Ethical Conduct of Clinical Research Involving Children (2004) / Chapter Skim
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4 Defining, Interpreting, and Applying Concepts of Risk and Benefit in Clinical Research Involving Children
4 Defining, Interpreting, and Applying Concepts of Risk and Benefit in Clinical Research Involving Children
Pages 113-145
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From page 113... ...
The committee was specifically asked to consider the regulatory definition of "minimal risk." Because this concept is closely related to several other concepts in the federal regulations on research involving children, the committee also examined certain of these concepts, including "minor increase over minimal risk," "disorder or condition," "commensurate experience," and "vital importance." In addition, the chapter discusses the regulatory requirements that risks to research participants be minimized and that the risks be reasonable in relation to the anticipated benefits. In this 113
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From page 114... ...
Still, a clear tension can exist between the goal of advancing clinical research that may benefit future children and the goal of limiting the risks to individual children who participate in clinical studies. That tension underscores the importance -- as discussed further in chapter 5 -- of a sound process for explaining to parents and, as appropriate, children the purposes of a study, its potential harms and benefits, and the rights of prospective research participants to refuse participation.
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From page 115... ...
For certain studies involving children, however, federal regulations require consideration of possible benefits to other children. Specifically, as discussed below, when proposed research involves a minor increase over minimal risk and does not offer the prospect of direct benefit, the research must be limited to children with a disorder or condition and must be expected (among other criteria)
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From page 116... ...
Investigators and reviewers of research should normally consider such risks as part of their broader moral responsibility to minimize or prevent harm. In addition, certain research involving children may pose risks to members of ethnic, cultural, religious, or other communities.
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From page 117... ...
For research that involves a control group of healthy children without a disorder or condition and without prospect of direct benefit from the research, the research procedures for that group would have to involve no more than minimal risk. Defining Minimal Risk Subpart A of the DHHS regulations defines minimal risk as meaning "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" (45 CFR 46.102(i)
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From page 118... ...
; 21 CFR 56.111(b) Does research meet the regulatory criteria for research involving children?
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From page 119... ...
/ 50.54(a) Minor increase over minimal risk 46.406(a)
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From page 120... ...
For research involving lumbar puncture without conscious sedation, 32 percent of respondents classified the research as involving a minor increase over minimal risk when it involved ill children and 6 percent classified it as minimal risk; for healthy children, the corresponding figures were 16 and 2 percent. The respondents might have shown greater agreement if they had been reviewing real protocols, and it is not clear whether respondents were giving their own views or the views that they thought others held.
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From page 121... ...
Likewise, those reviewing a research protocol should explain the bases for their determinations about its approval or disapproval. Indexing Assessments of Minimal Risk to the Experience of Healthy Children in Daily Life The regulatory definition of minimal risk, which was first adopted in 1981, departs in some respects from the definitions offered by the National Commission in its 1977 report, Research Involving Children (see Chapter 1)
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From page 122... ...
(2004) , respondents asked to categorize risk level for research involving a lumbar puncture and conscious rated such research differed were more likely to categorize the research as presenting minimal risk when the example involved healthy children than when it involved ill children.
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From page 123... ...
Certain studies may include several different procedures that involve minimal risk or burden individually but that taken together present more than minimal risk. Similarly, although a single blood draw by needle stick normally involves minimal harm or discomfort, multiple needle sticks for blood draws in a short period could, depending on the child's age and other circumstances, present more than minimal risk of harm or discomfort.
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From page 124... ...
. during the performance of routine physical or psychological examinations or tests." Just as the committee concluded that the assessment of "risks of daily life" standard should be indexed to the experiences of normal, healthy, average children, it likewise concluded that the "routine examination" standard be interpreted with reference to the experiences of normal, healthy, average children.
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From page 125... ...
. In its discussion of procedures involving minimal risk, the National Commission mentioned -- in addition to physical examinations and psychological tests -- "immunization, modest changes in diet or schedule, .
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From page 126... ...
Recommendation 4.1: In evaluating the potential harms or discomfort posed by a research protocol that includes children, investigators, and reviewers of research protocols should · interpret minimal risk in relation to the normal experiences of average, healthy, normal children; · focus on the equivalence of potential harms or discomfort antici pated in research with the harms or discomfort that average, healthy, normal children may encounter in their daily lives or experience in routine physical or psychological examinations or tests; · consider the risk of harms or discomfort in relation to the ages of the children to be studied; and · assess the duration as well as the probability and magnitude of potential harms or discomfort in determining the level of risk. Defining Minor Increase over Minimal Risk and Associated Terms Minor Increase over Minimal Risk In its 1977 report on research involving children, the National Commission recommended that children with a disorder or condition be allowed to participate in research that does not hold the prospect of directly benefiting them if the research involves no more than a minor increase over
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From page 127... ...
That is, consistent with the interpretation of minimal risk, what constitutes "a bit more" risk in research involving children is not relative and does not allow a higher threshold for children with high-risk or high-burden conditions than for children with less serious conditions. Recommendation 4.2: In evaluating the potential harms or discomfort posed by a research protocol that includes children who have a disorder or condition but no prospect of benefiting from participation, investi gators and reviewers of research protocols should
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From page 128... ...
Disorder or Condition Just as federal regulations at 45 CFR 46.406 and 21 CFR 50.53 offer no definition of a minor increase over minimal risk, they likewise offer no definitions of "disorder" or "condition." Again, this section of the regulations, among other provisions, allows children to be enrolled in studies that involve a minor increase over minimal risk but no prospect of direct benefit. Thus, the approval of much research that may ultimately benefit various groups of children hinges on the definition and interpretation of these terms.
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From page 129... ...
