Clinical studies in lysosomal storage diseases: past, present and future.

Lysosomal storage disorders (LSDs) are made of over 40 diseases. Costly treatments have been developed. In this review, we consider the regulatory context in which LSDs studies are performed, and highlight design specificities and operational aspects. Orphan drug legislations in Europe and US were effective to stimulate LSDs drug development. However the flexibility of regulators to facilitate approval is inconsistent leading to worldwide differences in access to LSD treatments. Study designs are impacted because only few patients can be studied. This implies LSDs treatments need to demonstrate a large efficacy effect. Otherwise the level of evidence is difficult to demonstrate. While biomarkers could accelerate approvals, in LSDs none have been accepted as primary outcome of efficacy. Enrichment of study population can increase the chance of success, especially with clinical outcome. Adaptive designs are challenging. Innovative methods of analysis can be used, notably using a patient as his/her own control and responder analysis. Other characteristics include extension phases and patient registries to further data collection. Few patients are available per centers and more centers need to be initiated in multiple countries. This impacts time-lines and budget. For LSDs, development program should be individualized. Regulators flexibility will be essential to provide patients access to innovative treatments.