted in compliance to the protocol which has received EC approval
Principles of ICH GCP
bull Subject Care
Medical decisions responsibility of qualified physician
bull Qualified staff
By education training experience in their area of responsibility
bull Informed Consent
Principles of ICH GCP
bull Clinical Trial data
Recorded handled and stored to enable accurate reporting interpretation and verification
bull Confidentiality
Principles of ICH GCP
bull Investigational Product
Manufactured handled and stored as per GMP
Principles of ICH GCP
bull Quality Assurance
Systems and procedures to ensure the Quality of every aspect of the trial
Indian GCP guidelines
bull Released in Dec 2001(Developed by CDCSO and endorsed by DCGI)
bull In general in line with ICH GCP
bull Has Revised Schedule Y (Jan 2005) addressed discrepancies
bull SAFEGUARD PUBLIC HEALTH
bull ASSURE CONSUMER PROTECTION STANDARDS
bull FACILITATE AVAILABILITY OF SAFE AND EFFECTIVE PRODUCTS
bull ELIMINATE INCONSISTENT STANDARDS INTERNATIONALLY
bull FACILITATE MUTUAL ACCEPTANCE OF DATA FROM CLINICAL TRIALS
GOALS OF INTERNATIONAL HARMONIZATION OF
REGULATORY REQUIREMENTS
Study DocumentationDuring the study
The investigator must keepndash Source documents
bull Medical records (including access to computer records)
bull Laboratory reports
bull ECGs X-rays etc
bull Any other medical records reports or notes (hospital admissions and discharges)
ndash A subject identification list
ndash Copies of all study related documentation
Medical Records
bull In particular they should contain notes on
ndash Sufficient information to support subject eligibility
ndash This should be well documented (signed and dated)
ndash Subjectrsquos participation in the study
ndash Dates of visits
ndash Procedures investigations done
ndash Observations diagnoses
ndash Medications taken (including study medication)
ndash Adverse events
ndash Completion or withdrawal (reason) from the study
Study DocumentationAfter the study
The sponsor needs from the investigator
ndash Final drug accountability records
ndash All used and unused supplies and medication
ndash All required documents completed
Conclusion
70
Thanks
ldquoWhen a doctor [goes] wrong he is
the first of criminals He has nerve
and he has knowledgerdquo
- Sherlock Holmes
References
httpwwwwmanetepolicyb3htm
wwwhhsgovohrphumansubjectsguidancebelmonthtml
wwwhhsgovohrpreferencesnurcodehtml
wwwicmrnicinguidelinesGCLP
wwwcdsconicin
wwwubedurecercaBioeticadocDeclaracio_Helsinki_2013
wwwjewishvirtuallibraryorgjsourceHolocaustnazi_experiments
wwwichorgfileadminPublic_WebICHE6_R1__Guideline
ICH Guidelines examples
bull Efficacy ndash clinical trials etc
bull Safety ndash pharmacovigilance adverse drug reaction
reporting
bull Quality ndash raw materials impurities residual solvents etc
bull Multidisciplinary ndash common technical document electronic
submission coding systems
What is GCP
A standard for the design conduct performance monitoring auditing recording analyses and reporting of clinical trials that provide assurance that the data and the reported results are credible accurate and that the rights integrity and confidentiality of trial subjects are protected
Why is it needed
bull To ensure the rights safety and well being of the trial subjects are protected
bull Ensure the credibility of clinical trial data
The ICH GCP guideline
bull Provide a unified standard for the EU Japan and USA regions to facilitate mutual acceptance of clinical trial data by the regulatory authorities in
these regions
bull 8 sections
ICH GCP guideline
1 Glossary
Common language for investigatorssponsorsethics committees
2Principles of Good Clinical Practice
13 tenets of ICH GCP
3Requirements for IRBIEC
Roles responsibilities and composition
ICH GCP guideline
4Responsibilities of the investigator
5Responsibilities of the sponsor
6Requirements for clinical trial protocol and protocol amendments
7Responsibility of the sponsor in the development of investigatorrsquos brochure
8Essential documents
Principles of ICH GCP
bull Ethical conduct as per
Declaration of Helsinki
GCP
Regulatory Requirements
Risk- Benefit
Primary concern- Subject
Principles of ICH GCP
bull Supportive data
bull Protocol
Scientifically sound clear detailed
bull Ethical Clearance
Study to be conducted in compliance to the protocol which has received EC approval
Principles of ICH GCP
bull Subject Care
Medical decisions responsibility of qualified physician
bull Qualified staff
By education training experience in their area of responsibility
bull Informed Consent
Principles of ICH GCP
bull Clinical Trial data
Recorded handled and stored to enable accurate reporting interpretation and verification
bull Confidentiality
Principles of ICH GCP
bull Investigational Product
Manufactured handled and stored as per GMP
Principles of ICH GCP
bull Quality Assurance
Systems and procedures to ensure the Quality of every aspect of the trial
Indian GCP guidelines
bull Released in Dec 2001(Developed by CDCSO and endorsed by DCGI)
bull In general in line with ICH GCP
bull Has Revised Schedule Y (Jan 2005) addressed discrepancies
bull SAFEGUARD PUBLIC HEALTH
bull ASSURE CONSUMER PROTECTION STANDARDS
bull FACILITATE AVAILABILITY OF SAFE AND EFFECTIVE PRODUCTS
bull ELIMINATE INCONSISTENT STANDARDS INTERNATIONALLY
bull FACILITATE MUTUAL ACCEPTANCE OF DATA FROM CLINICAL TRIALS
GOALS OF INTERNATIONAL HARMONIZATION OF
REGULATORY REQUIREMENTS
Study DocumentationDuring the study
The investigator must keepndash Source documents
bull Medical records (including access to computer records)
bull Laboratory reports
bull ECGs X-rays etc
bull Any other medical records reports or notes (hospital admissions and discharges)
ndash A subject identification list
ndash Copies of all study related documentation
Medical Records
bull In particular they should contain notes on
