A Comparison of EMA and FDA Decisions for New Drug Marketing Applications 2014-2016: Concordance, Discordance, and Why.

The Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have robust scientific and technical collaborations. As a window to the impact of these activities we compared the agencies' decisions on drug marketing applications. Decisions were compared for 107 new drug applications with a regulatory outcome at both agencies in the period 2014-2016. Further analysis addressed individual applications for which the agencies had differing outcomes in terms of marketing approval, type of approval, and approved indication, including reasons underlying differences. The EMA and the FDA had high concordance (91-98%) in decisions on marketing approvals. Divergence in approval decisions, type of approval, and approved indication were primarily due to differences in agencies' conclusions about efficacy based on review of the same data or differing clinical data submitted to support the application. This high rate of concordance suggests that engagement and collaboration on regulatory science has a positive impact.

Establishing medical plausibility in the context of orphan medicines designation in the European Union.

In the European Union, sponsors have the responsibility to demonstrate the "intention to diagnose, prevent or treat" a serious and rare condition before the Committee of Orphan Medicinal Products (COMP), for a medicinal product to meet the criteria for Orphan Designation. This requirement is commonly referred to as "medical plausibility" and the justification of this intention is assessed on the merits of each application by the COMP, which deliberates over the scientific evaluation of the evidence submitted. The scientific assessment of the applications for orphan designation by the Committee is based on the review of non-clinical (such as in vitro and in vivo) and/or clinical data submitted by the sponsor. Several challenges regarding the evidence provided emerge when the sponsor is applying for a designation at an early stage of development. Herein we discuss specific examples from the experience of the COMP, in order to elaborate on the type and level of evidence generally considered necessary for the purpose of justification of the intention to treat an orphan condition. Importantly, it is pointed out that bridging of data from other products, irrespectively of how comparable they may be, or from settings not directly associated with the condition as applied for designation, is by and large not a successful exercise and may only be exceptionally considered. It is further exemplified that, as reflected in the updated 'Guideline on the format and context of the applications for designation' and the guidance document 'Recommendation on elements required to support the medical plausibility and the assumption of significant benefit for an orphan designation' available on the EMA website, the sponsor should provide data with the specific product as applied for in specific models of the condition or in patients affected by the same condition subject of each application.

Use of biomarkers in the context of orphan medicines designation in the European Union.

The use of biomarkers within the procedures of the Committee of Orphan Medicinal Products (COMP) of the European Medicines Agency (EMA) is discussed herein. The applications for Orphan Medicinal Product designation in the EU are evaluated at two stages. At the time of orphan designation application, the file undergoes an assessment to establish whether the proposed condition is a distinct and serious condition affecting not more than 5 in 10,000 people in the EU, and whether the product is plausible as a therapy for that condition. In cases where therapies already exist, the significant benefit of the candidate product over existing therapies is also evaluated. The orphan criteria are reassessed at the time of marketing authorisation, so that marketing exclusivity for the product in the orphan medical condition can be granted. Within this context, biomarkers have been used in submissions in order to define an orphan condition and to justify that the criteria for orphan designation are met. The current work discusses specific examples from the experience of the COMP, where biomarkers have played a decisive role. Importantly, it identifies the proposal of sub-sets of non-rare conditions based on biomarkers as a challenging issue in the evaluation of applications. In particular two specific requirements for the candidate orphan medicines in relation to the biomarker-based subsets are highlighted: the "plausible link to the condition" and the "exclusion of effects outside the subset".

A regulatory overview about rare diseases.

Rare diseases attract very little interest for drug development. To create more favourable conditions, incentives for development (scientific advice, research grants) and marketing of medicines (market exclusivity, regulatory fee reductions) are offered by several orphan legislations. These incentives have proven to be a valuable stimulus for research and development for new products for treatment, prevention and diagnosis of rare diseases. In the US almost 2000 products have been designated as orphan medicines and about 340 have received marketing authorisation. Rare diseases have also gained attention from regulators in the last years. Nowadays it is acknowledged that rare diseases deserve specific attention and individual regulatory guidance. Also, regulatory authorities have developed different mechanisms to put products on the market considering specific limitations of data availability (conditional marketing authorisation, exceptional circumstances authorisation). In the future more initiatives will have to address the need for networking scientific knowledge and research capabilities to address the difficulties to generate data in rare diseases.