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BIORESEARCH MONITORING AND IN VITRO DIAGNOSTICS

SYBIL WELLSTOOD, PH.D.OFFICE OF COMPLIANCE

DIVISION OF BIORESEARCH MONITORING

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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

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BIORESEARCH MONITORING PROGRAM (BIMO)

COMPREHENSIVE AGENCY-WIDE COMPLIANCE PROGRAM TO MONITOR FDA-REGULATED RESEARCH

-Inspections -Data Audits

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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)

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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.

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WHO WE ARE OFFICE OF COMPLIANCE DIVISION OF BIORESEARCH MONITORING Program Enforcement Branch I Program Enforcement Branch II IVDs Preclinical studies

IDE

Division of Bioresearch Monitoring

Food and Drug Administration

Center for Devices and Radiological Health

Office of Compliance

A ssur ing r esear ch in tegr i ty thr oughhuman subject pr otection

& data in tegr i ty audi ts

Investigational device ad

Complaint

Integrity issue

510(k)

PDP

PMA

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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

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WHO WE INSPECT

SPONSORS-INCLUDING IVD MANUFACTURERS MONITORS, CLINICAL RESEARCH

ORGANIZATIONS CLINICAL INVESTIGATORS INSTITUTIONAL REVIEW BOARDS NONCLINICAL LABORATORIES325 + TOTAL BIMO INSPECTIONS IN FY 2003

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21 CFR 812.2 (c)(3)

EXEMPTS DIAGNOSTICS SUBMITTED AS510(K)S FROM REQUIRING ANINVESTIGATIONAL DEVICE EXEMPTION (IDE) TO CONDUCT STUDIES.

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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.”

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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

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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.

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21 CFR PARTS 50/56 REQUIREMENTS

IRB REVIEW/APPROVAL OF STUDIES INFORMED CONSENT -Must contain all required elements

in 21 CFR 50.25.

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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

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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

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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

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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.

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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.

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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).

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RESPONDING TO 483 ITEMS Explain any special circumstances

regarding observations.

Describe specific actions taken or planned that will correct and prevent future deviations.

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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.

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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.

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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

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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.

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AIP CONSEQUENCES

STOPS REVIEW OF ALL SPONSOR’S APPLICATIONS CURRENTLY UNDER REVIEW.

STOPS REVIEW OF ANY NEW SUBMISSIONS.

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FDA’s ACTIONS

Issue AIP letter to applicant

Suspends review of in-house and future applications

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APPLICANT’S RESPONSIBILITIES

Conduct internal review independent outside consultant

Submit corrective action plan (CAP)

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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

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FDA FOLLOW UP

REQUEST VOLUNTARY WITHDRAWAL

OF PENDING APPLICATIONS.

RESCIND CLEARANCE/APPROVAL MARKETED PRODUCTS; REMOVE FROM MARKET.

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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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DIVISION OF BIORESEARCH MONITORING

Internet Home Page Address:

http://www.fda.gov/cdrh/ comp/bimo.html