Ensuring Quality in Medical Device Clinical Trials

1. Ensuring Quality in Medical Device Clinical Trials Paul Below, CCRA Clinical Research Consultant P. Below Consulting Great Plains Chapter ACRP Omaha, NE October 25, 2007

2. Acknowledgement This presentation is based upon similar recent presentations and articles by Michael Marcarelli, Director, Division of Bioresearch Monitoring, Office of Compliance, Center for Devices and Radiological Health (CDRH) Picture Source: Medical Device & Diagnostic Industry (Jul 2006): pg. 60.

3. Disclosure • I do not have a financial interest, arrangement or affiliation with a commercial organization that may have a material interest in the subject matter of my presentation.

4. Learning Objectives • Describe the FDA’s Bioresearch Monitoring Program (BIMO). • Review CDRH BIMO inspection activities and results. • Describe common sponsor and investigator deficiencies found during inspections. • Discuss strategies that sponsors can employ to improve GCP compliance and clinical trial quality.

5. BIMO Program Overview • Established in 1977 and expanded in 1992. • Comprehensive program of on-site inspections and data audits to monitor all aspects of the conduct and reporting of FDA regulated research. • Each FDA Center has its own BIMO program staff with overall coordination by the Office of Regulatory Affairs. • Implemented domestically and internationally resulting in over 1000 inspections annually.

6. BIMO Program Objectives • To ensure the quality and integrity of data submitted in support of investigational and marketing clearance submissions [IDEs, PMAs, and 510(k)s]. • To ensure that human subjects taking part in investigations are protected from undue hazard or risk.

7. Who is Inspected? • Clinical Investigators • Sponsors/Monitors/CROs • Institutional Review Boards • Non-Clinical Labs (aka GLP)

8. CDRH BIMO Inspection Rates Source: “Device Clinical Trials and More….”, Michael E. Marcarellii, MassMEDIC, May 2007

9. CDRH Inspection Categories Source: “Device Clinical Trials and More….”, Michael E. Marcarellii, MassMEDIC, May 2007

10. Inspections by FDA Center (05) Source: FDA Website

11. CDRH Inspection Triggers • Marketing application submission • Novel technology • Vulnerable population • Complaint

12. Inspection Process • FDA field inspectors from 19 district offices conduct inspections (according to BIMO Compliance Program Manuals 7348.808-811). • After inspection, FDA field inspector writes an establishment inspection report (EIR). • After district office review, the completed EIR package is sent to CDRH BIMO. • Once the EIR is received, it is assessed and classified by CDRH.

13. BIMO Review Milestones Source: “Building Quality into Device Clinical Trials, Part 2,” Michael E. Marcarelli et al., MDDI (Oct 2006)

14. Inspection Classifications • No Action Indicated (NAI) = the FDA field inspector did not identify objectionable practices or identified only minor issues that did not justify further action. • Voluntary Action Indicated (VAI) = indicates that objectionable practices were uncovered during the inspection, but were not significant.

15. Inspection Classifications • Official Action Indicated (OAI) = inspection uncovered significant objectionable practices, which could affect data reliability or compromise human subject protection. Generally results in the issuance of a Warning Letter or some other higher-level compliance action. • 15 day response required - failure to take action may result in administrative or regulatory action without further notice.

16. CDRH Warning Letters Source: “Device Clinical Trials and More….”, Michael E. Marcarellii, MassMEDIC, May 2007

17. Investigator Compliance Source: “Device Clinical Trials and More….”, Michael E. Marcarellii, MassMEDIC, May 2007

18. Sponsor Compliance Source: “Device Clinical Trials and More….”, Michael E. Marcarellii, MassMEDIC, May 2007

19. OAI Rates by FDA Center • Long-term OAI rates: • CDRH = 13% • CDER = 3% • Investigator warning letters issued in 2005: • CDRH = 20 • CDER = 2 • CBER = 4 Source: “Improving Clinical Compliance in the Medical Device Industry,” Barry Sall, MDDI, March 2006 & FDA Website

20. Investigator Deficiencies Source: “Building Quality into Device Clinical Trials, Part 2,” Michael E. Marcarelli et al., MDDI (Oct 2006)

21. Sponsor Deficiencies Source: “Building Quality into Device Clinical Trials, Part 2,” Michael E. Marcarelli et al., MDDI (Oct 2006)

22. Improving Quality • Marcarelli has proposed the following methods for sponsors to improve GCP compliance and clinical trial quality: • Implement a Quality Systems approach to the oversight and management of clinical trials • Employ the five habits of “highly effective” sponsors

23. Quality Systems • Quality systems regulations for medical devices are part of GMP and highlighted in 21 CFR part 820. • Covers quality management and organization, device design, buildings, equipment, purchase and handling of components, production and process controls, packaging and labeling control, device evaluation, distribution, installation, complaint handling, servicing, and records.

