There are about 36 million patients in the EU who are suffering from one of the 7 000 existing rare/orphan diseases.
Most Advanced Therapy Medicinal Products (ATMPs) that have been authoirsed for marketing in the European Union, are also classified as orphan medicinal products. However on the contrary, during the revision process of European regulation on orphan medicinal products (Regulation (EC) n°141/2000), it has been highlighted that the market of orphan medicinal products had “started to look more similar to ‘standard’ medicines”[1]than innovative medicines like ATMPs.
Obtaining the orphan designation gives access to financial and regulatory incentives aimed at improving the attractivity of research and development of innovative medicinal products for rare diseases.
[1] European Commission, Commission Staff Working Document, Executive summary of the evaluation, op. cit., p. 2.
Stakeholders
Committee for Orphan Medicinal Products (COMP). This Committee has been created within the European Medicines Agency by Regulation (EC) n°141/2000. It is in charge of providing scientific advice and most importantly of evaluating orphan designation applications. It also advises and assists the European Commission on matters related to orphan medicines. The COMP is composed of one member appointed by each of the European Union Member States and European Economic Area countries plus Iceland, Liechtenstein, Norway, and Switzerland; three members nominated by the European Commission to represent patients’ organisations; three members nominated by the Commission on the basis of a recommendation from the Agency, and a Chairperson.
The European Commission will decide whether or not to grant the orphan designation to a medicine based on the opinion of the COMP.
The sponsor is the researcher or pharmaceutical industry seeking to obtain or having obtained an orphan designation for the investigational medicinal product.
Definitions
The very definition of an orphan medicinal product is disputed because many distinct and sometimes diverging definitions may exist in the literature of what constitutes an orphan diseases and medicinal product [2].
According to European Union (EU) law, an orphan medicinal product is designated when three criteria are gathered: there is no satisfactory method of diagnosis, prevention or treatment; the disease is chronic and serious if not life-threatening; and last but not least, the disease either concerns less than 5 cases in 10 000, or it is unlikely to be economically attractive enough for researchers and industries to develop a medicinal product without public incentives.
Yet, some criteria of this EU definition may change in the future. In fact, the currently ongoing revision of the legal framework of the pharmaceucical legislation, including the revision of Regulation (EC) n°141/2000 on orphan medicinal products, is calling it into question. It was highlighted that the threshold of less than 5 in 10 000 patients may not be adapted as the growth of personnalised medicine sometimes leads to an “unnecessary multiplication of rare diseases out of common diseases” and thus to an abusive recourse to the incentives meant for actual orphan diseases and an undue proliferation of exclusivity periods [3].
[2] T. Richter et al., ‘Rare disease terminology and definitions – a systematic global review: report of the ISPOR rare disease special interest group’, Value in Health (13) (2015) 906-914. [3] European Commission, Commission Staff Working Document, Executive summary of the evaluation, op. cit., p. 2.
Challenges
Scientific challenge: The major issue with the development of orphan medicinal products relies in the rare and scattered knowledge and expertise throughout Europe and throughout the world. This is enhanced in the case of Orphan medicinal products being also Advanced Therapy Medicinal Products as the latter raise the same scientific challenge given their innovativeness and complexity.
Healthcare challenge: These scattered knowledge and expertise may result in delays and errors of diagnosis and treatment for patients.
Economic/research & innovation challenge: These scattered knowledge and expertise also results in duplication of very expensive research efforts that remain too limited, because too isolated, to be significant. The final prices of these medicines being both ATMPs and Orphan is generally to high to be affordable to all the patients who may need them through the European Union national health systems, especially as the costs of research & innovation are passed on a limited number of medicines to be commercialised due to a limited number of targeted patients (rare diseases).
Legal / Public health ethics challenge: The Commission recently recognized that “the information available does not allow a direct link to be drawn between the public funding and the medicines effectively developed”[4] in the field of rare diseases.
