Risk Determinations and Research with Children Angela Bain, IRB Specialist abain@uga.edu 706-542-3821

Standards for determining risk The Procedure Based Standard Categorizes as minimal risk only those procedures that people regularly encounter during ordinary life. The Relative Standard Categorizes as minimal risk those risks that the people enrolled regularly experience in daily life The Objective Standard Categorizes as minimal risk those risks that average, healthy, normal people experience during the course of daily life. At the last IRB meeting, we discussed different standards that could be used in determining risk and we discussed how we, as a board, wish to standardize our determinations of levels of risk.

Why is it important? Multiple categories of risk trigger different requirements from the IRB. Waivers of consent requirements Expedited review How to apply Subpart D Why is it so important that we make these determinations of “minimal”, and “greater than minimal risk” ? When minimal risk is determined, IRBs are given the latitude to waive certain consent requirements, so long as certain conditions are met. When minimal risk is determined, IRBs may expedite the review relying on the review of a single member rather than the full committee. IRBs must also use determinations of risk in applying subpart D.

Why is it important? Adults vs. Minors Benefits to subjects or importance of anticipated knowledge = justification for some risk Minors More is needed to justify risk When subjects are adults, risks can be justified either by the anticipated benefit to the subject or by the importance of the anticipated knowledge. When subjects are children, anything more than low risk cannot be justified by the importance of anticipated knowledge. If there is no prospect of direct benefit, then studies with children must be restricted to low risk. So, these interventions or procedures with children must be categorized and assessed according to whether they do or do not offer the prospect of direct benefit

Levels of Risk for Children (and individuals who are impaired) Minimal Risk/Low Risk Minor Increase over Minimal Risk Greater than Minimal Risk There are some differences in terminology in describing the level of risk in children. The purpose of this difference is to allow protocols involving only a minor increase over minimal risks to proceed with only minimal additional protections. Three categories of risk, it has been argued, provide IRBs with more flexibility in requiring certain protections. Two categories of risk, it has been suggested, would prevent certain protocols from going forward since IRBs may believe that the additional protections would effectively bar research involving greater than minimal risk without the prospect for direct medical benefit.

Minimal/Low Risk – No Direct Benefit An intervention or procedure that presents no more than minimal risk may or may not offer a potential for direct benefit.

Minor Increase over Minimal Risk No Direct Benefit An intervention or procedure approved under this category must also involve “experiences to subjects that are reasonably commensurate with those inherent in their actual or expected... situations” and be “likely to yield generalizable knowledge about the subjects' disorder or condition that is of vital importance for the understanding or amelioration of the subjects' disorder or condition.”

Greater than Minimal Risk/ Prospect of Direct Benefit FDA regulations permit pediatric research involving an intervention or procedure that presents more than a minor increase over minimal risk only if it “holds out the PDB for the individual subject” or “is likely to contribute to the subject’s well-being.” FDA regulations permit pediatric research involving an intervention or procedure that presents more than a minor increase over minimal risk only if it “holds out the PDB for the individual subject” or “is likely to contribute to the subject’s well-being.”

Greater than Minimal Risk/ Prospect of Direct Benefit Such interventions or procedures must meet two conditions: “the risk is justified by the anticipated benefit to the subjects;” and 2) “the relation of the anticipated benefit to the risk is at least as favorable to the subjects as that presented by available alternative approaches” Whether the risks of an experimental intervention are justified by the potential direct benefits is a complex evaluation. There should be empirical evidence of sufficient direct benefit (i.e., “scientifically sound” expectation of success)to justify exposure to the risks. The risks of an intervention or procedure can only be justified by the benefits to be expected from that same intervention or procedure. The justification of risk can include: the possibility of avoiding greater harm from the disease; the provision of important anticipated benefit to the individual exposed to risk; the severity of the disease (e.g., degree of disability, life-threatening); and the availability of alternative treatments.

Risk and Subpart D DHHS regulations limit research involving children to those activities that meet one of four categories of research. These categories are based on the level of risk and potential for benefit to the individual participant.

