1. “The Facility’s Perspective”
(FDA) Inspections

2. The Speaker
Patrick R. Ayd RN, MBA
2

3. The Facility‘s Perspective
How to prepare
for an FDA Inspection
Understanding the Goal of the Auditor
3

4. Why Does the FDA Conduct Inspections?
•
•
Assess adherence to federal laws and regulations
•
•
Confirm validity of data supporting INDs and NDAs
Determine that the safety, rights and welfare of
subjects were protected through consent and IRB/EC
procedures
Determine whether the trial was well controlled and
conducted according to the trial protocol/SOPs/
contracts/regulatory guidelines/CFRs
4

5. Major Federal Regulations Governing Clinical Research
Title 21, Code of Federal Regulations
Electronic Records; Electronic Signatures:
Part 11
Protection of Human Subjects:
Part 50
Financial Disclosure by Clinical Investigators:
Part 54
Institutional Review Boards:
Part 56
Investigational New Drug Applications:
Part 312
(Subpart D), Responsibilities of Clinical Investigators
and Sponsor
New Drug Applications:
Part 314
5

6. Inspection of Clinical Investigators
•
Does the principal investigator retain control of the trial and
has any authority been delegated?
•
If authority has been delegated, has the principal
investigator retained control of the trial or has he/she given
full or partial control to someone else who FDA may not be
aware of until they initiate their inspection?
•
FDA inspectors will conduct interviews and review
documentation in effort to identify all other physicians,
assistants, and any other personnel who are, or were,
associated with the trial; and to assess compliance to
protocol/SOPs/regulations
6

7. Three Types of Inspections of Clinical Investigators
Trial Oriented Inspection
• Primary focus is on verification of reported trial data related to an
NDA submission (pivotal trials)
Investigator Oriented Inspection
• Investigator Oriented: an inspection in which the focus is related
to suspicious behavior by the clinical investigator
Bioequivalence/Bioavailability Inspection
• Focus is mainly related to the conduct of the trial and collection
of data
7

8. Routine Inspections
Advance Notice
Usually Inspect trials That Were Completed and Reported in NDA
Inspections Usually Last 3-4 Days
8

9. Why is “My” Site Being Audited
 Investigator is conducting a significant # of clinical trials
 Investigator is conducting clinical trials outside his/her field of
specialization
 The investigator reports efficacy for a drug that appears to be too
good compared with the results of other investigators conducting
the same trial
 The investigator reports few adverse drug reactions as compared
with other investigators conducting the same trial
 Luck
9

10. “For Cause” Inspections
No Advance Notice (1 day if lucky)
More Stressful Than Routine Inspections
Can Last for Weeks or Months with Intermittent Visits
May Involve FDA HQ Personnel
10

11. What Could Prompt a “For Cause” Audit
 Complaint Related To Safety, Informed Consent, Coercion
 The Investigator Is Conducting Clinical Trials Outside His/Her Field
Of Specialization
 The FDA has received complaints from a patient or the sponsor
that the investigator is in alleged violation of the regulations,
protocol, or human rights
 The Investigator Reports Few Adverse Drug Reactions As
Compared With Other Investigators Conducting The Same Trial
11

12. Four Major Segments of an FDA Inspection
Announcement of an
Inspection
Conduct of the Inspection
Exit Interview
Post Inspection
12

13. They’re Here!
Now what?????
13

14. Upon Arrival of the Auditor
 Contact Appropriate Personnel
 Confirm Credentials
 Receive FDA Form 482
 Determine Purpose
 Request Guidelines/expectations (Schedule, Debriefing,
Etc.)
 Assign an Appropriate Room
 FDA Inspection SOP
14

15. Upon Announcement of an Inspection,
 Notify sponsor
cont.
 Retrieve CRFs for each
subject
 Establish roles
• primary/secondary
contacts
 Gather source
documents
• documentation
• making copies
 Retrieve & review trial
file & trial protocol
 Alert & prepare support
staff
 Visit/alert ancillary
facilities ( pharmacy,
clinical laboratory, etc.)
15

16. Conduct of Inspection

Tour/Facility Inspection

Accompany At All Times
• Allow Inspector Quiet Time To Work
• Set Expectations
• Check Periodically To Answer Questions

Staff Interviews

Data Reviews

Daily Debriefing
16

17. Investigator Interview and Facility Inspection
People-Related Issues
 Who assisted in performing the trial?
 What were each person’s specific duties?
 How were the trial subjects recruited?
 Describe the monitoring (quality control)
procedures & your interaction with the monitor
• frequency of visits
• frequency of telephone calls
• information provided by monitor
17

18. Investigator Interview and Facility Inspection, cont.
Facility-Related Issues
 Where was the trial conducted?
 What protocol specific equipment was used?
Where is it located?
 How and where were data recorded and stored?
 Where was investigational drug stored?
 What records provide documentation of drug
accountability to and from the sponsor?
18

19. Review of Investigator Trial File
•
•
•
•
Protocol
Investigators Brochure
1572 with CV(s)
IRB/EC approval
letter(s) &
correspondence
•
Sample IRB/IEC
approved informed
consent form
•
Randomization
schedule
•
•
•
•
•
Monitoring documentation
•
Signed consent form for each
subject
•
Copies of completed CRFs
IND Safety Reports
Drug Accountability records
Lab Certification/CV(s)
Notification of trial end to
IRB/IEC & sponsor
19

20. Review of the Subjects’ Consent Forms
•
Review of the Signed Original And/or Revised Consent
Forms for Selected trial Subjects
•
Verify Who Obtained or Witnessed Consent Process
•
Verify Date of Consent to Ensure the Process Was
Before the Date of the First Trial Procedure
•
Verify That Subjects Were Consented With the IRBApproved Form
•
Verify That Each Subject Received a Copy of the
Original Signed Consent Form
20

