Conducting Multi-Site Collaborative Studies

1	SACHRP RESEARCH INVOLVING CHILDREN SUBCOMMITTEE 4^th Report for SACHRP Consideration Clarifying 45 CFR Subpart D Definitions
2	Subpart D Subcommittee Meeting Attendees June 15, 2004 Members Celia B. Fisher, Ph.D. Co-Chair Susan Kornetsky, M.P.H. Co-Chair Alan Fleischman, M.D. Eric Kodish, M.D. Samuel D. Maldonado, M.D. M.P.H. Robert Nelson, M.D., Ph.D. Ronald J. Steingard, M.D. OHRP Representatives Bernard A. Schwetz, D.V.M., Ph.D. SACHRP Executive Secretary and Acting Director, OHRP Catherine Slatinshek, M.A. SACHRP Executive Director Kelley Boocher, SACHRP Ex Officio Members Gilman Graves, M.D., (NICHD) Sara Goldkind, M.D., Ph.D., (FDA) Additional OHRP/HHS Representatives Irene Stith-Coleman, Ph.D. Laura Odwazny, J.D., (OGC) Julie Kaneshiro, Ph.D. Ivor Pritchard Judith Brooks Kelley Booher SACHRP Members: Felix Khin-Maung-Gyi, Pharm.D., M.B.A., CIP
3	Meeting Goals Clarification and consensus on Subpart D regulations for “non-beneficial” research involving children: §45 CFR 46.404 “Minimal Risk” §45 CFR 46.406 “Minor increase over minimal risk” These terms are interrelated and determine the overall adequacy of Subpart D
4	Defining Minimal Risk for Research Involving Children
5	Uniform v. Relative Risk?
6	History: Uniform Definition
7	1981 Shift to “Relative” Definition
8	Subpart A Definition
9	Justice Arguments for Minimal Risk Standard
10	False Assumption of Relative Argument
11	Rationale for Uniform Standard
12	Rationale for Uniform Standard
13	"Adopt a UNIFORM standard for..." Adopt a UNIFORM standard for the definition of “minimal risk” for research involving children under Subpart D: DHHS Additional Protections for Children Involved as Subjects in Research. SACHRP conditionally approved this recommendation at its July meeting
14	Proposal 2: Reference Point for Uniform Definition
15	Justification for Language
16	Proposal 3: Minimal Risk Should be Age indexed
17	Limitations of Daily Life and Routine Examination Indexing: Over or Under-Estimation of Risk
18	IRB approval decisions limited to “minimal risk” research
19	Case 1: Smoke Puff Potential Underestimation of Risk Exposure to small puffs of smoke may be minimal risk for healthy children, but greater than minimal risk for severely asthmatic children
20	Proposal 4: Upper Limits of Risk & Harm
21	Case 2: Dextroamphetamine Possible Over-Estimation of Risk Goal: to understand and compare ADHD children’s brain reactions to those of normal children. Procedure: Very small dose of dextroamphetamine for children with and without ADHD for purpose of imaging the effect on the brain. The probability and magnitude of harm are both very small, but……
22	But……. Administration of dexatroamphetamine is not part of “normal” children’s daily life nor well child doctor visit (equivalent might be a lot of caffeinated sodas or cough medicine) Although magnitude and probability of harm is very low, an IRB might use 406 (minor increase over minimal risk) as justification for ADHD group which has a condition If not assessed as minimal risk, administration of the dexatroamphetamine to the “normal” children must go to a 407 review.
