1. Slide 1 How to Review: Research Involving Children & Adolescents in 5 Steps Susan Kornetsky, MPH, CIP Director, Clinical Research Compliance Children’s Hospital, Boston

2. Slide 2 Is this the way it feels trying to review pediatric research? Protocol IRB Subpart D

3. Slide 3 The 5 Steps Select 1 of the 4 risk/benefit categories Determine whether assent of child/adolescent is required Determine whether permission from one, two or no parents/guardian is required Consider any special ethical issues as they pertain to children/adolescents (payment, confidentiality) Document findings in records (minutes, files)

4. Slide 4 Conflict in Belmont Principles? Respect for Persons Protect Those with Limited Autonomy Limit Research with Children Justice Fair Share Research Benefits Promote Research in Children (Conflict) (Equal Moral Force)

5. Slide 5 The Pendulum Swings Protect/Restrict Therapeutic orphans Liability High Cost Small Market Promote/Provide Incentives NIH Inclusion FDA Patent Extensions

6. Slide 6 Investigator IRB Layers of Protection for Risk/ Benefit Assessment Parent/Child Sponsor

7. Slide 7 National Commission: Principles for Guidance Pediatric Research “ Sliding scale" for research involving children –classified into one of four categories according to the risk and the direct benefit to the child. –as risk-benefit relationship of the research become less favorable, additional requirements must be satisfied, more protections Concept of permission from parent guardian/assent from child or adolescent Both requirements incorporated into regulations

8. Slide 8 Risk/Benefit Assessment and Definitions Step 1: Select 1 of the 4 risk/benefit categories

9. Slide 9 Federal Regulations:Children Category Requirements I : Minimal risk (46.404, 50.51) II: Greater than minimal risk; potential for direct benefit (46.405, 50.52) Parental Permission Child’s assent Risk justified by benefit Risk/benefit is as favorable as alternative Parental permission, child / assent

10. Slide 10 Federal Regulations:Children Category Requirements III. Greater than minimal: no potential for direct benefit;yield generalizable knowledge about subject disorder or condition (46.406, 50.53) Minor increase over minimal Intervention presents experiences commensurate with those inherent in actual or expected situations Procedure likely to yield knowledge of vital importance to understanding or alleviating a condition Both parents permission, child assent

11. Slide 11 Federal Regulations:Children Category Requirements IV: Not otherwise approvable but opportunity to understand, prevent, alleviate serious problem of children (46.407, 50.54) HHS/ FDA panel of experts to review Public Comment Parental permission/assent

12. Slide 12 Minimal Risk for Research Involving Children §46.404 Research not involving greater than minimal risk. DHHS 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.

13. Slide 13 How Do we Define Minimal Risk? Subpart A Minimal Risk definition is specifically referred to in Subpart D Standards 46.404-407, 50.51-54) : 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.

14. Slide 14 Daily Life: Lack of Definitional Consensus Do risks “ordinarily encountered in daily life” or the “routine physical or psychological examinations or tests” refer to an absolute standard (e.g., the healthy child) or to a relative standard (e.g., the type of risks to which a particular child or population involved in experimentation are typically exposed). “healthy children” National Commission 1977 Preamble to regs “relative” to subject “healthy persons” Subpart C 1979 “general population” NBAC 2001 “normal, average children” and “the socially allowable risks parents permit their normal, health, average children to be exposed to in their ordinary lives.” NHRPAC 2001

15. Slide 15 Minimal Risk Guidance NHRPAC, IOM, SACHRP* endorse the “absolute” interpretation of minimal risk. –Risks encountered by normal, average, healthy children living in safe environments –Interpretation refers to equivalence of magnitude and probability of risk as those encountered in daily life, routine physical and psychological tests Duration Cumulative characteristics Reversibility of harm *Under review by SACHRP

16. Slide 16 Why an absolute standard?  Children whose lives ordinarily involve greater risk (e.g., children already taking toxic drugs to treat cancer; children who live in violence- prone neighborhoods) should not be subjected to greater research risk than other children under the umbrella of the “minimal risk” definition.  Children living in unsafe environments may be exposed routinely to risks (i.e., exposure to unhealthy levels of lead), but such risks are neither socially desirable nor ethical when introduced through experimental procedures defined as minimal risk.

