Investigator-Initiated Research: Opportunities and Obstacles

1. Investigator-Initiated Research: Opportunities and Obstacles Michael R. Hamrell, Ph.D. MORIAH Consultants February 2007

2. Investigator-Initiated Originated by or in collaboration with an investigator at your institution

3. Distinguishing Features • Not typical multicenter trial • Not a large national study • Important to your investigator

4. What is Research ? • A systematic investigation, including research development, testing and evaluation, designed to develop or contribute to generalizable knowledge. Activities which meet this definition constitute research for purposes of this policy, whether or not they are conducted or supported under a program which is considered research for other purposes

5. What is a Clinical Investigation ? • “… any experiment in which a drug is administered… to one or more human subjects that is subject to requirements for submission to FDA or the results are intended to be submitted to FDA • “…an experiment is any use of a drug, except for the use of a marketed drug in the course of medical practice” 21 CFR §312.3

6. Clinical Investigation or Not ? • Are you studying an investigational or marketed product in human subjects? • Are you using the product according to the prescribing information? • Are you collecting data for analysis or reporting (such as for publication)?

7. Research vs. Practice The Belmont Report in 1979 defined the differences between ‘practice’ and ‘research’. • “…the term "practice" refers to interventions that are designed solely to enhance the well-being of an individual patient or client and that have a reasonable expectation of success. The purpose of medical or behavioral practice is to provide diagnosis, preventive treatment or therapy to particular individuals. • By contrast, the term "research' designates an activity designed to test an hypothesis, permit conclusions to be drawn, and thereby to develop or contribute to generalizable knowledge…”

8. Research Practice • “..a departure in a significant way from standard or accepted practice, the innovation does not, in and of itself, constitute research. The fact that a procedure is "experimental," in the sense of new, untested or different, does not automatically place it in the category of research…”

9. Is the Project Research? • Does it meet 45 CFR 46.102 (d) definition? Is it a systematic investigation designed to develop or contribute to generalizable knowledge? • Are human “subjects” involved? • Data collection through interaction or intervention • Identifiable private information • Does it meet 21 CFR 50.3(C) definition of clinical investigation? • Experiment involving test article administered to subjects • Subject to FDA requirement for prior submission; or results are intended for FDA submission

10. Federal Regulations (45 CFR §46) • “…this policy applies to all research involving human subjects conducted, supported or otherwise subject to regulation by any Federal Department or Agency which takes appropriate administrative action to make the policy applicable to such research….” • “..research that is neither conducted nor supported by a Federal Department or Agency, but is subject to regulation as defined … must be reviewed and approved, in compliance with …this policy, by an Institutional Review Board (IRB) that operates in accordance with the pertinent requirements of this policy….”

11. Federal Regulations • Applicability of the Department of Health and Human Services (HHS) regulations for the protection of human research subjects • Definition of researchat 45 CFR 46.102(d) • Definition of human subject at 45 CFR 46.102(f) • Research exemptions at 45 CFR 46.101(b) ■ education tests, survey/interview, public observations [b(2)] ■ collection/study of existing data w/o identifiers [b(4)] ■ research/demonstration projects to examine public benefit and service programs [b(5)]

12. When is chart review/data collection research? • Is data collection systematic (v. single chart review)? • Is activity designed to improve generalizable knowledge? • Does data collection involve private identifiable information or biological specimens? • See OHRP guidance at http://www.hhs.gov/ohrp/humansubjects/guidance/ cdebiol.pdf

13. Who is an Investigator ? • An Investigator is an individual who actually conducts a clinical investigation • A Sponsor-Investigator means an individual who both initiates and conducts an investigation and under whose direction the investigational drug is administered

14. Which “Hat” is the Clinician/Investigator Wearing? • Clinician – unbiased medical judgment as to best interests of patient • Investigator – focus on generation of data based on the administration of a product to a number of participants and the analysis of safety and effectiveness

15. Who is a Sponsor ? • A sponsor is a person or entity who initiates a clinical investigation, but who does not actually conduct the investigation (i.e., a Pharma/Biotech company)

16. What is a Test Article ? • The test article means any drug, device, biologic, or any other article subject to regulation under the FD&C Act or PHS Act • also referred to as the ‘investigational product’

17. What is an IND ? • An application (to FDA) for permission to ship an investigational product to investigators for use in a clinical study • An IND is required to be submitted to the FDA if the clinical study will be conducted with an investigational product (test article)

