The Proposed Regulation on Medicines for Paediatric Use

The Council of Ministers (made up of representatives of Member States) has backed the proposed EU Regulation¹ on medicines for children. The draft Regulation can now proceed to the second reading in the European Parliament and could become law by 2007. The Regulation aims to improve the health and safety of children in Europe by increasing the research, development and authorisation of medicines for use in children. It is hoped that this will be achieved without subjecting children to unnecessary clinical trials.

There are 100 million children in the 25 Member States of the European Union. This represents over 20% of the EU population. Whilst medicines authorised for use in adults must undergo extensive testing, including clinical trials, to ensure that they are safe, of high quality and effective, this is not the case for medicines used to treat children in Europe. It has been shown that more than 50% of medicines used in children have not been tested and are not authorised for use in children. In practice, this means that when a doctor prescribes for a child, the decision to use a particular medicine at a certain dose is not evidence- based. This is relevant since the paediatric population has age-related differences to drug handling and side effects; this may lead to under or over dosing and an increase in adverse effects. In addition the doctor is limited in what can be prescribed since there are practical problems of administration; a child may not be able to swallow a tablet and obtaining the right dose using an adult formulation can be difficult.

Currently the pharmaceutical industry is free to choose which medicines to develop, authorise and market. Their choices are driven by the predicted overall return on investment, which is dependent on the size of the target market and the price achievable within the market-place. Unfortunately, children are not as lucrative as adults in this respect, since the number of children suffering specific diseases is generally lower than in the adult population. Additionally, studies in the paediatric population are more complex due to the wide variation within the population; from a premature baby to a 15 year old. Market forces alone have proved insufficient to stimulate adequate research into medicines for children, since the potential return is considered insufficient to justify such investment into research and development.

The draft Regulation aims to address the issues of the lack of research and authorised medicines for use in children.

The key elements are:

• A Paediatric Investigation Plan ("PIP"). This is the research and development programme aimed at ensuring the necessary data are generated in order to authorise the medicine for use in children. Two principles need to be applied when drawing up this plan, first, the study should only be conducted if there is a potential therapeutic benefit to children, and secondly, the requirements for studies in children should not delay the authorisation of medicines for adults.

• The data resulting from the agreed PIP will be required at the time of the marketing authorisation application.

A system of waivers from the Requirement for a PIP and the resulting data will exist for medicines that are unlikely to benefit children; mainly medicines that have been developed for diseases that occur only in adults, such as Alzheimers disease. In addition, there will be a system of deferrals from the Requirement for data, to ensure medicines are tested in children only when it is safe to do so and to prevent the delay of authorisation of medicines for adults.

• As compensation for the extra costs involved in conducting clinical trials before authorisation of drugs and as an incentive for more research and development, companies will be granted a six month extension of their patent in the form of a six month extension to the Supplementary Protection Certificate ("SPC").

• For orphan medicines the incentive will be an additional two years of market exclusivity to the existing ten years awarded under the EU Orphan Regulations. Orphan medicines are those intended for rare and life threatening diseases or medicines that are unlikely to be developed under normal market conditions.

• The draft Regulation creates a Paediatric Committee, which will assess the PIPs and waiver or defer the Requirements where necessary.

• The creation of a fund to finance research into the possible adaptation of medicines used in adults for use by children.

• The setting up of a network of researchers and research centres designed to prevent duplication of research and tests on children.

The draft Regulation has come under attack from various fields. Poland voted against the draft Regulation as it disagreed with the fixed six month extension to the SPC, arguing that this delayed the marketing of cheaper generic products, thereby restricting patients’ access to therapies and increasing expenditure in national healthcare budgets. Poland’s objections will not prevent the adoption of the Regulation. Latvia also expressed concerns about the SPC extension although it voted in favour of the Regulation. The European Generic Medicines Association has argued that the six month extension should only apply to low selling products and not to blockbusters, since this would generate up to two billion Euros per year in additional costs to healthcare systems. The European Union Geriatric Medicine Society has pointed out that the number of people aged over 80 years is set to double every ten years, yet the majority of medicines given to older people have not been studied in clinical trials in older populations.

Clearly there are a number of issues to consider:

• whilst the Requirements have been deemed necessary since market forces alone have failed to stimulate sufficient research, there must be a cost-benefit balance such that the incentive is adequate to stimulate research but not excessive. A disproportionately high reward could stimulate research for the wrong motive;

• the reward/incentive must strike a balance between the gain for the innovative industry and the potential costs to society; the burden on the healthcare system and the costs to the generic industry. By extending patent life, generic competition will be delayed. The potential public health benefits of having safe and effective medicines for children is thought to justify the loss of profit to the generics sector and the increase in costs to the healthcare system; and finally

• perhaps the Paediatric Committee should target research by considering the existing evidence on factors such as adverse outcomes from the use of certain medicines. This could avoid studies into medicines where there is no problem.

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