17. Slide 17 What is routine physical and psychological examinations or tests ? Physical: Well child care is one reasonable basis for comparison Psychological ( There is really no “routine”) –Intelligence testing –Mental and motor scales –Standard educational tests –Tests of social development –Family and peer relations –Emotional regulation –Feelings of sadness or hopelessness Under review by SACHRP

18. Slide 18 Minimal Risk? Some examples to consider Routine history taking Venipuncture / finger stick / heel stick Urine collection via bag Chest x-ray Bone density test Wrist x-ray for bone age Vision and hearing testing Neurological test Oral glucose challenge Class Room observation Psychological tests

19. Slide 19 46.405 Greater than Minimal Risk with Prospect of Direct Benefit DHHS 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: (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.

20. Slide 20 46.405 Criteria Ceiling on risk is determined by whether it is proportional to the probability and magnitude of benefit Anticipated benefits are at least as favorable to the subjects as those available in alternative approaches Any benefit of research or monitoring should be related to the objective of the study, not incidental Each research procedure needs to be evaluated independently for risks and benefits alone, avoid “package plan” Under review by SACHRP

21. Slide 21 Acceptable under 46.405? PI proposes to use Botox injection to correct pyloric stenosis, avoids surgical procedure Surgical procedure is a simple, safe and fast surgical procedure with very, very small morbidity risk and corrects the condition Both procedures will involve anesthesia Botox subjects will need to hospitalization for observation. Surgical correction discharged same day Is there a potential for direct benefit? Are the anticipated benefits at least as favorable to the subjects as those available in alternative approaches?

22. Slide 22 Acceptable under 46.405? Phase 1 cancer trial of children who have not responded to therapy. PI provides in formation that based on preclinical or adult data, there is an estimated 6-8% probability of direct benefit through tumor shrinkage associated with longer survival.

23. Slide 23 Acceptable Under 46.405? Phase 1 cancer trial of children who have not responded to therapy. Preclinical data and biological markers indicate the dose will be non-toxic. Level of dose is not anticipated to ameliorate the subject condition or influence disease management but will give early safety data.

24. Slide 24 Acceptable under 46.405? A research study uses conscious sedation and an MRI to study brain activity in children with ADHD. PI states the protocol has direct benefit because in some children they may find a nascent silent tumor. There is no evidence that children with ADHD are more prone to tumors.

25. Slide 25 46.406 Criteria DHHS 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: The risk represents a minor increase over minimal risk; 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; 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 Adequate provisions are made for soliciting assent of the children and permission of their parents or guardians.

26. Slide 26 Minor Increase The risk represents a minor increase over minimal risk Increase in risk is “only slightly” more than minimal. Consider using the following to assist in this determination –Harms are transient and reversible –No or extremely small probability that stress, discomfort, pain, or harm will be experienced as severe by the subject. –Investigator has presented sufficient evidence to support previous two conditions are met for the specific subject population and the qualifications of the research personnel Under review by SACHRP

27. Slide 27 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;

28. Slide 28 Commensurate Commensurate applies to the parents’ and/or child’s understanding of the experimental procedures during parental permission and assent, not to the level of risk National Commission –"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 intervention of procedure and effect, The use of procedures that are familiar or similar to those used in treatment of the subjects should not, however, be used as a major justification for their participation in research, but rather as one of several criteria regarding the acceptability of such participation” Under Review by SACHRP

29. Slide 29 Commensurate In judging whether procedures are commensurate, an IRB should determine that the interventions or procedures are reasonably similar to those procedures and interventions that children with the condition or disorder as a class have or are expected to experience Under review by SACHRP

30. Slide 30 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

31. Slide 31 Disorder or Condition The term condition should be interpreted as referring to a specific (or a set of specific) physical, psychological, neurodevelopmental, or social characteristic(s) that an established body of scientific or clinical evidence has shown to negatively affect children’s health and well-being or to increase their risk of developing a health problem in the future Under review by SACHRP

32. Slide 32 Vital Importance For interventions or procedures to be considered of “vital importance” there must clear and significant scientific evidence that their use is likely to yield generalizable knowledge that would contribute to understanding the etiology, prevention, diagnosis, pathophysiology, amelioration or treatment of the condition or disorder. Under review by SACHRP

