1. FDA Compliance Enforcement Actions: What you need to know for clinical device trials
The 3rd Annual FDA Regulatory and Compliance Symposium
Track 3- Pharma Product Development and Clinical Trials
August 23, 2007
Cambridge, MA

2. The 3rd Annual FDA Regulatory and Compliance Symposium
PRESENTED BY:
Sonali P. Gunawardhana M.P.H., J.D., LL.M. Regulatory Counsel Food and Drug Administration
Center for Devices and Radiological Health Office of Compliance Division of Bioresearch Monitoring

3. Devices vs. Drugs
How do studies with investigational devices differ from those with drugs and biologics?
Nature of industry
Statutory distinctions
Regulatory distinctions
Research distinctions

4. Device Firms Entrepreneurial firms common
93% have fewer than 100 employees
Venture capitalized
Diverse and specialized products
Principles of operation and intended uses
Device “developer” often involved
Minimal clinical trial experience
Rapid product cycles limiting testing time

5. Statutory Distinctions
Devices lack market exclusivity provisions
Waxman-Hatch (drugs)
Orphan drug (drugs/biologics)
Differences in standards of approval
“Substantial” adequate and well-controlled trials (drug)
“Reasonable” valid scientific evidence (device)
Devices must down regulate
FDAMA (1997) “least burdensome” provision

6. Valid Scientific Evidence*
Well-controlled investigations
Partially controlled studies
Studies and objective trials without matched controls
Well-documented case histories by qualified experts
Reports of significant human experience with a marketed device
* 21 CFR 860.7

7. Research Applications
Investigational New Drug (IND) application
Covers all research (drugs and biologics)
21 CFR Part 312
Investigational Device Exemption (IDE)
Covers significant risk research
Implants, life-threatening, or sight-threatening
21 CFR Part 812

8. Regulatory Distinctions
IDE exempt studies
In vitro diagnostics (IVDs)
In commercial use before May 28, 1976
Consumer preference testing
Solely for veterinary use
Post Approval Studies

9. Marketing Applications
New Drug Application (NDA)
Innovator
21 CFR Part 314
Abbreviated New Drug Application (ANDA)
Substantial equivalence
Biologics Licensing Application (BLA)
21 CFR Part 601
Premarket Approval Application (PMA)
New Use, Technology, or Class III
21 CFR Part 814
Premarket Notification (510(k))
Substantial equivalence
21 CFR Part 807
Humanitarian Device Exemption (HDE)
Similar to Orphan Product
In Vitro Diagnostics (IVDs)
21 CFR Part 809

10. Product Distinctions
vs.

11. Charging for Investigational Products
Devices: Always have been able to charge in order to recoup the research cost. This request for reimbursement is generally submitted in the IDE.
Drugs: Special request is made for reimbursement – this was not the norm in the past but now there is a move towards making it easier for reimbursement.

12. Combination Products Types of products
Drug/device, biologic/device, drug/biologic, or drug/device/biologic
Products are assigned to lead Center based upon primary mode of action
Other Centers provide consulting reviews
Product is required to follow regulation of lead Center
Important to seek early consultation
FDA’s Office of Combination Products

13. Enforcement Actions REASONS WHY SOME OF THESE ACTIONS ARE IMPLEMENTED:
Untitled Letters/Warning Letters
Application Integrity Policy/ Integrity Hold
Notice of Initiation of Disqualification Proceedings and Opportunity to Explain (NIDPOE)

14. Compliance Tools
Invoke Application Integrity Policy or Integrity Hold
Revoke marketing or research permit
Civil Money Penalties
Injunction
Prosecution
Untitled/Warning letter
Re-inspection
Informal conference
3rd party audits
Rejection of site data
Disqualification
CI, IRB, or GLP
85% of the time, you will receive an UL or an OK letter
DQ new to CDRH
CMP available to CDRH BIMO program not other Centers’ BIMO program

15. Untitled Letters
■ Untitled Letters are issued when substantial violations are documented during inspection and requests voluntary corrective action.
■Unlike Warning Letters, Untitled Letters are not posted on the FDA website.

16. Warning Letters
The Warning Letter is the agency’s principal means of notifying regulated industry of violations (prior notice) and achieving prompt voluntary correction.
The Warning Letter clearly states that if there is a failure to promptly achieve correction the FDA may take enforcement action without any further notice.

