# Presentation: 664058

## Analysis of Research Protocols Involving Children:Combining Subparts A and D

- Robert M. Nelson, M.D., Ph.D.
- Associate Professor of Anesthesia and Pediatrics
- The Children’s Hospital of Philadelphia
- University of Pennsylvania

- Pediatric Ethics Subcommittee of Pediatric Advisory Committee, September 10, 2004

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## Apply general criteria of Subpart A

- Risks to subjects minimized by using procedures which
- are consistent with sound research design;
- do not expose subjects to unnecessary risk;
- are performed for diagnostic or treatment purposes.
- Selection of subjects is equitable.
- Evaluate anticipated benefits, if any, of research to subjects, and importance of knowledge that may result.
- Include additional safeguards to protect rights and welfare of children.

- 45 CFR 46.111 and 21 CFR 56.111

- 09-10-2004

## Review of Research Involving Children

- _Subpart A_ – All Subjects
- Risks are reasonable in relation to anticipated benefits, _if any_, to subjects _and_ importance of knowledge that may reasonably be expected to result
- 45CFR§46.111; 21CFR§56.111
- _Subpart D_ - Additional Safeguards for Children
- _Restricts allowable risk exposure_ for research not offering the prospect of direct benefit
- 45CFR§46.404 & §46.406; 21CFR§50.51 & §50.53
- _Restricts justification of risk exposure_ for research that offers prospect of direct benefit
- 45CFR§46.405; 21CFR§50.52

- 09-10-2004

**Notes:**
ADULT RULES ALLOW FOR EITHER BENEFIT OR KNOWLEDGE TO JUSTIFY RISK!
FOR CHILDREN, NEED “SPECIAL PROTECTIONS.”  WHAT ARE THESE?  THE KEY IS THAT THE RISKS TO WHICH A CHILD CAN BE EXPOSED IN THE ABSENCE OF THE PROSPECT OF DIRECT BENEFIT ARE RESTRICTED.  WHAT ARE THESE RESTRICTIONS AND WHY IS THE TOPIC OF OUR DISCUSSION THIS MORNING.
CIOMS (May 2001): 
“In research involving persons who are unable to consent the employment of interventions or procedures that do not hold out the prospect of direct benefit for the individual person requires careful ethical justification.”
“Guideline 5: Justification of risk in research involving individuals who are not capable of giving informed consent.”
“When research involves participants who are permanently or temporarily unable to consent, the risk from interventions that do not hold out the prospect of direct benefit to the individual should be no more likely and not greater than the risk attached to routine medical or psychological examination of such persons. Slight or minor increases above such risk may be permitted when an ethical review committee is persuaded that the object of the research is sufficiently important.” 
From 45 CFR §46.111:
Risks to subjects are reasonable in relation to anticipated benefits, if any, to subjects, and the importance of the knowledge that may reasonably be expected to result. In evaluating risks and benefits, the IRB should consider only those risks and benefits that may result from the research (as distinguished from risks and benefits of therapies subjects would receive even if not participating in the research). The IRB should not consider possible long-range effects of applying knowledge gained in the research (for example, the possible effects of the research on public policy) as among those research risks that fall within the purview of its responsibility.

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- 09-10-2004

## Definition of Minimal Risk

- Minimal risk means that the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests [for normal, average, healthy children living in safe environments].

- 45 CFR 46.102(i); 21 CFR 56.102(i); SACHRP 07-26-2004

- 09-10-2004

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## Parental Permission & Child Assent

- All four categories also require...
- Adequate provisions for soliciting the children’s assent and permission of their parents/guardians [§46.408/50.55]
- Parent/Guardian Permission
- Permission of one parent sufficient, if consistent with State law, for research under §46.404/50.51 or §46.405/50.52
- For research under §46.406/50.53 and §46.407/50.54, both parents must give permission unless one parent is deceased, unknown, incompetent, or not reasonably available, or when only one parent has legal responsibility for the child if consistent with State law.

- 09-10-2004

## Child Assent

- Adequate provisions for soliciting assent when (in judgment of IRB) children capable of providing assent
- Take into account age, maturity, and psychological state of either some or all the children involved in the research
- Assent not a necessary condition for proceeding with the research if IRB determines that:
- Capability of some or all of the children is so limited that they cannot reasonably be consulted, or
- Intervention or procedure involved in the research holds out prospect of direct benefit important to health or well- being of the children and is available only in the research.

- 45 CFR 46.408a; 21 CFR 50.55a-c

- 09-10-2004

## Again, general criteria of Subpart A

- When appropriate, there are adequate provisions for monitoring the data collected to ensure the safety of subjects.
- §46.111(a)(6)
- When appropriate, there are adequate provisions to protect subject privacy and to maintain data confidentiality.
- §46.111(a)(7)

- 45 CFR 46.111 and 21 CFR 56.111

- 09-10-2004

## The Task for Today

- Overall Charge to the Pediatric Ethics Subcommittee
- Provide advice and recommendations to Pediatric Advisory Committee on FDA’s and certain HHS regulatory issues.
- Outcome
- Develop recommendation whether protocol should proceed
- Specifically, address whether (and how)...
- research does (or can) satisfy conditions of 45 CFR 46.404, 46.405, or 46.406 (HHS), and 21 CFR 50.51, 50.52, or 50.53 (FDA), _or_
- the following conditions are (or can be) met by the research:
- reasonable opportunity to understand, prevent, or alleviate serious problem affecting the health or welfare of children;
- conducted in accordance with sound ethical principles; and
- adequate provisions are made for soliciting the assent of children and the permission of their parents or guardians

- 09-10-2004