Discussions about involving children in research usually center on protecting them from harm, and rightly so. Is there such a thing as too much caution? In a recent analysis of over 60,000 trials registered with ClinicalTrials.gov, researchers at Duke University found that only about 8% focused on children. The lack of pediatric safety and efficacy data for new therapies might place children at greater risk than they would have encountered in a carefully controlled research environment.
Both HHS and FDA recognize the importance of collecting pediatric data on biomedical, social, behavioral and educational interventions that are likely be used in children. The additional requirements that must be satisfied to include children in research are found at 45 CFR 46, Subpart D, and 21 CFR 50, Subpart D, respectively:
- Category 1 – 45 CFR 46.404 / 21 CFR 50.51
This category is limited to studies that involve no greater than minimal risk. In this context, “minimal” is often interpreted to mean the risk is no greater than would be encountered by normal, healthy children in daily life. It may also apply to studies whose risks do not exceed those of a child’s routine clinical care.
An IRB must determine the specific requirements for parental permission and child assent for each study, including those that pose minimal risk. Category 1 requires the permission of at least one parent or legal guardian, along with the assent of the child when appropriate. Verbal and non-verbal expressions of dissent should be respected.
- Category 2 – 45 CFR 46.405 / 21 CFR 50.52
Studies in this category involve greater than minimal risk to children, along with the potential for direct benefit. Category 2 studies are usually treatment protocols that seek to modify or enhance routine care.
The requirements for parental permission and child assent are the same as for Category 1, except that dissent is more nuanced. If a study will provide important benefits that are not otherwise available, it may not be appropriate to tell children they can say “no”. They can (and should) be included in other decisions as appropriate to their age and developmental status.
- Category 3 – 45 CFR 46.406 / 21 CFR 50.53
Category 3 studies present a minor increase over minimal risk with no prospect of direct benefit to the children who participate. They cannot be exposed to greater overall risk than they would face otherwise, and the study must be related to their disease or condition, or its treatment. Any benefits that do arise from these studies will accrue to future patients.
Permission is required from both parents or guardians, except in situations where one parent or guardian is not reasonably available, and assent must be sought as appropriate to each child’s age and level of development. Children should be allowed to dissent since they are unlikely to receive any personal benefit from the research.
- Category 4 – 45 CFR 46.407 / 21 CFR 50.54
Studies that pose greater than minimal risk with no prospect of direct benefit cannot be approved under Category 1, 2 or 3. They can be considered under Category 4 if they have the potential to yield important new information about children’s health or welfare. In addition to IRB review and approval, a Category 4 study must be reviewed by an expert panel; the public or the local community must have an opportunity to comment; and the HHS Secretary and/or the Commissioner of Food and Drugs must approve the research. The source of funding determines who is responsible for obtaining the expert and public reviews.
There is no clear dividing line between Categories 3 and 4 because there is no consensus on what constitutes “a minor increase over minimal risk”. The requirements for parental permission and child assent are essentially the same as those for Category 3.
- Additional considerations for children who are wards
One subgroup of children receives additional protections under 45 CFR 46.409 / 21 CFR 50.56. Children who are wards of the state “or any other agency, institution or entity” can be enrolled in Category 3 or Category 4 studies only if the research has direct relevance to their status as wards, or is conducted in settings where most of the children involved are not wards (i.e., children who are wards may be included in the population of interest but are not specifically targeted).
Additionally, an independent advocate is to be appointed for each child who is a ward, for the duration of their involvement in the research. “Independent” means the advocate is not otherwise associated with the research, the investigators or the organization of which the child is a ward. The advocate can be an IRB member, however. Depending on where the research is to be conducted, there may be other requirements to satisfy state and/or local laws.
In brief, Subpart D reminds us of the need to balance research objectives with the rights, safety and welfare of society’s youngest members. The additional safeguards are not intended to discourage the involvement of children in research. They exist to ensure that children can take part in research without being exploited, as they so commonly were in the past.
Special thanks to Jenni Beadles, M.Ed., CIP, Dena Johnson, M.Ed., CCRP, CIP, Wendy Lloyd, BA, LPN, CCRP, CIP, Julie Ozier, MHL, CIP and Jan Zolkower, MSHL, CIP, CCRP of Vanderbilt University for their review of this article.