The role of the REB

Raphael Saginur, M.D.

Ottawa Hospital Research Ethics Board

REB roles

• protection of human subjects

• protection of investigator, institution

• protection of academic freedom

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

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

Respect

• listen

• treat PI with respect

• demand respect

• don’t quibble about trivia

• have reasoned opinions based in rationale and/or regulation

• be consistent

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

Why do I need to know regulation?

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)

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

REB tries to base decisions in principle

• principle takes priority

• regulations follow– U.S.: mired in regs, rediscovering principle

What are important principles?

• autonomy

• avoidance of coercion

• justice

• beneficence, non-maleficence

• confidentiality

• privacy

Autonomy

• right to self determination

• translates into informed consent

• avoidance of coercion

• problem: incompetence– can be subtle– can be transient (acute illness) or intermittent

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

Justice

• equitable distribution of risk

• equitable distribution of benefit

• complex: change of thinking around AIDS crisis

Justice II

• appropriateness of study– future costs to health care system– future availability of test, treatment

• not really addressed

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

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

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

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

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?

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

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

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

Conflict of interest

• investigator– developer of product– stockholder– grant: excessive inducement– travel, publication, consulting opportunities

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

Often conflicting issues

• how to handle:– take patient perspective– except: avoid excessive inducement

Application process

• application form is condensed version of protocol plus it teases out certain issues usually missed in protocol

• cumbersome, slow, expensive

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

Application

• bad science is bad ethics

• various sections of our forms describing science

• REB not peer review committee

Application

• advertisements– avoidance of overzealous or outright false

claims– sufficient information– consistency with College of Physicians rules re

physician advertising

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

Application

• DSMBs, stopping rules

• management of risk– changing regulatory demands (NIH, FDA)

• funding– excess: conflict of interest– insufficient: burden on Hospital

Application

• staffing– competence– e.g.,outbreak of hepatitis C

• resource impact– management

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

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

Genetic testing: risk

• risk may be borne by individual, family, community

• opportunity for counseling

• decisions to be made regarding linkage of results with individuals

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

Consent form

• Intro:rationale• Procedure, including

randomization, blinding

• Voluntary nature; right to withdraw

• Confidentiality

• Risks• Benefits• Alternatives• Compensation clause• Signature

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

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

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

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?

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