BIMO Program Update an operational perspective

Transcription

1 BIMO Program Update an operational perspective Clinical Trials Summit San Juan, Puerto Rico May 9, 2018 Anne E. Johnson Program Division Director FDA/ORA/OBIMO Division I (East) 1

2 Objectives Program Alignment BIMO Program Metrics Inspectional Trends Post-Inspection Activities New Guidances 2

3 Bioresearch Monitoring (BIMO) Program A comprehensive, agency-wide program of on-site inspections and data audits, designed to monitor all aspects of the conduct and reporting of FDAregulated research 3

4 Bioresearch Monitoring (BIMO) Nonclinical Laboratory Institutional Review Board Clinical Investigator Sponsor 4

5 BIMO Program Objectives To protect the rights, safety, and welfare of human research subjects To ensure the quality, reliability, and integrity of data collected To maintain the integrity of the FDA review process by ensuring that FDA-regulated research is conducted in compliance with applicable regulations 5

6 BIMO Programs Protection of Human Subjects 21 CFR Part 50 Investigational New Drugs 21 CFR Part 312 Financial Disclosure 21 CFR Part 54 Institutional Review Boards 21 CFR Part 56 New Drug Applications 21 CFR Part 314 Bioequivalence Good Laboratory Practice 21 CFR Part CFR Part 320 6

7 BIMO Programs, cont d Post-marketing Adverse Drug Experiences 21 CFR Part Risk Evaluation and Mitigation Strategies FDAAA,

8 Modernize and strengthen the FDA workforce to improve public health response FDA Program Alignment Charge 8

9 Product Specific Centers Office of Foods and Veterinary Medicine Center for Food Safety and Applied Nutrition Center for Veterinary Medicine Office of Medical Products and Tobacco Center for Biologics, Evaluation and Research Center for Drugs, Evaluation and Research Center for Devices and Radiological Health Center for Tobacco Products 9

10 The Field Office of Global Regulatory Operations and Policy Office of International Programs Office of Regulatory Affairs 10

11 OLD Geographically Aligned Organizational Model 11

12 Program Alignment: Key Changes From Geographic management of operations SES Regional Food & Drug Directors Degrees of program specialization for investigations, compliance and operational managers 20 District Directors who manage the geographic district and all programs operations within the district One import district and a range of import operations embedded within the 16 other districts To Program management of operations, management teams based on staff: Bioresearch Monitoring 2 management teams Biologics 2 management teams Human and Animal Food 12 management teams Medical Device and Radiological Health 3 management teams Pharmaceutical Quality 4 management teams Tobacco Plus Imports as a program 5 management teams SES Program Directors Exclusive specialization in one program for investigations, compliance and operational managers 20 District Directors who manage the geographic district and only one program for operations. Plus eight new program division directors who manage program operations only total 28 management teams Five import divisions (four new import divisions) covering all borders, managing import operations nationally as a program 12

13 Office of Regulatory Science 13

14 Office of Enforcement and Import Operations 14

15 Office of Human and Animal Food Operations Michael Rogers, MS Assistant Commissioner Office of Human and Animal Food (HAF) Operations Ellen Buchanan Director Audit Staff Vinetta Howard-King Director Office of HAF Operations-East (acting) Joann Givens Director Office of HAF Operations-West Laurie Farmer Director Office of State Cooperative Programs (acting) 15

16 Office of Human and Animal Food Operations 16

17 Office of Medical Products and Tobacco Operations Ellen Morrison Assistant Commissioner Office of Medical Products and Tobacco Operations Director Tobacco Staff [vacant] Ginette Michaud, MD Director, Office of Biological Products Operations Chrissy Cochran, PhD Director, Office of Bioresearch Monitoring Operations Jan Welch Director, Office of Medical Device and Radiological Health Operations Alonza Cruse Director, Office of Pharmaceutical Quality Operations 17

18 Office of Biological Products Operations 18

19 Office of Medical Device and Radiological Health Operations 19

20 Office of Pharmaceutical Quality Operations 20

21 Office of Bioresearch Monitoring Operations Chrissy Cochran, PhD Director, Office of Bioresearch Monitoring Operations 21

22 Office of Bioresearch Monitoring Operations 22

23 Inspection Process Center Review Division Regulatory Correspondence/ Follow-up Center BIMO Staff Inspection Assignment Program Division Inspection & EIR 23

24 Inspection Process Clinical data FDA Investigator Sponsor/Clinical Investigator 24

25 FY2017 BIMO Inspections Conducted Center CBER CDER CDRH CVM Total CI IRB n/a 156 Sponsor GLP BA/BE n/a 268* n/a n/a 268 PADE n/a 88 n/a n/a 88 REMS n/a 9 n/a n/a 9 Total *Includes 60 BE analytical inspections completed by CDER/OSIS 25

26 FY2017 BIMO Inspections Classified Center CBER CDER CDRH Total CI IRB 10 79* Sponsor GLP BA/BE n/a 355 n/a 355 PADE n/a 97 n/a 97 REMS n/a 15 n/a 15 Total *Includes 2 Radioactive Drug Research Committee (RDRC) inspections 26