18. When is an IND NOT Needed ? • Product is approved by FDA and being used according to the approved labeling • Investigation is not intended to be reported to FDA or support any significant labeling or advertising change • Investigation does not involve a change in route or dosage that changes the risk to the population • Investigation is conducted in compliance with IRB and Informed Consent regulations

19. Warning Letter 02-HFD-45-0303

20. Exceptions to the Rule • FDA has indicated that there are exceptions to the rule, such as for approved cancer therapies • Studies of new combinations, new schedules or new routes of administration are exempt if there is sufficient clinical experience described in the literature to determine that the treatment is safe • Studies of new compounds, new adjuvants, or a new use for an approved product without adequate support would generally not be exempt

21. Off-Label Use • Under the practice of medicine, a practitioner can use any approved product for other than an approved use, based on their medical knowledge, training and general standards of practice, ethics and medicine • This applies to an individual, case-by-case decision for a patient under their care • As soon as you begin doing it for all patients and collecting data to document the outcome, it becomes research

22. What About the IRB? • Physician investigators, particularly but not only those outside of institution setting, may assume that neither IND filing nor IRB review is required • FDA position, as articulated in recent Warning Letters, is that even in IND – exempt study, IRB approval is necessary • Failure to get IRB approval = failure to qualify for IND exemption because one criteria for IND exemption is compliance with IRB regulations • Does a physician in private practice conducting research with FDA regulated product need IRB approval? Yes. If doctor can’t obtain an IRB, FDA can help

23. Protection of Human Subjects • No Investigator may involve a human being as a subject in research covered by these regulations unless the Investigator has obtained the legally effective informed consent of the subject or the subject’s legally authorized representative 45 CFR §46.116 and 21 CFR §50.20

24. Protection of Human Subjects • Some limited exceptions to informed consent regulations • life-threatening emergency use • emergency use research • Dept. of Defense waiver (cancelled) • All have very strict controls

25. Other Subject Protection Sections • Subpart B – Additional protections for fetuses, pregnant women and Human in vitro fertilization • Subpart C – Additional protections for biomedical or behavioral research involving prisoners • Not implemented by FDA • Subpart D – Additional Protections for children as subjects

26. Some Other Exemptions • Most educational testing • Taste tests • Behavioral surveys • Most interview studies • Some types of retrospective record review

27. Subject Privacy HIPAA of 1996 • Adds new regulation at 45 CFR §164 regarding patient medical records and right to privacy • Research medical record review is not exempt • Does not prevent PIs and Sponsors from completing required reporting under FDA regulations (i.e., SAEs) • 45 CFR §164.512(b)(iii)

28. Research Use/Disclosure with Individual Authorization/Consent • The authorization for PHI may be combined with the traditional informed consent document used in research • Under the Common Rule a research participant will sign a consent authorizing the use of patient information for research purposes. In this case, documentation of an IRB waiver is NOT required • The Privacy Rule also permits covered entities use and the disclosure of the information about the patient him or herself

29. What is the Institution’s duty under its OHRP Assurance? • Compliance with HHS regulations regardless of funding source, as agreed to by institution • Institution bears responsibility for what happens inside the entity • Institutions may affirmatively require staff holding privileges to 1) notify the institution of the intent to conduct research and 2) agree that such research will be conducted in accordance with the Assurance

30. How is Conflict of Interest going to be controlled? • Investigator – initiated research may be particularly vulnerable to potential bias due to direct relationship between researcher and product manufacturer • 42 CFR Part 50 Subpart F reporting only applies to federally supported research, but state laws may apply

31. What should the Institution Ask When it Learns About Investigator – Initiated Research? • Did an IRB Approve? • What does the consent form say? • Does the institution billing department know? • Does it use any institution resources? • Does the conflict of interest committee know? • Were there any adverse events? • Does OHRP need to be notified? • Does FDA need to be notified?

32. How Does an Institution ControlWhat Goes on Inside its Borders? • Policy of internal reporting/approval before commencement of any research activity • Policy that any publication go through central office for determination of involvement of human subjects • Strengthen record retention policies • Clarify system for creating medical record/research record • Take action against violators • Have a plan to address adverse publicity • Educate staff and IRB

33. FDA Actions • As a result of problems at U Penn in gene therapy (GT) trial in 1997, FDA sent a letter to all sponsors of GT trials • Requested information on GCP and oversight plans • Conducted GCP audits of 69 ongoing GT trials

34. FDA Survey Of GT Research Three areas of concern/confusion • Duties of sponsor vs. investigator • Initiating a trial vs. monitoring a trial • Monitoring a trial vs. auditing a trial

