What impact the EU Regulation on Medicinal Products for Paediatric Use will have on you?

After multiple rounds of public consultation and years of debate the European Union has introduced the EU Regulation on Medicinal Products for Paediatric Use. This Regulation (EC) 1901/2006 was published in the Official Journal on December 27, 2006. It came into force across the EU on January 26, 2007 although the application of its main provisions will be staggered over the next two to three years.

The Regulation aims to facilitate the development and accessibility of drugs for use in children; to ensure products for children are subject to high-quality ethical research and to improve the information available on the use of medicinal products in different paediatric populations.

Q: What are the rewards for completing paediatric studies in an agreed time frame?
A: There are three main potential rewards for companies completing paediatric studies within an agreed timeframe.

Firstly, eligible drugs that are protected by a supplementary protection certificate (SPC), or by a patent which is eligible for an SPC, will benefit from a six-month extension of the SPC.

This applies for both new and existing products. The extension can be obtained even if the paediatric studies do not, in fact, lead to the authorisation of a new paediatric indication, as long as the results are reflected in the product's Summary of Product Characteristics (SmPC) and/or Patient Information Leaflet (PIL).

Secondly, products not covered by intellectual property (IP) rights will gain full data exclusivity (under the 8+2+1 rules) through a separate Paediatric Use Marketing Authorisation (PUMA) for a new indication exclusively developed for use in the paediatric population. This will be available from July 26, 2007.

PUMA-authorised products will be entitled to capitalise on the same brand name established for the adult version if the Marketing Authorisation Holder (MAH) and active substance are the same, whether or not they are authorised under the centralised procedure.

Thirdly, orphan drugs may gain an extra two years of orphan market exclusivity. As an incentive, the European Medicines Agency (EMEA) will offer free scientific advice on the design and conduct of paediatric studies, pharmacovigilance and risk management systems.

Moreover, the incentives and rewards will not compromise eligibility for other incentives provided by the Community or Member States - for example, for research conducted under the EU's Framework Programmes.

The Community will also provide funding for research into medicinal products for children, which are not protected by a patent or an SPC.

Q: What is a PIP and why is it necessary?
A: A paediatric investi-gation plan (PIP) is defined as an R&D programme aimed at ensuring the necessary data are generated determining the conditions in which a drug may be authorised for paediatric use.

Pharma companies seeking and/or qualifying for marketing authorisation (MA) for new products, an SPC extension, or a PUMA must design and submit a PIP to the EMEA's Paediatric Committee for agreement. This must specify the timing and measures proposed to assess the quality, safety and efficacy of the drug in all subsets of the paediatric population, in addition to measures for adapting the drug's formulation for use in children.

The EMEA must establish the Paediatric Committee by July 26, 2007. Proposed PIPs must be submitted for agreement early in the product's development and no later than the completion of adult pharmaco-kinetic studies.

Q: What waivers and deferrals are available?
A: The Paediatric Committee will operate a system of waivers (both class and product-specific) and deferrals in relation to paediatric studies. The Committee may of its own motion adopt an opinion in favour of either a class or product-specific waiver (for example, where the product concerned is likely to be unsafe or in-effective for children, where it does not represent any significant therapeutic advantage over existing treatments for children, or where the target indication is limited to adults). Companies may also apply for product-specific waivers.

On submitting a PIP, companies can request a deferral of the initiation or completion of some or all of the measures set out in the PIP. Such a request must be justified on technical or public health grounds.

Q: Is eligibility for rewards restricted?
A: Eligibility for rewards is restricted. New non-orphan products, or non-orphan products that are protected either by a patent which is eligible for an SPC, or by an SPC itself, will benefit only if the product is authorised in all Member States. This may prove a hurdle to those products not authorised under the centralised procedure, especially in view of EU enlargement.

Additionally, firms will have to carefully evaluate and choose between alternative forms of extended protection available as the six-month extension of an SPC will not be allowed if an MAH has gained an additional year of marketing exclusivity for a new paediatric indication on grounds of significant clinical benefit compared with existing therapies under other EU medicines legislation.

The Regulation also restricts the time for applying for an extension of an SPC by amending the EU legislation governing the granting of SPCs (Regulation (EEC) 1768/92). Applications for an extension of the duration of an SPC will have to be filed either with the SPC application itself; while the application is pending or not later than two years before expiry of the SPC. The latter period is temporarily extended to permit extension applications up to six months before SPC expiry until January 26, 2012.

Paediatric studies in respect of products already authorised in the Community, which were either completed or initiated by January 26, 2007, can be included in a PIP. However, although data from such studies will be taken into account by competent authorities, the rewards mentioned previously will only be granted where `significant studies' contained in the PIP are completed after that date.

The Commission has issued a draft guideline setting out the criteria for assessing significance and the types of studies that are likely to be considered significant.

Q: What are the obligations under the Regulation?
A: There are several obligations that MAHs must adhere to under the Regulation.

Paediatric studies completed before January 26, 2007 in respect of products already authorised in the Community must be submitted to the competent authorities for assessment no later than January 26, 2008.

All other MAH-sponsored paediatric studies involving an authorised product must be submitted to the competent authorities within six months of completion, whether or not they are conducted in accordance with a PIP or whether the MAH intends to rely on them to support authorisation of a paediatric indication. This may lead to variations to update SmPCs and/or PILs.

Subject to waiver or deferral, whenever companies apply for:

• an MA for a new product not previously authorised in the Community; or

• a variation or extension of an existing MA concerning a new indication (including a paediatric indication), pharmaceutical form or route of administration for a product which is protected by either an SPC-eligible patent or an SPC,

- they must also submit paediatric data in the form of results of studies conducted in compliance with an agreed PIP. These filing obligations apply from July 26, 2008 and January 26, 2009, respectively for the above applications.

The above filing obligations do not apply in respect of: generics or biosimilars; 'well-established use' products; or homeopathics or herbals.

The conducting and collecting of paediatric data is voluntary for off-patent medicines. There are additional post-authorisation pharmacovigilance and marketing requirements.

Enforcement
Companies that infringe the Regulation or its implementing provisions could face potential liability, and reputational and financial exposure.

Member States are tasked with implementing effective, proportionate and persuasive penalties for infringements. They are also obliged to notify the Commission immediately of any litigation instituted for infringement.

There is provision for the Commission to directly impose financial penalties for infringement and to 'name and shame' anyone who infringes the Regulation or its implementing provisions.

Increased costs
The new obligations to generate and collect paediatric data will inevitably increase the cost of bringing new products to market for innovator pharmaceutical firms and also the costs of maintaining existing innovative products on the market (not forgetting the additional pharmacovigilance measures that will be required).

It is too early to assess how many, or what type of MAHs will achieve net benefits under the Regulation.

It is conceivable that some innovator pharmaceutical companies may seek to specialise in exempt products to avoid the costs of additional clinical trials, while other companies may specialise in the voluntary extension of the indications of off-patent medicines to take advantage of the generic data access provisions and the availability of the centralised procedure for PUMA-authorised products.

The Authors
Sarah Hanson, Shuna Mason, CMS Cameron McKenna's international lifesciences practice