Basics of ICH-GCP, Good Clinical Practice Yves Geysels, PhD and Martijn Griep, PhDSymposium Klinische Studies; ervaringen van onderzoekers,KULeuven Campus KortrijkOctober 11, 2012 1
Agenda1 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
Agenda2 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
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
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
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.
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
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
The Need to Harmonize What is ICH GCP?The International Conference on Harmonisation of TechnicalRequirements for the Registration of Pharmaceuticals forHuman 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
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
ICH GCP1. Glossary2. Principles of ICH GCP3. Responsibilities of ethics committees/institutional review boards (IEC/IRB)4. Responsibilities of the Investigator5. Responsibilities of the Sponsor6. Clinical Trial Protocol and Protocol Amendments7. Investigator’s Brochure8. Essential Documents for the Conduct of a Clinical Trial
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
Basic Principles of ICH GCP 2 of 28. All individuals involved – qualified by education, training and experience9. Freely given fully informed consent10. Accurate reporting, interpretation and verification of data11. All records to be confidential12. Products manufactured to GMP (Good Manufacturing Practice) and used only according to the protocol13. Systems with procedures that assure quality of every aspect to be implemented
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
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
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
Credible and Accurate DataRecords• 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
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 )
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.
FDA assessment of adequacy ofsupervision 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.
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.
Adequate Supervision of the Conductof 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
Protocol Violations that PresentUnreasonable 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.
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
Odds Ratio (OR) of Protocol DeviationsCompared 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
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 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 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 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 31
Profile of Ideal site, practical • Understanding international environment • Proactive approach and collaboration • Acceptance of global competitive recruitment 32
Summary - Conclusion Summary / Conclusion Basics of ICH-GCP
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 Investigators Brochure
ICH GCP Objectives SOPs ICH GCP Protection of Credibility and reliability of trial subjects study data
EMA Requirements for ElectronicSource DocumentAttributableLegibleContemporaneous ALCOAOriginal ALCOACCEAAccurateCompleteConsistentEnduringAvailable when needed