The Role of the Investigator in Clinical Research

1. The Role of the Investigator in Clinical Research Pat Beers Block Good Clinical Practice Program February 27, 2004

2. Clinical Investigators • As THE point of contact with study subjects, the Investigator is a critical control point • The success of sponsors, IRBs and FDA in meeting their responsibilities depends on the investigator meeting his/her responsibilities • FDA’s inspection program for clinical research has therefore focused most heavily on inspections of clinical investigators

3. Definition of Clinical Investigator • An individual who actually conducts a clinical investigation (i.e., under whose direction the drug is administered or dispensed to a subject) • In the event an investigation is conducted by a team of individuals, the investigator is the responsible leader of the team --21 CFR 312.3

4. Definition of Clinical Investigator • The definition is important because the clinical investigator assumes responsibility for the study site • FDA can take administrative or even criminal action against a clinical investigator for repeated or deliberate violations of FDA regulations

5. Subinvestigator(s) • Other members of the team • Should be directly involved with subjects in the study • It is the investigator (and not the subinvestigator[s]) who is held responsible for the study site and subject to enforcement action for violations of FDA regulations

6. The Form FDA “1572” • For any IND study, the Clinical Investigator must complete and sign a Form FDA “1572” and provide this to the study sponsor • Name and address of CI • Name and code number of any protocol(s) • Name and address of research facility and any clinical labs • Name and address of the responsible IRB • Names of subinvestigators • Signed commitment by the investigator

7. The “1572” Commitment • The investigator is committing to follow all FDA regulations that relate to investigator responsibilities • FDA assumes that in signing this commitment, the clinical investigator is familiar with and freely undertakes these regulatory responsibilities

8. Medical Device Studies • Key difference from FDA’s drug/biologics regulations: • No FORM FDA 1572 for devices • Instead, FDA device regulations require a signed investigator’s agreement

9. Device Investigator’s Agreement (21 CFR 812.43(c)) • Still requires a signed statement of the investigator’s commitment to: • Abide by the agreement, investigational plan, regulations, and IRB/FDA conditions of approval • Supervise all testing involving human subjects • Ensure informed consent • Provide accurate financial disclosure information

10. Clinical Investigator’s Responsibilities -1- • Personally conduct or supervise investigations • Assure that all persons assisting in the conduct of the studies are informed of their obligations

11. What FDA Looks For • The extent of personal involvement by the clinical investigator • Is there over-delegation ? • Is there adequate personal training and supervision of staff ? • Is the investigator devoting adequate time ? • What are the limits: • How many studies? How many subjects?

12. Clinical Investigator’s Responsibilities -2- • Ensure informed consent (21 CFR Part 50) and IRB review, approval, and reporting requirements (21 CFR Part 56) are met

13. What FDA Looks For • Informed consent is more than a form -- it is a process • How personally involved is the investigator in this process ?

14. Clinical Investigator’s Responsibilities -3- • Read and understand the information in the Investigator’s Brochure, including the potential risks and side effects of the drug • Note: FDA device regulations do not require an Investigator’s Brochure but rather a report of prior investigations of the device (in addition to a copy of the investigational plan)

15. Clinical Investigator’s Responsibilities -4- • Conduct studies according to the relevant, current protocol • Make changes in a protocol only after notifying the sponsor and the IRB • Except where necessary to eliminate apparent, immediate hazards to the human subjects

16. Clinical Investigator’s Responsibilities -5- • Maintain adequate and accurate records • Records of the disposition of the drug including dates, quantity and use by subjects • Case histories • Case histories and supporting data

17. What FDA Looks For • Does the Investigator understand and apply the basic elements of data quality ? • Attributable • Legible • Contemporaneous • Original • Accurate

18. What FDA Looks For • Can the investigator produce source data to corroborate the case report form ? • FDA considers source data to be the first commitment of data to durable medium • Generally where data are FIRST recorded

19. Clinical Investigator’s Responsibilities -6- • Retention of Study Records • For 2 years following date marketing application is approved for the drug for the indication it was investigated • If no application is to be submitted or if the application is not approved for an indication until two years after the investigation is discontinued and FDA is notified

20. Clinical Investigator’s Responsibilities -7- • Maintain control of the investigational product • Administered under his/her personal supervision or under the supervision of a subinvestigator responsible to him/her

21. What FDA Looks For • Is the drug secure and properly stored ? Does drug handling preserve “blinding” of the study ? • Is drug administered only under the investigator’s personal supervision or under supervision of a subinvestigator responsible to the investigator ?

