Pediatric Research What Counts as Minimal Risk? When Should Assent be Required?

1. Pediatric ResearchWhat Counts as Minimal Risk?When Should Assent be Required? The views and opinions expressed in this talk are my own. They do not reflect any position or policy of the NIH, DHHS, or U.S. government.

2. Who is a Child? Legally and culturally who is considered a child varies from place to place.

3. Minimal Risk

4. Previous Regulations • Previously, many guidelines prohibited pediatric research on the grounds that children cannot consent. • German guidelines of 1931: research with children “shall be prohibited if it in any way endangers the child.”

5. The Need for Pediatric Research • More recently, it has been recognized that pediatric research is needed to improve pediatric medicine. • It is estimated that less than 1/3 of drugs prescribed to children have been tested in children, even for basic safety and efficacy.

6. Clinical Trials in Children • “In the absence of specific trial-based data in children, clinicians, families and policy-makers are forced to extrapolate from results of studies in adults. This extrapolation is often inappropriate because children have a different range of diseases, and metabolise medications differently, resulting in responses to treatment that are unpredictably different to adults.” Caldwell PHY, Murphy SB, Butow PH, Craig JC Lancet 2004; 364:803811.

7. Prospect of Benefit Research • The need to conduct pediatric research must be balanced with the need to protect individual pediatric research participants • It seems acceptable to enroll children in research that offers them a compensating chance for clinical benefit, such as phase III studies of new medications.

8. ‘Non-Beneficial’ Research • More worrisome is pediatric research that does not offer a compensating chance for clinical benefit. • To assess lopinavir/ritonavir in children with HIV, investigators first gave children single doses to assess which dose levels they could tolerate. • These studies, necessary for future efficacy studies, did not offer a chance of medical benefit.

9. McCormick and Ramsey • ‘Non-beneficial’ pediatric research has been subject of ethical debate for over 25 years. • Most famously, McCormick and Ramsey debated whether non-beneficial pediatric research is ethical.

10. The Debate • Ramsey argued that non-beneficial pediatric research necessarily involves exploitation, exposing children to risks for the benefit of others. • McCormick offered a number of arguments in response, including the claim that children would consent if they could.

11. Minimal Risks • The theoretical argument over the ethical acceptability of non-beneficial pediatric research continues. • In practice, most current guidelines allow children to be enrolled in non-beneficial research when the risks are sufficiently low.

12. Minimal Risk Defined • Most regulations, Council of Europe, Uganda, CIOMS, British MRC, Canada Tri-Council, U.S., Australia and South African MRC, define ‘minimal’ risks based on the risks of daily life. • On this standard, children may be enrolled in non-beneficial research when the risks are no greater than the risks children encounter in daily life.

13. Other Uses • Indian CMR and South African MRC guidelines use the risks of daily life to determine when research may be conducted with a waiver of informed consent. • Guidelines, including Nepal’s guidelines for health research, use the minimal risk standard to assess research with prisoners. • Other research guidelines, including Uganda’s, allow fetuses to be involved in non-beneficial research only when the risks are minimal.

14. Whose Daily Life? • Enrolling children in riskier research simply because they face greater risks in their daily lives seem unethical. • To protect these children, most commentators define minimal risk as the risks “average, healthy, normal children may encounter in their daily lives.” (IOM report)

15. Inter-Country Variation • The risks that children face in daily life vary enormously from country to country, with children in some countries (e.g. Iraq, Congo) facing extremely high risks. • The South African guidelines limit minimal risks to the risks of average healthy children in “stable” societies.

16. Applying the Definition • Are the following procedures minimal risk? • MRI without sedation in healthy 11 year-olds • Allergy skin testing in healthy 11 year-olds

17. Survey of U.S. IRB Chairpersons (%; N=188) MR > MR • 10 cc Blood Draw 81 18 • MRI 48 44 • Survey Sexual Activity 44 48 • Allergy Skin Testing 23 70 • Lumbar Puncture 2 94

18. Judgment Without Data • IRB members may assume they are familiar with the risks of daily life and rely on their own judgement. • Yet, psychological studies show individual risk perception is prone to systematic mistakes. We focus on how familiar an activity is and our level of control over it.

19. The Need for Data • Review committees should not assess the risks of pediatric research using just their own personal judgements. • Instead, review committees need data on the risks of research procedures, and the risks of daily life.

20. The Risk Threshold • The activities of daily life pose a range of risks; riding a bike is riskier than taking a nap. • To qualify as not greater than the risks of daily life, research risks must fall within this range. • In practice, IRBs needs data on the top of the range, or ‘riskier’ activities in daily life

21. Risks of Everyday Life • There are very few data on the risks of ordinary activities in the US. Thus, there is a need to collect more and better data. • Existing data bases provide some information, especially on the risks of driving and participating in sports in the US.

22. Mortality Risks in the U.S. • The activity of daily life that poses the highest risk of mortalityin the U.S.is riding in a car • For every million car trips, the risk of death is .06 for children 1-14 and 0.4 for children 15-19. • For every million ‘riskier’ trips, the risk of death is 0.7 for children 1-14 and 5.0 for children 15-19.

