1. Carolyn Hommel Good Clinical Practice Program FDA February 25, 2004
FDA’s Oversight of Clinical Trials Overview of GCP Bioresearch Monitoring Program
Carolyn Hommel
Good Clinical Practice Program
FDA
February 25, 2004

2. “BIMO”
FDA calls its program of on-site inspections for GCP and GLP its “Bioresearch Monitoring Program” or “BIMO”
The program includes inspections of:
Clinical Investigators
Sponsors, monitors, CROs
Institutional Review Boards
Bioequivalence Laboratories and Facilities
GLP Facilities (nonclinical studies)
Inspection assignments are issued by the Centers.
GCP responsible for HSP/GCP policy. Coordinates program across the centers to ensure consistency in HSP/GCP policy (HSP GCP - Steering Committee). Coordinates GCP BIMO Operational activities via the GCP Roundtable.

3. GCP “BIMO” Inspections (Clinical Trials)
Each year, FDA conducts approximately 1100 GCP BIMO inspections most inspections are of clinical investigators
Clinical Investigators (700/year)
IRB’s (250/year)
Sponsors/CRO’s (100/year)
Bioequivalence Facilities (50/year)
Inspections may be conducted anywhere in the world for studies submitted to FDA

4. Focus of FDA Inspections
Data auditing is a major component of GCP BIMO inspections conducted at clinical investigator and sponsor sites
IRB inspections are more oriented toward the process of IRB review and the maintenance of required records

5. BIMO Inspections Completed By Program Type All Centers - FY’036%
11%
28%
55%
n= 1,138

6. BIMO Inspections Completed FDA FY 2003
11%
31%
0.2%
Slide datasheet has “10” instead of “2” for CFSAN; otherwise slice would not appear. “2” is the correct number of BIMO inspections done for CFSAN in 2003
57%
n= 1,138
2/19/04

7. Program Objectives
To verify the quality and integrity of bioresearch data
To protect the rights and welfare of human research subjects

8. Bioresearch Monitoring (BIMO) Compliance Programs
FDA has compliance programs which serve as written procedures for conducting BIMO inspections
Good Laboratory Practice CP
Clinical Investigator CP
Institutional Review Board CP
Sponsor, CRO Monitors CP
In Vivo Bioequivalence CP

9. Clinical Investigator Program
Provides for study specific inspections and audits of physicians, veterinarians, and other investigators conducting clinical trials of human and veterinary drugs, medical devices, biologicals, etc.

10. Clinical Investigator Regulations
In order to receive investigational articles, each clinical investigator must sign an agreement to follow regulations governing use of investigational products
Regulations
21 CFR 312 (Human Drugs)
21 CFR 812 (Medical Devices)
21 CFR 511 (Veterinary Drugs)
Form 1572 for Drugs and Biologics
“Agreements” per Device regs (812.20(b)(4))

11. Primary Regulatory Obligations Include Commitment to
Follow the approved protocol or research plan
Obtain informed consent and adhere to FDA regulations regarding protection of human research subjects
Maintain adequate and accurate records of study observations
Administer test article only to subjects under control of the investigator

12. Nature of Program Study specific data audits announced in advance
Inspection includes interview with clinical investigator and in-depth data audit to validate study findings and verify investigator compliance with regulations

13. GCP “BIMO” Inspections
Performed for every NDA
May be performed during the IND at any phase of product development
May be assigned based on complaints received by FDA (from subjects, IRBs, industry)

14. Complaints Received: 1992-2003 (CDER)
139
119
110
110
106* 15 13 11 11 9 8 9

15. CI “For Cause” Inspection Assignments (CDER, FY 1992 - 2003)
109 69 64 61 29 FY

16. GCP Inspections: Routine Vs. Directed
Inspections assigned for NDA/PMA’s
Directed
Problems identified at IND/IDE stage
Complaints to FDA
FDA, other Agencies
Sponsors/monitors
Institutions/IRB’s
Subjects/Public

17. Compliance Classifications
NAI- No Action Indicated
No objectionable conditions or practices were found during the inspection (or the objectionable conditions found do not justify further regulatory action)
VAI-Voluntary Action Indicated
Objectionable conditions or practices were found, but FDA is not prepared to take or recommend any administrative or regulatory action.

