Pediatric Clinical Research A Regulatory and Everyday Perspective

1. Pediatric Clinical ResearchA Regulatory and Everyday Perspective Linda DiMeglio, MD, MPH; Lucy Miller, RN, BSN, CCRP; Jody Harland, MS, CIP Department of Pediatrics, IU School of Medicine Shawn Axe, CIP Research Compliance Administration, IUPUI

2. Objectives • To understand: • federal regulations related to the involvement of children in research • the IRB’s and investigator’s responsibilities in reviewing pediatric clinical research • the assent process in clinical research with children

3. Relevant Regulatory Citations • DHHS: The Common Rule at 45 CFR 46, Subpart D • FDA: 21 CFR 50, Subpart D • Regulations largely mirror each other; however, FDA does not allow for a waiver of parental permission. • DHHS regulations do not require written documentation of assent (they give IRBs the latitude to make this determination); however, FDA guidance states that written documentation (via “separately designed, written assent form or the written informed consent) should be obtained.

4. How do the federal regulations define “children?” “Persons who have not attained the legal age for consent to treatments or procedures involved in the research, under the applicable law of the jurisdiction in which research will be conducted” (45 CFR 46, Subpart D) (21 CFR 50, Subpart D) • Children/adolescents = less than 18 years of age

5. Special vulnerability of children • Children are considered a “vulnerable population” • Children have not reached their full physical or emotional capacities • Children are unable to provide legally-valid consent for themselves (with a few exceptions) • Children are particularly vulnerable to potential coercion

6. Why is pediatric clinical research important? • National Institutes of Health (NIH) policy on inclusion of children (1998) • Best Pharmaceuticals for Children Act (2002) • Involving children can extend the length of the patent • Pediatric Research Equity Act (2003)

7. IRB responsibilities in reviewing pediatric clinical research • Review all research in which children are the target population or may make up some of the population • Have members with expertise in pediatrics

8. IRB responsibilities in reviewing pediatric clinical research • Designate a “category” of research involving children • Risk/benefit ratio • Adequate plan for obtaining parental consent and child assent (if applicable)? • One parent/guardian or both? • Child’s agreement to participate needed or not?

9. Category 1 Research • (§46.404): Not involving greater than minimal risk to children. • Adequate plan for soliciting the assent of the children and the permission (parental/guardian informed consent) of each parent or guardian • Justification if permission from only one parent or guardian will be solicited. • IRB can determine that permission (e.g., informed consent) of one parent/guardian is sufficient.

10. Category 2 Research • (§46.405): Involving greater than minimal risk but presenting the prospect of direct benefit to the individual child. • Adequate plan for soliciting the assent of the children and the permission (parental/guardian informed consent) of each parent or guardian • Justification if permission from only one parent or guardian will be solicited. • IRB can determine that permission (e.g., informed consent) of one parent/guardian is sufficient.

11. Category 3 Research • (§46.406): Involving greater than minimal risk and no prospect of direct benefit to the individual child, but likely to yield generalizable knowledge about the child’s disorder or condition. • Adequate plan for soliciting the assent of the children and the permission (parental/guardian informed consent) of each parent or guardian • Permission of both parents/guardians must be obtained (unless one is not reasonably available, etc.)

12. Category 4 Research • (§46.407): Research not otherwise approvable under one of the above categories, which presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children. • Adequate plan for soliciting the assent of the children and the permission (parental/guardian informed consent) of each parent or guardian • Permission of both parents/guardians must be obtained (unless one is not reasonably available, etc.) • The Secretary of HHS must approve, after consultation with a panel of experts following publication and public comment.

13. Investigator responsibilities when conducting pediatric research • Obtain approval from IRB before enrolling children into a study • Make initial determination as to the appropriate “category” of research involving children

14. Investigator responsibilities when conducting pediatric research • Present the IRB with parental informed consent statement or rationale for requested waiver of informed consent • Ensure the protocol/submission describes if and how assent will be obtained and documented (or rationale for requested waiver of assent)

15. Investigator responsibilities when conducting pediatric research • Waiver of informed consent for parents • Certain types of research involving minimal risk • Where permission of parents is not reasonable • This may require involvement of a court-appointed guardian. • Not an option for FDA-regulated research.

16. Investigator responsibilities when conducting pediatric research • Assent of child subjects • A child’s affirmative agreement to participate • Present a plan to the IRB for whether and how assent will be obtained

17. Investigator responsibilities when conducting pediatric research • Assent • Typically required of children ages 7 and above • Could use an oral script (for very young) • Could create a separate written document • Could use the Informed consent itself (with appropriate language and additional signature lines – often appropriate for older adolescents) • Should be in a language appropriate to child’s age/developmental level

18. Investigator responsibilities when conducting pediatric research • Waiver of assent • May be requested by PI when believes that obtaining assent is unreasonable due to subject condition (e.g., presence of a ventilator or serious psychiatric disorders). • When a waiver is granted, this means that the child does not have to provide assent to participate in the research.

19. Investigator responsibilities when conducting pediatric research • Waiver of assent • Must be requested prospectively and granted by the IRB • Can be done as a “blanket” (e.g., for all participants) or on a “case-by-case” basis • PI cannot make this determination alone • If waiver is granted by IRB, an age-appropriate Information Sheet shall be provided to the child

20. Regulatory summary: • Individuals less than 18 years old are considered “children” from a regulatory perspective. • Before children are enrolled on a study, IRB must approve their inclusion. • IRBs must consider carefully the involvement of children in research and make specific determinations about their involvement in research. • When conducting pediatric research, PIs must provide detailed information to the IRB on whether and how parental permission and child assent will be obtained.

