Welcome to the IRB

1. Welcome to the IRB Elizabeth L. Hohmann MD Chair and Director Partners IRBs MGH, BWH, FH

2. Our Topics in 55 Slides • What is the IRB and how does it work? • Research ethics and essence – somewhat distilled. • Mechanics: how to review a protocol. • Questions, issues, considerations.

3. What Is an IRB? • IRBs are required by federal law to review human research that is either federally funded or subject to FDA oversight. We had and took the option to apply these requirements to any and all research we do. • There is a required minimum of 5 members but these 5 must include: 1 scientist, 1 nonscientist and one person who is not affiliated with the institutions. • We have physicians, scientists, nurses, clergy, statisticians, ethicists, pharmacists, social workers and lawyers to name but a few.

4. IRBs Can Be Special • IRBs can be part of an institution such as ours or they can be commercial entities such as Western IRB or they can serve as “central” IRBs such as the NCI IRBs. • DFCI, Spaulding and McLean hospitals all have specialized IRBs. • The HSPH also has a specialized IRB in that they are configured to review prisoner research. • We are not. • IRBs can be created to focus review on continuing reviews and adverse events.

5. IRB Review As Peer Review • We’re not machines. • We strive for consistency but different reviewers can and do have different opinions. • We have regular meetings of our IRB chairs in order to create and communicate consistent approaches, requirements, regulations. • The system is not perfect but it is effective.

6. The Individual IRB Member • What do you add to the process? • Your unique professional and personal perspective. • This includes your scientific, social, ethical, community, minority, legal, administrative or operational perspectives, maybe all of these.

7. Current IRB Chairs • Libby Hohmann, MD • Melissa Abraham, PhD, MS • Jonathan Alpert, MD, PhD • Diane Carroll, RN, PhD • Lucy Field, RN, PhD • Melissa Frumin, MD, MS • Judy Scheer, SM, RN • Julian Seifter, MD • David Smith, MD • Lawrence Tsen, MD • Steve Vacirca, MD • Delia Wolf, MD, JD

8. Regulations and Guidelines • DHHS: CFR 45 Part 46 (4CFR$^) • FDA: CFR 21 Parts 50, 56, 312, 812 • National Research Act of 1974 • ICH Good Clinical Practice • The regulations are open to interpretation • 45 CFR 46, OHRP is the interpreter • 21 CFR and it subparts are interpreted by the FDA

9. Guiding Ethical Principles • Nuremberg Code of 1947 • Declaration of Helsinki, 1964 (last updated in 2004) • Belmont Report 1979

10. Nuremberg Code • Voluntary consent of subject must be obtained. • Prior animal experimentation is needed to assess risks. • Human experimentation must be performed by qualified individuals.

11. Belmont Report • Respect for persons • People are autonomous and have the right to self determination • Obtain informed consent, protect privacy and confidentiality • Beneficence • Do no harm, provide benefit when possible, limit risks • Justice • Equitable selection of subjects • Equal distribution of risks and benefits

12. Regulatory Requirements for IRB Approval • Risks to subjects are minimized. • Risks are reasonable in relation to anticipated benefits – if any. • Selection of subjects is equitable. • Informed consent will be sought and appropriately documented. • When appropriate, the research plan makes adequate provision for monitoring the data collected to ensure the safety of subjects.

13. Regulatory Requirements for IRB Approval • When appropriate, there are adequate provisions to protect the privacy of subjects and to maintain the confidentiality of data. • When some or all of the subjects are likely to be vulnerable to coercion or undue influence, such as children, prisoners, pregnant women, mentally disabled persons, or economically or educationally disadvantaged persons, additional safeguards have been included to protect the rights and welfare of these subjects.

14. Review Processes • Full Review – convened meeting of the IRB • Expedited Review – Chair or designee • Expedited Criteria (45 CFR 46.110) • Exemptions Plus : Innovative Diagnosis and Therapy – NOT pilot studies or off label use

15. Expedited Review • An IRB may use the expedited review procedure to review either or both of the following: • (1) some or all of the research appearing on the list and found by the reviewer(s) to involve no more than minimal risk, • (2) minor changes in previously approved research during the period (of one year or less) for which approval is authorized.

16. Some CommonExpedited Review Categories • Blood collection – within limits. • Collection of other biological specimens. • Collection of data through non invasive procedures such as MRI, EKG. • Research on existing data, specimens, materials collected for NON research purposes. • Surveys, questionnaires.

