Responsible Conduct of Research Spring-1, 2014

1. Responsible Conduct of ResearchSpring-1, 2014 Delia Y. Wolf, MD, JD, MSCI Associate Dean Regulatory Affairs and Research Compliance Harvard School of Public Health (HSPH) Email: dywolf@hsph.harvard.edu RCR Lecture-1, January 31 2014

2. Topics to be Covered • Regulations and guidelines governing research involving human subjects • Ethical Principles • Definitions • Relevant regulations and guidelines governing human research • General responsibilities of the IRB and investigators • How to avoid/correct violations

3. Landmark Documents • The Nuremberg Code of 1947 • “Permissible Medical Experiments” Trials of War Criminals before the Nuremberg Military Tribunals under Control Council Law No.10, 1949 • Declaration of Helsinki • World medical association (1964, ‘75, ‘83, ‘89, ‘96, ’00, ‘08) • Belmont Report of 1979 • Report of the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, DHEW, April, 1979

4. Ethical Principles & Regulations Ethical Principles BASIS Federal Regulations

5. Applications of Ethical Principles

6. Relevant Regulations • Code of Federal Regulations (CFR) Title 45 Part 46: • Protection of Human Subjects • CFR 21, Parts • 50 Protection of Human Subjects • 56 Institutional Review Boards • 312 Investigational new drug • 812 Investigational device exemptions

7. Know Your ABC’s • DHHS: Dept. of Health and Human Services • OHRP: Office for Human Research Protection • NIH: National Institutes of Health • FWA: Federal Wide Assurance • FR: Federal Register • ICH: International Conference on Harmonisation • GCP: Good Clinical Practice

8. Know Your ABC’s (cont.) • CFR: Code of Federal Regulations • IND: Investigational New Drug • NDA: New Drug Application • IDE: Investigational Device Exemption • DSMB: Data Safety and Monitoring Board • IB: Investigator’s Brochure

9. Definitions • RESEARCH: A systematic investigation, including research development, testing and evaluation, designed to develop or contribute to generalizable knowledge • HUMAN SUBJECTS: A living individual about whom an investigator conducting research obtains data through intervention or interaction with the individual, or identifiable private information

10. Definitions (cont.) • PRIVATE INFORMATION: information about behavior that occurs in a context in which an individual can reasonably expect that no observation or recording is taking place, and information which has been provided for specific purposes by an individual and which the individual can reasonably expect will not be made public (i.e., medical records). • INTERACTION: Communication or interpersonal contact between investigator and subject.

11. Definitions (cont.) • INTERVENTION: both physical procedures by which data are gathered (i.e., blood draw, x-ray) and manipulations of the subject or the subject's environment that are performed for research purposes. • IRB (Institutional Review Board): A specially constituted review body established or designated by an entity to protect the welfare of human subjects recruited to participate in biomedical or behavioral research.

12. Definitions (cont.) • MINIMAL RISK: the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests • ANONYMOUS: Samples or data that were obtained and stored without any identification that may link to a specific individual. Anonymous samples may have population information (e.g., the samples may come from patients with diabetes)

13. Definitions (cont.) • ANONYMIZED/DE-IDENTIFIED: Samples or data that may have been acquired from identified humans subjects, but all identifiers or codes have been removed and destroyed • CODED: Samples labeled with a code (e.g., a number), rather than a person’s name or other personal identifier. Such code can be traced or linked back to sample donor by an investigator, who usually keeps the key to the code. As long as a link exists, data are considered indirectly identifiable and therefore, not anonymized

14. IRB Membership At least five members, with varying backgrounds No IRB consists entirely of men or women At least one scientist, one non-scientist and one non-affiliated member No IRB may have a member participate in the IRB's initial or continuing review of any project in which the member has a conflicting interest, except to provide information requested by the IRB Use of consultant is permissible, but such person may not vote

15. IRB Authority To approve, require modification in research to secure approval, defer action, or disapprove all research activities, including proposed changes in ongoing, previously approved, human subject research. To suspend or terminate the approval of ongoing, previously approved research that is not being conducted in accordance with the IRB's requirements or that has been associated with unexpected, serious harm to subjects.

16. IRB Responsibilities Conducting initial review Conducting continuing review Notifying the investigators about IRB decisions Determining which studies require review more often than annually Review and approval of changes in research activities Determining which device studies pose significant or non-significant risk

17. IRB Responsibilities (Cont.) • Ensuring that changes in approved research are not initiated without IRB review and approval except where necessary to eliminate apparent immediate hazards to subjects • Ensuring prompt reporting to appropriate institutional officials, regulatory agencies and funding sources of: • unanticipated problems involving risks to subjects or others • serious or continuing noncompliance with federal regulations • suspension or termination of IRB approval

18. Criteria for IRB Approval Risks to subjects are minimized Risks are reasonable in relation to anticipated benefits Selection of subjects is equitable Informed consent is sought from each subject Informed consent is appropriately documented Data collection is monitored to ensure subject safety Privacy and confidentiality of subjects is protected Additional safeguards are included for vulnerable populations