21. Frequently Asked Questions (FAQs) re: children in research

22. FAQs Q1:When can a “minor” consent for himself/herself to participate in a research study?

23. FAQs A1: A minor can consent for himself/herself if any of the following are true: • By law the minor is considered emancipated; • The minor is at least fourteen (14) years old, not dependent on a parent for support, is living apart from parents or from an individual in loco parentis (e.g., someone who acts in the place of a parent), AND is managing his/her own affairs; • The minor is or has been married; • The minor is in the military service of the United States; OR • The minor is authorized to consent to the health care by any other statute. • If none of the above are true, and informed consent has not been waived prospectively by the IRB, parent(s)/guardian(s) must provide permission for the participation of their child or ward in research.

24. FAQs Q2: What are the different ways in which assent can be obtained from children?

25. FAQs • A2: Assent should be conducted in a manner that is developmentally appropriate and which takes into account the ages, maturity, and psychological state of the children involved. Typical recommendations are as follows: • For younger children (e.g., less than 7 years old), an oral conversation/script in very simple language might be appropriate. • For children ages 7-12 years old, a separate assent document written simply and at an appropriate developmental level would be acceptable. • For children (adolescents) ages 13-17 years old, a separate assent document may be used or the parent(s)/guardian(s)’ informed consent may be used if it contains appropriate signature lines (e.g., a signature line for the parent(s)/guardian(s) and adolescent) and is written in “you/your child or adolescent” language.

26. FAQs Q3: How much information should be included in an assent form? Couldn’t too much information be scary?

27. FAQs • A3: See an Assent Template at: http://www.iupui.edu/%7Eresgrad/irbpacket/assent03-03.rtf • The study should be described in enough detail to appropriately convey to the subject what will happen during the study, but not be so detailed that the subject cannot comprehend it. • Keep in mind the target audience; use different versions for different ages of children/adolescents.

28. FAQs A3 (cont.): Think carefully about how to convey risks. EX: Don’t have to describe the myriad potential risks of each study drug which the child might receive, but child should know that: • he/she will be participating in a research study (like a science experiment) • that doctors don’t know if the medicines will help the child or not • that the child will have to come to the hospital for treatments over the next several weeks • that the child may feel some discomforts (like nausea, etc.) during that time • For anxious child who will worry about complex plans, use a “staged” assent process – this breaks up the protocol into more manageable pieces of information (e.g., one assent document to cover the first cycle/phase of treatment, a second document to be presented when the child enters the second cycle/phase, etc.).

29. FAQs Q4: How do I request a waiver of assent from the IRB?

30. FAQs • A5: For new study submissions, you can request a “blanket” waiver of assent. • A “blanket” waiver would be applied to all children to be enrolled in the study. • Requested in Section III, Part A.1. of the SSS when responding to the statement regarding provisions for soliciting assent of the children. • Provide as much detail as possible when explaining why obtaining assent from that subject population is not reasonable. • Note: “because the information may scare the subject” is not sufficient justification for requesting a waiver of assent.

31. FAQs • A5 (cont.): If you are conducting a study and it is thought that a particular potential subject cannot appropriately give assent, a request for a waiver of assent for that particular subject can be made (e.g., on a “case-by-case basis”). • Request should be submitted as a memo to the Board. • Memo should be very detailed regarding the specific circumstances and why it is thought that the subject cannot provide assent. • An Information Sheet (that would be presented to the child) should also be submitted to the IRB detailing what will happen during the study in language appropriate for the subject population. • If the Board approves the waiver of assent for the particular subject, the Information Sheet must then be given to the subject.

32. FAQs Q6: I have a child that will qualify to participate in a research study, but the child is currently placed in foster care. Who can provide informed consent for the child’s participation in the research study?

33. FAQs A6: Typically, consent for the child who is in foster care would be provided for by the judicially-appointed guardian; however, the identity of that individual may not always be immediately evident. As such, the investigator should contact the Research Compliance Administration office (317/274-8289) for guidance. Because such arrangements are often complicated and can differ from situation to situation, RCA may need to contact University Counsel for an appropriate, case-specific legal opinion and recommendation.

34. FAQs Q7: When you have a child whose parents are divorced, and there is no proof available regarding who has custody/ability to consent to healthcare, how do you know who can sign the informed consent statement?

35. FAQs A7: IRB’s SOP on Children in Research describes who is authorized to consent for children for healthcare purposes (per Indiana Code 16-35-1-5). Section is extrapolated to research. Consent to health care for a minor may be given by any of the following individuals: • A judicially appointed guardian of the person or a representative appointed. • A parent or an individual in loco parentis if: • There is no guardian or other representative described in the first bullet point above; • The guardian or other representative is not reasonably available or declines to act; or • The existence of the guardian or other representative is unknown to the health care provider. • An adult sibling of the minor if: • There is no guardian or other representative described in 4.14.1 above; • A parent or an individual in loco parentis is not reasonably available or declines to act; or • The existence of the parent or individual in loco parentis is unknown to the health care provider.

36. FAQs A7 (cont.): In this situation, without evidence of who has the authority to consent to healthcare, the investigator should contact the Research Compliance Administration office (274-8289) for guidance before approaching anyone for obtaining informed consent. Because custody arrangements are often complicated and can differ from situation to situation, RCA may need to contact University Counsel for an appropriate, case-specific legal opinion and recommendation.

37. Everyday experiences with an assent process • Comments from a pediatric faculty researcher • Comments from a pediatric research nurse

38. Questions or Comments?

39. Thank You!