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
Inspected Entity
2002
2003
2004
2005
2006
Sponsor 72 81 73 70 53
Investigator
151
170
183
200
IRB
128 85 48 59
Lab 6 9 19 31 24
Source: “Device Clinical Trials and More….”, Michael E. Marcarellii, MassMEDIC, May 2007

10. Inspections by FDA Center (05)
Inspected Entity
CDER
CBER
CDRH
Sponsor 31 5 70
Investigator
382 98
183
IRB
113 10 48
TOTAL
526
301
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 ).
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 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) (
“Building Quality into Device Clinical Trials, Part 1,” Michael E. Marcarelli et al., MDDI (Jul 2006): pg (
“Building Quality into Device Clinical Trials, Part 2,” Michael E. Marcarelli et al., MDDI (Oct 2006): pg (
“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 (
“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
FDA BIMO Compliance Program Manuals (online at

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