Evolution of disease modifying therapy clinical trial design and therapeutic endpoints for Parkinson's disease

The traditional approach of using double-blind, placebo controlled, parallel group trial designs has confirmed the efficacy of a large number of agents in relieving the symptoms of Parkinson's disease (PD) but has not, to date, led to the discovery of any disease-modifying treatments for PD. There are multiple potential reasons underlying the failure to find disease modifying approaches, which may in part relate to; inadequate understanding of PD pathophysiology and therefore inappropriate target selection; the possibility that even good candidate drugs may simply fail to reach and to ultimately engage with their putative targets at the required dose; and the significant heterogeneity of the disease both in terms of its pathophysiology and its motor and non-motor symptoms. PD also has some additional challenges that may be addressed by careful consideration of trial design. This includes; its generally slow rate of disease progression necessitating long follow-up times to identify evidence of disease slowing; lack of understanding regarding the optimal stage of disease that might be most amenable to intervention; as well as lack of consensus regarding which outcome measures best capture patient relevant disease progression, and which biomarkers might consistently and objectively provide the earliest indication of disease progression. In this review we will discuss these issues and potential approaches that may help in the evolution of clinical trial design and thus ultimately provide a pathway to increase the likelihood of successful identification of disease-modifying treatments for Parkinson's disease.