FDA’s Oversight of Clinical Trials
Overview of GCP Bioresearch
Monitoring Program
Carolyn Hommel
Good Clinical Practice Program
FDA
February 25, 2004
“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)
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
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
BIMO Inspections Completed
By Program Type
All Centers - FY’03
6%
11%
CI
IRB
S/M
BEQ
28%
55%
n= 1,138
BIMO Inspections Completed
FDA FY 2003
11%
0.2%
31%
CDRH
CDER
CFSAN
CBER
57%
n= 1,138
2/19/04
Program Objectives
• To verify the quality and integrity of
bioresearch data
• To protect the rights and welfare of
human research subjects
Bioresearch Monitoring
(BIMO) Compliance Programs
• FDA has compliance programs which serve as written
procedures for conducting BIMO inspections
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–
–
–
–
Good Laboratory Practice
Clinical Investigator
Institutional Review Board
Sponsor, CRO Monitors
In Vivo Bioequivalence
CP 7348.808
CP 7348.811
CP 7348.809
CP 7348.810
CP 7348.001
http://www.fda.gov/oc/gcp/compliance.html
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.
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)
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
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
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)
Complaints Received: 1992-2003
(CDER)
139
140
106*
120
119 110 110
100
80
60
40
20
11 9
13 11
15
8
9
0
92 93 94 95 96 97 98 99 00 01 02
03
CI “For Cause” Inspection Assignments
(CDER, FY 1992 - 2003)
120
109
100
80
69
61
64
60
40
29
16
5
12 11
93 94
95
6
9
8
20
0
FY
92
96
97 98
99 00
01
02 03
GCP Inspections:
Routine Vs. Directed
• Routine
– 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
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.
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)
Clinical Inspections
Center for Drug Evaluation and Research - FY’03
(Domestic & International)
6%
5%
OAI
VAI
NAI
Pending
37%
n = 369
52%
2/19/04
Clinical Investigator Deficiency
Categories
FY’03
39%
40%
35%
29%
30%
25%
20%
15%
10%
5%
13%
7%
7%
Protocol
Records
Consent
Drug Ac
AEs
n=369*
0%
*Inspections conducted
for CDER
Regulatory/Administrative Follow-up
• Rejection of study
• Disqualification
• Prosecution
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.
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
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
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
IRB Classifications
All Centers - FY’03
11%
7%
26%
NAI
VAI
OAI
Pending
56%
n = 313
2/19/04
IRB Inspections - Deficiencies
(FY’02: CDER assigned)
40%
40%
35%
30%
25%
36%
27%
22%
19%
20%
15%
9%
8%
10%
5%
0%
N= 161
Regulatory/Administrative
Follow-up
• Restriction of IRB approval of new studies
or entry of subjects
• Disqualification
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
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
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
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
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
Sponsor/Monitor/CRO Inspections
Common Deficiencies - FYs 1998-2000
n= 39
25%
Failure to adequately
monitor study
23%
21%
20%
Failure to document
monitoring visits
18%
15%
15%
Failure to have or
follow SOPs
13%
10%
10%
Failure to maintain
drug acct. records
5%
Failure to select
qualified monitors
0%
Failure to assure IRB
approval of study
Sponsor/Monitor/CRO Inspections
All Centers - FY 03
12%
17%
36%
NAI
VAI
OAI
Pending
35%
n = 127
Updated 2/19/04
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
Bioequivalence Inspection Program
• Bioequivalence studies supporting NDAs
may be inspected when appropriate
– Pivotal to decision-making
– Concerns about data integrity
Bioequivalence Regulations
• 21 CFR 320, 314, 312
• 21 CFR 50, 56 (Consent, IRB)
Bioequivalence Inspection Program
• Inspection of clinical facilities and analytical labs
associated with bioequivalence studies
• Focus is on bioequivalence studies supporting
ANDAs; in particular:
–
–
–
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New facilities
Previously violative sites
Suspicious data
Non-conventional study
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
Bioequivalence Inspections
92
100
82
87
83
75
74
61
80
70
60
40
20
0
FY 96
97
98
99
00
01 02
03
Bioequivalence Inspections
Classifications
FY’03
28%
NAI
Pending
OAI
VAI
64%
4%
4%
n =84
*Updated 2/19/04
GCP Help and Information
• FDA Web Site dedicated to GCP
Information:
• http://www.fda.gov/oc/gcp
• Contact the OGCP Staff:
• Email: gcpquestions@oc.fda.gov
• Telephone:
301-827-3340
• Facsimile:
301-827-1169
Where to Get Help
– Write: Food and Drug Administration
5600 Fishers Lane, HF-34
Parklawn Building, Room 9C-24
Rockville, MD 20857