1. The FDA Inspection Process
February 17, 2010

2. Topics Discuss the FDA inspection process
Describe the type of outcomes
Review material that is reviewed during an inspection

3. Who Performs the Inspections?
Office of the Commissioner
Office of Regulatory Affairs
Bioresearch
Monitoring
Program
(BIMO)
6 Region Offices
CDER
20 District Offices
CBER
130 Resident Posts
CDRH

4. FDA Inspections in Clinical Research
BIMO INSPECTION PROGRAM (CDER)
Good Laboratory Practice (GLP)
* In vivo Bioequivalence
Good Clinical Practice (GCP)
* Institutional Review Boards
* Clinical Investigators
* Sponsor-Monitors, CROs

5. Essential Pieces

6. Project Cohesiveness

7. Complete Application

8. BIMO Inspections
Inspections can be performed during any phase of the development process
“Directed” inspections are typically assigned during the IND phase
Inspections conducted during the NDA phase can be “Routine”, “For Cause”, or “Directed”

9. Regulatory Authority to Conduct Inspections/Audits
21 CFR
“An investigator shall upon request from any properly authorized officer or employee of FDA, at reasonable times, permit such officer or employee to have access to, and copy and verify any records or reports made by the investigator pursuant to ”

10. General Goals of Inspection: Clinical Investigator Program
Adherence to applicable regulations with respect to Good Clinical Practice
Validity of studies in support of marketing applications
Ensuring that rights, safety and welfare of study subjects have been protected

11. Inspection Preparation

12. Preparing Ahead For an FDA Inspection
General Tips
The time to start preparing for an FDA inspection is at the beginning of a study!
Keep all records and documents current and appropriately filed (easily accessible)
Keep all communications from different studies separate from each other

13. Preparing Ahead For an FDA Inspection
General Tips (continued)
Document and file all pertinent communication with key sponsor personnel and with other external personnel (vendors, project partners, etc.)
Conduct periodic QC reviews to ensure data integrity
Identify/know team/personnel who will interact/respond to FDA during an inspection
Ensure all staff are educated on proper conduct during an FDA inspection
Know GCPs, regulations/guidelines, SOPs and study specific information (or at least know how to access resources to get the information)

14. Preparing Ahead for an FDA Inspection
General Tips (continued)
-Use an “adequate” NTF system to explain situations or provide information that doesn’t fit nicely into other categories.
The NTF should have the following elements:
Identify and correct the problem
Record changes in procedure to prevent future occurrences
Follow through – document that a new process/procedure is in place

15. FDA Inspection Outcomes
No inspectional findings
FDA 483 Observations
Documents non-compliance with regulations only (can not cite for non-compliance with guidelines)
May be left at the site at the end of the inspection or sent later
EIR (Establishment Inspection Report)
Will list findings: non-compliance with both regulations and guidelines
Site/Organization may or may not receive a copy

16. FDA Compliance Program Guidance 7348
FDA Compliance Program Guidance Bioresearch Monitoring Clinical Investigators

17. What will FDA Inspect? Determining facts surrounding study
Who performed specific tasks
Degree of delegation of authority
Where study procedures were performed
How and where data was recorded
How test article accountability was maintained
How monitor communicated with investigator
How monitor evaluated the study’s progress

18. What will FDA Inspect? Subjects exist and have disease
Study data
Subjects exist and have disease
Subjects meet inclusion/exclusion criteria
Protocol followed
AEs reported and all reports adequate
Consent obtained
IRB approval obtained
CRFs accurate
Dropout subject documentation
Retention of study blind

19. What will FDA Inspect? The Investigator
Authority and Administration
How investigator was notified of study specifics
Was delegation appropriate?
What laboratory was used. If local, was laboratory facility adequate
Determine if and why investigator discontinued study before completion
Protocol Compliance
Test Article Accountability
Electronic Records and Signatures
Consent of Human Subjects
IRB Interactions

20. What will FDA Inspect? Subject Records AE Documentation and Reporting
Records Retention
Sponsor
Was copy of ICF provided to sponsor?
Were periodic reports submitted?
Determine if and how AEs were reported to sponsor
Timeliness of CRF submission to sponsor
Were all intercurrent illnesses/concomitant therapies reported to sponsor
How was study monitored; method and frequency
Review all 1572’s

21. Fair game for the inspection?
ECGs
Videos (i.e. 2nd. Look laparoscopic procedures)
Diaries
Electronic records
X-rays
Flyers/Radio Ads
Post-it-notes
Audit Reports

