Research · 6 min read
What Has to Be True Before a Child Can Join a Trial
Adult research asks for consent. Research in children asks for two separate things — a parent's permission and the child's own assent — and sorts every study into one of four risk categories before either is sought.
Key takeaways
- Subpart D of 21 CFR part 50 sorts research in children into categories by risk and by whether the individual child stands to benefit, and a review board must place each study before it can approve it.
- For a more-than-minimal-risk study offering direct benefit, the risk-benefit relation must be at least as favorable as that of available alternatives.
- A more-than-minimal-risk study with no direct benefit is limited to a minor increase over minimal risk, commensurate experiences, and knowledge of vital importance about the subjects' own condition.
- A study fitting none of the categories can proceed only with the Commissioner's determination after expert consultation and an opportunity for public review and comment.
- Parental permission may be one parent's in the lower categories, and must be both parents' in the higher ones subject to stated exceptions; children who are wards require an independent advocate.
- FDA's draft weight-reduction guidance recommends change in body mass index rather than body weight as the pediatric primary parameter, plus body composition measurement and assessments of depression, suicidality and neuropsychiatric function for centrally acting drugs.
Answer first: a study has to fit one of four categories, and a board decides which
Subpart D of 21 CFR part 50 governs research in children, and it opens by handing the decision to a review board. Under 21 CFR 50.50, each board must review clinical investigations involving children as subjects and approve only those that satisfy the criteria described in one of three sections, plus the conditions of the rest of the subpart.
Those three sections describe categories of increasing risk, and a fourth route exists for studies that fit none of them.
The first category, at 50.51, covers investigations presenting no greater than minimal risk. A board may permit children only if it finds that no greater than minimal risk is presented, and that adequate provisions are made for soliciting the assent of the children and the permission of their parents or guardians.
Minimal risk has a definition, at 21 CFR 56.102(i): 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. The comparison is to ordinary life, not to the child's illness.
The two categories above minimal risk, and what separates them
Section 50.52 covers research presenting more than minimal risk where the intervention or procedure holds out the prospect of direct benefit for the individual subject, or where a monitoring procedure is likely to contribute to the subject's well-being. A board may permit children only if it finds that the risk is justified by the anticipated benefit to the subjects; that the relation of anticipated benefit to risk is at least as favorable to the subjects as that presented by available alternative approaches; and that adequate provisions are made for assent and parental permission.
That middle finding is the one to notice. It is not enough that a study's benefits outweigh its risks. The balance has to be at least as good as what is otherwise available to that child.
Section 50.53 covers the harder case: more than minimal risk, with no prospect of direct benefit to the individual subject, but likely to yield generalizable knowledge about the subjects' disorder or condition. Here the board must find four things. That the risk represents a minor increase over minimal risk. That the intervention or procedure presents experiences reasonably commensurate with those inherent in the subjects' actual or expected medical, dental, psychological, social or educational situations. That the intervention is likely to yield generalizable knowledge about the subjects' disorder or condition that is of vital importance for understanding or ameliorating it. And that adequate provisions are made for assent and parental permission.
Three constraints stacked on one another: only a minor increase over minimal risk, only experiences a child in that situation would already recognize, and only for knowledge of vital importance about that same condition.
The fourth route requires the Commissioner and a public comment period
Section 50.54 handles a study that a board does not believe meets any of the three categories. Such an investigation may proceed only if two things happen.
First, the board finds that the investigation presents a reasonable opportunity to further the understanding, prevention, or alleviation of a serious problem affecting the health or welfare of children.
Second, the Commissioner of Food and Drugs — after consultation with a panel of experts in pertinent disciplines, which the regulation illustrates as science, medicine, education, ethics and law, and following opportunity for public review and comment — determines either that the investigation in fact satisfies one of the three categories, or that the investigation presents that reasonable opportunity, will be conducted in accordance with sound ethical principles, and has adequate provisions for assent and parental permission.
An opportunity for public review and comment is an unusual thing to require before a single study may begin. It is the regulation's way of saying that this route is exceptional and should be visible when it is used.
Permission and assent are two different signatures
Section 50.55 separates them carefully. The board must determine that adequate provisions are made for soliciting the assent of the children when, in the board's judgment, the children are capable of providing it — and in judging capability the board must take into account the ages, maturity and psychological state of the children involved. That judgment may be made for all children under a protocol, or child by child, as the board deems appropriate.
Assent is not always required. It is not a necessary condition for proceeding if the board determines that the capability of some or all of the children is so limited that they cannot reasonably be consulted, or that the intervention 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 investigation.
The board may also waive assent even where children are capable of giving it, if it finds and documents that the investigation involves no more than minimal risk, that the waiver will not adversely affect the subjects' rights and welfare, that the investigation could not practicably be carried out without the waiver, and that whenever appropriate the subjects will be provided with additional pertinent information after participation.
Parental permission has its own structure, and this is the detail that most often surprises people. For investigations under 50.51 or 50.52 — the minimal-risk and direct-benefit categories — the board may find that the permission of one parent is sufficient. For investigations under 50.53 or 50.54, both parents must give permission, unless one parent is deceased, unknown, incompetent, or not reasonably available, or unless only one parent has legal responsibility for the care and custody of the child.
There is a further protection for children who are wards. Under 50.56, wards may be included in investigations approved under 50.53 or 50.54 only if the research is related to their status as wards, or is conducted in settings such as schools, camps, hospitals or institutions in which the majority of children involved as subjects are not wards. Where such an investigation is approved, the board must require appointment of an advocate for each child who is a ward — an advocate who serves in addition to any guardian, who has the background and experience to act in the child's best interest for the duration of participation, and who must not be associated in any way with the investigation, the investigators, or the guardian organization.
