1. Introduction

2. Research with Minors A Harvard Longwood QIP Education Session Matthew Stafford Assistant Director, Clinical Research Compliance

3. Abuses of Human Subjects: Tuskegee Syphilis Study Willowbrook Study Fernald School Study

4. Willowbrook: From 1963 to 1966, the Willowbrook Study involved a group of children diagnosed with mental retardation, who lived at the Willowbrook State Hospital in Staten Island, New York.

5. Willowbrook: These innocent children were deliberately infected with the hepatitis virus; early subjects were fed extracts of stools from infected individuals and later subjects received injections of more purified virus preparations.

6. Willowbrook: Investigators defended the injections by pointing out that the vast majority of them acquired the infection anyway while at Willowbrook, and it would be better for them to be infected under carefully controlled research conditions.

7. Willowbrook: The study's purpose was to study the history of the disease when left untreated and later to assess the effects of gamma globulin as a therapeutic intervention.

8. Willowbrook: This study generated a variety of concerns, such as the deliberate infection of the children and the attempts to convince the parents to enroll them in the study in exchange for admission to the hospital (which was deliberately short of space).

9. Fernald School Study: The Fernald School was the site of the 1946– 53 joint experiments by Harvard University and MIT that exposed young male children to tracer doses of radioactive isotopes.

10. Fernald School Study: The experiment was conducted in part by a research fellow sponsored by the Quaker Oats Company. MIT Professor of Nutrition Robert S. Harris led the experiment, which studied the absorption of calcium and iron.

11. Fernald School Study: The boys were encouraged to join a "Science Club", which offered larger portions of food, parties, and trips to Boston Red Sox baseball games. The 57 club members ate iron- enriched cereals and calcium-enriched milk for breakfast.

12. Fernald School Study: In order to track absorption, several radioactive calcium tracers were given orally or intravenously. Radiation levels in stool and blood samples would serve as dependent variables.

13. Fernald School Study: Neither the children nor their parents ever gave adequate informed consent for participation in a scientific study.

14. Protection of Human Subjects: Nuremburg Code (1947) Declaration of Helsinki (1964) The Belmont Report (1978) FDA Regulations and the Common Rule (1979, etc)

15. Nuremberg Code The voluntary consent of the human subject is absolutely essential. This means that the person involved: should have legal capacity to give consent; should be so situated as to be able to exercise free power of choice, without the intervention of any element of force, fraud, deceit, duress, over-reaching, or other ulterior form of constraint or coercion; and should have sufficient knowledge and comprehension of the elements of the subject matter involved as to enable him/her to make an understanding and enlightened decision.

16. The Belmont Report, 1978 Basic Ethical Principles:

17. The Belmont Report, 1978 Basic Ethical Principles: Respect for persons

18. The Belmont Report, 1978 Basic Ethical Principles: Respect for persons Beneficence

19. The Belmont Report, 1978 Basic Ethical Principles: Respect for persons Beneficence Justice

20. The Belmont Report, 1978 Applications: Respect for persons - Informed Consent Beneficence Justice

21. The Belmont Report, 1978 Applications: Respect for persons - Informed Consent Beneficence - Assessment of Risks and Benefits Justice

22. The Belmont Report, 1978 Applications: Respect for persons - Informed Consent Beneficence - Assessment of Risks and Benefits Justice - Selection of Subjects

23. CRITERIA for approval

24. 45CFR46* (1979, 1991, 2009) Code of Federal Regulations TITLE 45 PUBLIC WELFARE DEPARTMENT OF HEALTH AND HUMAN SERVICES PART 46 PROTECTION OF HUMAN SUBJECTS *aka The Common Rule

25. §46.109 IRB review of research. (a) An IRB shall review and have authority to approve, require modifications in (to secure approval), or disapprove all research activities covered by this policy.

26. §46.111 Criteria for IRB approval of research. (a) In order to approve research covered by this policy the IRB shall determine that all of the following requirements are satisfied:

27. §46.111 Criteria for IRB approval of research. (1) Risks to subjects are minimized: (i) By using procedures which are consistent with sound research design and which do not unnecessarily expose subjects to risk, and

28. §46.111 Criteria for IRB approval of research. (1) Risks to subjects are minimized: (ii) whenever appropriate, by using procedures already being performed on the subjects for diagnostic or treatment purposes.