22. Clinical Investigator’s Responsibilities -8- • Promptly report adverse effects to the sponsor • Any adverse event that may be reasonably regarded as caused by, or probably caused by the drug • Ensure that any alarming adverse effects are immediately reported • Serious and unexpected adverse events

23. Clinical Investigator’s Responsibilities -9- • Promptly report to the IRB all unanticipated risk to human subjects or others • This language derives from the “Common Rule” (applicable across U.S. federal agencies including and beyond FDA) • For FDA-regulated research, “unanticipated risk” is most often interpreted as serious and unexpected AEs

24. Clinical Investigator’s Responsibilities -10- • Timeframes for CI reporting are even more explicit in FDA device regulations • Submit to the sponsor and IRB a report of any unanticipated device effect ASAP, but no later than 10 working days after CI learns of effect (21 CFR 812.150(a)(1))

25. What FDA Looks For • Are adverse events appropriately, accurately, and promptly identified, recorded and reported ? • Is there immediate reporting of serious and unexpected AEs to facilitate sponsor reporting requirements ? • Are CIs submitting reports to both sponsors and IRBs as required ?

26. Clinical Investigator’s Responsibilities -11- • Required Reports to the Sponsor • Progress Reports (to facilitate sponsor annual reporting requirements to FDA) • Safety Reports (as above) • Final Report • “An adequate report shortly after completion of the investigator’s participation” • Financial Disclosure Reports

27. Financial Disclosure • FDA regulations require that an applicant for a marketing application to FDA submit financial certification or disclosure information on each investigator or subinvestigator (including spouse/ dependent children) who is directly involved in the treatment or evaluation of subjects in covered studies • FDA investigator regulations require that the sponsor be provided with sufficient accurate information to meet this requirement

28. Clinical Investigator’s Responsibilities -12- • Make records available for FDA inspection (to copy and verify) • Not required to divulge subject names unless records require more detailed study or unless there is reason to believe records do not represent actual case studies or results • Agree to comply with all other requirements in FDA regulations

29. Sponsor-Investigators • FDA regulations allow an individual to be both study sponsor and clinical investigator • This may include individuals who are studying an unapproved drug for academic purposes and not for commercial development of the drug • For example, Physiology studies

30. Sponsor-Investigators • Sponsor-Investigators must comply with BOTH sponsor and clinical investigator regulations • FDA is currently reviewing its approach to sponsor-investigators due to recent problems (including deaths of subjects) in two sponsor-investigator studies

31. Who Can Be a Clinical Investigator • Sponsors are responsible for choosing clinical investigators based on their having appropriate qualifications, training, and experience • Usually a medical doctor, although dentists or other medical professionals may serve as clinical investigators if they are appropriately qualified to personally conduct or supervise the protocol

32. Who Can Be a Clinical Investigator • There is no U.S. government sponsored certification or training program for clinical investigators • However, there are private training and certification programs for investigators in the U.S. • The FDA does not endorse any particular program

33. How Does FDA Identify Clinical Investigators • FDA maintains a publicly available list of all clinical investigators who have been involved in a study under a U.S. IND • Bioresearch Monitoring Information System (BMIS) File • Accessible at www.fda.gov/oc/gcp under “Related Web Sites” • Includes all U.S. investigators as well as non-U.S. investigators who have been part of an IND study or submitted a “1572”

34. How Does FDA Identify Clinical Investigators • BMIS List • Different from FDA’s list of inspected investigators and different from FDA’s list of disqualified or restricted investigators • Being on this list does NOT imply anything about the clinical investigator’s qualifications or performance

35. Challenges for FDA • The list of clinical investigators continues to grow • There are always new clinical investigators • Many will participate in only a single trial • The number of non-U.S. investigators on the list has grown 16-fold between 1991 and 1999 • Protocols are becoming more complex • Education and training are the key to quality

36. How to Reach Us • Good Clinical Practice Programs • 5600 Fishers Lane, Rm. 9C24 • Rockville, MD 20857 • 301-827-3340 • www.fda.gov/oc/gcp • Gcpquestions@oc.fda.gov