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

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FDA Compliance Enforcement Actions: What you need to know for clinical device trials


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    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 CounselFood and Drug Administration Center for Devices and Radiological HealthOffice of ComplianceDivision 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. 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 Research Applications

    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. New Drug Application (NDA) Innovator 21 CFR Part 314 Abbreviated New Drug Application (ANDA) Substantial equivalence 21 CFR Part 314 Biologics Licensing Application (BLA) Innovator 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 21 CFR Part 814 In Vitro Diagnostics (IVDs) 21 CFR Part 809 Marketing Applications

    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 CombinationProducts

    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. 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 Injunction Prosecution Compliance Tools

    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 INSPECTIONSFiscal Years 2002 - 2006

    18. CDRH BIMO INSPECTIONSFiscal Years 2002 - 2006

    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 - 2006

    26. CDRH Clinical Investigator Compliance Rates

    27. CDRH Clinical Investigator Compliance Rates

    28. 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

    29. CDRH IRB Compliance Rates

    30. IRB DeficienciesFiscal Years 1999 - 2006 Addendum: FY06 – Lack of Quorum & Reporting Non-Compliance 12%

    31. 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

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

    33. CDRH BIMO COMPLIANCE RATESFY06: All Inspections vs. Complaints All Inspections Complaints 11% 35% 36% 48% 17% 53% 333% higher OAI rate in complaint follow-ups

    34. CDRH BIMO COMPLIANCE RATESFY97-06: All Inspections vs. Complaints All Inspections Complaints 14% 26% 31% 46% 55% 28% 230% higher OAI rate in complaint follow-ups over a 10 year period

    35. What does AIP mean?

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

    37. 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…”

    38. 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

    39. 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

    40. 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

    41. 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

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

    43. 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

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

    45. 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.

    46. 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

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

    48. Application Integrity Program • “Fraud, Untrue Statements of Material Facts, Bribery, and Illegal Gratuities; Final Policy,” 56 F.R. 46191, 9/10/91 http://www.fda.gov/ora/fr/fraud_ill_grat.html

    49. Application Integrity Program • ApplicationIntegrity Policy RPM Chapter 10 http://www.fda.gov/ora/compliance_ref/rpm_new2/rpm10aip.html • “Points to Consider for Internal Reviews and Corrective Action Operating Plans” http://www.fda.gov/ora/compliance_ref/aip_points.html