Requirements for Ethical Institutional Review Boards Human Research A mechanism for oversight of research • A valid and important question An attempt to implement the ethical • Valid methodology principles important to research • Balance between risks/benefits Dale Hammerschmidt, M.D. • Independent ethical review University of Minnesota • Informed consent Thanks to Zeke Emanuel The global, “motherhood Beecher: and apple pie” answer: • (In talking about consent)... “A far more dependable • The purpose of safeguard … is the IRBs is to protect presence of a truly human research responsible investigator.” subjects • There really are several Fundamental Constructs: “purposes” of IRBs; • Beneficence (do no harm) • Many of these can be wrapped • Justice (distribute risk and benefit together: fairly; treat individuals fairly) • Autonomy / respect for persons “Helping investigators recognize (need for consent) and address human subjects’ These are age-old, but higher profile and issues in their research” more codified in last 50 years 1
Why a Greater Emphasis? Why a Greater Emphasis? • Education of patients/subjects • High-profile scandals • Public funding War atrocities ( ⇒ Nürnberg Code) • News reporting Beecher’s 1966 article: “Ethics and Clinical • Desire for access Research” N Engl J Med 274: 1354ff [June • Scandal 16th] • Near misses (thalidomide) Tuskegee natural history study of syphilis • Scandal ...latter two said problems are mainstream, not fringe Results of Scandals and Near-Misses: Why a Greater Emphasis? • 1962 Amendment to the Pure Food, • Near misses Drug and Cosmetic Act Thalidomide not licensed in US through a • Helsinki Declaration and other codes regulatory fluke rather than through having of ethics a good process to ensure safety; • National Research Act of 1974; Birth defects in countries where it was Belmont Commission & Report licensed were a wake-up call • Federal research regulations to protect research subjects Helsinki Declaration: Helsinki Declaration I(§2): • First edition 1964; several revisions …in an experimental protocol which • (WMA) Went beyond Nuremberg should be transmitted for Code, to address research with consideration, comment and therapeutic intent guidance to a specially appointed • Also addressed diminished committee independent of the competence investigator and the sponsor… • Called for oversight of research IRBs called “Helsinki Committees” in some venues 2
Tuskegee: 1974: “Defense of Tuskegee Tuskegee” ” 1974: “Defense of • Natural history study of untreated Elliot Richardson ⇒ ⇒ Charles McCarthy Charles McCarthy: : Elliot Richardson syphilis in 400 black men ∃ ∃ No • • No Effective Defense Effective Defense • Patients allowed to believe they were • ∴ ∴ Need Mechanism to being treated Need Mechanism to • Prevent Recurrence Prevent Recurrence • New treatments ( e.g. PCN) neither studied nor offered as they became • 45 CFR §46: Basic DHHS • 45 CFR §46: Basic DHHS available Policy re: Human Subjects Policy re: Human Subjects PHS funding; PHS researchers, etc. Promulgated for NIH: May, 1974; Expanded & revised 1991 45 CFR § 45 CFR § 46: 46: Also Important: Also Important: • Subpart A: • Subpart A: • • Lots of other regs, codes and Lots of other regs, codes and “The Common Rule “ The Common Rule” ” statutes might apply, depending statutes might apply, depending • Subpart B: • Subpart B: on the type of research and on the type of research and Reproductive Issues Reproductive Issues where it’ ’s done s done where it • Subpart C: Prisoners • Subpart C: Prisoners • (FDA, JCAHO, VA, local (FDA, JCAHO, VA, local • • Subpart D: Children • Subpart D: Children statutes, statutes, etc etc .) .) • Subpart E: Subpart E: Decisionally Decisionally Impaired Impaired • (never formally adopted) (never formally adopted) Institutional Review Boards: Composition of IRBs: • Prospective review of research • Investigators and Non-investigators proposals • People linked to the institution and • Continuing review of ongoing people independent of it research • People with useful expertise (in • Idea is to protect human subjects science, ethics, law, community from inappropriate risk concerns) Ideally a coöperative venture with the Ideally a body with a broad background, investigator, rather than a police function capable of independent action 3
IRBs ask about conflict of IRBs ask about scientific merit: interest: • Does the scientific merit warrant • Is there something that might adversely impact clinical decision making? putting subjects at risk? • Is there something that might distort the • Have the risks been minimized consent process? insofar as is practicable? • Are these bad enough that they need to be disclosed? • General scientific merit review is • Is disclosure a sufficient remedy? usually better done elsewhere Academic misconduct issues re: C-of-I usually belong elsewhere The most important questions IRBs also must ask: IRBs ask: • Does the research conform to federal regulations? • Are the risks and benefits (personal and societal) in reasonable balance? • How about local ordinances and institutional policies? • Is the information and consent process adequate? • How about relevant ethical norms? • Are there justice concerns re: inclusiveness or vulnerable groups? IRB Reporting Lines: It’s crucial to remember: • To the institution – Administratively • We’re all in favor of good science – Maintaining an effective IRB is • We’re all in favor of doing the right something the institution guarantees thing by research subjects to the feds • To the feds • We all have things to teach one another – Substantively • We’ll do a far better job as colleagues – OHRP and FDA than we will as adversaries Obligations to feds and to subjects may require decisions in tension with institution’s interests 4
Review: IRB: Institutional Review Board “…irrespective of funding source” Regulatory Authority--- Office of Human Subjects Protection (OHRP) Not just federal monies Food and Drug Administration (FDA) Important Regulatory Authority Important Regulatory Authority 45 CFR §46 Federal-Wide Assurance of Compliance • Basic federal regs covering human • Institutional agreement with the feds that subjects we will follow the rules • AKA “OPRR Regs” (historically) • Includes the assurance that all research done at an institution will be done in AKA “OHRP Regs” (currently) accordance with federal rules • Rules establishing and guiding the • Thus, IRB review is for all human Office for Human Research Protection subjects’ research Important Regulatory Authority Review Continuum Level of risk determines 45 CFR §46 route of review • Defines “human subject,” “research” • Sets standards for IRB composition Exempt Expedited Full and function • Defines levels of review for different types of research Lowest Low High • Sets expectations (rules) re: consent, protections, reporting, special classes of research subjects, etc. 5
Exemptions Exemptions � Certain research may be exempt � Certain research may be exempt from IRB review because it doesn’t because an individual investigator’s meet the regulatory definition of part of the study may be remote from “research.” human subjects. � Certain research may be exempt because it doesn’t meet the regulatory definition for involving “human subjects.” Exemptions Exemption Categories: � Federal regulatory criteria for low- T YPICAL I NVESTIGATOR P ROCESS : � Certain research may be exempt risk research because an individual investigator’s File an abbreviated form with the IRB, in which � Six specific categories of research part of the study may be remote from the claim of exempt status is set forth and � Cannot involve vulnerable human subjects. explained … the IRB then decides if it really population qualifies as exempt � Certain research may be exempt � Qualifying studies usually are of because it is of such low risk that IRB short duration review would be overkill. � Cannot create a durable confidentiality risk (no permanent record of individual) Exemption Examples: Important Regulatory Issue • Investigator has an inherent conflict in � Anonymous re-use of data deciding if research is exempt; � Anonymous questionnaires on non- • Investigator, Dept. Chair, etc. may well sensitive topics not know the regs well enough to make � Observation of public behavior the right call; without recording identities • Regulatory expectation (FDA/OHRP) � Field testing educational strategies or is that there will be a process for curricula making this decision knowledgeably; • At most centers it’s having the IRB office screen for exempt status. 6
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