FDA Inspectional Process in Clinical Research An FDA Perspective. Annette Melendez, MPHsN Investigator Office of Biological Products Operations

Transcription

1 FDA Inspectional Process in Clinical Research An FDA Perspective Annette Melendez, MPHsN Investigator Office of Biological Products Operations

2 Outline BIMO PROGRAM OVERVIEW PROGRAM COVERED AREAS INSPECTIONAL PROCESS 2

3 References FDA Regulations Title 21 Code of Federal Regulations NIH Regulations: Title 45, Part 46 Protection of Human Subjects Clinical Trial Guidance Documents ( m htm 3

4 FDA Regulated Research BIORESEARCH INTENDED FOR SUBMISSION TO THE FDA IN SUPPORT OF A RESEARCH OR MARKETING PERMIT Marketing Permits New Drug Application (NDA): Human Drugs Abbreviated New Drug Application (ANDA): Human Drugs Premarket Approval Application (PMA): Medical Devices Biologics License Application (BLA): Biologic Products Research Permits Investigational New Drug (IND): New Drugs/Biologics to Humans Investigational Device Exemption (IDE): New Medical Devices THE FEDERAL FOOD, DRUG AND COSMETIC ACT Requires an FDA approved marketing or research permit be obtained before moving into interstate commerce commodities such as new human drugs, medical devices, veterinary drugs, food additives, etc. 4

5 FDA Regulated Research Objectives To verify the quality and integrity of bioresearch data To protect the rights and welfare of human research subjects BIMO Program involves on-site inspections and data audits to monitor conduct and outcome of regulated research 5

6 FDA Regulated Research BIMO Program Applied Inspections and data audits (unannounced and announced) on Routine or For Cause basis Inspections include physical inspections of laboratory facilities and operations as well as data audit of selected studies Inspections include physicians, dentists, veterinarians, and others who conduct clinical trials of human and vet drugs, medical devices, biological products, etc. 6

7 FDA Regulated Research All inspections issued by FDA Centers (CDER, CDRH, CBER, CFSAN, CTP) Routine Audit of data for studies in support of a marketing permit and/or research permit Directed/For Cause Suspicion of false or fraudulent data Unrealistic data Information received from outside sources alerting to possible misconduct 7

8 Institutional Review Board Board designated to review and approve BIMOs involving human subjects Assure protection of rights and welfare of human subjects Data validation is not the purpose Inspections are regularly scheduled to verify compliance CP

9 Sponsor, CRO, Monitor Parties responsible for initiating, overseeing, and submitting the results of research to FDA Objective: regulatory compliance and data validation Principal areas covered Organization and personnel Selection of clinical investigators Monitors and monitoring procedures Reporting of AEs Test article accountability and characterization CP

10 Clinical Investigator Clinical Investigators responsible for conducting research on human subjects Objective: verify data, ensure protection, verify compliance Principal areas covered Who did what Delegation of authority Training received Oversight Facility review Data review Monitoring activities CP

11 Other Facilities Good Laboratory Practice (Nonclinical Laboratories) Typically animal facilities or facilities that process animal tissue for work in support of pre-human trials CP Good Laboratory Practice Program (Nonclinical Laboratories) EPA Data Audit Inspections Similar to above program but work is in support of EPA CP A Radioactive Drug Research Committee Much like an IRB but specialized for radioactive drugs CP A 11

12 Pre-Inspection Announcement May be pre-announced via phone call Availability All study documentation Knowledgeable personnel Facility Desk, chair, photocopier Expected duration Routine Inspections: 3 to 7 days Directed/For-Cause: 7 days or more 12

13 During Inspection Initial interview Presentation of credentials and Form FDA 482, Notice of Inspection Interview of Clinical Investigator and key study personnel Facility walkthrough BEQ: Retention sample examination Review study records Discussion of issues and obtain documents Exit interview Presentation of Verbal Observations and/or Form FDA 483, Inspectional Observations 13

14 Inspection Documentation Regulatory Subject Records Protocol IRB Approved (minimum annually) Retention of all versions used Inclusion/Exclusion Required tests Correctly implemented Consent Form IRB Approved (minimum annually) Retention of all versions used Signed prior to study procedures Advertisement IRB Approval Correspondence Delegation of Authority Investigator Agreement/Form FDA 1572 Subject proof of existence Availability during study Consent form Inclusion/Exclusion Disease/Condition Study Visits Observations Tests AEs Case Report Forms 14

15 Inspection Documentation Sponsor If and how were periodic reports submitted AE and SAEs reported Case Report Forms submitted Accountability Disposition to authorized person Accountability records Receipt dates and quantities Disposition dates and quantities Return dates and quantities Storage records Confirmation of identity Security 15

16 Inspection Red Flags Inspection Complaints High enrollment Above average response Inspection delays Disasters Documentation Limited access Missing documentation Similar writing Correction fluid Photocopies No strikethrough 16