19. Types of IRB Review • Full board review • Initial and subsequent continuing review • Others (i.e., major amendment, unanticipated problem, serious or continuing non-compliance) • Expedited review – by IRB/IEC Chairs and/or designees • Initial and subsequent continuing review • Exemption determination (per US federal regulations) • Amendment (minor changes to the protocol) • Other reports from investigators, i.e., minor protocol violations, adverse events

20. Full Review • a majority of the members of the Committee must be present and at least one nonscientist must be present • if the required number of members is lost during a meeting, no action may be taken until it is restored • in order for research to be approved, it must receive the approval of a majority of those members present at the meeting • consultants with expertise in special areas may attend meeting, but they may not vote

21. Full Review at HSPH & HMS • The Office of Human Research Administration (OHRA) processes all applications submit by the HSPH/HMS/HSDM researchers: • Deadline: completed submission must be received by OHRA three weeks before the meeting date (www.hsph.harvard.edu/ohra) • Each submission under review is assigned to a Primary and a Secondary Reviewer • Although the IRB may request that an investigator attend a meeting or be available via phone.  The investigator may not be present for the discussion and vote

22. Expedited Review • An IRB may use the expedited review procedure to review either or both of the following: • some or all of the research appearing on the F.R. list and found by the reviewer(s) to involve no more than minimal risk, • minor changes in previously approved research during the period (of one year or less) for which approval is authorized.

23. Expedited Review Categories • Blood collection – within limits (i.e. from healthy, non-pregnant adults who weigh at least 110 pounds) • Prospective collection of biological specimens for research purposes by noninvasive means, i.e. hair and nail clippings, buccal swab • Collection of data through noninvasive procedures such as moderate exercise, MRI, EKG • Research on existing data, specimens, materials collected solely for NON-research purposes • Collection of data from voice, video, digital, or image recordings made for research purposes • Research on Individual/group characteristics/behavior

24. Expedited Review Categories • Continuing review where • the research is permanently closed to the enrollment of new subjects; all subjects have completed all research-related interventions; and the research remains active only for long-term follow-up of subjects; or • no subjects have been enrolled and no additional risks have been identified; or • the remaining research activities are limited to data analysis, or • Other seven categories do NOT apply, BUT • IRB determined and documented at a convened meeting that the research involves no more than minimal risk

25. Exemptions Determination • Under Federal regulations, certain categories of activity are considered human subjects research, but may be declared exempt from IRB review • Exemptions, however, must be granted by the IRB Chairperson or designee by reviewing the Exemption Application submitted by the principal investigator • The principal investigator may not make these determinations

26. Exemption Determination • Category #1 • The activities are normal educational practices • Practice would be expected to go on anyway • Randomized designs/cross-over designs are suspect • The setting is an established or commonly accepted educational setting • Schools, medical offices, hospitals, boot camps are established or commonly accepted educational settings • Country fairs, shopping malls are not established or commonly accepted educational settings

27. Exemption Determination (cont.) • Category #2 • Use of educational tests, survey procedures, interview procedures (i.e. focus groups) or observation of public behavior – no identifiers recorded • If human subjects can be identified, directly or through identifiers linked to the subjects, any disclosure of the human subjects' responses outside the research could reasonably place the subjects at risk of criminal or civil liability or be damaging to the subjects' financial standing, employability, or reputation

28. Exemption Determination (cont.) • Category #4 • Research involving the collection or study of existing data, documents, records, pathological specimens, or diagnostic specimens, if these sources are • publicly available or • recorded with no identifiers (no links) • Examples of links to identifiers make a study not exempt: • Hospital number • Student ID • Phone number

29. IRB Review Actions • Approval • No additional action required • Require Modification • The IRB provides the investigator with specific modifications to study-related materials • Investigator’s response can be reviewed by an IRB Chair or his/her designee • The investigator may not start any study-related activity until all modifications required by the IRB are made AND the IRB final approval is granted

30. IRB Review Actions (cont.) • Deferral • The IRB needs additional information or clarification from the investigator • If the research was initially reviewed by the full board, the PI's response and revised materials must be reviewed at a subsequent convened meeting • Disapproval • The Investigator may not re-submit the same protocol for review

31. Investigator Responsibilities • Assuring IRB review and approval • Obtaining informed consent • Financial disclosure • Conducting study according to signed investigator statement, protocol, and applicable regulations and institutional requirements • Controlling of investigational drugs/devices

32. IRB Review and Approval • No study activity can be initiated without IRB final approval • Conducting research in accordance with IRB-approved protocol • Continuing review and approval by the IRB • Implementing amendment to the protocol only after receiving IRB approval

33. Informed Consent • Obtaining INFORMED consent from each subjects • Elements of informed consent • Eight basic elements • Six additional elements • Documentation of informed consent • Sign and date • A signed and dated copy to each subject