17. CDRH BIMO INSPECTIONS Fiscal Years 2002 - 2006

18. CDRH BIMO INSPECTIONS Fiscal Years 2002 - 2006
Inspected Entity
2002
2003
2004
2005
2006
Sponsor 72 81 73 70 53 CI
151
170
183
200
IRB
128 85 48 59
GLP 6 9 19 31 24

19. CDRH BIMO Warning Letters

20. CDRH BIMO Warning Letters

21. CDRH BIMO Compliance Rates

22. CDRH BIMO OAI Rates (with & w/o “For Cause” Inspections)
NFC = No “For Cause” inspections included

23. CDRH Sponsor Compliance Rates

24. CDRH Sponsor Compliance Rates

25. Sponsor Deficiencies Fiscal Years 1999 - 2006FY
1999
2000
2001
2002
2003
2004
2005
2006
Inadequate monitoring
65%
68%
33%
37%
40%
24%
23%
Failure to secure investigator compliance
27%
44%
19%
21%
15%
13%
Inadequate device accountability
28% 7%
16%
18%
Obtain FDA/IRB approval 4%
11% 8% 5%

26. CDRH Clinical Investigator Compliance Rates

27. CDRH Clinical Investigator Compliance Rates

29. Common Investigator Deficiencies
Follow investigational plan, investigator agreement, or protocol
Protocol deviations
Inadequate subject protection or informed consent
Inadequate device accountability
Lack of FDA or IRB approval
Inadequate reporting of UADEs to Sponsor or IRB

30. CDRH IRB Compliance Rates

31. IRB Deficiencies Fiscal Years 1999 - 2006FY
1999
2000
2001
2002
2003
2004
2005
2006
Inadequate initial &/or continuing review
64%
56%
39%
24%
25%
50%
37%
38%
Inadequate minutes
61%
42%
35%
11%
28%
17%
20%
Lack of or incorrect SR/NSR determination
58%
57%
10%
16%
34%
22% 7%
Inadequate membership roster
31%
30%
13%
21%
12%
Addendum: FY06 – Lack of Quorum & Reporting Non-Compliance 12%

32. CDRH BIMO OAI Follow-up Inspections (as of 9/30/06)
Recidivist OAIs evenly distributed across program areas:
GLP = 17%
IRB = 25%
CI = 33%
S/M = 25%
N = 64

33. CDRH BIMO Vulnerable Population Inspections
OAI split among Sponsor (44%) and Clinical Investigator (56%) programs
N = 164

34. CDRH BIMO COMPLIANCE RATES FY06: All Inspections vs. Complaints
11%
35%
36%
48%
17%
53%
333% higher OAI rate in complaint follow-ups

35. CDRH BIMO COMPLIANCE RATES FY97-06: All Inspections vs. Complaints
14%
26%
31%
46%
55%
28%
230% higher OAI rate in complaint follow-ups over a 10 year period

36. What does AIP mean?

37. Application Integrity Policy
■What is “Wrongful Act”?
■What is an “Untrue Statement of Material Fact”?

38. Wrongful Act
“…A wrongful act is any act that may subvert the integrity of the review process. A wrongful act includes but is not limited to, submitting a fraudulent application, offering or promising an illegal gratuity, or making an untrue statement of material fact. A wrongful act also includes submitting data that are otherwise due to, for example, a pattern of errors whether caused by incompetence, negligence, or a practice such as inadequate standard operating procedures or a system-wide failure to ensure the integrity of data submissions…”

39. Untrue Statement of Material Fact
“…An “untrue statement of material fact” is a false statement, misstatement, or omission of fact. A determination that an untrue statement is material is necessary for purposes of invoking the AIP…”
Materiality- Under Development
Agent- Under Development

40. Examples of Wrongful Acts
Submit Fraudulent Application
Offer Bribe/Illegal Gratuity
Make Untrue Statement of Material Fact
Submit Data Otherwise Unreliable
Omitted Data
Manufactured Data
Altered Data
Other Data Inconsistencies

41. Examples of Data Integrity Problems
Falsification of Specific Data or an Entire Submission
Omission of Relevant and Important Data and Information
Inability to Account for Patient Population
Inability to Account for Investigational Devices
Failure to Maintain Adequate Investigational Records
Unreported Changes to the Investigational Device

42. Process: Pre-Discovery Stage
Tips from Anonymous/Known Informant
Current/Former Employees
Former Business Partners
Patients
Other Agencies (SEC, FTC, CMS)
Suspicious Data Found During Scientific/Clinical Review
Observations During Pre-Approval Inspection

43. Process: Inspection Stage
Inspection of Company/ Sponsor
Inspection of Clinical Sites
Inspections of CRO’s
Data Audit
System Audit
Company Internal Documents

44. Invoking the AIP Pattern or Practice of Wrongful Conduct
Significant Question of Data Reliability
System-wide Failures
Decision made by Center Director, The Division of Bioresearch Monitoring and The Office of Device Evaluation Integrity Officer

45. Agency’s Action Defer Scientific Review Issues Letter to Applicant
Conducts Validity Assessment
Scope, extent of problem
Inspection
Audit Report

46. Applicant’s Responsibilities
Cooperation with FDA
Internal Review (Audit)
Independent Outside Consultant
Identify/Remove Individuals
Submit CAP
Commit to Safety, Efficacy and Quality
Describe Ethics/Compliance Programs
Standard Operating Procedures
Steps to Address and Prevent Wrongful Acts
Application Withdrawal, Patient Notification, Product Recall etc.

