Device Clinical Trials and More…

Michael E. Marcarelli, PharmD

Director, Division of Bioresearch Monitoring

Office of Compliance

Center for Devices and Radiological Health

US Food and Drug Administration

BIMO Program Description

• A comprehensive, Agency-wide program of on-site inspections and data audits designed to monitor all aspects of the conduct and reporting of

FDA-regulated research.

BIMO Program Objectives

• Protect the rights, safety, and welfare of human research subjects

• Assure the quality, reliability, and integrity of data collected

FDA Organization Chart

FDA

CDER CFSAN CVMCDRHNCTR CBER

Office of Compliance

Division of BIMO

ORA

PROGRAM ENFORCEMENT

BRANCH

SPECIAL INVESTIGATIONS

BRANCH

CDRH BIMO Program Responsibilities

• Regulatory Inspections– Develop and issue inspection assignments– Review and assess EIRs– Determine proper compliance action

• Integrity Program - Application Integrity Policy (AIP) - Integrity Hold (IH)

• Promotion and Advertising (P&A)– Investigational Devices

• Educational outreach

Who does CDRH BIMO Inspect?

• Clinical Investigators (CI)• Sponsors/Monitors/CROs• Institutional Review Boards (IRB)• Non-Clinical Labs (aka GLP)

CDRH Inspection Triggers

• Marketing application subject to MDUFMA • Novel Technology• Vulnerable Population• Complaint• Surveillance

• IRBs

What do we look at?

• Compliance programs• 7348.808/9/10/11• http://www.fda.gov/ora/compliance_ref/bimo/

• Intangibles• FDA Perception• Corporate culture• Oversight and control• Patterns of behavior or failures• Attitude

BIMO Inspections

• Section 704 FD&C Act• Generally will call to schedule

– What if they don’t?

• Credentials/NOI (Form FDA 482)• Use FDA Compliance Program

– Inspectional focus• Usually a specific study• Interviews• Document Reviews• Intangibles

BIMO Inspections (cont’d)

• INSPECTIONAL FINDINGS

– CLOSEOUT DISCUSSION w/MANAGEMENT

– SIGNIFICANT OBSERVATIONS (FDA Form 483)

• Prompt and adequate responses may be helpful.

• Help CIs respond to noted observations.

Written 483 Responses

• Assessment of the root cause of the problem

• Any corrective actions to correct the problem

• An evaluation of the extent of the problem

• Any preventative actions to avoid recurrence

• Supporting documentation

• Timelines for implementation

Written 483 Responses Should Include:

Compliance Tools

• Untitled/Warning letter• Re-inspection• Informal conference• 3rd party audits• Rejection of site data• Disqualification

– CI, IRB, or GLP

• Invoke Application Integrity Policy or Integrity Hold

• Revoke marketing or research permit

• Civil Money Penalties• Seizure• Injunction• Prosecution

CDRH BIMO INSPECTIONSFiscal Years 2002 - 2006

357 353 350332 336

100

200

300

400

500

FY02 FY03 FY04 FY05 FY06

CDRH BIMO INSPECTIONSFiscal Years 2002 - 2006

Inspected Entity 2002 2003 2004 2005 2006

Sponsor 72 81 73 70 53

CI 151 170 183 183 200

IRB 128 85 73 48 59

GLP 6 9 19 31 24

14

44

3024

9

31

0

5

10

15

20

25

30

35

40

45

50

FY01 FY02 FY03 FY04 FY05 FY06

CDRH BIMO Warning Letters

7

2018

10

6

3

7

3

3

1

24

17

7

2

7

3

0

10

20

30

40

50

FY02 FY03 FY04 FY05 FY06

GLP

IRB

Sponsor

CI

CDRH BIMO Warning Letters

CDRH BIMO Compliance Rates

13% 12%17%

24%

15%11%

0%

10%

20%

30%

40%

50%

60%

70%

10 Years FY02 FY03 FY04 FY05 FY06

NAI

VAI

OAI

CDRH Sponsor Compliance Rates

19%

10%

24%

31%

15%11%

0%

10%

20%

30%

40%

50%

60%

70%

10 Years FY02 FY03 FY04 FY05 FY06

NAIVAIOAI

Most Common CDRHMost Common CDRHSponsor DeficienciesSponsor Deficiencies

• Inadequate monitoring

• Failure to secure investigator compliance

• Inadequate device accountability

• Failure to obtain FDA/IRB approval

CDRH Clinical Investigator Compliance Rates

11%15% 17%

21%

11%

17%

0%

10%

20%

30%

40%

50%

60%

70%

10 Years FY02 FY03 FY04 FY05 FY06

NAI

VAI

OAI

Common Investigator Deficiencies

• Failure to follow investigational plan, investigator agreement, or protocol

• Protocol deviations

• Inadequate subject protection or informed consent

• Inadequate device accountability

• Lack of FDA or IRB approval

What’s new?

• FDA Guidances– Final guidance: Use of Computerized

Systems in Clinical Trials– Draft guidance: AE Reporting to IRBs– Draft guidance: Supervisory Responsibilities

of Investigators

• CDRH– PAS– Pre IDE/PMA

What can be done to modernize clinical trials?

• Build quality into each step of the clinical trials process

• Utilize a risk-based approach to variation; define acceptable levels

• Modify regulatory approaches to enhance continuous improvement

• Develop and implement standardization for each step of process

Web Sites

Device Advicewww.fda.gov/cdrh/devadvice

CDRH BIMO sitewww.fda.gov/cdrh/comp/bimo.html

Good Clinical Practiceswww.fda.gov/oc/gcp/

Contact Information

Michael E. Marcarelli, PharmD

FDA, CDRH, Office of Compliance

9200 Corporate Blvd

HFZ-310

Rockville, MD 20850

(240) 276-0125

Michael.Marcarelli@fda.hhs.gov