May 7, 2013 | By Márcio Barra
Regulatory week continues, today with a small article on the European Pediatric Regulation for medicines. Hope you enjoy it, and if you do, please share!
European Pediatric Regulation for medicines
It’s common knowledge that before any medicinal product is authorized for use in adults, a sponsor must conduct extensive clinical trials on its pharmaceutical entity to ensure that it is of high quality, safe and effective for the adult population. As for children, this approach is rarely followed. Studies show that, in Europe, more than 50% of the medicines that are used to treat children have not been adequately tested, and their use is not authorized for children. Seeing that no suitable authorized medicinal products often exist for children, physicians have no alternative other than prescribe the medicine “off-label”, a decision that might prove risky. Children have age-related differences in how they handle the drug, usually requiring specific dosages and formulations not available in the market (1).
In this scenario, EMA and the EC introduced the Pediatric Regulation, comprised of Regulation (EC) No 1901/2006(2), on medicinal products for pediatric use, and Regulation (EC) No 1902/2006(3), an amending regulation with some changes in the original text in the decision procedures of the European Commission.
Regulation (EC) No 1901/2006 introduced the paediatric investigation plan (PIP) in the legal framework concerning medicinal products for human use, and created the PDCO. The overall objective of the new Regulation is to improve the health of the children of Europe by(2):
- increasing the development of medicines for use in children,
- ensuring that medicines used to treat children go through high quality research, and are appropriately authorized for use in this population,
- improving the information available on the use of medicines in children,
- achieving the above objectives without subjecting children to unnecessary clinical trials or delaying the authorization of medicines in the adult population.
The PIP is proposed by the sponsor, and contains a full overview of the studies and their timings necessary to support a paediatric use indication for a product that covers all paediatric age groups, with age appropriate formulations, as defined in ICH E11(1). The PIP is submitted to the European Medicines Agency’s Pediatric Committee (PDCO), which is responsible for their evaluation. The PIP must be submitted to the PDCO no later than upon completion of the pharmacokinetic studies in adults, to allow time for eventual modifications(4).
The PIP was indeed the main measure of the regulation, made compulsory on every MAA due to the fact that many of the drugs administered to adults are also administered to children, with no proper clinical data backing its use and no appropriate dosing information or formulation for children.
For a better understanding on how the PIP procedure works, it is useful to break the medicinal products down into three different groups:
– medicinal products still in development
– authorised medicinal products still covered by patents or supplementary protection certificates
– authorised medicinal products with their patent expired
The default position of the regulation states that all applications for medicinal products still in development, including orphan drugs, must contain the results from all the studies conducted in agreement with a previously approved PIP, as per Articles 45-46(2). The Pediatric Regulation requires PIPs to be submitted EMA early, wherever possible. As for rewards and incentives, sponsors are provided with a six-month SPC extension for their medicinal product, even if in the end a pediatric indication is not granted. Other rewards include patent protection, and market and data exclusivity. As for orphan drugs, the traditional ten year market exclusivity is extended to twelve-years if the requirements for data on use in children are fully met(4, 5).
These requirements also apply to requests to add a new indication, new pharmaceutical forms or new routes of administration for medicines still covered by patent protection. However, medicines already in the market that are still covered by patent product aren’t obliged to present a PIP, unless they wish to broaden the target population of their product and seize the benefits of presenting a PIP(4).
It’s worth noting that the development plan of a medicine can be modified as its development goes on and the knowledge about it increases. In some case where the current knowledge no longer matches what was stated in the PIP, modifications can be applied to the PIP.
Moreover, in some cases, the studies can be deferred until studies in adults have been completed and a more robust set of information on the drug is acquired, to ensure that clinical research in children is only done when it is safe.
For diseases that don’t affect children, for example Alzheimer’s disease, presenting a PIP is obviously unnecessary. This is called a waiver, and there are various drug classes that are included in these waivers.
Waivers can be given to drug products which(6):
- are likely to be ineffective or unsafe in part or all of the pediatric population,
- are intended for conditions that occur only in adult populations,
- do not represent a significant therapeutic benefit over existing treatments for pediatric patients.
For the last group, medicines that are already authorized and no are no longer covered by intellectual property rights, like a patent or a supplementary protection certificate, the regulation introduced the pediatric use marketing authorization (PUMA)(2).
A PUMA is a dedicated MA for an out of patent medicinal product, for exclusive use in the pediatric population, with, if necessary, an age-appropriate formulation. The introduction of the PUMA was meant to stimulate and promote the pediatric development of medicines which no longer have IP protection. For that, a PIP first has to be presented and agreed upon with the PDCO, and the PUMA application has to contain the results of all studies performed according to the PIP.
For motivating companies to conduct clinical research in children, benefits are granted to sponsors like regulatory data and market protection for their PUMA for 8+2 years, direct access to the centralized procedure, exemption from some fees and the name of their product may be retained(2, 7).
In conclusion, the PIP was introduced by EMA to better serve the needs of the pediatric population. By demanding that all new products that may be used by children to present a PIP, EMA is safeguarding the health and well-being of children all around Europe. Since the regulation was adopted, the proportion of pediatric trials as a percentage of all clinical trials has moderately increased (from 8.2 to 9.4% of all trials, 2011 data), but some critical areas are still missing PIP’s and dedicated pediatric investigation, like high-risk neuroblastoma(8). While the mentioned increase is not very significant – it may reflect the fact that pediatric trials are generally deferred (82%) until after adult development is completed – companies are definitely trying harder to conduct more trials in children(9).