23. Morbidity Risks in the U.S. • The activity of daily life that poses the highest risk of morbidity in the US is playing sports, particularly (American) football. • For every million events of football: • 3,800 injuries • 910 of which are broken bones • 270 require surgery

24. Other Risks • IRBs should take into account all the risks research poses to children, including the psychological, economic and social risks. • While research typically does not pose economic or social risks to children, it can pose psychological risks.

25. Data on Psychological Risks • Data in healthy children in the U.S. show that 27% “sometimes” and 3% “often” or “always” feel scared or afraid. • In addition, 26% of healthy children “sometimes” and 7% “often” or “always” worry about what will happen to them.

26. Limitations • These data do not provide information on the severity of psychological risks or estimates for the psychological risks posed by individual activities, such as riding on a roller coaster or attending a funeral. • However, they suggest research procedures may qualify as minimal risk even when they pose some psychological risks.

27. Implications • Currently, many IRBs are rejecting as too risky pediatric studies whose risks seem appropriate, and are no greater than the risks of daily life. • In other cases, the risks of daily life standard may have the potential to allow inappropriately high risks.

28. Justification for the Standard • Do the risks of daily life provide the appropriate standard for assessing the risks of non-beneficial pediatric research? • Freedman: the risks of daily life has “normative as well as descriptive force, reflecting a level of risk that is not simply accepted, but is deemed socially acceptable.”

29. Objections • Many of the risks children face in daily life, such as the risks of crime and parental abuse, exist because we can’t seem to eliminate them. • In addition, many other risks are considered acceptable because they are tied to beneficial activities, such as playing sports.

30. One Alternative • These concerns suggest the “risks of daily life” may be too broad for assessing the risks of non-beneficial pediatric research. • Kopelman: define minimal risks based on “the routine examinations all people might ordinarily encounter.”

31. Applied to Children? • What examinations do all children receive? Height and weight, single blood draws? In some countries there is no routine medical care for healthy children. • Also, this standard seems subject to the criticism that routine medical examinations are justified by the potential benefit to the individuals who receive them.

32. What’s the Problem Here? • It seems we are looking for a standard for what risks are acceptable on their own, independent of any potential benefits. • How could there be risks that we consider acceptable for children without any potential benefits?

33. Alternative I: “Background” Risks • How about the risks we accept without thinking about them, such as riding in a car? • We don’t think about these risks because they are part of the “background” to our daily lives. • Since research is not part of daily life, we assess the risks explicitly, suggesting there may be a gap between our moral and psychological evaluations.

34. Alternative I I: Charitable Participation Standard • Non-beneficial research is worrisome precisely because it poses risks to participants for the benefit of others. • This suggests that we need a standard for when it is acceptable to expose children to risks for the benefit of others.

35. Charitable Activities • We often expose children to risks to help others. • Helping an infirm neighbor; saving a drowning infant; habitat for humanity

36. Indirect Benefits • One might argue that we allow children to participate in charitable activities because of the ‘indirect’ benefits they receive. • Indirect benefits do not seem necessary. However, even if they are, there is no reason to think that participation in research offers fewer indirect benefits than other charitable activities we allow.

37. Alternative III: Living in Society • We take children in the car for the benefit of a sibling; that is a price of living in a family. • Can we say: we put children in non-beneficial research to benefit others; that is the price of living in a society?

38. Assent and Dissent in Pediatric Research

39. He Still Seems Crazy to Me Why participants at a research ethics conference in Blantyre, Malawi questioned Dave’s sanity.

40. The Case of Jimmy • Jimmy was a smart 8 year old with a rare variant of a rare inborn immune deficiency • Obtaining some of Jimmy’s white cells for laboratory studies could lead to important insights into his disease.

41. The Procedure • The procedure required Jimmy to sit in a chair for about 20 minutes, with two needles in his arms. • Jimmy was informed that the procedure would not help him. He was also informed that he could refuse.

42. Quiz Question #1 Should the investigators have asked Jimmy whether he wanted to be in the study?

43. Quiz Question #2 Guess what Jimmy said when he was asked whether he was willing to undergo the procedure?

44. Permission and Assent • With a few exceptions, children should be enrolled in ‘non-beneficial’ research only with the permission of their legal guardian, typically their parents. • Most guidelines also require the positive agreement (called “assent”) of children who are capable of providing it.

45. Regulations • ICMR: “the assent of the child should be obtained to the extent of the child’s capabilities.” • CIOMS: “the agreement (assent) of each child has been obtained to the extent of the child’s capabilities.” • Uganda : “Adequate provisions have been made for the solicitation of the children’s assent.”

46. Dissent • Some guidelines require that investigators also respect the dissent of all children in the context of non-beneficial research. • Tanzania: Researchers “must recognize when a child is very upset by a procedure and accept that as genuine dissent from their being involved.”

47. 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.

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

49. 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.”

50. IRB Survey Results • 54% of U.S. IRBs leave the decision of which children are capable of assent to the judgement of the investigators. • The remainder use an age cuttoff: 22% use age seven; 9% use age 5 or 6; 18% use age 8-12.