1. Subject Selection and Assent in Pediatric Research

2. Disclaimer The views and opinions expressed in this talk are my own. They do not represent any position or policy of the NIH, or the U.S. government.

3. Subject Selection

4. Goals of Subject Selection 1. Distribute burdens and benefits fairly 2. Ensure social value of research 3. Enhance scientific validity 4. Minimize risks to subjects 5. Maximize benefits to subjects 6. Protect the vulnerable

5. Research as a Benefit  Exclusion without a good reason may be unfair or discriminatory.  People are clamoring for access to clinical trials...demanding they, and others like them, are owed such as a matter of justice. (Levine, 1994)

6. Fairness  To ensure fairness, begin by assuming everyone is eligible.  Exclude individuals from this pool only with good reason.

7. Priority of Science  The scientific goals of the study should be the primary consideration in determining who can enroll.  This involves ensuring the value of the study and enhancing its validity.

8. Ensuring Value  Exclude individuals not suitable for answering the scientific question.  For instance, individuals with conditions that make it impossible to assess the drug being tested (e.g. brain tumors).

9. Enhancing Validity  Exclude individuals who cannot satisfy the protocol requirements.  For instance, subjects who cannot (or do not) make the required clinic visits.

10. Minimize Physical Risks  Exclude individuals who would face significantly higher risks.  For instance, individuals with poor kidney function in a phase II study of a drug with renal clearance.

11. Maximize Benefits  Select subjects who are more likely to benefit from participation.  For instance, a study of a new anti-HIV drug may focus on individuals with low CD4 counts.

12. Protect the Vulnerable  While all children are vulnerable, some are more vulnerable than others.  Protect those who are especially vulnerable, such as wards of the state and the very sick and the very young.

13. Potential Conflicts  In some cases, the different goals of subject selection may conflict.  For instance, older children who understand more may face increased risks compared to infants.

14. Another Conflict  Similarly, sick children may have the potential to benefit in the future from research that offers no prospect of direct benefit.  Yet, these same children may be more vulnerable.

15. Tradeoffs In cases of conflict, investigators, ethics review committees, and sponsors must “balance” the competing goals.

16. Assent

17. Permission and Assent  With a few exceptions, children should be enrolled in research that does not offer a compensating prospect of direct benefit only with the permission of their legal guardian.  Most guidelines also require the positive agreement (“assent”) of children who are capable of providing it.

18. Assent Process  More work is needed on the appropriate process for obtaining assent.  For example, should children’s assent be solicited together with parents’ permission, or separately?

19. Children in ER ( Cohn et al. AJOB 2005;5:70-74 ) 16 participants stated it was not or may not have been their choice to participate. Of these, 14 stated they were glad they participated; 2 “maybe” glad. [ N=70, RR=74%,11-19 yo, mean 13.7 yo, mostly AA males] My choiceMaybe/ No Parent/family member in room1710 Alone in room243

20. Information versus Assent  It is important to distinguish the importance of giving information from the importance of making decisions.  Exclusive reliance on the assent form will fail to provide appropriate information when assent is not required.

21. Dissent  Some guidelines, but not the US, require investigators to respect the dissent of all children in the context of research that does not offer a compensating potential for clinical benefit.  Tanzania: Researchers “must recognize when a child is very upset by a procedure and accept that as genuine dissent from their being involved.”

22. Assess Sources of Distress  The dissent requirement does not imply that children should be removed from research at the first sign of distress.  Instead, investigators first should try to identify and remove the source of distress.

23. Sustained Dissent Children should be removed when they continue to experience on-going and greater than minor distress.

24. Which Children Can Assent?  Most guidelines do not specify which children are capable of assent.  For instance, the U.S. regulations state that this determination should take into account the “age, maturity and psychological state of the children.”

25. Basis for Assent Capacity  Respect for children  Respect for the family unit  Rule of 7s  Respect for “developing” autonomy  Respect for ability to understand  Able to make own decisions

26. Respect for Children  Many commentators emphasize the importance of appropriate respect.  However, respect typically is understood as treating individuals as they deserve to be treated. Hence, this consideration seems to beg the question of the age at which children should be asked to assent.

27. Respect for Family Unit  Some conclude that respect for the family implies there should be no general requirement. Instead, parents should decide.  Others conclude that the assent requirement should be based on how families make decisions.

28. Rule of 7s  The “rule of 7s” states children under age 7 are not rational, ages 7-14 children are not rational unless proven otherwise, and by age 14 they are rational unless proven otherwise.  Many conclude that capable of assent at age 7, but seems to imply age should be 14. Also, not clear how this is relevant.

29. Respect for “Developing” Autonomy  The National Commission argued that an assent threshold of age 7 helps children learn to become autonomous.  However, it is not clear why teaching children to become autonomous should begin at age 7.

30. Respect for Ability to Understand  The National Commission also cited data that at age 7 children begin to understand some aspects of their research participation.  Yet, children younger than age 7 can understand some aspects of research, such as the need to stay over night, and that needles hurt, and most 7 year olds do not understand other aspects, such as long term risks.

31. Respect for Autonomy  Respect for autonomy implies individuals who can make their own decisions should be able to decide whether to enroll in research.  This justification suggests the assent threshold should be the age at which most children are able to understand and make their own research decisions.

32. Current Data  There is a paucity of data regarding children’s decision making abilities.  The existing data suggest most children are able to make their own research decisions by age 12-15.