Site Inspections: Are You Ready?

1. Site Inspections: Are You Ready?

2. Who performs site inspections? • Sponsor/CRO CRA or monitor, regulatory affairs, QA • Pre-Study visit • Site initiation visit • Routine monitoring visits • For cause monitoring visit • Study close-out visit • FDA • Routine inspection/Surveillance • For cause

3. Monitoring Clinical Trials ICH E6: GCP 5.18.1 The purposes of trial monitoring are to verify that: (a) The rights and well-being of human subjects are protected. (b) The reported trial data are accurate, complete, and verifiable from source documents. (c) The conduct of the trial is in compliance with the currently approved protocol/amendment(s), with GCP, and with applicable regulatory requirement(s).

4. Monitoring Clinical Trials 21CFR312.56 • The sponsor shall monitor the progress of all clinical investigations being conducted under its IND. (b) A sponsor who discovers that an investigator is not complying with the signed agreement (Form FDA-1572), the general investigational plan, or the requirements of this part or other applicable parts shall promptly either secure compliance or discontinue shipments of the investigational new drug to the investigator and end the investigator's participation in the investigation.

5. Monitoring Visits • Verify informed consent was obtained prior to any study-related procedures • Ensure investigator and staff are performing procedures per the current approved protocol • Review drug accountability logs • Verify accuracy of case report form data by reviewing all original source documentation

6. Prepare for Monitoring Visits • Patient medical records available • Source documents and worksheets completed • Case report forms completed and accurate • Regulatory documents available and current • Drug accountability logs up to date • Follow up on all outstanding issues from previous visit

7. Time and Space • Your Monitor needs time with: • Investigator + • Sub-Investigator +/- • Study Coordinator +++ • Nuclear medicine technologist +/- • Your Monitor needs space for • Reading charts and case report forms • Writing reports • Utilizing Post-it notes®

8. Monitoring Visits are… your best preparation for an FDA audit!

9. FDA Audits/Inspections 21CFR312.68 Inspection of investigator's records and reports. An investigator shall upon request from any properly authorized officer or employee of FDA, at reasonable times, permit such officer or employee to have access to, and copy and verify any records or reports made by the investigator….

10. Notice of Inspection • May be pre-announced by telephone • Work with FDA Inspector to schedule inspection • Do not delay inspection • Notify sponsor of planned inspection • Sponsor may conduct audit in preparation for FDA inspection

11. Preparing for Inspection Have the following available: • Most responsible clinical investigator/designee for inspection day • Personnel knowledgeable about all aspects of the study • A quiet area to conduct inspection with access to a photocopier • All study documents including electronic records if applicable • Standard Operating Procedures (SOPs) “Preparing for a Medical Device Clinical Investigator Inspection” Presented by Allen Lou, Consumer Safety Officer, FDA Available online at http://www.fda.gov/Training/CDRHLearn/ucm176841.htm

12. Inspection Day • FDA personnel (Field Investigators, Center personnel, etc.) present his or her credentials • Issuance of Form FDA 482, Notice of Inspection • Request that a summary of any inspectional findings be provided at the end of each day • Inspection is conducted during normal business hours “Preparing for a Medical Device Clinical Investigator Inspection” Presented by Allen Lou, Consumer Safety Officer, FDA Available online at http://www.fda.gov/Training/CDRHLearn/ucm176841.htm

13. What is Inspected? • Protocol (original & revisions) • Investigator agreements & financial disclosures • Case report forms and source documents • Inclusion/Exclusion criteria • Informed consent forms • Adverse events • Other required reports • Electronic records • Other study subject records “Preparing for a Medical Device Clinical Investigator Inspection” Presented by Allen Lou, Consumer Safety Officer, FDA Available online at http://www.fda.gov/Training/CDRHLearn/ucm176841.htm

14. What is Inspected, Cont. • Qualification records for Clinical Investigators • Training records • Study delegation sheet • Correspondence • Drug accountability records • SOPs for conduct of study “Preparing for a Medical Device Clinical Investigator Inspection” Presented by Allen Lou, Consumer Safety Officer, FDA Available online at http://www.fda.gov/Training/CDRHLearn/ucm176841.htm

