1. What FDA Looks for When Inspecting IRBs and Sponsors Marian J. Serge Nurse Consultant Division of Bioresearch Monitoring Office of Compliance Center for Devices and Radiological Health FDA

2. Objectives/Agenda Institutional Review Board Inspection Institutional Review Board Inspection Background Background Techniques used in FDAs Inspections Techniques used in FDAs Inspections Frequently found IRB Deficiencies Frequently found IRB Deficiencies Sponsor Inspection Sponsor Inspection Background Background Techniques used in FDAs Inspections Techniques used in FDAs Inspections FDA Administrative Actions FDA Administrative Actions Frequently found Sponsor Deficiencies Frequently found Sponsor Deficiencies

3. FDAs Compliance Program-IRB Background Background Title 21 Code of Federal Regulations Parts 50, 56, 312, 812 Title 21 Code of Federal Regulations Parts 50, 56, 312, 812 Goal is to achieve IRB compliance with regulations Goal is to achieve IRB compliance with regulations FDAs Center personnel issue requests FDAs Center personnel issue requests Field Investigators/District Office conducts inspections Field Investigators/District Office conducts inspections

4. What FDA Looks For IRB Inspection FDA Compliance Program Manual FDA Compliance Program Manual http://www.fda/gov/ora/cpgm/default.htm http://www.fda/gov/ora/cpgm/default.htm http://www.fda/gov/ora/cpgm/default.htm Four components Four components Interviews Interviews Review of written procedures Review of written procedures Review of records and reports Review of records and reports Exit meeting Exit meeting Followed by: Centers review and assessment

5. Techniques of IRB Inspection Interviews Interviews Questions about Questions about IRB membership, IRB membership, responsibilities, responsibilities, functions and operations, and records functions and operations, and records

6. Techniques used in IRB Inspection Review IRB Written Procedures Review IRB Written Procedures Sufficient detail Sufficient detail Compare with information gathered at interview Compare with information gathered at interview Compare with regulations Compare with regulations

7. Techniques used in IRB Inspection Review records and reports (copies made) Review records and reports (copies made) Research studies Research studies Protocol versions Protocol versions Informed consent versions Informed consent versions Continuing review reports Continuing review reports Adverse events reports Adverse events reports New findings given to subjects New findings given to subjects IRB minutes IRB minutes Correspondence Correspondence IRB roster IRB roster

8. Techniques used in IRB Inspection Exit meeting with management Exit meeting with management Form FDA 483 Form FDA 483 Other observations Other observations Centers assessment of inspection-report Centers assessment of inspection-report Untitled Letters/Warning Letters and other FDA administrative actions Untitled Letters/Warning Letters and other FDA administrative actions Centers follow up to ensure IRB comply Centers follow up to ensure IRB comply

9. Common IRB Deficiencies Written procedures Written procedures Incomplete – inadequate – not followed Incomplete – inadequate – not followed Expedited review Expedited review Device SR/NSR Device SR/NSR Inadequate continuing reviews Inadequate continuing reviews Minutes insufficient Minutes insufficient Vote not recorded by number of votes Vote not recorded by number of votes Adverse events not adequately reviewed Adverse events not adequately reviewed

10. Common IRB Deficiencies Majority of members not at meeting Majority of members not at meeting Majority of members not present for vote Majority of members not present for vote Non-scientific member not present Non-scientific member not present Fail to report to FDA when study is suspended or terminated Fail to report to FDA when study is suspended or terminated

11. FDA Compliance - Sponsors Background Background Techniques Techniques Interviews Interviews Review of procedures and records Review of procedures and records Exit interview Exit interview FDAs administrative actions FDAs administrative actions Frequently found deficiencies Frequently found deficiencies

12. FDAs Compliance Program Sponsors Background Background Objective: determine how Sponsors assure validity of data and comply with regulations Objective: determine how Sponsors assure validity of data and comply with regulations Title 21 Code of Federal Regulations Parts 312, 314, 812, 814, 58, 21, 50, and 56 Title 21 Code of Federal Regulations Parts 312, 314, 812, 814, 58, 21, 50, and 56 Differences between drug and device inspect. Differences between drug and device inspect. Criteria to choose Sponsor for inspection Criteria to choose Sponsor for inspection

