Clinical trials of medicines in children

Concern has been raised by health professionals 1 2 and politicians3 regarding the lack of scientific data on the use of medicines in children. Such data are usually obtained from clinical trials by the pharmaceutical industry and used to obtain a product license, and these trials are almost invariably conducted entirely in adults. Studies throughout Europe have shown that health professionals are forced to use medicines that are either not licensed for use in children or used at a different dose, for a different indication, or by an alternative route from that recommended (“off label”).4 Two thirds of children in hospital4 and 90% of sick newborn infants5 receive medicines that are unlicensed or off label. Little information is available about the risk of such prescribing, but one study has suggested that there is an increased risk of toxicity.6

The pharmaceutical industry has been reluctant to study medicines in children for various reasons. These include the limited financial returns, the difficulty of organising clinical trials in children, and concerns about possible toxicity.7 To improve this unsatisfactory situation there have been major legislative changes in the United States.8 The Food and Drug Administration Modernisation Act provides the financial incentive of a six month extension on the patent for medicines which are studied in children and for which the Food and Drug Admininstration has issued a written request. This legislation, introduced in 1997, has resulted in numerous clinical trials of medicines in children,8 though I and others have raised concerns that the medicines being studied in the United States are not those of greatest need in children, but those where the greatest profit can be obtained (GW Jong et al, unpublished data).

There are practical difficulties in organising clinical trials in children.9 The research subjects have to be paediatric patients rather than adult volunteers; there may be problems developing an appropriate formulation, such as a suspension that a child can swallow; and there may be difficulties in recruiting both centres and children. These difficulties, however, can be overcome by trained investigators with experience of working on clinical trials in children. A particular weakness in the United Kingdom is the shortage of paediatric clinical pharmacologists (there are only three, all in the Midlands). A training programme in London and Aberdeen is underway but will take seven years to train two individuals.

In contrast to the developments in North America there has been little progress within Europe. Within Britain the Medicines Control Agency and the Association of the British Pharmaceutical Industry have recognised that the situation needs improving. The Medicines Control Agency is limited by the constraints of the Medicines Act of 1968, which, although written in response to tragedies that affected developing fetuses (thalidomide) and newborn infants (chloramphenicol), has resulted in a situation whereby the pharmaceutical industry is not encouraged to study medicines in children. There is an urgent need for research and training in paediatric therapeutics. This has been achieved in the United States through the funding of 13 centres in a paediatric pharmacology research unit network.10 In Britain, however, the Department of Health and the major research councils and charities have been slow to recognise that this is an area where investment is needed. A conference last month organised by the Faculty of Pharmaceutical Medicine showed that clinical trials in children are both ethical and possible to organise if health professionals with experience of working with children are consulted at an early stage and involved in designing the protocol.

The cost of studying medicines in children is greater than in trials in healthy adult volunteers. The concept of a financial incentive is therefore appropriate. It is important that Europe and Britain learn from the American experience and ensure that clinical trials are carried out in children for medicines that are likely to be of major benefit. This is in accordance with recent guidance from the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, which categorises new medicines in relation to clinical need.8 A small working group consisting of paediatricians, the Association of the British Pharmaceutical Industry, and the Faculty of Pharmaceutical Medicine was established following the conference to try and take the matter forward.

As a paediatric clinical pharmacologist I have a clear conflict of interest in that I wish to ensure that appropriate clinical trials are carried out. However, as a parent and a paediatrician I have a bigger conflict of interest in that I wish to ensure that children receive medicines that have been proved to be effective, safe, and of high quality. Medicines are clearly essential for the care of children. These medicines need to be tested scientifically as part of a controlled clinical trial. The alternative is to continue to force paediatricians to use these medicines without an evidence base. Such a situation has already resulted in the death of at least 15 children from the use of propofol as a sedative in critically ill children.11 If propofol had been studied as part of a clinical trial, one death would have led to an urgent reappraisal of the trial and treatment. We cannot allow the lives of other children to be put at risk by not establishing an evidence base for the use of medicines in children.