29. §46.111 Criteria for IRB approval of research. (2) Risks to subjects are reasonable in relation to anticipated benefits, if any, to subjects, and the importance of the knowledge that may reasonably be expected to result.

30. §46.111 Criteria for IRB approval of research. In evaluating risks and benefits, the IRB should consider only those risks and benefits that may result from the research (as distinguished from risks and benefits of therapies subjects would receive even if not participating in the research).

31. §46.111 Criteria for IRB approval of research. The IRB should not consider possible long-range effects of applying knowledge gained in the research (for example, the possible effects of the research on public policy) as among those research risks that fall within the purview of its responsibility.

32. §46.111 Criteria for IRB approval of research. (3) Selection of subjects is equitable. In making this assessment the IRB should take into account the purposes of the research and the setting in which the research will be conducted and should be particularly cognizant of the special problems of research involving vulnerable populations, such as children, prisoners, pregnant women, mentally disabled persons, or economically or educationally disadvantaged persons.

33. §46.111 Criteria for IRB approval of research. (4) Informed consent will be sought from each prospective subject or the subject's legally authorized representative, in accordance with, and to the extent required by §46.116.§46.116

34. §46.111 Criteria for IRB approval of research. (5) Informed consent will be appropriately documented, in accordance with, and to the extent required by §46.117.§46.117

35. §46.111 Criteria for IRB approval of research. (6) When appropriate, the research plan makes adequate provision for monitoring the data collected to ensure the safety of subjects.

36. §46.111 Criteria for IRB approval of research. (7) When appropriate, there are adequate provisions to protect the privacy of subjects and to maintain the confidentiality of data.

37. §46.111 Criteria for IRB approval of research. (b) When some or all of the subjects are likely to be vulnerable to coercion or undue influence, such as children, prisoners, pregnant women, mentally disabled persons, or economically or educationally disadvantaged persons, additional safeguards have been included in the study to protect the rights and welfare of these subjects.

38. Protection vs. Access

39. Nuremberg Code The voluntary consent of the human subject is absolutely essential. This means that the person involved: should have legal capacity to give consent; should be so situated as to be able to exercise free power of choice, without the intervention of any element of force, fraud, deceit, duress, over-reaching, or other ulterior form of constraint or coercion; and should have sufficient knowledge and comprehension of the elements of the subject matter involved as to enable him/her to make an understanding and enlightened decision.

40. Kefauver-Harris Act, 1962 Required that drugs be tested for safety, efficacy and dosage in children and pregnant women before being approved for use to treat illness in such patients.

41. NIH Proposed Rule, 1973 Children do differ from adults in their physiologic responses, both to drugs and to disease; if the health of children is to be improved, it is necessary to know the nature and extent of these differences, and to have a full understanding of normal patterns of growth and development, metabolism, and biochemistry in the perinatal, infant, early childhood, pubertal and adolescent stages of development.

42. NIH Proposed Rule, 1973 Furthermore, there are diseases which cannot be induced in laboratory animals, and occur only rarely, if at all, in human adults. In such cases, children are the only subjects in whom the disease process and possible modes of therapy can be studied.

43. Subpart D pediatric regulations

44. 45CFR46, Final Rule, 1983 version Subpart D… § 46.404 – Research not involving greater than minimal risk § 46.405… § 46.406… § 46.407…

45. 45CFR46, Final Rule, 1983 version Subpart D… § 46.404 … § 46.405 – Research involving greater than minimal risk but presenting the prospect of direct benefit to the individual subjects § 46.406… § 46.407…

46. 45CFR46, Final Rule, 1983 version Subpart D… § 46.404… § 46.405… § 46.406 - Research involving greater than minimal risk and no prospect of direct benefit to individual subjects but likely to yield generalizable knowledge about the subjects disorder or condition § 46.407…

47. 45CFR46, Final Rule, 1983 version Subpart D… § 46.404… § 46.405… § 46.406… § 46.407- Research not otherwise approvable which presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children.

