1. Research With Children The Ethical Imperative: Don’t Underprotect or Overprotect Ernest D. Prentice, Ph.D. University Of Nebraska Medical Center Revised 12/20/02

2. The Basic Premise Children are vulnerable and need to be protected. They should not, however, be overprotected. Finding the right balance is crucial to the advancement of pediatric research for the ultimate benefit of children.

3. Objectives Review selected historical perspectives Discuss the National Commission Discuss 45 CFR 46, Subpart D Discuss 21 CFR 50, Subpart D Describe the categories of pediatric research Discuss interpretations of Subpart D, ethical and regulatory issues

4. Genesis of concern about protecting children involved in research.

5. The Landmark Willowbrook Hepatitis Study 1956-1972

6. Willowbrook Hepatitis Study 1956-1972 Study Site: Willowbrook State School Subjects: Severely mentally retarded children Purpose: Study the natural history of hepatitis Intervention: Subjects were fed viral laden extracts of stool (gg+v and v only). Potential Risk: Chronic liver disease ( v only ) Potential Benefit: Immunity via a sub clinical infection Parental Consent: Coerced by admittance restriction

8. 22 examples of unethical research including the Willowbrook study Highly funded and nationally recognized investigators at prestigious institutions Declarations of Helsinki and Nuremberg code violated NEJM 274:1354-60, 1966 Henry Beecher’s Exposé

9. “What seem to be breeches of ethical conduct in experimentation are by no means rare, but are almost, one fears, universal... Whoever gave the investigator the god- like right of choosing martyrs?” Henry Beecher, 1966

10. Congress Reacts to Willowbrook and Other Ethical Lapses Appointment of The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research marks the beginning of the era of “protectionism” Public Law 93-348, July 1974

11. Charge to the National Commission Determine how to best to protect children who participate in research. ….

12. Research Involving Children The report and recommendations of the National Commission lead to the promulgation of additional protections for children involved in research. National Commission Report FR 43 (No. 9), January 13, 1978

13. HHS Regulations at 45 CFR 46, Subpart D Additional Protections for Children Involved as Subjects in Research. FR 48 (No. 46), March 8, 1983 effective June 6, 1983

14. FDA Adopts Subpart D The Children’s Health Act of 2000 required FDA to ensure that FDA regulated clinical investigations comply with Subpart D by April 17, 2001. Title XXVII, Section 2701, Children’s Health Act, (Public Law 106-310)

15. FDA Regulations at 21 CFR 50, Subpart D Additional Safeguards for Children in Clinical Investigations of FDA Regulated Products. FR 66 (No. 79), April 24, 2001 effective April 30, 2001 “Interim Final Rule”

16. Categories of Pediatric Research 46.405 50.52 46.406 50.53 46.407 50.54 46.404 50.51

17. The Risk-Benefit Protections Escalation Principle As the risk increases in relation to the presence or absence of direct subject benefit, the criteria for IRB approval under Subpart D categories become more stringent.

18. The Risk Threshold Subpart D uses the standard of “minimal risk” as a threshold level of risk.

19. National Commission’s Definition of Minimal Risk Minimal risk is the probability and magnitude of physical or psychological harm that is normally encountered in daily lives, or in the routine medical or psychological examination, of healthy children. National Commission Report FR 43 (No. 9), January 13, 1978; p 2085

20. HHS – FDA Regulatory 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. 45 CFR 46.102(i); 21 CFR 56.102(i)

21. Question When assessing whether research presents minimal risk or greater than minimal risk should the investigator and the IRB use an absolute or a relative standard?

22. Absolute v. Relative Standard of Minimal Risk The absolute standard uses the risks associated with the daily life of healthy children in the general population. The relative standard uses the risks associated with the daily life of the children (e.g. cancer patients) who will participate in the research.

23. NHRPAC Guidance “Daily life” is interpreted to mean the daily life of healthy children in the general population. In evaluating whether a given procedure or intervention qualifies as “minimal risk” the IRB should consider whether the risks are comparable to the risks that parents may ordinarily allow their children to experience in the course of daily life or as a consequence of routine tests using an “equivalence of risk basis”. NHRPAC Report August 2002

24. Determination of Risk Classification What is the category of risk(s) associated with the study: physical, psychological, social, economic or legal? What is the probability that a risk will materialize into harm and what is the likely magnitude and reversibility of that harm? How can the risk(s) be minimized to the greatest extent possible? Should the risk(s) be classified as minimal or greater than minimal?

25. Examples of Interventions by Risk Classifications* Blood sampling 3ml/kg/8wkIndwelling IV cath. Fresh catch urine collectionUrinary cath. MRI (no sedation)MRI, IV contrast agent Moderate exMax treadmill test Standard psy testingExtensive psy testing Routine diagnostic x-rayCT scan; PET scan ECGElectromyography UltrasoundSkin biopsy No more than minimal riskGreater than minimal risk * Repetitive procedures and vulnerability may increase risk.

