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

Keywords::

• drug development
• health technology assessment
• incentives
• orphan designation
• orphan medicines research
• orphan regulation

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 flow 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.

Research support

The efficiency of research and development processes is of particular interest considering the current difficult economic situation. The complexity of basic medical research should not be underestimated. However, besides stimulating basic science, research aimed at medicine development needs to be supported as well, in order for advances in basic science to be translated into plausible developments. Examples of initiatives in this direction are E-rare [104] at the European level or IRDiRC [105] at a global level, the goal of which is to develop 200 new therapies by 2020. IRDiRC was originally proposed by the Research Directorate at the European Commission and the US National Health Institute in an attempt to achieve global collaboration and coordination between funding institutes to make joint efforts possible and achieve maximum efficiency of funding structures. Currently, IRDiRC is engaging founders from more than ten countries and finalizing the establishment of its governance structure as well as its first recommendations on research programs. In our view, public funding should focus on those products that, in spite of having great potential for successful development, will be developed only if sufficient public funding is provided, rather than on those that already have access to private resources for development.

Thus, ensuring coordination of global efforts on research to avoid unnecessary replication or overlap of initiatives should be part of the objectives of any suprastructure created with the view of improving coordination and efficiency of research.

Information provided by sponsors on the stage of development of products could be used by the European Medicines Agency to identify specific needs and bottlenecks in different therapeutic fields where international collaborative research would bring progress. Involvement of regulatory agencies, which have privileged access to information on the latest development, could also provide information on the specific needs at various stages of development of orphan drugs where hurdles are commonly met.

Development support

Development of products for rare diseases faces specific challenges directly derived from the very nature of the disease. Due to a combination of different reasons such as the absence of simple diagnostic methods, the lack of research resources and the fact that patients are geographically scattered, clinical development and in particular the conduct of clinical trials present many feasibility challenges. Addressing these issues to facilitate clinical research and lowering the administrative burden on clinical trials should be a priority in Europe. Initiatives facilitating the organization and conduct of clinical trials should be promoted, as well as flexible approaches and innovative methodologies for gathering clinical data of sufficient quality to support recommendations on treatment outside classical methodologies [3,106].

Drug development is a highly regulated activity where quality standards have to be kept very high to protect public-health interests. Meeting these standards may be a cumbersome enterprise for small-size developers; therefore, collaboration in this field should be encouraged either through mechanisms allowing the sharing of experience and know-how or with the creation of programs or entities to support promising development. The creation of a ‘not-for-profit’ contract research organization to support development for medicines for rare diseases has been proposed several times; nevertheless, this initiative has not been developed even though the potential gains for the community could be relevant in terms of facilitating drug development by helping companies with limited experience in drug development to overcome development hurdles. In a similar direction, collaboration on the development of sharing mechanisms in creating disease registers for rare diseases has been recently debated. This could be a pioneer activity that might break some well-established paradigms that complicate epidemiological research in relation to data ownership, data collection in collaboration and possibility of access to data for different purposes [107].

Regulatory support

Medicines developed after thorough programs will reach the market only if these are able to meet regulatory standards for marketing and are able to show a positive benefit–risk ratio. The contribution of regulators in scientific advice/protocol assistance increases the chance of a successful development of the orphan medicinal product [4]. The experience with authorizations of medicines for rare diseases shows that even though marketing authorization applicants are dealing with extremely complicated development programs and regulatory authorities are faced with limited data in comparison with frequent diseases, it is still feasible to bring to the market safe and effective products for rare diseases in ratios that are comparable with nonrare diseases [5,6].

Regulators are aware of the challenges that lie ahead, in particular with the development of personalized medicines, advanced therapies and the advancement of medicine. Recently developed initiatives by regulators, such as validation of biomarkers or validation of novel methods for drug development are aimed at the alignment between the results of the advance of medical science and the regulatory approach to the development of medicines.

These issues and the increased globalization of drug development have prompted regulators to promote international collaboration in coordinating efforts to provide consistent advice on development, increase predictability of the whole development process, thereby improving the chances for safe and efficacious products reaching patients in the shortest regulatory time necessary. Confidentiality agreements and extensive collaboration are already in place between the EU, including EMA/the Committee for Orphan Medicinal Products, and the US FDA/Office of Orphan Products Development. Collaboration with Canada and Japan is ongoing and has been initiated with Australia.

The ultimate goal for any policy or incentive for development and marketing of medicines for rare diseases is to make the product accessible to the patients in need. Recently, we have contributed to an extremely exciting debate around the accessibility of medicines for rare diseases, including the process of health-technology assessment and the schemes for reimbursement of drugs in the different Member states of the EU. In this field, significant advances have been made in recent years, including the establishment of EUnetHTA, the development of innovative and flexible systems for pricing and reimbursement and the active involvement of patient organizations in this debate. Special considerations for health technology assessment have been made for rare diseases and professionals in this field are reflecting on the methodologies that better reflect the needs of rare diseases [108]. European Initiatives, such as the Clinical Added Value of Orphan Medicinal Products information flow, supported by the European Commission, are addressing ways to facilitate the scientific assessment of the clinical effectiveness of orphan medicines by improving the exchange of valuable information on rare diseases and orphan medicinal products and promoting development of HTA methodologies adapted for rare diseases [7].

Rare diseases have been actively supported for the last decade and our society is now gaining from all the investment on research and development made. We should recognize this and collectively congratulate all stakeholders. Nevertheless, some well-known and many new challenges lie ahead in an environment that demands continuous support for efficient research and drug development. It is necessary to promote innovative ways to ensure drug availability while achieving social justice and a rational use of resources.

Disclaimer

The views expressed in this article are the personal views of the authors and may not be understood or quoted as being made on behalf of or reflecting the position of the EMA or one of its committees or working parties.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.