23	Proposal 5: Equivalent Procedures Procedures that are equivalent in probability and magnitude of harm to risks of daily life or routine physical or psychological examinations or tests experienced by average, healthy, normal children living in safe environments should be considered as consistent with the definition of “minimal risk.” (NHRPAC, 2002; IOM, 2004)
24	Reminder: To Which Procedures do Regulations Apply? In evaluating the magnitude of harm and probability of risks IRBS should consider only those risks that may result from the research. See §46.111.2
25	Proposal 6: Equivalence Criteria Is the probability and magnitude of harm equivalent in: duration cumulative characteristics reversibility of harm. to risks of daily life or routine examinations
26	Duration & Cumulative Duration: Length of time child will be involved in experimental procedure Cumulative: Number of procedures included in a protocol or the number of times that an individual procedure is repeated in a given period of time. (IOM, 2004, p. 4-8)
27	Reversibility Spontaneous Reversals of Effects The discomfort of a needle prick will have a short duration and any puncture marks will spontaneously heal in a brief time). Investigator Actions Providing juice or place to lie down to child who feels faint after a blood draw can quickly reverse such untoward effects; Procedures to allay a child’s anxiety before and if necessary after an MRI can reduce the probability and magnitude of harm (anxiety about the procedure)
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29	Well-Child Procedures • Physical examinations • Measurement of height, weight, head circumference • Assessment of obesity with skin-fold calipers • Collection of blood or voided urine • Measurement of heart rate and blood pressure • Hearing and vision tests • Modest changes in diet or schedule • Testing of fine and gross motor development • Non-invasive physiological monitoring • Medical and social history • Psychological examinations or tests • Guidance and education (for the child, the parents, or both)
30	Proposal 8: Well-Child Visit: Referent for Routine Psychological Examinations or Tests Routine Child or Family History Questions Typical of Well-Child Visit To identify potential health risks (e.g., relevant family medical history, poor diet, lack of seat belt or car seat use) [or for adolescents] exploration of sexual, smoking, illicit drug use, and other health compromising behaviors; relevant family health behavior history (IOM, 2004, 4-10)
31	Proposal 9: Index Routine Psychological Tests to Standardized Screening or Assessment Measures
32	Possible Exceptions to Routine Psychological Tests as Minimal Risk For some populations questions about physical or sexual abuse or other childhood traumas, suicidal ideation, or criminal activities may result in greater than minimal risk.
33	Reminder: Proposal 4 The uniform, age-indexed definition of minimal risk should represent the upper not lower limits of risk to which children can be exposed under §46.404. Rationale: Research procedures should not fall under §46.404 for children who because of health or other reasons would be at greater risk of harm from procedures which are minimal risk for normal, average, healthy children living in safe environments.
34	Proposal 10: Criteria for Possible Exceptions to Routine Psychological Tests DURATION: 1 – 3 hours (age indexed) or short intervals across 1 or 2 days; PERSISTENT POST-EXPERIMENTAL REACTIONS: Suggested by an established body of evidence PLANS: Identification, follow-up and remediation of negative reactions to planned procedures if they occur
35	Not all Socially Approvable Daily Risks are Minimal Risk “…that an action [in children’s daily lives] has majority social approval and is legal does not necessarily make it an appropriate basis of comparison for the assessment of risks to child participants in research. IOM, 2004 Public opinion, state laws or school board policies may permit spanking as part of school life (IOM, 2004) Risks of broken bones are socially acceptable within the context of organized sports contributing to physical and social development
36	Proposal 11: Possible Exceptions to Daily Life Equivalence Some risks in the daily lives of normal, healthy, average children may not be minimal in probability and magnitude of harm Such risks may be socially acceptable because the activities associated with the risks are perceived by society as promoting those children’s growth and development. These same risks would are not acceptable as minimal risk if introduced solely for the purpose of non-beneficial research.
37	International Research
38	Proposal 12: The Uniform Standard Must Apply Internationally Under § 46.404 in the U.S. and abroad research approved under HHS federal regulations can study risks of daily life that are greater than minimal risk as long as they do not add to the risk or introduce greater than the U.S. based minimal risk standard of harm.
39	"Uniform standard" Uniform standard Normal, average, healthy child living in safe environments Age indexed Upper limits Equivalence Equivalence factors Contextual restraints Well-child equivalence for routine medical procedures Well-child equivalence for routine psychological procedures Standardized psychological test equivalence Exceptions to psychological test indices International application
40	§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:
41	§46.406 Criteria 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, as set forth in § 46.408.