ndash Sufficient information to support subject eligibility
ndash This should be well documented (signed and dated)
ndash Subjectrsquos participation in the study
ndash Dates of visits
ndash Procedures investigations done
ndash Observations diagnoses
ndash Medications taken (including study medication)
ndash Adverse events
ndash Completion or withdrawal (reason) from the study
Study DocumentationAfter the study
The sponsor needs from the investigator
ndash Final drug accountability records
ndash All used and unused supplies and medication
ndash All required documents completed
Conclusion
70
Thanks
ldquoWhen a doctor [goes] wrong he is
the first of criminals He has nerve
and he has knowledgerdquo
- Sherlock Holmes
References
httpwwwwmanetepolicyb3htm
wwwhhsgovohrphumansubjectsguidancebelmonthtml
wwwhhsgovohrpreferencesnurcodehtml
wwwicmrnicinguidelinesGCLP
wwwcdsconicin
wwwubedurecercaBioeticadocDeclaracio_Helsinki_2013
wwwjewishvirtuallibraryorgjsourceHolocaustnazi_experiments
wwwichorgfileadminPublic_WebICHE6_R1__Guideline
What is GCP
A standard for the design conduct performance monitoring auditing recording analyses and reporting of clinical trials that provide assurance that the data and the reported results are credible accurate and that the rights integrity and confidentiality of trial subjects are protected
Why is it needed
bull To ensure the rights safety and well being of the trial subjects are protected
bull Ensure the credibility of clinical trial data
The ICH GCP guideline
bull Provide a unified standard for the EU Japan and USA regions to facilitate mutual acceptance of clinical trial data by the regulatory authorities in
these regions
bull 8 sections
ICH GCP guideline
1 Glossary
Common language for investigatorssponsorsethics committees
2Principles of Good Clinical Practice
13 tenets of ICH GCP
3Requirements for IRBIEC
Roles responsibilities and composition
ICH GCP guideline
4Responsibilities of the investigator
5Responsibilities of the sponsor
6Requirements for clinical trial protocol and protocol amendments
7Responsibility of the sponsor in the development of investigatorrsquos brochure
8Essential documents
Principles of ICH GCP
bull Ethical conduct as per
Declaration of Helsinki
GCP
Regulatory Requirements
Risk- Benefit
Primary concern- Subject
Principles of ICH GCP
bull Supportive data
bull Protocol
Scientifically sound clear detailed
bull Ethical Clearance
Study to be conducted in compliance to the protocol which has received EC approval
Principles of ICH GCP
bull Subject Care
Medical decisions responsibility of qualified physician
bull Qualified staff
By education training experience in their area of responsibility
bull Informed Consent
Principles of ICH GCP
bull Clinical Trial data
Recorded handled and stored to enable accurate reporting interpretation and verification
bull Confidentiality
Principles of ICH GCP
bull Investigational Product
Manufactured handled and stored as per GMP
Principles of ICH GCP
bull Quality Assurance
Systems and procedures to ensure the Quality of every aspect of the trial
Indian GCP guidelines
bull Released in Dec 2001(Developed by CDCSO and endorsed by DCGI)
bull In general in line with ICH GCP
bull Has Revised Schedule Y (Jan 2005) addressed discrepancies
bull SAFEGUARD PUBLIC HEALTH
bull ASSURE CONSUMER PROTECTION STANDARDS
bull FACILITATE AVAILABILITY OF SAFE AND EFFECTIVE PRODUCTS
bull ELIMINATE INCONSISTENT STANDARDS INTERNATIONALLY
bull FACILITATE MUTUAL ACCEPTANCE OF DATA FROM CLINICAL TRIALS
GOALS OF INTERNATIONAL HARMONIZATION OF
REGULATORY REQUIREMENTS
Study DocumentationDuring the study
The investigator must keepndash Source documents
bull Medical records (including access to computer records)
bull Laboratory reports
bull ECGs X-rays etc
bull Any other medical records reports or notes (hospital admissions and discharges)
ndash A subject identification list
ndash Copies of all study related documentation
Medical Records
bull In particular they should contain notes on
ndash Sufficient information to support subject eligibility
ndash This should be well documented (signed and dated)
ndash Subjectrsquos participation in the study
ndash Dates of visits
ndash Procedures investigations done
ndash Observations diagnoses
ndash Medications taken (including study medication)
ndash Adverse events
ndash Completion or withdrawal (reason) from the study
Study DocumentationAfter the study
The sponsor needs from the investigator
ndash Final drug accountability records
ndash All used and unused supplies and medication
ndash All required documents completed
Conclusion
70
Thanks
ldquoWhen a doctor [goes] wrong he is
the first of criminals He has nerve
and he has knowledgerdquo
- Sherlock Holmes
References
httpwwwwmanetepolicyb3htm
wwwhhsgovohrphumansubjectsguidancebelmonthtml
wwwhhsgovohrpreferencesnurcodehtml
wwwicmrnicinguidelinesGCLP
wwwcdsconicin
wwwubedurecercaBioeticadocDeclaracio_Helsinki_2013
wwwjewishvirtuallibraryorgjsourceHolocaustnazi_experiments
wwwichorgfileadminPublic_WebICHE6_R1__Guideline
Why is it needed
bull To ensure the rights safety and well being of the trial subjects are protected
bull Ensure the credibility of clinical trial data
The ICH GCP guideline
bull Provide a unified standard for the EU Japan and USA regions to facilitate mutual acceptance of clinical trial data by the regulatory authorities in
these regions
bull 8 sections
ICH GCP guideline
1 Glossary
Common language for investigatorssponsorsethics committees
2Principles of Good Clinical Practice
13 tenets of ICH GCP
3Requirements for IRBIEC
Roles responsibilities and composition
ICH GCP guideline
4Responsibilities of the investigator
5Responsibilities of the sponsor
6Requirements for clinical trial protocol and protocol amendments
7Responsibility of the sponsor in the development of investigatorrsquos brochure
8Essential documents
Principles of ICH GCP
