1. 1 BIORESEARCH MONITORING AND IN VITRO DIAGNOSTICS SYBIL WELLSTOOD, PH.D. OFFICE OF COMPLIANCE DIVISION OF BIORESEARCH MONITORING

2. 2 OBJECTIVES PROVIDE OVERVIEW OF THE CDRH BIORESEARCH MONITORING PROGRAM (BIMO) -What it is -What we do -Who we are DISCUSS HOW THE BIMO PROGRAM APPLIES TO IN VITRO DIAGNOSTIC (IVD) STUDIES CONDUCTED UNDER 510(K) PREMARKET NOTIFICATIONS

3. 3 BIORESEARCH MONITORING PROGRAM (BIMO)  COMPREHENSIVE AGENCY-WIDE COMPLIANCE PROGRAM TO MONITOR FDA-REGULATED RESEARCH -Inspections -Data Audits

4. 4 RESEARCH SUBJECT TO FDA’s BIMO PROGRAM Research Conducted for Submission to FDA to Support Applications for Research or Marketing Permits: Clinical Studies-Humans (Safety & Effectiveness) PreClinical, Nonclinical Laboratory Studies- Analytical tests, Animals (Safety)

5. 5 BIMO MISSION VERIFY QUALITY AND INTEGRITY OF DATA/INFORMATION SUBMITTED IN RESEARCH OR MARKETING APPLICATIONS INCLUDING 510(k)s. PROTECT THE RIGHTS AND WELFARE OF HUMAN RESEARCH SUBJECTS PARTICIPATING IN FDA-REGULATED STUDIES.

6. 6 WHO WE ARE  OFFICE OF COMPLIANCE DIVISION OF BIORESEARCH MONITORING Program Enforcement Branch I Program Enforcement Branch II IVDs

7. 7 WHAT WE DO DEVELOP AND ISSUE INSPECTION ASSIGNMENTS TO FDA FIELD OFFICES EVALUATE AND CLASSIFY ESTABLISHMENT INSPECTION REPORTS (EIRS) INITIATE FOLLOW-UP REGULATORY ACTIONS AND CORRESPONDENCE

8. 8 WHO WE INSPECT SPONSORS-INCLUDING IVD MANUFACTURERS MONITORS, CLINICAL RESEARCH ORGANIZATIONS CLINICAL INVESTIGATORS INSTITUTIONAL REVIEW BOARDS NONCLINICAL LABORATORIES 325 + TOTAL BIMO INSPECTIONS IN FY 2003

9. 9 21 CFR 812.2 (c)(3) EXEMPTS DIAGNOSTICS SUBMITTED AS 510(K)S FROM REQUIRING AN INVESTIGATIONAL DEVICE EXEMPTION (IDE) TO CONDUCT STUDIES.

10. 10 FDA EXPECTATIONS FOR IDE EXEMPT STUDIES MUST FOLLOW GOOD RESEARCH PRACTICES. SUBMIT VALID SCIENTIFIC DATA TO DEMONSTRATE SAFETY AND EFFECTIVENESS. MEET REQUIREMENTS IN 21 CFR PARTS 50 AND 56 FOR HUMAN SUBJECT PROTECTION WHEN APPLICABLE. LABEL PRODUCT “FOR RESEARCH/INVESTIGATIONAL USE ONLY.”

11. 11 HUMAN SUBJECT PROTECTION 21 CFR PARTS 50 & 56 APPLY TO ALL STUDIES SUPPORTING RESEARCH OR MARKETING PERMITS FOR FDA-REGULATED PRODUCTS INVOLVING HUMAN SUBJECTS OR THEIR SPECIMENS

12. 12 HUMAN SUBJECT 21 CFR 812.3(p) A HUMAN WHO PARTICIPATES IN AN INVESTIGATION EITHER AS AN INDIVIDUAL ON WHOM, OR ON WHOSE SPECIMEN, AN INVESTIGATIONAL DEVICE IS USED OR USED AS A CONTROL.

13. 13 21 CFR PARTS 50/56 REQUIREMENTS IRB REVIEW/APPROVAL OF STUDIES INFORMED CONSENT -Must contain all required elements in 21 CFR 50.25.

