1. Thierry Le Chevalier, MD Good Clinical Practice Compliance

2. Objectives Discuss the importance of good clinical practice compliance in clinical trials Review current guidelines on good clinical practice Share practical insights and best practices

3. What Is Good Clinical Practice? Good Clinical Practice (GCP) is an international ethical and scientific quality standard for designing, conducting, recording, and reporting trials that involve human subjects Goals/purpose is to –Protect the rights, safety, and well-being of trial subjects –Ensure the quality and integrity of data obtained from clinical testing ICH Official.1996.

4. Evolution of GCP Leading to the International Conference on Harmonisation (ICH) CPMP = Committee for Proprietary Medicinal Products; GCP = Good Clinical Practices; EEC = European Economic Community; ICH = International Conference on Harmonisation; CIOMS = Council for International Organizations of Medical Sciences. Otte. Nucl Med Commun. 2005.

5. The International Conference on Harmonisation (ICH) The guideline was developed with consideration of the current good clinical practices of the European Union, Japan, and the United States, as well as those of Australia, Canada, the Nordic countries and the World Health Organization (WHO) ICH Official.1996. The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use is unique in bringing together the regulatory authorities and pharmaceutical industries of Europe, Japan and the US to discuss scientific and technical aspects of drug registration Establishment of global guidelines on GCP

6. GCP Adoption in Select Asian Countries CountryYear* Original ICH-GCP Guidelines1996 Singapore GCP1998 Chinese GCP1999 Malaysian GCP1999, revised 2004 Thailand2000 Indonesia2001 *Guidelines based on the framework of the original ICH-GCP guidelines. Vijayananthan. Biomed Imaging Interv J. 2008.

7. Which Trials Do the GCP Principles Apply To? All trials on medicinal products for human use –Not only drug development clinical trials (phases I–III) but also to trials involving medicinal products that are already registered on the market (phase IV) ICH Official.1996. Jørgensen. Basic Clin Pharmacol Toxicol. 2004;94:57-58.

8. Core Principles of GCP

9. ICH-GCP: 13 Core Principles 1 Adhere to ethical principles 2 Risk minimisation 3 Subjects’ welfare and rights 4 Study drug information 5 Scientifically sound protocols 6 IRB/IEC review and approval and protocol adherence 7 Qualified physician involved with subject care 8 Research personnel qualification 9 Voluntary informed consent 10 Study data integrity 11 Confidentiality of records 12 Study drug manufacturing standards 13 Quality assurance systems IRB/IEC = institutional review boards/independent ethics committees. Fromell. Hum Gene Ther. 2008;19:431-440. ICH Official.1996.

10. ICH-GCP: 13 Core Principles (1/13) Clinical trials should be conducted in accordance with ethical principles that have their origin in the Declaration of Helsinki and that are consistent with GCP and the applicable regulatory requirement(s) 1 Adhere to ethical principles ICH Official.1996.

11. Before a trial is initiated, foreseeable risks and inconveniences should be weighed against anticipated benefit for the individual trial subject and society. A trial should be initiated and continued only if the anticipated benefits justify the risks 2 Risk minimisation ICH-GCP: 13 Core Principles (2/13) ICH Official.1996.

12. The rights, safety and well-being of the trial subjects are the most important considerations and should prevail over interest of science and society 3 Subjects’ welfare and rights ICH-GCP: 13 Core Principles (3/13) ICH Official.1996.

13. The available non-clinical and clinical information on an investigational product should be adequate to support the proposed clinical trial 4 Study drug information ICH-GCP: 13 Core Principles (4/13) ICH Official.1996.

14. Clinical trials should be scientifically sound and described in clear, detailed protocol 5 Scientifically sound protocols ICH-GCP: 13 Core Principles (5/13) ICH Official.1996.

15. A trial should be conducted in compliance with the protocol that has received prior institutional review board (IRB)/independent ethics committee (IEC) approval/favourable opinion 6 IRB/IEC review and approval and protocol adherence ICH-GCP: 13 Core Principles (6/13) ICH Official.1996.