34. Elements of Informed Consent • a statement that the study involves research, an explanation of the purposes of the research and the expected duration of the subject's participation, a description of the procedures to be followed, and identification of any procedures which are experimental; • a description of any reasonably foreseeable risks or discomforts to the subject; • a description of any benefits to the subject or to others which may reasonably be expected from the research;

35. Elements of Informed Consent 4) a disclosure of appropriate alternative procedures or courses of treatment, if any, that might be advantageous to the subject; 5) a statement describing the extent, if any, to which confidentiality of records identifying the subject will be maintained; 6) for research involving more than minimal risk, an explanation as to whether any compensation and an explanation as to whether any medical treatments are available if injury occurs and, if so, what they consist of, or where further information may be obtained;

36. Elements of Informed Consent 7) an explanation of whom to contact for answers to pertinent questions about the research and research subjects' rights, and whom to contact in the event of a research-related injury to the subject; and 8) a statement that participation is voluntary, refusal to participate will involve no penalty or loss of benefits to which the subject is otherwise entitled, and the subject may discontinue participation at any time without penalty or loss of benefits to which the subject is otherwise entitled.

37. Proper Study Conduct • Selecting qualified investigators/study staff • Conducting study according to protocol • Obtaining protocol exception from the IRB and sponsor • Reporting protocol violations to IRB and sponsor • Ensuring proper record keeping and retention • Investigator reports • Progress reports • Safety reports/AE reports • Final report • Financial disclosure

38. Control of investigational products • An investigator shall administer/use the investigational drug/device only to subjects under the investigator’s personal supervision • An investigator must not supply an investigational drug/device to any unauthorized person

39. Why Do We Care?

40. Common Violations/Deficiencies • Informed consent • Investigator responsibilities • Protocol deviations • Study records • IRB approval • Regulatory documentation

41. Warning Letter Citations “Subject signed the consent form on …; however, the witness signed the consent on [redacted].” “You did not ensure that the witness dated the signature.” “Subjects signing the informed consent in most cases did not complete dates. It appears that the study coordinator…completed the date.” “The original consent forms could not be located for 18…subjects enrolled in the study. Copies were available in study binders and subject charts.” “You failed to provide study subjects with a copy of their signed informed consent document.”

42. Warning Letter Citations “You did not personally conduct or supervise this study.” “You misrepresented your presence at the institution by signing and dating source documents and consent forms on days you were, in fact, absent from the institution.” “Staff who were delegated the authority to perform certain functions were not adequately credentialed, trained, or monitored.” “An ultrasound was not done at six months for subject.” “You did not conduct certain follow up visits or document efforts to locate missing subjects.”

43. Warning Letter Citations “There is no record of who administered the study drug…Without a record of who administered the study drug, you cannot assure that these injections were performed by a member of the blinded study team.” “Source data for various assessments could not be located.” “The CRF contained blank fields.” “Records…were written in pencil, and many entries are illegible.” “There is no documentation of the name or initials of the person making entries in the records.” “All medical records/case reports audited had numerous write-over corrections which lacked dates and initials.”

44. Warning Letter Citations “Your IRB requires that a written report of the death of any research subject be made within 5 business days…five or more subject deaths have not been reported to the IRB.” “Revised case report forms identifying additional data to be collected…, for which IRB approval was not documented, were used after initiation of the study.” “The sponsor provided a log sheet, on which all study personnel are required to provide their signature, initials, title, responsibility for the study, and start and stop dates. The log is incomplete in that the start and stop dates were not recorded for several of the study personnel.”

45. Avoid and Correct Violations • Informed consent • Do not date for subjects • All individuals must sign and date the consent form for themselves • If someone forgets to date the consent form, write a signed and dated note-to-file explaining how and when the subject was consented • Write a signed and dated note-to-file explaining why dates are different

46. Avoid and Correct Violations • Informed consent • Always give subjects a copy of the signed and dated consent form • Document what was done • Always maintain the original signed and dated consent form in the subject file

47. Avoid and Correct Violations • Investigator Responsibilities - • Stay involved • Only delegate responsibilities to appropriate individuals who are qualified and trained • Maintain documentation of training for all staff • ALL study staff must be approved by the IRB • Take credit – document investigator's involvement, including monitoring activities

48. Avoid and Correct Violations • Protocol Deviations - • Obtain protocol exception prior to implementation • Report all protocol violations to the IRB • Develop and implement an adequate corrective action plan to avoid future violations • Modify the protocol if necessary

49. Avoid and Correct Violations • Study Records • All information entered on a CRF or data collection sheet must be supported by source documents • A signed and dated note-to-file can be used to explain: • How information was obtained • Who obtained information • Any discrepancies • Missing or incomplete data

50. Avoid and Correct Violations • IRB Requirements/Approval • Obtain IRB approval prior to initiating study • Obtain IRB approval for any changes made during the course of the study • Do not allow study to lapse. Submit continuing review prior to IRB-approval expiration • Report all adverse events according to institutional reporting requirements