The role of the REB

1. The role of the REB Raphael Saginur, M.D. Ottawa Hospital Research Ethics Board

3. REB roles • protection of human subjects • protection of investigator, institution • protection of academic freedom

4. Research ethics: a huge bureaucracy • in typical MCT, review at each of multiple sites: changing slowly • at each site, multiple copies of application (TOH: 18) • hard copies: slow migration to electronic • proprietary interests • lots of reading

5. The only independent review of protocol at site • only opportunity for administrative vetting (resource impacts, approval of thesis committee, etc.) • cost to sponsor, investigator • delay • questions, quibbles, disagrees, blocks • naturally antagonizes PI, sponsor • must earn respect : fair, transparent, accountable, tough

6. Respect • listen • treat PI with respect • demand respect • don’t quibble about trivia • have reasoned opinions based in rationale and/or regulation • be consistent

7. Regulations • not well known to PIs- a mystery. Almost never taught • PIs semi-autonomous within hospitals; medical staff members, not employees • PIs don’t like being told what to do • regulations and legislation were not enforced in the past; it is novelty that they now are: tough adjustment

8. Why do I need to know regulation?

9. Jurisdictions:complex • drug study at TOH/Faculty of Medicine: • GCP/HC • TCPS • FDA: maybe • U.S. Common Rule: • study group NIH-funded • study NIH funded • Provincial law (PHIPA), regulation (e.g., professional codes) • Federal law (criminal; privacy)

10. Jurisdictions, cont. • from PI perspective, jurisdiction mostly a matter of which form to sign (HC, FDA) • adverse events: PI hands off rapidly to sponsor; sponsor addresses rules • in general, jurisdiction more an REB and sponsor issue • issue becomes relevant to PI: renewals, amendments

11. REB tries to base decisions in principle • principle takes priority • regulations follow • U.S.: mired in regs, rediscovering principle

12. What are important principles? • autonomy • avoidance of coercion • justice • beneficence, non-maleficence • confidentiality • privacy

13. Autonomy • right to self determination • translates into informed consent • avoidance of coercion • problem: incompetence • can be subtle • can be transient (acute illness) or intermittent

14. Avoidance of coercion • multiple facets • illness: fear of death, urgency of decision-making • dependence on institution (impact of rationalization), on expert physician • example: thrombolytics in acute MI • often cannot be entirely avoided, always can be managed

15. Justice • equitable distribution of risk • equitable distribution of benefit • complex: change of thinking around AIDS crisis

16. Justice II • appropriateness of study • future costs to health care system • future availability of test, treatment • not really addressed

17. Beneficence, non-maleficence • do good • avoid doing harm • complex • cannot entirely avoid risk; attempting to do so fraught with danger • risk should be appropriate to circumstance, include severity of condition, alternatives, potential benefit

18. Beneficence, non-maleficence • study of cancer therapy in patients at risk of dying from disease, where existing therapy is toxic, would tolerate more risk of therapy than study of acne

19. Confidentiality • relates to protection of information from inappropriate scrutiny • charts, laboratory results • clinical trials: right of sponsor, regulator to audit • compromise: data cannot leave site; viewers on site bound by confidentiality rules/standards

20. Privacy • relates to knowledge of people and information related about them • classic infringements: • investigator sends letter inviting participation- how the . . . do they know about me, and how do they know about my condition? • Shopping in the next-door clinic

21. Privacy • difficulties: the demise of the solo doc • doctors, nurses work in groups with decision-making by committee, cross-coverage • who is privy to knowledge of patients?

22. Privacy: databases • multiple big databases are held for clinical and administrative purposes are held at TOH • divisional and departmental databases have become a cottage industry • linkage of databases within and without institution a productive line of research • database research is a risk to privacy; linkage adds fuel to the fire of risk

23. Privacy: new legislative context • HIPAA (U.S.) • PIPEDA (Canada) • Ontario PHIPA • explicit standards • generally enhance public consciousness of privacy • we are working on standards for databases and privacy: what is held, what is sent, how information is held; technical, policy, administative

24. Conflict of interest • multiple levels • institutional: • e.g., my recent call from CEO’s office about a project related to a local tech company • present or future donations, collaborations

25. Conflict of interest • investigator • developer of product • stockholder • grant: excessive inducement • travel, publication, consulting opportunities

26. Conflict of interest • the patient subject • undue incentive • desperation: disease • prolongation of life • reduction of toxicity • relationship with doctor • payments: how to define appropriate recompense for time

27. Often conflicting issues • how to handle: • take patient perspective • except: avoid excessive inducement

28. Application process • application form is condensed version of protocol plus it teases out certain issues usually missed in protocol • cumbersome, slow, expensive

29. Application • identification of investigators: responsibility • issue: students (the loose cannon phenomenon) • approval by administrator: • patient stewardship(risk, over-involvement in studies) • resource management • consistency with institutional mission,principles

30. Application • bad science is bad ethics • various sections of our forms describing science • REB not peer review committee

31. Application • advertisements • avoidance of overzealous or outright false claims • sufficient information • consistency with College of Physicians rules re physician advertising

32. Application • risks and discomforts • broadly defined • include prolongation of care; delay of care • delineation of what is attributable to study, what is attributable to routine management going on concomitantly

33. Application • DSMBs, stopping rules • management of risk • changing regulatory demands (NIH, FDA) • funding • excess: conflict of interest • insufficient: burden on Hospital

34. Application • staffing • competence • e.g.,outbreak of hepatitis C • resource impact • management

35. Genetics • genetic testing frequently insinuated into otherwise routine clinical trial • new science of pharmacogenomics; targeted therapy: opportunity for societal benefit by improving efficacy of therapy, reducing cost, reducing toxicity • risk • opportunity for new product development: Moore

36. Risk of genetic testing • nothing to do with pain and bruises (‘the phlebotomy misconception’) • relates to use of information • social, psychological risk • insurance, employment • marriageablity

37. Genetic testing: risk • risk may be borne by individual, family, community • opportunity for counseling • decisions to be made regarding linkage of results with individuals

38. Consent forms • pre-occupation with consent form and not consent process: a trap • pretty standard elements • grammar, spelling: rare forms of knowledge • lucidity of language, organization of thought uncommon virtues

39. Intro:rationale Procedure, including randomization, blinding Voluntary nature; right to withdraw Confidentiality Risks Benefits Alternatives Compensation clause Signature Consent form

40. Consent form • language: stated goal is Grade 8 level • never happens • not clear if feasible • more memorandum of understanding than contract: right to change mind (hard to remove that artificial heart) • excess length limits understanding, obscures key issues

41. Monitoring of studies: AEs • “more honoured in the breech than in the observance” • REBs not equipped to monitor AEs • REBs given inadequate information • create paper trail • all interventional studies need data monitoring plan

42. Expedited review • feasible in “minimal risk” study • TCPS: “no greater than those encountered by the subject in those aspects of his or her everyday life that relate to the research” • FDA: collection of hair, nails, deciduous teeth; excreta and external secretions; EEG,ECG; <451 ml blood; dental”plaque” and calculus; voice recordings; moderate exercise; existing records; etc. • consent may or may not be required

43. Minimal risk • difficult application to percutaneous radiologic image-guided procedures • what is risk of percutaneous ultrasound guided breast biopsy done by competent radiologist? How does it compare to risk of phlebotomy of 450 ml by a duffer?

44. Conclusions • REB works within regulatory framework • REB tries to base decisions on principles defined in ethics, and reflected in regulation • forms seek to elicit information to define ethical issues, allowing reasoned decision-making • www.ohri.ca/ohreb