42	§46.406 Justification and Caution Minor increment over minimal risk is the regulatory threshold for independent IRB approval of research involving children that includes no prospect of direct benefit. Foreseeable benefit to an identifiable class of children may justify a minor increment of risk to research subjects” (National Commission, 1977, p125). Simply because children have a disorder or condition does not mean it is fair to expose them to procedures with higher degrees of risk and no prospect of direct benefit (IOM, 2004; National Commission, 1977; NHRPAC, 2002).
43	Interpreting “Minor Increment”: Risks
44	“Minor Increment”: Uniform or Relative Standard?
45	Proposal 12: Uniform Standard IRBs should use a uniform criteria to determine whether the risks of an experimental procedure presents a minor increment over minimal risk. Minor increase should be indexed to the uniform minimal risk criteria recommended for 46.404 Risks of daily life or routine medical or psychological examinations or tests of the normal, average, healthy child living in safe environments
46	Proposal 13: Minor Increase Equivalence Criteria
47	What is a “Minor Increment?”
48	Proposal 14: Indexing “Minor” Increase to Common Medical or Psychological Diagnostic Procedures A minor increase over 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 “minor procedures” routinely performed in the diagnosis of common medical or psychological conditions. In general, such risks will be only slightly greater than those encountered in routine well-child visits or standardized psychological tests.
49	Examples of “Minor” Procedures Minor procedures may be associated with: Pain or discomfort of low intensity & short duration Physical restraints for younger children Medication use such as local anesthetics or conscious sedation Radiation exposure (X-rays, CT scans) Diagnostic questions exploring trauma or depressive symptoms in greater depth than standard well-child visit or psychological test IV fluids CT scan with sedation Lumbar puncture Repeated blood draws Medication use with a good anticipated safety profile (e.g., antibiotics) Prolonged or intensive psychosocial evaluations
50	Minor Increment is NOT Procedures associated with an appreciable risk of death, disability, or serious adverse effects. Procedures that require in-patient monitoring or follow-up evaluation (for the procedure itself) General anesthesia, repeated CT scans, organ biopsy
51	“Condition” §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;
52	What is a “Condition?”
53	Proposal 15: “Condition”
54	Vital Importance” §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;
55	Proposal 16: Vital Importance
56	Vital Importance Rationale Exposing children with a disorder or a condition to a greater level of risk than normal, healthy, average children living in safe environments in research with no prospect of direct benefit, should have a higher criteria for scientific and social benefit than minimal risk research.
57	“Commensurate” §46.406 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
58	Proposal 17: “Commensurate”
59	Equivalence of Commensurate Risk
60	"Should “their actual or..." Should “their actual or expected…situations” (§46.406) refer to Experiences of the child subject him or herself? Or situations that could be vicariously experienced? Example Based upon the “commensurate” standard the use for solely research purposes of a hyperglycaemic clamp might be considered an acceptable minor increment over minimal risk for children with diabetes who had previous experience with the clamp in the course of their treatment. Is it acceptable for a sibling of a diabetic child who had observed his sibling experience the clamp, but was neither diabetic nor had experienced the use of the clamp him or herself?
61	Proposal 18: Sequential Steps in §46.406 Decision-Making Algorithm Is the research risk a minor increment over minimal risk? If not refer to §46.404 or §46.407 2. Does the proposed child research population have a disorder or condition? if not refer to §46.407 Is the research likely to yield generalizable knowledge of vital importance to the understanding or amelioration of the subjects’ disorder or condition? If not refer to §46.407 Are the research procedures reasonably commensurate with those inherent in the subjects’ actual or expected medical, dental, psychological, social, or educational situations. If not refer to §46.407 IF YES CLASSIFY AS §46.406
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63	"Uniform standard" Uniform standard Equivalence Criteria Indexing “Minor” Increase to Common Medical or Psychological Diagnostic Procedures Condition Vital Importance Commensurate Decision-Making Algorithm
64	Future Steps Re-evaluate each recommendation not approved by SACHRP based upon: Feedback and guidance from SACHRP meeting Consider Classification of: Phase I studies Housing hazards studies Classification of different arms of and different procedures within clinical trials involving children §46.405 (Research with Possibility of Direct Benefit)