Welcome to the IRB

1. Welcome to the IRB Elizabeth L. Hohmann MD Chair and Director, Partner’s IRBs MGH and BWH

2. Today’s topics (55 slides) • What is the IRB and how does it work? • Research ethics essence: distilled! • Mechanics: How to review a protocol. • Your questions.

3. What are the IRBs? • Required by federal law to review federally funded research on human subjects (FWA). • 5 people minimum. • 1 scientist, 1 nonscientist, 1 nonaffiliated. • Physicians, Scientists, RNs, Lay members, Clergy, Statistician, Ethicists, Pharmacists, Genetic counselor, Lawyer, HMS.

4. IRBs - special types • Specialized panels • DFCI, Spaulding, McLean • Prisoners (e.g. Shattuck Hospital). • Continuing review • Adverse event review • Commercial or independent (e.g. Western) • “Centralized”: a matter of controversy.

5. The IRB is a peer review process, not a computer. Although we strive for consistency, different reviewers and different groups have different opinions.

6. What do you add to the process? • Your unique perspective, whatever it is. • Scientific, social, ethical, community, minority, legal, administrative, or operational. • The system is not perfect but it can work effectively. • Alternatives do not seem very viable.

7. NIH FDA OHRP Research Management (Inst. Official) Human Subject Protection Grants/Contracts IACUC Finance Facilities Quality Improvement IRB P.I. Research Pharmacy Biomed Engineering General Counsel CMO Nursing Rad Safety RDRC Innovative Therapy Depts Risk Mgmt GCRC COMS/Biosafety Laser

8. IRB Chairs • Libby Hohmann MD (Infectious Diseases) • Harry Demonaco RPh, MS (Pharmacy) • Andrew Budson MD • Lawrence Tsen MD • Julian Seifter MD (Nephrology) • Jonathan Alpert MD PhD (Psychiatry) • David Smith MD (Oncology) • Delia Wolf MD (QI/QA/International Res.) • Steven Vacirca MD (Radiology)

9. Guiding regulations • CFR Title 45 Part 46 (45CFR46) 1981 • General statements open to interpretation • OHRP (HHS) is the interpreter • Specific guidance not always forthcoming • Much based upon “case law” • National Research Act (IRB) 1974 • FDA regulations (IND, IDE) • ICH Good Clinical Practice

10. Guiding Principles • Hippocratic Oath (a long time ago) • Nuremberg Code 1947 • Declaration of Helsinki 1964 (update, 2001) • Belmont Report 1979

11. Nuremberg Code • Voluntary consent of the subject must be obtained. • Prior animal experimentation is needed to assess risks. • Human experimentation must be performed by qualified medical personnel.

12. Belmont Report • Respect for persons as autonomous individuals with right to self determination • obtain informed consent, protect privacy and confidentiality • Beneficience • do no harm, provide benefit, limit risks • Justice • equitable selection of subjects • equitable distribution of risks and benefits.

13. 7 Requirements for IRB approval • Risks to subjects must be minimized • sound scientific protocol which does not UNNECESSARILY expose subject to risk • Risks are reasonable w.r.t. potential benefit or knowledge gained. • Selection of subjects is equitable • Informed consent will be sought

14. 7 Requirements, cont’d. • Adequate provisions for monitoring of data collected to ensure subject’s safety. • Confidentiality must be maintained. • Vulnerable populations must be protected • Children, prisoners, pregnant women/fetus, mentally ill or incompetent, educationally, economically or socially disadvantaged

15. Review Mechanisms • Full Review (panel) • Expedited Review (chair only) • Innovative Diagnosis and Therapy • Special category for novel approaches to clinical care • NOT pilot studies or off label uses

16. Blood draw healthy adults (limits!) Observational studies Study of data already existing and collected for other reasons. Noninvasive “standard clinical tests” PE, U/S, MRI, history Blood from others Moderate exercise Studies of perception, views, thoughts Samples (buccal swab, tooth scrapings, saliva, urine) Phase IV post-market study of drugs/devices Minimal risk

17. How does the IRB work? • Primary and Secondary reviewer system, similar to NIH study section. • Discussion by full Committee, led by Chair. • Committee decides upon action and review interval (maximum: one year). IRB

18. Actions of the committee • Approval. • Requires modifications • requests for alterations, usually with specific directions • Deferred (not enough information to assess risk benefits, any substantive clarifications). • Disapproval (major scientific/ethical probs).

