FDA Inspections of Investigator Sites

1. MAGI's Clinical Trial Agreements, Budgets & Regulatory Conference FDA Inspections of Investigator Sites Paul Below Clinical Research Consultant P. Below Consulting, Inc.

2. Learning Objectives • Describe the FDA’s Bioresearch Monitoring Program (BIMO) • Define the BIMO inspection activities during an investigator inspection • Describe how inspections are classified • Identify resources available on the FDA website to obtain inspection findings MAGI’s Clinical Trial Agreements, Budgets & Regulatory Conference

3. BIMO Program Overview Established in 1977 and expanded in 1992 Comprehensive program of on-site inspections and data audits to monitor all aspects of the conduct and reporting of FDA regulated research Each FDA Center has its own BIMO program staff with overall coordination by the Office of Regulatory Affairs Implemented domestically and internationally resulting in over 1000 inspections annually MAGI’s Clinical Trial Agreements, Budgets & Regulatory Conference

4. Who is Inspected? Clinical Investigators Sponsors/Monitors/CROs Institutional Review Boards Non-Clinical Labs (aka GLP) MAGI’s Clinical Trial Agreements, Budgets & Regulatory Conference

5. Inspections by FDA Center (2006) Source: Compiled from BIMO presentations and statistics on the FDA website MAGI’s Clinical Trial Agreements, Budgets & Regulatory Conference

6. Inspection Triggers Marketing application submission (majority) Novel technology Vulnerable population “Investigator-oriented” or “For cause” inspections usually done when suspicion of integrity or human subject protection issue (often on-going studies) Complaints MAGI’s Clinical Trial Agreements, Budgets & Regulatory Conference

7. Investigator Inspections – Preliminaries Assigned by HQ BIMO staff FDA field inspectors from 19 district offices conduct inspections. They do all kinds of inspections (i.e., GCP, manufacturing, lab) For routine “study-oriented” inspections, scheduled with site within 2 weeks Inspectors show credentials (photo ID) and “Notice of Inspection” form (FDA Form 482) Permission or authorization to inspect of investigator sites is not required. FD&C Act provides criminal penalties for refusal to permit inspections MAGI’s Clinical Trial Agreements, Budgets & Regulatory Conference

8. Investigator Inspections – On-Site Activities Inspection Areas: Protocol compliance Informed consent Facilities Test article accountability Data audit Regulatory document review Detailed procedures for inspections contained in Compliance Program Guidance Manual for Clinical Investigators (7348.811) http://www.fda.gov/ora/compliance_ref/bimo/ MAGI’s Clinical Trial Agreements, Budgets & Regulatory Conference

9. Investigator Inspections – Completion End inspection with an exit interview with the investigator Findings of non-compliance are reported on an FDA Form 483 MAGI’s Clinical Trial Agreements, Budgets & Regulatory Conference

10. Most Common Investigator Deficiencies Failure to follow the investigational plan Protocol deviations Inadequate recordkeeping Inadequate accountability for the investigational product Inadequate subject protection – including informed consent issues MAGI’s Clinical Trial Agreements, Budgets & Regulatory Conference

11. Inspection Follow-up Process After inspection, FDA field inspector writes an establishment inspection report (EIR) After district office review, the completed EIR package is sent to the FDA Once the EIR is received, it is assessed and classified by FDA MAGI’s Clinical Trial Agreements, Budgets & Regulatory Conference

12. Inspection Classifications No Action Indicated (NAI) = the FDA field inspector did not identify objectionable practices or identified only minor issues that did not justify further action Voluntary Action Indicated (VAI) = indicates that objectionable practices were uncovered during the inspection, but were not significant Official Action Indicated (OAI) = inspection uncovered significant objectionable practices, which could affect data reliability or compromise human subject protection. Generally results in the issuance of a Warning Letter or some other higher-level compliance action MAGI’s Clinical Trial Agreements, Budgets & Regulatory Conference

13. Investigator Inspection Classification 2006 4% 51% 44% All Centers (n = 595) Source: “FDA Regulation of Pharmaceuticals and Devices” FDA presentation by Jean Toth-Allen, June 2007 MAGI’s Clinical Trial Agreements, Budgets & Regulatory Conference

14. Inspection Classifications Long-term OAI rates: CDRH = 13% CDER = 3% In general, OAI classification results in issuance of a warning letter about ~70% of the time Investigator warning letters issued in 2007: CDRH = 16 CDER = 6 CBER = 2 MAGI’s Clinical Trial Agreements, Budgets & Regulatory Conference

15. CDER “Investigator-Oriented” Inspections Source: Compiled from BIMO presentations and statistics on the FDA website MAGI’s Clinical Trial Agreements, Budgets & Regulatory Conference

16. Clinical Trial Complaints to CDER Source: Compiled from BIMO presentations and statistics on the FDA website MAGI’s Clinical Trial Agreements, Budgets & Regulatory Conference

17. Clinical Trial Complaints to CDER Complaints lead to on-site inspections approximately 30% of the time Most of the complaints are being submitted by drug sponsors and monitors, followed by private citizens The complaints most likely to trigger FDA inspections are being made by clinical trial subjects CDER views complaints as an increasingly important element of its emerging risk-based GCP compliance effort. Reporting information available at www.fda.gov/oc/gcp/complaints.html MAGI’s Clinical Trial Agreements, Budgets & Regulatory Conference

18. Office of Criminal Inspections Part of Office of Regulatory Affairs Conduct FDA criminal investigations Agents have law enforcement training Collaborate with US Attorney and Department of Justice for prosecution MAGI’s Clinical Trial Agreements, Budgets & Regulatory Conference

19. FDA Resources Warning Letters available on the FDA website at www.fda.gov/foi/warning.htm Some 483s (sponsor and IRB) available at www.fda.gov/ora/frequent/default.htm Notice of Initiation of Disqualification Proceedings and Opportunity to Explain (NIDPOE) Letters atwww.fda.gov/foi/nidpoe/default.html Clinical Investigator Inspection List available at www.fda.gov/cder/regulatory/investigators/default.htm MAGI’s Clinical Trial Agreements, Budgets & Regulatory Conference

20. Clinical Investigator Inspection List Source: www.fda.gov/cder/regulatory/investigators/default.htm MAGI’s Clinical Trial Agreements, Budgets & Regulatory Conference

21. This presentation and related references are posted on my corporate website at: www.pbelow-consulting.com/fda-inspections.html MAGI’s Clinical Trial Agreements, Budgets & Regulatory Conference

22. Contact Information Office: (952) 882-4083 E-mail: paul@pbelow-consulting.com Web: www.pbelow-consulting.com MAGI’s Clinical Trial Agreements, Budgets & Regulatory Conference