17. Some CommonExpedited Review Categories • Continuing Review when: the research is permanently closed to the enrollment of new subjects; (ii) all subjects have completed all research-related interventions; and (iii) the research remains active only for long-term follow-up of subjects; or • (b) where no subjects have been enrolled and no additional risks have been identified; where the remaining research activities are limited to data analysis.

18. Some CommonExpedited Review Categories • And when the IRB has determined and documented at a convened meeting that the research involves no greater than minimal risk and no additional risks have been identified.

19. How Our IRB System Works • Primary and Secondary Reviewers • Assignments made 1 week ahead of meeting • Discussion by Full Committee • Reviewers lead discussion • Everyone contributes • Committee Vote • Approve • Conditional Approval • Deferral • Disapprove • One year maximum approval

20. Determining an Action • Approval – the criteria for approval are met. • Conditional approval – IRB stipulates specific revisions requiring simple concurrence by the investigator, then the IRB Chair or another IRB member designated by the Chair subsequently approve the revised research protocol on behalf of the IRB. • Deferral - substantive clarifications or modifications required that are directly relevant to the criteria for approval. • Disapproval – major ethical or scientific issues – PI can respond to the IRB or start over.

21. Mechanics • About 2 weeks prior to next meeting, an RSVP is sent via email. • If you don’t use your email, give us an alternative method by which to communicate with you. • If you are part of a “reviewer team”, the further out you schedule the easier for all of us. • If you are an alternate you are expected to attend at least one meeting a month.

22. Quorum • Regulations require we meet quorum. • We define quorum as more than half the members present. • Since we can’t cut anyone in two, this means if there are 22 people on the board, we can’t start the meeting until 12 people are present. • We need your expertise. • Please be on time.

23. Your Review Materials • Initially daunting but you’ll soon be able to move through them quickly. • Check your assignments. • If you are primary or secondary – read in depth. • Otherwise, review the protocol summary, the consent forms and any advertisements. • Feel free to add to any discussion regardless of your assignment.

24. Your Review Materials • Applications, attestations, signatures • Protocol summary – sort of an executive summary • Detailed protocol – typically authored by sponsor or the PI • Recruitment materials: ads, letters, flyers • Diaries, information sheets, consent documents • NIH grant document • Drug/device brochures • Other tools • Additional review requirements: Nursing, Biomedical Engineering, Radiation Safety

25. Suggested Review Strategy • Review application • Look for special issues such as kids, radiation, emergency use issues, new drugs/devices, genetics, storing samples for future use • Read protocol summary • Look for site specific issues; can we logistically perform the study here? • Read detailed protocol • Look also at any study specific tools, letters, ads, extras

26. Suggested Review Strategy • Prepare your comments • Written and submitted are wonderful • Emailed is even better • Editing the consent form • Edit right on the document • Use legible handwriting • Submit marked up document • NIH grant • Review for consistency • Is the study captured in the grant • If PI says study pays, are there funds to pay

27. Background and Specific Aims • Should contain a cogent summary of previous work and rationale for the study • May be a cut and paste from the NIH grant • References should be included • Feel free to make use of the references • There should be clear aims and endpoints

28. Subject Selection and Enrollment • How are subjects identified? • Ads, charts, RPDR, referrals, PI’s own clinic, support groups, public records. • How, when and by whom are subjects for contacted about study? • In person? Should be by someone who has reason to know confidential medical information. • Letters? Letters should be co-signed by the MD know to the patient-subject. • No cold calls.

29. Subject Selection and Enrollment • Inclusion/Exclusion Criteria • Should be a concisive list • Should include appropriate laboratory parameters • Should include appropriate medical exclusions • Should not/rarely exclude non English speakers • Who obtains consent? Who gives consent?

30. Study Procedures • Should include sufficient detail to ascertain what subjects will actually experience while in study. • Time commitment. • Setting or site where study procedures occur. • Any “routine” agents to be used – such as sedation. • Consent form with detail in lay terms.

31. Biostatistics • A formal sample size is generally necessary. • Why does the PI need this many subjects? • Are there enough subjects to answer the study question? • How are the data to be analyzed? • Just because the PI says it is a pilot study doesn’t mean they don’t need statistics.

32. Risks and Discomforts • Should be listed clearly, quantitatively and in order of seriousness. • Should include risks of withdrawal from current medications. • Non medical risks? Social, legal, financial or psychological risks? • Is loss of confidentiality a legitimate risk or concern? • What about loss of privacy? • Is there a complete list of adverse events in the drug or device brochure? • Any foreseeable but maybe still theoretical risks – for example tumorigenesis?

