Balancing potential risks and benefits in pediatric research

Procedures undertaken for research purposes are, by definition, designed to produce information to benefit future patients[1]. Although in some forms of research, participants may additionally hope to benefit from the research, in most cases they are not undertaken with the direct aim of benefitting the research participant while in some cases even exposing the participants to a substantial level of risk. On the other hand, children have the fundamental right to the protection and care that is necessary for their well-being. In all actions relating to children, whether taken by public authorities or private institutions, the child's best interests must be a primary consideration[2]. Thus, balancing risks and benefits of the particular research is the crucial requirement for the researchers and research ethics committees. The Additional Protocol to the Convention on Human Rights and Biomedicine, concerning Biomedical Research as well as Clinical Trial Regulation defines two categories of permissible research involving children.

First, the research is permissible if it is expected to produce direct benefit for the minor taking part in the research outweighing the risks and burdens involved.

The essential precondition for the research that entails more than minimal risk to a child is that the research holds out the prospect of direct benefit for the child or may contribute to the child’s wellbeing. However, the risk benefit assessment in such research studies may be complicated as research is a complex activity consisting of multiple procedures and interventions, some of them being performed entirely for the research purposes and not for the benefit of the patient. For the further information on risk/benefit assessment please see the module “Core principles of research ethics”.

It is also worth mentioning that there is a legal imperative that no additional potential benefits of the research may be used to justify an increased level of risk or burden, i.e., no incentives or financial inducements may be given to the minor or his or her legally designated representative except for compensation for expenses and loss of earnings directly related to the participation in the clinical trial.

Second, the research that has no potential to produce the results of direct benefit to the health of a child is permissible if there are scientific grounds for expecting that participation in the research will produce some benefit for the population represented by the minor concerned and such a research study will pose only minimal risk to, and will impose minimal burden on, the minor concerned (such are, for example, observational studies, some pharmacokinetic studies, etc.)[3]. Benefit for the population includes increased knowledge on the condition, diagnosis, treatment or prevention relevant to the population represented by the minors concerned. The crucial requirement for the studies with no direct benefit for the study participant is that it may pose only minimal risk and minimal burden. Minimal risk is defined as that which, in terms of the nature and scale of the intervention(s), would result in an individual case at the most in a very slightly detrimental and temporary impact on the health of the person concerned[4] and minimal burden is defined as that for which the expected discomfort, which might be associated with the research, will be at most temporary and very slight for the individual. CTR adds that the risk should be minimal in comparison with the standard treatment of the minor's condition.

Even if the ethical review concludes that the level of risk and burden is minimal in comparison with the standard treatment, this does not necessarily mean that the trial is ethically acceptable. The foreseeable risks and burden should be justified and minimized[5] (EC recommendation, 2017).

Minimizing risk

Most guidelines emphasize the need to minimize risks (both by preventing potential harms and minimizing their negative impacts should they occur) to make research ethically acceptable[6]. The investigators and the ethics committees should make every attempt to prevent pain, fear, and any other foreseeable harm (risk and burden) in the study and minimize it when unavoidable. This may be done by integrating research procedures and interventions with clinical care and diagnostic procedures whenever possible; research studies should be performed by trained investigators with pediatric experience in the appropriate research environment; appropriate methods should be used to accustom children to the research environment and to decrease potential anxiety and discomfort whenever possible. Protocols should include specific rules setting limits on the number of unsuccessful attempts at a procedure or the length of time for completion of a questionnaire. Research procedures such as simple blood draws, noninvasive urine collections, questionnaires, and interviews with healthy children when performed once are deemed to be consistent with the definition of minimal risk. However, the same procedure performed repetitively over a short period may stil  not  constitute minimal risk[7].

It is also required to have a pediatric expertise in the ethical review process, to assess and balance the benefits, risks and burden of research with minors.

Parental consent and minors´ assent (or deliberate objection)

By definition, children (minors) are unable to consent in the legal sense, therefore the specific, written informed consent must be obtained from the one or both parents/legally designated representative on the child’s behalf prior to enrolling the child in a research.

But minors should also be involved in the process of informed consent as much as possible in a way adapted to their age and mental maturity[8],[9]. The evaluation to what extent a minor can understand provided information should not be based solely on chronological age, but also on individual factors such as developmental stage, intellectual capacities, life/disease experience and their family situation[10]. To provide age-appropriate information assent forms should be used for children, using language and communication tools (visuals, cartoons, videos etc.) appropriate to the participants’ age and maturity[11].

There is a general principle that the explicit wish of a minor who is capable of forming an opinion and assessing given information to refuse participation or to withdraw from the clinical trial at any time, i.e. dissent, must be respected even if the parents have given consent[12]. However, other international documents (e.g. CIOMS guidelines) make an exception stating that the dissent may be overridden by the need of treatment that is not available outside the context of research, the research intervention has a clear prospect of clinical benefit, and the treating physician and the legally authorized representative consider the research intervention to be the best available medical option for the given child or adolescent[13],[14].

Under a dissent requirement, children are not required to understand the research and make their own prospective decisions. Instead, they simply react to how the research is affecting them and indicate any distress they experience[15]. That makes it different form the assent, which may be a legal requirement. For example, it is stated in the CTR that without prejudice to national law requiring that, in addition to the informed consent given by the legally designated representative, a minor who is capable of forming an opinion and assessing the information given to him or her, shall also assent in order to participate in a clinical trial. (CTR art. 29, para 8).

As children’s ability to understand and evaluate this information increases, so does the moral weight of their assent and dissent. As adolescents near the age of majority, their agreement to participate in research may be ethically (but not legally) equivalent to consent[16]. Provision of information is a continual process during a trial. Once an adolescent is no longer a minor, or when he or she is an “emancipated minor”, he or she should be asked to provide written informed consent as soon as practically reasonable, as for any adult capable of giving consent.