When medicines are actually developed, they still fail in being equally accessible to patients in the different Member States, “mainly due to factors outside the scope of the regulations, such as strategic launch decisions by pharmaceutical companies and national pricing policies and reimbursement systems ».[5]
[4] European Commission, Commission Staff Working Document, Executive summary of the evaluation, Joint evaluation of Regulation (EC) No 1901/2006 of the European Parliament and of the Council of 12 December 2006 on medicinal products for paediatric use and Regulation (EC) No 141/2000 of the European Parliament and of the Council of 16 December 1999 on orphan medicinal products, SWD(2020) 163 final, Brussels, 11 August 2020, p. 2.
[5] European Commission, Commission Staff Working Document, Executive summary of the evaluation, op. cit., p. 3.
Opportunities and incentives
Reduced fee or Free protocol assistance from the European Medicine Agency’s Committee for Orphan Medicinal Products, which is determining to obtain an orphan designation and a marketing authorisation.
Centralised procedure for the authorisation of an orphan medicinal product to be commercialised in the EU territory.
10 years commercial exclusivity for an orphan medicinal product entering the EU internal market.
Research funding: Framework programms from the European Commission regularly fund activities in the field of rare diseases, as foreseen in article 9 of the European regulation on orphan medicinal products (Regulation (EC) n°141/2000). The funding has been gradually increasing from the 6th framework programm in 2002 until the current EU4health programm established by Regulation (EU) n°2021/522.[6] For instance, the European Commission launched the European Platform on rare disease registration in February 2019 in order to centralise and standardise data on rare diseases. It also more recently funded the European Joint Programme on Rare Diseases (EJP RD).[7]
[6]Regulation (EU) 2021/522 of the European Parliament and of the Council of 24 March 2021 establishing a Programme for the Union’s action in the field of health (‘EU4Health Programme’) for the period 2021-2027, and repealing Regulation (EU) No 282/2014
The sponsor of an orphan medicinal product can request protocol assistance to EMAprior to the submission of an application for Marketing Authorisation.[8] Protocol assistance is a form of scientific advice for orphan medicinal product allowing the sponsors to get answers to their questions “on the conduct of the various tests and trials necessary to demonstrate the quality, safety and efficacy of the medicinal product”.[9]
Interactions between the European Commission and experts on rare diseases:
Beyond the process of orphan designation itself, the representation of the interests of rare diseases patients in EU policies and legislations is permitted by multiple organs. In fact, the European Commission also created or supported several expert groups: the Rare Diseases Task Force in 2004 which was replaced by the EU Committee of Experts on Rare Diseases (EUCERD) in 2010 and finally in 2014 the European Commission Expert Group on Rare Diseases. It also supports the International Rare Diseases Research Consortium (IRDiRC) which goes beyond the European borders.
Interactions between the European Commission and stakeholders widely:
The Commission has launched an Open public consultation between 7 May 2021 and 30 July 2021on the revision of the legislation on medicines for children and rare diseases.[10] Stakeholders and members of the general public, including patients and doctors, Organisations representing patients and civil society active in public health, healthcare professionals and providers, academia, researchers and the pharmaceutical industry were welcomed to contribute.
Other interactions between stakeholders:
European Reference Networks (ERN) in the area of rare diseases were created on the basis of article 12 of Directive 2011/24/EU on cross-border health care. The creation of such ERNs is only voluntary, but supported by the European Union in order to facilitate knowledge exchange, debate and discussion on rare diseases, and in fine to improve access to diagnosis and quality care for patients suffering from a rare disease, for which expertise is missing in their country.[11]
Health professionals or patients associations and Non Governmental Organisations in the field of rare diseases have demonstrated to be essential and determining actors influencing European and international policies in favor of orphan disease patients.
[11]Directive 2011/24/EU of the European Parliament and of the Council of 9 March 2011 on the application of patients’ rights in cross-border healthcare; OJ L 88, 4.4.2011, p. 45–65
Acknowledgements
Published: 03/04/2023
Authors:
Eloïse Gennet, post-doctoral researcher in law (UMR 7318 DICE CERIC) and member of the EuroGCT ELSI Network of Expertise,