Everyday Preparedness for the Challenges of FDA-Regulated Research

1. Everyday Preparedness for the Challenges of FDA-Regulated Research Pat Ward & Diane Wilson UMMS Regulatory Affairs With special thanks to Kara Morgenstern, HSLO

2. Human Subject Research at UM • All – Governed by University policy • See UM HRPP OM at http://www.hrpp.umich.edu • Most – Under OHRP jurisdiction • Common Rule, etc. at http://www.hhs.gov/ohrp/ • Some – Under FDA jurisdiction • Various regulations and guidance, start at http://www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/default.htm • Others – DoD, DoEd, etc.

3. Important Themes for Today • Clinical research is a good thing for UMMS and its patients • UMMS clinical research is a part of the University’s overall HRPP program • FDA-regulated research as a Clinical Investigator team is hard • FDA-regulated research as a SPONSOR-Investigator team is VERY Hard • Compliant research takes infrastructure, supervision, and commitment • Mistakes happen • FDA investigators are VERY good at their jobs - if there are mistakes or concerns, the FDA will find them • Most mistakes and concerns can be satisfactorily addressed • Proactive preparations can help avoid mistakes and improve an inspection’s outcome • Advice and assistance are available!

4. Responsibilities

5. Responsibilities of Clinical Investigators and their teams • Follow investigational plan • Obtain and document informed consent • Clinical investigator personally conducts or supervises the investigation • Protect rights, safety, and welfare of participants • Ensure adequate medical care for the study participants • Obtain and maintain necessary approvals from IRB • Maintain and retain drug/device disposition • Maintain documentation of patient case history records • Provide written reports to the IRB and sponsor, as required • Ensure changes are not implemented without prior IRBand sponsor approval • Promptly report serious adverse events to the IRBand sponsor • Furnish progress and other reports, as required • Ensure all study team members are informed about their obligations noted above

6. Additional Responsibilities of Sponsor-Investigators (a.k.a. IND/IDE Holders) • Select qualified clinical investigators • Secure written agreements and financial disclosures • Provide information to other investigators and study staff to ensure study performed properly • Ensure proper monitoring of the study • Ensure the study is performed in accordance with the investigational plan • Submit necessary amendments/supplements to FDA • Ensure that FDA and investigators are promptly informed of significant new adverse effects or risks • Maintain adequate records • Maintain proper control of the study drug/device

7. Sponsor-Investigators assume both piles of responsibilities Responsibilities of Clinical Investigators Investigator Responsibilities Sponsor Responsibilities

8. FDA History at UM

9. FDA Inspections at UM

10. Possible FDA Determinations • NAI – No Action Indicated • VAI – Voluntary Action Indicated • OAI – Official Action Indicated • Untitled Letter • Warning Letter • NIDPO Letter • “Notice of Initiation of Disqualification Proceedings and Opportunity to Explain”

11. UM FDA Investigations NAI 25% OAI NAI VAI VAI No recent OAI Determinations!

12. FDA observations at UM

13. Clinical Investigator 483 Observations at UM (N=21 since 2008) • Investigation was not conducted in accordance with the investigational plan (11) • Failure to prepare or maintain adequate case histories with respect to data pertinent to the investigation (9) • Inadequate IRB approval or notification (8) • Problems with informed consent (7) • Control of investigational drug or device, or inadequate return of unused drug or drug disposition records inadequate (5)

14. Clinical Investigator 483 Observations at UM (N=21 since 2008) • Protocol adherence • Unreported/unapproved changes • Protocol deviations/violations • Ineligible subjects • Informed consent • Missing • Wrong version • Signature/date irregularities • Misleading/overly technical language

15. Clinical Investigator 483 Observations at UM (N=21 since 2008) • Documentation deficiencies • Incomplete/inaccurate CRFs • Missing source documents • Corrections not auditable • Missing or delayed IRB approval/reporting • Amendment implemented before approval • Missing or late reports • Lapse in IRB approval