bull Ethical conduct as per
Declaration of Helsinki
GCP
Regulatory Requirements
Risk- Benefit
Primary concern- Subject
Principles of ICH GCP
bull Supportive data
bull Protocol
Scientifically sound clear detailed
bull Ethical Clearance
Study to be conducted in compliance to the protocol which has received EC approval
Principles of ICH GCP
bull Subject Care
Medical decisions responsibility of qualified physician
bull Qualified staff
By education training experience in their area of responsibility
bull Informed Consent
Principles of ICH GCP
bull Clinical Trial data
Recorded handled and stored to enable accurate reporting interpretation and verification
bull Confidentiality
Principles of ICH GCP
bull Investigational Product
Manufactured handled and stored as per GMP
Principles of ICH GCP
bull Quality Assurance
Systems and procedures to ensure the Quality of every aspect of the trial
Indian GCP guidelines
bull Released in Dec 2001(Developed by CDCSO and endorsed by DCGI)
bull In general in line with ICH GCP
bull Has Revised Schedule Y (Jan 2005) addressed discrepancies
bull SAFEGUARD PUBLIC HEALTH
bull ASSURE CONSUMER PROTECTION STANDARDS
bull FACILITATE AVAILABILITY OF SAFE AND EFFECTIVE PRODUCTS
bull ELIMINATE INCONSISTENT STANDARDS INTERNATIONALLY
bull FACILITATE MUTUAL ACCEPTANCE OF DATA FROM CLINICAL TRIALS
GOALS OF INTERNATIONAL HARMONIZATION OF
REGULATORY REQUIREMENTS
Study DocumentationDuring the study
The investigator must keepndash Source documents
bull Medical records (including access to computer records)
bull Laboratory reports
bull ECGs X-rays etc
bull Any other medical records reports or notes (hospital admissions and discharges)
ndash A subject identification list
ndash Copies of all study related documentation
Medical Records
bull In particular they should contain notes on
ndash Sufficient information to support subject eligibility
ndash This should be well documented (signed and dated)
ndash Subjectrsquos participation in the study
ndash Dates of visits
ndash Procedures investigations done
ndash Observations diagnoses
ndash Medications taken (including study medication)
ndash Adverse events
ndash Completion or withdrawal (reason) from the study
Study DocumentationAfter the study
The sponsor needs from the investigator
ndash Final drug accountability records
ndash All used and unused supplies and medication
ndash All required documents completed
Conclusion
70
Thanks
ldquoWhen a doctor [goes] wrong he is
the first of criminals He has nerve
and he has knowledgerdquo
- Sherlock Holmes
References
httpwwwwmanetepolicyb3htm
wwwhhsgovohrphumansubjectsguidancebelmonthtml
wwwhhsgovohrpreferencesnurcodehtml
wwwicmrnicinguidelinesGCLP
wwwcdsconicin
wwwubedurecercaBioeticadocDeclaracio_Helsinki_2013
wwwjewishvirtuallibraryorgjsourceHolocaustnazi_experiments
wwwichorgfileadminPublic_WebICHE6_R1__Guideline
The ICH GCP guideline
bull Provide a unified standard for the EU Japan and USA regions to facilitate mutual acceptance of clinical trial data by the regulatory authorities in
these regions
bull 8 sections
ICH GCP guideline
1 Glossary
Common language for investigatorssponsorsethics committees
2Principles of Good Clinical Practice
13 tenets of ICH GCP
3Requirements for IRBIEC
Roles responsibilities and composition
ICH GCP guideline
4Responsibilities of the investigator
5Responsibilities of the sponsor
6Requirements for clinical trial protocol and protocol amendments
7Responsibility of the sponsor in the development of investigatorrsquos brochure
8Essential documents
Principles of ICH GCP
bull Ethical conduct as per
Declaration of Helsinki
GCP
Regulatory Requirements
Risk- Benefit
Primary concern- Subject
Principles of ICH GCP
bull Supportive data
bull Protocol
Scientifically sound clear detailed
bull Ethical Clearance
Study to be conducted in compliance to the protocol which has received EC approval
Principles of ICH GCP
bull Subject Care
Medical decisions responsibility of qualified physician
bull Qualified staff
By education training experience in their area of responsibility
bull Informed Consent
Principles of ICH GCP
bull Clinical Trial data
Recorded handled and stored to enable accurate reporting interpretation and verification
bull Confidentiality
Principles of ICH GCP
bull Investigational Product
Manufactured handled and stored as per GMP
Principles of ICH GCP
bull Quality Assurance
Systems and procedures to ensure the Quality of every aspect of the trial
Indian GCP guidelines
bull Released in Dec 2001(Developed by CDCSO and endorsed by DCGI)
bull In general in line with ICH GCP
bull Has Revised Schedule Y (Jan 2005) addressed discrepancies
bull SAFEGUARD PUBLIC HEALTH
bull ASSURE CONSUMER PROTECTION STANDARDS
bull FACILITATE AVAILABILITY OF SAFE AND EFFECTIVE PRODUCTS
bull ELIMINATE INCONSISTENT STANDARDS INTERNATIONALLY
bull FACILITATE MUTUAL ACCEPTANCE OF DATA FROM CLINICAL TRIALS
GOALS OF INTERNATIONAL HARMONIZATION OF
REGULATORY REQUIREMENTS
Study DocumentationDuring the study
The investigator must keepndash Source documents
bull Medical records (including access to computer records)
bull Laboratory reports
bull ECGs X-rays etc
bull Any other medical records reports or notes (hospital admissions and discharges)
ndash A subject identification list
ndash Copies of all study related documentation
Medical Records
bull In particular they should contain notes on
ndash Sufficient information to support subject eligibility
ndash This should be well documented (signed and dated)
ndash Subjectrsquos participation in the study
ndash Dates of visits
ndash Procedures investigations done
ndash Observations diagnoses
ndash Medications taken (including study medication)
ndash Adverse events
ndash Completion or withdrawal (reason) from the study
Study DocumentationAfter the study
The sponsor needs from the investigator
ndash Final drug accountability records
ndash All used and unused supplies and medication
