1. 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

2. 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.

3. BIMO Program Objectives Protect the rights, safety, and welfare of human research subjects Assure the quality, reliability, and integrity of data collected

4. FDA Organization Chart ORA PROGRAM ENFORCEMENT BRANCH SPECIAL INVESTIGATIONS BRANCH

5. 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

6. Who does CDRH BIMO Inspect? Clinical Investigators (CI) Sponsors/Monitors/CROs Institutional Review Boards (IRB) Non-Clinical Labs (aka GLP)

7. CDRH Inspection Triggers Marketing application subject to MDUFMA Novel Technology Vulnerable Population Complaint Surveillance IRBs

8. 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

9. 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

10. BIMO Inspections (cont’d) INSPECTIONAL FINDINGS –CLOSEOUT DISCUSSION w/MANAGEMENT –SIGNIFICANT OBSERVATIONS (FDA Form 483)

11. Prompt and adequate responses may be helpful. Help CIs respond to noted observations. Written 483 Responses

12. 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:

13. 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

14. CDRH BIMO INSPECTIONS Fiscal Years 2002 - 2006

15. Inspected Entity 20022003200420052006 Sponsor7281737053 CI151170183 200 IRB12885734859 GLP69193124

16. CDRH BIMO Warning Letters

18. CDRH BIMO Compliance Rates

19. CDRH Sponsor Compliance Rates

20. Most Common CDRH Sponsor Deficiencies Inadequate monitoring Failure to secure investigator compliance Inadequate device accountability Failure to obtain FDA/IRB approval

21. CDRH Clinical Investigator Compliance Rates

22. 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

23. 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

24. 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

25. Web Sites Device Advice www.fda.gov/cdrh/devadvice CDRH BIMO site www.fda.gov/cdrh/comp/bimo.html Good Clinical Practices www.fda.gov/oc/gcp/

26. 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