33. Slide 33 46.407 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. The IRB finds the research –does not meets §46.404, §46.405, or §46.406§46.404§46.405§46.406 –the research presents a reasonable opportunity to further the understanding, prevention, or alleviation of a serious problem affecting the health or welfare of children The Secretary, convenes a panel of experts, public review and comment, final determination Adequate provisions are made for soliciting the assent of children and the permission of their parents or guardians

34. Slide 34 Pediatric Risk/Benefit: An Example Children who are obese are at greater risk than normal weight children of developing Type 2 diabetes, associated with resistance to the physiologic action of insulin. Research scientists propose to examine the time course and mechanism of insulin resistance in obese children who are otherwise healthy. The procedure they will use is an euglycemic insulin clamp consisting of running intravenously glucose in one arm and insulin in the other arm for 4 hours to see what amount of insulin is needed to control the glucose. The study also involves a comparison group of normal health children.

35. Slide 35 Parental Permission/Assent Step 2: Determine whether assent of child/adolescent is required Step 3: Determine whether permission from one, two or no parents/guardians is required

36. Slide 36 How Do We Get Consent In Pediatric Research? Parents cannot give true "consent" – legally only an autonomous person can do that for themselves. But parents can and should be respected in their role as responsible for the child’s welfare ( Parental permission required) Children cannot give true "consent" – they may not have the legal or cognitive ability to make this decision. But this does not mean they should have no say regarding participation (Child assent required)

37. Slide 37 Parental Permission Parent/ Guardian sign a written document or another method approved by IRB IRB must determine if one parent/guardian is sufficient IRB must determine whether waiver or parental permission is acceptable

38. Slide 38 One or Both Parents Assumption is two parents unless –Legally only one parent –One parent is not reasonably available –IRB makes a determination one is sufficient ( only in 404 and 405) IRB needs to develop guidelines to decide. Some criteria to think about –Level of risk –Implications of research on family –Concerns about consensus –Family dynamics

39. Slide 39 3 Methods to Waive Parental Permission Definition of “Child” Waiver of consent Children’s regulations recognize a waiver *FDA does not recognize waivers of consent except in emergency situations

40. Slide 40 Definition of Child Children are 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 the research will be conducted. Legal counsel must define for institution “what is a child” based on interpretation of state law

41. Slide 41 Children’s Regulations Research protocol designed for conditions/subject population for which parental/guardian permission is not a reasonable requirement Must substitute an appropriate mechanism for protecting the children Waiver is not inconsistent with federal, state or local law

42. Slide 42 Examples Research involving a behavioral intervention to reduce alcohol use among teenagers Questionnaire on sexual activity and use of birth control Testing a new screening questionnaire to determine adolescents at risk substance abuse.

43. Slide 43 Waiver/Alteration of Consent Research involves minimal risk Waiver or alteration does not adversely affect the rights and welfare of the subject Research could not be practicably carried out without waiver or alteration When appropriate, subjects provided with additional pertinent information after participation

44. Slide 44 Assent Affirmative agreement Method to document is not specified Mere failure to object should not be construed as assent No specific age:consider maturity and, psychological, emotional, developmental state Required except when –child not capable; age, maturity, psychological state, coma –research presents direct benefit, important to child’s well being, available only in context of research

45. Slide 45 Special Ethical Issues Step 4: Consider any special ethical issues as they pertain to children/adolescents (payment, confidentiality)

46. Slide 46 Special Issues Adolescent Research –Emancipated Minors / Mature Minors –Confidentiality Parents requesting access to research information Pregnancy testing Pediatrics and Prisoners –Children in juvenile detention system are “prisoners”, –Many different arrangements for detention for children, need to be familiar with them –Need to apply both subpart C and subpart D –Consider this upfront if protocol involves high risk youth

47. Slide 47 Payments –Balance avoiding “undue influence” against “reducing barriers” –Avoid paying parents for use of children Consider 4 components –Reimburse (parking, transportation, meals) –Compensate (time) –Tokens of Appreciation (gifts, savings bonds, gift certificates, baby needs (formula, thank you note) –Incentives ( above and beyond those mentioned, used to influence decision) Ask who gets what (parent or child)? How decide?

48. Slide 48 Document, Document, Document Step 5: Document findings in records (minutes, files)

49. Slide 49 Documentation Responsibilities Pediatric expertise involved in review Risk/benefit determination including rationale Permission of one or both parents If parental permission waived, include justification Is assent required? Why or why not? Document consideration of special ethical issues

50. Slide 50