Jordi Llinares

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.

Regulatory watch: The orphan drug pipeline in Europe

The European framework for orphan medicinal products offers a range of incentives to encourage the development of medicinal products for the treatment of rare diseases. To qualify for these incentives, sponsors must obtain — at any stage of development — orphan designation status from the European Medicines Agency (EMA) by fulfilling a set of criteria (see Supplementary information S1 (box)). Once designation is granted, sponsors are required to submit annual reports to the EMA summarizing progress in development. However, little is known about the current state of development of the orphan designations (ODs) that have not yet obtained marketing authorization. With this in mind, we analysed the orphan drug pipeline in Europe by reviewing the active ODs granted between 2002 and 2012 for which an annual report was available in 2013 or 2014. For each OD, data related to the latest completed study, target therapeutic area and sponsor type were collected. We also applied standard success rates for each development phase to our dataset to estimate the number of ODs that may receive marketing authorization (see Supplementary information S1 (box) for details of the dataset and analysis). Between 2002 and 2012, our sample of ODs (n = 605) was spread across a portfolio of 21 therapeutic areas (FIG. 1a), suggesting that translation of rare disease research into product development and healthcare innovation is happening across an increasing number of diseases — notably R E G U L ATO RY WAT C H

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”.

The orphan framework as a new opportunity: an expert opinion

This is a review of the post-designation incentives framework that exists in Europe under its Orphan Medicinal Designation System. The aim of the article is to review and highlight specific regulatory mechanisms which are used or tailored to help in the development and licensing of products which receive an orphan designation. It is hoped that through this article there will be greater clarity of the post-designation incentives available to sponsors who obtain an Orphan Medicinal Designation.

Promoting the development of drugs against rare diseases: what more should be done?

Twelve years following its implementation, the Orphan Regulation [1] represents a powerful stimulus for development of medicines for rare diseases and has been a trigger of a significant number of marketing authorizations for medicines for rare diseases [2]. To date, more than 1000 designations have been adopted for orphan medicines [101] and more than 70 products have been authorized as orphan medicines, addressing the treatment of more than 60 different rare conditions. Importantly, these products represent the only authorized products existing for the treatment of these diseases in approximately a third of the cases. In parallel, most probably triggered by the increased awareness of rare diseases and the momentum gained in this field during the last years, a number of initiatives at EU and national level have begun, such as the establishment of the European Committee of Experts on Rare Diseases, the development of national plans and strategies for rare diseases, the establishment of research networks, the proposal of an International Rare Diseases Research Consortium (IRDiRC), the proliferation of scientific conferences and the multiplication of scientific publications on rare diseases [102]. Despite this very impressive f low of activity, patients with rare diseases still face substantial problems and only a minority of their needs have been addressed so far. In this sense, many rare diseases still lack an appropriate diagnostic test, patients suffer severe delays in diagnosis [103], and overall, most rare diseases are generally poorly known to doctors outside specialized areas. Therefore, patients affected by these diseases continue to face fundamental problems highlighted already in the recitals of the Orphan Regulation [1] and which triggered the need for a legislative effort to draft a specific regulation to promote research, development and marketing of medicinal products for rare diseases. Therefore, it is relevant to review which initiatives are still needed to further stimulate the global development of treatments for rare diseases and boost medical advancement in this field.

Orphan medicines: a success with a challenging future

The implementation of the European Union (EU) Regulation for orphan medicines has resulted in > 1000 designations and > 70 marketing authorisations. Of those, in 21 cases (27%) the orphan medicine was the first authorised in that disease. The number of designations is increasing by approximately 7% per year. In parallel, the awareness on rare diseases has increased across the EU with the establishment of research networks. Recently, the International Rare Diseases Research Consortium (IRDIRC) has been established, aimed at facilitating and coordinating research in rare diseases internationally. There is mounting pressure on health reimbursement systems for expensive medicines. The fragmentation of frequent diseases into multiple subsets clashes with the current designation criteria and draws on the limited incentives available. These are two of the biggest risks to the current system. The societal benefit of developing medicines for rare diseases, both in terms of social justice and scientific added value is an enormous opportunity for advancing development of successful treatments. In Europe, regulators are engaged in moving towards close collaboration with health technology assessment bodies to address those problems affecting orphan drugs and ensuring society benefits from drug development in this area.

Showing Efficacy in Treating Rare Pediatric Tumors: Introduction to European Regulatory and Scientific Support Available to Investigators

How to show in a convincing manner efficacy in the treatment of rare tumors and to advance treatment outcomes is a perpetual challenge to all stakeholders developing new medicinal products. Making pediatric anti-cancer medicines available to treat rare tumors is an important example of the public health agenda of the European Medicines Agency, as sadly, the much-quoted successes in treating some pediatric malignant diseases do not provide a fair representation of the outcomes of any such disease. In this context, stakeholders include pharmaceutical companies that are the developers and practically sole sources of new medicines, and academic researchers who may also be the treating physicians and who drive disease-specific iterative processes to improve cure. This chapter introduces the relevant scientific-regulatory guidelines, followed by a presentation of the principles and experience obtained in orphan medicine designations, to academic researchers as they contribute to medicinal product development. Then, this chapter presents available incentives and opportunities for scientific-regulatory interactions, aspects of trial conduct for the demonstration of efficacy, and finally, considerations on a lack of efficacy of a medicine in treating a rare tumor.