GCP 101GCP 101oror

Why we do What we do Why we do What we do the the

Way we do itWay we do it

Elaine DempseyElaine Dempsey

What is a Good Clinical Practice?What is a Good Clinical Practice?

Good Clinical Practice is defined as follows by Good Clinical Practice is defined as follows by the Institute for the Advancement of Clinical the Institute for the Advancement of Clinical Research:Research:

““Good Clinical Practice (GCP) is an international Good Clinical Practice (GCP) is an international ethical and scientific quality standard for the design, ethical and scientific quality standard for the design, conduct, performance, monitoring, auditing, conduct, performance, monitoring, auditing, recording, analyses and reporting of clinical trials. recording, analyses and reporting of clinical trials. GCP provides assurance that the data and reported GCP provides assurance that the data and reported results are credible and accurate, and that the rights, results are credible and accurate, and that the rights, integrity and confidentiality of trial subjects are integrity and confidentiality of trial subjects are respected and protected.”respected and protected.”

HistoryHistory• Ethics in MedicineEthics in Medicine

– Historically, concerns about the ethics in medicine Historically, concerns about the ethics in medicine centered around therapeutics and actual treatment of centered around therapeutics and actual treatment of illnessillness

– It wasn’t until the middle of the 20It wasn’t until the middle of the 20thth century (following century (following WWII) that we saw a new emphasis on medical researchWWII) that we saw a new emphasis on medical research

– When examples of abuses in medical research were When examples of abuses in medical research were publicized then national and international efforts to publicized then national and international efforts to protect the rights and welfare of human subjects in protect the rights and welfare of human subjects in research beganresearch began

– Most of these occurrences were situations where Most of these occurrences were situations where investigators ignored the fundamental rights of human investigators ignored the fundamental rights of human subjectssubjects

• Any investigation or study that uses human Any investigation or study that uses human subjects and subjects and – is intended to test the clinical effects of an is intended to test the clinical effects of an

investigational agent and/or investigational agent and/or – to identify any adverse reactions to an to identify any adverse reactions to an

investigational agent to assess the safety investigational agent to assess the safety and efficacyand efficacy

A Subject is………….A participant in research either as a recipient of the test article or control. A subject may be a healthy human or a patient

A Clinical Trial is………….

The Nuremberg Doctors The Nuremberg Doctors Trial of 1946Trial of 1946

• During WWII medical “experiments” were done on During WWII medical “experiments” were done on concentration camp internees to obtain information useful concentration camp internees to obtain information useful for the survival of German military personnel under for the survival of German military personnel under conditions that would be encountered in war. conditions that would be encountered in war.

• These were mostly survival studies; at high altitudes These were mostly survival studies; at high altitudes without oxygen, in frigid water, after wounds of various without oxygen, in frigid water, after wounds of various sorts and severity, after exposures to chemical and sorts and severity, after exposures to chemical and biological agents. biological agents.

• Many died as a result of these “experiments”.Many died as a result of these “experiments”.

• After a trial of the Nazi leadership by an International After a trial of the Nazi leadership by an International Military Tribunal, a trial known as the “Nazi Doctors Trial” Military Tribunal, a trial known as the “Nazi Doctors Trial” was conducted by judges and prosecutors from the U.S. was conducted by judges and prosecutors from the U.S. (U.S. vs. Karl Brandt et al.). (U.S. vs. Karl Brandt et al.). • The 23 defendants, including 20 physicians, were charged The 23 defendants, including 20 physicians, were charged with murder, torture and other atrocities. 15 were found guilty with murder, torture and other atrocities. 15 were found guilty and 7 were sentenced to death.and 7 were sentenced to death.

Nuremberg Code - 1947Nuremberg Code - 1947

• Informed consent of volunteers must be obtained without Informed consent of volunteers must be obtained without coercion in any formcoercion in any form

• Human experiments should be based on prior animal studiesHuman experiments should be based on prior animal studies

• Anticipated scientific results should justify the experimentAnticipated scientific results should justify the experiment

• Only qualified scientists should conduct medical researchOnly qualified scientists should conduct medical research

• Risk to benefit ratio should be commensurate with the problemRisk to benefit ratio should be commensurate with the problem

• Physical and mental suffering and injury should be avoidedPhysical and mental suffering and injury should be avoided

• There should be no expectation of death or disabling injury from There should be no expectation of death or disabling injury from the experimentthe experiment