22. Key Areas to control
PI Involvement
Adequate Staffing/time
Well documented screening
Processes to assure protocol compliance
Documentation, Documentation, Documentation
AEs taken seriously

23. Title 21 CFR Part 11 Validation Record generation and copying
Record protection
Access
Audit Trails
Operational system checks
Authority checks
Device/Terminal Checks
Training/User accountability
System document control
Controls for open systems
Electronic Signatures

24. GCP Tips VERY POPULAR ACRONYM (ALCOA) A – Attributable L – Legible
C – Contemporaneous
O – Organized
A – Accurate

25. GCP Tips cont. (RARE) R – reproducible A – accurate R – reliable
E – (able to be) evaluated

26. Compliance Classifications
NAI – No Action Indicated
Inspected firm is in compliance
VAI - Voluntary Action Indicated
Deviation(s) from the regulations
Voluntary correction is requested
OAI - Official Action Indicated
Because of serious non-compliance requiring regulatory or administrative action by FDA

27. Violative Actions
Revision to the protocol without obtaining the sponsor’s written concurrence
Failure to submit revised protocol to IRB for approval
Failure to obtain written informed consent and provide oral explanation of the study
Failure to update consent forms to reflect changes in the protocol
Over-delegation to non-physicians (e.g., diagnosis that qualifies/determines eligibility for entry into the study)
Improper corrections to essential documents - Erasures, white-out or obliteration of original data entered on either CRFs or medical charts
Changes made to study data without checking the source documents or without justification for change
Back dating consent forms and signatures
Failure to obtain IRB approval of consent form revisions
Changes to study data without the investigator’s concurrence, especially after the investigator has “signed-off” the completed CRF

28. Violative Actions
Creation of fake records or patients by using demographic data or using blood, urine and tissue samples from other subjects
Patients’ diaries altered to reflect a positive outcome
Using site personnel as subjects to which they did not meet inclusion criteria for study article under investigation
Destruction of study records

29. Consequences of non-compliance (not all inclusive)
Warning Letters
NIDPOE Letters
Disqualification
Untitled Letters

30. Clinical Investigator Deficiencies CDER Inspections (all) – FY 2006
35% of the deviations related to protocol deviations
23% related to records maintenance
9% related to drug accountability documentation
6% related to consent process
5% were related to reporting of AEs

31. Adequate FDA 483 Response Submit a prompt written response
-assess the root cause of the problem
-Explain actions to correct the problem
-Evaluate the extent of the problem
-Implement preventative actions to avoid recurrence
-include supporting documentation
-provide REALISTIC timelines for implementation and correction

32. Questionable Research
Scientific Misconduct Percentage in survey of US based scientists who engaged in questionable research practices
15.5% - Changed a study's results to satisfy a funding source
15.3% - Dropped data from analysis based upon a "gut feeling"
12.5% - Overlooked other's use of flawed/questionable data
10.8% - Withheld research results
7.6% - Circumvented minor rules protecting humans subjects
Source: Nature June 2005
n = 3247

33. Warning Letter
Failure to personally conduct or supervise the clinical investigation [21 CFR ].
“Specifically, during the FDA inspection you informed the FDA investigators that you did not personally meet with at least two sub-investigators … who conducted the study, nor reviewed their research or clinic records regarding the subjects they enrolled.
You also informed FDA investigators that you were not aware that all the screening x-rays obtained by the two sub- investigators were re-interpreted by a second radiologist at the end of the study and that you were also not aware that only the results from the second radiologist were reported to the sponsor.”

34. Warning Letter Citations
Failure to secure investigator compliance with the investigational plan and applicable FDA regulations [21 CFR (b)]
-”…despite several clinical monitoring visits from …monitors, …and [your] own audits documenting serious protocol violations and regulatory noncompliance by multiple clinical investigators, these violations persisted.
-”there were overwrites on several subjects’ signature dates; thus, the actual date the subject signed the consent document was not clear”

35. Warning Letter Citations
Failure to secure investigator compliance with the investigational plan and applicable FDA regulations [21 CFR (b)]
“We note that generation of numerous memos to file after all subjects have completed the study does not adequately secure compliance of an investigator.”
“… method for securing compliance (i.e., the generation of more than 125 memos to file for protocol and informed consent deviations noted at the site) was not adequate.”

36. Quality Assurance & Regulatory Compliance
Contact Information
Al Chester
Quality Assurance & Regulatory Compliance