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Putting children first — why paediatric clinical trials must be conducted

By Chi-Loon Cheung, Seau-Tak Sung and John Persaud

If there is one group of patients to whom the notion of "try everything" is applied it is children. Indeed, the current practice of paediatric medicine means that every child patient undergoes an experimental procedure. Alarming this may be, but it is not surprising given that approximately half of all medicines used in children are either unlicensed or used off-label.¹

Licensing laws and a lack of incentives have conspired to produce a real deficit in proven safe and efficacious treatment for ill children. Furthermore, drug companies cannot be compelled to have their medicines licensed for children. (Why bother when doctors will prescribe drugs whether they have licensed indications or not?) Unfortunately, these issues place an unnecessary burden on those of us who are involved in the care of this vulnerable group of patients.

What makes children special?

It is too simplistic to suggest that children are "small adults". Yet nearly all children's medicines are based on adult use, either as a result of estimating therapeutic doses or reformulating adult dosage forms (eg, converting tablets to liquid preparations).

Drug doses (as stated in the British national Formulary and manufacturers' datasheets) are partially derived from the metabolism of an average weight adult, usually 60kg. However, drugs perform differently in children because their liver and kidney functions have not fully developed and higher mg/kg doses than those for adults are not unusual in paediatric dose response/efficacy studies. Calculating child doses from those used in adults, without acknowledging children's physiological differences, may inevitably mean treatments ending in therapeutic failure (too little drug given) or toxicity (too much drug given).

Informative pharmacokinetic data from children is difficult to obtain. From a practical approach, at least two blood samples are required to define a straight line and three or more to verify linear relationship; an average pharmacokinetic study will use 10 samples to define the kinetic profile for a two-compartment model. Obviously, the removal of such blood volumes puts small babies and young children at clinical harm. For this reason, blood samples taken for paediatric research amount to less than 5 per cent of the circulating volume. However, improvements in non-invasive methods (eg, urinalysis, saliva analysis, breath testing) do offer new alternatives for drug monitoring.²

In an ideal world of medicines, tablets and capsules are the holy grail of dosage forms; they do offer an easy and convenient method for ingesting drugs. That is unless you are a child. For this person, swallowing a tablet is a mammoth task.

To an adult, a tablet is small and presents no problem as it travels from mouth to stomach. If presented to a two-year child, such an item would be the size of their thumb-tip. To complicate matters, they would then be told not to cause any damage to it inside their mouth, ie, "swallowed whole, not chewed". As children mature into adulthood the swallowing reflex becomes more sophisticated. Until then, liquid formulations remain the most convenient and comfortable method for giving medicines to young children.

The spectrum of disease also varies between adults and children. What may be common and relatively benign conditions in adults (eg, peptic ulcers) will tend to be rare, and usually more serious, in children. Although the occurrence of hypertension and heart failure in children is low, these conditions are associated with more serious morbidity. Also, the outcomes of depression and schizophrenia in children are different from the outcomes in adults.

Failing in our duty

Right from the beginning, a child is a person with special needs; children are solely dependent on the protection and support of adults. Yet, we fail in this duty by consistently administering medicines that have not been fully tested. The Medicines Act 1968 typically offers protection to the adult population.

The publication of "Better medicines for children"³ reveals that the European Commission has concerns about the lack of licensed paediatric medicines. A key theme of this document is the voluntary participation in the creation of licensed products for children. However, this approach may mean interested parties only focus on a narrow spectrum of disease, thereby encouraging multiple paediatric studies of "me too" drugs. Unless mandatory clinical trials are carried out in children, it is debatable whether the range of children's medicines will significantly increase. Indeed, the United States 1994 Pediatric Rule was criticised as an "abysmal failure".⁴ Its voluntary nature resulted in minimal participation by drug companies to conduct studies for determining paediatric use of adult licensed medicines.

Licensing is about safety, knowledge, and confidence. Adults can be reassured that every attempt has been made to reduce injury from drug treatment. Good clinical trials not only determine efficacious doses, but are also informative about the disease. In addition, clinicians can be confident that the drug they prescribe is effective, and are able to anticipate adverse effects of treatment.

The use of unlicensed preparations forces children to be constantly exposed to products where the quality of manufacture cannot be guaranteed, and the dangers from drug treatment are sometimes greater than disease. Adverse drug reactions, such as the "grey baby syndrome" with chloramphenicol⁵ and the propofol-infusion syndrome in critically ill children,⁶ might have been avoided by obtaining knowledge of metabolism through clinical trials. Furthermore, doctors and pharmacists are limited in what they can offer for children's therapy. In most cases, the use of unlicensed medicines are frowned upon by the medical profession.

Paediatric medicine is a relatively new specialty, and much has been achieved in a short period. Nevertheless, if marketing authorisation of paediatric medicines does not drastically increase, then conducting clinical trials in children will continue to be difficult. Ultimately, an evidence base and the achievement of best practice cannot be established in children. The ending of unlicensed and off-label medicines is long overdue but, more importantly, it would demonstrate an intention to put the needs of children first.