1. Good Clinical Practices and FDA Inspections
Patricia Holobaugh
Chief, Bioresearch Monitoring Branch
Division of Inspections and Surveillance
Office of Compliance and Biologics Quality
Good Clinical Practices and FDA Inspections - Holobaugh

2. Agenda Define Good Clinical Practices
Describe FDA’s Bioresearch Monitoring Program for on-site inspections of clinical and animal studies
Explain when and how inspections are performed
Describe common deficiencies and what happens after the inspection
.....common deficiencies and what happens after an inspection
Good Clinical Practices and FDA Inspections - Holobaugh

3. Good Clinical Practices
GCP is a standard for the design, conduct, performance monitoring auditing, recording, analysis, and reporting of clinical trials.

4. Regulations Investigational Application
21 CFR Part 312 IND drugs and biologics
21 CFR Part 812 IDE
21 CFR Part 809 IVD
Marketing Application
21 CFR Part 601 BLA biologics
21 CFR Part 314 NDA drugs
21 CFR Part 814 PMA devices

5. Regulations 21 CFR 50 Protection of Human Subjects Informed Consent
Safeguards for Children
21 CFR Part 56 Institutional Review Boards
21 CFR Part 11 Electronic Records; Electronic
Signatures

6. Examples of GCP Guidance Documents
Guideline for Monitoring Clinical Investigations (1998)
Information Sheets for IRBs and Clinical Investigators (1998)
ICH GCP Consolidated Guideline E6 (1997)

7. Regulations Guidance
Good Clinical Practices and FDA Inspections - Holobaugh

8. FDA’s Bioresearch Monitoring Program (BIMO)
Clinical Investigators
Sponsor/Monitor/Contract Research
Organizations
Institutional Review Boards
Nonclinical Laboratories

9. When are BIMO Inspections conducted?
Submission of BLA / PMA
Referrals from CBER staff
Referrals from other Centers/ORA
Complaints from sponsor, IRBs, and consumers
Routine surveillance of ongoing studies
target 50 pediatric sites this FY
CBER started its surveillance program in 2000 following the death of a subject in a gene therapy study.
We have issued approximately 200 surveillance inspections.
Have expanded surveillance to all product areas:
blood products under IND
vaccines
cell therapies
gene therapies
“other” OCTGT products
Good Clinical Practices and FDA Inspections - Holobaugh

10. Profile of CBER BIMO Inspections FY04-05 (thru 3/9/05)
189 Assignments issued
BLA PMA 15
CI surveillance 102
IRB
GLP
Complaints 12

11. True or False???
Clinical investigator: “I’m only doing phase 1 and 2 studies – I’ll never be inspected by FDA.”

12. True or False???
Clinical investigator: “I’m only doing phase 1 and 2 studies – I’ll never be inspected by FDA.”
FALSE
Clinical investigators of studies in all phases may (and are) inspected by FDA....
And ALL GCP regulations apply.

13. CBER continues its program to inspect ongoing studies under IND/IDE “Real-time” surveillance of phases 1/2/3
For FY 2005, we issued assignments to inspect 50 sites enrolling pediatric subjects
Cell therapies
Gene transfer
Vaccines
Blood products
Devices
We perform about 50 of these per year, and now cover all areas of active INDs and IDEs.
Good Clinical Practices and FDA Inspections - Holobaugh

14. History of CBER Surveillance Program
Started in 2000 following Gelsinger’s death in gene therapy study
Expanded to cell therapies, and then to all CBER IND/IDEs

15. Surveillance – Cross-Section of Sponsors (FY00-05)
Individuals 64
NIH + DOD 29**
Hospitals +
universities 11
“Big” companies 48
“Small” companies 84

16. Inspections for BLA / PMA How Many Sites per BLA/PMA?
Usually 3 to 5 study sites
...but sometimes more
Will inspect foreign sites when needed:
No US study or sites
Foreign data are critical
Good Clinical Practices and FDA Inspections - Holobaugh

17. Inspections for BLA / PMA Factors in Site Selection
Distribution of subjects
Distribution of subjects whose data are excluded
from S&E analyses
Inspection history of investigators
Inconsistent data for one site
increased efficacy
decreased incidence of adverse events

18. Inspections for BLA / PMA Factors in Site Selection
GCP problems reported by sponsor
Randomization cannot be reconstructed
Number of sub-investigators / sub-sites*
Pending workloads in FDA Districts

19. FDA Inspection “101”
Inspections are performed by ORA by specially-trained investigators
Center reviewers may participate
Most inspections are pre-announced
Interview: who did what, and how
Review of records
Closing discussion & issue Form FDA 483
CBER scientists can participate in the inspection, and can bring their knowledge of the application to look at specific aspects of the study.
For example, an OCTGT reviewer went on an inspection of NGVL vector labs.
Good Clinical Practices and FDA Inspections - Holobaugh

20. Comparison of Data in BLA / PMA to Source Data
Sponsor
Source Data
CRF
Good Clinical Practices and FDA Inspections - Holobaugh 15

21. Where is “Source Data” Defined?
NOT defined in 312 or 812
See GLP regs
21 CFR 58.3(k) – “raw data”
21 CFR (e) – describes how data are to be recorded, corrected, and describes automated systems.