24. Quality Systems - CAPA • The most useful element of the quality system, as it applies to clinical studies, is the application of a Corrective and Preventive Action (CAPA) program. • CAPA entails the following: • Problems are identified and investigated • Root causes are identified • Corrective and preventive actions are identified and implemented • Actions are tracked and effectiveness is verified

25. Quality Systems - CAPA • Submit information for management review on identified problems and actions taken. • Track the progress and resolution of each case.

26. CAPA Example • Scenario: During routine monitoring, a CRA identifies several trial subjects who did not meet study inclusion/exclusion criteria. The site was not aware of these violations and had not reported them to the sponsor or IRB. • What is the root cause of these deficiencies? Forgot protocol requirements? Lack of PI oversight? Overwork/too busy? Apathy? Inadvertent error?

27. CAPA Example • What needs to be done to immediately correct these deficiencies? • Promptly report to sponsor and IRB • Determine if subject can continue participation in the study • Ensure adequate documentation of deviation is added to the source documents • Suspend further enrollment?

28. CAPA Example • What can be done to prevent these deficiencies from occurring again? • Additional training on protocol • Provide protocol reference materials such as pocket cards • Ensure investigator review of criteria prior to study • Require additional or new study staff • Require sponsor review of screening data and OK prior to randomization

29. CAPA Example • How will these deficiencies be submitted for management review? • Documented in monitoring report • Cataloged in database • Discussed during regular project team meetings • How will this CAPA issue be tracked until resolution? • Follow-up by CRA documented in “pending action items” section of monitoring report • Issue “closed out” in database when resolved

30. 5 Habits of Effective Sponsors • BIMO reviewed all device sponsor audits classified as NAI by the division between October 2003 and February 2006. • The division diligently reviewed and evaluated all the information noted by FDA field inspectors in the EIRs and found common threads, which translated into what they termed as the “Five Habits of Highly Effective Device Sponsors.”

31. 5 Habits of Effective Sponsors • #1 – Establish SOPs for such functions as investigator site selection, adverse event reporting, data handling, clinical site initiation, personnel training and site monitoring. • #2 – Hire employees with experience in conducting studies, e.g., managers with a background in clinical studies; subject matter experts for protocol development; monitors with clinical backgrounds; and regulatory personnel with expertise in clinical trial regulations.

32. 5 Habits of Effective Sponsors • #3 – Utilize consultants such as Contract Resource Organizations (CROs) for study functions beyond the sponsor’s in-house capabilities. • #4 – Conduct internal/external audits of clinical study processes, procedures and personnel to include regular audits of the clinical study department and its related procedures, and regular on-site audits of monitoring personnel and the monitoring process.

33. 5 Habits of Effective Sponsors • #5 – Management review of clinical study issues by personnel with executive responsibilities. This review includes analyzing clinical study progress reports during management review meetings and presenting problem reports to top executives in real time.

34. References • “Device Clinical Trials and More…”, Michael Marcarelli (presented to MassMEDIC on May 18, 2007) (www.massmedic.com/docs/cdrh07.ppt) • “Building Quality into Device Clinical Trials, Part 1,” Michael E. Marcarelli et al., MDDI (Jul 2006): pg. 60 (www.devicelink.com/mddi/archive/06/07/011.html) • “Building Quality into Device Clinical Trials, Part 2,” Michael E. Marcarelli et al., MDDI (Oct 2006): pg. 56 (www.devicelink.com/mddi/archive/06/10/015.html) • “Five Habits of Highly Effective Device Sponsors,” Michael Marcarelli, The Monitor (Feb 2007): pg. 83

35. References • “Improving Clinical Compliance in the Medical Device Industry,” Barry Sall, MDDI, March 2006 (www.devicelink.com/mddi/archive/06/03/016.html) • “An Interview with Michael Marcarelli: Improvements Seen in the Oversight of Medical Device Research,” Susan Rockwell, The Monitor (Apr 2006): pg. 62 • CDRH BIMO Program Website (online at http://www.fda.gov/cdrh/comp/bimo.html) • FDA BIMO Compliance Program Manuals (online at www.fda.gov/ora/cpgm/default.htm#bimo)

36. This presentation and related references are posted on my corporate website at:www.pbelow-consulting.com/devices.html (You are free to download and use this presentation for non-commercial, education purposes - all other uses require permission from the presenter)

37. Contact Information • Office: (952) 882-4083 • E-mail: paul@pbelow-consulting.com • Web: www.pbelow-consulting.com