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
Most – Under OHRP jurisdiction
Common Rule, etc. at
Some – Under FDA jurisdiction
Various regulations and guidance, start at
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!
Coordinated by the Office for the Vice President for Research

4. Responsibilities
In a clinical trial inspection, FDA’s focus and relationship is direction with the Clinical Investigator.

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 IRB and sponsor approval
Promptly report serious adverse events to the IRB and 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. Responsibilities of Clinical Investigators
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. No recent OAI Determinations!
UM FDA Investigations
25%
OAI
NAI
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

20. Heavy Workload for Study Team
Supervision
Factors
Inexperienced Study Staff
Very Sick Patient Population
PI Conducting Large Number of Studies
Large Number of Participants in Active Intervention
Complexity of Study
Heavy Workload for Study Team
Heavy Clinical Obligations

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
Study team meetings to demonstrate supervision are documented with minutes
Document training to SOPs.(Compare to 2011 Warning letter to Yale Cohen, FDA WL Comment “In addition, we note that your study coordinator further informed FDA investigators that she was unaware of any active written clinical research procedures used at your site.”

22. General Lessons Learned:

23. learn from their mistakes”
“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
Failure to follow the investigational plan
How will you know?

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”
A PROTOCOL IS NOT A GUIDE---THIS IS NOT THE TIME TO BE A CREATIVE COOK
Most common observation include failure to follow investigational plan

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?
Enhancement to our Research Pharmacy include enhanced SOPs, standardized study initiation session with study team

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?
During recent FDA inspection, Inspector reiterated how important it is to document “WHO” at the Sponsor authorized a deviation from the eligibility criteria.

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 hold to 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, clear documentation 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 Guidance
IRBMED Training
MICHR Training
MICHR MIAP
 PEERRS

46. More Internal Resources
Public Access Requirements (for gov’t funded research)
Workshops
Safe computing:

47. External Resources
Information Sheet Guidance For IRBs, Clinical Investigators, and Sponsors
FDA Running Clinical Trials Page
Writing an Effective 483 Response (2009 FDA Presentation)
FDA Warning Letters

48. External Resources (continued)
WIRB Online Seminars (free)
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
CDRH Learn Courses

49. Thank you
Questions?