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Research With Children The Ethical Imperative: Don’t Underprotect or Overprotect

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. The Basic Premise.

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Research With Children The Ethical Imperative: Don’t Underprotect or Overprotect

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  1. Research With ChildrenThe 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

  7. Henry Beecher’s Exposé • 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

  8. “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

  9. 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

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

  11. 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

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

  13. 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)

  14. FDA Regulations at21 CFR 50, Subpart D Additional Safeguards for Children in Clinical Investigations of FDA Regulated Products. “Interim Final Rule” FR 66 (No. 79), April 24, 2001 effective April 30, 2001

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

  16. 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.

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

  18. National Commission’s Definition of Minimal Risk Minimal risk is theprobability and magnitude ofphysical or psychological harm that is normally encountered in dailylives, or in the routine medical or psychological examination, of healthychildren. National Commission Report FR 43 (No. 9), January 13, 1978; p 2085

  19. HHS – FDA Regulatory Definition Of Minimal Risk Minimal Risk means that the probability and magnitude of harmor 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)

  20. 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?

  21. Absolute v. Relative Standard of Minimal Risk • The absolute standard uses the risks associated with the daily life of healthychildren 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.

  22. 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

  23. 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?

  24. Examples of Interventions by Risk Classifications* No more than minimal risk Greater than minimal risk * Repetitive procedures and vulnerability may increase risk.

  25. 46.404 50.51 Category Research notinvolving greater than minimal risk.

  26. 46.404 50.51 Requirements 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

  27. 46.405 50.52 Category Research involving greater than minimalrisk butpresenting the prospect of directbenefit to the individual subjects.

  28. 46.405 50.52 Requirements (a) the risk is justifiedby the anticipated benefit to the subject.

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

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

  31. 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?

  32. 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.

  33. Example #1Component 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.

  34. 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]

  35. 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?

  36. 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.

  37. 46.405 50.52 Requirementscont’d (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.

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

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

  40. 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.

  41. 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

  42. 46.405 50.52 Requirements cont’d (c ) adequate provisions are made forsoliciting the assentof the children and permission of their parents or guardians, as set forth in 46.408; 50.55.

  43. 46.406 50.53 Category Research involving greater thanminimalriskand no prospect of direct benefit to individual subjects, but likely to yieldgeneralizableknowledgeabout the subject’s disorder or condition.

  44. 46.406 50.53 Requirements (a) the risk represents a minor increase over minimalrisk. (b) the intervention or procedure presentsexperiencesto subjects that are reasonably commensuratewith those inherent in theiractualorexpected medical, dental, psychological, social or educational situations.

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

  46. 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

  47. Analysis ofCommensurability “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

  48. 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

  49. 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

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