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

2. 2 MAGI’s Clinical Trial Agreements, Budgets & Regulatory Conference 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

3. 3 MAGI’s Clinical Trial Agreements, Budgets & Regulatory Conference 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

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

5. 5 MAGI’s Clinical Trial Agreements, Budgets & Regulatory Conference Inspections by FDA Center (2006) Inspected EntityCDERCBERCDRH Sponsor32553 Investigator408108200 IRB71859 TOTAL511121312 Source: Compiled from BIMO presentations and statistics on the FDA website

6. 6 MAGI’s Clinical Trial Agreements, Budgets & Regulatory Conference 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

7. 7 MAGI’s Clinical Trial Agreements, Budgets & Regulatory Conference 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

8. 8 MAGI’s Clinical Trial Agreements, Budgets & Regulatory Conference 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/

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

10. 10 MAGI’s Clinical Trial Agreements, Budgets & Regulatory Conference 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

11. 11 MAGI’s Clinical Trial Agreements, Budgets & Regulatory Conference 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

12. 12 MAGI’s Clinical Trial Agreements, Budgets & Regulatory Conference 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

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

14. 14 MAGI’s Clinical Trial Agreements, Budgets & Regulatory Conference 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

15. 15 MAGI’s Clinical Trial Agreements, Budgets & Regulatory Conference CDER “Investigator-Oriented” Inspections Inspection Type200420052006 Routine241312350 For Cause 110 (31%) 70 (18%) 58 (14%) Total351382408 Source: Compiled from BIMO presentations and statistics on the FDA website

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

17. 17 MAGI’s Clinical Trial Agreements, Budgets & Regulatory Conference 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

18. 18 MAGI’s Clinical Trial Agreements, Budgets & Regulatory Conference 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

19. 19 MAGI’s Clinical Trial Agreements, Budgets & Regulatory Conference 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 at www.fda.gov/foi/nidpoe/default.html  Clinical Investigator Inspection List available at www.fda.gov/cder/regulatory/investigators/ default.htm

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

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

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