Mind the gap Bridging the difference between efficacy and effectiveness of orphan drugs

In the European Union, a disease is called ‘orphan’ if it is a disorder that affects fewer than 5 per 10.000 of the population. Authorization of orphan drugs is often based on studies with several methodological shortcomings. Because of this, longer term effectiveness on clinically relevant outcome measures is often unclear at the time of authorization and some drugs that enter the market, may not be effective in the real-world. The aim of this thesis was to study the presence of a so-called efficacy-effectiveness gap of orphan drugs, and the factors that possibly contribute to it. We confirmed that indeed a gap exists in the case of orphan drugs for metabolic diseases and oncology. The most important factor that contributed to this gap was the type of primary endpoint used in the pivotal study. This information may be used when conducting future studies on orphan diseases. Furthermore, we showed that dose-finding studies in the case of metabolic and oncologic orphan drugs are not always conducted in the development program, while post-marketing evidence suggests that registered doses are not always considered as optimal. Also, we elaborated on how an adaptive pathway approach could have benefitted the development of enzyme replacement therapy for Fabry disease in several ways, including 1) iterative development, 2) an independent disease registry with independent data analysis and 3) prescription control. In conclusion, this thesis will contribute to an important discussion on the real-world effectiveness of orphan drugs.