Introduction to Clinical Trials and GCP
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JoBurmester.comClinical Research Knowhow
Clinical Trials
June 2020
Course Tutor: Jo Burmester
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JoBurmester.comClinical Research KnowhowAgenda
• Drug Development and Clinical Trial Phases • Approvals required• ICH GCP (R2) Introduction • o Principles of Good Clinical Practice
o Key Responsibilities for Clinical Trialso Contracting to CROs – key considerations
• Risk Assessment and Management • Safety Reporting and Serious Breaches
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What is a Clinical Trial
‘clinical trial’: any investigation in human subjects intended to discover or verify the clinical, pharmacological and/or other pharmacodynamic effects of one or more investigational medicinal product(s)….
Clinical Trials Directive, 2001/20/EC
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Introduction to Clinical Trials and GCP
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The Clinical Trial Process
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The Drug Development Process
• From molecule to market place…
Identification
In vitro research
Pre-clinical research
Clinical development
Marketed product
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Clinical Development Phases & Types of Clinical Trial
• Phase I• Phase II• Phase III – a and b• Phase IV• PASS/PAES• Post Marketing Observational• Epidemiology
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Introduction to Clinical Trials and GCP
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Clinical Trial Processes
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The life cycle of a clinical trial
Clinical Study Report Statistics, Final report, Submission?
Closeout Site Closeout, Final Queries, Database Lock
Recruitment Monitoring , Data Management, Compliance
Start up Feasibility, Approvals, Site Selection, Site Initiation
Design Hypothesis, Protocol
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ICH GCP
BackgroundContents
Responsibilities of Ethics Committees, Sponsors & InvestigatorsEssential documents
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Introduction to Clinical Trials and GCP
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• International Council on Harmonisation• US, EU and Japan• Purpose:– Harmonise marketing authorisation
requirements– Reduce timelines and cost– Reduce subject exposure to investigational
products
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quality topics
safety topics
efficacy topics
multidisciplinary topics
QSEM
ICH Guidelines
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ICH Guidelines• Efficacy topics–Many Guidelines– E6 is the GCP Guideline– E8 General Considerations– E3 is Structure and Content of Clinical Study
Reports
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Introduction to Clinical Trials and GCP
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ICH GCP
• ICH guideline E6• No legal force• Accepted by most
countries now
Subject Safety Data Quality
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JoBurmester.comClinical Research KnowhowICH GCP
1. Glossary2. Principles3. Institutional Review
Board/Independent Ethics Committee
4. Investigator5. Sponsor6. Protocol / amendments7. Investigator’s Brochure8. Essential Documents
Responsibilities
Documentation
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ICH E6 Addendum
• Finalised November 2016• Increased complexity and globalisation• Makes additions but no changes to original
text
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Introduction to Clinical Trials and GCP
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Who is responsible?
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Who is responsible?
• Informed Consent – Investigator• Funding - Sponsor• Medical Care - Investigator• Insurance - Sponsor• Design - Sponsor• Safety assessment - Sponsor
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Update to ICH E6
• Proposals to facilitate– Implementation of new
technologies– Risk Management– Risk Based Monitoring– Focus on critical study elements
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Introduction to Clinical Trials and GCP
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ICH E8 and E6 “Renovation”
• ICH consulting on revision of E8 (General Considerations) and E6
• E8 draft version now available – public meeting 31 October 2019
• E6 also being revised• More information on ICH website
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ICH GCP
Responsibilities
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ICH GCPIRBs & IECs (Chapter 3)
CompositionCollectively have qualifications and experience to review and evaluate
science, medical and ethics.
≥ 5 members; at least 1 non-scientific; at least 1 independent of site.
Responsible for reviewing study to safeguard rights, safety and well-being of trial subjects
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Introduction to Clinical Trials and GCP
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ICH GCPInvestigator (Chapter 4)
• Appropriately qualified & trained– e.g. familiar with Investigator Brochure, GCP, etc.
• Adequate resources • Medical care of subjects• Communication with IRB/IEC• Compliance with protocol
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ICH GCPInvestigator (Chapter 4)
• IMP accountability• Randomisation and unblinding• Informed consent• Maintaining accurate and complete records• Safety reporting• Study termination & final reports
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ICH GCPSponsor (Chapter 5)
May be Pharma company, Investigator, Trust, University etc.
Responsible for funding and management of study
Monitor responsibilities included here
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Introduction to Clinical Trials and GCP
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ICH GCPSponsor (Chapter 5)
• QA & QC systems to ensure compliance• Transfer of responsibilities to CRO
– NOTE: Ultimately Sponsor always retains responsibility!
