Rational prescribing for children

Many drugs used to treat children are unlicensed or off label.¹ Three recent news stories highlight how children, like adults, are at risk from overprescribing and inappropriate prescribing. A systematic review conducted by the National Institute for Health and Clinical Excellence has shown fluoxetine (with or without cognitive behavioural therapy) to be the only selective serotonin reuptake inhibitor that is more effective than placebo in teenage patients with depression.² Furthermore, the US Food and Drug Administration and the Medicines Healthcare Products Regulatory Agency have shown that most randomised controlled trials have reported higher rates of “possibly suicide-related event” and “suicide attempt event” among adolescents and children taking selective serotonin reuptake inhibitors than in those taking placebo.³ The systematic review on fluoxetine included children as young as 7 years old and found no conclusive evidence of increased suicidal behaviour or ideation in studies lasting seven to 12 weeks.² It may be surprising or even confusing for the public, nevertheless, to find that the European Medicines Agency recently licensed fluoxetine for use in children as young as 8 years old (European Medicines Agency press release 6 June 2006). Furthermore, a new US study has just reported a marked increase in antipsychotic drug use in US children and adolescents with no robust evidence of any increase in psychotic illnesses.⁴ Indeed, the number of prescriptions for psychotropic drugs—including antipsychotics, antidepressants, and drugs for attention-deficit/hyperactivity disorder—in children and adolescents has increased in most countries, catching up with trends in the United States.⁵

Societal influences no doubt affect such prescribing decisions. For example, the perceived need for treatment of attention-deficit/hyperactivity disorder is likely to increase in post-agrarian Western societies where passing exams becomes ever more important to gain a satisfactory job and pass rates in school exit exams continue to rise year on year.

Many drug trials (which are commonly industry sponsored) do not ask the right questions about new drugs, let alone test them on children. The trials usually test news drugs against placebo when they should test against established treatments. Furthermore, when an established treatment is already known to have an unacceptable side effect profile, further molecules derived from the primary entity will probably suffer the same fate.⁶

Thus it is worrying that, in an area with a very poor track record (slimming therapies), a new definition of child obesity and overweight has been agreed (apparently with industry influence) that would define far more children as obese.⁷ So far, only increased exercise, spending less time sitting in front of television or computer screens, and decreased consumption of carbonated drinks have been shown to be effective in reducing obesity in children. According to the proposed new definition, 25% of US toddlers and almost 40% of children aged 6-11 years could be classified as “overweight and obese.”⁷ If the new definition is accepted and drugs for reducing obesity prove acceptable, these children will represent a very big market.

Well recorded catastrophes associated with drugs for children have led to new legislation that provides financial incentives to extend the testing of drugs to child patients.⁸ Led by the US Food and Drug Administration,⁹ the European Medicines Agency has followed suit.¹⁰ The agency now offers a licence extension to those who have conducted testing in children for new drugs and a newly created licence entitled “paediatric use marketing authorisation” (PUMA) for old drugs.

What challenges must be met and mechanisms used to ensure that good clinical studies can be practically achieved? The Medicines for Children Research Network has now been established in England by the Department of Health at a cost of £20m. The network comprises six local research networks, coordinated from Liverpool, and will have the potential to recruit children from a child population of five million. The network's aim is to carry out high quality clinical studies and expand the evidence base in relation to drugs for children, both for new chemical entities and for those already used off label or unlicensed. For example, a randomised placebo controlled trial of melatonin in sleep disordered children will soon be conducted via the network, and funded by the Health Technology Assessment Programme of the Department of Health. Simultaneously, the European Medicines Agency is coordinating the collaboration of many national European networks for research on drugs for children.

New non-invasive methods such as breath tests, saliva samples, reverse iontophoresis, and sparse data analysis for pharmacokinetic and pharmacodynamic testing of drugs will be more acceptable and less distressing to both children and parents, making data collection easier.¹¹ However, such techniques still require further development, particularly in data analysis and interpretation.

Doctors prescribing drugs for children are already being helped by the British national formulary for children.¹² This widely welcomed manual brings together available evidence concerning both licensed and unlicensed drugs for children, and a second edition will be published soon.

While these initiatives represent constructive steps forward, should we be prescribing psychotropic drugs or antiobesity drugs to young children when there are so few drops of rain in this evidence based desert? The answer must be the same as for adults: practitioners should only prescribe drugs with clear evidence of favourable ratio of benefit to risk. Practitioners need to remain wary of both industry influence and societal pressures.