35. Sponsor vs. Investigator • IND Sponsors who themselves are clinical investigators often failed to differentiate between their responsibility as an Investigator vs. as a Sponsor

36. Monitoring vs. Oversight • Sponsors/investigators often did not distinguish between initiating a trial and monitoring a trial • Academic sponsor/investigators generally rely on institutional or other monitoring committees, e.g., IRB, DSMB, FDA • Confusion between monitoring and auditing

37. You failed to properly monitor the studies and to select qualified monitors… Sponsor-Investigator IND “- There were no standardoperating procedures for monitoring or for selecting appropriate monitors for your studies. - There was no evidence that the studies had been monitored. - There was no documentation that the study coordinator(s) had received adequate training….” Warning Letter g4595d

38. Planning Your Work • Determine if the plan would be considered research • Determine if it will require an IND and permission from FDA • Obtain IRB approval and subject consent

39. Other Government Agencieswith Research Oversight

40. Other Government Agencies Office of Research Integrity • Office within HHS that reviews PHS awardee and institutions to deal with reports of possible fraud, misconduct, or abuse http://ori.dhhs.gov • Authorized in regulations • 42 CFR §50 & 93

41. Other Committees with Research Oversight

42. Research Oversight • Scientific Review Committee • Institution’s own group to look at scientific merit of study • Resource Utilization Committee • Are institution’s resources being properly utilized (and billed) • Radiation Safety Committee • Typically required for any study involving patient exposure to radiation • NIH – Recombinant Advisory Committee • Data/Safety Monitoring Committees

43. Recombinant Advisory Committee • Scientific Review Committee at NIH • Required to review any research activities at any institution that receives Federal funding that involves recombinant technology • Looks at science and ethics of research plans

44. Data Monitoring Committees • Role – to periodically monitor data from a study for evidence of safety concerns or continuation of study • Organization • Independent of Sponsor • Typically unblinded • Expertise covers clinical, safety, biostatistics, epidemiology

45. DSMB • Often used in studies where there is an endpoint with morbidity/mortality or other significant risk to subjects • Multicenter, blinded trials • Monitors progress of trial • Endpoints • Safety • Ethics of continuation

46. NIH Safety Monitoring • June 1998 – Policy on Data and Safety Monitoring Board (DSMB) for Phase 1 & 2 trials • June 2000 - requires investigators to submit monitoring plan for Phase 1 & 2 trials before the trial begins • NIH requires DSMB for Phase 3 studies • FDA has issued similar draft guidance

47. Failure to ensure that the investigation is conducted according to the investigational plan (protocol) “Subjects who failed to meet the eligibility criteria were allowed to participate in the clinical trial. The protocol included a provision that selection criteria may be waived by the sponsor-investigator if approved by the IRB on a case-by-case basis”. However, for several subjects, you failed to obtain advanced IRB approval to waive the entry criteria. You submitted an “Eligibility Criteria Waiver request form for subject A to the IRB on 2/13/98, eleven months after you initiated the trial and nine months after the subject’s death. In fact, subjects X, Y & Z were dead by the time you submitted an “Eligibility Criteria Waiver’ request form to the IRB for these subjects..” NIDPOE Letter n16l

48. You administered the investigational product to numerous subjects eventhough they should have been excluded.. “Your response letter explains that ‘the protocol did not always reflect the rapidly evolving understanding of the pathophysiology of melanoma’. If the protocol requires revision based on new information or because there should be a change in procedure, amendments should be submitted to the FDA and to the IRB for review and approval. Further, your response explains that you submitted Eligibility Criteria Waiver request forms to the IRB when you “became aware” of the requirement to do so. We do not accept your explanation because, as the author of the protocol you established these requirements..” NIDPOE Letter n16l

49. Failure to adequately protect the safety and welfare of human subjects in the study…. “You (PharmD) or in some cases, XX, Ph.D., a psychologist sub-investigator, wrote orders for study drug, evaluated patient responses to study drug, and, based on responses, made dosage adjustments. You maintain that as PI you were authorized to perform these activities. We disagree, and the State Board of Medicine supports our position that these activities are within the practice of medicine. You are not licensed to practice medicine…..” Warning Letter wl45-0701

50. Failure to obtain informed consent in accordance with the provisions of Part 50 Sponsor-Investigator IND “Several of the consent forms used in your clinical studies are deficient in that they do not contain all of the required elements of informed consent. Although the IRB approved some of these deficient consent forms, you are responsible, as a Sponsor and clinical investigator, for ensuring that the consent forms meet federal requirements.” Warning Letter m2551n