33. Benefits • Compensation is not a benefit. • If there are benefits to the individual subjects these should be discussed first, then any potential benefits to future society. • A common error we see is the “overstatement” of benefits. Example of good benefit statement: There will be no direct health benefits to you as a result of your participation in this study.

34. Safety Monitoring • How are the data to be monitored and by whom? • All studies involving more than minimal risk require a data and safety monitoring plan. • Not all studies require a DSMB but if one is necessary who does it involve? Is it independent? Should it be? • Are there objective criteria for withdrawal of subjects when safety is in question? • Are there stopping rules? • Is there a plan for reporting to the IRB? • Does the PI state that Partners IRB AE reporting guidelines will be followed?

35. Common Review Issues • PI has failed to provide information about reasonable clinical context or apparent withholding of standard of care. • Failure to minimize risk. • Inadequate information about collaborating sites, especially when international sites are involved. • Poor preparation of materials – cutting and pasting errors. • Poor writing skills, no proof reading.

36. Who Is the IRB Again? • We are a scientific and ethical review board. • We review studies at a convened meeting that are more than minimal risk and when a IRB reviewer has referred a matter to the board.

37. Bottom Line • It is not ethical to subject people to risks, discomforts or inconveniences for research that cannot contribute meaningfully to science! • If the IRB can’t understand the submission, then the PI hasn’t done a good job.

38. Consent Process and Forms • Consent is a process and not just a form. • The form is the document that captures the signature and records the process of agreement to participate. • Timing is important – PI should give us details. • Once consent is signed, person is considered enrolled in study.

39. Consent and Assent • Adults = those greater than and equal to age 18. • Adults and sophisticated teens can use the “adult” consent form. • Anyone less than 18 must have a parent or guardian’s permission (at least one) in order to participate. • We have an assent form template for kids 7-14. • But assent may be obtained verbally. • We do consider some kids emancipated such as pregnant teenagers.

40. Who May Obtain Consent? • People can obtain consent for activities commensurate with their usual clinical practice in medicine: • Mammogram technologist • BA study coordinator – DPP study • RN – DPP – GTT, lab work • RNP – DM, study initiation and education for FDA approved drugs • Licensed MD – investigational drugs and device studies

41. Surrogate Consent • Why can’t the subject give consent? • Massachusetts state law doesn’t cover research but we have guidance – see our web page policies. • How do we consider when surrogate consent is appropriate? • Potential/likely benefit is required and/or risk must be very small indeed. • Who can be a surrogate? Spouse? Children? Siblings?

42. Continuing Review • Reporting on study to date • Reality check on how it is really going • Any new developments in alternatives? • Risks and discomforts haven’t changed? • Benefits haven’t changed? • Any new risks identified? • Are the initial statistical assumptions still valid

43. Continuing Review • Have any/all amendments been incorporated into the protocol document? • Have any/all amendments been incorporated into the consent document? • If NIH funded, is the progress report consistent with the continuing review report?

44. Other Commonly Vexing Details • Or things that will make you tear your hair out…

45. Ethical and Regulatory Considerations • When, why is an IND required or not? • Why this device is a non significant risk device. • Why this device is not. • Why is this study design ethical or not? • Why are these risks worth taking or not? • Why is any risk worth taking or not? • Why this special population, group or site is included or excluded.

46. International Research • OHRP says if the study is federally funded, then our rules prevail. • Do we know enough about the local situation to review the study? • Can we get the information if needed? • Is there an IRB or ethics committee over there? • Can we get things translated? • Do we have an expert on this area/population? • Can be an IRB member or the PI or a consultant.

47. Medical Devices • IDE device; FDA’s “full Monty” • Category A device: Medicare won’t pay • Category B device: Medicare might pay • NSR device: non significant risk device – the IRB must actively make this determination • SR device: generally an implanted device, generally will be used to sustain life

48. Investigator Conflicts of Interest • All PIs must be in compliance with the Harvard rules. • We must flag any conflicts we become aware of during our reviews. • We will refer PIs to OGC and the Professional Conduct and Conducts Committee.

49. Study Staff • Their qualifications should match their responsibilities. • PIs can delegate but must be specific. • When someone is assigned as “back up”, what does this mean to us?

50. At the Meeting • Primary reviewer, present a 2-3 minute summary of the study • Present clear, concise, well defined review • Focus on major consent form issues, leave grammar and typos to the consent team • Assume everyone else has read their assignments • Present your recommended disposition • Secondary reviewer, add anything that the Primary didn’t touch on