Compliance Today - April 2021

Child assent

In order to enroll a pediatric patient in a clinical trial, the child must assent, and permission must be granted by the parent(s) or legal guardian(s), as opposed to obtaining traditional “consent” from the patient (as appropriate, per 45 C.F.R. § 46.408 and 21 C.F.R. § 50.55 ). Assent is defined as a child’s affirmative agreement to participate in a clinical investigation.^[5] Mere failure to object should not, absent affirmative agreement, be construed as assent. Obtaining informed consent or assent does not merely consist of an individual signing and dating an arbitrary piece of paper; rather, it is a process that begins with the initial interaction between the investigator and potential subject through completion of the clinical trial.

Assent has long been a controversial topic among those in the research community, with much of the debate arising where the regulations are silent. The regulations do not clearly define what information about the clinical investigation should be provided in the assent, or at what age clinicians should begin seeking assent from subjects.

Informed consent

Our medical practitioners are keenly aware that, apart from a few exceptions, the practitioner must obtain informed consent before treating the patient.^[6] One stark contrast between getting consent from an adult and a pediatric patient is that a child is legally unable (i.e., has no legal standing) to provide informed consent on their own behalf, so investigators (and the child) are dependent on the child’s parent(s) or legal guardian(s) to assume this duty.^[7]

In 1991, the Common Rule established that the following components be addressed during the informed consent process, although a new element has since been added:^[8],[9]

1. Explanation of the research;

2. Foreseeable risks;

3. Potential benefits;

4. Alternative treatment;

5. Confidentiality of records, compensation, and research-related injury;

6. Description of available medical care and compensation should an injury occur;

7. Contact information; and

8. Statement of voluntary participation.

These requirements of an informed consent still apply today; however, additional safeguards for children have also been established. These safeguards, as they are described in subpart D of 45 C.F.R. § 46 , address:

• Additional duties of the IRB;

• Clinical investigations not involving greater than minimal risk;

• Clinical investigations involving greater than minimal risk but presenting the prospect of direct benefit to individual subjects;

• Clinical investigations involving greater than minimal risk and no prospect of direct benefit to individual subjects but likely to yield generalizable knowledge about the subject’s disorder or condition;

• Clinical investigations not otherwise approvable that present an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children;

• Requirements for permission by parents or guardians and for assent by children; and

• Children who are wards of the state or any other agency or institution.

Although the components of information that are required to be provided to the prospective child participant have not been clearly described in the regulations, it would be reasonable to also include information about the child’s condition, about what will happen and what to expect, and asking the child whether they would like to participate.

It is also imperative to ensure that the assent process be age and developmentally appropriate. A child’s understanding and their preference for being included in decisions about their care are essential components of assent. Shared decision-making between the child, parent, and practitioner is a strong foundation on which to base assent. This process should be empowering and respectful, regardless of the child’s age.^[10]

Additional duties of the IRB

Although the absence of guidance in the C.F.R. does allow each IRB flexibility to implement assent requirements for their institution, it also affords the pediatric research community opportunities for inconsistencies across organizations during the assent process. Ensuring that additional safeguards and practices surrounding pediatric research are followed will certainly involve increased effort and more responsibility from the IRB; however, these safeguards are essential to ensuring meaningful and respectful research involving children.

While the IRB is expected to comply with general clinical research regulations, when enrolling a child for the participation in a clinical trial, 45 C.F.R. § 46.408 notes that the IRB must also determine that adequate provisions are made for soliciting the assent of the children and the permission of their parent(s) or guardian(s). These provisions include taking into consideration the child’s age, maturity, and psychological state to ensure the child has the ability to assent. This determination may be performed for all children enrolled in a particular clinical trial, or on a case-by-case basis, as the IRB deems appropriate.^[11]

In addition to ensuring that IRB membership requirements are met, 45 C.F.R. § 46.107 emphasizes that if an IRB regularly reviews research that involves a vulnerable class of subjects, such as children, consideration shall be given to the inclusion of one or more individuals who are knowledgeable about and experienced in working with those subjects.

An IRB may also determine that assent is not necessary or may waive the assent requirement in certain situations. For example, the assent of children is not a necessary prerequisite for proceeding with a clinical investigation if the IRB determines that the intervention or procedure involved in the clinical investigation holds out a prospect of direct benefit that is important to the health or well-being of the child and is available only in the context of the clinical investigation.^[12]

Likewise, the IRB can waive the assent requirement for children who are capable of assenting if the IRB finds and documents that the clinical investigation involves no more than minimal risk to the subjects; the waiver will not adversely affect the rights and welfare of the subjects; the clinical investigation could not practicably be carried out without the waiver; and, when appropriate, the subjects will be provided with additional pertinent information after participation. ^[13] Parental permission requirements remain in these circumstances.

Pediatric patients

First, let’s discuss the pediatric patient. Children are not just small adults. Their growth and development, physiological capabilities, metabolic pathways and rates, pharmacokinetic profiles, and pharmacodynamic characteristics are considerably different from that of an adult.^[14] But the differences don’t stop here. A large portion of the pediatric population can’t read or even write their name; so how does one go about obtaining a child’s consent to participate in a clinical trial and subsequently allow them to receive the essential and often critical and life-sustaining treatment?

The human subject research regulations define children as “persons who have not attained the legal age for consent to treatments or procedures involved in the [clinical investigations], under the applicable law of the jurisdiction in which the research will be conducted.”^[15] Even though the age of majority for most states in the United States is 18 years old, this number does not provide a hard stop on the age at which a child’s assent and parental permission are no longer necessary. As we’ve discussed, there are many other conditions and situations that must be considered.

