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 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 /9/10/11 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 INSPECTIONS Fiscal Years

Inspected Entity Sponsor CI IRB GLP

CDRH BIMO Warning Letters

CDRH BIMO Compliance Rates

CDRH Sponsor Compliance Rates

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

CDRH Clinical Investigator Compliance Rates

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 Advice CDRH BIMO site Good Clinical Practices

Contact Information Michael E. Marcarelli, PharmD FDA, CDRH, Office of Compliance 9200 Corporate Blvd HFZ-310 Rockville, MD (240)