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Clinical trials of medicines in children are essential. So it may seem strange, despite recent lobbying and legislation, to discuss when clinical trials in children can be avoided. One specific aim of the Paediatric Regulation was that it should improve the health of children in Europe without subjecting children to unnecessary trials.1 A clinical trial in children should only take place when the information cannot be gained from a trial in the adult population. This should always be kept in mind when planning a protocol. Can the information be reliably obtained from adults? The article by Mulla et al in this month's Drug therapy is a good example of how this can be put into practice and clinical trials in children avoided.2
Differences in pharmacokinetics and pharmacodynamics, and adverse reactions, are common in children compared to adults. Growth and maturation processes, as well as certain specific diseases, are unique to children.3 However, it is rare that a phase I study takes place in children. Phase I trials are the first stage of testing in human subjects. Normally, a small group of healthy adult volunteers (20–80) is selected.
Phase II trials are performed on larger groups (20–300) and are designed to assess the clinical efficacy of the therapy, as well as to continue safety assessments in a larger group. These rarely occur in children initially as a safe dose is established in adults, except when a disease is exclusive to the paediatric population, for instance, bronchopulmonary dysplasia in the premature neonate requiring treatment with surfactant.
One aspect of the paediatric investigation plan that is submitted during drug development is that a suitable formulation should be available for children. The importance of this is highlighted by Mulla et al.2 They show that different formulations even when prepared to clinically acceptable standards can have significant differences in bioavailability, and hence potential clinical impact. Such research is therefore important for children but can be very difficult to perform in that population. The pharmacokinetic analysis needed blood samples taken at regular intervals (up to 10 h) after dose administration.
This study would have been unethical in children and would have had to be performed using children already taking captopril, thus exposing them to potential clinical consequences. Techniques such as population pharmacokinetics, that take smaller numbers of blood samples from larger numbers of children, would have needed to be employed.4 Their study highlights how healthy adult volunteers can be used to gain useful information for paediatric clinical practice and decrease unnecessary exposure in children.
Are there any other ways that trials can be avoided?
It is unethical to unnecessarily replicate trials in children. This can only be avoided by ensuring that information gained in any trial is made available to researchers and the public. This can be achieved by all trials being registered on an international database so that ongoing research is visible to all. Article 41 of the Paediatric Regulation (Regulation (EC) No 1901/2006) provides the legal basis for the publication of information on paediatric clinical trials entered in the European Medicines Agency database (http://eudract.emea.europa.eu) and their details to be made public.
Many medicines in paediatrics are used in an off-label or unlicensed manner.5 6 This does not always mean that further clinical trials are required. At least two efficacy and two pharmacokinetic trials, and a comparable safety profile between children and adults, constitute the required level of evidence for registration and regulatory purposes. Tafuri et al highlighted the case of proton pump inhibitors (PPIs), in the treatment of gastro-oesophageal reflux disease.7 Of the five authorised PPIs in Europe, only one, omeprazole, has a paediatric indication (in children >2 years of age), yet omeprazole, esomeprazole and lansoprazole showed a satisfying level of clinical evidence for paediatric use. This also highlights the issue of the number of medicines in each class that need to be available for paediatric use. In fact, the amount of information available for omeprazole makes the performing of further trials on a molecule of the same class, such as rabeprazole, unethical unless within comparative trials to prove additional benefit (such as better formulation, improved palatability or decreased dosing schedules).
When a change of formulation or route is considered, then this can be explored in adults prior to a definitive trial in children. An example of this would be rectal diazepam and buccal midazolam. A pharmacokinetic study of the buccal absorption of midazolam in 10 healthy adult volunteers showed EEG changes within 5–10 min of buccal administration.8 This then paved the way for a randomised controlled trial in children which confirmed that buccal midazolam was more effective than rectal diazepam for children presenting to hospital with acute seizures.9
In conclusion, clinical trials in children are important. The Food and Drug Administration Modernisation Act (USA) and the Paediatric Regulation (Europe) ensure all new licensed medicines undergo evaluation in children if appropriate. Paediatric-use marketing authorisations promote the development of new indications and appropriate formulations for children.10 However, every time we design a trial we do need to consider whether it is necessary. What evidence can be gained from the adult population, current literature and clinical practice? Does this trial need to take place?
Competing interests Helen Sammons is a member of the Ethics Advisory Board for the TINN (Treat Infection in Neonates) Project.
Provenance and peer review Commissioned; internally peer reviewed.
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