ndash All required documents completed
Conclusion
70
Thanks
ldquoWhen a doctor [goes] wrong he is
the first of criminals He has nerve
and he has knowledgerdquo
- Sherlock Holmes
References
httpwwwwmanetepolicyb3htm
wwwhhsgovohrphumansubjectsguidancebelmonthtml
wwwhhsgovohrpreferencesnurcodehtml
wwwicmrnicinguidelinesGCLP
wwwcdsconicin
wwwubedurecercaBioeticadocDeclaracio_Helsinki_2013
wwwjewishvirtuallibraryorgjsourceHolocaustnazi_experiments
wwwichorgfileadminPublic_WebICHE6_R1__Guideline
ICH GCP guideline
1 Glossary
Common language for investigatorssponsorsethics committees
2Principles of Good Clinical Practice
13 tenets of ICH GCP
3Requirements for IRBIEC
Roles responsibilities and composition
ICH GCP guideline
4Responsibilities of the investigator
5Responsibilities of the sponsor
6Requirements for clinical trial protocol and protocol amendments
7Responsibility of the sponsor in the development of investigatorrsquos brochure
8Essential documents
Principles of ICH GCP
bull Ethical conduct as per
Declaration of Helsinki
GCP
Regulatory Requirements
Risk- Benefit
Primary concern- Subject
Principles of ICH GCP
bull Supportive data
bull Protocol
Scientifically sound clear detailed
bull Ethical Clearance
Study to be conducted in compliance to the protocol which has received EC approval
Principles of ICH GCP
bull Subject Care
Medical decisions responsibility of qualified physician
bull Qualified staff
By education training experience in their area of responsibility
bull Informed Consent
Principles of ICH GCP
bull Clinical Trial data
Recorded handled and stored to enable accurate reporting interpretation and verification
bull Confidentiality
Principles of ICH GCP
bull Investigational Product
Manufactured handled and stored as per GMP
Principles of ICH GCP
bull Quality Assurance
Systems and procedures to ensure the Quality of every aspect of the trial
Indian GCP guidelines
bull Released in Dec 2001(Developed by CDCSO and endorsed by DCGI)
bull In general in line with ICH GCP
bull Has Revised Schedule Y (Jan 2005) addressed discrepancies
bull SAFEGUARD PUBLIC HEALTH
bull ASSURE CONSUMER PROTECTION STANDARDS
bull FACILITATE AVAILABILITY OF SAFE AND EFFECTIVE PRODUCTS
bull ELIMINATE INCONSISTENT STANDARDS INTERNATIONALLY
bull FACILITATE MUTUAL ACCEPTANCE OF DATA FROM CLINICAL TRIALS
GOALS OF INTERNATIONAL HARMONIZATION OF
REGULATORY REQUIREMENTS
Study DocumentationDuring the study
The investigator must keepndash Source documents
bull Medical records (including access to computer records)
bull Laboratory reports
bull ECGs X-rays etc
bull Any other medical records reports or notes (hospital admissions and discharges)
ndash A subject identification list
ndash Copies of all study related documentation
Medical Records
bull In particular they should contain notes on
ndash Sufficient information to support subject eligibility
ndash This should be well documented (signed and dated)
ndash Subjectrsquos participation in the study
ndash Dates of visits
ndash Procedures investigations done
ndash Observations diagnoses
ndash Medications taken (including study medication)
ndash Adverse events
ndash Completion or withdrawal (reason) from the study
Study DocumentationAfter the study
The sponsor needs from the investigator
ndash Final drug accountability records
ndash All used and unused supplies and medication
ndash All required documents completed
Conclusion
70
Thanks
ldquoWhen a doctor [goes] wrong he is
the first of criminals He has nerve
and he has knowledgerdquo
- Sherlock Holmes
References
httpwwwwmanetepolicyb3htm
wwwhhsgovohrphumansubjectsguidancebelmonthtml
wwwhhsgovohrpreferencesnurcodehtml
wwwicmrnicinguidelinesGCLP
wwwcdsconicin
wwwubedurecercaBioeticadocDeclaracio_Helsinki_2013
wwwjewishvirtuallibraryorgjsourceHolocaustnazi_experiments
wwwichorgfileadminPublic_WebICHE6_R1__Guideline
ICH GCP guideline
4Responsibilities of the investigator
5Responsibilities of the sponsor
6Requirements for clinical trial protocol and protocol amendments
7Responsibility of the sponsor in the development of investigatorrsquos brochure
8Essential documents
Principles of ICH GCP
bull Ethical conduct as per
Declaration of Helsinki
GCP
Regulatory Requirements
Risk- Benefit
Primary concern- Subject
Principles of ICH GCP
bull Supportive data
bull Protocol
Scientifically sound clear detailed
bull Ethical Clearance
Study to be conducted in compliance to the protocol which has received EC approval
Principles of ICH GCP
bull Subject Care
Medical decisions responsibility of qualified physician
bull Qualified staff
By education training experience in their area of responsibility
bull Informed Consent
Principles of ICH GCP
bull Clinical Trial data
Recorded handled and stored to enable accurate reporting interpretation and verification
bull Confidentiality
Principles of ICH GCP
bull Investigational Product
Manufactured handled and stored as per GMP
Principles of ICH GCP
bull Quality Assurance
Systems and procedures to ensure the Quality of every aspect of the trial
Indian GCP guidelines
bull Released in Dec 2001(Developed by CDCSO and endorsed by DCGI)
bull In general in line with ICH GCP
bull Has Revised Schedule Y (Jan 2005) addressed discrepancies
bull SAFEGUARD PUBLIC HEALTH
bull ASSURE CONSUMER PROTECTION STANDARDS
bull FACILITATE AVAILABILITY OF SAFE AND EFFECTIVE PRODUCTS
bull ELIMINATE INCONSISTENT STANDARDS INTERNATIONALLY
bull FACILITATE MUTUAL ACCEPTANCE OF DATA FROM CLINICAL TRIALS
GOALS OF INTERNATIONAL HARMONIZATION OF
REGULATORY REQUIREMENTS
Study DocumentationDuring the study
The investigator must keepndash Source documents
bull Medical records (including access to computer records)
bull Laboratory reports
bull ECGs X-rays etc
bull Any other medical records reports or notes (hospital admissions and discharges)
ndash A subject identification list
ndash Copies of all study related documentation
