PREPARING FOR AN FDA AUDIT

1. PREPARING FOR AN FDA AUDIT ANDREA BRANCHE INVESTIGATOR USFDA Houston Resident Post Dallas District

2. The Inspection Process: Perspective and Approach Purpose is quality assurance, not quality control/monitoring Inspections must serve both a compliance function as well as a review function Individual sites serve as indicators of system controls • Supplemented, as appropriate, with inspections of sponsor/monitor/CRO

3. What Defines GCP in the United States FDA has GCP regulations governing the approval, conduct, review and reporting of clinical research intended for submission • 21 CFR 312: IND regulations (rev.1987) • 21 CFR 50: Informed consent (rev.1981) • 21 CFR 56: IRB (rev.1981) • 21 CFR 314: NDA regulations (rev. 1985) These are legally enforceable requirements

4. Routine vs. Directed Inspections Routine • Inspections assigned for PMA’s and NDA’s Directed (“for cause”) • Problems identified during review process • Complaints reported to DSI • FDA, other Agencies • Sponsors/monitors • Institutions/IRB’s • Subjects/Public

5. Directed vs. Routine

6. Directed Inspection Criteria Suspicion of false or fraudulent data Data that appear unrealistic Evidence that a sponsor has rejected data from an investigator Evidence of delay in submitting adverse clinical findings Evidence of inadequately monitored clinical investigations Evidence of inadequate or inappropriate informed consent Evidence of delayed or inappropriate IRB approval Evidence that an investigator has a significant financial interest in the product

7. Inspection Programs: GCP Clinical Investigator • Inspections assigned for each pending NDA/PMA • Supplements are routinely inspected only when there is a significant public health impact (eg., significant new indication; significant new population); justification is required in the request • May be assigned for active IDE/IND, if indicated

8. How We Do It!!!! Clinical investigator inspections usually done by appointment Opening interview with investigator and study coordinator(s) Facilities inspection Record review Periodic discussion with investigator, sub-investigators, study coordinator, technicians, laboratory personnel Pharmacy records/drug accountability review Exit interview - conveyance of FDA 483 inspection findings to investigator of record (or his/her designee)

9. And……. Opening interview with investigator and study coordinator(s) • Emphasis on understanding who did what; how specific study taks may have been delegated • To what extent did the investigator of record maintain control over the study • How were subjects screened and allocated to treatment groups • Who was responsible for determining subject eligibility and at what point in the study was this accomplished • What degree of unblinding occurred

10. More…. • How compliant were the study subjects with the protocol • What notable serious or unexpected adverse experiences occurred • Can the investigator identify sources of bias in the study • What is the completeness of required documentation • Can the investigator identify difficulties with the study and/or CRF design that made the protocol difficult to follow • If the study were to be repeated, what would the investigator do differently

11. More….. Record keeping: What is the completeness of required documentation? • Not just paper! FDA inspectors can ask to see actual x-ray films, ultrasound recordings, pulmonary function test tracings, and other true “source” materials to substantiate data submitted in CRFs • Are consent forms available for all subjects? Do they bear signature dates prior to the subjects’s start of participation in the trial? • Are investigator copies of CRFs present for all subjects? • Are supporting medical records/source documents available for all subjects? • What is the nature of original documentation for study-specific procedures, such as biopsy reports, special tests?

12. Medical history information Medical examination results All lab results Demographic data DOB, sex, weight, age, race, height Concomitant meds Patient ID number Study number Drug dispensing information Informed consent IRB approval Visit dates Concurrent illness Source Data

13. Hospital Records Clinic and office charts Laboratory reports Memoranda Subject diaries Pharmacy dispensing records X-rays, CT scans, MRIs Case report forms when data is entered directly Magnetic media Photographic negatives Source Documents

14. And…… Additional inspectional activities/areas of concern: • Compare investigator’s version of the protocol to the version submitted by the sponsor to FDA • Check the integrity of the randomization process • Observe and note reasons for protocol violations • Note reporting of serious adverse experiences, including time frames • Observe evidence of unreported interim analyses • Note correspondence/telecons between clinical investigator and the IRB, monitor, and sponsor, referring physicians, and consultants

15. What is Generated After an Inspection FDA Form 483: Inspectional observations Left with CI at close of inspection Immediately available via FOI Establishment Inspection Report (EIR) Prepared by field investigator after inspection Includes exhibits supporting observed deficiencies Supervisory endorsement from District Office Brief summary statement Field recommendations

16. Maxine-Says Money can't buy happiness -- but somehow it’s more comfortable to cry in a Porsche than in a Hyundai.

17. QUESTIONS?????? ANDREA BRANCHE abranche@ora.fda.gov (713) 802-7521 THANK YOU

18. There are worse jobs than being a QA Auditor