Good Clinical Practices and FDA Inspections

1. Good Clinical Practices andFDA Inspections Patricia Holobaugh Chief, Bioresearch Monitoring Branch Division of Inspections and Surveillance Office of Compliance and Biologics Quality

2. Agenda • Define Good Clinical Practices • Describe FDA’s Bioresearch Monitoring Program for on-site inspections of clinical and animal studies • Explain when and how inspections are performed • Describe common deficiencies and what happens after the inspection

3. Good Clinical Practices GCP is a standard for the design, conduct, performance monitoring auditing, recording, analysis, and reporting of clinical trials. www.fda.gov/oc/gcp/

4. Regulations Investigational Application 21 CFR Part 312 IND drugs and biologics 21 CFR Part 812 IDE 21 CFR Part 809 IVD Marketing Application 21 CFR Part 601 BLA biologics 21 CFR Part 314 NDA drugs 21 CFR Part 814 PMA devices

5. Regulations 21 CFR 50 Protection of Human Subjects Informed Consent Safeguards for Children 21 CFR Part 56 Institutional Review Boards 21 CFR Part 11 Electronic Records; Electronic Signatures

6. Examples of GCP Guidance Documents Guideline for Monitoring Clinical Investigations (1998) Information Sheets for IRBs and Clinical Investigators (1998) ICH GCP Consolidated Guideline E6 (1997)

7. Regulations Guidance

8. FDA’s Bioresearch Monitoring Program (BIMO) Clinical Investigators Sponsor/Monitor/Contract Research Organizations Institutional Review Boards Nonclinical Laboratories

9. When are BIMO Inspections conducted? • Submission of BLA / PMA • Referrals from CBER staff • Referrals from other Centers/ORA • Complaints from sponsor, IRBs, and consumers • Routine surveillance of ongoing studies target 50 pediatric sites this FY

10. Profile of CBER BIMO InspectionsFY04-05 (thru 3/9/05) 189 Assignments issued BLA 45 PMA 15 CI surveillance 102 IRB 22 GLP 12 Complaints 12

11. True or False??? Clinical investigator: “I’m only doing phase 1 and 2 studies – I’ll never be inspected by FDA.”

12. True or False??? Clinical investigator: “I’m only doing phase 1 and 2 studies – I’ll never be inspected by FDA.” FALSE Clinical investigators of studies in all phases may (and are) inspected by FDA.... And ALL GCP regulations apply.

13. Cell therapies Gene transfer Vaccines Blood products Devices For FY 2005, we issued assignments to inspect 50 sites enrolling pediatric subjects CBER continues its program toinspect ongoing studies under IND/IDE“Real-time” surveillance of phases 1/2/3

14. History of CBER Surveillance Program • Started in 2000 following Gelsinger’s death in gene therapy study • Expanded to cell therapies, and then to all CBER IND/IDEs

15. Surveillance – Cross-Section of Sponsors (FY00-05) Individuals 64 NIH + DOD 29** Hospitals + universities 11 “Big” companies 48 “Small” companies 84

16. Inspections for BLA / PMAHow Many Sites per BLA/PMA? Usually 3 to 5 study sites ...but sometimes more Will inspect foreign sites when needed: No US study or sites Foreign data are critical

17. Inspections for BLA / PMAFactors in Site Selection • Distribution of subjects • Distribution of subjects whose data are excluded from S&E analyses • Inspection history of investigators • Inconsistent data for one site increased efficacy decreased incidence of adverse events

18. Inspections for BLA / PMAFactors in Site Selection GCP problems reported by sponsor Randomization cannot be reconstructed Number of sub-investigators / sub-sites* Pending workloads in FDA Districts

19. FDA Inspection “101” • Inspections are performed by ORA by specially-trained investigators Center reviewers may participate • Most inspections are pre-announced • Interview: who did what, and how • Review of records • Closing discussion & issue Form FDA 483

20. Comparison of Data in BLA / PMA to Source Data Data in BLA/PMA Sponsor Source Data CRF

21. Where is “Source Data” Defined? NOT defined in 312 or 812 See GLP regs 21 CFR 58.3(k) – “raw data” 21 CFR 58.130(e) – describes how data are to be recorded, corrected, and describes automated systems.

22. Elements of Data Quality = ALCOA Attributable Legible/readable Contemporaneous Original Accurate

23. After the Inspection • Inspected party may respond in a letter - send to address on the Form FDA-483. • May also ask the FDA investigator for the HQ Center address • The inspection report is written by the FDA investigator and sent to the Center.

24. After the Inspection (2) • The Center evaluates the report, and determines the corrective action. • Classifications • NAI – No Action Indicated • VAI – Voluntary Action Indicated • OAI – Official Action Indicated • We write a letter following most inspections

25. Most Common CI Violations Failure to follow the protocol example: Required testing is incomplete Recordkeeping errors Informed consent problems

26. Most Significant Violations • Enrollment of ineligible subjects • Violation of protocol affecting safety • Extensive data corrections and questionable changes • Inadequate oversight of study personnel Inappropriate delegation of authority Poor oversight of satellite sites • No Informed consent • Failure to communicate with IRB

27. Significance of Violations Do the violations ...affect rights, safety, or welfare of subjects? ...directly impact integrity of data set? ...indicate systemic problems within the study? sponsor problems? Did the sponsor report the problems to FDA? ...indicate that other studies at that site might be impacted? investigator problems

28. Inappropriate delegation to subinvestigators Investigator – individual who actually conducts an investigation (i.e., under whose immediate direction the drug is administered or dispensed to subjects. How many miles (or states!) away ???? Sponsor should assure that the CI controls the study

29. Possible Administrative Actions • Warning Letter • Determine if the data are reliable • Complete and accurate? • Delay approval of BLA/PMA • Clinical hold • Disapproval of IDE • Initiate termination of IND • Initiate disqualification of investigator • Initiate Application Integrity Policy • Refer to Office of Criminal Investigations

30. Your Questions for CBER Can case report forms be source documents? Yes – protocol should specify how data are to be captured and records are to be maintained. Are diaries, questionnaires, photos subject to inspection? Yes –these need to be maintained by CI per 21 CFR 312.62(c)

31. Your Questions for CBER What data points should be captured on case report forms? What data should be entered into a database for analysis? Data critical to determining safety and efficacy endpoints. Protocol is roadmap for required tests. Consult FDA review team.

32. Your Questions for CBER Does FDA audit systems & databases to ensure they are validated? FDA does not audit computerized systems for clinical trials. Sponsor is responsible for QA of computerized systems used by the sponsor, and for determining whether systems used by investigator sites are suitable for their study. See FDA Guidance “Computerized Systems Used in Clinical Trials” http://www.fda.gov/ora/compliance_ref/bimo/ffinalcct.htm

33. Your Questions for CBER For clinics without medical records system in place, how should study records and source documents be maintained when subjects participate in one or more studies? Do you recommend that subject source records and health information be maintained in a central file, with study-specific CRFs maintained separately? No regulation for this. Records should be retrievable and meet 312.62(c) retention requirements. Records must be maintained at site if clinical investigator departs. Recommend SOPS explaining how an alternate record system is utilized.

34. If You have GCP Questions...... • Contact CBER’s Bioresearch Monitoring Branch -- Pat Holobaugh 301-827-6347 holobaugh@cber.fda.gov OR • Contact your IND/IDE reviewer