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Discovery & Development Formulation

Small Pharma

In 2007, new legislation compelled drugmakers to test new products in pediatric populations – a big step forward for children. Doctors should never again be put in the position of having no information on whether a new medicine is safe or effective for younger patients. Unfortunately, there is a catch. The vast majority of drugs being prescribed for children are not new – they are old drugs often used off label.

Off label doesn’t always mean no evidence – take amoxicillin. Until recently, the label for amoxicillin meant that most children under the age of 10 were being treated off label. In the UK at least, it was common use and we had precise guidelines on dosages. The risks for children in this instance were very small.

However, there are other medicines, much more rarely used in children, where very little information exists. In those cases, we base the off-label doses on anecdotal evidence or on the theory of a group of experienced clinicians. But with no pharmacokinetic studies, we often make an educated guess at best. For medicines like salbutamol, when used intravenously in acute asthma, there is a large variation in practice in terms of speed of administration and exact dosage. Given that the drug is typically given to very sick children, it raises some concerns.

Dosage is not the only issue. We also need formulations that are appropriate for all age groups. A lot of medicines don’t have a palatable oral formulation, so it can be a real challenge to get a child to take them. Or we have a tablet for adults but a child’s dose is a tenth of that, so we’re having to dissolve the tablet, dilute it and then take a tenth of the dose out. A small error in this process could have serious consequences.

Historically, drug companies have (understandably) shied away from pediatric trials. Carrying out clinical trials in children is challenging and by their nature all clinical trials carry some level of risk. However, research and evidence-based practice should now be considered part of everyday care, especially in children. The pediatric population is one of the very few where consent is not given by the person taking part in the study, so issues of assent and consent do require careful handling. Older children are encouraged to participate in decision-making but definitive advice is difficult since there is such a wide range in children’s ability to understand risk. Even adults often find it hard to conceptualize a 1-in-1000 risk versus a 1-in-100,000 risk, so finding ways to clearly communicate risk to children is vital.

Pediatricians are in a better position than ever before when it comes to medicines hitting the market.

There are practical issues too – something that both industry and academic researchers sometimes fail to consider. I sit on an ethics committee for pediatric studies and some of the proposals we receive have clearly been copied word for word from the adult protocol. That might include taking 10 blood samples in the first 24 hours, which could be very distressing and potentially harmful to young children. Though it may make trials more expensive, there are ways around this – for example taking research samples only when clinical samples are being taken, scavenging samples from clinical practice and using a cannula for repeated samples. Computer modeling can be used to pull together samples from many different children, so that each child only has to give a few.

Spurred on by the 2007 legislation, the pharma industry has made big steps forward in planning and conducting pediatric studies for new drugs. I believe pediatricians are in a better position than ever before when it comes to medicines hitting the market today. But while the same legislation also provided a number of incentives to develop off-patent drugs for pediatric indications, only one drug has come though this pathway so far. It’s evident that the current incentives are not capturing pharma’s interest, and need to be reviewed. There are a number of pediatric and neonatal academic networks conducting studies on off-patent drugs, but we need all stakeholders, including pharma, on board if we’re to keep the momentum going for children’s medicines.

The real proof of progress comes down to a simple question: if your child comes into hospital today, how likely are they to be given an unlicensed or off-label medicine? Unless we can update older drug product labels with solid pediatric trial data, the answer will remain “likely”.

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About the Author
Helen Sammons

Dr Helen Sammons is Associate Professor of Child Health at the University of Nottingham, a trained Pediatric Clinical Pharmacologist and a Consultant Pediatrician at the Derbyshire Children's Hospital. Dr Sammons is current chair of the RCPCH Joint Medicines Committee.  She was part of the working group for the Nuffield Bioethics Foundation report - Children and clinical research: ethical issues. Her research interests include clinical drug trials in children and neonates (including the TINN and TINN 2 FP7 projects), safe and effective prescribing and the ethics of pediatric clinical trials. Her published work includes the ethical issues surrounding clinical trials and the European Legislation, safety in clinical trials, sedation for diagnostic imaging and prescribing assessment.

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