. The National Commission did not, however, explicitly define "condition."4 Views on the meaning of "condition or disorder" cover a wide spectrum.
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From page 130... ...
Recommendation 4.4: For purposes of determining whether proposed research involving a minor increase over minimal risk and no direct benefit can be approved, institutional review boards should make a determination that · the children to be included in the research have a disorder or condition; · the research is likely to generate vital knowledge about the children's disorder or condition; · the research procedures or interventions present experiences that are commensurate with, that is, reasonably comparable to, experiences already familiar to the children being studied on the basis of their past tests or treatments or on their knowledge and understanding of the treatments that they might undergo in the future; and
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From page 131... ...
As a synonym for commensurate, the National Commission referred to research activity that was "reasonably similar" to procedures that prospective research participants ordinarily experience. Dictionary definitions of commensurate or commensurable also emphasize the concepts of sameness, as well as proportionality or correspondence (American Heritage, 1992; Merriam-Webster, 2003)
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From page 132... ...
When a research procedure or intervention has the prospect of directly benefiting child research participants, it can be approved even if it presents more than a minor increase over minimal risk. In addition, the relationship between the anticipated direct benefit and the risk or potential harm should be at least as favorable for the proposed research procedure as for the alternatives available to the children.
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From page 133... ...
Such a trial does not hold out the prospect of direct benefit. In contrast, clinical trials involving children usually follow studies with adults (and possibly special laboratory and animal studies)
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From page 134... ...
Such a practice should help reviewers of research identify more clearly the evidence or other bases for their judgments. In addition, the committee concluded that useful guidance can be provided to pediatric investigators and reviewers of pediatric research if continued efforts are made to develop consensus identifications of procedures that present minimal risk or no more than a minor increase over minimal risk to children participating in research (NBAC, 1998; Kopelman, 2000)
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From page 135... ...
The Office for Human Research Protections (OHRP) can also assist TABLE 4.1 Common Research Procedures by Category of Risk Category of Risk More Than a Minor Increase Minor Increase Procedure Minimal over Minimal over Minimal Routine history taking X Venipuncture/fingerstick/heelstick X Urine collection via bag X Urine collection via catheter X Urine collection via suprapubic tap X Chest X-ray X Bone density test X Wrist X-ray for bone age X Lumbar puncture X Collection of saliva X Collection of small sample of hair X Vision testing X Hearing testing X Complete neurological exam X Oral glucose tolerance test X Skin punch biopsy with topical pain relief X Bone marrow aspirate with topical pain relief X Organ biopsy X Standard psychological tests X Classroom observation X NOTE: The category of risk is for a single procedure.
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From page 136... ...
should continue the work of its predecessor committee by developing additional consensus descriptions of procedures or inter ventions that present minimal risk or no more than a minor increase over minimal risk. In addition, the Office for Human Research Protec tions and the Food and Drug Administration should cooperate to de velop and disseminate guidance and examples for investigators and institutional review boards to clarify important regulatory concepts and definitions (including definitions of minimal risk, minor increase over minimal risk, condition, and prospect of direct benefit)
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From page 137... ...
One answer is that a research protocol should be assessed and approved as a whole -- even if some components do not individually meet the criteria for approval -- as long as the level of risk overall is reasonable in relation to the anticipated benefit.6 An alternative view -- which the committee adopted -- is that not only must the research be considered as a whole, but each intervention or procedure must also be assessed independently against the regulatory criteria for approval. Thus, for pediatric studies, the presence of an intervention or procedure that offers the prospect of direct benefit cannot be used to justify the exposure of a child to other procedures that present more than a minor increase over minimal risk but no prospect of direct benefit.
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From page 138... ...
Assessing Whether Risks Are Reasonable in Relation to Anticipated Benefits: Clinical Trials and Clinical Equipoise Current regulations provide that a child should not be exposed to more than a minor increase over minimal risk unless the research intervention or procedure offers a prospect of direct benefit. In its report on children, the National Commission argued further that a child should not be disadvantaged by being enrolled in a research study (National Commission, 1977)
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From page 139... ...
When these other alternatives are taken into account, a child's health or welfare should not be placed in jeopardy by the decision to enter the child into a research protocol. The argument of the National Commission bears some resemblance to the concept of "clinical equipoise" (or "research equipoise")
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From page 140... ...
Similarly, the recent revision of the Guidelines of the Council of International Medical Organizations stated that placebo controls can be ethical (1) when there is no established effective intervention, (2)
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From page 141... ...
the potential harms to which children in the placebo control arm would be exposed are no more than minimal or involve only a minor increase over minimal risk. Although ethical and regulatory principles allow adults to give their informed consent to participate in research involving more risk, they do not allow parents or children to agree to accept such research risk for a child.
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From page 142... ...
At a minimum, such research wastes the time of research participants. Depending on its particular faults, poorly designed research can also expose research participants to avoidable harm and can dissipate potential benefits.
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From page 143... ...
Even within pediatric centers, research involving high-risk procedures, for example, gross surgical resections and stem cell transplants may involve higher risks if they are performed by staff and institutions that are less experienced with those highly specialized procedures or the management of their side effects in children with specific cancers. Thus, reviewers of research protocols may consider the relevance of specialization in facilities and personnel when making their determinations about risk.
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From page 144... ...
Can the investigators collect the required information using procedures that the child participants will undergo as part of normal therapy or monitoring? · Have prior laboratory studies, animal research, studies with adults, or other data provided a sufficient basis for proceeding with research involving children?
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From page 145... ...
included in the four sections of the DHHS and FDA regulations that set criteria for permissible research involving children. Applications for IRB approval and IRB records should include rationales related to each of the key concepts.
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