16. The medical care given to and medical decisions made on behalf of subjects should always be the responsibility of a qualified physician or, when appropriate, of a qualified dentist 7 Qualified physician involved with subject care ICH-GCP: 13 Core Principles (7/13) ICH Official.1996.

17. Each individual involved in conducting a trial should be qualified by education, training, and experience to perform his or her respective task(s) 8 Research personnel qualification ICH-GCP: 13 Core Principles (8/13) ICH Official.1996.

18. Freely given informed consent should be obtained from every subject prior to clinical trial participation 9 Voluntary informed consent ICH-GCP: 13 Core Principles (9/13) ICH Official.1996.

19. All clinical trial information should be recorded, handled, and stored in a way that allows its accurate reporting, interpretation and verification 10 Study data integrity ICH-GCP: 13 Core Principles (10/13) ICH Official.1996.

20. The confidentiality of records that could identify subjects should be protected, respecting the privacy and confidentiality rules in accordance with the applicable regulatory requirement(s) 11 Confidentiality of records ICH-GCP: 13 Core Principles (11/13) ICH Official.1996.

21. Investigational products should be manufactured, handled and stored in accordance with applicable Good Manufacturing Practice (GMP). They should be used in accordance with the approved protocol 12 Study drug manufacturing standards ICH-GCP: 13 Core Principles (12/13) ICH Official.1996.

22. ICH-GCP: 13 Core Principles (13/13) Systems with procedures that assure the quality of every aspect of the trial should be implemented 13 Quality assurance systems ICH Official.1996.

23. Mechanisms to Ensure GCP

24. Procedures to Ensure the Adherence of GCP Guidelines IRB/IEC review and approval of the trial protocol and other materials Freely obtained informed consent from each subject Safety monitoring requirements Data handling and record keeping Clinical trial responsibilities of the IRB/IEC, investigator and sponsor GCP ICH Official.1996.

25. IRB/IEC “An IRB/IEC should safeguard the rights, safety, and well-being of all trial subjects. Special attention should be paid to trials that may include vulnerable subjects.” IRB/IEC = Institution review board/independent ethics committee. ICH Official.1996.

26. IRB/IEC Composition and Function IRB/IEC = Institution review board/independent ethics committee. Fromell. Hum Gene Ther. 2008;19:431-440. ICH Official.1996. Membership composition At least 5 members At least one member whose primary interest is in a non-scientific area At least one member who is independent of the institution/trial site Only members independent of the research sponsor or investigator may vote on trial-related matters Documents for review Protocol and all amendments Written informed consent form and all updates Subject recruitment procedures, including advertisements Written information to be provided to subjects Investigator’s Brochure Available safety information Information on payments or compensation to subjects Investigator qualifications (including CV and other relevant information) Any other documents the IRB/IEC requires to fulfil its responsibilities Review outcomes Approval or favourable opinion Modifications to the research prior to its approval/favourable opinion Disapproval or negative opinion Termination or suspension of any approval/favourable opinion Record keeping (to be kept at least 3 years after trial completion) Standard operation procedures Membership list Lists of occupation/affiliation of members Submitted documents Meeting minutes Correspondence

27. Ensures the protection of trial subjects according to the ethical principles outlined in the Declaration of Helsinki Informed Consent ICH Official.1996. Otte. Nucl Med Commun. 2005.

28. Informed Consent in Various Phases of a Clinical Trial –IRB/IEC approval of consent form –Consent procedures for the emergency case –No influence to enroll –Attention to language of oral and written information –Full information on all aspects of trial –Subject must agree to authorised review of confidential information –Subject must understand they can withdraw at any time –Consent must be documented by dated signature of subject and person conducting informed consent discussion –Subject must receive copy of signed and dated consent form –Consent form must be revised and approved by IRB/IEC –Relevant information must be provided on ongoing trial participants Pre-trial At recruitment Prior to trial During trial in case of important new information ICH Official.1996. Otte. Nucl Med Commun. 2005.