48. § 46.404 HHS will conduct or fund research in which the IRB finds that no greater than minimal risk to children is presented, only if the IRB finds that 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.§46.408

49. § 46.405 HHS will conduct or fund research in which the IRB finds that more than minimal risk to children is presented by an intervention or procedure that holds out the prospect of direct benefit for the individual subject, or by a monitoring procedure that is likely to contribute to the subject's well-being, only if the IRB finds that:

50. § 46.405 (a) The risk is justified by the anticipated benefit to the subjects; (b) The relation of the anticipated benefit to the risk is at least as favorable to the subjects as that presented by available alternative approaches; and (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.§46.408

51. § 46.406 HHS will conduct or fund research in which the IRB finds that more than minimal risk to children is presented by an intervention or procedure that does not hold out the prospect of direct benefit for the individual subject, or by a monitoring procedure which is not likely to contribute to the well-being of the subject, only if the IRB finds that:

52. § 46.406 (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;

53. § 46.406 (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; and (d) Adequate provisions are made for soliciting assent of the children and permission of their parents or guardians, as set forth in §46.408.§46.408

54. § 46.407 HHS will conduct or fund research that the IRB does not believe meets the requirements of §46.404, §46.405, or §46.406 only if: (a) the IRB finds that the research presents a reasonable opportunity to further the understanding, prevention, or alleviation of a serious problem affecting the health or welfare of children; and

55. § 46.407 …(b) the Secretary, after consultation with a panel of experts in pertinent disciplines (for example: science, medicine, education, ethics, law) and following opportunity for public review and comment, has determined either: (1) that the research in fact satisfies the conditions of §46.404, §46.405, or §46.406, as applicable,

56. § 46.407 …or (2) the following: (i) the research presents a reasonable opportunity to further the understanding, prevention, or alleviation of a serious problem affecting the health or welfare of children; (ii) the research will be conducted in accordance with sound ethical principles; (iii) adequate provisions are made for soliciting …

57. Federal Regulations Define assent as “a child’s affirmative agreement to participate in research, mere failure to object should not be construed as assent Allow the IRB to determine whether assent is required and how assent must be documented. IRB may waive the assent requirement – “if the IRB determines...that the intervention or procedure involved in the research holds out a prospect of direct benefit that is important to the health or well being of the children, and – is available only in the context of the research.”

58. Issues that May Influence Parental Permission/Assent Pathophysiology of the population Developmental level of the child Stress level of the family Setting of research Previous experience with research Expected course of this child Therapeutic Misconception

59. Assent Interactive process between child and researcher Involves disclosure, discussion, obtaining limited understanding of process and determining child preference Serves following purpose – Provide information to minor about research – Establish shared decision making between child and proxy – Make an assessment of child’s understanding – Solicit child’s expression of willingness

60. How to provide understandable information Discuss procedures risks and benefits, alternatives, voluntary participation Let child and proxy know they can ask questions or withdraw How much information – Clinical care goal is patient centered – Research goal is new knowledge – Need to minimize therapeutic misconception – If no benefits, this needs to be stated – If benefits, risk must also be stated – Standard of “reasonable person” often difficult in research setting Needs to be tailored to cognitive and emotional development Caution for children who are disabled or speak other languages Need to also understand comprehension

61. How do you know participation is voluntary Needs to be free of undue influence – Importance of parental figure – Tendency to defer to authority figures – Improper rewards – Children vulnerable to undue influence Subject feels free to stop at any time Need to consider location and timing – Avoid pressure or stressful situations – Give parents children, time to consider

62. Other issues to consider Parent present or absent Other tools to help children understand, videos, pictures, websites

63. And now… Vignettes!

64. Thank you! Matthew Stafford Assistant Director, Clinical Research Compliance Email: matthew.stafford@childrens.harvard.edumatthew.stafford@childrens.harvard.edu Tel: (617) 355-4965 www.childrenshospital.org/research/irb