14. 14 BIMO IVD 510(k) INSPECTIONS REQUESTED BY OIVDS- DATA APPEAR SUSPICIOUS, FRAUDULANT, UNREALISTIC  INVESTIGATE VALID COMPLAINTS/ WHISLEBLOWER ALLEGATIONS  FOLLOW UP ON PREVIOUS INSPECTIONS INVOLVING SERIOUS NONCOMPLIANCE ISSUES f

15. 15 BIMO IVD 510(K) INSPECTIONS Directed-Submission Based Monitor compliance (Human subject protection) Assess data quality Verify accuracy of data submitted in application For Cause-Problem or Complaint Based focus on special issues/problems compliance follow-up often include interviews May include sworn affidavits

16. 16 BIMO INSPECTION PROCESS Telephone call-short notice FDA investigator shows credentials Investigator issues a written notice of inspection to most responsible person (FDA-482) Investigator discusses the general nature of the inspection

17. 17 During the inspection….. Facilities tour. Ongoing discussion of inspectional proceedings and findings; no surprises at conclusion. Collect records to substantiate observations/facts. May collect sworn affidavits.

18. 18 Concluding the inspection… Summary discussion of findings. Investigator may issue Form FDA- 483-a written report of the objectionable conditions observed reflecting deviations from regulations. Deviations from guidelines do not appear on the Form FDA-483, but may be included in the discussion.

19. 19 FDA 483s and responding… If issued, respond verbally during the final discussion (investigator will include response in EIR). Send a written response to District Office and Center contact. You may opt to do both (most do today).

20. 20 RESPONDING TO 483 ITEMS Explain any special circumstances regarding observations.  Describe specific actions taken or planned that will correct and prevent future deviations.

21. 21 ESTABLISHMENT INSPECTION REPORT (EIR) Prepared by the Investigator or team of Investigators performing the inspection following every inspection. -details inspection and findings. -includes exhibits to document findings. -provides a preliminary classification. EIRs for BIMO inspections sent to assigning Centers for review and final classification. Assigning Centers issue post-inspectional correspondence and initiate follow up actions. Only available by FOIA.

22. 22 EIR INSPECTION CLASSIFICATIONS NAI – NO ACTION INDICATED No objectionable conditions or practices. VAI – VOLUNTARY ACTION INDICATED Objectionable conditions; not at threshold to take or recommend administrative or regulatory action.  OAI – OFFICIAL ACTION INDICATED Serious or numerous objectionable conditions found. Regulatory actions recommended.

23. 23 POST INSPECTIONAL REGULATORY ACTIONS Correspondence- Warning Letter Re-inspection Informal conference 3rd party validation Study/data rejection Disqualification (CIs) Injunction Revoke marketing permit Terminate research permit Prosecution Civil Penalties Application integrity policy(AIP)invoked

24. 24 APPLICATION INTEGRITY POLICY (AIP)  ADMINISTRATIVE ACTION USED WHEN THERE IS EVIDENCE THAT SUBMISSIONS CONTAIN FALSE, MISLEADING, OR UNRELIABLE INFORMATION. PATTERN OR PRACTICE OF WRONGFUL ACTS.

25. 25 AIP CONSEQUENCES STOPS REVIEW OF ALL SPONSOR’S APPLICATIONS CURRENTLY UNDER REVIEW. STOPS REVIEW OF ANY NEW SUBMISSIONS.

26. 26 FDA’s ACTIONS Issue AIP letter to applicant Suspends review of in-house and future applications

27. 27 APPLICANT’S RESPONSIBILITIES  Conduct internal review independent outside consultant Submit corrective action plan (CAP)

28. 28 FDA FOLLOW UP Review CAP Inspect to verify internal audit completed and CAP implemented Headquarters reviews EIR Letter to applicant of findings --Remove AIP; continue review

29. 29 FDA FOLLOW UP REQUEST VOLUNTARY WITHDRAWAL OF PENDING APPLICATIONS.  RESCIND CLEARANCE/APPROVAL MARKETED PRODUCTS; REMOVE FROM MARKET.

30. 30 SUMMARY The FDA BIMO programs audit and inspect clinical research and research data to assure: -- the reliability/integrity of research data submitted in marketing/research permits. --assures that human subject protections are in place. Oversight includes studies for diagnostics submitted as 510(k)s.

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32. 32 DIVISION OF BIORESEARCH MONITORING Internet Home Page Address: http://www.fda.gov/cdrh/ comp/bimo.html