16. Auditable = ALCOA

17. Clinical Investigator 483 Observations at UM (N=21 since 2008) • Poor test article accountability • Missing or delayed reports to sponsor • AEs and protocol deviations • Special issues for FDA Sponsor-Investigators • Inadequate monitoring • Missing or delayed reports to FDA

18. OAI Example : BUSY Clinician & Clinical Investigator

19. Busy clinician ends up with multiple “observations” on a Form 483 • Failure to obtain informed consent • Failure to follow investigational plan • Failure to report all changes to the IRB

21. Built a Robust CAPA • PI self-imposed moratorium on clinical research • Certification training in FDA’s Clinical Investigator course • Adopt departmental QA program • New QA position • Enhanced SOPs • Documented training to SOPs • Weekly supervisory meetings with study team • Experienced colleague serving in advisory/mentor capacity • Oversight committee • Re-allocated some industry studies to other faculty • Successful external audit required before research allowed to resume • Prepare for FDA follow-up inspection

22. General Lessons Learned:

23. “All men make mistakes, but only WISE men learn from their mistakes” Winston Churchill

24. FDA-Regulated Research… Top Tips for Everyday Preparedness From lessons we learned the hard way

25. #1 Train Well • Take advantage of training opportunities and resources • PEERRS, IRB courses, MICHR courses, sponsor training, FDA’s on-line modules and Clinical Investigator Training Program, etc. • Consider steps toward certification by a professional organization (SOCRA, ACRP, etc.) • Seek an experienced mentor • If you don’t know (or don’t know that you don’t know) -- ASK!

27. #2 Help Your PI Supervise Well • Communicate frequently with/between team members • Spot-check for quality of work – swap with another team for “fresh eyes” • Identify and resolve confusion, problems, etc. • Stay organized and current on documentation The buck may stop at the PI’s desk, but s/he needs your support to stay ahead of potential problems

28. #3 Qualifications of Study Team • Identify all qualified Co-Is and staff needed and complete paperwork • Are study team members properly credentialed to complete medical procedures in protocol? • Has all training (including study-specific training) of study team members been completed and documented? • Are Co-Is on the FDA 1572 (drug study) or investigator agreement (device study), if applicable? • Is the delegation log accurate and up-to-date? • Are any conflicts of interests identified and managed?

29. #4 Have a well-written,“doable” protocol How will you know? Doable Protocol Failure to follow the investigational plan

30. #5 Test Run Protocol, Documents, and Other Systems • Are protocol procedures and timing feasible? • Are there inconsistencies between protocol, CRFs, investigator brochure, other study tools? • Do alerts and alarms work? If not…

31. #6 Once You Commit to a Protocol… If you feel like something is outside the bounds, speak up! The protocol is not just a “guideline”

32. #7 Implement Controls for Study Article Accountability • Study Drug Have you defined the roles and responsibilities for the Research Pharmacy? • PI may delegate actions, but retains ultimate responsibility • Study Device Are all components of the investigational device strictly tracked and controlled (locked down) to avoid access by unauthorized users?

33. #8 Use Study Monitors Effectively • Whether a S-I or CI industry trial, ask yourself: • Can I rely on my monitor? • Does sponsor/monitor’s advice make sense? • Does my regulatory file document directions given by sponsor/monitor and addressed by my team?

34. #9 Document To Tell Entire Story Ask yourself: • If you ran off to the Fiji Islands, would the documentation you left behind tell the entire story? • Why you deviated from the protocol? • Who from sponsor approved the deviation? • When and why a CRF value was corrected? • Who made the changes? • Why any CRF data are inconsistent with source documents?