Category I Research not involving greater than minimal risk DHHS - 45 CFR 46.404 FDA - 21 CFR 50.51 When the IRB finds that no greater than minimal risk to children is presented, the IRB may approve the proposal only if the IRB finds that adequate provisions are made for soliciting assent of the children and the permission of their parents or guardians. This is the same for studies regulated by DHHS and the FDA.

Category II Research involving greater than minimal risk but presenting the prospect of direct benefit to the individual subjects. DHHS – 45 CFR 46.405 FDA – 21 CFR 50.52 If the IRB finds that more than minimal risk to children is presented by an intervention or procedure but that the intervention or procedure holds out the prospect of direct benefit for the individual subject, or by a monitoring procedure that is likely to contribute to the subject’s well being, the IRB may approve the research only if it finds that: (a) the risk is justified by the anticipated benefit to the subject (b) the relation of the anticipated benefit to the risk is at least as favorable t the subjects as that presented by available alternative approaches (c) adequate provisions are made for soliciting the assent of the children and permission of their parents or guardians. These criteria are the same for DHHS and FDA regulated research.

Category III Research involving greater than minimal risk and no prospect of direct benefit to individual subjects, but likely to yield generalizable knowledge about the subject's disorder or condition DHHS – 45 CFR 46.406 FDA – 21 CFR 50.53 If the IRB finds that more than minimal risk to children is presented by an intervention or procedure that does not hold out the prospect of direct benefits for the individual subject, or by a monitoring procedure which is likely to contribute to the well being of the subject, the IRB may approve the research only if the it finds that (a) The risk represents a minor increase over minimal risk; (b) The intervention or procedure presents experiences to subjects that are reasonably commensurate with those inherent in their actual or expected medical, dental, psychological, social, or educational situations; (c) The intervention or procedure is likely to yield generalizable knowledge about the subjects' disorder or condition which is of vital importance for the understanding or amelioration of the subjects' disorder or condition; and (d) Adequate provisions are made for soliciting assent of the children and permission of their parents or guardians, as set forth in §46.408. These criteria are the same for DHHS and FDA regulated research

Category IV Research not otherwise approvable which presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children. DHHS – 45 CFR 46.407 FDA – 21 CFR 50.54* The regulations governing research involving children subjects provide for a special review process to address studies that offer the subjects no prospect of direct benefit and that would pose greater than a minor increment over minimal risk. The process begins by requiring that, an IRB determine that a study in this category "presents a reasonable opportunity to further the understanding, prevention, or alleviation of a serious problem affecting the health or welfare of children." Upon such a finding, the Secretary may convene a panel of experts in pertinent disciplines to review the study and should provide the public an opportunity to review and comment on the study.228 After the panel’s review and the public comment period, the study may be approved if the Secretary has determined: (1) that the study actually falls into a category of research that the IRB could have approved on its own,229 or (2) that the research does present the "opportunity to further the understanding, prevention, or alleviation of a serious problem affecting the health or welfare of children, that the research will be conducted in accordance with sound ethical principles, [and] that adequate provisions are made for soliciting the assent of [the] children and the permission of their parents or guardians." *FDA regulations differ in that they provide for reporting to the FDA Commissioner

Requirements for Parental Permission Categories I and II – Permission of one parent is sufficient Categories III and IV – Both parents must give permission unless one parent is deceased, unknown, incompetent, or not reasonably available.

Waiver of Parental Permission If the research is designed to study conditions or participants for which parent or legal guardian permission is not a reasonable requirement to protect the participants (for example, neglected or abused children), the IRB may consider a request to waive those consent requirements provided the following conditions are met: An appropriate mechanism for protecting the children who will participate as subjects in the research is substituted, and The waiver is not inconsistent with Federal, State, or local law.

Waiver of Parental Permission The FDA does not allow waivers of parental permission

Summary When research involves children, there are additional protections to put in place. Making proper risk determinations gives the IRB the necessary tools to apply protections appropriately