DIA GCP/QA SIAC Presentation IRBs from the Inside David Forster, J.D., M.A., CIP Vice President, Office of Compliance, Western IRB Auxiliary Faculty, Department of Medical History and Ethics, University of Washington

Outline IRB basics – Regulations and Ethics Common causes for tabling research Hot topics

Regulatory Framework FDA regulations 21 CFR Parts 50 and 56, and also Parts 312, 812, and 814. However, IRBs also operate under numerous other sets of regulations and laws.

Examples of other Federal agencies National Institutes of Health (NIH) Department of Defense (DOD) components Environmental Protection Agency (EPA) Department of Justice (DOJ) Veteran’s Affairs (VA)

Regulatory Framework State laws, such as California, Massachusetts. International Conference on Harmonization. HIPAA Accreditation standards under Association for the Accreditation of Human Research Protection Programs (AAHRPP). End result is a complex regulatory environment

Ethical Framework The Belmont Report - 1979 Principles of Respect for Persons, Justice, and Beneficence These principles provide a framework, but do not provide direct solutions to issues.

Dual Role of IRBs – Ethics Committee and Regulated Committee There are ethical dilemmas involved in research. Example: Justice versus Beneficence. Is it ethical for a protocol to be limited to English speaking subjects only?

IRB Basics - Membership 21 CFR 56.107: 5 members, diverse membership, at least one non-scientist, one scientist, one non-affiliated person, one of each gender. No conflicted members can vote. Consultants can be used, but can’t vote.

IRB Basics Must have SOPs. Must review protocol, IB, and consent form and other materials seen by subjects. Can use expedited review for minimal risk research and changes in research. Can suspend or terminate research if problems

IRB Basics – Criteria for Approval (i. e IRB Basics – Criteria for Approval (i.e., potential reasons for tabling) 56.111(a)(1): Risks to subjects are minimized: (i) By using procedures which are consistent with sound research design and which do not unnecessarily expose subjects to risk, and (ii) whenever appropriate, by using procedures already being performed on the subjects for diagnostic or treatment purposes.

Examples Pregnancy an exclusion criteria, but no pregnancy test is in the protocol. Use of injectable local anesthetics without crash cart on site. Failure to exclude subjects with high likelihood of adverse events (e.g., former allergic reactions to similar products)

IRB Basics – Criteria for Approval (i. e IRB Basics – Criteria for Approval (i.e., potential reasons for tabling) 21 CFR 56.111(a)(2): Risks to subjects are reasonable in relation to anticipated benefits, if any, to subjects, and the importance of the knowledge that may be expected to result.

Examples Risk in placebo arm is too high. The research is not scientifically valid, so no knowledge will result to benefit society (e.g., poor design, sample size too small). Studying a product in children before doing adult studies.

IRB Basics – Criteria for Approval (i. e IRB Basics – Criteria for Approval (i.e., potential reasons for tabling) 21 CFR 56.111(a)(3): Selection of subjects is equitable. In making this assessment the IRB should take into account the purposes of the research and the setting in which the research will be conducted and should be particularly cognizant of the special problems of research involving vulnerable populations.

Examples Study population is all one race (However, can be appropriate if information for that race necessary). Study population is all one gender. Incapacitated adult subjects are included when the research could be conducted with capable adults. Wards of the state are used because they are convenient. Subjects are in developing world but the intervention will not be affordable there.

IRB Basics – Criteria for Approval (i. e IRB Basics – Criteria for Approval (i.e., potential reasons for tabling) 21 CFR 56.111(a)(4) and (a)(5): Informed consent will be sought from each prospective subject or the subject's legally authorized representative, and informed consent will be appropriately documented.

Examples Improper request for waiver of consent for an FDA regulated study of tissue samples. Consent form is cut and pasted from the protocol, with extremely high reading level. Consent will be obtained from stroke victims in the back of an ambulance.

IRB Basics – Criteria for Approval (i. e IRB Basics – Criteria for Approval (i.e., potential reasons for tabling) 21 CFR 56.111(a)(6): The research plan makes adequate provision for monitoring the data collected to ensure the safety of subjects.

Examples Provisions for monitoring subjects are not sufficient, perhaps only a visit every 3 weeks when once a week would be safer. Insufficient description of who will be monitoring data. No DSMB in a study where it is warranted. Lack of follow up after initial intervention (particularly a problem with implantable devices).

IRB Basics – Criteria for Approval (i. e IRB Basics – Criteria for Approval (i.e., potential reasons for tabling) 21 CFR 56.111(b): When some or all of the subjects, such as children, prisoners, pregnant women, handicapped, or mentally disabled persons, or economically or educationally disadvantaged persons, are likely to be vulnerable to coercion or undue influence, additional safeguards have been included in the study to protect the rights and welfare of these subjects.

Examples Population is employees, but no provisions are in place to protect employees from pressure to join from supervisor. Medical students will be recruited by their professors. Inclusion/exclusion section of protocol requires consent for the subject, but ethics section allows subject or LAR to provide consent.

Hot Topics - Assent Move away from written documentation from children. Assent from incapacitated adults when possible.

Hot Topics – Compensation for Injury Don’t waive rights of subjects by saying “No compensation is available.” Instead, say “No compensation is planned,” or “compensation is not routinely available.”

Hot Topics - Costs WIRB is receiving more subject complaints about being billed for research procedures. Costs statements in consent forms are usually vague. Department of Justice is looking more closely at Medicare billing. IRB generally not involved in billing issues, not in a good position to improve consent statement on this issue.

Hot Topics – protocol variances Also known as deviations, violations, etc. Since publication of ICH in 1996, IRBs have received an ever increasing amount, most trivial. At WIRB we only want to receive variances that affect subject safety or study design.

Hot Topics – AEs, SAEs, Unanticipated problems Significant change regarding IRB responsibilities for review of AEs, IND safety reports, etc. By regulation, IRBs are only responsible for reviewing “unanticipated problems involving risks to human subjects or others.” Over time, sponsors ended up sending nearly every AE to the IRB. IRBs are flooded with these reports, and for most part IRB review provides no increase in subject protection.

Hot Topics – AEs, SAEs, Unanticipated problems New OHRP guidance and draft FDA guidance say the IRB only has to review “unanticipated problems involving risks to human subjects or others.” FDA: http://www.fda.gov/OHRMS/DOCKETS/98fr/07d-0106-gdl0001.pdf OHRP: http://www.hhs.gov/ohrp/policy/AdvEvntGuid.htm

Hot Topics – AEs, SAEs, Unanticipated problems Most IRBs are implementing a policy of rejecting without review any AE or protocol variance that does not meet this standard. If an IND safety report meets this criteria, it should be accompanied by a sponsor assessment of implications.