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Over the last two decades, important contributions were made at national, European and international levels to foster collaboration into rare diseases research. The European Union (EU) has put much effort into funding rare diseases research, encouraging national funding organizations to collaborate together in the E-Rare program, setting up European Reference Networks for rare diseases and complex conditions, and initiating the International Rare Diseases Research Consortium (IRDiRC) together with the National Institutes of Health in the USA. Co-ordination of the activities of funding agencies, academic researchers, companies, regulatory bodies, and patient advocacy organizations and partnerships with, for example, the European Research Infrastructures maximizes the collective impact of global investments in rare diseases research. This contributes to accelerating progress, for example, in faster diagnosis through enhanced discovery of causative genes, better understanding of natural history of rare diseases through creation of common registries and databases and boosting of innovative therapeutic approaches. Several examples of funded pre-clinical and clinical gene therapy projects show that integration of multinational and multidisciplinary expertize generates new knowledge and can result in multicentre gene therapy trials. International collaboration in rare diseases research is key to improve the life of people living with a rare disease.

Background We determined whether the market exclusivity incentive of the European Orphan Drug Regulation results in a market monopoly or that absence of another Orphan Medicinal Product (OMP) for the same rare disorder, a so-called follow-on OMP, is a matter of time or market size. In the interest of rare disorder patients better understanding of the effect of the market exclusivity incentive on follow-on OMP development is warranted. Methods First, the impact of various market-, product- and disease-related characteristics on follow-on OMP development in the EU was determined by comparing rare disorders with an approved OMP and at least one follow-on OMP (N = 26), with rare disorders with an approved OMP and no follow-on OMP (N = 18). Next, we determined whether manufacturers continued development of a follow-on OMP upon approval of the first OMP for the intended rare disorder. Since in the EU significant benefit of an OMP has to be established, we determined for each follow-on OMP for which development was continued on what grounds significant benefit was assumed by the sponsor. Data were collected from the public domain only. Results The likelihood of a rare disorder with an approved OMP to obtain at least one follow-on OMP development was strongly associated with disease prevalence, turnover of the first OMP, disease class, disease-specific scientific output and age of onset. Out of a total of 120 follow-on OMPs only one follow-on OMP could be identified for which development was discontinued upon approval of the first OMP for the same rare disorder. Only a substantial level of discontinuation of follow-on OMP development would have indicated the existence of a market monopoly. Moreover, sponsors that continued development of a follow-on OMP predominantly assumed that their product had an improved efficacy compared to the first approved OMP. Conclusions This study provides evidence that absence of follow-on OMP development is a matter of time or market size, rather than that the market exclusivity incentive of the European Orphan Drug Regulation creates a market monopoly.

Rare diseases have a prevalence of lower than 5 in 10,000 inhabitants and are life-threatening or chronically debilitating. It is estimated that worldwide more than 5000 rare diseases exist, which account for over 55 million patients in the EU and the US together. However, the development of drugs for rare diseases, so called orphan drugs has not been an area of high priority for the pharmaceutical industry so far. Therefore, dedicated orphan drug legislation has been introduced that aims to stimulate the development of these high medical need products. This thesis identifies strategies for enhancing the development and marketing of orphan drugs. In the first chapter, bottlenecks and opportunities for translating biomedical research on rare diseases into early orphan drug development were studied. This chapter highlighted the importance of basic biomedical research for orphan drug development. Moreover, the studies determined the importance of strong pharmaceutical innovation in general, including patent applications, R&D expenditure and the existence of small and medium enterprises in the pharmaceutical industry, for the successful translation of biomedical research into orphan drug development. The second chapter focussed on characteristics of orphan drugs associated with a positive or negative outcome of the marketing authorisation application (by the FDA or EMEA). First, sponsors with prior experience in (orphan) drug development were more likely to develop another orphan drug. Orphan drugs based on existing molecules had also more chance to get market approval. Second, the choice of the target population for the orphan drug and the choice of the primary endpoint in the pivotal clinical trial was determined to be associated with the outcome of the regulatory assessment. Finally, a higher level of interaction between sponsors and regulators was shown to be positively associated with successful market authorisation. The third chapter of the thesis described the challenges of orphan drugs after approval. As a result of differences in healthcare systems and other reasons, including the sometimes-high prices of orphan drugs, not all orphan drugs are available to the patients throughout the EU. In the thesis, the use of orphan drugs is compared to other centrally authorised drugs in the EU and this appeared not to be significantly different. Second, due to the limited clinical experience with orphan drugs before approval, the risk for unexpected adverse events of orphan drugs may be higher than for other drugs. We reveal that the number of written safety warnings and black box warnings for orphan drugs is not significantly different from that for other drugs.

Rare diseases have a prevalence of lower than 5 in 10,000 inhabitants and are life-threatening or chronically debilitating. It is estimated that worldwide more than 5000 rare diseases exist, which account for over 55 million patients in the EU and the US together. However, the development of drugs for rare diseases, so called orphan drugs has not been an area of high priority for the pharmaceutical industry so far. Therefore, dedicated orphan drug legislation has been introduced that aims to stimulate the development of these high medical need products. This thesis identifies strategies for enhancing the development and marketing of orphan drugs. In the first chapter, bottlenecks and opportunities for translating biomedical research on rare diseases into early orphan drug development were studied. This chapter highlighted the importance of basic biomedical research for orphan drug development. Moreover, the studies determined the importance of strong pharmaceutical innovation in general, including patent applications, R&D expenditure and the existence of small and medium enterprises in the pharmaceutical industry, for the successful translation of biomedical research into orphan drug development. The second chapter focussed on characteristics of orphan drugs associated with a positive or negative outcome of the marketing authorisation application (by the FDA or EMEA). First, sponsors with prior experience in (orphan) drug development were more likely to develop another orphan drug. Orphan drugs based on existing molecules had also more chance to get market approval. Second, the choice of the target population for the orphan drug and the choice of the primary endpoint in the pivotal clinical trial was determined to be associated with the outcome of the regulatory assessment. Finally, a higher level of interaction between sponsors and regulators was shown to be positively associated with successful market authorisation. The third chapter of the thesis described the challenges of orphan drugs after approval. As a result of differences in healthcare systems and other reasons, including the sometimes-high prices of orphan drugs, not all orphan drugs are available to the patients throughout the EU. In the thesis, the use of orphan drugs is compared to other centrally authorised drugs in the EU and this appeared not to be significantly different. Second, due to the limited clinical experience with orphan drugs before approval, the risk for unexpected adverse events of orphan drugs may be higher than for other drugs. We reveal that the number of written safety warnings and black box warnings for orphan drugs is not significantly different from that for other drugs.