• Investigator should be prepared to stop the experiment if there Investigator should be prepared to stop the experiment if there is indication of dangeris indication of danger

• Subjects should be able to withdraw without penaltySubjects should be able to withdraw without penalty

The Declaration of Helsinki - The Declaration of Helsinki - 19641964

Written by the World Federation of Physicians and Written by the World Federation of Physicians and adopted in 1964:adopted in 1964:

• Incorporated the Nuremberg CodeIncorporated the Nuremberg Code

• Defined therapeutic vs. non-therapeutic researchDefined therapeutic vs. non-therapeutic research

• Allowed enrollment of certain subjects in Allowed enrollment of certain subjects in therapeutic research without consent so that they therapeutic research without consent so that they might benefit from important medical advancesmight benefit from important medical advances

• Allowed legal guardians to enroll patients in Allowed legal guardians to enroll patients in therapeutic and non-therapeutic research trialstherapeutic and non-therapeutic research trials

Willowbrook 1963-66Willowbrook 1963-66

• This study enrolled institutionalized mentally This study enrolled institutionalized mentally retarded children in order to investigate the natural history of retarded children in order to investigate the natural history of viral hepatitis with which they were deliberately infected. viral hepatitis with which they were deliberately infected.

• Willowbrook was overcrowded and only the research wing had Willowbrook was overcrowded and only the research wing had room for new patients. Parents had to give permission for their room for new patients. Parents had to give permission for their children to be in the study in order for them to be placed at children to be in the study in order for them to be placed at Willowbrook.Willowbrook.

• Coercing parents to enroll their children, using a captive and Coercing parents to enroll their children, using a captive and vulnerable subject population for research, and putting minors at risk for vulnerable subject population for research, and putting minors at risk for no benefit to them violated all of the ethical principles that should guide no benefit to them violated all of the ethical principles that should guide physicians doing research.physicians doing research.

Tuskegee Study of Untreated Syphilis in Tuskegee Study of Untreated Syphilis in

Negro Males (1932 – 1972)Negro Males (1932 – 1972) • A study to determine the course of untreated syphilis was A study to determine the course of untreated syphilis was

designed by an agency of the USPHS that later became the designed by an agency of the USPHS that later became the CDCCDC

• Conducted in Tuskegee, Alabama starting in 1932 Conducted in Tuskegee, Alabama starting in 1932 • 200-300 black males were to be enrolled 200-300 black males were to be enrolled • The study was to end with a non-therapeutic spinal tap in May The study was to end with a non-therapeutic spinal tap in May

1933 1933 • Went on for the next 10 years without reviewWent on for the next 10 years without review• Penicillin accepted as the treatment for Syphilis in 1943Penicillin accepted as the treatment for Syphilis in 1943• Subjects were continued in the study untreated and exempted Subjects were continued in the study untreated and exempted

from the WWII draftfrom the WWII draft• By 1951 PCN was widely available but subjects were still not By 1951 PCN was widely available but subjects were still not

treated because it was realized that the study represented a treated because it was realized that the study represented a “never again opportunity”“never again opportunity”

Tuskegee Study of Untreated Tuskegee Study of Untreated Syphilis in Negro Males - contdSyphilis in Negro Males - contd

• An expose' was published in the Atlanta An expose' was published in the Atlanta Constitution (1972)Constitution (1972)

• Senate hearings led to federal regulations (1973) Senate hearings led to federal regulations (1973) • The CDC told survivors that the government would The CDC told survivors that the government would

pay their medical bills for the remainder of their pay their medical bills for the remainder of their lives lives

• In 1975 medical coverage was extended to wives In 1975 medical coverage was extended to wives and children with congenital syphilisand children with congenital syphilis

• President Clinton publicly apologized to 8 survivors President Clinton publicly apologized to 8 survivors and their families at a white house ceremony in and their families at a white house ceremony in May 1997May 1997

• National Center for Bioethics in Research National Center for Bioethics in Research established at Tuskegee U. in 1999established at Tuskegee U. in 1999

Protection of Human Subjects in Protection of Human Subjects in Research ProgressionResearch Progression

The process will continue to evolve and refine!