Medical Records
bull In particular they should contain notes on
ndash Sufficient information to support subject eligibility
ndash This should be well documented (signed and dated)
ndash Subjectrsquos participation in the study
ndash Dates of visits
ndash Procedures investigations done
ndash Observations diagnoses
ndash Medications taken (including study medication)
ndash Adverse events
ndash Completion or withdrawal (reason) from the study
Study DocumentationAfter the study
The sponsor needs from the investigator
ndash Final drug accountability records
ndash All used and unused supplies and medication
ndash All required documents completed
Conclusion
70
Thanks
ldquoWhen a doctor [goes] wrong he is
the first of criminals He has nerve
and he has knowledgerdquo
- Sherlock Holmes
References
httpwwwwmanetepolicyb3htm
wwwhhsgovohrphumansubjectsguidancebelmonthtml
wwwhhsgovohrpreferencesnurcodehtml
wwwicmrnicinguidelinesGCLP
wwwcdsconicin
wwwubedurecercaBioeticadocDeclaracio_Helsinki_2013
wwwjewishvirtuallibraryorgjsourceHolocaustnazi_experiments
wwwichorgfileadminPublic_WebICHE6_R1__Guideline
Principles of ICH GCP
bull Ethical conduct as per
Declaration of Helsinki
GCP
Regulatory Requirements
Risk- Benefit
Primary concern- Subject
Principles of ICH GCP
bull Supportive data
bull Protocol
Scientifically sound clear detailed
bull Ethical Clearance
Study to be conducted in compliance to the protocol which has received EC approval
Principles of ICH GCP
bull Subject Care
Medical decisions responsibility of qualified physician
bull Qualified staff
By education training experience in their area of responsibility
bull Informed Consent
Principles of ICH GCP
bull Clinical Trial data
Recorded handled and stored to enable accurate reporting interpretation and verification
bull Confidentiality
Principles of ICH GCP
bull Investigational Product
Manufactured handled and stored as per GMP
Principles of ICH GCP
bull Quality Assurance
Systems and procedures to ensure the Quality of every aspect of the trial
Indian GCP guidelines
bull Released in Dec 2001(Developed by CDCSO and endorsed by DCGI)
bull In general in line with ICH GCP
bull Has Revised Schedule Y (Jan 2005) addressed discrepancies
bull SAFEGUARD PUBLIC HEALTH
bull ASSURE CONSUMER PROTECTION STANDARDS
bull FACILITATE AVAILABILITY OF SAFE AND EFFECTIVE PRODUCTS
bull ELIMINATE INCONSISTENT STANDARDS INTERNATIONALLY
bull FACILITATE MUTUAL ACCEPTANCE OF DATA FROM CLINICAL TRIALS
GOALS OF INTERNATIONAL HARMONIZATION OF
REGULATORY REQUIREMENTS
Study DocumentationDuring the study
The investigator must keepndash Source documents
bull Medical records (including access to computer records)
bull Laboratory reports
bull ECGs X-rays etc
bull Any other medical records reports or notes (hospital admissions and discharges)
ndash A subject identification list
ndash Copies of all study related documentation
Medical Records
bull In particular they should contain notes on
ndash Sufficient information to support subject eligibility
ndash This should be well documented (signed and dated)
ndash Subjectrsquos participation in the study
ndash Dates of visits
ndash Procedures investigations done
ndash Observations diagnoses
ndash Medications taken (including study medication)
ndash Adverse events
ndash Completion or withdrawal (reason) from the study
Study DocumentationAfter the study
The sponsor needs from the investigator
ndash Final drug accountability records
ndash All used and unused supplies and medication
ndash All required documents completed
Conclusion
70
Thanks
ldquoWhen a doctor [goes] wrong he is
the first of criminals He has nerve
and he has knowledgerdquo
- Sherlock Holmes
References
httpwwwwmanetepolicyb3htm
wwwhhsgovohrphumansubjectsguidancebelmonthtml
wwwhhsgovohrpreferencesnurcodehtml
wwwicmrnicinguidelinesGCLP
wwwcdsconicin
wwwubedurecercaBioeticadocDeclaracio_Helsinki_2013
wwwjewishvirtuallibraryorgjsourceHolocaustnazi_experiments
wwwichorgfileadminPublic_WebICHE6_R1__Guideline
Principles of ICH GCP
bull Supportive data
bull Protocol
Scientifically sound clear detailed
bull Ethical Clearance
Study to be conducted in compliance to the protocol which has received EC approval
Principles of ICH GCP
bull Subject Care
Medical decisions responsibility of qualified physician
bull Qualified staff
By education training experience in their area of responsibility
bull Informed Consent
Principles of ICH GCP
bull Clinical Trial data
Recorded handled and stored to enable accurate reporting interpretation and verification
bull Confidentiality
Principles of ICH GCP
bull Investigational Product
Manufactured handled and stored as per GMP
Principles of ICH GCP
bull Quality Assurance
Systems and procedures to ensure the Quality of every aspect of the trial
Indian GCP guidelines
bull Released in Dec 2001(Developed by CDCSO and endorsed by DCGI)
bull In general in line with ICH GCP
bull Has Revised Schedule Y (Jan 2005) addressed discrepancies
bull SAFEGUARD PUBLIC HEALTH
bull ASSURE CONSUMER PROTECTION STANDARDS
bull FACILITATE AVAILABILITY OF SAFE AND EFFECTIVE PRODUCTS
bull ELIMINATE INCONSISTENT STANDARDS INTERNATIONALLY
bull FACILITATE MUTUAL ACCEPTANCE OF DATA FROM CLINICAL TRIALS
GOALS OF INTERNATIONAL HARMONIZATION OF
REGULATORY REQUIREMENTS
Study DocumentationDuring the study
The investigator must keepndash Source documents
bull Medical records (including access to computer records)
bull Laboratory reports
bull ECGs X-rays etc
bull Any other medical records reports or notes (hospital admissions and discharges)
ndash A subject identification list
ndash Copies of all study related documentation
Medical Records
bull In particular they should contain notes on
ndash Sufficient information to support subject eligibility
ndash This should be well documented (signed and dated)
ndash Subjectrsquos participation in the study
ndash Dates of visits