26. Research not involving greater than minimal risk. 46.404 50.51 Category

27. Adequate provisions are made for soliciting the assent of the children and the permission of their parents or guardians, as set forth in 46.408; 50.55 46.404 50.51 Requirements

28. Research involving greater than minimal risk but presenting the prospect of direct benefit to the individual subjects. 46.405 50.52 Category

29. (a) the risk is justified by the anticipated benefit to the subject. 46.405 50.52 Requirements

30. Question How should the risk-benefit relationship of research be assessed when the subjects are children?

31. Answer There are two methods which may be used to assess the risk-benefit relationship of research: a) component analysis and b) collective analysis

32. Component Analysis of Research Risks and Anticipated Benefits What are the risks (if any) that are associated with each intervention? What is the probability that any given risk will materialized into a harm? What is the likely magnitude and reversibility of any harm?

33. Component Analysis of Research Risks and Anticipated Benefits Cont’d What are the anticipated benefits to the subject (if any) that are associated with each intervention? What is the likelihood of occurrence, magnitude and time frame of anticipated benefits to the subject, which are associated with each intervention? Risks of an intervention that offers no benefit to the subject cannot be justified by benefits offered by other interventions.

34. Example #1 Component Analysis If a RCT evaluating drug A v. B using children as subjects has a PK component (indwelling IV; serial blood sampling) but the PK data will not be used to alter dosing (i.e. no benefit to the child) the potential therapeutic benefit of the drugs cannot be used to justify the risks of the PK component.

35. Example #1 Cont’d The risks of drug A and B must be justified by the anticipated direct benefits of the drugs to the subject. [46.405; 50.52] The risks of the PK testing (PKT) are greater than minimal with no direct subject benefit. The PKT must be justified under [45.406; 50.53]

36. Collective Analysis of Research Risks and Anticipated Benefits What is the sum total of the risks to which the subject will be exposed? What are the anticipated benefits to the subject? What are the anticipated benefits to others?

37. Example #1 Collective Analysis The risks of drug A and drug B and the PKT must be justified by anticipated direct benefits to the subject ( i.e. from the study drugs). The risks of the PKT ( that has no therapeutic benefit) are greater than minimal but the study as a whole offers direct benefit to the subject. The study may be approvable under 46.405; 50.52.

38. (b) the relation of the anticipated benefit to the risk is at least as favorable to the subjects as that presented by available alternate approaches. 46.405 50.52 Requirements cont’d

39. Clinical Equipoise RCT- Alternative Drug C Drug A Drug B Research Risk and Benefits Compared With the Alternatives

40. Question Can a placebo controlled RCT qualify for approval under 46.405/50.52?

41. Circumstances Where a Placebo Control May Be Permissible There is no standard treatment with proven efficacy. The standard treatment has significant toxicity compared to the active study drug. Possible assignment to the active study drug offers significant therapeutic benefit compared with standard treatment. The study employs a cross-over design. The predicted placebo response is high.

42. The Bottom Line in Placebo Ethics In all placebo controlled clinical trials: 1.) The best science requires use of a placebo 2.) The risk of no treatment associated with placebo must not be significant 3.) The risk of placebo must be minimized. (e.g. withdrawal and treatment) Adapted from the AAP guidelines

43. (c ) adequate provisions are made for soliciting the assent of the children and permission of their parents or guardians, as set forth in 46.408; 50.55. 46.405 50.52 Requirements cont’d

44. 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. 46.406 50.53 Category

45. (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. 46.406 50.53 Requirements

46. Question How should the investigator and the IRB interpret commensurability?

47. Commensurability “The requirement of commensurability of experience should assist children who can assent to make a knowledgeable decision about their participation in research, based on some familiarity with the procedure and it’s effects. More generally, commensurability is intended to assure that participation in research will be closer to the ordinary experiences of the subjects” National Commission Report FR 43 (No 9), January 13, 1973; p 2086

48. Analysis of Commensurability “actual or expected” “Actual” fits with intent of the National Commission (that is, familiarity with procedures and effects) Does “expected” mean what a child should be experiencing with that condition (i.e., if they were receiving standard care), or what a child will be experiencing in the future as the condition progresses? Note: Neither definition of “expected” fits with the intent of the National Commission

49. Examples Illustrating Commensurability A venipuncture in a normal child is commensurate with experiences inherent in the child's actual medical situation (that is, a normal child might expect to undergo venipuncture in the course of routine medical care) A bone marrow aspirate is commensurate with experiences inherent in the actual medical situation of a child with leukemia A bone marrow aspirate, however, would not be commensurate with experiences in the life of a healthy child

50. Commensurability of Experience v. Risk Exposure “…intervention or procedure presents experiences … that are reasonably commensurate…” Experiences must be commensurate, not the risks of the experiences The risks of a bone marrow biopsy in a leukemic child are similar to those of a liver biopsy (pain, bleeding, infection), but the experiences are not the same; a liver biopsy is not commensurate with experiences in the life of a child with leukemia

51. Question How should the investigator and the IRB interpret the requirement that the risks of the research be no more than a minor increase over minimal risk?