17 Device or Animal Studies Device Investigator Agreement Form FDA 1571/1572 not required Non-Significant Risk NSR determination by IRB IRB approval Abbreviated regulations Animal Study Agreement From FDA 1571/1572 not required Notice of Claimed Investigational Exemption Institutional Animal care and Use Committee (IACUC) 17

18 End of Inspection Discussion of Inspection Findings/Observations Discussion (verbal) items Form FDA 483, Inspectional Observations Form FDA 484, Receipt of Samples 18

19 End of Inspection Sites are strongly encouraged to respond, in writing, to the Form FDA 483 within 15 business days Establishment Inspection Report (EIR) ed to POC once finalized by the Center 19

20 Post Inspection Activities CSO completes and Establishment Inspection Report (EIR) EIR forwarded to the assignment originating center Review and Final Classification Written Communication is initiated by FDA s corresponding center 20

21 COMPLIANCE CLASSIFICATIONS NAI-No Action Indicated -Firm is in compliance VAI-Voluntary Action Indicated - Voluntary Action Required, marginal compliance OAI-Official Action Indicated -Serious non-compliance requiring regulatory or administrative action 21

22 POSSIBLE OUTCOMES OF FDA INSPECTIONS Untitled Letters Warning Letters Rejection of study data Deficiency Letter Application withdrawal 22

23 OUTCOMES.. Disqualification (CI, IRB) Prosecution(Investigator and or staff) IRB restrictions (no new studies) Application of Integrity Policy 23

24 Accessing FDA Inspection Report Inspection final classification is received at the district office District sends/ a copy of EIR to clinical investigator /Facility (Field Management Directive 145) EIR is available to anyone under FOI 24

25 MOST COMMOM CI DEFICIENCIES Failure to follow the investigational plan and/or regulations Protocol Deviations Inadequate recordkeeping Inadequate accountability for the investigational product Inadequate communication with the IRB Inadequate subject protection-failure to report Aes and informed consent issues 25

26 Most common IRB deficiencies Inadequate initial and/or continuing review Inadequate SOPs Inadequate membership rosters Inadequate meeting minutes Quorum issues Subpart D issues Inadequate communication with CI/institution Specific to devices lack of or incorrect SR/NSR determination

27 Most common S/M deficiencies Inadequate monitoring Failure to bring investigators into compliance Inadequate accountability for the investigational product Failure to obtain FDA and/or IRB approval prior to study initiation

28 Most common BEQ deficiencies Recordkeeping Inclusion/exclusion criteria issues Informed consent issues Dosage issues Analytical concerns Validation Stability Inadequate SOPs

29 INSPECTION FINDINGS-CI Dr.****failed to adhere to the protocol by enrolling and administering study drug to seven out of nine subjects who were ineligible for the study Subjects *****represent 50% of the subjects who you enrolled in Protocol***.This one-half of the subjects you enrolled were not eligible for the study. 29

30 INSPECTION FINDINGS-CI You failed to take adequate precautions to prevent theft or diversion of an investigational drug that is subject to the Controlled Substances Act*** The inspection conducted at your site revealed that you failed to follow the investigational plan and did not accurately randomize study subjects 30

31 Inspection Findings-CI The FDA inspector found no documentation to confirm when and how disposal of used or unused devices was accomplished. There was no device accountability record documenting the disposition of all devices, such as whether devices were used in a subject, used in other subjects, unused or returned to the sponsor. 31

32 Inspection Findings-CI Failure to utilize the IRB-approved informed consent document violates there rights, safety and welfare of subjects enrolled in the study. You failed to adequately supervise individuals to whom you delegated study tasks. 32

33 Inspection Findings-CI the teratogenic effects of ***, a pregnancy category D drug, were not included in informed consent documents although female subjects of child-bearing potential were enrolled in the study 33

34 Inspection Findings-SM The inspection revealed that in your role as sponsor you did not adequately monitor the progress of the studies listed above. Documentation was not available for five of the six studies to show monitoring was conducted to ensure compliance with the protocol and the investigational plan. 34

35 Inspection Findigns-SM The review of source documents conducted during the FDA inspection found that a total of 35 subjects deaths were not included in either section 1.2 or Appendix of the Annual Report. 35

36 Inspection Findings-BEQ You failed to meet the regulatory requirements for retention of reserve samples for bioavailability or bioequivalence studies. 36

37 Some Tips Understand Protocol requirements/limitations Do your own site qualification Establish/ document delegation of authority Always use the latest version of the approved IC All study records meet ALCOA principles Maintain communication with sponsor, monitor, IRB, site s staff Maintain all records generated during the study 37

38 Aspects to be considered for implementation in your clinical trial operations Implementation of SOPs Quality Control, Quality Assurance Reviews Formal training/proficiency program for research site staff Root cause analysis when errors occurred Implementation of corrective actions 38

39 ACHIEVING COMPLIANCE Those of us in clinical trials, regardless of our role or position, must recognize that we have individual as well as collective responsibility for integrity and quality assurance. Failure to assume this responsibility will have deleterious effects on all of us as well as on the entire field of trials on which we rely for identifying safe and effective treatments. Scientific Motivation/Responsibility DeMets and Meinert,

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