Analysis Of The Ethical Challenges In Paediatric Research

Introduction

Medical research in paediatrics is vital in ensuring that the delivery of clinical care is optimal in this patient population. The saying “children are not small adults” is true in many aspects; not only do children have a different physiology, susceptibility to different diseases, varying tolerances and responses to medication compared to adults, they have additional unique ethical interests that may make research in this population particularly challenging.

These complexities stem from multiple factors: there may be a lack of agreed-on end points, ethical issues surrounding consent for a minor and also the perception that children are vulnerable study subjects. Despite these complexities, thoughtful, efficient and ethical research can be conducted in order to provide evidence which can inform the best practice for clinical care in this age group.

The ethical considerations in research with children occur at all stages of the research process, and is paralleled by challenges in every stage of the research process. Some important questions come to mind when we consider medical research in children:

• What is the risk of conducting (or not conducting) the research?
• Who has the right to decide the level of risk exposure to the child?
• Does the child have a say in agreeing to participate in research?
• Does the goal of the research justify the risks associated with the study?

Ethical Principles to Guide Paediatric Research

The ethical principles from The Belmont Report is a useful guide in informing research in human subjects, and this can be applied to the paediatric population.

• Beneficence, a principle based on kindness and is a moral obligation to act for one’s benefit, to help one further their interest, without causing harm. In applying this principle to research involving children, the research should not pose any harm to the subject and should avoid exploiting the vulnerability of minors who may be unable to give true assent for study participation. It remains debatable regarding the role of beneficence for the subject who may not directly benefit from the research but who may contribute to the overall benefit of the group of patients through understanding of disease and advancement of disease management.
• Justice involves the fair distribution of risks and benefits throughout the population when conducting research, where subject selection should be equitable without exploitation of vulnerable subjects. Practically, this would mean that the inclusion and exclusion criteria for subject recruitment should be based on sound scientific reasoning rather than discriminatory factors or ease of enrolment.
• Respect for persons, the concept which denotes that every person deserves the right to fully exercise their autonomy, is perhaps the main challenge in paediatric research. An automatous individual is one who has the capacity to make an informed decision. This is in contrast to the paternalistic approach, which is the belief that an individual incapable of making an informed decision requires a surrogate to make the decision in the best interest of the individual.

While performing human research, consent would depend on the subject’s ability to make an informed decision regarding voluntary participation, given the perceived benefits and risks. While this decision is understandable for adults, it is more challenging in children who may not have the ability to make that autonomous decision. If we apply the principle of paternalism, when would it be considered in the best interest of the subject to be part of the research may be more obvious in some cases (e.g. participating in a trial that may have potential cure for a particular disease) and more ambiguous in other cases (e.g. undergoing x-ray evaluation to contribute to population norms for bone age). The next part of the essay would discuss how the processes of informed consent and assent can best be applied to paediatric research in order to ensure that the best interests of the child is not compromised.

Informed Consent and Assent in Paediatric Research

The standards of informed consent in research include: (1) providing information to the potential subject such that they can make a decision on whether to participate in the research; (2) providing information in a way that is easy to understand; (3) the understanding that participation is entirely voluntary and (4) the understanding that withdrawal from the research can occur at any time. While these are technically solid standards, it is again challenging to apply these to paediatric patients, which has a range of varying ages, from the neonatal age group to the adolescent age group. In the younger pre-verbal age group, it would be impossible to meet the standards listed out above even with our best efforts.

As such, the process has to involve the child’s parent or legal guardian who would be placed in a position to make the decision on behalf of the patient, with their best interest as a guiding principle for their involvement in the research. Review boards must put in place safeguard measures to ensure that the participation of children and their families in the study is without coercion.

Assent is the concept of providing agreement to participation in research where full consent is not possible. This involves the child’s agreement for participation in the study. For children below the legal age of consent but who may have an understanding of the underlying process (i.e. usually > 7 years old), it becomes imperative that the study team endeavour to explain the study to the subject in the most appropriate way that will allow them to understand the objectives and processes of the study- and they should be required to assent to the study. While younger children generally are not expected to sign an assent form, most ethical board guidelines have a separate assent form for adolescent subjects to document a process which requires involvement of the adolescent in participation in the research.

The reality is that clear evidence on the process of assent in paediatric research is still lacking. There is not much in the way of how the ethics review board would determine whether assent is required, guidance on how researchers should solicit children’s assent, what children comprehend in various types of research and what would constitute a successful assent procedure. Some evidence suggests that the capacity to provide meaningful consent or assent matures beyond 14 years of age but is very limited before nine years old. Whether we like it or not, even with procedures for assent put in place, children below the age of nine or who persistently lack the capacity (e.g. intellectual disability, developmental delay) would still need to rely on their guardians and caregivers to act on their best interests. If the process of assent is to be taken seriously, dissent, which is the voicing of a desire not to take part in research) should be respected.

Undoubtedly this is a challenging area, but the “respect for persons” principle requires that researchers in child health provide information that is accessible and appropriate for children, to solicit valid consent or assent, and to be proactive in the ongoing assessment of the continuing validation of a child’s or the parents’ agreement to participate in research.

Improving the Process in Conducting Research in Paediatric Patients- Ensuring a Clinically and Ethically Sound Research

Some important ways in which a paediatric research study can be designed and reviewed to protect the interest of children participating in research include the following:

• Children should be invited to participate in research only when it is necessary to answer an important scientific question that is paediatric-specific
• Where possible, data from similar adult studies should be studies carefully to anticipate (and circumvent if possible) potential adverse effects which may occur in children
• A sound and answerable research question forms the basis of minimizing risk and maximising benefit to study participants. In designing the study question, interventions must be perceived as equitable and not with a known inferiority
• The nature of the research question should be specific and should clearly describe the scientific uncertainty leading to the study design
• The choice of an appropriate control group should be based on both scientific and ethical principles, where the primary focus of having a control should be to demonstrate the efficacy or safety of an intervention
• Having a dedicated team within the Ethics Review Board for reviewing paediatric research, consisting of experts who are well versed with the challenges and issues pertaining to paediatric research and the need to safeguard children participating in research
• Specific training and modules for paediatric research, highlighting the intricacies and challenges faced when dealing with this population and ways to safeguard the subjects

Conclusion

Research involving children is important for the benefit of all children and should be supported, encouraged and conducted in an ethical manner. While there are various ethical challenges surrounding research in children, it is important that we realise one thing: forgoing paediatric research and extrapolating adult data to make clinical decisions on the care for paediatric patients may be unethical in itself, as paediatric patients could be faced with the harm of the lack of evidence-based approach to guide clinical decision-making. There are also conditions that uniquely affect children which makes it impossible to study in an adult-only population: Kawasaki’s disease, neuroblastoma, patent ductus arteriosus in a preterm infant are just a few examples.

Rather than shy away from conducting medical research on paediatric subjects, the key is to incorporate safeguard measures and design robust methodologies based on sound research questions, with close monitoring of the research outcomes throughout the study to ensure that the risk-benefit balance of continuing the study remains in favour of the study participants, and be ready to terminate the study if subjects are shown to encounter harm either directly or indirectly through their participation in the study.