Should we 'experiment' on children? (update)
Summary
Children are generally treated with smaller doses of medicines which have been tested on adults, yet children can react differently to such medicines. As new and more effective medicines continue to be developed, how can we find an ethical and safe way of testing their effectiveness on children? Prof Alan Craft examines this area and provides a commentary on a recent US attempt to achieve this.
Key Points
- Medicine aims increasingly to practice on the basis of evidence of efficacy (‘evidence-based medicine’).
- Children do not react identically to adults, and consequently medical practice in children needs to be based on evidence derived from children.
- Experimentation in children raises serious and particular ethical difficulties, especially in relation to competence and consent.
- Particular problems relate to the involvement in research of healthy children who cannot themselves receive any benefit from that research.
- The recent referral by the FDA in the US of proposed research on the effect of dextroamphetamine in ADHD to a special committee may demonstrate how research on children might be facilitated.
Declaration of interests: No conflict of interests declared
Children have never been healthier. Much of the improvement in health has been due to non-medical factors, largely social, and there is still an enormous disparity in health between rich and poor. However, medical interventions have had a significant part to play and will continue to do so. The last few years have seen a determination to move from eminence-based to evidence-based medicine, and the randomised controlled trial methodology has gained even more importance. We have also seen a move to much more open communication between professionals and patients, and detailed explicit consent is now required before entry into clinical research. The 60-page standard ethics form from the Department of Health in England is a clear expression of this.1
Children are different from adults. We cannot extrapolate automatically from the results of research undertaken in adults and expect that similar results would have been obtained in children. There are, for example, fundamental physiological differences which influence the metabolism of drugs. If we want evidence-based medicine for children we will have to do investigations in children to provide that evidence. However, there are many special issues around research in children which need to be considered. Babies and young children cannot give consent, so parents or guardians must take on this role. The age at which children/young people should be involved in decision-making and are competent to give consent is also a matter of debate.
The Royal College of Paediatrics and Child Health (RCPCH) recognises the need for research in children and produced guidance in 2000 on the ethical conduct of medical research in children.2 This is still relevant. The guidance is based around six principles.
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Research involving children is important for the benefit of all children and should be supported, encouraged and conducted in an ethical manner.
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Children are not small adults; they have an additional, unique set of interests.
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Research should only be done on children if comparable research on adults could not answer the same question.
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A research procedure which is not intended directly to benefit the child subject is not necessarily either unethical or illegal.
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All proposals involving medical research on children should be submitted to a research ethics committee.
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Legally valid consent should be obtained from the child, parent or guardian as appropriate. When parental consent is obtained, the agreement of school age children who take part in research should also be requested by researchers.
The issue of using healthy children for research is also of considerable debate and is included in principle 4 above. The guidance is usually that the intervention should do, or have the potential for, either no or minimal ‘harm’ to the healthy child.
A recent proposal for a study in the US highlights many of the issues alluded to above. The National Institute for Mental Health proposed a study of a single dose of 10 mg of dextroamphetamine in young people with behavioural disorders, including attention deficit hyperactivity disorder (ADHD), and also in normal children who would act as controls. Very detailed investigation would be undertaken, including both psychological testing and diagnostic and functional magnetic resonance imaging of the brain. The initial proposal was to give each family a payment of $570 for taking part. Similar studies had been done 20 years ago but without the benefit of brain imaging.
The main ethical problem with this study was the question of giving a controlled drug to normal children and, therefore, the need to determine the potential risk to these children. Approval could not be agreed through the usual routes, so the problem was referred to a new committee set up by the Office of the Commissioner of the Food and Drug Administration (FDA) for just this purpose. On 10 September 2004 the Pediatric Ethics Sub Committee of the Pediatric Advisory Committee met to discuss the matter. It was chaired by Dr Robert (Skip) Nelson, a paediatric anaesthetist/intensivist. The questions addressed were:
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What are the potential benefits of the research, if any, to the subjects and to children in general?
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What are the types and degree of risk that the research presents to the subjects?
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Are the risks reasonable in relation to anticipated benefits? Will research result in generalisable knowledge?
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Does the research present an opportunity to further the understanding of a serious problem affecting children?
The Sub Committee found that although there would be no direct health benefit to the children involved in the research, it could provide a greater understanding of ADHD and the contribution to it of genetic factors, as one part of the study involved twins. It was also felt the research would improve understanding of ADHD and could be generalisable.
The degree of risk for participants was considered to be a ‘minor increase over minimal risk’. For those with ADHD there was a risk in withholding current medication for 36 hours and for normal subjects the risk was of the potential behavioural side-effects of amphetamines. However, the latter was considered low-risk because of the 30 years or more of experience with the drug where there have been no long-term hazards from a single dose.
Finally the Sub Committee recommended a nominal payment of $100 for each research subject. This seems reasonable as it could not be seen as a major incentive to induce parents to allow their children to take part. It is not common practice to pay child research subjects in the UK, but small monetary gifts are offered when children take part in post graduate examinations.
With other minor modifications, mainly to improve the quality of the science, the protocol was approved. This is an important case because it shows the value of an independent review of a research protocol by a prestigious national body.
References
- Central Office for Research Ethics Committees. Standard Research Ethics Committee application form v.3 2004.
- McIntosh N, Bates P, Brykczynska G et al. Guidelines for the ethical conduct of medical research involving children. Royal College of Paediatrics, Child Health: Ethics Advisory Committee. Arch Dis Child 2000; 82(2):177–82.
- Food and Drug Administration: Pediatric Advisory Committee: Pediatric Ethics Sub-Committee: meeting of 10 September 2004: Briefing Information