New EU Regulation of medicinal products for paediatric use

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New obligations imposed upon innovator Marketing Authorisation Holders and Applicants by the new EU Regulation on medicines for paediatric use to generate and collect paediatric data will inevitably increase the cost of bringing new products to market and also the costs of maintaining existing innovative products on the market. While it is too early to assess how many, or what type of net benefits Marketing Authorisation Holders will achieve under the Regulation, innovator companies should be re-assessing their development portfolios and marketing strategies to exploit the benefits and/or to manage or avoid the expenses and obligations of additional paediatric clinical trials, filing and post-authorisation obligations.

After much consultation and debate the EU regulation on medicinal products for paediatric use (Regulation (EC) 1901/2006, as amended by Regulation (EC) 1902/2006 - the ‘Regulation’) came directly into force across the EU on 26 January 2007. The application of the main provisions is staggered till approximately mid-2009.



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



Rewards & Incentives

As a reward for completing agreed paediatric studies within an agreed timeframe:



  • qualifying medicines which are protected by a SPC, or by a patent which is eligible for a 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 SmPC and/or PIL.
  • products not covered by IP rights will gain full data exclusivity (under the 8+2+1 rules) under a separate Paediatric Use Marketing Authorisation (PUMA) for a new indication exclusively developed for use in the paediatric population. This will be available from 26th July 2007. PUMA-products will be entitled to capitalise upon the same brand name established for the adult version if the MAH and active substance are the same, irrespective of whether they are authorised under the centralised procedure or not.
  • Orphan medicinal products may gain an extra two years of orphan market exclusivity. Again, 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 SmPC and/or PIL.

Incentives in the form of free scientific advice from the EMEA are offered on the design and conduct of paediatric studies, pharmacovigilance and risk management systems and uncompromised eligibility for other Community or member state medicines research, development or availability incentives, for example, research conducted under the EU’s Framework Programmes.



Paediatric investigation plans (PIPs)

A PIP is defined as a research and development programme aimed at ensuring the necessary data are generated determining the conditions in which a medicine may be authorised for paediatric use. Companies seeking and/or qualifying for:



  • MA for new products not previously authorised in the Community;
  • SPC extension; or
  • a PUMA


must design and submit a PIP to the EMEA’s new Paediatric Committee for agreement. This must specify the timing and measures proposed to assess the quality, safety and efficacy of the product in all subsets of the paediatric population, as well as measures for adapting the product’s formulation for use in children.



The EMEA must establish the Committee by 26th July 2007. Proposed PIPs must be submitted for agreement early in the development of a product and in general no later than the completion of adult pharmacokinetic studies.



Waivers and Deferrals

The Paediatric Committee will operate the system of waivers (both class and product-specific) and deferrals in relation to paediatric studies. The Committee may itself adopt an opinion in favour of either a class or product-specific waiver (e.g. where the product concerned is likely to be unsafe or ineffective; 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 on technical or public health grounds.

Restricted access to the rewards

Eligibility for the rewards is restricted. New, non-orphan products, or non-orphan existing products which are protected either by a patent which is eligible for a SPC, or by a SPC itself, will benefit from the SPC extension only if the product is authorised in all the member states. This may prove a hurdle to those products not authorised under the centralised procedure, especially in view of EU enlargement. Additionally, companies with eligible products will have to carefully evaluate and choose between alternative forms of extended protection available as the six-month extension of a SPC will not be allowed if a MAH has obtained an additional year of marketing exclusivity for a new paediatric indication on grounds of significant clinical benefit in comparison with existing therapies under Directive 2001/83/EC (as amended) or Regulation (EC) 726/2004.

The Regulation requires applications for an extension of the duration of a SPC to be filed either with the SPC application itself; while this 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 26th January 2012.

Paediatric studies in respect of products already authorised in the Community, which were either completed or initiated by 26th January 2007, are eligible for inclusion in a PIP. However, although data from such studies will be taken into account by competent authorities the above rewards will only be granted where “significant studies” contained in the PIP are completed after that date. The Commission will be issuing guidelines to establish criteria for assessing significance.

MAH / MAA Obligations

Obligations include:

  • Subject to waiver or deferral, submitting paediatric data in the form of the results of studies conducted in compliance with an agreed PIP whenever companies apply for a: MA for a new product not previously authorised in the Community; or 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 a SPC-eligible patent or a SPC,
  • These filing obligations apply from 26 July 2008 and 26 January 2009 respectively. However, they do not apply in respect of: generics or biosimilars; ‘well-established use’ products; homeopathics or herbals.
  • Submission by 26 January 2008 of paediatric studies already completed by 26th January 2007 in respect of products already authorised in the Community to the competent authorities for assessment. This may result in variations to update SmPCs and/or PILs.
  • Submission of all other MAH-sponsored paediatric studies involving an authorised product to competent authorities within six months of completion, irrespective of whether they are conducted in accordance with a PIP or whether the MAH intends to rely upon them to support authorisation of a paediatric indication. Again, this may result in variations to update SmPCs and/or PILs.
  • Marketing existing products, once authorised with a paediatric indication, within two years of paediatric authorisation.
  • Post-authorisation obligations to ensure follow-up of efficacy and possible adverse reactions. For example, the new EMEA guideline on pharmacovigilance for paediatric medicines envisages the submission of 6-monthly PSURs for the two years following authorisation of a paediatric indication to an existing product and the discussion of paediatric issues in a separate section of the PSUR, in certain circumstances.

Enforcement

There is potential liability, reputational and financial exposure for companies who infringe the Regulation or its implementing provisions. Member states must implement effective, proportionate and persuasive penalties for infringements. They must also notify the Commission immediately of any litigation instituted for infringement. There is provision for the Commission to directly impose financial penalties for infringement (though the relevant legal instrument for this is not yet finalised) and to ‘name and shame’ anyone who infringes the Regulation or its implementing provisions.

Conclusion

The new obligations to generate and collect paediatric data will inevitably increase the cost of bringing new products to market for innovator pharmaceutical companies and also the costs of maintaining existing innovative products on the market (not forgetting the additional pharmacovigilance measures which will be required). It is too early to assess how many, or what type of, MAHs will achieve net benefits under the Regulation. Companies may wish to re-assess their product development and marketing portfolios and arrangements in the light of the new opportunities and obligations. For example, some innovator companies may seek to specialise in products which fall within a waiver category to avoid the costs of additional clinical trials or extra filing obligations while others may choose to take advantage of the generic data access provisions and the availability of the centralised procedure for PUMA-products by specialising in developing and marketing off-patent products through obtaining voluntary paediatric use indications.