29. Monitoring “The act of overseeing the progress of a clinical trial, and of ensuring that it is conducted, recorded, and reported in accordance with the protocol, Standard Operating Procedures (SOPs), Good Clinical Practice (GCP), and the applicable regulatory requirement(s).” Purpose –The purpose of trial monitoring is to verify that The rights and well-being of human subjects are protected The reported trial data are accurate, complete, and verifiable from source documents The conduct of the trial is in compliance with the currently approved protocol/amendment ICH Official.1996.

30. Safety Monitoring The protocol should provide -Specification of safety parameters -Procedures for eliciting reports of, and for recording and reporting, adverse events and intercurrent illnesses -The methods and timing for assessing, recording and analysing safety parameters -The type and duration of the follow-up of subjects after adverse events Includes monitoring, recording, and managing of all adverse events during the course of the study, including serious adverse events and previously unknown events ICH Official.1996. Otte. Nucl Med Commun. 2005.

31. Data Handling and Record Keeping The confidentiality of records that could identify subjects should be protected, respecting the privacy and confidentiality rules in accordance with the applicable regulatory requirement(s) The allocation of responsibilities for record-keeping and handling of data should be specified in the protocol or other written agreement(s) between the sponsor and investigator(s) A basic aspect of the integrity of data is the safeguarding of “blinding” with regard to treatment assignment. It starts with the randomisation of patients into treatment groups and is maintained through all steps of data processing up to the moment when the decision to break the code is formally taken All clinical trial information should be recorded, handled, and stored in a way that allows its accurate reporting, interpretation and verification. ICH Official.1996.

32. Participants of GCP and Their Respective Responsibilities GCP ParticipantsResponsibilities Regulatory Authorities Review submitted clinical data and conduct inspections Sponsor Individual, company, institution or organisation Initiate, manage and/or finance the clinical trial Monitor Usually appointed by sponsor Oversee progress of the trial to ensure that the study is conducted and data are handled in accordance with the protocol, GCP, and applicable ethical and regulatory requirements Investigator Team leader Responsible for conduct of clinical trial Pharmacist at trial location Responsible for maintenance, storage and dispensing of investigational products ICH Official.1996. Vijayananthan. Biomed Imaging Interv J. 2008.

33. Responsibilities of the Investigator - A Closer Look Comply with GCP and applicable regulatory requirements Ensure that he/she understands and can fulfill protocol requirements Submit appropriate documentation to the IRB/IEC, sponsor and relevant authorities Ensure adequate qualified staff and facilities Obtain informed consent from subjects or their legally acceptable representatives Provide all relevant information to study site-staff and subjects Receive and properly manage drug supplies Oversee the rights and well-being of study subjects Collect, record and report data properly and accurately Ensure the confidentiality of all information as appropriate Immediately notify the sponsor, IRB/IEC and regulatory authorities (as appropriate) in the case of serious adverse events Make all trial-related documents available during the study Confirm the integrity of the data Arrange for archiving of appropriate study-related materials ICH Official.1996. Otte. Nucl Med Commun. 2005.

34. Responsibilities of the Sponsor - A Closer Look Maintain written standard operating procedures Agree with the investigator on the protocol and the responsibilities of the trial Select the investigator and site Ensure that appropriate documentation is submitted to regulatory authorities Provide study personnel with all relevant information Oversee proper handling of safety-related events Ensure that appropriate and required reports are prepared Provide compensation, insurance or indemnification (ie, legal and financial coverage) ICH Official.1996. Otte. Nucl Med Commun. 2005.

35. Responsibilities of the Monitor - A Closer Look Ensure all study site-staff have adequate information and facilities to conduct the trial Oversee the protocol, GCP guidelines, and standard operating procedures Coordinate communication between the sponsor and the investigator Verify data and check that informed consent was obtained appropriately Oversee proper handling of clinical supplies Assist the investigator with submission of data to authorities and sponsor Document site visits, phone contacts, and correspondence Ensure confidentiality of subject records Determine if all adverse events and serious adverse events are reported ICH Official.1996. Otte. Nucl Med Commun. 2005.

36. Summary Good Clinical Practice is an internationally recognised standard for the conduct of research involving humans to ensure the rights, safety, and well-being of trial subjects as well as accurate and credible clinical data It is essential to adhere to these GCP principles in conducting clinical trials