On 3 February 2014 the Commission promulgated its delegated Regulation (EU) No. 357/2014 (the "Delegated Regulation") supplementing Directive 2001/83/EC and Regulation (EC) No. 726/2004. The Delegated Regulation aims to give guidance to the national competent authorities and to the European Medicines Agency as well as to the Commission as to when PAES should be required.
New medicinal products have to undergo extensive studies, including clinical efficacy trials, before they can get market access by way of marketing authorisation. Without sufficient evidence as to their effectiveness medicinal products should not be authorised. However, Article 21a (f) of Regulation 2001/83/EC as well as Article 9 (4) (c) of Regulation (EC) No. 726/2004 provide for the authorisation of medicinal products on the condition that additional evidence as to the efficacy of the respective product is provided after the authorisation by way of PAES in circumstances where concerns in regard to the efficacy, and in particular due to the product characteristics, can only be resolved after the authorisation. Moreover, the necessity to carry out PAES may result from post-authorisation information, i.e. collected in a post-authorisation safety study ("PASS"), calling for additional confirmatory efficacy data. In both situations the respective competent authority may oblige the marketing authorisation holder to conduct PAES. Article 22b of Directive 2001/83/EC and Article 10b of Regulation (EC) No. 726/2004 empower the Commission to specify the situations in which the PAES may be required. It is the purpose of the Delegated Regulation in question to specify the relevant situations and to create transparency and legal certainty in this regard. The Delegated Regulation has binding effect.
The main elements of the Regulation
The obligation to conduct PAES should address well-reasoned concerns which could have a direct impact on the maintenance of the marketing authorisation. It should not be used as a justification for premature granting of a marketing authorisation.
Article 1 (2) of the Delegated Regulation provides for the carrying out of PAES in two cases, namely a) where concerns relating to some aspects of efficacy of the medicinal product are identified and can be resolved only after the medicinal product has been marketed or b) where the understanding of the diseases, the clinical methodology or the use of the medicinal product under real-life conditions indicate that previous efficacy evaluations might have to be revised significantly.
The preamble of the Regulation gives the reasons for the two different cases in accordance with the respective rules of Directive 2001/83/EC and of Regulation (EC) No. 726/2004. The first case deals with therapeutic areas where surrogate endpoints, such as biomarkers, or tumour shrinkage in oncology have been used as a tool to define the efficacy of medicinal products in exploratory or confirmatory clinical studies. To substantiate the assessment based on those endpoints it may be relevant to generate further efficacy data in the post-authorisation phase to verify the impact of the intervention on clinical outcome or disease progression. In those cases it may also be necessary to verify whether the overall survival data in the post-authorisation phase is discordant or confirmative of the outcome of a surrogate endpoint. The second case deals with information gathered after the product authorisation. That is, with regard to different populations to which the product is administered, showing in real life different reactions to the product which are relevant to a benefit-risk balance in regard to a specific sub-population while not necessarily precluding an overall positive benefit-risk balance. Or, in regard to cases where observations were made under real-life conditions, relevant to the assessment of the efficacy of the product which lead to the assessment that the previous efficacy evaluations might have to be revised significantly. Such assessment may also arise in the context of PASS. The Regulation gives some more examples by way of explanation in its preamble, which it takes up more specifically in Article 1 (2).
Article 1 (2) sets out in more detail when the performance of a PAES may be required by the competent authorities, namely only if one or more of the cases listed in Article 1 (2) arises. The wording "shall only apply" in that paragraph makes clear that the cases listed there define a final catalogue and may not be used by the competent authorities as mere examples in order to extend the requirement to conduct a PAES to other cases not listed in Article 1 (2). Only cases listed in Article 1 (2) can justify a request to carry out a PAES. Generally it can be concluded from the catalogue that in cases where concrete and objective scientific factors call for a reassessment of the initial evaluation of the efficacy of a medicinal product under the catalogue set out in Article 1 (2) a PAES may be required. Article 1 (3) in this context makes clear that any other obligation on the holder of a marketing authorisation to conduct a PAES in accordance with the situations listed in Article 1 (3) remains unchanged.
The Delegated Regulation does not create any additional obligations on the pharmaceutical industry in regard to the conducting of PAES. All applicable obligations are already set out in Regulation (EC) No. 726/2004 and in Directive 2001/83/EC. The purpose of the new Delegated Regulation is to clarify the conditions on which the competent authorities may require the conducting of a PAES as set out in more general terms in the provisions of the Directive and the Regulation. The catalogue of cases justifying the request to carry out a PAES as set out in Article 1 (2) is final and therefore in cases where an authority requests a PAES serves as a set of test criteria determining whether or not the request is consistent with the respective rules and regulations. To what extent the competent authorities will make use of the possibility to request the conducting of PAES remains to be seen. In addition, the Delegated Regulation may play a role in keeping the right balance between ensuring the safety of medicinal products based on a sensible risk-benefit analysis on the one hand and medical innovation and scientific feasibility including a sensible cost measurement on the other.