Food and Drug Act of 1906

Food, Drug and Cosmetic Act – 1938

The Nuremburg Code – 1947

Kefauver-Harris Amendments – 1962

The Helsinki Declaration – 1964

USPHS IRB / Informed Consent – 1966

The Belmont Report – 1969

Consolidated DHHS/FDA Regulations – 1981

ICH Requirements – 1990

Common Rule – 1991

National Bioethics Advisory Committee – 1995

DSMBs - 1997, 1999

OHRP Established – 2000

ISO – 2001

GCP Document of the Americas – 2005

WHO Handbook for Good Clinical Practices - 2006

ICH – International Conference on ICH – International Conference on HarmonisationHarmonisation

• Designed to streamline the process for Designed to streamline the process for developing and marketing new drugs developing and marketing new drugs internationallyinternationally

• Composed of representatives for the pharma Composed of representatives for the pharma industry and the regulatory bodies of the US, industry and the regulatory bodies of the US, Japan, and the European UnionJapan, and the European Union

• Observers include Canada, the European Free Observers include Canada, the European Free Trade Area and WHOTrade Area and WHO

ICHICH

• Established several international standards of Established several international standards of good clinical practice (GCP) good clinical practice (GCP)

• Many countries adopted the guidance as “law”Many countries adopted the guidance as “law”• The U.S. (FDA), however, only adopted the ICH The U.S. (FDA), however, only adopted the ICH

as guidanceas guidance– Not regulationNot regulation– Does not have the force of lawDoes not have the force of law– Compliance is voluntaryCompliance is voluntary

The Belmont Report (1979)The Belmont Report (1979)

• Based on a comprehensive federally-Based on a comprehensive federally-commissioned review which explored the commissioned review which explored the ethical and human rights considerations of ethical and human rights considerations of human biomedical and behavioral human biomedical and behavioral experimentation experimentation

• Resulted in more strenuous protection for Resulted in more strenuous protection for human research subjects based on three human research subjects based on three ethical principles that form the basis for ethical principles that form the basis for informed consent:informed consent:– Respect for PersonsRespect for Persons– BeneficenceBeneficence– JusticeJustice

Respect for PersonsRespect for Persons

• Autonomous agentsAutonomous agents– individuals able to make their own individuals able to make their own informedinformed decisions decisions

• Persons with diminished capacity are entitled Persons with diminished capacity are entitled to increased protection.to increased protection.– includes children, mentally disabled, includes children, mentally disabled,

prisoners, and pregnant womenprisoners, and pregnant women

BeneficenceBeneficence

• Do no harm. Do no harm. • Assess the risk benefit ratioAssess the risk benefit ratio

– maximize benefits and minimize risksmaximize benefits and minimize risks• Although there is a need to protect Although there is a need to protect

subjects from risk, there is also a need to subjects from risk, there is also a need to compare the substantial benefits that may compare the substantial benefits that may be gained from researchbe gained from research

JusticeJustice

• Should not involve persons not likely to Should not involve persons not likely to benefit from researchbenefit from research

• Requires fairness in selection of subjectsRequires fairness in selection of subjects

• Should not systemically draw subjects from Should not systemically draw subjects from certain groups simply because of availabilitycertain groups simply because of availability– Welfare patients/economically Welfare patients/economically

disadvantaged, racial or ethnic minorities, disadvantaged, racial or ethnic minorities, institutionalized individuals, very sick institutionalized individuals, very sick patients, or prisonerspatients, or prisoners

Informed ConsentInformed Consent• Form vs processForm vs process• Freely given consent to participate in a clinical Freely given consent to participate in a clinical

research studyresearch study– No coercionNo coercion– Emphasis on “informed”Emphasis on “informed”– Obtained prior to enrolling the subjectObtained prior to enrolling the subject

Requirements:Requirements:• Lay languageLay language• Participant must have sufficient time to consider consentingParticipant must have sufficient time to consider consenting• Reading levelReading level• Adequate presentation of the facts to the subject and/or Adequate presentation of the facts to the subject and/or representativerepresentative

ProtocolProtocol• A document that describes the objective(s), A document that describes the objective(s),

design, methodology, statistical design, methodology, statistical considerations, and organization of a clinical considerations, and organization of a clinical trial trial

• Usually gives the background and reason the Usually gives the background and reason the trial is being conducted, but these could be trial is being conducted, but these could be provided in other documents referenced in provided in other documents referenced in the protocol (Investigator’s Brochure)the protocol (Investigator’s Brochure)

• A study plan on which the clinical trial is A study plan on which the clinical trial is based based

• Describes, among other things, what types of Describes, among other things, what types of people may participate in the trial; the people may participate in the trial; the schedule of tests, procedures, medications, schedule of tests, procedures, medications, and dosages; and the length of the study and dosages; and the length of the study