Determination for assent based solely upon chronological age is insufficient. A child aged 10 with a mental capacity of a three-year-old would not be expected to assent to participation. Participants of appropriate intellectual maturity should personally sign and date either a separately designed, written assent form or the written informed consent form. In any case, child “participants should be made aware of their rights to decline to participate or to withdraw from the study at any time.”^[16]

Children who are wards of the state can participate in approved research; however, the IRB must appoint an advocate for each child, in addition to any other individual acting on behalf of the child as guardian or in loco parentis.^[17]45 C.F.R. § 46.409 requires that the advocate have “the background and experience to act in, and agrees to act in, the best interests of the child for the duration of the child’s participation in the research.” They must not be “associated in any way (except in the role as advocate or member of the IRB) with the research, the investigator(s), or the guardian organization.”

Another unique population within pediatrics are the emancipated or mature minors.^[18] This group of people who are under 18 years old or who would otherwise be defined as a minor by local laws may be capable of giving autonomous informed consent as opposed to assent. This would include minors who are married, active-duty military, or those living on their own and managing their own finances.^[19] Should you find yourself getting consent from a patient that falls in this group, confirm that documentation of their status is included in their medical record.

Parent(s) and legal guardian(s)

As we have already briefly discussed, the child’s parent(s) or legal guardian(s) must provide permission, and the child must assent to participate in a clinical trial. But what does it look like to obtain parental permission? There are many factors to take into consideration, especially when both parents may not be involved in the child’s care.

45 C.F.R. § 46.408 requires the IRB to make adequate provisions in soliciting the permission of both parents or the guardian(s); however, the IRB may find that the permission of one parent is sufficient for research that does not involve greater than minimal risk or for research that does involve greater than minimal risk but presents direct benefit to the individual subject. For research that does not fall under these two categories, “both parents must give their permission unless one parent is deceased, unknown, incompetent, or not reasonably available, or when only one parent has legal responsibility for the care and custody of the child.”

The IRB may also determine that parental or guardian permission is not a reasonable requirement and may be waived in order to protect the subject (e.g., neglected or abused children). These situations are often contentious, as it is unclear as to whether the parents’ interests are in line with what is best for the child.

Investigator

Physicians are expected to serve as advocates for their patients, and maybe even more so with the pediatric population. They have a special responsibility to foster their pediatric patient’s individual and evolving capacities, and they should accordingly make every effort to provide their patients and their patients’ parents with the tools to allow their children to think independently. Properly implemented, these efforts and tools permit the child to make rational and valid age-appropriate decisions. Children learn to make good, sound decisions with practice and by relying on those they trust.^[20]

It is essential that the investigator, most often a physician, ensures that both the legal guardian or parent and the patient fully understand any known or potential risks, harms, discomforts, embarrassments, and breaches of privacy or confidentiality associated with the research.^[21] The challenge here lies within explaining the required elements in such a manner and using terminology that the pediatric patient understands. Communication with this special population may necessitate some creativity on the investigator’s behalf. For example, illustrations may be useful on the patient assent form to more appropriately capture and explain research activities and to facilitate age-appropriate dialogue. In general, parents are appreciative of this accommodation, and IRBs are usually willing to consider abridged, illustrated documents in lieu of longer text-based assent forms.

The regulations do not “require the use of a written assent form (see [ 21 C.F.R. § 50.55(g) ]); however, when a written assent process is appropriate or required by the IRB, FDA strongly encourages the use of a separate assent form that is ‘child-oriented’ and developmentally appropriate. A separate assent form does not need to include all of the elements of a consent form, but should focus on those aspects of the clinical investigation that may impact on a child’s willingness to participate.”^[22]

Additional considerations

Over the course of a clinical trial, recognizing that a child’s maturity and competency are ever evolving, it may be necessary to reassess the assent of a child. If a child enrolled in a clinical investigation with parental permission reaches the legal age of consent and is no longer considered a child, the investigator should obtain the subject’s informed consent as an adult prior to performing any further research interventions and/or procedures involving that adult subject.^[23]

One distinct challenge in providing care to pediatric patients arises when there are disagreements between the parent(s) or legal guardian(s), the child, and/or the treating physician/investigator regarding treatment decisions. “[T]here may be circumstances in therapeutic studies for serious or life-threatening diseases in which, in the opinion of the investigator and parent(s) or legal guardian, the welfare of a pediatric patient would be jeopardized by his or her failing to participate in the study. In such a situation, continued parental or legal guardian consent should be sufficient to allow participation in the study”^[24] even if the child does not assent.

The dissent of a pediatric patient should carry considerable weight when the proposed intervention is not essential or can be deferred without substantial risk; however, in general, pediatric patients should not be given authority to refuse life-saving treatment even when the parents agree with them.^[25] When disagreements or conflicts arise, the healthcare team should enlist the involvement of other team members, such as the institution’s ethics committee, psychologists, psychiatrists, chaplains, and palliative care team. While seeking legal intervention may be available, this should be a last resort.

Local regulations related to confidentiality and privacy should continue to be followed for the pediatric population. Institutional policies that promote clinical research transparency are also relevant in pediatric clinical research. A fundamental principle of research is the public availability of objective and unbiased clinical study results to enhance clinical research; to avoid unnecessary clinical trials, especially in children; and to inform clinical decisions in pediatric practice.