Most of the research protocols active at CHOP involve children as research subjects. Understanding the regulations governing participation of children in research is vital.
Children are neither legally nor developmentally capable of consenting to their own treatment or participation in research. No one can consent for an individual other than that person. As a result, a proxy, such as a parent, must provide permission in lieu of consent and children who are deemed capable, must provide their assent.
Who is a child (and who is not)?
45 CFR 46.402
(a) 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 where the research will be conducted.
(b) Assent means a child's affirmative agreement to participate in research. Mere failure to object should not, absent affirmative agreement, be construed as assent.
(c) Permission means the agreement of parent(s) or guardian to the participation of their child or ward in research.
(d) Parent means a child's biological or adoptive parent.
(e) Guardian means an individual who is authorized under applicable State or local law to consent on behalf of a child to general medical care. (A guardian is the equivalent of a legally authorized individual acting on behalf of an incapacitated adult.)
Note:The FDA definition uses the term clinical investigation instead of research but is otherwise the same.
In order to decide whether or not the additional protections of Subpart D apply, the IRB must first determine if any of the subjects will be children.
The definition of who is a child varies by state because the laws regulating when children may consent for treatment varies. In Pennsylvania, New Jersey and Delaware the age of majority is 18 years but there are many situations where minors may consent to their own treatment prior to turning 18. Whenever a minor can consent to treatment, the minor is not considered a child under the regulations and may consent for themselves provided that they have the capacity to protect their own interests and the research is related to the care for which they have consented. The Guttmacher Institute provides An Overview of Minors’ Consent Law on their website. The Overview summarizes a minor's right to consent for sexual or reproductive health services, state by state.
The CHOP Policy on Consent, located in the Patient Care Manual outlines the circumstances under which a minor may consent for their own treatment. IRB SOP 505 includes additional information including specifics for the states (PA, NJ and DE) served by CHOP and its satellites.
Children as Vulnerable Subjects
21CFR50 Subpart D
- 21 CFR 50.51 equivalent to 45 CFR 46.404
- 21 CFR 50.52 equivalent to 45 CFR 46.405
- 21 CFR 50.53 equivalent to 45 CFR 46.406
- 21 CFR 50.54 equivalent to 45 CFR 46.407
- 21 CFR 50.55 similar to 45 CFR 46.408 (Consent Requirements)
- 21 CFR 50.56 similar to 45 CFR 46.409 (Wards)
Because children cannot protect their own interests, they are considered vulnerable in the research context. The Common Rule includes Subpart D: additional protections for children as research subjects. Subpart D - Additional Protections for Children Involved as Subjects in Research establishes risk - benefit categories for research involving children. Only research that fits into one of the 3 categories may be approved by an IRB; a 4th category requires the approval of the Secretary of the Department of Health and Human Services.
The FDA Subpart D regulations are nearly identical. Although only the Common Rule regulations are cited on this web page, the FDA regulations listed in the box on the right are comparable and apply to all research regulated by the FDA.
Subpart D Protections: Risk-Benefit Categories
Subpart D categorizes research that is approvable by an IRB by level of risk and prospect for direct benefit or not.
46.404: Minimal Risk
45 CFR 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, as set forth in see the Parental Permission and Assent.
Despite a regulatory definition, ethicists, IRBs and clinical investigators have struggled with the meaning of minimal risk and controversy remains. For more information about the CHOP IRB's current understanding of Minimal Risk.
When the risks of the research are not greater than minimal, any child, regardless of health status, may participate. Waiver of consent and waiver of documentation of consent are also limited to research that is minimal risk.
Parental Permission and Assent Requirements for 404 Studies:
Permission of a single parent and assent of the child (if applicable) are required for research approved under §46.404. For more information about the requirements for parental permission and assent for participants in 404 studies, see the following two webpages: Parental Permission and Assent and Assent of Children>.
46.405: Greater than Minimal Risk with a Prospect for Direct Benefit
45 CFR 46.405
Research involving greater than minimal risk but presenting the prospect of direct benefit to the individual subjects
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, as set forth in §46.408.
Nancy King has defined three types of benefit (Journal of Law, Medicine & Ethics: 2000; v28, vi, pg332)
- direct benefit to subjects, which is properly defined as benefit arising from receiving the intervention being studied;
- collateral benefit to subjects... which is benefit arising from being a subject, even if one does not receive the experimental intervention (for example, a free physical exam and testing, free medical care and other extras, or the personal gratification of altruism);
- aspirational benefit,... or benefit to society and to future patients, which arises from the results of the study.
Research offers a prospect for direct benefit when there is a reasonable and plausible expectation based on prior research, pre-clinical data or other basis that participants will receive a meaningful, clinical benefit.
The IRB applies a similar risk-benefit assessment process to research in this category as a clinician and patient would for other types of clinical decision-making, namely that the proposed participation offers benefits that outweigh the probability and magnitude of harm.
Parental Permission and Assent Requirements for 405 Studies:
Permission of a single parent and assent of the child (if applicable) are required for research approved under #46.405. For more information about the requirements for parental permission and assent for participants in 405 studies, see the following two webpages: Parental Permission and Assent and Assent of Children>.
