An FDA Audit: What the Investigator and Sponsor Need to Know

1. An FDA Audit: What the Investigator and Sponsor Need to Know • Joseph P. Salewski, Chief • Bioresearch Monitoring Branch • Center for Biologics Evaluation and Research • 301-827-6220 • FAX 301-827-6748

2. At the Beginning • Read and understand your obligations under: • Form FDA 1571 • Form FDA 1572 • Protocol

3. Form FDA 1571 • Not begin study until 30 days after FDA’s receipt of IND • Not to begin or continue studies that are placed on hold • An IRB that complies with 21 CFR Part 56 is responsible for the initial and continuing review of the study

4. Form FDA 1571 • An agreement to follow all other applicable requirements • Name of individuals who are responsible for monitoring the conduct and progress of the study • Name of individuals who are responsible for the review and evaluation of safety information

5. Form FDA 1572 • Will assure that the study will not start prior to review and approval by the IRB • Will conduct and personally supervise the study according to the relevant protocol • Will only change the protocol after notifying the sponsor and obtaining IRB approval prior to implementing the change

6. Form FDA 1572 • Will seek a properly constituted IRB and obtain initial and on-going review • Will obtain informed consent of subjects and submit progress reports to the IRB at intervals not to exceed 1 year • Will prepare and maintain adequate and accurate case histories designed to record all pertinent observations for each subject

7. Form FDA 1572 • Will prepare and maintain adequate and accurate drug accountability records • Will collect and report the data in a way to accurately and completely reflect the observations noted during the study • Will report immediately and promptly if adverse events are alarming

8. Form FDA 1572 • Will assure that the study will not start prior to review and approval by the IRB • Will conduct and personally supervise the study according to the relevant protocol • Will only change the protocol after notifying the sponsor and obtaining IRB approval prior to implementing the change

9. Form FDA 1572 • Will communicate to sub-investigators information on scientific matters of importance related to the investigation • Will ensure that the drug is administered according to the stated dosing regime, including dose, route, rate, and duration, and maintains records documenting such facts

10. Form FDA 1572 • Will certify that the drugs are being tested for investigational purposes and will obtain informed consent of subjects or their representative prior to enrollment

11. FDA Preparation • Review Compliance Program • Review Applicable Regulations • Review Prior Inspection Record • Review Assignment Package

12. FDA Preparation: Assignment Package • Background on: • Product development • Clinical trial • Subject population • Protocol • Signed 1572

13. FDA Preparation: Assignment Package • Line listings • Adverse event(s) • Informed Consent Form • Number of subjects enrolled • Site specific outcome(s)

14. What Is Reviewed • Administrative • Protocol/Informed consent forms • Amendments to protocol/consents • Drug accountability records • Sponsor/IRB correspondence • IRB Approvals/Progress reports/AE reports • FD-1572s/Investigator Agreements

15. What Is Reviewed • Case Report Forms • How data is recorded/corrected • Compared to source documents • Supporting Files(Source Documentation) • Hospital Chart • Clinic Chart • Research Chart

16. What Is Reviewed • Informed Consent Forms • Are all required elements included • Are additional elements relevant • Was it approve by the IRB • Were they signed and dated by subjects • Does FDA have current version

17. What Is Inspected • Interview study staff • Test article storage area • Data Audit • Examine case report forms and compare with source documents • Compare sponsor tabulations with source documents and case report forms

18. Critical Issues • Is study entry recorded? • Is there a subject/diagnosis? • Is drug administration documented? • Is there study raw data? • Did an IRB approve all significant stages? • Did each subject provide proper informed consent prior to study entry?

19. Critical Issues • Were all screened subjects entered • Does amount of test article used coincide with number of subjects treated • Was test article properly disposed • Was blind maintained • Was randomization scheme followed

20. Exit Interview • Discuss inspection findings • May issue an FD-483 • Represents deviations from federal regulations for clinical investigators • Verbal response to FD-483

21. Common Deficiencies at Clinical Sites • Protocol non-adherence • Failure to report concomitant therapy • Inadequate and inaccurate records • Failure to report adverse events • Inadequate drug accountability • IRBproblems • Informed consent

22. What Goes Wrong Most Often at the Clinical Site • Most commonly observed deficiencies in these areas include • Failure to follow the protocol • Violation of inclusion/exclusion criteria • Failure to perform required tests • Failure to maintain adequate and accurate records • absence of supporting source documents • inaccurate or incomplete source documents

23. Tips for a Successful Study:Enhancing Protocol Adherence • Protocol design should be as simple as possible, promoting collection of quality data without compromising study objectives • Focus on essential data points • Explain significance in terms of study objectives (efficacy/safety) or subject protection • Avoid ambiguity and vagueness • Inclusion/exclusion criteria • Adverse experiences

24. Tips for a Successful Study:Enhancing Protocol Adherence • Fully understand protocol limits and the importance of strict compliance • How much latitude is available for clinical treatment (e.G. Concomitant therapy)? • Is it ok to use the hospital or clinic protocol for performing routine procedures (e.G. Chemotherapy)? • Is it ok to skip procedures that are not medically necessary (lab tests, PEs, biopsies)? • Which protocol procedures can be performed by non-physician study support staff?

25. Tips for a Successful Study:Enhancing Record Quality • Clearly understand what records are to be maintained and how they should be completed • Original source data for critical study endpoints • Use your site’s indigenous record-keeping system to the maximum extent possible, discuss this with the sponsor up front • All records should meet the ALCOA test

26. Tips for a Successful Study:Understand the Elements of Data Quality • Attributable • Legible • Contemporaneous • Original • Accurate

27. Tips for a Successful Study:Enhancing Record Quality • Minimize the need for transcription • Don’t throw anything away especially originals • Expect the worst • FDA will be inspecting the records

28. Tips for A Successful Study:Understand Regulatory Responsibilities • Read the following before you sign-on • ICH GCP Consolidated Guideline • FDA GCP Regulations • FDA Information Sheets for IRB’s and Clinical Investigators: • http://www.fda.gov/oc/oha/irb/toc.html • 21 CFR Part 312 http://www.access.gpo.gov/nara/cfr/index.html

29. Tips for A Successful Study:Communicate • With the IRB • Protocol changes • Continuing review • With sponsor and monitors • Openly address problems • With regulatory authorities • Understand expectations • Honor reporting obligations

30. Preparing for Site Visit • FDA investigator follows compliance program CP 7348.811 (clinical investigator inspections) and 21 CFR 312.60 • Have available: • All study documents • Person knowledgeable about the study • A place to review records • Access to a photocopier