Directive 2001/20/EC of the European Parliament Citation[1], which provides a detailed framework for the conduct of clinical trials, became law in the member states of the EU in May 2004. This new legislation specifically directs that the clinical development of drugs, which will be used in children, should be undertaken through clinical trials in the target age group. The new legislation should inspire a large increase in the involvement of minors in clinical research in Europe. The use of many currently available drugs in children has been extrapolated from clinical trials conducted in the adult population Citation[2]. This limited evaluation of drugs in minors largely results from the ethical and practical difficulties in conducting clinical trials with children.
Pediatric vaccine research generally utilizes healthy children and usually involves both the administration of an investigational vaccine to a child and other interventions including venepuncture. Since minors are a vulnerable group in society, care needs to be taken to ensure that they are not exploited. The new EU Clinical Trials Directive identifies the need to involve children in the decision-making process before their participation in a research trial and requires that those who are able to do so, give their consent or assent Citation[1]. This advocacy for a child’s involvement in the decision to take part in research is supported in the Declaration of Helsinki, which also refers to the need for researchers to obtain the assent of minors who are able to understand the issues surrounding participation Citation[3]. However, there has been only limited appraisal of the process of consent by healthy children involved in a clinical trial and most published comment in this area utilizes hypothetical situations Citation[4,5].
Consent is the authorization by the individual to undergo a medical procedure and has been a prerequisite for participation in almost all medical research since the NŸremberg Trials. As children have underdeveloped autonomy, the giving of consent is the responsibility of the parent or legal guardian and it must represent the presumed will of the child. Children under the age of 17 who are deemed Gillick competent, can give consent for medical treatment Citation[6]. However, the legal position is not clear in the UK with regard to consent by competent minors to participate in research (rather than a medical procedure), although good practice dictates that parental consent should be sought in addition to that of the competent minor. In the case of children too young to be competent to give consent, parental consent is required. Even though noncompetent children cannot formally give consent, it is acknowledged that it is ethically important, even for these children, to be involved in the decision to take part in the research. This is perhaps particularly important when the research has no clear benefit to the child.
Directive 2001/20/EC of the European Parliament Citation[1], Article 4, Clinical trials on minors:
‘Consent must be obtained from parents or guardians and without any financial inducement. Children who can form an opinion may refuse participation in a clinical trial and information should be provided in a way that the child can understand.
There should be some direct benefit for the group of patients obtained from the clinical trial and it should only be conducted in children if it is not possible to do so in adults. Pain, discomfort, fear and any other foreseeable risk should be minimized. The study should be reviewed by an ethics committee with pediatric expertise and the interests of the subject prevail over those of science and society.’
In acknowledgement of the need to involve children in healthcare decisions, the concept of assent has been developed. To satisfy the assent process, children should be informed, in a developmentally appropriate manner, of the general purpose of the study, what participation entails and the risks and benefits of taking part. It must also be made clear that participation is voluntary, that withdrawal is acceptable at any stage of the trial and that all information will remain confidential. The concept allows a child who is not old enough, or sufficiently competent, to say whether or not they wish to take part. An implication of the concept of assent is that if, after being informed, the child says that they do not wish to take part, then this refusal should be respected, even if parental consent has been given. In the case of nontherapeutic research, it is rarely considered ethically acceptable to impose a research procedure on a child who is actively resisting, even with parental consent.
Although the explicit wish of a minor capable of forming an opinion must be considered by the researcher Citation[1], this provides little guidance regarding precisely when a minor’s opinion should count. Many parents would say their 2-year-old had the ability to form an opinion. In reality, a 2-year-old’s objection is unlikely to prevent their participation in a clinical trial, but it is not at all clear when the views of a young child should take precedence over the wishes of a parent who has given their consent. The Directive also states that a child’s dissent should not automatically lead to nonparticipation if a parent has given permission based on the child’s presumed will Citation[1]. This suggests that the child’s point of view should be considered, but not necessarily respected, which would appear to leave the researcher in a compromized position with authority to decide about the child’s participation. Conversely, unless there is a reason to believe otherwise, it does not seem acceptable to override parental autonomy for the sake of a minor’s autonomy when it is not clear whether the child understands what they are objecting to. A young child is unlikely to volunteer to have venepuncture and an immunization for either altruistic reasons or for personal benefit (without coercion) and, provided there is no evidence of wrong doing, a parent who provides their consent should, perhaps, have the right to bring up the child as they so wish.
The UK Royal College of Paediatrics and Child Heath guidelines on consent in children state that where appropriate, the decision to participate in a research study should be the child’s if there is no direct benefit to themselves Citation[7]. These guidelines also indicate that a procedure should not take place if the child demonstrates significant unwillingness or stress before or during the process. However, it has been suggested that children under 10 years of age have difficulty understanding some of the assent requirements Citation[8]. Furthermore, there is disagreement over the age at which a minor has the ability to understand these assent requirements. There is a need to identify the quality and quantity of information that should be presented to children under 10 years of age, such that the assent process can be meaningful. It makes a mockery of children if they are asked to give their assent to take part in a study, when we already know that many aspects of the process are too abstract for them to understand. If younger children are unable to comprehend all of the issues required for assent then perhaps it would be developmentally appropriate merely to inform them of what is going to happen. The concept of permission rather than assent might be more appropriate.
Even if the parent’s decision concerning the child’s participation in research overrides that of the child, there is still a further issue to consider. If the ethical test for participation was the more straightforward concept of permission, what would constitute significant unwillingness or stress that should prevent continuation of a research procedure? A toddler is unlikely to sit still for venepuncture and a certain level of restraint is always used. Would struggling with a toddler’s arm during venepuncture constitute significant unwillingness? How much distress can be tolerated during a brief procedure, such as venepuncture, before the procedure is discontinued?
While it is widely acknowledged that children should be involved in decisions regarding participation in research that affects them, it is unclear what should be expected of them when making these decisions and how much weight their expressed opinion should carry. The existing guidelines regarding consent in children and the new clinical trials regulations which rightly emphasize these ethical considerations, do not provide a practical framework for the investigator. Careful re-evaluation of the process of consent for research involving children is urgently needed to ensure that clinical trials are conducted in a manner that is ethically acceptable to society.
References
- Directive 2001/20/EC of the European Parliament and of the Council of 4th April 2001 on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use. Official J. Eur. Comm. L 121/34–121/44 (2001).
- Koren G. Healthy children as subjects in pharmaceutical research. Theories Med. Bioethics24(2), 149–159 (2003).
- World Medical Association. Declaration of Helsinki Ethical Principles for medical research involving human subjects. World Medical Association, October (2000).
- Abramovitch R, Freedman JL, Thoden K, Nikolich C. Children’s capacity to consent to participation in psychological research: empirical findings. Child Dev.62, 1100–1109 (1991).
- Hurley JC, Underwood MK. Children’s understanding of their research rights before and after debriefing: informed assent, confidentiality and stopping participation. Child Dev.73(1), 132–143 (2002).
- Kennedy I, Grubb A. Medical Law Text and Materials. Butterworth, London, UK (1989).
- Royal College Of Paediatrics And Child Health: Ethics Advisory Committee. Guidelines for the ethical conduct of medical research involving children. Arch. Dis. Child.82, 177–182 (2000).
- Ondrusek N, Abramovitch R, Pencharz P, Koren G. Empirical examination of the ability of children to consent to clinical research. J. Med. Ethics24, 158–165 (1998).