27 Inspectional Classifications No Action Indicated (NAI) No objectionable conditions or practices Voluntary Action Indicated (VAI) Objectionable conditions or practices Not at threshold to take or recommend administrative or regulatory action Official Action Indicated (OAI) Serious objectionable conditions found Regulatory action recommended 27

28 Clinical Investigator Inspections FY2017 Failure to follow protocol Protocol deviations Inadequate recordkeeping Subject protection inadequate IC, AEs IP accountability IRB communication IP represented as safe/effective NAI VAI OAI 1% 26% 73% n=701 28

29 Sponsor/Monitor/CRO Inspections FY2017 Inadequate monitoring Failure to bring investigators into compliance Inadequate accountability for IP Failure to obtain FDA and/or IRB approval prior to study initiation 30% NAI VAI OAI 6% 64% n=104 29

30 Bioequivalence Inspections FY2017 Recordkeeping Inclusion/exclusion criteria issues Informed consent issues Dosage issues Analytical concerns Validation Stability Reserve Samples 27% NAI VAI OAI 5% 68% n=355 30

31 Good Laboratory Practice Inspections FY2017 NAI VAI OAI Organizational or personnel inadequacies Inadequate/incomplete/ no study records Inadequate archiving Inadequate/no SOPs Protocol deviations 35% 0% 65% n=34 31

32 FY 17 Institutional Review Board Inspections Classified NAI 2% VAI OAI *Inspections classified in FY17 by all Centers with jurisdiction over studies involving human subjects. Some inspections may have occurred in a different FY. 32

33 Common IRB Deficiencies* Inadequate initial and/or continuing review Inadequate written procedures Inadequate meeting minutes, membership rosters Quorum issues Prompt reporting of non-compliance, suspension or termination Subpart D issues Lack of or incorrect SR/NSR determination *Institutional Review Board (CP ) deficiencies identified in FDA Form 483 issued at close of inspections. 33

34 Official Action Indicated (OAI) Regulatory violations uncovered during the inspection is/are repeated, deliberate, and/or involve submission of false information to FDA or the sponsor in any required report. Regulatory violations are significant/serious and/or numerous, and the scope, severity, or pattern of violations support a finding that: Subjects have been (or would be) exposed to an unreasonable and significant risk of illness or injury. Subjects rights have been (or would be) seriously compromised. Data integrity or reliability has been compromised. CPGM Clinical Investigator Inspections: 34

35 Form FDA 483 Inspection Observations List of inspection observations 483 language: This document lists observations made by the FDA representative during the inspection of your facility. They are inspectional observations, and do not represent a final Agency determination regarding your compliance. Additional 483 information available from FDA Investigations Operations Manual (IOM) at /ora/inspect_ref/iom/ 35

36 483 Responses There is no regulatory requirement for you to respond to the FDA 483. However, a well-reasoned, complete, and timely 483 response is in your best interest. 36

37 9 Suggestions for 483 Responses 1. Include a commitment from most responsible officials. 2. Address each observation separately. 3. Note whether you agree or disagree [documents?]. 4. Provide both corrective and preventive actions. 5. Provide both completed and planned actions. 6. Provide timelines for completion. 7. Provide a method of verification or monitoring the effectiveness of the actions. 8. Submit documentation (training, SOPs, CAP, records). 9. Submit the response within 15 working days, if at all possible. 37

38 Where do I send my 483 response? ATTN: District Director, District Office (address on 482 and 483) Encourage electronic cc: to: ORABIMOE.Correspondence@fda.gov OR ORABIMOW.Correspondence@fda.gov 38

39 Warning Letters 15 Days Response Reinspection Close-out Letter 39

40 Where do I send my WL response? Issuing ORA Product Center Address found within the WL or other correspondence All post-inspectional correspondence includes a point of contact 40

41 Post Inspection Close-out Letters FMD-145 Copies of Establishment Inspection Reports surveillance NAI or VAI * narrative section only closed 30 business days by mail 41

42 Final Rules Human Subject Protection; Acceptance of Clinical Data from Clinical Investigations for Medical Devices February 21, 2018 New Animal Drugs for Investigational Use; Disqualification of a Clinical Investigator December 28,

43 New Compliance Programs Risk Evaluation and Mitigation Strategies (REMS) March 21, 2018 Institutional Review Boards April 16, 2018 Radioactive Drug Research Committees April 16,

44 New Guidance Documents E6(R2) Good Clinical Practice: Integrated Addendum to ICH E6(R1) March 1, 2018 Acceptance of Clinical Data to Support Medical Device Applications and Submissions: Frequently Asked Questions February 21,

45 Information Sheets Payment and Reimbursement to Research Subjects Information Sheet January 29,

46 Anne E. Johnson Director, Philadelphia District Office (PA, DE) Director, Bio-Research Monitoring Division I (EAST) Office of Bioresearch Monitoring Operations Office of Regulatory Affairs (ORA) U.S. Food and Drug Administration (215) anne.johnson@fda.hhs.gov 46