The medicines for children agenda in the UK

Abstract

Children can expect the medicines prescribed for them to have at least as good an evidence base as in adult practice. Current licensing arrangements in the UK ensure a rigorous assessment of most drugs used for adults, whereas prescribing outside the licence is relatively common for children. Until the evidence base is increased, consensus guidelines or formularies, such as the new British National Formulary for Children, provide some protection for children and prescribers. For the future, there is optimism that the dearth of research on which to base children’s prescribing will be addressed by new initiatives, such as the UK Medicines for Children Research Network and draft EU legislation providing incentives to industry.

Children can expect the medicines prescribed for them to have at least as good an evidence base as in adult practice. This requires research. Children have the right to have research undertaken on the diseases that affect them and the drugs used to treat them. They also have the right to safeguards from that research and the researchers, the right to informed consent (or their parents’ consent) and the right to research governance.

The practice agenda

Before a pharmaceutical company can promote a drug, it must obtain a licence [1]. The process differs between countries, but the principles are similar: the company must demonstrate the quality, efficacy and safety of the drug when given in the dose and for the disease and age group recommended in the Summary of Product Characteristics (SPC). Drugs are increasingly licensed throughout the European Union (EU). In the UK, doctors can legally prescribe drugs without a licence (unlicensed) (e.g. as a different formulation) or outside the terms of the licence (off-label) (e.g. in a different dose or for a different disease or age group). Prescribing outside the licence is relatively common for hospitalized children [2–5]. In one neonatal intensive care unit, 90% of the infants received unlicensed or off-label drugs. In primary care, 11–33% of prescriptions for children were unlicensed or off-label [6, 7].

The current licensing arrangements ensure a rigorous assessment of most drugs used for adults. In contrast, when an unlicensed or off-label medicine is prescribed for children these safeguards are absent. Extrapolation from adult data is necessary, despite the great biological differences between adults and children [8, 9] and between children of different ages [10], and children may be given inadequate doses or exposed to unknown risks. There is also some evidence suggesting that adverse drug reactions are more likely with unlicensed or off-label medicines [11]. Furthermore, outside the licence standardized postmarketing surveillance will not occur, spontaneous reporting of adverse drug reactions may be less common, and the Patient Information Leaflet (PIL) will confuse the parents if it states ‘not to be used in children’.

Adverse events can be very different in children, as the well-known examples of tooth staining with tetracyclines and the ‘grey baby’ syndrome with chloramphenicol show. The more recent withdrawal of many selective serotonin reuptake inhibitors (SSRIs) for childhood depression because of an increased risk of suicide reinforces the danger of assuming that children are ‘mini adults’ and extrapolating automatically from adult data. Randomized controlled trials were presented as indicating some limited efficacy in children. The increased risk of suicidal ideation over placebo was an adverse effect seen in trials in adolescents and children, not adults. No medicine was licensed for the treatment of depressive illness in children and adolescents, but SSRIs have been used in this population off label. The UK review by the Committee on Safety of Medicines in 2003 was initiated following receipt of clinical trial data advising that in patients aged under 18 years with depressive illness, the balance of risks and benefits for paroxetine was unfavourable. There was subsequent criticism that pharmaceutical companies had published only a subset of trials on SSRIs in children showing a favourable benefit-to-harm balance and had withheld unfavourable data [12] and that trial authors had had financial interests [13].

The current professional position of prescribers in the UK

The Royal College of Paediatrics and Child Health (RCPCH) has issued the following advice:

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  Those who prescribe for a child should choose the medicine that offers the best prospect of benefit for that child, with due regard to cost.

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  The informed use of some unlicensed medicines or licensed medicines for unlicensed applications is necessary in paediatric practice.

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  Health professionals should have ready access to sound information on any medicine they prescribe, dispense, or administer, and its availability.

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  In general, it is not necessary to take additional steps, beyond those taken when prescribing licensed medicines, to obtain the consent of parents, carers and child patients to prescribe or administer unlicensed medicines or licensed medicines for unlicensed applications.

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  NHS Trusts and Health Authorities should support therapeutic practices that are advocated by a respectable, responsible body of professional opinion.

In the absence of data from randomized trials, the Health Technology Assessment Committee and the Quality of Practice Committee of the RCPCH recommend consensus methods [14]. Consensus from authors within the UK and funding from a charitable grant from the Nuffield Foundation was used to produce the formulary entitled Medicines for Children[15, 16], until recently the best authority on prescribing unlicensed or off-label medicines for children (see the British National Formulary for Children below).

