1. Basics of ICH-GCP, Good Clinical Practice
Yves Geysels, PhD and Martijn Griep, PhD
Symposium Klinische Studies; ervaringen van onderzoekers,
KULeuven Campus Kortrijk
October 11, 2012
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2. Agenda
1 of 2
• What is ICH GCP?
– Origins/History of GCP
– Principles of ICH GCP
• Starting the Clinical Trial
– Clinical Trial Process
– Protocol and Protocol Amendments
– Investigator’s Brochure
– Ethics Committee
– Selecting the Investigator
• Responsibilities of the Clinical Investigator
– Informed Consent
3. Agenda
2 of 2
• Responsibilities of the Sponsor
• Safety Reporting
– Investigator and Sponsor
• Credible and Accurate Data
– Investigator and Sponsor
• Compliance
– Monitoring
– Auditing
• Role of the Regulatory Authorities
• Conclusion
5. Good Clinical Practice is …
“an international ethical and scientific quality
standard for designing, conducting, recording,
and reporting trials that involve the participation
of human subjects”
Provides assurance that:
• clinical trial data are credible and accurate
• trial subjects’ rights, integrity and
confidentiality are protected
GCP
6. Patient Protection:
Drug disasters, fraud, abuse of rights
• Sulphanilamide incident 1938 Drug laws introduced to
(1937) regulate safe manufacturing of
drugs
• Nuremberg War Crimes Trial 1949 Nuremberg Code: required
voluntary “informed consent”
• Tuskegee study (syphilis) 1979 Belmont report: interest of
(1932 – 1972) individual is above interest of
society
• Thalidomide (birth defects) 1962 Kefauver Amendments:
prove drugs are both safe and
effective
7. World Medical Association (WMA)
Declaration of Helsinki
• Adopted by the 18th WMA general assembly,
Helsinki - June 1964
• Established ethical principles for medical
research involving human subjects
• Informed consent must be documented
• Independent review of protocol by ethics
committee (IRB/IEC*)
*IRB - Institutional Review Board / IEC- Independent Ethics Committee.
8. Declaration of Helsinki
• October 2000 - latest revision from 52nd WMA
General Assembly, Edinburgh
• Clarifications 2002 and 2004:
– Placebo controlled trials now appropriate to
conduct in some cases (benefit > risk)
– Sponsor should address how subjects will be
treated after study termination
– Ability of country to afford medication (i.e. AIDs
trials in Africa)
• WMA updated last in October 2008
9. European Union GCP - History
• 1960s: Concept of GCP in EU countries focused on
ethical responsibility of the
clinical investigator
• Sept 1991: EC Directive 91/507/EEC
• May 2001: EC Directive 2001/20/EC
• April 2005: EC Directive 2005/28/EC
10. The Need to Harmonize
What is ICH GCP?
The International Conference on Harmonisation of Technical
Requirements for the Registration of Pharmaceuticals for
Human Use
1990 – ICH established with government and pharmaceutical
industry representatives from USA, EU and Japan
WHO, Canadian Health Board and European Free Trade
Association observed proceedings
Set up to improve efficiency of the process for developing and
registering new medicinal products
11. ICH GCP = foundation of all practices
Local
Working
Practices
Sponsor/Institution/Investigator
Specific Guidelines
Sponsor/Institution/Investigator
Local Laws
Country and/or State Specific
Good Clinical Practice
12. ICH GCP
1. Glossary
2. Principles of ICH GCP
3. Responsibilities of ethics committees/institutional review
boards (IEC/IRB)
4. Responsibilities of the Investigator
5. Responsibilities of the Sponsor
6. Clinical Trial Protocol and Protocol Amendments
7. Investigator’s Brochure
8. Essential Documents for the Conduct of a Clinical Trial
13. Basic Principles of ICH GCP
1 of 2
1. Studies conducted according to Declaration of
Helsinki and GCP
2. Anticipated benefits must justify the risk
3. Subjects rights, safety and well being come first
4. Adequate information available to support the
proposed study
5. Protocol – scientifically sound, clearly described
and detailed
6. Ethical committee approval
7. Qualified physician responsible for medical care
and decisions
14. Basic Principles of ICH GCP
2 of 2
8. All individuals involved – qualified by education,
training and experience
9. Freely given fully informed consent
10. Accurate reporting, interpretation and verification of
data
11. All records to be confidential
12. Products manufactured to GMP (Good Manufacturing
