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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.

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Presentation on theme: "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."— Presentation transcript:

1 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

2 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

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

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

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

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

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

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

9 Marketing Applications New Drug Application (NDA) New Drug Application (NDA) Innovator Innovator 21 CFR Part CFR Part 314 Abbreviated New Drug Application (ANDA) Abbreviated New Drug Application (ANDA) Substantial equivalence Substantial equivalence 21 CFR Part CFR Part 314 Biologics Licensing Application (BLA) Biologics Licensing Application (BLA) Innovator Innovator 21 CFR Part 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

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

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

14 Compliance Tools Untitled/Warning letter Untitled/Warning letter Re-inspection Re-inspection Informal conference Informal conference 3rd party audits 3rd party audits Rejection of site data Rejection of site data Disqualification Disqualification CI, IRB, or GLP CI, IRB, or GLP Invoke Application Integrity Policy or Integrity Hold Revoke marketing or research permit Civil Money Penalties Injunction Prosecution

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

16 Warning Letters The Warning Letter is the agencys principal means of notifying regulated industry of violations (prior notice) and achieving prompt voluntary correction. The Warning Letter is the agencys 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. 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

18 Inspected Entity Sponsor CI IRB GLP

19 CDRH BIMO Warning Letters

20

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 CDRH Sponsor Compliance Rates

24

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

26 CDRH Clinical Investigator Compliance Rates

27

28

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

30 CDRH IRB Compliance Rates

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

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

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

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

35 CDRH BIMO COMPLIANCE RATES FY97-06: All Inspections vs. Complaints 14% 31% 55% All InspectionsComplaints 28% 26% 46% 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 Wrongful Act? What is an Untrue Statement of Material Fact?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… … 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… …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 Materiality- Under Development Agent- Under Development Agent- Under Development

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

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

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

43 Process: Inspection Stage Inspection of Company/ Sponsor Inspection of Company/ Sponsor Inspection of Clinical Sites Inspection of Clinical Sites Inspections of CROs Inspections of CROs Inspection of Clinical Sites Inspection of Clinical Sites Data Audit Data Audit System Audit System Audit Company Internal Documents Company Internal Documents

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

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

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

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

48 FDA Responsibilities Review of Corrective Action Plan Review of Corrective Action Plan Field Onsite Inspection & Recommendation Field Onsite Inspection & Recommendation Headquarters Review Headquarters Review Letter to Applicant Letter to Applicant Center Directors Signature Center Directors Signature

49 Application Integrity Program Fraud, Untrue Statements of Material Facts, Bribery, and Illegal Gratuities; Final Policy, 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 Application Integrity Policy RPM Chapter 10 Points to Consider for Internal Reviews and Corrective Action Operating PlansPoints to Consider for Internal Reviews and Corrective Action Operating Planshttp://www.fda.gov/ora/compliance_ref/aip_points.html

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

52 Notice Of Initiation Of Disqualification Proceedings And Opportunity To Explain Applies to Clinical Investigators 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. 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 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. 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 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. 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. 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. 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. 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 Consent Agreements List specific responsibilities of the Clinical Investigator in terms of coming into compliance. 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 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. 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 Notice Of Initiation Of Disqualification Proceedings And Opportunity To Explain What does disqualification mean for the Sponsor? 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) 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. 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 Notice Of Initiation Of Disqualification Proceedings And Opportunity To Explain What does disqualification mean for the clinical investigator? 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. 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. 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. Some might feel that it has had a negative impact on their reputations.

62 Web Sites Device Advice CDRH BIMO site

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


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