18. Compliance Classifications
OAI- Official Action Indicated
Regulatory and/or Administrative actions will be recommended due to significant objectionable observations
Warning Letters and other correspondence
Accessible from the GCP Website
(Enforcement Information)

19. Clinical Inspections Center for Drug Evaluation and Research - FY’03 (Domestic & International)6% 5%
37%
n = 369
52%
2/19/04

20. Clinical Investigator Deficiency Categories FY’03
39%
29%
13%
7% %
n=369*
*Inspections conducted
for CDER

21. Regulatory/Administrative Follow-up
Rejection of study
Disqualification
Prosecution

22. Institutional Review Board (IRB)
Means any board, committee or other group formally designated by an institution to review, to approve the initiation of, and to conduct periodic review of, biomedical research involving human subjects.
The primary purpose of such review is to assure protection of the rights and welfare of the human subjects.

23. Regulatory Basis of Program
All FDA regulated research involving human subjects must be covered by an IRB operating in accordance with 21 CFR 56
Informed consent must be obtained from all human research subjects in accordance with CFR 50
OHRP regulations may also apply if the study involves and FDA regulated product, AND is Federally funded.

24. Nature of Program
Program provides for regularly scheduled inspections of IRBs to verify compliance with regulations
IRBs associated with active INDs (Form FDA 1572)
Program objective is protection of human research subjects, rather than data validation

25. Nature of Program Inspections are announced and scheduled in advance
Consists of interviews with responsible IRB staff
In-depth review of SOPs, files and records
Active studies used to assess IRB operations and conformance to regulatory requirements

26. IRB Classifications All Centers - FY’03
11%
26% 7%
On the data sheet for this chart, there is one pending case, but “2” was entered so that the slice would be visible.
56%
n = 313
2/19/04

27. IRB Inspections - Deficiencies (FY’02: CDER assigned)
40%
36%
27%
22%
19% 9% 8%
Written
Procedures
Continuing
Review
Consent
Elements
Exp.
Review
Minutes
Quorum
Members
N= 161

28. Regulatory/Administrative Follow-up
Restriction of IRB approval of new studies or entry of subjects
Disqualification

29. Sponsor, Contract Research Organization, Monitor Program
Program provides for inspections of those parties responsible for initiating, overseeing, and submitting the results of research to FDA
Regulations
21 CFR 312
21 CFR 812
21 CFR 50, 54, 56

30. Regulatory Obligations of Sponsors
Label investigational products appropriately
Initiate, withhold, or discontinue clinical trials as required
Refrain from commercialization of investigational products
Control the distribution and return of investigational products
Select qualified investigators to conduct and monitor studies

31. Sponsor Obligations (continued)
Disseminate appropriate information to investigators
Evaluate and report adverse experiences
Maintain adequate records of studies
Submit progress reports and the final results of studies

32. Nature of Program
Study specific inspections routinely announced in advance consisting of records audit and interviews
Inspection assigned for each NME in CDER and each PMA in CDRH
Objective is to evaluate compliance with regulations and validate data

33. Nature of program (continued)
Principal areas covered:
Organization and personnel
Selection of clinical investigators
Selection of monitors and monitoring procedures followed
Reporting of adverse experiences and reactions
Test article characterization and accountability

34. Sponsor/Monitor/CRO Inspections Common Deficiencies - FYs 1998-2000
23%
21%
18%
15%
13%
10%

35. Sponsor/Monitor/CRO Inspections All Centers - FY 03
12%
17%
36%
35%
n = 127
Updated 2/19/04

36. Regulatory Requirements
Bioequivalence studies are conducted primarily
To support an abbreviated new drug application (ANDA) for generic copy
For new dosage form or formulation of marketed drug

37. Bioequivalence Inspection Program
Bioequivalence studies supporting NDAs may be inspected when appropriate
Pivotal to decision-making
Concerns about data integrity

38. Bioequivalence Regulations
21 CFR 320, 314, 312
21 CFR 50, 56 (Consent, IRB)

39. Bioequivalence Inspection Program
Inspection of clinical facilities and analytical labs associated with bioequivalence studies
Focus is on bioequivalence studies supporting ANDAs; in particular:
New facilities
Previously violative sites
Suspicious data
Non-conventional study

40. Nature of Inspections
Includes physical inspection and technical evaluation of laboratory facilities and methods; multiple facilities may be involved
Includes audit of analytical and clinical data
Conducted by inspection team including laboratory chemist and field investigator

41. Bioequivalence Inspections92 87 83 82 75 74 70 61 FY

42. Bioequivalence Inspections Classifications FY’03
28%
64% 4% 4%
n =84
*Updated 2/19/04

43. GCP Help and Information
FDA Web Site dedicated to GCP Information:
Contact the OGCP Staff:
Telephone:
Facsimile:

44. Where to Get Help
Write: Food and Drug Administration Fishers Lane, HF Parklawn Building, Room 9C Rockville, MD 20857