19. Mechanics! • IRB staff will contact you about 2 weeks before meeting to get attendance. • If you don’t “email” reliably, let us know. • Please respond promptly. • Alternates are each expected to attend one monthly meeting. • Setting up a schedule and forwarding to IRB is strongly encouraged!

20. The magic number: quorum • 50% of membership, plus one. • We cannot conduct business without a quorum; members who don’t show are highly detrimental. • Plus, we are counting on your expertise! • ‘Single’ members are expected to attend 75% of annual meetings. • Please do your best to be on time…..

21. What to do with the package • Review the agenda and check your assignments! • Typically 1-2 new full protocols; several continuing reviews. • Skim other titles and protocol summaries - do you have any special expertise to offer? • Bring it with you to the meeting.

22. Each full protocol has • Attestations, Signatures, and Data Sheets. • Protocol Summary (Lay reader) • Detailed Sponsor- or PI-initiated protocol. • Recruitment letters, ads, drug forms (std) • Diaries, information sheets, consent(s) • NIH grant, IDB, questionnaires, tools. • Ancillary: radiation, nursing, BME

23. Suggested review tactics-1 • Go through data sheets - flags special items: • Kids? Radiation? Emergency? Drugs/devices? Genetics? Storage of samples/future use? • Read protocol summary, looking esp. for site specific details if industry sponsored. • Read detailed protocol, tools, letters, ads, IDB, extras and consent forms.

24. Suggested review tactics-2 • Written comments, esp. if e-mailed, are highly desirable. Reviewer sheets provided. • Consent form changes may be made on the form itself. Please do so legibly! • NIH grants: federal requirement. • Scan for consistency. Focus on human subjects pieces: risks, compensation, special subjects, interface with routine care.

25. At the meeting • Present a 2-3 minute SUMMARY of the study if you are the primary reviewer. • Assume your colleagues did their part…. • Present defined, succinct criticisms. • Discuss major consent form problems. • Present your probable disposition of study • Secondary reviewer comments: focus on highlighting or adding new points.

26. Background Specific Aims Subject selection Subject enrollment Study procedures Biostatistics Risks and Discomforts Potential Benefits References Ethical and Regulatory Considerations Site specific details Consent process Qualifications and Responsibilities Full Protocol

27. General Pointers -1 • Separate personalities and process. • Contact the PI if you wish for additional information (at your discretion, entirely). • We do not give out reviewers assignments. • IRB membership lists are public information. • A committee exists in part to keep you off the hot seat.

28. Do’s: • Remove yourself from the room if you are a co-investigator or have another possible conflict of interest on a study. • Feel free to answer questions from the chair or members if you are a co-PI. • Abstain if you don’t feel comfortable voting. • Consensus vs. unanimity.

29. Don’ts • Discuss IRB meetings outside the room or with colleagues other than the PI - IRB meetings are confidential! • Confidential sponsor information • Potentially problematic information about colleagues could be dispersed • Competition issues • Scientific disputes

30. Background and specific aims • Cogent summary of previous work and rationale for this study. • Cut and paste from NIH grant! • References should be given, keyed to text. • You might wish to look up a reference! • Clear aims and endpoints • Primary, secondary, “while we’re there” F.E.P.

31. Subject selection/enrollment • How are subjects identified ? • Ads, charts, RPDR, referrals, own clinic, support groups, public records etc. • How, when and by whom are subjects first contacted about the study? • Letter? In person? By whom? Someone who has reason to know confidential medical info. • Letters must be cosigned by MD know to pt. • No “cold calls!”

32. Recruit/enroll • Inclusion and exclusion criteria? • Bulleted lists! • Tests done with no parameters set • “Hepatic or renal disease”; “CHF”. • Exclusionary meds • English speaking (CAUTION!) • Who consents? When? Coercion? F.E.P.

