Proposals for reform of EU Paediatric Regulation postponed - EC to take another look at orphan incentives for paediatric medicines

On 26 October 2017 the European Commission delivered its much awaited Report to the European Parliament and Council on the state of paediatric medicines in the EU, reviewing the experience of 10 years of the Paediatric Regulation. The Report makes no concrete proposals for reform, instead announcing a further two year evaluation of the combined effects of the Orphan and the Paediatric Regulations in driving medicines development in paediatric subpopulations of particular need.

The Paediatric Regulation was inspired by legislative approaches in the United States to address the relative neglect of paediatric product development which had led to the widespread off label use of adult medicines in children. A system of obligations, rewards and incentives aims to ensure that medicines are regularly researched, developed and authorised to meet children’s therapeutic needs.  The Commission reports that one of the Regulation’s undisputed achievements is to bring more attention and financial investment to paediatric development. Between 2007 and 2016 over 260 new medicines for use by children were authorised. 1,000 paediatric investigation plans (PIP) have been authorised in the first ten years, with over 60% finalised in the last three years. Noting that reimbursement decisions and national prescribing habits also play a role in limiting availability of a product to all paediatric patients in the EU, the Commission estimates that the increase in available medicines was 5-10%. This underlines a disappointing inertia which, in the Commission’s view, is unlikely to be addressed by legislative initiatives at European Union level.

The Report examines whether the use of deferrals, waivers and incentives has been effective in guiding paediatric development in areas of greatest need for children. It finds that there is no evidence that the paediatric requirements have delayed the processing of adult applications, whilst observing that experience shows that that recruitment of patients in paediatric trials becomes more difficult if the start of a paediatric trial is delayed until after the adult authorisation. The EMA and its Paediatric Committee are currently reviewing past practices to ensure consistency and to avoid significant deferrals in future.

The Commission’s analysis of agreed PIPs shows that they cover a wide range of therapeutic areas, transforming, for instance, the treatment of children with rheumatological disease. Progress in the development of treatments for children with cancer, the leading cause of death from disease in children past infancy, has been less impressive. In some paediatric cancers, the most used medicines date back to the 1990’s, if they exist at all. The Commission is unsure whether the possibility that the requirements for a PIP can be waived if the product is likely to be ineffective or unsafe for children have contributed to the relative lack of new cancer treatments for children compared to the surge in innovative adult cancer medicines entering the market in the last few years. A review of the basis on which class waivers would be granted in 2015 has limited its scope and it is too early to assess whether it has had the desired effect.

The Commission also remains puzzled why the rewards available under the Orphan Regulation have not produced the same stimulus to the development of new treatments in for cancer in children as they have done in adult oncology, especially given that all paediatric cancers would qualify for incentives under the Orphan Regulation.

The Report expresses disappointment that the Paediatric Regulation has failed so far to advance the development of medicines designed purely to address the unmet needs of children.  The Regulation tends to encourage paediatric research linked to the development of new medicines for adults.  Indeed, the Commission observes that some argue that the PIP process adds an additional layer of complexity for a product destined only to treat children. The concept of the Paediatric Use Marketing Authorisation (PUMA) has failed, it admits; only three PUMAs have been granted to date. PUMAs were intended to encourage the development of new paediatric indications in off-patent compounds and the Commission speculates that national pricing strategies and fear of continued off-label use may lie behind their limited appeal to companies. The Report appears to concede defeat in concluding that legislative incentives cannot compensate for limited economic success.

The innovative pharmaceutical industry will be much relieved to see the conclusion of the Commission’s analysis of the economic value of the supplementary protection certificate (SPC) reward. To date, 40 medicines have benefitted from the SPC reward which compensates companies for the additional costs of paediatric research. Overall, taking into account the benefits received from paediatric research on the 45% of products that were not able to qualify for a reward and the additional R&D investment that paediatric development creates more generally, the Commission concludes, that the benefits of the Regulation outweigh the costs of the additional monopoly granted by an SPC. This must be a strong pointer to the Commission leaving the details of the SPC reward untouched in any future proposals for revision of the Regulation.

The economic value of the orphan reward of two years’ additional marketing exclusivity proved less easy to estimate; only seven products have qualified to date. The Commission hints that the structure of the orphan reward may have fallen behind the times since it was mainly geared towards off-patent products whilst 90% of newly authorised orphan products are on-patent. Companies cannot claim the SPC reward, which would protect non-orphan and orphan indications from generic competition for an additional six months, and maintain orphan status. Casting this as a weakness inherent in the current regime suggests that the Commission may be minded to propose some flexibility here in future.

The Report concludes that the Regulation has, overall, produced positive results from a socioeconomic perspective. There remain instances of over- and under-compensation, however, and the Commission is particularly concerned that major therapeutic advances for children have failed to emerge in diseases that are rare or unique to children. Before proposing any amendments to the Paediatric Regulation, therefore, the Commission intends to make an evaluation of the combined effects of the Orphan and the Paediatric Regulations in driving medicines development in subpopulations of particular need.  The results of this evaluation should by published by 2019.