47. Global Industry Issues
Systems to identity and/or address regulatory shortcomings
Systems to correct/prevent recurring issues
Accountable company culture
Environment of conflict of interest

48. FDA Responsibilities Review of Corrective Action Plan
Field Onsite Inspection & Recommendation
Headquarters Review
Letter to Applicant
Center Director’s Signature

49. Application Integrity Program
“Fraud, Untrue Statements of Material Facts, Bribery, and Illegal Gratuities; Final Policy,”
56 F.R , 9/10/91

50. Application Integrity Program
Application Integrity Policy
RPM Chapter 10
“Points to Consider for Internal Reviews and Corrective Action Operating Plans”

51. Program Offices/Contacts
ODE/OIVD Integrity Officer
Carl DeMarco:
Division of Bioresearch Monitoring, Office of Compliance
Michael Marcarelli:
Application Integrity Policy Committee
FDA Office of Criminal Investigations

52. Notice Of Initiation Of Disqualification Proceedings And Opportunity To Explain
Applies to Clinical Investigators
Some clinical investigators may have already received a Warning Letter but in some cases violations discovered on the first inspection are serious enough for the Center to issue the NIDPOE.

53. Disqualification Of Clinical Investigators

54. Disqualification Of Clinical Investigators
A NIDPOE letter informs the recipient clinical investigator that FDA is initiating an administrative proceeding to determine whether the clinical investigator should be disqualified from receiving investigational products pursuant to the Food and Drug Administration's regulations. Generally, FDA issues a NIDPOE letter when it believes it has evidence that the clinical investigator repeatedly or deliberately violated FDA's regulations governing the proper conduct of clinical studies involving investigational products or submitted false information to the sponsor.

55. Notice Of Initiation Of Disqualification Proceedings And Opportunity To Explain
Definition under CFR
If FDA has information indicating that an investigator has repeatedly or deliberately failed to comply with the requirements of part 812, part 50, or part 56 of this chapter, or has repeatedly or deliberately submitted false information either to the sponsor of the investigation or in any required report, the Center for Devices and Radiological Health will furnish the investigator written notice of the matter under complaint and offer the investigator an opportunity to explain the matter in writing, or, at the option of the investigator, in an informal conference.

56. Notice Of Initiation Of Disqualification Proceedings And Opportunity To Explain
If an explanation is offered and accepted by the Center for Devices and Radiological Health, the disqualification process will be terminated. If an explanation is offered but not accepted by the Center for Devices and Radiological Health, the investigator will be given an opportunity for a regulatory hearing under part 16 of this chapter on the question of whether the investigator is entitled to receive investigational devices.

57. Notice Of Initiation Of Disqualification Proceedings And Opportunity To Explain
After evaluating all available information, including any explanation presented by the investigator, if the Commissioner determines that the investigator has repeatedly or deliberately failed to comply with the requirements of this part, part 50, or part 56 of this chapter, or has deliberately or repeatedly submitted false information either to the sponsor of the investigation or in any required report, the Commissioner will notify the investigator, the sponsor of any investigation in which the investigator has been named as a participant, and the reviewing IRB that the investigator is not entitled to receive investigational devices. The notification will provide a statement of basis for such determination.

58. Notice Of Initiation Of Disqualification Proceedings And Opportunity To Explain
Each investigational device exemption (IDE) and each cleared or approved application submitted under this part, subpart E of part 807 of this chapter, or part 814 of this chapter containing data reported by an investigator who has been determined to be ineligible to receive investigational devices will be examined to determine whether the investigator has submitted unreliable data that are essential to the continuation of the investigation or essential to the approval or clearance of any marketing application.

59. Notice Of Initiation Of Disqualification Proceedings And Opportunity To Explain
Consent Agreements
List specific responsibilities of the Clinical Investigator in terms of coming into compliance.
Can last for a specific amount of time or can be an agreement the disqualification is permanent.
Can be viewed as a tool to bring the Clinical Investigator into compliance which in turn serves as a way to educate the Clinical Investigator as to their regulatory responsibility for the current and future clinical trials.

60. What does disqualification mean for the Sponsor?
Notice Of Initiation Of Disqualification Proceedings And Opportunity To Explain
What does disqualification mean for the Sponsor?
The data from the disqualified clinical site can not be used in their submission. (Monetary and Ethical considerations)
Sponsor is responsible for oversight of all clinical investigators so there might be some serious issues in terms of monitoring which can lead to further regulatory action.

61. What does disqualification mean for the clinical investigator?
Notice Of Initiation Of Disqualification Proceedings And Opportunity To Explain
What does disqualification mean for the clinical investigator?
Their name is added to a list on the FDA website that indicates that they are disqualified from participation in any type of clinical trial.
Generally it means that they have incurred legal fees and it can open them up to more eminent liability.
Some might feel that it has had a negative impact on their reputations.

62. Web Sites Device Advice www.fda.gov/cdrh/devadvice CDRH BIMO site

63. Contact Information
Sonali P. Gunawardhana
FDA, CDRH, Office of Compliance
9200 Corporate Blvd
HFZ-310
Rockville, MD 20850
(240)