Practice) and used only according to the protocol
13. Systems with procedures that assure quality of every
aspect to be implemented
15. Objectives of the ICH GCP Guideline
• Protect the subject/patient
– Approval by IRB/IEC
– Informed consent
– Qualified Physician responsible for medical care and decisions
– Assessment of safety information
– Confidentiality
– Compensation for trial related injury
• Ensure credible/accurate data
– Provide a unified standard (specifically for EU, USA, Japan)
– Enhance the mutual acceptance of clinical data by regulatory
authorities
16. Investigator Responsibilities
1 of 4
• (4.1) Qualifications and agreements
• (4.2) Have adequate resources
• (4.3) Medical care of trial subjects
• (4.4) Communicate with the ethics committee
• (4.5) Comply with the protocol
• (4.6) Be accountable and manage the investigational
product as per sponsor’s instructions including explaining
use to subject
17. Investigator Responsibilities
2 of 4
• (4.7) Follow randomisation procedures and unblinding
• (4.8) Informed consent of subjects
• (4.9) Records and reports
• (4.10) Progress reports
• (4.11) Safety reporting
• (4.12) Premature termination or suspension
• (4.13) Final report
18. Credible and Accurate Data
Records
• Investigator should ensure the accuracy, completeness, legibility,
and timeliness of the data
• Data on CRF are derived from and consistent with source
documents
• Change or correction to CRF should be dated, initialled, and
explained, if necessary
– not obscure original entry
– audit trail maintained
19. ALCOACCEA
• Accurate: all data required are captured and data are captured in a consistent manner.
• Legible: readable at the input and output stage in a form meaningful to an independent
reviewer
• Contemporaneous: the recording of a clinical observation is made at the same time as
when the observation occurred.
• Original: this must be the first record made by the appropriate person.
• Attributable: the person undertaking the action should be recorded by the system
(Unique user identification is necessary). It is important that electronic data are
time/date stamped when the data are created/generated.
• Complete and consistent: it should be possible to fully reconstruct the activities
performed, changes should be traceable. There should only be one source defined at
any time for any data element.
• Enduring, Available when needed: protected from destruction, continue to be available,
readable and understandable by a human being when required.
(European Medicines Agency, 09 June 2010, Reflection paper on expectations for
electronic source data and data transcribed to electronic data collection tools in clinical
trials )
20. Delegation
• It is common practice for investigators to delegate certain study-
related tasks to
– employees,
– colleagues, or
– other third parties (individuals or entities not under the direct
supervision of the investigator).
• When tasks are delegated by an investigator, the investigator is
– responsible for providing adequate supervision of those to
whom tasks are delegated.
– accountable for regulatory violations resulting from failure to
adequately supervise the conduct of the clinical study.
21. FDA assessment of adequacy of
supervision by an investigator
• FDA focuses on four major areas:
1. whether individuals who were delegated tasks were qualified to
perform such tasks,
2. whether study staff received adequate training on how to
conduct the delegated tasks and were provided with an
adequate understanding of the study,
3. whether there was adequate supervision and involvement in
the ongoing conduct of the study, and
4. whether there was adequate supervision or oversight of any
third parties involved in the conduct of a study to the extent
such supervision or oversight was reasonably possible.
22. Documentation of qualification
• The investigator should maintain a list of the appropriately
qualified persons to whom significant trial-related duties
have been delegated.
1. describe the delegated tasks,
2. identify the training that individuals have received that
qualifies them to perform delegated tasks, and
3. identify the dates of involvement in the study.
23. Adequate Supervision of the Conduct
of an Ongoing Clinical Trial
Level of supervision:
– Sufficient time
– A plan for supervision and oversight, even for highly
qualified individuals.
