INNsight articles by Duncan Curley

Introduction

On 26 January 2007, European legislation to support the clinical development of medicines for children came into force.  Many drugs are not licensed for use in children or are prescribed to children off-label.  Whilst unlicensed and off-label prescribing do not often cause adverse drug reactions in children, there are clearly health risks involved in not properly researching the effect of medicines in the paediatric population before they are widely used.  The Paediatric Regulation (Regulation (EC) No. 1901/2006 as amended by Regulation (EC) No 1902/2006) makes available certain rewards and incentives in order to encourage clinical trials of medicines in children.  In particular, the new law will reward the innovative pharmaceutical industry with an additional six months of market exclusivity for paediatric studies, both of new drug products (still under development) and patent-protected products that have already been authorised. 

Compulsory paediatric studies

The main obligation in the Paediatric Regulation is the requirement that all applications for marketing authorisations for new medicines should contain the results of clinical trials carried out in children, in accordance with a plan that has been agreed in advance with the EMEA. This requirement will enter into force on 26 July 2008.  It will not apply to generics or biosimilars.  From 26 January 2009, the Paediatric Regulation will also apply to applications for variation or extension of an existing marketing authorisation for an approved patent-protected product (such as for a new indication, a new pharmaceutical form or a new route of administration).  Since not all medicines developed for use in adults will be suitable for children, or will be needed to treat children, the Paediatric Regulation will offer the possibility of obtaining a product-specific waiver.  In addition, the EMEA will be able to defer paediatric studies when they might delay the authorisation of products in the rest of the population. 

Paediatric Investigation Plans

A Paediatric Committee will be established within the EMEA by 26 July 2007.  It will take primary responsibility for the scientific assessment of and agreement to proposals made by sponsors for clinical studies in children.  Paediatric Investigation Plans will need to be agreed between sponsors and the Paediatric Committee early on in product development and well before the application for marketing authorisation is submitted.  There will be a check for compliance with the Paediatric Investigation Plan at the validation step for marketing authorisation applications.  The fact that all of the measures contained in the Paediatric Investigation Plan have been complied with will be recorded in the marketing authorisation and this will be the basis upon which companies can obtain the rewards for compliance (see below). 

Rewards for the innovators: a six month SPC extension

The Paediatric Regulation will reward companies for undertaking the necessary additional clinical trials in children with the possibility of a six month extension to the duration of a supplementary protection certificate (SPC).  A SPC is the European equivalent of a patent extension.  It confers rights that can be asserted in court in order to prevent the use of a patent-protected active ingredient (or combination of active ingredients) in a medicinal product that has received a marketing authorisation in a EU Member State.  If granted, a SPC can confer a maximum of five years of extra protection beyond the date of expiry of the basic patent designated in the SPC.  The immense value of SPCs to the innovative pharmaceutical industry is well known and the possibility of a six month extension is a generous reward to research-based companies that is likely to be significantly in excess of the cost of conducting additional clinical trials in children. 

Conditions for obtaining the reward

It is important to note that the reward of an extra six months to the term of a SPC is not conditional upon demonstrating the effectiveness of a product in paediatric studies.  The grant of the reward only requires that studies described in the Paediatric Investigation Plan be completed - it does not require them to be successful.  In order to get a paediatric extension, all of the measures in the Paediatric Investigation Plan must be complied with.  The product must also be authorised in all of the EU Member States.  Until 26 January 2012, it will be possible for innovators to apply for an extension to the duration of a SPC following completion of paediatric trials, provided that they do so not later than six months before the relevant SPC expires.  After 26 January 2012, the extension to the SPC must be applied for not later than two years before the SPC expires. 

Can existing paediatric studies be taken into account?

Some companies have already conducted clinical trials in children.  The results of previous paediatric studies and all paediatric studies that were started before the Paediatric Regulation came into force can be included in a Paediatric Investigation Plan and they will be taken into consideration by the Paediatric Committee when assessing Paediatric Investigation Plans.  However, rewards will only be available provided that "significant" clinical studies are completed after 26 January 2007.  It is not yet known what will constitute "sufficient" studies for this purpose. 

When will the first European paediatric extensions be granted?

A major issue for the generics industry is to understand the timing of the first paediatric extensions.  It seems unlikely that there will be any applications for paediatric extension this year (2007), because the Paediatric Committee will not be established until July 2007 and it cannot consider any Paediatric Investigations Plans until then.  After that, it is not known how long the Paediatric Committee will take in order to agree and approve Paediatric Investigation Plans submitted to it, or how long it will take innovators to do "significant" further clinical studies in children (supplemental to those carried our prior to 26 January 2007) so that they can be considered as part of a Paediatric Investigation Plan.

Not all bad news for generics...

The Paediatric Regulation establishes a new type of marketing authorisation: the Paediatric Use Marketing Authorisation (PUMA).  A PUMA will be available for off-patent products that are already authorised and that are further developed exclusively for use in the paediatric population.  Companies that successfully apply for a PUMA will receive ten years of data exclusivity, i.e. no other company will be able to rely on the data collected by the holder of a PUMA until ten years has elapsed from the date of the marketing authorisation.  A PUMA will not provide market exclusivity.  Other companies will in theory be able to apply for their own PUMA, although in practice the Paediatric Committee may refuse to sanction further clinical trials in children of the same drug, on ethical grounds.  Thus, in practice, this system may reward the company that is first in the queue with its application. 

An application for a PUMA will need to include data on the use of the product in children assembled pursuant to a Paediatric Investigation Plan approved in advance by the Paediatric Committee.  PUMAs will theoretically be available from 26 July 2007, although it will of course be necessary first to obtain the agremment of the Paediatric Committee to a Paediatric Investigation Plan and then to conduct the studies described in that plan before any application for a PUMA can be submitted. 

Conclusion

A 2004 report on the likely impact of the Paediatric Regulation concluded that the incentive of a PUMA would be much less valuable to manufacturers of generic medicines than the six month extension of a SPC would be to the innovative industry.  Although designed with the off-patent sector in mind, a PUMA will not necessarily result in higher sales, whereas the reward of a six month SPC extension will usually more than offset the additional cost of paediatric testing.  The principle behind the Paediatric Regulation is eminently laudable, but one has to question whether it has succeeded in achieving a fair balance between the interests of the two sides of the pharmaceutical industry.