intro to cr and gcp handout - joburmester.com

Introduction to Clinical Trials and GCP

© JoBurmester.com 2020 1

JoBurmester.comClinical Research Knowhow

Clinical Trials

June 2020

Course Tutor: Jo Burmester

1

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

2


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

3




The Clinical Trial Process

4


The Drug Development Process

• From molecule to market place…

Identification

In vitro research

Pre-clinical research

Clinical development

Marketed product

5


Clinical Development Phases & Types of Clinical Trial

• Phase I• Phase II• Phase III – a and b• Phase IV• PASS/PAES• Post Marketing Observational• Epidemiology

6




Clinical Trial Processes

7


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

8


ICH GCP

BackgroundContents

Responsibilities of Ethics Committees, Sponsors & InvestigatorsEssential documents

9



JoBurmester.comClinical Research KnowhowICH

• International Council on Harmonisation• US, EU and Japan• Purpose:– Harmonise marketing authorisation

requirements– Reduce timelines and cost– Reduce subject exposure to investigational

products

10


quality topics

safety topics

efficacy topics

multidisciplinary topics

QSEM

ICH Guidelines

11


ICH Guidelines• Efficacy topics–Many Guidelines– E6 is the GCP Guideline– E8 General Considerations– E3 is Structure and Content of Clinical Study

Reports

12




ICH GCP

• ICH guideline E6• No legal force• Accepted by most

countries now

Subject Safety Data Quality

13

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

14


ICH E6 Addendum

• Finalised November 2016• Increased complexity and globalisation• Makes additions but no changes to original

text

15




Who is responsible?

16


Who is responsible?

• Informed Consent – Investigator• Funding - Sponsor• Medical Care - Investigator• Insurance - Sponsor• Design - Sponsor• Safety assessment - Sponsor

17


Update to ICH E6

• Proposals to facilitate– Implementation of new

technologies– Risk Management– Risk Based Monitoring– Focus on critical study elements

18




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

19


ICH GCP

Responsibilities

20


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

21




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

22


ICH GCPInvestigator (Chapter 4)

• IMP accountability• Randomisation and unblinding• Informed consent• Maintaining accurate and complete records• Safety reporting• Study termination & final reports

23


ICH GCPSponsor (Chapter 5)

May be Pharma company, Investigator, Trust, University etc.

Responsible for funding and management of study

Monitor responsibilities included here

24





• 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

25



• 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

26

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.

27




• 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

28

JoBurmester.comClinical Research KnowhowExercise

• Thinking about the list of sponsor responsibilities how do you think the sponsor can demonstrate oversight of the trial?

29


• 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!”

30




CONTRACTING TO CROS

31


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

32


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

33




Contracts

• Ongoing contract management needed• Current contract• Awareness of contract obligations• Contract Expiry• Contract extension/amendment

34


RISK ASSESSMENT AND MANAGEMENT

35


Risk Assessment

• What factors might affect the risks in a clinical trial?

36




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?

37


Risk AssessmentIdentify

Evaluate

Control/plan

Communicate

Review

Report

Likelihood

Impact

Detectability

Key Risk Indicators

Quality Tolerance Limits

KRIs

QTLs

Escalation

Mitigation Escalation

Mitigation

38


SAFETY REPORTING

39




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

40


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

41


Adverse Event Reporting

• Case Studies

42




SERIOUS BREACHES

43

JoBurmester.comClinical Research Knowhow1928

• 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.

44


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.

45




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.

46

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

47


Thank you!• Exam• Certificates• Additional Resources• Feedback

48