22. Elements of Data Quality = ALCOA
Attributable
Legible/readable
Contemporaneous
Original
Accurate

23. After the Inspection
Inspected party may respond in a letter - send to address on the Form FDA-483.
May also ask the FDA investigator for the HQ Center address
The inspection report is written by the FDA investigator and sent to the Center.
The items listed on this form will likely have been discussed during the inspection. By the closing of the inspection, these items should not be a suprise.
This is an opportunity for the inspected party to provide documents not located during the inspection.
Good Clinical Practices and FDA Inspections - Holobaugh

24. After the Inspection (2)
The Center evaluates the report, and determines the corrective action.
Classifications
NAI – No Action Indicated
VAI – Voluntary Action Indicated
OAI – Official Action Indicated
We write a letter following most inspections
Good Clinical Practices and FDA Inspections - Holobaugh

25. Most Common CI Violations
Failure to follow the protocol
example: Required testing is incomplete
Recordkeeping errors
Informed consent problems

26. Most Significant Violations
Enrollment of ineligible subjects
Violation of protocol affecting safety
Extensive data corrections and questionable changes
Inadequate oversight of study personnel
Inappropriate delegation of authority
Poor oversight of satellite sites
No Informed consent
Failure to communicate with IRB

27. Significance of Violations
Do the violations
...affect rights, safety, or welfare of subjects?
...directly impact integrity of data set?
...indicate systemic problems within the study? sponsor problems?
Did the sponsor report the problems to FDA?
...indicate that other studies at that site might be impacted? investigator problems

28. Inappropriate delegation to subinvestigators
Investigator – individual who actually conducts an investigation (i.e., under whose immediate direction the drug is administered or dispensed to subjects.
How many miles (or states!) away ????
Sponsor should assure that the CI controls the study
For example, we inspected a California investigator who had sub-investigators in Arizona and Nevada. The investigator NEVER visited the subinvestigators to see that the study was being properly performed.
EACH site should have had a clinical investigator sign a 1572 to be responsible for the study.
Good Clinical Practices and FDA Inspections - Holobaugh

29. Possible Administrative Actions
Warning Letter
Determine if the data are reliable
Complete and accurate?
Delay approval of BLA/PMA
Clinical hold
Disapproval of IDE
Initiate termination of IND
Initiate disqualification of investigator
Initiate Application Integrity Policy
Refer to Office of Criminal Investigations
We summarize the findings of our inspection in a BIMO Summary Review Memo to the BLA review committee
Good Clinical Practices and FDA Inspections - Holobaugh

30. Your Questions for CBER
Can case report forms be source documents?
Yes – protocol should specify how data are to be captured and records are to be maintained.
Are diaries, questionnaires, photos subject to inspection?
Yes –these need to be maintained by CI per 21 CFR (c)

31. Your Questions for CBER
What data points should be captured on case report forms?
What data should be entered into a database for analysis?
Data critical to determining safety and efficacy endpoints. Protocol is roadmap for required tests. Consult FDA review team.

32. Your Questions for CBER
Does FDA audit systems & databases to ensure they are validated?
FDA does not audit computerized systems for clinical trials.
Sponsor is responsible for QA of computerized systems used by the sponsor, and for determining whether systems used by investigator sites are suitable for their study.
See FDA Guidance “Computerized Systems Used in Clinical Trials”

33. Your Questions for CBER
For clinics without medical records system in place, how
should study records and source documents be
maintained when subjects participate in one or more
studies?
Do you recommend that subject source records and
health information be maintained in a central file, with
study-specific CRFs maintained separately?
No regulation for this. Records should be retrievable
and meet (c) retention requirements. Records
must be maintained at site if clinical investigator
departs. Recommend SOPS explaining how an alternate
record system is utilized.

34. If You have GCP Questions......
Contact CBER’s Bioresearch Monitoring Branch --
Pat Holobaugh OR
Contact your IND/IDE reviewer