1. “The FDA Inspector Cometh”
Inspection Process for Clinical Trials
Welcome (Slide Show has already been running)
As we get started let’s get a brief video picture by viewing a 2 minute portion of the “Obligations of Investigators” video and a dialog between an experienced and new investigator

2. ACCME Requirement: CMEs
The University of Michigan Medical School is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The University of Michigan Medical School takes responsibility for the content, quality, and scientific integrity of this CME activity
The University of Michigan Medical School designates this educational activity for a maximum of category 1 credits towards the AMA Physician’s Recognition Award. Each physician should claim only those credits that he/she actually spent in the activity.
CMEs for each part ot the series
Everyone needs to fill out the orange cards, as the training must be documented in official UM database, in addition to the sign in sheet
Use this slide when the intro slide show has not been run to publicly state CMEs

3. 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?
I would like to address these questions at this session

4. What has happened at UMHS?
Some Metrics
Ask for a show of hands from audience for those who have directly been involved in an FDA inspection

5. FDA Inspection History at UMHS
>24 investigators and/or drug trials since 1981
Hematology/Oncology
Endocrinology/Metabolism
Neurosurgery
Rheumatology
Human Genetics
Gastroenterology
Dermatology
Opthamology
Pharmacology
Urology
Cardiology
Radiology
Anaesthesiology
Pulmonary
FDA Inspections of investigators since 1977
Last known inspections on July 9, 2002 (Oncology) and 3 in 2003, Dr. Kaminsky [Yes, Kaminski was audited for Corixa's NDA, May 19-June 4] , Dr Locke and Dr Brewer
21 different UMHS investigators such that a couple have been inspected >1time
Limited list since this only covers drug trials with oversight by CDER (Center for Drug Evaluation and Research)

6. 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
Information supplied by IRBMED
Usually IRBs are targeted separately by FDA, but common for investigators at locations where the IRB resides for them to make a visit. Example: Dermatology experience where the FDA visited the IRB first to obtain a master list of studies done by a specific investigator

7. Who conducts inspections?
Hint:
Motto: Compliance, Science, Protection
Comment briefy on 3 part motto
Science/Medicine (The data)
Protection (The subject)
Compliance (The rules)

8. Office of Regulatory Affairs (ORA) http://www.fda.gov/ora/
Headquarters:
Rockville, MD
Regional Office: Philadelphia, PA
UM (all locations) sits in the Central Region and typically has inspectors from the downtown Detroit office (but possible from other regional offices, eg, Grand Repids), but for cause inspections can send someone from headquarters.
District Office:
Detroit, MI

9. 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.”
To assure adherence to regulations
To assure adherence to guidelines
To validate the study (data)
To protect the subjects
Interested in really examining the paper record

10. Who and What are Inspected?
Today’s Focus:
GCP-Related People and Places
GLP (animal laboratories)
GMP (manufacturing facilities)
Are also inspected with regards to research and new products

11. 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)
Main target is the investigator, then IRBs, then sponsor /CRO (very small numbers)
US and International based
Other groups listed on overhead usually are ancillary dependent on the questions and needs posed by FDA investigators

12. 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)
Other: IND
Drugs, Biologics, Devices, combinations
Bioequivalence (I.e., pharmacokinetics)
For cause changes the whole mix, then any study is fair inspection game

13. What is the inspection process?
10 Steps
for
Investigators
Although slides, I have created a flow chart and a table for posting and file retention

14. 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
Inspectors manual cites these metrics….

15. Reasons: “For Cause” Inspections
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
Will cover some case studies in the last of the series
However, do not want the NIH folks to get to comfortable. Just this year, a patient complained about an NIH study to FDA and they visited for 3 weeks.

16. 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)
Be in a state of readiness at all times. Eg: files organized and accessible
No notice = “for cause” inspection. Example: One UM investigator (and study coordinator) arrived after FDA who already visited the IRB, then stayed 6 weeks.
Be ready to validate patient existence. One study coordinator had this question posed….and had to generate lists of the screened patients, too (who did not get on study)

17. 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
1 day to 6 weeks is the known range
Data inspection: 1 study
For Cause: all studies are possible

18. 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
for unannounced inspections
for IRBMED notification
OGC Rachel Nosowsky
IRBMED: Send to general mailbox (June Insco and/or Pat Ward)
Want to start tracking centrally what is happening. Have not been so good about this to date
In case problems, need to address together.
Do not have the sponsor present at the inspection

20. 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

21. 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
Normal business hours, although recent example, was arrival at 7 am.
Usual data inspection, one inspector, common for 2 or more during for cause inspections

22. FDA Form 482

23. 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
Copy or keep very detailed list of documents, and make the copies for them, perhaps gather through the day and do all at once (ready for the next day, if multi-day inspection)
Pull all the requested patient charts (it takes a while to gather them because of the complexity of UMHS system)
Examples: Could locate all, but one. Placed the chart of the complaining patient on top of pile, upfront, shrewd and set a good tone for the inspection

24. 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)
Data needs to be directly related to the study generated data

25. 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
Target the expert, and the level headed and the knowledgeable ones

26. Tips for Anticipating FDA Questions
Compliance Program Guidance Manuals (CPGMs)
Clinical Investigator CPGM Headers:
Authority and Administration
Protocol
Subjects’ Records
Other Study Records
Consent of Human Subjects
Institutional Review Board
Sponsor
Investigational Product Accountability
Records Retention
Electronic Records and Signatures
Animal Clinical Studies (if applicable)
Device Studies (if applicable)
Report Format
Sample Collection (if applicable)

27. 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
Be cool, calm, collected and concise!
FDA inspector from Detroit nicknamed “Columbo” Self effacing, same question for numerous people, tenacious until satisfied with the answer (oh yes, also wore a rumpled lab coat that he brought along)

28. 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
Daily summaries for next day preparation and information gathering
Exit interview: Management/Investigator and key person, study coordinator
Important piece of discussion especially if a written response is needed in the future

29. 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
Goal: Try not to get one

30. FDA Form 483

31. 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
Does not discriminate between minor and major (misspelled words in a consent versus many missing consents)

32. 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
Informed consents typically reviewed post inspection
EIRs sent to site of inspection, uncensored, but anyone can request under Freedom of Information (FOIA requests)

33. 10. FDA classifies Inspection
When evaluation is completed, FDA classifies inspection and sends a letter to site
Describe classifications, can view on line, that the problem situations and warning letters are subject of future date in this series

34. FDA Inspection Process
FDA Office
Site Location
Select Site
Contact Site
Schedule Site
4. Arrive (482)
5. Review Records
6. Interview Staff
Included in packet
Green = FDA office activities
Purple = Site activities
Remind about CME cards
Remind about feedback
Remind about next class: Oct 20, 2003
Q and A
Remind about speaking into microphone
7. Present Findings
8. Depart (483)
9. Write Report (EIR)
10. Classify Inspection