Why the same drug produces a different number in a pediatric trial
The review-board rules connect back into part 56. Under 21 CFR 56.109(h), where some or all subjects are children, a board must determine at initial review that the study complies with subpart D, and 56.111(c) repeats that as a condition of approval.
The measurement changes too. FDA's draft guidance on developing weight-reduction drugs states that because linear growth should be considered when assessing changes in the body weight of children and adolescents, the primary efficacy parameter in weight-reduction trials of pediatric subjects should be a function of the change in body mass index — its example is the mean percentage change in that index. It adds that height measurements should be obtained at all study visits using a wall-mounted stadiometer following procedures specified in the protocol.
That single recommendation is why a percentage from a pediatric trial and a percentage from an adult trial are not interchangeable. They are percentages of different quantities.
The guidance sets out further pediatric expectations. It recommends that trials include a representative sample of subjects who meet the criteria for severe obesity, at 30 percent or greater. It says the lifestyle-modification program should continue following randomization with its importance emphasized at appropriate intervals. It recommends baseline and follow-up measurement of body composition by dual-energy x-ray absorptiometry or a suitable alternative. And beyond standard safety evaluations specific to growing children — it names assessing Tanner stage and bone age at baseline and endpoint — it says trials of centrally acting weight-reduction drugs in pediatric subjects should also include fit-for-purpose assessments of depression, suicidality, and neuropsychiatric function.
None of that describes what any child should do. It describes why a pediatric result takes longer to produce, costs more to produce, and cannot be inferred from an adult one.
Sources
- 21 CFR 50.50 through 50.54 — IRB duties and the risk categories for clinical investigations involving childrenThe board's duty to approve only investigations satisfying 50.51, 50.52 or 50.53; the minimal-risk category and its findings; the greater-than-minimal-risk category with prospect of direct benefit and its requirement that the benefit-risk relation be at least as favorable as available alternatives; the greater-than-minimal-risk category without direct benefit and its four required findings including minor increase over minimal risk, commensurate experiences and vital importance; and the 50.54 route requiring the Commissioner's determination after consultation with a panel of experts and an opportunity for public review and comment.
- 21 CFR 50.55 — Requirements for permission by parents or guardians and for assent by children, and 21 CFR 50.56 — WardsThe assent determination and the factors of age, maturity and psychological state; the two circumstances in which assent is not a necessary condition; the four findings supporting a waiver of assent; the one-parent and two-parent permission rules by category with their exceptions; and the ward provisions including the required independent advocate and the bar on that advocate being associated with the investigation, investigators or guardian organization.
- 21 CFR 56.102 — Definitions, 21 CFR 56.109 — IRB review of research, and 21 CFR 56.111 — Criteria for IRB approval of researchThe definition of minimal risk; the requirement that a board determine compliance with part 50 subpart D at initial review where some or all subjects are children; and the corresponding approval criterion.
- Obesity and Overweight: Developing Drugs and Biological Products for Weight Reduction — Guidance for Industry (Draft Guidance)The recommendation that, because linear growth must be considered, the primary efficacy parameter in pediatric weight-reduction trials be a function of the change in body mass index such as mean percentage change, with height measured at all study visits using a wall-mounted stadiometer; the recommended representative sample of subjects meeting criteria for severe obesity at 30 percent or greater; the continuation of the lifestyle-modification program after randomization; baseline and follow-up body composition measurement by dual-energy x-ray absorptiometry or a suitable alternative; and the recommended assessments of Tanner stage and bone age plus fit-for-purpose assessments of depression, suicidality and neuropsychiatric function for centrally acting weight-reduction drugs.
Frequently asked questions
Who decides whether children may be enrolled in a study?
A review board. Under 21 CFR 50.50 it must approve only investigations satisfying the criteria in 50.51, 50.52 or 50.53 plus the other conditions of subpart D, and under 21 CFR 56.109(h) it must determine compliance with subpart D at initial review.
What does minimal risk mean?
Under 21 CFR 56.102(i), 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 routine physical or psychological examinations or tests.
Can a study with no benefit to the child be approved?
Only under 21 CFR 50.53, and only if the board finds the risk is a minor increase over minimal risk, the experiences are reasonably commensurate with those inherent in the subjects' actual or expected situations, and the study is likely to yield generalizable knowledge about their own disorder or condition that is of vital importance for understanding or ameliorating it.
Do both parents have to agree?
It depends on the category. Under 21 CFR 50.55(e), for investigations under 50.51 or 50.52 the board may find one parent's permission sufficient. For investigations under 50.53 or 50.54, both parents must give permission unless one is deceased, unknown, incompetent, not reasonably available, or unless only one has legal responsibility for the child's care and custody.
Does the child have to agree as well?
Assent must be solicited where the board judges the children capable of providing it, taking into account ages, maturity and psychological state. It is not required where capability is so limited the children cannot reasonably be consulted, or where the intervention offers an important prospect of direct benefit available only in the study, and it may be waived on documented findings including that the research involves no more than minimal risk.
Why is a pediatric weight-trial percentage not comparable to an adult one?
Because the measurement differs. FDA's draft weight-reduction guidance says that because linear growth must be considered, the primary efficacy parameter in pediatric weight-reduction trials should be a function of the change in body mass index, such as the mean percentage change in that index, with height measured at all study visits using a wall-mounted stadiometer.