52. "Minor Increase" “A risk which, while it goes beyond the narrowed boundaries of minimal risk… poses no significant threat to the child's health or well being" 1 HHS and FDA Regulations provide no definition and leave it to the judgment of the IRB on a case by case basis. 2 1.National Commission Report: FR 43 (No. 9) January 13, 1973; p 2112 2.45CFR46, Sub DFR 48, March 8, 1983; p 9816

53. Interpretations of “Minor Increase Over Minimal Risk" –Absolute standard (the same small amount of additional risk over minimal risk for all subjects – sick or healthy) –Relative standard (more additional risk allowable for sick children than for healthy children)* Based on the idea that commensurability applies to both experiences and associated risks The intervention must present experiences and associated risks that are reasonably commensurate with those inherent in the child’s actual situation * NHRPAC Report August 2002

54. Examples of a "Minor Increase over Minimal Risk" A single bone marrow aspirate performed solely for research purposes in children with leukemia may be a “minor increase over minimal risk” because it is commensurate. A bone marrow aspirate performed in healthy children is not commensurate with the experience of the child and therefore is not a “minor increase over minimal risk” NHRPAC Report August 2002

55. (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. 46.406 50.53 Requirements cont’d

56. Questions What is the meaning of the term “subjects’ disorder or condition”? What level of importance meets the criteria of “vital importance”?

57. Disorder or Condition A “disorder” is a defined medical disorder. (e.g. diabetes…) A “condition” need not be a medical condition and could apply to predispositions such as: 1) an increased risk of developing a disorder (eg. genetic based; obesity…) 2) a demographic or socioeconomic factor (eg. poverty; pollution….) NHRPAC Report August 2002

58. Vital Importance “Vital importance” means that the research is designed to answer a very important question regarding the health and/or welfare of the children in the study.

59. Question Must all subjects (including controls) have a disorder or condition in order to participate in a 46.406; 50.53 study?

60. Inclusion of Normal Controls A “strict interpretation” of 46.406(c); 50.53(c) precludes the use of normal, healthy controls who do not have a disorder or condition related to the research. The use of normal, healthy controls would likely not meet the 46.406(b); 50.53(b) commensurability requirement. National Commission Report FR 43 (No. 9) January 13, 1973; p2086

61. (d) adequate provisions are made for soliciting assent of the children and permission of their parents or guardians, as set forth in 46.408; 50.55 46.406 50.53 Requirements Cont’d

62. Research not otherwise approvable which presents an opportunity to understand, prevent or alleviate a serious problem affecting the health or welfare of children. 46.407 50.54 Category

63. The research does not meet the other Subpart D categories. The research presents a reasonable opportunity to further the understanding, prevention, or alleviation of a serious problem affecting the health or welfare of children. 46.407 50.54 Requirements

64. Requirements Cont’d An HHS-OHRP / FDA panel of experts must review a 407/54 Application which includes the IRB’s review, determination, rationale and documentation. Provide recommendations to HHS-OHRP /FDA on approvability of the research. Opportunity for public review and comment. Final decision made by HHS/FDA 46.407 50.54

65. Application of Subpart D to a Placebo Control Study Using a Post V. Pre – Randomization Analysis of Potential Benefit

66. The Study A phase 2 RCT is designed to assess the efficacy and safety of BSGH (arm A) v. Placebo (arm B) in children with Turner’s Syndrome. BSGH and placebo will be given 3x/wk sc for 36 months. Alternative therapy does not exist.

67. Post-Randomization Analysis If the risks of BSGH (Arm A) are justified by the anticipated benefit of BSGH to subjects then Arm A is approvable under 46.405; 50.52 but Arm B is not since the placebo offers no benefit to subjects Arm B may be approvable under 46.406;50.53 if the IRB finds that sc injections of placebo 3x/wk for 36 wks are only a minor increase over minimal risk and there is commensurability… Inability to approve the study under the lower categories of subpart D requires a 46.407; 50.54 panel review

68. Pre-Randomization Analysis All subjects have a 50% chance of receiving BSGH (Arm A) which may benefit them directly by increasing their height. If the 50% chance of receiving benefit from BSGH is sufficient to justify the risk of being assigned to placebo (Arm B), then the study may be approvable under 46/405; 50.52.

69. Question Which analysis ( pre or post randomization) achieves the goal of protecting children and still allows research which is both ethical and beneficial to children as a class?

70. Answer ?

71. THE END