46.406: Greater than Minimal Risk Without Prospect for Direct Benefit
45 CFR 46.406
Research involving greater than minimal risk and no prospect of direct benefit toindividual subjects, but likely to yield generalizable knowledge about the subject's disorder or condition
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:
- (a) the risk represents a minor increase over minimal risk;
- (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;
- (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; and
- (d) adequate provisions are made for soliciting assent of the children and permission of their parents or guardians, as set forth in §46.408.
If the research activity or a component of the research is purely for research purposes and is not for the participants direct benefit, the IRB can only approve the research if the risks are not more than a minor increase above Minimal Risk. Since the meaning of the definition of minimal risk is controversial, so is the definition of minor increase. It is the investigator's responsibility to provide the IRB with as much information as possible about the probability and magnitude of all possible harms from the procedure or intervention.
This category of research is limited to children with the disease or condition that is the target (aspirational benefit) of the research. For example, a Phase I pharmacokinetic study of a new drug is approvable under §46.406 provided that the risks were a minor increase above minimal and the prospective participants had the disease or condition targeted for drug development.
The CHOP IRB (and many others) consider the risk of a new drug to be at least a minor increase above minimal, which means that normal, healthy children may not take part.
Parental Permission and Assent Requirements for 406 Studies:
Permission of a both parents and assent of the child (if applicable) are required for research approved under §46.406. If one parent is not reasonably available, the consent of a single parent may suffice.
“Not reasonably available” is not intended to mean that a parent is temporarily unavailable, unless there are specific circumstances where time is of the essence. “Not reasonably available“ does not apply to situations when a parent is at work, at home, traveling, not immediately available by electronic means, or living in another state or country, without more to justify the investigator’s inability to reach the parent and seek permission.
The 2018 recommendation from the Secretary's Advisory Committee on Human Research Protections provides examples of situations when one may reasonably conclude that a parent is not reasonably available could include the following situations:
- The parent is incarcerated and not contactable.
- The parent is on active military duty and not contactable.
- The parent’s whereabouts are unknown.
- The parent is known but, upon inquiry, there is reason to believe that requesting permission would be inconsistent with the parent/child relationship, such as where there is reason to believe there is or has been domestic violence or other situations involving harm to the health or welfare of the child.
Both parents’ signatures do not necessarily have to be obtained at the same study visit. For example,
- The mother takes the child to the visit. The study team sends a consent form to the family (e.g. mail, email, fax). The investigator calls the father the night before the study visit to obtain consent. The mother brings the form (signed by the father) to the visit the next day. The mother provides consent at the visit and signs the consent form.
- The father takes the child to the study visit. The mother stays at home taking care of younger siblings. The mother joins the consent conference by phone and provides consent. She signs the consent form and faxes it (or scans and emails) the signed form to the investigator. The father signs the consent form at the visit.
The investigator should create a consenting note to document e.g. why signatures were obtained on two separate dates or on two separate consent documents.
Investigators are encouraged to consult the IRB in specific situations for guidance.
If investigators foresee that obtaining consent remotely from the second parent (by e.g. fax, mail) may be necessary for a study, the consenting plan submitted for IRB review and approval should include how this would be accomplished.
46.407: Research that is not Otherwise Approvable
45 CFR 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
DHHS will conduct or fund research that the IRB does not believe meets the requirements of §46.404, §46.405, §46.406 only if:
- (a) the IRB finds that the research presents a reasonable opportunity to further the understanding, prevention, or alleviation of a serious problem affecting the health or welfare of children; and
- (b) the Secretary, after consultation with a panel of experts in pertinent disciplines (for example: science, medicine, education, ethics, law) and following opportunity for public review and comment, has determined either:
- (1) that the research in fact satisfies the conditions of §46.404, §46.405, or §46.406
as applicable, or
- (2) the following:(i.) the research presents a reasonable opportunity to further the understanding, prevention, or alleviation of a serious problem affecting the health or welfare of children; (ii) the research will be conducted in accordance with sound ethical principles; (iii) adequate provisions are made for soliciting the assent of children and the permission of their parents or guardians, as set forth in §46.408.
- (1) that the research in fact satisfies the conditions of §46.404, §46.405, or §46.406
If the IRB determines that the research does not fit into §46.404, 405 or 406, then the only way for the research to proceed is if the Secretary of Health and Human Services determines that it meets the criteria of §46.407.
The Secretary requests the FDA's Pediatric Subcommittee to review the proposal and make a determination. The Pediatric Subcommittee could either find that the research fits into one of the other 3 categories, or that the research meets the requirements of §46.407 or that the research is not approvable.
Referrals for a 407 determination were, until recently, quite rare. To date CHOP's IRB has never referred a protocol for a 407 determination.
Parental Permission and Assent Requirements for 407 Studies:
Permission of a both parents and assent of the child (if applicable) are required for research approved under §46.407. For more information about the requirements for parental permission and assent for participants in 407 studies, see Assent of Children.