ndash Procedures investigations done
ndash Observations diagnoses
ndash Medications taken (including study medication)
ndash Adverse events
ndash Completion or withdrawal (reason) from the study
Study DocumentationAfter the study
The sponsor needs from the investigator
ndash Final drug accountability records
ndash All used and unused supplies and medication
ndash All required documents completed
Conclusion
70
Thanks
ldquoWhen a doctor [goes] wrong he is
the first of criminals He has nerve
and he has knowledgerdquo
- Sherlock Holmes
References
httpwwwwmanetepolicyb3htm
wwwhhsgovohrphumansubjectsguidancebelmonthtml
wwwhhsgovohrpreferencesnurcodehtml
wwwicmrnicinguidelinesGCLP
wwwcdsconicin
wwwubedurecercaBioeticadocDeclaracio_Helsinki_2013
wwwjewishvirtuallibraryorgjsourceHolocaustnazi_experiments
wwwichorgfileadminPublic_WebICHE6_R1__Guideline
Principles of ICH GCP
bull Subject Care
Medical decisions responsibility of qualified physician
bull Qualified staff
By education training experience in their area of responsibility
bull Informed Consent
Principles of ICH GCP
bull Clinical Trial data
Recorded handled and stored to enable accurate reporting interpretation and verification
bull Confidentiality
Principles of ICH GCP
bull Investigational Product
Manufactured handled and stored as per GMP
Principles of ICH GCP
bull Quality Assurance
Systems and procedures to ensure the Quality of every aspect of the trial
Indian GCP guidelines
bull Released in Dec 2001(Developed by CDCSO and endorsed by DCGI)
bull In general in line with ICH GCP
bull Has Revised Schedule Y (Jan 2005) addressed discrepancies
bull SAFEGUARD PUBLIC HEALTH
bull ASSURE CONSUMER PROTECTION STANDARDS
bull FACILITATE AVAILABILITY OF SAFE AND EFFECTIVE PRODUCTS
bull ELIMINATE INCONSISTENT STANDARDS INTERNATIONALLY
bull FACILITATE MUTUAL ACCEPTANCE OF DATA FROM CLINICAL TRIALS
GOALS OF INTERNATIONAL HARMONIZATION OF
REGULATORY REQUIREMENTS
Study DocumentationDuring the study
The investigator must keepndash Source documents
bull Medical records (including access to computer records)
bull Laboratory reports
bull ECGs X-rays etc
bull Any other medical records reports or notes (hospital admissions and discharges)
ndash A subject identification list
ndash Copies of all study related documentation
Medical Records
bull In particular they should contain notes on
ndash Sufficient information to support subject eligibility
ndash This should be well documented (signed and dated)
ndash Subjectrsquos participation in the study
ndash Dates of visits
ndash Procedures investigations done
ndash Observations diagnoses
ndash Medications taken (including study medication)
ndash Adverse events
ndash Completion or withdrawal (reason) from the study
Study DocumentationAfter the study
The sponsor needs from the investigator
ndash Final drug accountability records
ndash All used and unused supplies and medication
ndash All required documents completed
Conclusion
70
Thanks
ldquoWhen a doctor [goes] wrong he is
the first of criminals He has nerve
and he has knowledgerdquo
- Sherlock Holmes
References
httpwwwwmanetepolicyb3htm
wwwhhsgovohrphumansubjectsguidancebelmonthtml
wwwhhsgovohrpreferencesnurcodehtml
wwwicmrnicinguidelinesGCLP
wwwcdsconicin
wwwubedurecercaBioeticadocDeclaracio_Helsinki_2013
wwwjewishvirtuallibraryorgjsourceHolocaustnazi_experiments
wwwichorgfileadminPublic_WebICHE6_R1__Guideline
Principles of ICH GCP
bull Clinical Trial data
Recorded handled and stored to enable accurate reporting interpretation and verification
bull Confidentiality
Principles of ICH GCP
bull Investigational Product
Manufactured handled and stored as per GMP
Principles of ICH GCP
bull Quality Assurance
Systems and procedures to ensure the Quality of every aspect of the trial
Indian GCP guidelines
bull Released in Dec 2001(Developed by CDCSO and endorsed by DCGI)
bull In general in line with ICH GCP
bull Has Revised Schedule Y (Jan 2005) addressed discrepancies
bull SAFEGUARD PUBLIC HEALTH
bull ASSURE CONSUMER PROTECTION STANDARDS
bull FACILITATE AVAILABILITY OF SAFE AND EFFECTIVE PRODUCTS
bull ELIMINATE INCONSISTENT STANDARDS INTERNATIONALLY
bull FACILITATE MUTUAL ACCEPTANCE OF DATA FROM CLINICAL TRIALS
GOALS OF INTERNATIONAL HARMONIZATION OF
REGULATORY REQUIREMENTS
Study DocumentationDuring the study
The investigator must keepndash Source documents
bull Medical records (including access to computer records)
bull Laboratory reports
bull ECGs X-rays etc
bull Any other medical records reports or notes (hospital admissions and discharges)
ndash A subject identification list
ndash Copies of all study related documentation
Medical Records
bull In particular they should contain notes on
ndash Sufficient information to support subject eligibility
ndash This should be well documented (signed and dated)
ndash Subjectrsquos participation in the study
ndash Dates of visits
ndash Procedures investigations done
ndash Observations diagnoses
ndash Medications taken (including study medication)
ndash Adverse events
ndash Completion or withdrawal (reason) from the study
Study DocumentationAfter the study
The sponsor needs from the investigator
ndash Final drug accountability records
ndash All used and unused supplies and medication
ndash All required documents completed
Conclusion
70
Thanks
ldquoWhen a doctor [goes] wrong he is
the first of criminals He has nerve
and he has knowledgerdquo
- Sherlock Holmes
References
httpwwwwmanetepolicyb3htm
wwwhhsgovohrphumansubjectsguidancebelmonthtml
wwwhhsgovohrpreferencesnurcodehtml
wwwicmrnicinguidelinesGCLP
wwwcdsconicin
wwwubedurecercaBioeticadocDeclaracio_Helsinki_2013
wwwjewishvirtuallibraryorgjsourceHolocaustnazi_experiments
wwwichorgfileadminPublic_WebICHE6_R1__Guideline
Principles of ICH GCP
bull Investigational Product
Manufactured handled and stored as per GMP
Principles of ICH GCP
bull Quality Assurance
