1. Pediatric Ethics Subcommittee of Pediatric Advisory Committee, September 10, 2004 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

5. 09-10-200445 CFR 46.111 and 21 CFR 56.111 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.

6. 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

7. 09-10-2004 Assess the level of risk presented by each research intervention or procedure. Minimal Risk §46.404/50.51 More than Minimal Risk Approve, Disapprove, or Consider §46.407/50.54

8. 09-10-200445 CFR 46.102(i); 21 CFR 56.102(i); SACHRP 07-26-2004 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].

9. 09-10-2004 Evaluate the possibility of direct benefit to the child from each intervention or procedure Prospect of direct benefit §46.405/50.52 More than Minimal Risk Approve, Disapprove, Consider §46.407/50.54 No prospect of direct benefit (1)Risk justified by anticipated benefit, and (2)Relation of anticipated benefit to risk as favorable as available alternatives.

10. 09-10-2004 Evaluate level of risk Minor increase over minimal risk §46.406/50.53 No Prospect of Direct Benefit More than a minor increase over minimal risk §46.407/50.54

11. 09-10-2004 Understand or ameliorate child's disorder or condition? Minor increase over minimal risk §46.406/50.53 Experiences reasonably commensurate? Yield generalizable knowledge of vital importance? YES NO Disapprove or Consider §46.407/50.54 Approve Disapprove NO

12. 09-10-2004 Reasonable opportunity to understand, prevent or alleviate serious problem affecting children's health or welfare? Greater than a minor increase over minimal risk §46.407/50.54 Conducted in accord with sound ethical principles? YES NO Disapprove Consider §46.407/50.54

14. 09-10-2004 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.

15. 09-10-200445 CFR 46.408a; 21 CFR 50.55a-c 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.

16. 09-10-200445 CFR 46.111 and 21 CFR 56.111 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)

17. 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