The importance of paediatric drug formulations and clinical trials in children was highlighted at this month's American Association of Pharmaceutical Scientists (AAPS) conference in San Diego.
"Different governments have begun to realise that a lot of drugs have not been studied in children that have been around for awhile," Bristol-Myers Squibb group director Dr Jethro Ekuta told in-PharmaTechnologist.com at the conference. In the past few years, legislation and regulations have come into force around the area of drug safety and efficacy studies on children. The conference speech comes at time when masses of cough and cold drugs for under two-year-olds were voluntarily taken off shelves by drug makers last month in what they called a precautionary measure against overdosing on the drugs, which had been reported in "rare instances". Since then a panel of experts in the US have recommended that cough and cold medicines, specifically those that contain antihistamines, decongestants and antitussives, should not be used in children under the age of two. The advisory panel also suggested manufacturers needed to conduct further clinical trials to show the drugs were efficacious in children and that drug labels should carry stronger language. Ekuta said in the past, children's dosage forms had been based on adult dosages with paediatricians having to guess what was appropriate and titrating down from a higher age range based on the child's body weight or body surface area. "This was a guessing game," Ekuta said. "[But] children just don't behave the same way as adults. Some studies find that some drugs are just not appropriate in children, and others where a higher dosage is needed and others where a lower dose is needed, and children can develop certain adverse events not seen in adults. It's essential to not just assume the dose in children." Big pharma had stayed away from testing for safety and efficacy in children due to cost, time and ethics factors, Ekuta said. That had not been a problem until recently. As a result of the new thinking, the US Food and Drug Administration (FDA) introduced an incentive with the 1997 Modernisation Act and the Best Pharmaceuticals for Children Act, which gives manufacturers a six-month exclusivity if they conduct studies in children. The European Medicines Agency (EMEA) has also introduced a six-month incentive similar to the US, giving already marketed drugs an edge in the market. But rules have become tighter still, especially for drugs yet to be approved. The EU has introduced a Paediatric Investigation Plan (PIP) to make sure data on children is included in drug development, not as an optional extra. From 27 July next year, an approved PIP must be included when submitting a Marketing Authorisation Application (MAA) or the drug will be automatically rejected. The only way out is to request a waiver or a deferral so as to focus on adults first, but these have to be approved prior to MAA submission. In December 2003, the US introduced the Paediatric Research and Equity Act (PREA) which says all US pharmaceutical companies must provide data on children for all new drugs, new indications, new dosage forms, new administration routes, new dosing regimens and new active pharmaceutical ingredients.
It is understood the FDA is currently undergoing a review of the acts and paediatric medicine research with the aim of providing documentation to Congress. The regulations put a hefty onus onto the pharmaceutical companies, who now have to take into account changes in formulation for paediatric applications of adult drugs, the ethics of enrolling children in clinical trials, the finding of clinical investigators for the trials, and the cost and time involved, Ekuta said. "Every pharma company knows it's important to study drugs in children. Everyone is looking for ways to conduct these studies. It has become an integral part of the drug development programme. But it is still new so a lot of companies are still not sure what it means for the company." Last week, the Washington Post published an article claiming there was still a massive hole in the knowledge of how many medicines actually work and are safe in the paediatric population. About two-thirds of the thousands of medicines used in children remain untested, the article said.
Meanwhile, of those that had so far been tested in children, findings showed about one in five drugs that worked in adults were ineffective in children; one in five required the doses to be changed; and about one in three drugs caused unexpected side effects in children, the article reported.