1. Overview of Gene Therapy Surveillance Inspections Joseph P Salewski, Chief Bioresearch Monitoring Branch CBER

2. PURPOSE of BIMO To ensure the quality and integrity of data submitted to FDA in support of a marketing permit (IND, PLA/BLA, IDE, NDA) To ensure the protection of the rights and welfare of research subjects

3. FDA’s BIMO Program Each Center has a BIMO Program staff Program is coordinated by the Office of Regulatory Affairs/ Office of Enforcement Inspections are conducted by ORA field staff, with Center experts as needed

4. Bioresearch Monitoring Compliance Programs CP 7348.808Nonclinical Laboratories CP 7348.809Institutional Review Boards CP 7348.810Sponsors, Monitors/Contract Research Organizations CP 7348.811Clinical Investigators

5. When does BIMO become involved? Submission of PLA/BLA Referrals from CBER staff Referrals from other Centers

6. BIMO Involvement Complaints from Sponsors, IRBs, consumers Routine Surveillance

7. Typical 10 Month Review Cycle Day 0 Day 45 Day 10 Day 300 CBER Receives PLA/BLA Pre-PLA/BLA Meeting 1st Committee meeting Filing letter sent or RTF BIMO review of PLA -prepare assignments Internal Review Clinical and Manufacturing BIMO Inspections EIR’s come in BIMO Summary to Committee ACTION

8. Site Selection Factors Number of subjects at each site Geographical distribution of sites Inspectional history of investigators Inconsistency of data at site Review committee’s concerns

9. Site Selection Factors Number of subjects at each site Geographical distribution of sites Inspectional history of investigators Inconsistency of data at site Review committee’s concerns

10. Assignment Content Background info on study and product Specific concerns/questions of review staff –adverse events –protocol followed –blinding –dosage and schedule –endpoint met?

11. Classifications No Action Indicated (NAI) Voluntary Action Indicated (VAI): –objectionable conditions or practices are found, but the agency is not prepared to take administrative or regulatory action Official Action Indicated (OAI): –regulatory and/or administrative actions will be recommended

12. Correspondence Non-titled letter –for NAI and VAI classifications Titled letters –Warning Letters –Notice of Initiation of Disqualification Proceedings and the Opportunity to Explain

13. Administrative Actions Determination that data is unreliable Refusal to file PLA/BLA Clinical hold Termination of IND Disqualification Initiation of Application Integrity Policy

14. GT Inspections Randomized selection of 30 active INDs out of 211 active INDs Resulted in: 24 Sponsors 70 Clinical Investigators

15. GT Inspections Sponsors: –commercial6 = 25% –government1 = 4.1% –independent17 = 70.8%

16. GT Inspections Clinical Investigators: –commercial46 = 65.7% –government 5 = 7.1% –independent19 = 27.1%

17. GT Inspections Field time expended: –total hours4042.5 hours –range24 hrs to 208 hrs –average74.86 hours/inspection –FTE equivalent4.44 operational FTEs

18. GT Inspections Overall results: –Wash Outs11 = 15.7% –NAI23 = 32.8% –VAI33 = 47.1% –OAI 3 = 4.2%

19. GT Inspections Voluntary Action Indicated: –objectionable conditions or practices are found but the agency is not prepared to take or recommend administrative or regulatory action Official Action Indicated: –regulatory and/or administrative actions will be recommended

20. GT Inspections Commercial sponsors46 CI WO 6 = 13%8.5% overall NAI14 = 30.4%20% " VAI23 = 50%32.8% " OAI 3 = 6.5% 4.2% "

21. GT Inspections Government:5 CIs WO0 NAI3 = 60%4.2% overall VAI2 = 40%2.8% "

22. GT Inspections Independent:19 CIs WO5 = 26.3%7.1% overall NAI6 = 31.5%8.5% " VAI8 = 42.1%11.4% "

23. GT Inspections a comparison NAIVAIOAI GT38%55.9% 5.0% 2000 total30.9%57.1%11.9% 2000w/o GT21.4%60%18.5% 199928.5%54.2%17.1% 199834.9%53%12%

24. GT Inspections The random surveillance inspections of Phase 1 and 2 gene therapy clinical trails indicates that the trials were being properly conducted with fewer deviations than found in Phase 3 studies.

25. GT Inspections most common deficiencies Failure to follow the protocol Inadequate Consent Form Lack of supporting data for CRF entries Discrepancies between source documents and CRFs Inadequate drug accountability records Failure to notify IRB of AEs and deaths Failure to notify IRBs of protocol changes