“The FDA Inspector Cometh”

1. “The FDA Inspector Cometh” Inspection Process for Clinical Trials

2. FDA “Good Clinical Practice” Inspections • What has happened at UMHS? • Who conducts the inspections? • Who and what are inspected? • What is the inspection process? • How can the process go better?

3. What has happened at UMHS? Some Metrics

4. Hematology/Oncology Endocrinology/Metabolism Neurosurgery Rheumatology Human Genetics Gastroenterology Dermatology Opthamology Pharmacology Urology Cardiology Radiology Anaesthesiology Pulmonary FDA Inspection History at UMHS • >24 investigators and/or drug trials since 1981 http://www.fda.gov/cder/regulatory/investigators/default.htm

5. FDA Inspection History at UMHS • FDA has inspected IRBs since 1980 • Per IRBMED: • Inspections occur about every 5 years • Known inspections • 1992 • 1997 • Latest in Oct, 2001

6. Who conducts inspections? Hint: Motto: Compliance, Science, Protection

7. Office of Regulatory Affairs (ORA)http://www.fda.gov/ora/ Headquarters: Rockville, MD Regional Office: Philadelphia, PA District Office: Detroit, MI

8. FDA Field Investigators • Conduct inspections to enforce the Food, Drug and Cosmetic Act • Train themselves in “evidence collection” • “If it’s not documented, it didn’t happen.”

9. Who and What are Inspected? Today’s Focus: GCP-Related People and Places

10. Who? • Investigators (Doctors) and Study Coordinators • IRB (IRBMED) • Sponsor, if applicable (Industry) • Contract Research Organization, if involved • Laboratories (e.g., Mlabs) • Pharmacy (e.g., Investigational Drug Services) • Devices (e.g., Biomedical Engineering)

11. What studies? • Usual Emphasis: Phase 3 • Adequate and well controlled • Blinded • Safety and Efficacy • Multi-site • High patient enrolling sites • Recent marketing application (e.g. New Drug Application) filed to an Investigational New Drug (IND)

12. What is the inspection process? 10 Steps for Investigators

13. 1. FDA selects Site(s) • FDA selects site for inspection: • Usually within 6 months of marketing application [NDA] (Data Audit) • Selects 3 sites (average) per study, if multi-site • May concurrently inspect the associated IRB: • If no previous inspection; or • Last inspection >5 years OR • May conduct a “For Cause” Audit

14. Study of “singular importance” in product approval Study has major impact on medical practice Sponsor reports concerns about investigator Patient complaint Investigator conducts too many studies Investigator works outside of specialty area Safety or efficacy findings are inconsistent with other investigators Lab results are outside range of biological expectations Reasons: “For Cause” Inspections

15. 2. FDA Investigator contacts Site • FDA investigator from local District Office contacts responsible person at site: • Gives short advance notice or no notice of visit • Becomes suspicious on attempts to delay visit (e.g., >10 days without valid reason) • Previews internally following subject related data: • Number of total subjects, dropouts and evaluable subjects • List of AEs and deaths (with description and cause)

16. 3. FDA and Site agree on Visit Date • FDA investigator and site person agree on appointment for site visit: • Averages 3-5 days for appointment • Targets typically one study, but may review other studies performed by same investigator

17. Preparation Tips for Site • Notify all staff involved in AND/OR knowledgeable about the study: • Key staff, “information providers” are on standby • Office of General Counsel • Industry sponsor, if any • Review UMHS procedures • http://www.med.umich.edu/i/policies/umh/01-01-020.htmlfor unannounced inspections • http://www.med.umich.edu/irbmed/ae/oriotwoc.htm#audit for IRBMED notification

19. Preparation Tips for Site • Assign a site escort/facilitator • Assemble all study documents in 1 place • Include list of staff responsibilities and training • Request all patient charts • Prepare a list of investigator’s studies • Reserve adequate work space for field investigator for entire inspection • Assure accessible photocopier

20. 4. FDA presents Notice of Inspection • Upon arrival FDA displays credentials (eg., photo ID) and FDA Form 482, Notice of Inspection • Conducts inspection during routine business hours • May “meet and greet” 1-3 FDA investigators

21. FDA Form 482

22. 5. FDA requests data and documents • FDA investigator requests related trial data and documents during site visit • May need copies of documents • Make 2 copies: • Give 1 copy to FDA • Keep 1 copy at site to facilitate future communications

23. Tips on Document Requests • Do not provide or copy these information for FDA: • Financial data (salary information, budgets) • (except financial disclosure of clinical investigators) • Personnel data (performance appraisals) • (except qualifications [job descriptions] and training records)

24. 6. FDA interviews Site Staff • FDA investigator interviews site staff directly involved in trial activities and processes • May question any staff member during inspection • May use Compliance Program Guidance Manual as interview guide

25. Tips for Anticipating FDA Questions • Compliance Program Guidance Manuals (CPGMs) http://www.fda.gov/ora/cpgm/default.htm

26. Tips for Handling FDA Questions • Answer • Politely, cooperatively, understanding them (ask for clarification), factually, briefly, within one’s expertise (seek expert), directly (remain within scope), without speculation or guesswork • Avoid • Unsolicited questions, hypothetical questions, long delays to requests, affidavits

27. 7. FDA conducts “Exit Interview” • [Review findings with FDA investigator at end of each inspection day] • At site visit completion, FDA investigator conducts “exit interview” with responsible site personnel to: • Review findings • Clarify misunderstandings • Describe any deviations from current regulations • Suggest corrective action, if appropriate

28. 8. FDA presents Notice of Observations • If deviations, FDA investigator leaves a FDA Form 483, Notice of Observations • Submits findings to local District Office for any additional needed actions

29. FDA Form 483

30. Most Common Observations (for Investigators) • Protocol non-adherence • Inadequate and inaccurate records • Failure to report adverse events • Failure to report concomitant therapy • Inadequate drug accountability • IRB/IEC problems • Informed consent issues

31. 9. FDA writes Inspection Report • Upon return to local District Office, FDA investigator: • Writes an Establishment Inspection Report (EIR); and • Forwards to headquarters for evaluation

32. 10. FDA classifies Inspection • When evaluation is completed, FDA classifies inspection and sends a letter to site

33. Select Site • Contact Site • Schedule Site 4. Arrive (482) 5. Review Records 6. Interview Staff 7. Present Findings 8. Depart (483) 9. Write Report (EIR) 10. Classify Inspection FDA Inspection Process FDA Office Site Location