ISSUES noted in trials with
Inexperienced study staff
Demanding workload for study staff
Complex clinical trials (e.g., many observations, large amounts of data
collected)
Large number of subjects enrolled at a site
A subject population that is seriously ill
Conducting multiple studies concurrently
24. Protocol Violations that Present
Unreasonable Risks
• There are occasions when a failure to comply with the protocol may be
considered a failure to protect the rights, safety, and welfare of subjects
because the non-compliance exposes subjects to unreasonable risks.
– For example, failure to adhere to inclusion/exclusion criteria that are specifically
intended to exclude subjects for whom the study drug or device poses
unreasonable risks (e.g., enrolling a subject with decreased renal function in a trial
in which decreased function is exclusionary because the drug may be
nephrotoxic) may be considered failure to protect the rights, safety, and welfare of
the enrolled subject.
• Similarly, failure to perform safety assessments intended to detect drug
toxicity within protocol-specified time frames (e.g., CBC for an oncology
therapy that causes neutropenia) may be considered failure to protect the
rights, safety, and welfare of the enrolled subject.
• Investigators should seek to minimize such risks by adhering closely to the
study protocol.
25. Peer Reviewed study
• Haeusler, Jean-Marc C. “Certification in good clinical
practice and clinical trial quality: A retrospective analysis
of protocol adherence in four multicenter trials in the
USA.” Clinical Research and Regulatory Affairs, 2009;
26 (1-2), pp20-23.
Assess the impact of formal training in GCP on the
quality of clinical trials
Quality Endpoint = # Protocol Deviations
Methodology= Retrospective Analysis of 4 U.S.
Multicenter Trials
26. Odds Ratio (OR) of Protocol Deviations
Compared To No Certified PI or CRC
• OR = 1.20 • OR = 0.70 • OR = 0.37
• 95% • 95%Confidence • 95%
Confidence • [0.513–0.953] Confidence
• [0.852–1.688] • p = 0.0256 • [0.273–0.507]
• p = NS • p < 0.0001
CCRC CCRC and
Only CPI Only CPI
27. Profile of Ideal site, practical
• Facilitating and encouraging clinical trials
• Added value to make clinical trials visible
• Realistic and timely estimate of feasibility
• Suitable medical records
• Principal investigator is project manager and has
adequately delegated the tasks
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28. Profile of Ideal site, practical
• Timely detection of staff changes
• Backups for critical functions
• Perform only tasks for which staff is trained
• Adequate temperature control for medication storage
• Validation of equipment
• Realistic recruitment plan taking into account inclusion
criteria
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29. Profile of Ideal site, practical
• For each inclusion criterium clear how it is assessed and
documented
• Traceability of inclusion criteria in medical file
• Carefull handling of SUA reports
• Insight in the protocol and how assessments are
performed by whom, how and when
• Anticipate potential protocol deviations
• Compy with protocol even if it differes from routine
medical care
• Planning and follow up of subject visits
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30. Profile of Ideal site, practical
• Ensure all SAEs are detected and notified within 24
hours
• Deficitions of clinical significance according to protocol
and GCP
• 24 hour reachability for urgent medical questions and
deblinding
• Availability during monitoring visits
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31. Profile of Ideal site, practical
• Understanding international environment
• Proactive approach and collaboration
• Acceptance of global competitive recruitment
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33. ICH GCP
• Guidance that describes the responsibilities and
expectations of all participants in the conduct of
clinical trials, including investigators, monitors,
sponsors and ethics committees.
• Guidance that cover aspects of monitoring, reporting
and archiving of clinical trials and incorporating
addenda on the Essential Documents and on the
Investigator's Brochure
34. ICH GCP Objectives
SOPs ICH GCP
Protection of Credibility and reliability of
trial subjects study data
35. EMA Requirements for Electronic
Source Document
Attributable
Legible
Contemporaneous ALCOA
Original
ALCOACCEA
Accurate
Complete
Consistent
Enduring
Available when needed