Systems and procedures to ensure the Quality of every aspect of the trial
Indian GCP guidelines
bull Released in Dec 2001(Developed by CDCSO and endorsed by DCGI)
bull In general in line with ICH GCP
bull Has Revised Schedule Y (Jan 2005) addressed discrepancies
bull SAFEGUARD PUBLIC HEALTH
bull ASSURE CONSUMER PROTECTION STANDARDS
bull FACILITATE AVAILABILITY OF SAFE AND EFFECTIVE PRODUCTS
bull ELIMINATE INCONSISTENT STANDARDS INTERNATIONALLY
bull FACILITATE MUTUAL ACCEPTANCE OF DATA FROM CLINICAL TRIALS
GOALS OF INTERNATIONAL HARMONIZATION OF
REGULATORY REQUIREMENTS
Study DocumentationDuring the study
The investigator must keepndash Source documents
bull Medical records (including access to computer records)
bull Laboratory reports
bull ECGs X-rays etc
bull Any other medical records reports or notes (hospital admissions and discharges)
ndash A subject identification list
ndash Copies of all study related documentation
Medical Records
bull In particular they should contain notes on
ndash Sufficient information to support subject eligibility
ndash This should be well documented (signed and dated)
ndash Subjectrsquos participation in the study
ndash Dates of visits
ndash Procedures investigations done
ndash Observations diagnoses
ndash Medications taken (including study medication)
ndash Adverse events
ndash Completion or withdrawal (reason) from the study
Study DocumentationAfter the study
The sponsor needs from the investigator
ndash Final drug accountability records
ndash All used and unused supplies and medication
ndash All required documents completed
Conclusion
70
Thanks
ldquoWhen a doctor [goes] wrong he is
the first of criminals He has nerve
and he has knowledgerdquo
- Sherlock Holmes
References
httpwwwwmanetepolicyb3htm
wwwhhsgovohrphumansubjectsguidancebelmonthtml
wwwhhsgovohrpreferencesnurcodehtml
wwwicmrnicinguidelinesGCLP
wwwcdsconicin
wwwubedurecercaBioeticadocDeclaracio_Helsinki_2013
wwwjewishvirtuallibraryorgjsourceHolocaustnazi_experiments
wwwichorgfileadminPublic_WebICHE6_R1__Guideline
Principles of ICH GCP
bull Quality Assurance
Systems and procedures to ensure the Quality of every aspect of the trial
Indian GCP guidelines
bull Released in Dec 2001(Developed by CDCSO and endorsed by DCGI)
bull In general in line with ICH GCP
bull Has Revised Schedule Y (Jan 2005) addressed discrepancies
bull SAFEGUARD PUBLIC HEALTH
bull ASSURE CONSUMER PROTECTION STANDARDS
bull FACILITATE AVAILABILITY OF SAFE AND EFFECTIVE PRODUCTS
bull ELIMINATE INCONSISTENT STANDARDS INTERNATIONALLY
bull FACILITATE MUTUAL ACCEPTANCE OF DATA FROM CLINICAL TRIALS
GOALS OF INTERNATIONAL HARMONIZATION OF
REGULATORY REQUIREMENTS
Study DocumentationDuring the study
The investigator must keepndash Source documents
bull Medical records (including access to computer records)
bull Laboratory reports
bull ECGs X-rays etc
bull Any other medical records reports or notes (hospital admissions and discharges)
ndash A subject identification list
ndash Copies of all study related documentation
Medical Records
bull In particular they should contain notes on
ndash Sufficient information to support subject eligibility
ndash This should be well documented (signed and dated)
ndash Subjectrsquos participation in the study
ndash Dates of visits
ndash Procedures investigations done
ndash Observations diagnoses
ndash Medications taken (including study medication)
ndash Adverse events
ndash Completion or withdrawal (reason) from the study
Study DocumentationAfter the study
The sponsor needs from the investigator
ndash Final drug accountability records
ndash All used and unused supplies and medication
ndash All required documents completed
Conclusion
70
Thanks
ldquoWhen a doctor [goes] wrong he is
the first of criminals He has nerve
and he has knowledgerdquo
- Sherlock Holmes
References
httpwwwwmanetepolicyb3htm
wwwhhsgovohrphumansubjectsguidancebelmonthtml
wwwhhsgovohrpreferencesnurcodehtml
wwwicmrnicinguidelinesGCLP
wwwcdsconicin
wwwubedurecercaBioeticadocDeclaracio_Helsinki_2013
wwwjewishvirtuallibraryorgjsourceHolocaustnazi_experiments
wwwichorgfileadminPublic_WebICHE6_R1__Guideline
Indian GCP guidelines
bull Released in Dec 2001(Developed by CDCSO and endorsed by DCGI)
bull In general in line with ICH GCP
bull Has Revised Schedule Y (Jan 2005) addressed discrepancies
bull SAFEGUARD PUBLIC HEALTH
bull ASSURE CONSUMER PROTECTION STANDARDS
bull FACILITATE AVAILABILITY OF SAFE AND EFFECTIVE PRODUCTS
bull ELIMINATE INCONSISTENT STANDARDS INTERNATIONALLY
bull FACILITATE MUTUAL ACCEPTANCE OF DATA FROM CLINICAL TRIALS
GOALS OF INTERNATIONAL HARMONIZATION OF
REGULATORY REQUIREMENTS
Study DocumentationDuring the study
The investigator must keepndash Source documents
bull Medical records (including access to computer records)
bull Laboratory reports
bull ECGs X-rays etc
bull Any other medical records reports or notes (hospital admissions and discharges)
ndash A subject identification list
ndash Copies of all study related documentation
Medical Records
bull In particular they should contain notes on
ndash Sufficient information to support subject eligibility
ndash This should be well documented (signed and dated)
ndash Subjectrsquos participation in the study
ndash Dates of visits
ndash Procedures investigations done
ndash Observations diagnoses
ndash Medications taken (including study medication)
ndash Adverse events
ndash Completion or withdrawal (reason) from the study
Study DocumentationAfter the study
The sponsor needs from the investigator
ndash Final drug accountability records
ndash All used and unused supplies and medication
ndash All required documents completed
Conclusion
70
Thanks
ldquoWhen a doctor [goes] wrong he is
the first of criminals He has nerve
and he has knowledgerdquo
- Sherlock Holmes
References
httpwwwwmanetepolicyb3htm
wwwhhsgovohrphumansubjectsguidancebelmonthtml
wwwhhsgovohrpreferencesnurcodehtml
