Medical Alley Advanced Monitoring Workshop

1. Medical Alley Advanced Monitoring Workshop Paul Below P. Below Consulting, Inc. October 19, 2005

2. Disclosure • The presenter does not have a significant equity interest in any of the companies/products referenced here • The presenter has a consulting relationship with the following: • GlaxoSmithKline • Boehringer Ingelheim Pharmaceuticals • Southeast Louisiana Chapter ACRP

3. This presentation and related references are posted on my website at: www.pbelow-consulting.com/monitoring.html

4. Objectives • The role of monitoring in Good Clinical Practices (GCPs) • Activities involved in on-site visits • Common site problems and findings • Addressing non-compliance • Fraud and misconduct • Electronic records

5. Objectives • Interactive case studies of real-life monitoring situations

6. The Role of Monitoring in Good Clinical Practices

7. Why Do We Monitor? • Required to by regulation • Ensure the acceptance of trial data by regulatory authorities (i.e., FDA)

8. Why Do We Monitor? • Verify that rights and well-being of human subjects are protected • Verify that reported data are accurate, complete and verifiable • Verify trial is conducted in compliance with protocol, GCP and applicable regulatory requirements

9. Good Clinical Practice • “A unified standard for designing, conducting, recording, and reporting trials that involve the participation of human subjects” • Federal regulations (Title 21 CFR) • Other federal regulations & state laws • FDA “guidance documents”

10. GCP Regulations • Protection of human subjects - informed consent (part 50) • Institutional review boards (part 56) • Financial disclosure (part 54) • Electronics records and signatures (part 11) • Investigational new drugs (part 312) and application to market a new drug (part 314) • Investigational device exemptions (part 812) & premarket approval of medical devices (part 814)

11. Other Federal Regulations • Nuclear Regulatory Commission regulations (10 CFR 35) for the medical use of radioactive substances • Department of Transportation regulations for the shipment of infectious materials (49 CFR) • HIPAA Privacy Rule (45 CFR 160-164) for the use and disclosure of protected health information

12. State Laws • Many states have laws that impact clinical research in the following areas: • Age of consent • Legally authorized representative • Clinical research registration • Medical records privacy • Gene research • STD/HIV reporting

13. GCP Guidance Documents • FDA Information Sheets (www.fda.gov/oc/ohrt/irbs/default.htm) • Guideline for the Monitoring Clinical Investigations (January 1988) • ICH Guidelines for Good Clinical Practice (Published in Federal Register - May 9, 1997)

14. FDA Guidance • Represents the agency’s “current thinking” on how to comply with the regulations • Not legally binding • Non-compliance should not be cited in a FDA Form 483 • An alternative approach can be used if acceptable to FDA

15. What is ICH? • International Conference on the Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use • Comprised of representatives from the U.S., European Union and Japan • Establish guidelines to promote mutual acceptance of data

22. Monitoring Requirement • “Sponsors are responsible for … ensuring proper monitoring of the investigation” (812.40 and 312.50) • “The sponsor shall monitor the progress of all investigations involving an exception to informed consent” (812.47 and 312.54)

23. Monitoring Plan • For significant risk device and treatment use trials, FDA requires written procedures for monitoring in the investigational plan (812.25, 812.40) • FDA can withhold or pull approval of an application if the monitoring plan is inadequate (812.30)

24. Monitoring Plan (cont) • Monitoring plan based on: • Trial objectives, design, endpoints • Trial complexity • Number/location of investigators • Type of investigational product • Disease under study

25. Type of Monitoring • “Personal contact” should be maintained with the investigator throughout the trial • Need for on-site visits before, during and after the trial • In exceptional circumstances, central monitoring can be used

26. Selection of Monitors • “A sponsor shall select monitors qualified by training and experience” (812.43) • A list of names and addresses of all monitors is included with the investigational plan (812.25) • Monitoring functions can be transferred to a CRO (312.52)

27. Monitor Selection • Need not be qualified to diagnose or treat disease under study • Thoroughly familiar with test article, protocol and informed consent, sponsor’s SOPs, and GCPs and FDA regulations • Qualifications should be documented