15. Inspection Conclusion • FDA Investigator conducts a close out meeting with clinical investigator • FDA Investigator issues a Form FDA 483, Inspectional Observations for significant deviations from the regulations • Form FDA 483 does not represent a final Agency determination • Opportunity to respond to observations “Preparing for a Medical Device Clinical Investigator Inspection” Presented by Allen Lou, Consumer Safety Officer, FDA Available online at http://www.fda.gov/Training/CDRHLearn/ucm176841.htm

16. Post Inspection Process • The FDA investigator completes Establishment Inspection Report (EIR) • The EIR, FDA 483 (if issued), supporting documentation, and the preliminary district classification is forwarded to the Agency within FDA • Agency evaluates the report and determines the final classification for the inspection • Inspection findings and preliminary recommendations are reported to the appropriate Agency review division • Consult with other FDA Centers (CDRH, CBER, CDER) “Preparing for a Medical Device Clinical Investigator Inspection” Presented by Allen Lou, Consumer Safety Officer, FDA Available online at http://www.fda.gov/Training/CDRHLearn/ucm176841.htm

17. Inspection Classification No Action Indicated (NAI) • No objectionable conditions or findings Voluntary Action Indicated (VAI) • Objectionable conditions or findings, but not at threshold to take or recommend administrative or regulatory action Official Action Indicated (OAI) • Serious objectionable conditions found; Regulatory action recommended “Preparing for a Medical Device Clinical Investigator Inspection” Presented by Allen Lou, Consumer Safety Officer, FDA Available online at http://www.fda.gov/Training/CDRHLearn/ucm176841.htm

18. Written Response to 483 • An evaluation of the extent of the problem • Assessment of the root cause of the problem • Any corrective actions • Not just a statement that you will correct or plan to correct the problem • What was corrected? • When was it completed? • Is the problem systemic? • Preventive actions to prevent recurrence of the problem in future studies • Time frame for training • Supporting documentation “Preparing for a Medical Device Clinical Investigator Inspection” Presented by Allen Lou, Consumer Safety Officer, FDA Available online at http://www.fda.gov/Training/CDRHLearn/ucm176841.htm

19. Inspection Manual

20. Informed Consent Process • Who (investigator, nurse, study coordinator, etc.) explained the investigational study and consent document to prospective study subjects, and was it provided in a language understandable to each subject? • How did the informed consent process take place? (e.g., was this explanation given orally, by video, through a translator, etc.)? FDA Inspection Manual Excerpts

21. Informed Consent, cont. • Was consent obtained prior to enrollment in the study (i.e., prior to performance of any study related tests and administration of the test article)? • After signing and dating the informed consent document, was each subject or the subject's legally authorized representative given a copy of the consent document? FDA Inspection Manual Excerpts

22. Informed Consent, cont. • Was the appropriate IRB-approved version of the informed consent document used for all subjects? • If the short form was used (per 21 CFR 50.27(b)(2)), was the informed consent process appropriately documented? FDA Inspection Manual Excerpts

23. Test Article Control Compare the amount of test article shipped, received, used, and returned or destroyed. Verify the following: • Receipt date(s), quantity received, and the condition upon receipt; • Date(s), subject number, and quantity dispensed; and • Date(s) and quantity returned to sponsor. If not returned to sponsor, describe the disposition of the test article. FDA Inspection Manual Excerpts

24. Other Records Study-related information may also be recorded in other documents. • Determine if the clinical investigator maintains other records pertinent to the study, e.g., administrative study files, correspondence files, master subject list, appointment books, sign-in logs, screening lists, and MedWatch forms. • Review these records to ensure that all pertinent information has been reported to the sponsor. • Document any discrepancies found. FDA Inspection Manual Excerpts

25. Summary • Sponsor monitoring visits are your best preparation for an FDA inspection • Document the informed consent process • All records are eligible for inspection • Provide written response to 483

26. Resources • Compliance Program Inspection manual http://www.fda.gov/ICECI/EnforcementActions/BioresearchMonitoring/ucm133562.htm • “Preparing for a Medical Device Clinical Investigator Inspection” presented by Allen Lou, Consumer Safety Officer, FDA http://www.fda.gov/Training/CDRHLearn/ucm176841.htm