Presentation on theme: "The 3rd Annual FDA Regulatory and Compliance Symposium"— Presentation transcript:
1 FDA Compliance Enforcement Actions: What you need to know for clinical device trials The 3rd Annual FDA Regulatory and Compliance SymposiumTrack 3- Pharma Product Development and Clinical TrialsAugust 23, 2007Cambridge, 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 AdministrationCenter for Devices and Radiological Health Office of Compliance Division of Bioresearch Monitoring
3 Devices vs. DrugsHow do studies with investigational devices differ from those with drugs and biologics?Nature of industryStatutory distinctionsRegulatory distinctionsResearch distinctions
4 Device Firms Entrepreneurial firms common 93% have fewer than 100 employeesVenture capitalizedDiverse and specialized productsPrinciples of operation and intended usesDevice “developer” often involvedMinimal clinical trial experienceRapid product cycles limiting testing time
5 Statutory Distinctions Devices lack market exclusivity provisionsWaxman-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 regulateFDAMA (1997) “least burdensome” provision
6 Valid Scientific Evidence* Well-controlled investigationsPartially controlled studiesStudies and objective trials without matched controlsWell-documented case histories by qualified expertsReports of significant human experience with a marketed device* 21 CFR 860.7
7 Research Applications Investigational New Drug (IND) applicationCovers all research (drugs and biologics)21 CFR Part 312Investigational Device Exemption (IDE)Covers significant risk researchImplants, life-threatening, or sight-threatening21 CFR Part 812
8 Regulatory Distinctions IDE exempt studiesIn vitro diagnostics (IVDs)In commercial use before May 28, 1976Consumer preference testingSolely for veterinary usePost Approval Studies
9 Marketing Applications New Drug Application (NDA)Innovator21 CFR Part 314Abbreviated New Drug Application (ANDA)Substantial equivalenceBiologics Licensing Application (BLA)21 CFR Part 601Premarket Approval Application (PMA)New Use, Technology, or Class III21 CFR Part 814Premarket Notification (510(k))Substantial equivalence21 CFR Part 807Humanitarian Device Exemption (HDE)Similar to Orphan ProductIn Vitro Diagnostics (IVDs)21 CFR Part 809
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/biologicProducts are assigned to lead Center based upon primary mode of actionOther Centers provide consulting reviewsProduct is required to follow regulation of lead CenterImportant to seek early consultationFDA’s Office of Combination Products
13 Enforcement Actions REASONS WHY SOME OF THESE ACTIONS ARE IMPLEMENTED: Untitled Letters/Warning LettersApplication Integrity Policy/ Integrity HoldNotice of Initiation of Disqualification Proceedings and Opportunity to Explain (NIDPOE)
14 Compliance ToolsInvoke Application Integrity Policy or Integrity HoldRevoke marketing or research permitCivil Money PenaltiesInjunctionProsecutionUntitled/Warning letterRe-inspectionInformal conference3rd party auditsRejection of site dataDisqualificationCI, IRB, or GLP85% of the time, you will receive an UL or an OK letterDQ new to CDRHCMP 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 LettersThe 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.
29 Common Investigator Deficiencies Follow investigational plan, investigator agreement, or protocolProtocol deviationsInadequate subject protection or informed consentInadequate device accountabilityLack of FDA or IRB approvalInadequate reporting of UADEs to Sponsor or IRB
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 DevelopmentAgent- Under Development
40 Examples of Wrongful Acts Submit Fraudulent ApplicationOffer Bribe/Illegal GratuityMake Untrue Statement of Material FactSubmit Data Otherwise UnreliableOmitted DataManufactured DataAltered DataOther Data Inconsistencies
41 Examples of Data Integrity Problems Falsification of Specific Data or an Entire SubmissionOmission of Relevant and Important Data and InformationInability to Account for Patient PopulationInability to Account for Investigational DevicesFailure to Maintain Adequate Investigational RecordsUnreported Changes to the Investigational Device
42 Process: Pre-Discovery Stage Tips from Anonymous/Known InformantCurrent/Former EmployeesFormer Business PartnersPatientsOther Agencies (SEC, FTC, CMS)Suspicious Data Found During Scientific/Clinical ReviewObservations During Pre-Approval Inspection
43 Process: Inspection Stage Inspection of Company/ SponsorInspection of Clinical SitesInspections of CRO’sData AuditSystem AuditCompany Internal Documents
44 Invoking the AIP Pattern or Practice of Wrongful Conduct Significant Question of Data ReliabilitySystem-wide FailuresDecision 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 AssessmentScope, extent of problemInspectionAudit Report
46 Applicant’s Responsibilities Cooperation with FDAInternal Review (Audit)Independent Outside ConsultantIdentify/Remove IndividualsSubmit CAPCommit to Safety, Efficacy and QualityDescribe Ethics/Compliance ProgramsStandard Operating ProceduresSteps to Address and Prevent Wrongful ActsApplication Withdrawal, Patient Notification, Product Recall etc.
47 Global Industry Issues Systems to identity and/or address regulatory shortcomingsSystems to correct/prevent recurring issuesAccountable company cultureEnvironment of conflict of interest
48 FDA Responsibilities Review of Corrective Action Plan Field Onsite Inspection & RecommendationHeadquarters ReviewLetter to ApplicantCenter 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 PolicyRPM Chapter 10“Points to Consider for Internal Reviews and Corrective Action Operating Plans”
51 Program Offices/Contacts ODE/OIVD Integrity OfficerCarl DeMarco:Division of Bioresearch Monitoring, Office of ComplianceMichael Marcarelli:Application Integrity Policy CommitteeFDA Office of Criminal Investigations
52 Notice Of Initiation Of Disqualification Proceedings And Opportunity To Explain Applies to Clinical InvestigatorsSome 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.
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 CFRIf 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 AgreementsList 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 ExplainWhat 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 ExplainWhat 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 InformationSonali P. GunawardhanaFDA, CDRH, Office of Compliance9200 Corporate BlvdHFZ-310Rockville, MD 20850(240)