wwwicmrnicinguidelinesGCLP
wwwcdsconicin
wwwubedurecercaBioeticadocDeclaracio_Helsinki_2013
wwwjewishvirtuallibraryorgjsourceHolocaustnazi_experiments
wwwichorgfileadminPublic_WebICHE6_R1__Guideline
bull SAFEGUARD PUBLIC HEALTH
bull ASSURE CONSUMER PROTECTION STANDARDS
bull FACILITATE AVAILABILITY OF SAFE AND EFFECTIVE PRODUCTS
bull ELIMINATE INCONSISTENT STANDARDS INTERNATIONALLY
bull FACILITATE MUTUAL ACCEPTANCE OF DATA FROM CLINICAL TRIALS
GOALS OF INTERNATIONAL HARMONIZATION OF
REGULATORY REQUIREMENTS
Study DocumentationDuring the study
The investigator must keepndash Source documents
bull Medical records (including access to computer records)
bull Laboratory reports
bull ECGs X-rays etc
bull Any other medical records reports or notes (hospital admissions and discharges)
ndash A subject identification list
ndash Copies of all study related documentation
Medical Records
bull In particular they should contain notes on
ndash Sufficient information to support subject eligibility
ndash This should be well documented (signed and dated)
ndash Subjectrsquos participation in the study
ndash Dates of visits
ndash Procedures investigations done
ndash Observations diagnoses
ndash Medications taken (including study medication)
ndash Adverse events
ndash Completion or withdrawal (reason) from the study
Study DocumentationAfter the study
The sponsor needs from the investigator
ndash Final drug accountability records
ndash All used and unused supplies and medication
ndash All required documents completed
Conclusion
70
Thanks
ldquoWhen a doctor [goes] wrong he is
the first of criminals He has nerve
and he has knowledgerdquo
- Sherlock Holmes
References
httpwwwwmanetepolicyb3htm
wwwhhsgovohrphumansubjectsguidancebelmonthtml
wwwhhsgovohrpreferencesnurcodehtml
wwwicmrnicinguidelinesGCLP
wwwcdsconicin
wwwubedurecercaBioeticadocDeclaracio_Helsinki_2013
wwwjewishvirtuallibraryorgjsourceHolocaustnazi_experiments
wwwichorgfileadminPublic_WebICHE6_R1__Guideline
Study DocumentationDuring the study
The investigator must keepndash Source documents
bull Medical records (including access to computer records)
bull Laboratory reports
bull ECGs X-rays etc
bull Any other medical records reports or notes (hospital admissions and discharges)
ndash A subject identification list
ndash Copies of all study related documentation
Medical Records
bull In particular they should contain notes on
ndash Sufficient information to support subject eligibility
ndash This should be well documented (signed and dated)
ndash Subjectrsquos participation in the study
ndash Dates of visits
ndash Procedures investigations done
ndash Observations diagnoses
ndash Medications taken (including study medication)
ndash Adverse events
ndash Completion or withdrawal (reason) from the study
Study DocumentationAfter the study
The sponsor needs from the investigator
ndash Final drug accountability records
ndash All used and unused supplies and medication
ndash All required documents completed
Conclusion
70
Thanks
ldquoWhen a doctor [goes] wrong he is
the first of criminals He has nerve
and he has knowledgerdquo
- Sherlock Holmes
References
httpwwwwmanetepolicyb3htm
wwwhhsgovohrphumansubjectsguidancebelmonthtml
wwwhhsgovohrpreferencesnurcodehtml
wwwicmrnicinguidelinesGCLP
wwwcdsconicin
wwwubedurecercaBioeticadocDeclaracio_Helsinki_2013
wwwjewishvirtuallibraryorgjsourceHolocaustnazi_experiments
wwwichorgfileadminPublic_WebICHE6_R1__Guideline
Medical Records
bull In particular they should contain notes on
ndash Sufficient information to support subject eligibility
ndash This should be well documented (signed and dated)
ndash Subjectrsquos participation in the study
ndash Dates of visits
ndash Procedures investigations done
ndash Observations diagnoses
ndash Medications taken (including study medication)
ndash Adverse events
ndash Completion or withdrawal (reason) from the study
Study DocumentationAfter the study
The sponsor needs from the investigator
ndash Final drug accountability records
ndash All used and unused supplies and medication
ndash All required documents completed
Conclusion
70
Thanks
ldquoWhen a doctor [goes] wrong he is
the first of criminals He has nerve
and he has knowledgerdquo
- Sherlock Holmes
References
httpwwwwmanetepolicyb3htm
wwwhhsgovohrphumansubjectsguidancebelmonthtml
wwwhhsgovohrpreferencesnurcodehtml
wwwicmrnicinguidelinesGCLP
wwwcdsconicin
wwwubedurecercaBioeticadocDeclaracio_Helsinki_2013
wwwjewishvirtuallibraryorgjsourceHolocaustnazi_experiments
wwwichorgfileadminPublic_WebICHE6_R1__Guideline
Study DocumentationAfter the study
The sponsor needs from the investigator
ndash Final drug accountability records
ndash All used and unused supplies and medication
ndash All required documents completed
Conclusion
70
Thanks
ldquoWhen a doctor [goes] wrong he is
the first of criminals He has nerve
and he has knowledgerdquo
- Sherlock Holmes
References
httpwwwwmanetepolicyb3htm
wwwhhsgovohrphumansubjectsguidancebelmonthtml
wwwhhsgovohrpreferencesnurcodehtml
wwwicmrnicinguidelinesGCLP
wwwcdsconicin
wwwubedurecercaBioeticadocDeclaracio_Helsinki_2013
wwwjewishvirtuallibraryorgjsourceHolocaustnazi_experiments
wwwichorgfileadminPublic_WebICHE6_R1__Guideline
Conclusion
70
Thanks
ldquoWhen a doctor [goes] wrong he is
the first of criminals He has nerve
and he has knowledgerdquo
- Sherlock Holmes
References
httpwwwwmanetepolicyb3htm
wwwhhsgovohrphumansubjectsguidancebelmonthtml
wwwhhsgovohrpreferencesnurcodehtml
wwwicmrnicinguidelinesGCLP
wwwcdsconicin
wwwubedurecercaBioeticadocDeclaracio_Helsinki_2013
wwwjewishvirtuallibraryorgjsourceHolocaustnazi_experiments
wwwichorgfileadminPublic_WebICHE6_R1__Guideline
References
httpwwwwmanetepolicyb3htm
wwwhhsgovohrphumansubjectsguidancebelmonthtml
wwwhhsgovohrpreferencesnurcodehtml
wwwicmrnicinguidelinesGCLP
wwwcdsconicin
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