Now that the new Paediatric Regulation has arrived, Dr Robert Harris, head of formulation development at Penn Pharmaceutical Services highlights its implications for drug developers
Before a new medicine becomes available for general use the safety and efficacy of the medicine has to be demonstrated through a rigorous clinical trial programme - in adults. So what if a physician wishes to prescribe a medicine for use in a child? How do they know what dose to give?
An alarming statistic is that for over 50% of medicines that are prescribed for use in children there have been no studies conducted in paediatrics to determine the safe and effective doses for children. Most often when there is a necessity to treat a child with a medicine developed for adult use, the physician has to judge what dose is appropriate based on the age and size of the child. Also, there are often administration issues with giving medicines intended for an adult to a child. For instance, many medicines for oral administration are tablets and capsules which are not easy for a child to swallow, this has led to the practice of producing extemporaneous preparations - commercial products intended for adults that are modified for administration to children (e.g. crushing tablets and suspending the resulting powder in a sweetened, flavoured solution).
Although this is a common practice for preparing medicines for children, it is far from satisfactory as a practice, often providing a far from satisfactory product.
On 26 January 2007, new legislation concerning the development of medicines for children came into practice within the European Union in the form of the Paediatric Regulation1. This regulation is aimed at addressing the current issues in prescribing medicines for use by children. The objective of the Paediatric Regulation is to:
- Facilitate the development and availability of medicines for children aged 0 to 17 years;
- Ensure that medicines for use in children are of high quality, ethically researched and authorised appropriately, and
- Improve the availability of information on the use of medicines for children.
Unauthorised medicines: As of 26 July 2008, all market authorisation applications for new medicinal products will require inclusion of results of studies conducted according to a paediatric investigation plan (PIP) and a new scientific committee - the Paediatric Committee (PDCO) - has been created within the EMEA to assess and approve PIPs. Therefore, there is now an obligation on behalf of organisations developing new medicines to include clinical evaluation in paediatrics as part of the overall clinical trials programme.
However, if a new medicine is considered unsafe or inappropriate for use in children (e.g. if its intended use is specifically for treating diseases in the elderly population, such as senile dementia) then EMEA approval for a waiver to the inclusion of PIP data should be submitted.
The PIP will include details of the programme intended to determine the conditions in which a medicinal product may obtain a paediatric indication. It will include a description of the studies to be conducted (covering the age range from birth to adolescence) and how the medicine will be formulated and administered for paediatric use.
In certain cases it may be appropriate for the new medicine to be first evaluated in adults before initiating studies in children, in which case EMEA approval for a deferral in the initiation of the PIP should be submitted. Requests for a waiver or deferral need to be made to the PDCO within the EMEA.
The execution of a PIP will allow a six-month extension of the supplementary protection certificate, provided that the results are included in the product information and that the product is authorised in all EU states.
Orphan drugs: Orphan medicinal products are those which have not been developed for general use due to lack of commercial interest, despite being potentially useful in medicine. As for any other new medicine, the market authorisation application for an orphan drug medicine will need to include clinical data from a PIP (unless a waiver or deferral to a PIP has been approved).
The execution of a PIP for an orphan medicine will allow an additional two years on the current 10 years market exclusivity granted under the EU Orphan Regulation2, provided that the results are included in the product information and that the product is authorised in all EU states.
Authorised, patented medicines: As of 26 January 2009, any application for a variation or extension to an existing marketing authorisation (e.g. to cover a new indication or new dosage form) will require inclusion of data from a PIP. A waiver or deferral to a PIP may be granted by the EMEA if deemed appropriate. The execution of a PIP will allow a six-month extension of the supplementary protection certificate.
Off-patent medicines: Those formulated and developed specifically for paediatric use will be eligible for application for a new marketing authorisation - the Paediatric Use Marketing Authorisation (PUMA). The submission process and requirements for authorisation are the same as for a conventional marketing authorisation. It will be mandatory for the labelling on PUMA products to carry a generic symbol (due to be published by the PDCO by 26 January 2008) to indicate paediatric use. The granting of a PUMA for a new product will allow 10 years of data protection on the product.
This legislation makes it obligatory for a company to plan and execute clinical studies in paediatrics to obtain a market authorisation in the EU (unless a waiver or deferral has been obtained). The clinical trial programme for a new medicinal product will therefore become more complicated and inevitably more expensive.
The PIP will need to take into consideration the practicalities of evaluating the clinical effectiveness of the medicinal product over a wide range of ages, from babies to teenagers. There will be a need to ensure that the drug can easily and comfortably be administered to the child - which will force companies to consider suitable strategies for paediatric administration at the very beginning of the life cycle of a new medicinal product, rather than as a potential line extension (if at all).
Also, there will obviously be a need to address the risks and ethical issues associated with administering "experimental" medicines to children. Although, is this any more of an ethical concern than treating children with medicines that have been developed and tested only in the adult population?
The financial incentives for purposely developing paediatric medicines for orphan drugs and for off-patent drugs will certainly spark interest in small to medium sized pharmaceutical companies and may well lead to the creation of niches that specialise in the development and manufacture of paediatric medicines.
All in all, the Paediatric Regulation is an important and well overdue piece of legislation that will command safer practices in the way that medicines are developed and used to treat an important but often overlooked group in our population - our children.
The EMEA's website includes a "Medicines for Children" section which provides further information on the Paediatric Regulation, the responsibilities of the Paediatric Committee and guidance for applicants with regard to PIPs, waivers and deferrals. There are also useful links to sites for further paediatric related information (www.emea.europa.eu).