Overview of Good Clinical Practices (GCPs)

1. Overview of Good Clinical Practices (GCPs) Barbara Pennington, RN, MS PPD

2. Why Regulate Clinical Research? • Ensure the rights, safety, and well-being of participants • Scientific Integrity of data

3. Good Clinical Practices (GCPs) Standards for designing, conducting, performing, monitoring, auditing, recording, analyzing, and reporting clinical trials.

4. GCP FDA OHRP ICH 21 CFR 45 CFR 46 International • Electronic Docs. • Inf. Consent • $ Disclosure • IRBs • IND regs. • IRBs • Inf. Consent • Women • Prisoners • Children • glossary • principles • IRBs • Investigator • Sponsor • Essential Docs

5. U.S. FDA(Food and Drug Administration) • Branch of the United States Department of Health and Human Services • Regulates all aspects of pharmaceutical industry • Title 21 of the Code of Federal Regulations (CFR)

6. CFR Title 21 Parts applicable to clinical research: • Part 11 - Electronic Records and Signatures • Part 50 - Protection of Human Subjects • Part 54 - Financial Disclosure by Clinical Investigators • Part 56 - Institutional Review Boards • Part 312 - Investigational New Drug Application • Part 314 - Applications for FDA Approval to Market a New Drug or an Antibiotic Drug • Part 600 - Biological Products • Part 812 - Medical Devices

7. Form FDA 1572 • Contract between FDA and Investigator • Logistics such as names and addresses • Section 9 • Commitments of the Investigator

8. Investigator of Record (IOR) Agreement • For Non-IND studies • Identifies key personnel, facilities, labs, IRBs • Also lists the commitments of the investigator

9. Commitments of the IOR • Comply with protocol • Ensure compliance of IRB and consent process with 45CFR 46 • Report AEs • Accurate record keeping and access • No changes to study without permission of Sponsor and IRB

10. This is a Non-IND Study • Do we have to worry about FDA?

11. Office for Human Research Protections (OHRP) • OHRP responsible for ensuring the safety and welfare of people who participate in HHS sponsored research • Under the DHHS Assistant Secretary of Health • 45 CFR part 46 • Formerly OPRR

12. 45 CFR part 46 • IRB • Informed Consent • Protection of Fetuses, Pregnant Women • Protection of Prisoners • Protection of Children

13. 45CFR 46 Subpart A • The “Common Rule” • Protection of Human Subjects • IRB/IEC • Informed Consent • Variations from FDA Regulations

14. 45CFR 46 Subpart B • Protections for Pregnant Women, Fetuses and Neonates • Definitions • Recent revisions

15. 45CFR 46 Subpart C • Additional Protections for Prisoners involved in research • Definition of Prisoner • Additional IRB Duties • Permitted Research

16. 45CFR 46 Subpart D • Additional Protections for Children involved in Research • Assent • Minimal risks

17. International Conference on Harmonisation (ICH) Guidelines for Good Clinical Practices

18. Objectives of ICH guidelines • Provide a unified standard • EU; US; Japan • To facilitate mutual acceptance of clinical data • Developed in accordance with existing standards in US, EU, Japan, Australia, Canada, Nordic Countries, and WHO

19. ICH GCP Consolidated Guideline E6 • Glossary • Principles of ICH GCP • Information regarding: • IRB/IEC • Investigator • Sponsor • Protocol • Investigator’s Brochure • Essential Documents

20. Principles of ICH GCP • Conduct trials according to GCP • Weigh risks vs. benefits • Protect the subjects • Have adequate information to justify trial • Write a sound protocol • Receive IRB/IEC approval • Use qualified physicians

21. Principles of ICH GCP • Use qualified support staff • Obtain informed consent • Record information appropriately • Protect confidentiality • Handle investigational products appropriately • Implement quality systems

22. Local Regulations • May have more detailed regulations that apply locally • Do not conflict with national regulations

23. Sponsor Policies • US Department of Health and Human Services • NIH/DAIT/DAIDS • Essential Document and Source Document SOP

24. Internal SOPs Standard Operating Procedures (SOPs) • Detailed instructions describing the what, when, where, and by whom of performing an activity

25. Compliance = • Adherence to • GCPs • Sponsor policies • local regulations

26. Investigator Responsibilities

27. Investigator Responsibilities* • Investigator Qualifications and Agreements • qualified by education, training and experience • familiar with protocol, IB, IP • aware of and compliant with GCPs and applicable regs • permit monitoring • list of qualified personnel who are delegated duties • *(ICH 4.1-9)

29. Investigator Responsibilities* • Adequate Resources • recruit adequate subjects • sufficient time • qualified staff and adequate facilities • Medical Care of Subjects • responsible for all trial related medical decisions • *(ICH 4.1-4.9)

30. Investigator Responsibilities* • Communication with IRB • approvals • ensure compliance • Compliance with Protocol • Investigational Product (IP) • proper delegation of duties • *(ICH 4.1-4.9)

31. How can the PI be held responsible for what the IRB does or does not do? Document ALL interaction (verbal, electronic, written) with IRB including reminders of upcoming review requirements

32. Investigator Responsibilities* Regulations require IRB is aware of changes in research activity “…OHRP finds that changes to research protocol were implemented by investigators without IRB approval…”

33. Investigator Responsibilities* • Randomization & Unblinding • Informed Consent • Records and Reports • ensure accuracy, completeness, legibility and timeliness of data • data on CRF derived from Source Documents • changes made appropriately • allow direct access • *(ICH 4.1-4.9)

34. Regulatory Authorities will inquire about: • Source of study subjects • Did they have the disease under study • Did they meet inclusion/exclusion criteria • Was the protocol precisely followed • Were AEs reported appropriately

35. Common OHRP Findings • IRB failed to review the research at a convened meeting • failure to review grant applications • Investigators failed to promptly report unanticipated problems involving risks to subjects to IRB, OHRP and Sponsor

36. Common OHRP Findings • Continuing review of research was NOT substantive nor meaningful • include a summary of AEs and unanticipated problems • # of subjects accrued • summary of recent literature, findings amendments, modifications since last review • relevant reports, information • current consent form

37. Common OHRP Findings • IRB did not ensure additional protections for vulnerable subjects • IRB members with conflicting interest participated in review • IRB meeting convened without Quorum (Non-scientist absent)

38. Common OHRP Findings • IRB review of NIH approved consent • any changes to the sample consent form related to risks or alternative procedures must be justified in writing by the investigator, approved by IRB and reflected in the IRB minutes

39. OHRP Finds that the IRB: • Lacks diversity • is overburdened by large volume • level of staff support is insufficient • members lack detailed understanding of regs. for protection of human subjects • inadequate procedures for reporting of unanticipated problems

40. We Applaud COMPLIANCE • GCPs • Protocol • DAIT/DAIDS procedures • Local regulations