28. Recent FDA Warning Letter “Study monitors were not qualified by training and experience. Neither of the two individuals who conducted monitoring visits for the [redacted] study had previous experience in clinical monitoring; one of the two monitors had no training in clinical trials prior to conducting independent monitoring trials.” CDRH Warning Letter to Celsion Corporation (May 7, 2004)

29. Outstanding Monitor Traits • Quick scientific learners • Independent problem solvers • Can hack the travel • Can see the forest and the trees • Regulatory experts • Technologically proficient

30. Activities Involvedin On-Site Visits

31. On-Site Visit Types • Pre-Investigation • Periodic Monitoring • Close-Out

32. Selection of Investigators • “A sponsor shall select investigators qualified by training and experience to investigate the device” (812.43)

33. Investigator Selection • Preliminary phone contacts and on-site visit to determine if the investigator: • Understands and accepts trial obligations • Understands and accepts regulatory obligations • Can demonstrate potential for recruitment based on retrospective data • Has adequate facilities • Has sufficient time • Has adequate number of qualified staff for duration of trial

34. Investigator Selection • Other Considerations: • Past company performance • Past performance with other sponsors • References from colleagues • Publication record • Key opinion leaders • FDA Debarment and Disqualified Lists • FDA Warning Letters • CDER Clinical Investigator Inspection List

35. FDA Investigator Lists • Debarment List: • Convicted of a felony under Federal law for conduct relating to development or approval of any drug product • www.fda.gov/ora/compliance_ref/debar/default • Disqualified/Restricted/Assurances Lists: • Disqualified through hearing process or restricted through consent agreement • www.fda.gov/ora/compliance_ref/bimo/dis_res_assur.htm

39. FDA Investigator Lists • Clinical Investigators Inspection List: • Contains information gathered from inspections of clinical investigators who have performed studies with investigational human drugs • The inspections were conducted as part of FDA’s Bioresearch Monitoring Program • www.fda.gov/cder/regulatory/investigators/default.htm

40. Pre-Investigation Visit • Location • All facilities where trial conduct will occur • Materials • Investigator’s Manual • Device • Agenda

41. Pre-Investigation Visit • Participants • Principal Investigator/Co-Investigators • Study coordinator/research nurse • Other medical staff (technicians)

42. Pre-Investigation Activities • Discussion of device background, protocol procedures • Discussion of resources • Staff availability and training • Adequate time and workload • Interest and motivation level • Available patients (review retrospective data) • Competing trials

43. Pre-Investigation Activities • Review case report forms and required source documentation • Discussion of regulatory obligations • IRB review • Informed consent • Record keeping • Investigational product • Company policies and procedures

44. Pre-Investigation Activities • Tour facilities • Patient evaluation and treatment facilities • Emergency facilities and staff • Laboratory • Device storage and security • Files storage (administrative and patient) • Collect investigator documentation

45. Investigator Documentation • CV and/or statement of relevant experience (812.43) • If involved in a terminated trial, explanation of circumstances (812.43) • Signed Investigator Agreement (812.43) • Financial disclosure information (812.43)

46. Investigator Documentation • IRB approval documentation (812.42) • Provide the investigator with the investigational plan and report of prior investigations of the device (812.45) • Other records (ICH): • Local lab certification, normal ranges • IRB membership roster • Medical license

47. Periodic Visit Planning • Participants • Study coordinator • Principal investigator • Technicians • Timing • Follow monitoring plan • Flexibility for problem sites • First visit early

48. Periodic Visit Planning • Materials • Protocol • List of enrolled patients • Reference manuals • Site specific material/documents • Office supplies • Assigned work space • Assigned time with investigator and trial staff

49. Periodic Visit Objectives • Review compliance with protocol, GCPs, and sponsor SOPs • Review data • Review investigational product • Verify adequacy of facilities & resources • Review essential (regulatory) documents

50. Protocol/GCP Compliance • Protocol deviations explained (812.140) • Enrolling only eligible patients • Informed consent obtained before each subject’s trial participation (and case history statement, 812.140) • All required reports to sponsor and IRB • Adverse events appropriately reported