FDA Compliance Enforcement Actions: What you need to know for clinical device trials The 3 rd Annual FDA Regulatory and Compliance Symposium Track 3-3 Pharma Product Development and Clinical Trials August 23, 2007 Cambridge, MA
The 3 rd 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
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
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
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
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
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 threatening 21 CFR Part 812
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
Marketing Applications 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
vs. Product Distinctions
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.
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 s Office of Combination Products
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)
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 Injunction Prosecution
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.
Warning Letters The Warning Letter is the agency s 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.
500 CDRH BIMO INSPECTIONS Fiscal Years 2002-2006 400 300 357 353 350 332 336 200 100 FY02 FY03 FY04 FY05 FY06
CDRH BIMO INSPECTIONS Fiscal Years 2002-2006 Inspected Entity 2002 2003 2004 2005 2006 Sponsor 72 81 73 70 53 CI 151 170 183 183 200 IRB 128 85 73 48 59 GLP 6 9 19 31 24
CDRH BIMO Warning Letters 50 45 40 35 30 25 20 44 15 10 5 14 9 31 30 24 0 FY01 FY02 FY03 FY04 FY05 FY06
CDRH BIMO Warning Letters 50 40 3 7 30 20 7 7 10 1 3 6 3 3 GLP IRB Sponsor CI 10 2 17 24 20 18 0 7 FY02 FY03 FY04 FY05 FY06
CDRH BIMO Compliance Rates 70% 60% 50% 40% 30% 24% NAI VAI OAI 20% 13% 12% 17% 15% 11% 10% 0% 10 Years FY02 FY03 FY04 FY05 FY06
CDRH BIMO OAI Rates (with & w/o For Cause Inspections) OAI (NFC) OAI NFC = No For Cause inspections included 30% 24% 20% 10% 10% 17% 13% 16% 15% 9% 11% 7% 5% 0% 10 Years FY03 FY04 FY05 FY06
CDRH Sponsor Compliance Rates 70% 60% 50% NAI VAI OAI 40% 30% 31% 20% 10% 19% 10% 24% 15% 11% 0% 10 Years FY02 FY03 FY04 FY05 FY06
CDRH Sponsor Compliance Rates 70% 60% 50% 40% 30% 20% 10% 0% 19% 10 Years 10% 24% 31% 15% NAI VAI OAI 11% 10% FY02 FY03 FY04 FY05 FY06 FY06 (NFC)
Sponsor Deficiencies Fiscal Years 1999-2006 FY 1999 2000 2001 2002 2003 2004 2005 2006 Inadequate monitoring Failure to secure investigator compliance Inadequate device accountability Obtain FDA/IRB approval 65% 68% 65% 33% 37% 40% 24% 23% 27% 44% 27% 19% 24% 21% 15% 13% 23% 28% 19% 7% 19% 16% 18% 15% 4% 18% 11% 8% 5%
CDRH Clinical Investigator Compliance Rates 70% 60% 50% 40% NAI 30% 20% 11% 15% 17% 21% 17% 11% VAI OAI 10% 0% 10 Years FY02 FY03 FY04 FY05 FY06
CDRH Clinical Investigator Compliance Rates 70% 60% 50% 40% 30% 20% 11% 15% 17% 21% 17% 11% NAI VAI OAI 10% 7% 0% 10 Years FY02 FY03 FY04 FY05 FY06 FY06 (NFC)
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
CDRH IRB Compliance Rates 70% 60% 50% 40% 30% 20% 17% NAI VAI OAI 10% 0% 13% 10 Years 9% 7% 14% 8% FY02 FY03 FY04 FY05 FY06 FY06 (NFC) 5%
IRB Deficiencies Fiscal Years 1999-2006 FY 1999 2000 2001 2002 2003 2004 2005 2006 Inadequate initial &/or continuing review Inadequate minutes Lack of or incorrect SR/NSR determination Inadequate membership roster 64% 56% 39% 24% 25% 50% 37% 38% 61% 42% 35% 11% 42% 28% 17% 20% 58% 42% 57% 10% 16% 34% 22% 7% 31% 22% 30% 13% 20% 21% 12% 12% Addendum: FY06 Lack of Quorum & Reporting Non-Compliance 12%
CDRH BIMO OAI Follow-up Inspections (as of 9/30/06) Recidivist OAIs evenly distributed across program areas: GLP = 17% IRB = 25% CI = 33% 18% 30% 52% NAI VAI OAI S/M = 25% N = 64
CDRH BIMO Vulnerable Population Inspections 10% OAI split among Sponsor (44%) and Clinical Investigator (56%) programs 32% NAI VAI OAI 58% N = 164
CDRH BIMO COMPLIANCE RATES FY06: All Inspections vs. Complaints All Inspections Complaints 11% 36% NAI 35% 53% VAI OAI 48% 17% 333% higher OAI rate in complaint follow-ups
CDRH BIMO COMPLIANCE RATES FY97-06: All Inspections vs. Complaints All Inspections Complaints 14% 31% NAI 26% VAI 46% 55% OAI 28% 230% higher OAI rate in complaint follow-ups over a 10 year period
What does AIP mean?
Application Integrity Policy What is Wrongful Act? What is an Untrue Statement of Material Fact?
Wrongful Act A 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
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
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
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
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
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
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
Agency s s Action Defer Scientific Review Issues Letter to Applicant Conducts Validity Assessment Scope, extent of problem Inspection Audit Report
Applicant s 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.
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
FDA Responsibilities Review of Corrective Action Plan Field Onsite Inspection & Recommendation Headquarters Review Letter to Applicant Center Director s s Signature
Application Integrity Program Fraud, 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
Application Integrity Program Application Integrity 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
Program Offices/Contacts ODE/OIVD Integrity Officer Carl DeMarco: 240-276 276-3993 Division of Bioresearch Monitoring, Office of Compliance Michael Marcarelli: 240-276 276-0125 Application Integrity Policy Committee FDA Office of Criminal Investigations
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.
Disqualification Of Clinical Investigators
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 igator repeatedly or deliberately violated FDA's regulations governing the proper conduct of clinical studies involving investigational products or submitted false information to the sponsor.
Notice Of Initiation Of Disqualification Proceedings And Opportunity To Explain Definition under CFR 812.119 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.
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.
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.
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.
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.
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.
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.
Web Sites Device Advice www.fda.gov/cdrh/devadvice CDRH BIMO site www.fda.gov/cdrh/comp/bimo.html
Contact Information Sonali P. Gunawardhana FDA, CDRH, Office of Compliance 9200 Corporate Blvd HFZ-310 Rockville, MD 20850 (240)276-0246 0246 sonali.gunawardhana@fda.hhs.gov