35. #10 Ongoing Quality Assessment • Know how things are going! Share this with your PI! • Has there been staff turnover? • Are research participants withdrawing or complaining? • Are IRB submissions of good quality and submitted timely? • What is outcome of monitoring reports? • What is outcome of In-house audits reports? • Office of Human Research Compliance Review (OHRCR) • If issues are arising. . . • Consider putting the project on holdto protect participants and data integrity • Report to IRB • Conduct root cause analysis (“5 Whys”) • Implement corrective and preventive actions

36. Will FDA Inspection lightning strike you?

37. Objectives of FDA Inspections • FDA Biomedical Monitoring (BIMO) Program Objectives • To protect the rights, safety, and welfare of subjects • To verify the accuracy and reliability of clinical trial data • To assess compliance with FDA's regulations governing the conduct of clinical trials

38. Triggers for FDA Inspections • PI conducts many studies • PI is high enroller • Rapid or late enrollment • Pivotal trial for new drug application • Test article of focused FDA interest • PI conducts study outside his/her specialty area • Inconsistent data or unusual safety profile • Complaints • Non-compliance reported to FDA

39. When FDA Calls (or appears)… • Inspections are usually scheduled in advance • 7-10 days notice • Will try to accommodate research team’s schedule • Before the call comes: • Prep anyone who might take that call • During the call, also politely ask: • Reason for inspection (data audit, for-cause, particular study?) • Names of inspectors coming • What would they like prepared in advance • After the call -- call us! • RA and/or IRBMED • We are prepared to advise/assist you

40. What Do FDA Inspectors Do? • Hold you to… • FDA regulations • Sponsor’s protocol • IRB approval • Your own (and University) policies and procedures Keep to the code. The code is the law…

41. What do FDA Inspectors Do? • Compare CRFs to source documents to verify… • Subjects met inclusion/exclusion criteria • IRB review/approval obtained • Informed consent obtained from subjects • Study was conducted according to the protocol • Primary efficacy measures • Adverse events reported • Safety data (labs, etc.) • Accountability of investigational agent

42. What do FDA Inspectors Do? • Interview members of the study team and key institutional representatives (IRB, etc.) • Who did what? • What was the practice/expectation at time X? • Do interviewees understand their respective responsibilities?

43. FDA’s View of Principal Investigator A PI should…. • Live, breathe, and follow the protocol • Be actively and fully engaged in supervising study staff • Be attentive to subject safety and rights • Make required reports to IRB, sponsor, etc. • Ensure accurate, cleardocumentation that fully tells the story • “Get It” With FDA…. It’s all about the PI !

44. When we inspire their confidence, the FDA can go from this… …to this!

45. Internal Resources • IRBMED Guidancehttp://med.umich.edu/irbmed/guidance.htm • IRBMED Traininghttp://med.umich.edu/irbmed/education.htm • MICHR Traininghttp://www.michr.umich.edu/education • MICHR MIAP https://www.michr.umich.edu/services/regulatorysupport/miap •  PEERRS http://my.research.umich.edu/peerrs/

46. More Internal Resources • Public Access Requirements (for gov’t funded research) http://orsp.umich.edu/nih/public/ • www.Clinicaltrials.gov Workshops • http://ttc.iss.lsa.umich.edu/ttc/?s=clinicaltrials.gov&submit=Search • Safe computing: • http://www.safecomputing.umich.edu/dataguide/

47. External Resources • Information Sheet Guidance For IRBs, Clinical Investigators, and Sponsors http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126553.pdf • FDA Running Clinical Trials Page http://www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/default.htm • Writing an Effective 483 Response (2009 FDA Presentation) http://www.fda.gov/downloads/BiologicsBloodVaccines/NewsEvents/WorkshopsMeetingsConferences/UCM102921.pdf • FDA Warning Letters http://www.fda.gov/iceci/enforcementactions/warningletters/default.htm

48. External Resources (continued) • WIRB Online Seminars (free) http://ie6.wirb.com/Pages/EducationServices.aspx • Importance of an effective corrective and preventive action program • How to survive an FDA inspection of your clinical trial site • Feasibility issues – should I agree to do this trial? • Many other topics • ICH Guideline E6: Good Clinical Practices http://www.fda.gov/downloads/Drugs/Guidances/ucm073122.pdf • CDRH Learn Courses http://www.fda.gov/training/cdrhlearn/default.htm

49. Questions? Thank you