• Medical expertise• Trial design• Trial management, data handling, record keeping, etc.• Investigator selection• Allocation of duties and functions• Compensation to subjects and investigators• Financing
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ICH GCPSponsor (Chapter 5)
• Notification/submissions to regulatory authorities• Confirmation of review by IEC/IRB• Information on IMP• Manufacture, packaging, labelling and coding of IMP• Supply and handling of IMP• Record access• Safety information• ADR reporting• Monitoring
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JoBurmester.comClinical Research KnowhowICH GCP - Sponsors (Chapter 5)
Monitoring:– Purpose :• Subjects are protected• Trial data are accurate, complete &
verifiable• Trial conduct in compliance with
approved protocol, GCP, etc.
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Introduction to Clinical Trials and GCP
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• Ultimate responsibilities– Sponsor
• Funding• Regulatory requirements
• Ensuring Protocol, GCP and GMP compliance
– Investigator• Trial Conduct at site• Subject safety and wellbeing
• Can delegate task but not responsibility• Need very clear documentation
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JoBurmester.comClinical Research KnowhowExercise
• Thinking about the list of sponsor responsibilities how do you think the sponsor can demonstrate oversight of the trial?
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JoBurmester.comClinical Research KnowhowICH GCP
• Essential Documents– Protocol and Amendments
• How the study is to be conducted – Investigator’s Brochure
• All about the investigational product
– Trial Master File/ Investigator Site File• All documentation and
correspondence– CRF
• Where all the study data are recorded
“If it’s not documented it didn’t happen!”
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Introduction to Clinical Trials and GCP
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CONTRACTING TO CROS
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Contracts
• SOP for preparation, review and execution– Who is responsible– Requirement for clear delegation– Required standards of service– Contract should not take precedence over the protocol– Process for vendor subcontracting– How safety information will be provided– QC checks for contract
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Contracts
• Allocation of duties clearly stated– All aspects of trial and site management e.g.
• SOPs to be used• TMF and archiving – incl transfer of ownership• Reporting of Serious Breaches• Responding to inspection findings
• Sponsor can delegate tasks/duties but not responsibility
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Introduction to Clinical Trials and GCP
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Contracts
• Ongoing contract management needed• Current contract• Awareness of contract obligations• Contract Expiry• Contract extension/amendment
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RISK ASSESSMENT AND MANAGEMENT
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Risk Assessment
• What factors might affect the risks in a clinical trial?
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Introduction to Clinical Trials and GCP
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Risk Assessment• Critical processes and data identified
What processes will give us the data?
What data do we need to reach the key endpoints
What are the key endpoints?
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Risk AssessmentIdentify
Evaluate
Control/plan
Communicate
Review
Report
Likelihood
Impact
Detectability
Key Risk Indicators
Quality Tolerance Limits
KRIs
QTLs
Escalation
Mitigation Escalation
Mitigation
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SAFETY REPORTING
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Introduction to Clinical Trials and GCP
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Safety Review
• Ongoing risk benefit– Animal toxicology– Adverse event reporting– Efficacy review
• Annual Report – DSUR–Within 60 days of IDBD– All research related events– ICH E2F
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Adverse Event Reporting
• AE• ADR• SAE• SSAR• SUSAR• DSUR
Adverse Event: Any untoward medical occurrence which happens to a participant in a clinical trial, regardless of
relationship to test productAdverse Drug Reaction: An AE which
has a causal relationship to test productSerious AE:
FatalLife threateningHospitalisation
Congenital anomalyDisbabling/Incapacitating
Suspected Serious Adverse Reaction
Suspected Unexpected Serious Adverse ReactionEXPEDITED REPORTING
Development Safety Update Report:Annual report of all safety information related to research
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Adverse Event Reporting
• Case Studies
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Introduction to Clinical Trials and GCP
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SERIOUS BREACHES
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• Notification of Serious Breaches– Sponsor to notify licensing authority in writing of
serious breaches of GCP or the Protocol within 7 days of becoming aware
– Serious breach is one which is likely to significantly affect the wellbeing of subjects or the scientific value of the trial.
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Serious Breach?
• One subject was administered 6 additional doses of IMP. The subject was to receive IMP on day 1 and 8 but instead received IMP on days 1 to 8. The subject experienced a severe adverse event as a result.
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Introduction to Clinical Trials and GCP
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Serious Breach?
• A subject took IMP that had expired two days ago. The subject did not experience any adverse events and this issue was not likely to affect the data credibility of the trial.
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JoBurmester.comClinical Research KnowhowSummary
• Drug Development and Clinical Trial Phases • Approvals required• ICH GCP (R2) Introduction • o Principles of Good Clinical Practice
o Key Responsibilities for Clinical Trialso Contracting to CROs – key considerations
• Risk Assessment and Management • Safety Reporting and Serious Breaches
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Thank you!• Exam• Certificates• Additional Resources• Feedback
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