From research on rare diseases to new orphan drug development

Abstract

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.