# Presentation: 345931

## 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)

**Notes:**
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.

## 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

**55%**

**11%**

**28%**

**n= 1,138**

**6%**

## BIMO Inspections Completed FDA  FY 2003

- n= 1,138

- 57%

- 31%

- 11%

- 0.2%

- 2/19/04

**Notes:**
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

## 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)

**Notes:**
Form 1572 for Drugs and Biologics
“Agreements” per Device regs (812.20(b)(4))

## 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)

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

- 11

- 9

- 13

- 11

- 8

- 15

- 9

- 106*

- 119

- 110

- 110

- 139

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

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

-     16      5      12    11      6       9      8

- 29

- 61

- 69

- 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)

- Clinical Inspections Center for Drug Evaluation and Research - FY’03(Domestic & International)

- n = 369

- 37%

- 52%

- 5%

- 6%

- 2/19/04

## Clinical Investigator Deficiency CategoriesFY’03

- 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

**Notes:**
OHRP regulations may also apply if the study involves and FDA regulated product, AND is Federally funded.

## 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

- n = 313

- 56%

- 26%

- 11%

- 2/19/04

- 7%

**Notes:**
On the data sheet for this chart, there is one pending case, but “2” was entered so that the slice would be visible.

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

**Members**

** ****Minutes**

**Written **
**Procedures**

**Consent **
**Elements**

**40%**

**36%**

**27%**

**22%**

**19%**

**N= 161**

**Continuing **
**Review**** **

**Exp.**
** ****Review**

**9%**

**8%**

**Quorum**

## 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

- 23%

- 21%

- 18%

- 15%

- 13%

- 10%

## Sponsor/Monitor/CRO Inspections All Centers - FY 03

- 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

- FY    96    97    98    99     00     01   02    03

- 82

- 83

- 92

- 75

- 61

- 70

- 74

- 87

## Bioequivalence InspectionsClassificationsFY’03

- 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](mailto: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