FDA’s Oversight of Clinical TrialsOverview of GCP Bioresearch

Monitoring Program

Carolyn HommelGood Clinical Practice Program

FDAFebruary 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 CompletedBy Program Type

All Centers - FY’03

CIIRBS/MBEQ

55%

11%

28%

n= 1,138

6%

BIMO Inspections Completed FDA FY 2003

CDRHCDERCFSANCBER

n= 1,13857%

31%

11%

0.2%

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– 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

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)

0

20

40

60

80

100

120

140

92 93 94 95 96 97 98 99 00 01 02 03

11 913 11

815

9

106*119110110

139

CI “For Cause” Inspection Assignments(CDER, FY 1992 - 2003)

0

20

40

60

80

100

120

FY 92 93 94 95 96 97 98 99 00 01 02 03

16 5 12 11 6 9 8 29

6169

64

109

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)

OAIVAINAIPending

n = 369

37%

52%

5%6%

2/19/04

Clinical Investigator Deficiency Categories

FY’03

0%

5%

10%

15%

20%

25%

30%

35%

40%

ProtocolRecordsConsentDrug AcAEs

n=369*

39%

29%

13%

7% 7%

*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 ClassificationsAll Centers - FY’03

NAIVAIOAIPending

n = 31356%

26%11%

2/19/04

7%

IRB Inspections - Deficiencies (FY’02: CDER assigned)

0%

5%

10%

15%

20%

25%

30%

35%

40%

Mem

bers

Min

utes

Writ

ten

Proce

dure

s

Con

sent

El

emen

ts

40%

36%

27%

22%

19%

N= 161

Con

tinui

ng

Rev

iew

Exp

. R

evie

w

9% 8%

Quo

rum

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 InspectionsCommon Deficiencies - FYs 1998-2000

0%

5%

10%

15%

20%

25%Failure to adequatelymonitor study

Failure to documentmonitoring visits

Failure to have orfollow SOPs

Failure to maintaindrug acct. records

Failure to selectqualified monitors

Failure to assure IRBapproval of study

n= 39

23%21%

18%

15%13%

10%

Sponsor/Monitor/CRO Inspections All Centers - FY 03

NAI

VAI

OAI

Pending

36%

12%

n = 127

35%

17%

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:– 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

0

20

40

60

80

100

FY 96 97 98 99 00 01 02 03

8283

92

75

6170

74

87

Bioequivalence InspectionsClassifications

FY’03

NAI

Pending

OAI

VAI

28%

64%

n =84 *Updated 2/19/04

4%

4%

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