Consensus guidelines or formularies also provide some protection for individual prescribers. In UK law, the legal principles surrounding the required standard of care have been established through case law. The two cases most often quoted are Bolam and Bolitho [17, 18]. From these cases, it is held that health carers must act reasonably within their own abilities, following practice that is respected by a responsible body of opinion and has been logically thought through. The importance of peer concurrence (of which the formulary Medicines for Children is an example) can be traced to the Bolam judgement of 1957: ‘A doctor is not guilty of negligence if he has acted in accordance with a practice accepted as proper by a responsible body of medical men skilled in that particular art’.

A second edition of Medicines for Children followed, but the sustained production of repeated and updated editions could not be guaranteed on the basis of goodwill and charity. The Children’s National Service Framework emphasized that health professionals should have access to authoritative, regularly updated information on paediatric prescribing in a single source. Subsequently, the UK Department of Health became committed to funding the dissemination of a children’s version of the very successful British National Formulary, which will be revised annually.

The British National Formulary for Children

The UK Department of Health has distributed free of charge the first edition of the British National Formulary for Children (BNFC) to all UK doctors. This is a collective publication by the RCPCH, British Medical Association, Neonatal and Paediatric Pharmacists Group and the Royal Pharmaceutical Society of Great Britain and is now the definitive reference source for safe and effective use of medicines for children. The BNFC is aimed at all healthcare professionals involved in the prescribing, dispensing and administration of medicines to children. Like the main BNF, the BNFC will be available on-line free of charge to healthcare professionals in the developing world. Currently, when a new edition of the BNF is published, copies of the previous printed version are collected and distributed to developing countries through the Commonwealth Association’s Pharmaid project. A similar arrangement will be put in place for BNFC.

The research agenda

The May 2004 report Safer and Better Medicines for Children from the RCPCH [19], which was commissioned by the Department of Health, the Medical Research Council and the Association of British Pharmaceutical Industry, established the state of play in children’s research. As a consequence of the paucity of data to support evidence-based treatment for children, children’s medicine is one of the first areas developed under the umbrella of the new UK Clinical Research Collaboration (UKCRC), which will provide infrastructure and networks to enable medical studies in a range of targeted medical fields [20].

The Institute of Child Health in Liverpool was selected as the coordinating centre for the Medicines for Children Research Network (MCRN) (http://www.liv.ac.uk/mcrn). The key purpose of this network is ‘to facilitate the conduct of randomized prospective trials and other well-designed studies of medicines for children, including those for prevention, diagnosis, and treatment’.

The Coordinating Centre recently called for proposals to establish regionally based local research networks. Local research networks will receive considerable funding to improve the infrastructure to support the conduct of multicentre clinical studies addressing medicines for children. The MCRN has also started to develop Clinical Studies Groups made up of clinicians, consumers, funding bodies and other stakeholders to suggest research priorities ‘bottom-up’ in each field of paediatrics. The MCRN will also develop, for the network, a training programme, information systems and processes to help negotiate the complex regulatory framework.

New draft European legislation

This is designed to encourage more research on medicines for children and hence to address the lack of data to underpin evidence-based prescribing. In 2000, the EU Council called on the European Commission to make proposals in the form of incentives, regulatory measures or other supporting measures in respect of clinical research and development to ensure that new medicinal products for children and medicinal products already on the market are fully adapted to the specific needs of children.

The key measures included in the draft European paediatric regulation for new medicines [21] include a mixed reward and incentive in the form of 6 months’ extension in all licensed age groups to the supplementary protection certificate (in effect, a 6-month patent extension on the active moiety). This is a reward for undertaking studies in children, irrespective of whether the outcome of the studies show a benefit for children. For orphan medicines [22], an additional 2 years of market exclusivity will be added to the existing 10 years awarded under the EU orphan regulation. For older medicines, a new type of marketing authorization, the Paediatric Use Marketing Authorization (PUMA), will allow 10 years of data protection for medicines that are solely for paediatric use.

This proposal is currently under consideration by the Council and the European Parliament in a codecision procedure.

Conclusion

At present there is a lack of evidence to support much of the drug prescribing for children. Measures are in place within the UK and Continental Europe to encourage more research on drugs in children. The British National Formulary for Children provides an authoritative information source which should help standardize and rationalize children’s prescribing, thereby protecting both children and prescribers.