Investigational New Drug Investigational New Drug (IND)(IND)

• Federal law requires that a drug must have Federal law requires that a drug must have an approved marketing application prior to an approved marketing application prior to being transported or distributed across being transported or distributed across state linesstate lines

• When a sponsor screens a new molecule When a sponsor screens a new molecule for pharmacological activity and toxicity in for pharmacological activity and toxicity in animals and wants to test the drugs animals and wants to test the drugs diagnostic or therapeutic potential on diagnostic or therapeutic potential on humanshumans– At this point, the molecule changes in legal At this point, the molecule changes in legal

statusstatus– Under Federal Food, Drug, and Cosmetic Act, it Under Federal Food, Drug, and Cosmetic Act, it

becomes a new drug subject to regulationbecomes a new drug subject to regulation

Serious Adverse Event Serious Adverse Event (SAE)(SAE)

• DeathDeath• Life-threatening (risk of death)Life-threatening (risk of death)• HospitalizationHospitalization• DisabilityDisability• Requires further intervention to prevent Requires further intervention to prevent

additional impairment or disabilityadditional impairment or disability

RandomizationRandomization

• Random assignment of subjects to either the Random assignment of subjects to either the experimental group or the control groupexperimental group or the control group

• Used to control the imbalance of risk factors Used to control the imbalance of risk factors within the treatment groupswithin the treatment groups

• Control of the randomization should rest with Control of the randomization should rest with a neutral party, if possible a neutral party, if possible – Sealed envelopesSealed envelopes– Randomization centerRandomization center

• Various ways of randomizingVarious ways of randomizing– SS #SS #– Random number generatorRandom number generator

Pre-clinical StudiesPre-clinical Studies

• Usually used to test drugs and Usually used to test drugs and toxicology on animalstoxicology on animals

• Used to evaluate a compoundUsed to evaluate a compound• Pre-human testingPre-human testing• During this phase, the “IND’ may be During this phase, the “IND’ may be

submitted to the FDAsubmitted to the FDA

Phase IPhase I TrialsTrials

• Used to evaluate and test the pharmacology of Used to evaluate and test the pharmacology of the investigational drug and/or the dosing the investigational drug and/or the dosing rangerange– toxicitytoxicity

• Usually uses healthy subjects to determine Usually uses healthy subjects to determine safetysafety issues issues

• N = usually <100 subjects (20 – 80 is optimal)N = usually <100 subjects (20 – 80 is optimal)

Phase II TrialsPhase II Trials

• Occurs after the safety of the drug has been Occurs after the safety of the drug has been determined in a Phase I trialdetermined in a Phase I trial

• Primarily used to collect data on the safety and Primarily used to collect data on the safety and efficacy of the drug in subjects with the efficacy of the drug in subjects with the disease the drug is intended to treatdisease the drug is intended to treat

• Usually, about 100-300 subjects Usually, about 100-300 subjects

• Subjects must fit the inclusion/exclusion Subjects must fit the inclusion/exclusion criteriacriteria

Phase III TrialsPhase III Trials

• Designed to collect data on the side effects, Designed to collect data on the side effects, idiosyncrasies, and the effectiveness of the idiosyncrasies, and the effectiveness of the drugdrug

• Usually >1,000 subjects, multi-centeredUsually >1,000 subjects, multi-centered

• Usually randomized, blinded and placebo Usually randomized, blinded and placebo controlledcontrolled

Phase IV TrialsPhase IV Trials

• Designed to expand the indications for the Designed to expand the indications for the drug. Takes place after IND is approved and drug. Takes place after IND is approved and the drug is availablethe drug is available

• Used to re-document the safety of the drug Used to re-document the safety of the drug and to gather more information regarding and to gather more information regarding drug interactionsdrug interactions

• To study the drug on additional populationsTo study the drug on additional populations

Clinical Trials TimelineClinical Trials Timeline

YES!YES!

The data and subsequent analysis must be The data and subsequent analysis must be accurate. This requires strenuous quality control accurate. This requires strenuous quality control and validation of results as well as and validation of results as well as documentation of statistical methods. Good documentation of statistical methods. Good Clinical Practices apply because it is our Clinical Practices apply because it is our responsibility to ensure the quality of the data responsibility to ensure the quality of the data

and to perform the analysis in the proper way.and to perform the analysis in the proper way.

Are Statisticians and Are Statisticians and Programmers responsible for Programmers responsible for

upholding Good Clinical upholding Good Clinical Practices?Practices?