FDA

1
FDAs Oversight of Clinical TrialsOverview 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)

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)
• IRBs (250/year)
• Sponsors/CROs (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 CompletedBy Program TypeAll
Centers - FY03
6
11
28
55
n 1,138
6
BIMO Inspections Completed FDA FY 2003
11
31
0.2
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 7348.808
• Clinical Investigator CP 7348.811
• Institutional Review Board CP 7348.809
• Sponsor, CRO Monitors CP 7348.810
• In Vivo Bioequivalence CP 7348.001
• http//www.fda.gov/oc/gcp/compliance.html

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)

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
92 93 94 95 96 97 98 99 00 01 02
03
15
CI For Cause Inspection Assignments(CDER, FY
1992 - 2003)
109
69
64
61
29
16 5 12 11 6 9 8

FY 92 93 94 95 96 97
98 99 00 01 02 03
16
GCP InspectionsRoutine Vs. Directed

• Routine
• Inspections assigned for NDA/PMAs
• Directed
• Problems identified at IND/IDE stage
• Complaints to FDA
• FDA, other Agencies
• Sponsors/monitors
• Institutions/IRBs
• 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
• http//www.fda.gov/oc/gcp (Enforcement
  Information)

19
Clinical Inspections Center for Drug Evaluation
and Research - FY03(Domestic International)
6
5
37
n 369
52
2/19/04
20
Clinical Investigator Deficiency CategoriesFY03
39
29
13
7 7
n369
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 21 CFR 50

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 ClassificationsAll Centers - FY03
11
26
7
n 313
56
2/19/04
27
IRB Inspections - Deficiencies (FY02 CDER
assigned)
40
36
27
22
19
9
8
Written Procedures
Continuing Review
Consent Elements
Exp. Review
Members
Minutes
Quorum
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 InspectionsCommon
Deficiencies - FYs 1998-2000
n 39
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 Inspections
92
87
83
82
75
74
70
61
FY 96 97 98 99 00 01 02
03
42
Bioequivalence InspectionsClassificationsFY03
28
64
4
4
n 84
Updated 2/19/04
43
GCP Help and Information

• FDA Web Site dedicated to GCP Information
• http//www.fda.gov/oc/gcp
• Contact the OGCP Staff
• Email gcpquestions_at_oc.fda.gov
• Telephone [phone]
• Facsimile 301-827-1169

44
Where to Get Help

• Write Food and Drug Administration 5600 Fishers
  Lane, HF-34 Parklawn Building, Room 9C-24
  Rockville, MD 20857