13. What FDA Looks For Sponsor Inspection FDA Compliance Program Manual FDA Compliance Program Manual http://www.fda/gov/ora/cpgm/default.htm http://www.fda/gov/ora/cpgm/default.htm Interviews Interviews Organization – responsibilities – authority – contractor oversight- adverse event review Organization – responsibilities – authority – contractor oversight- adverse event review Selection of clinical investigators Selection of clinical investigators

14. What FDA Looks For Sponsor Inspection Selection of Clinical Investigator (CI) Selection of Clinical Investigator (CI) Signed FDA 1572 or Investigator agreements Signed FDA 1572 or Investigator agreements Criteria for selection of CIs Criteria for selection of CIs Necessary information given to CI Necessary information given to CI How sponsor obtained compliance from non-compliant CI How sponsor obtained compliance from non-compliant CI

15. What FDA Looks For Sponsor Inspection Selection of Monitors Selection of Monitors Responsibilities Responsibilities Written monitoring procedures Written monitoring procedures Frequency of site visits Frequency of site visits Scope and processes Scope and processes Review monitoring records to verify procedures Review monitoring records to verify procedures

16. What FDA Looks For Sponsor Inspection Review of Records Review of Records CI selection criteria CI selection criteria Monitoring procedures and activities Monitoring procedures and activities Subjects records and clinical data Subjects records and clinical data IRB approval IRB approval Informed consents Informed consents Automated data entry Automated data entry Test article accountability Test article accountability

17. What FDA Looks For Sponsor Inspection Review of records Review of records Adverse event (AE) reporting Adverse event (AE) reporting Difference between drug/biologics and devices Drug/biologics telephone report within 7 calendar days for fatal or life-threatening situation and a written report within 15 days for both serious and unexpected AE Drug/biologics telephone report within 7 calendar days for fatal or life-threatening situation and a written report within 15 days for both serious and unexpected AE Device studies – written report within 10 working days for unanticipated AE Device studies – written report within 10 working days for unanticipated AE

18. What FDA Looks For Sponsor Inspection Copies made of documents, example Copies made of documents, example Written procedures Written procedures Organizational charts Organizational charts Written agreements transferring responsibility Written agreements transferring responsibility List of monitors/job descriptions/qualifications List of monitors/job descriptions/qualifications List of clinical investigators List of clinical investigators Protocol amendments, changes Protocol amendments, changes Research article accountability Research article accountability Notices to Clinical Investigators/subjects Notices to Clinical Investigators/subjects

19. Exit meeting with management (Sponsors may clarify any misunderstandings during the inspection) At exit meeting Field Investigator meets with most responsible person and others. Discuss Form FDA 483 observations Discuss Form FDA 483 observations Other observations Other observations Sponsor participates Sponsor participates

20. FDA Administrative Actions Center personnel review and analyze inspectional report from Field Investigators to assess Sponsors compliance Center personnel review and analyze inspectional report from Field Investigators to assess Sponsors compliance Untitled Letters Untitled Letters Warning Letters Warning Letters Rejection of clinical data in marketing application Rejection of clinical data in marketing application Application Integrity Policy Application Integrity Policy Civil Penalties Civil Penalties Seizure of product or Injunction Seizure of product or Injunction Prosecution Prosecution

21. Frequently Found Sponsor Deficiencies Inadequate monitoring Inadequate monitoring Lack of CI training Lack of CI training Lack of product accountability Lack of product accountability Insufficient recordkeeping Insufficient recordkeeping Failure to report all unanticipated AEs Failure to report all unanticipated AEs Inadequate sample Informed Consent Inadequate sample Informed Consent Application has false or fabricated data Application has false or fabricated data Failure to secure CI compliance Failure to secure CI compliance

22. Summary Institutional Review Board Inspection Institutional Review Board Inspection Background Background Techniques used in FDAs Inspections Techniques used in FDAs Inspections Frequently found IRB Deficiencies Frequently found IRB Deficiencies Sponsor Inspection Sponsor Inspection Background Background Techniques used in FDAs Inspections Techniques used in FDAs Inspections FDA Administrative Actions FDA Administrative Actions Frequently found Sponsor Deficiencies Frequently found Sponsor Deficiencies