Managing Clinical Study Processes & Procedures to Facilitate a Successful BIMO Inspection

1. Managing Clinical Study Processes & Procedures to Facilitate a Successful BIMO Inspection Ginger Clasby, MS Promedica International 714-799-1617 x 25 gclasby@promedica-intl.com

2. What is BIMO? • BIoresearch Monitoring Organization established to assure quality & integrity of new product approval data • Reports into Office of Compliance • Program involves comprehensive on-site inspections & data audits

3. General Procedures for BIMO Compliance Program Implementation • ORA Program Guidance Manual References • IRBs – 7348.809 • Sponsors, CROs & Monitors – 7348.810 • Clinical Investigators – 7348.811

4. Entities Involved in FDA-Regulated Research: Study Sponsor • Initiates, but does not actually conduct, the study of a medical product

5. Entities Involved in FDA-Regulated Research: Study Monitor • Designated by sponsor to oversee study progress

6. Entities Involved in FDA-Regulated Research: Study Investigator • Provides immediate direction regarding test product administration to study subjects • If study conducted by a team of individuals, investigator is responsible leader of team

7. Entities Involved in FDA-Regulated Research: IRB • Formally designated committee reviewing biomedical research involving human subjects • Must be established, operated & function in conformance with 21 CFR Part 56 (Institutional Review Boards)

8. Entities Involved in FDA-Regulated Research: Study Subject • Receives test or control product in accordance with study protocol

9. Obligations of Study Sponsors21 CFR 312, 21 CFR 812 • Obtain FDA approval prior to study initiation • Manufacture & label product appropriately • Initiate, withhold, or discontinue clinical trials as required • Refrain from commercialization of product

10. Obligations of Study Sponsors 21 CFR 312, 21 CFR 812 • Control distribution & return of product • Select qualified investigators to conduct studies • Disseminate appropriate information to investigators • Select qualified persons to monitor study conduct

11. Obligations of Study Sponsors 21 CFR 312, 21 CFR 812 • Monitor clinical investigations adequately • Evaluate & report adverse events • Maintain adequate study records • Submit study progress reports & final results

12. BIMO Inspection Focus • Study organization & personnel • Investigator selection & monitoring • Monitoring procedures & activities • Data collection & handling • Investigational product accountability

13. Clinical Study Organization & Personnel: Contractors • If CRO, central lab, reading center, etc. provides study-related activities, execute written contract • Maintain written summary of key study activities & associated responsibilities

14. Clinical Study Organization & Personnel: Clinical Research Dept • Maintain organization chart, including designated product team • Reflect team membership changes & dates of effectivity • Support with regularly updated resumes & summaries of relevant training

15. Clinical Study Organization & Personnel: Study Investigators • Maintain list of study investigators with whom investigator agreements were executed • Supplement with study enrollment numbers by investigator • List should reflect dates of study participation initiation & completion

16. Clinical Study Organization & Personnel: Protocol & Related Documents • Maintain master copy of original protocol & amendments • Maintain master copy of ICD template • Maintain master copy of original CIB or report of prior investigations & amendments

17. Clinical Investigator Selection & Monitoring Assessment • Sponsor should maintain filing system containing relevant documentation for each study investigator

18. Clinical Investigator Selection & Monitoring: Investigator Files • Protocol Section • Fully executed signature page for original protocol & each amendment • CIB/Rpt of Prior Investigations Section • Fully-executed signature page for original report & each amendment

19. Clinical Investigator Selection & Monitoring: Investigator Files • Investigator Agreement Section • Fully-executed NDA & investigator agreement(s) & each amendment • Investigator financial disclosure questionnaire, curriculum vitae & medical license

20. Clinical Investigator Selection & Monitoring: Investigator Files • IRB Approval Section • Documentation of approval of investigator(s), protocol(s) & consent document(s) • May also include approvals of subject recruitment or information materials; declarations of translation

21. Clinical Investigator Selection & Monitoring: Investigator Files • IRB Correspondence Section • IRB membership list(s) or multiple assurance number • Periodic progress reports • Notification of AEs • Miscellaneous correspondence

22. Clinical Investigator Selection & Monitoring: Investigator Files • Monitoring Section • Monitoring log indicating dates of each visit & monitor who performed • Site visit reports

23. Clinical Investigator Selection & Monitoring: Investigator Files • Product Accountability Section • Documentation of product shipment, receipt, use or return

24. Clinical Investigator Selection & Monitoring: Investigator Files • Study Management Logs Section • Signature authorization logs • Screening/enrollment logs • Calibration/service logs

25. Clinical Investigator Selection & Monitoring: Investigator Files • Memos to File Section • Sponsor-Investigator Correspondence Section • Adverse Event Correspondence Section • Internal Correspondence Section

26. Monitoring Procedures & Activities Assessment • Be prepared for detailed review of: • Inspector-designated monitoring reports & subject records • All unanticipated, product-related & serious AE reports

27. Monitoring Procedures & Activities: Monitoring Plan & Procedures • Plan should include: • Monitor responsibilities & training plans • Monitoring procedures & checklists/logs • Guidelines for reporting AEs • Guidelines for reporting protocol deviations • Should be subject to change controls

28. Monitoring Procedures & Activities: Subject Data Line Listings • Facilitate efficient comparison of computerized data vs. CRFs by: • Generating listings physically resembling CRFs • Segregate listings by subject

29. Monitoring Procedures & Activities: Data Queries • Query documentation should be chronologically ordered & readily available for review with CRFs • Query log should be maintained to track queries generated & their resolution

30. Monitoring Procedures & Activities: Adverse Events • Maintain a log of unanticipated, product-related & serious adverse events • Log may contain: • Date of initial event report • Dates of initial IRB & FDA notification • Documentation of follow-up reporting • Date of notification of other investigators (if applicable)

31. Monitoring Procedures & Activities: Protocol Deviations • Maintain a log of protocol deviations to enable quick assessment of non-compliance by deviation type & investigator

32. Data Collection & Handling Assessment • BIMO inspector evaluates integrity of data collection, management & analysis activities in support of submission

33. Data Collection & Handling: Clinical Study Summary • Maintain a list of clinical studies included in marketing application • Be prepared to address rationale for studies not submitted

34. Data Collection & Handling: Data Management Plan & Procedures • Plan should include: • Annotated CRFs • Database field definitions • Automated edit checks • Database validation plan • Data collection, maintenance & analysis procedures • Should be subject to change controls

35. Data Collection & Handling: Statistical Analysis Plan & Procedures • Plan should include: • How study population(s) analyzed • General analysis conventions • Subject disposition definitions • Variables to be analyzed & analysis methodology • Sample tables & supporting listings

36. Data Collection & Handling: Data Tables Confirmation • Maintain well-labeled data listings supporting each study data table • Listings should contain confirmation of verification vs. associated table

37. Investigational Product Accountability Assessment • Records should be logically organized (e.g., by sterilization lot) so inspector can readily review

38. Investigational Product Accountability: Manufacturing, Labeling, Release, Storage • Typically maintained within sponsor manufacturing procedures • Procedures should include checklists/logs to confirm conformity with procedural requirements

39. Investigational Product Accountability: Product Distribution • Maintain detailed log of product shipment, use, return or disposal

40. Conclusion • These suggestions should provide stimulus for planning & maintaining clinical program operations to facilitate: • Efficient project performance • An uneventful BIMO inspection