21. Audit of Subjects’ Records
•
Review of Organization, Completeness, Condition, and
Location of Subjects’ Records
•
Review of Documentation to Assure That the Trial
Subjects Did Exist and Were Alive and Available for
Trial Participation
•
Review and Cross-comparison of Selected Case
Report Forms With Corresponding Source
Documentation
21

22. Audit of Subjects’ Records, cont.
•
Review and evaluation of Serious Adverse Events,
and how and when they were reported to the IRB/IEC
and Sponsor
•
Review for subject Drop-Outs
• Are they being reported to the sponsor?
•
What are the reported reasons for Drop-Outs?
• Did patient move, experience some type of adverse
event, or decide to voluntarily withdraw?
22

23. Examples of Areas Reviewed
•
Compare adherence to
practices & procedures
to Contract/SOPs/
protocol/guidelines
•
Identify
departments/functions/
key personnel
•
Authority delegated
•
Authority to review & approve
reports & data tables,
evaluations , AE’s
•
Review contractual
agreement
•
Organization charts
•
Names/titles of
responsible persons
•
Job descriptions, CV’s,
training records
•
Facility
•
Subject records
•
Drug accountability
23

24. Be Prepared to Discuss
•
Responsibilities
•
SOPs
•
Organization Chart
•
Roles/Functions
•
Training
• general
• trial specific
•
Transfer of obligations
•
Tracking of activities
•
•
•
•
•
•
•
•
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Central Files
Source Documents
Trial Documentation
Problem Resolution
Subject Screening/Decisions
AE Reporting
Validation
Equipment
Quality Assurance
24

25. Be Prepared to Discuss
Essentially,
anything related to your job,
internal processes
and the project
25

26. During the Interview…...
 be able to clearly & succinctly
explain your job responsibilities,
processes (know your job
description, SOPs, contracts,
protocol, etc.)
 think before you speak
 make sure you understand the
question
• DON’T ASSUME
• clarify if necessary
26

27. During the Interview…… cont.
 answer ONLY questions asked
• don’t volunteer
• get comfortable with ‘pregnant
pause’
 answer ONLY questions related to
your position
 answer ONLY questions you
know, otherwise
• I don’t know
• I will/someone else will follow up
 answer truthfully
27

28. During the Interview…… cont.
 Correct Erroneous Information
Provided
 Know & Refer Back to Processes
 Refer Back to Protocol, Reports, and
Other Documents
 Know Contract & Protocol
Expectations
 Be Positive
 Be Polite
 Be Prepared
 Be Alert to Hallway Talk
28

29. During the Interview…… cont.
 Do Not Argue
 Do Not Deny the Obvious
 Do Not Get Hooked on ‘Fishing
Expeditions’
 Do Not Comment on Quality
 Do Not Respond to Casual
Comments
29

30. During the Interview…… cont.
 Do Not Express Frustrations
or Editorialize
 Do Not Respond to Questions
Unless QA/Management Is
Present
 Do Not Read or Sign
Affidavits or Statements
 Do Not Provide Copies of Any
Documents (QA/Management)
30

31. FDA is trained in
interviewing &
interrogation
techniques
31

32. Conclusion
 Know & Follow SOPs, Protocol, Contract, Plans,
etc.
 Ensure Your CV, Training Records Are Current
 Document & Follow up With Problems
 Be Aware of Quality Trends
 Ensure Documentation Is Adequate & Accurately
Reflects Activities
32

33. Most Common Reasons for FDA to Reject a Trial
•
Source Documentation Not Available
•
Failed to Follow the Protocol
•
Unreported Concomitant Medications That Might
Interfere With Evaluation of the Drug
•
Unreported Adverse Experiences That Could Be
Associated With the Investigational Drug
33

34. Investigator-Oriented Inspections Results (FDA)
Inadequate and
inaccurate records
52%
failure to adhere
to protocol
52%
Inadequate subject
consent form
44%
inadequate record of
drug accountability
28%
Failure to inform IRB/IEC
of changes / progress
14%
34

35. Investigator-Oriented Inspections Results (FDA),
Deficiency
cont.
451 Inspections
Unapproved Concomitant Therapy
11%
Submission of False Data
11%
Problems With Records Availability
9%
Inappropriate Follow-up of Adverse Reactions
7%
Inappropriate Delegation of Authority
5%
Failure to Obtain IRB Approval
3%
Sub-investigators Not Listed
4%
June, 2008 to October, 2009
35

36. Trial Oriented Inspections Results (FDA)
Deficiency
483 Inspections
Inadequate Consent Form
49%
Failure to Adhere to Protocol
31%
Inadequate and Inaccurate Records
26%
Inadequate Drug Accountability
20%
Failure to Inform IRB of Changes / Progress
7%
Inappropriate Follow-up of Adverse Reactions
3%
Unapproved Concomitant Therapy
3%
Failure to Obtain IRB Approval
3%
Problems With Record Availability
3%
Sub-investigators Not Listed
2%
Failure to Obtain Informed Consent
1%
June, 2008 to October, 2009
36

37. Possible Adverse Consequences of FDA’s
Observation of Deficient Clinical Research
Investigator
Sponsor
•
Restrictive Sanctions
•
Rejection of Invalid Data
•
Disqualification
•
Delay of NDA Review
and Approval
•
Criminal Prosecution
•
Unapproved NDA
37

38. Contact ClinPharm Network at info@clinpharmnetwork.com