33. Study procedures. • In sufficient detail to ascertain what really happens, and risks to subjects. • Time commitment? • Setting or site? Operators? • “Routine”agents used -e.g. sedation? • Consent form has more detail than protocol. • Not logical, chronological, rationalized, or prioritized. F.E.P.

34. Biostatistics • Why do you need this many subjects? • Is it enough to answer the question posed? • Formal sample size calculation is generally needed! • How is the data analyzed? • Calling something a “PILOT” does not grant divine statistical absolution! F.E.P.

35. Risks and Discomforts • List them clearly, quantitatively, and in order of seriousness. • Don’t forget opportunity costs and risks of withdrawal of current medications! • Don’t forget non-medical risks (social and psychological), esp. of genetics research • Potential loss of confidentiality. • Complete but not exhaustive list of IDB AE’s. • Forseeable theoretical risks, e.g. tumorigenesis. F.E.P.

36. Benefits • HEALTH benefits not financial compensation. • State benefits to individual then society. • Clearly, overstatement of benefit a common error. • “ There will be no direct health benefits to you as a result of your participation.” F.E.P.

37. Safety monitoring • How is data monitored and by whom? • Every study needs a safety monitoring PLAN! • Is a DSMB needed? Who? ?Independent? • Provide objective criteria for withdrawal of subject for safety reasons! • Stopping rules? • Reports to IRB! • Must follow Partners AE reporting guidelines. F.E.P.

38. Other common difficulties • Failure to provide reasonable clinical context, or apparent withholding of std care. • Failure to minimize risk. • Inadequate information about collaborating sites, esp. international. • Secretary’s Hatchet Job. • The TOEFL protocol: non English speaker. • Genetics!!

39. “Safe” but stupid? • Who are you to question my science? • We are a scientific and ethical review. • Full committee review = more than minimal risk according to the federal regulations.

40. Bottom lines • It is not ethical to subject people to risks, discomforts and inconveniences for research that cannot contribute meaningfully to medical science! • If the IRB can’t understand it, the investigator has not done their job.

41. Consent-1 • Consent is a process not a form, but the form is the formal record/document. • Ongoing reaffirmation of consent • Timing is important - give us the details. • Anyone who signs a consent form in considered formally enrolled.

42. Consent-2 • Adults >18, sophisticated teens may read adult form. (9th grade level) • All minors require parent/guardian to sign. • Child assent form (7-14): template, custom. • Assent for treatment studies: may be verbal. • Emancipated minor : e.g. pregnant teens.

43. Consenting: Who? • Consent for activities commensurate with their typical clinical practice in medicine. • Mammogram Technologist. • B.A. Study coordinator (DPP study). • RN (DPP - GTT, lab work). • RNP (DM- initiation and education for FDA approved drugs). • Licensed MD - investigational drugs/devices

44. Surrogate Consent • Why is the person incompetent to consent? • Extra care needed! • Massachusetts law: no surrogate consents for research, unlike treatment. • Potential (likely) benefit is required, or risk must be very small indeed. • Who: Spouse? Multiple children? Sibs?

45. Continuing Review -1 • A “reality check” based upon data generated so far. • ?New developments in alternatives?? • Risks/Discomforts and benefits similar to when study initiated? • New risks for protocol and consent? • Are statistical assumptions still valid?

46. Continuing Review - 2 • Have amendments been incorporated into the new protocol, and consents reflective of all changes and modifications? • Is NIH progress report consistent with the continuing review? • Remember: we already approved it!

47. Other commonly vexing details

48. Ethical and Regulatory Considerations • Why and an IND is or is not needed? • Why I think this study design is ethical • placebos, risks to normals, blinding • Why I think large risks are worth taking • Why I think any risk is worth taking • Why a special population or group or site is included or excluded, how decisions made. • Compromised subjects or special groups?

49. International research • Complicated! • May require intnt’l subcontractor to have an FWA if NIH funded. • Foreign “IRB equivalent” • Translations may be needed • Difficult to balance local traditions and US standards at times. • ?Experience of “local context?”

50. Qualifications and Responsibilities • Define study staff’s duties and roles if it is not obvious, or you are making special requests. • Formal medical training and experience. • Specific tasks assigned. • Clarify “back up.”