Screening potential therapies: lessons learned from new paradigms used in Parkinson disease.

In Parkinson Disease (PD) as well as in stroke research there is an urgent need to both optimize the use of resources (number of patients, costs, and time) and select potential effective neuroprotective agents. The processes used to identify and study new therapies for PD may be applicable to the search for new therapies in stroke. The National Institute of Neurological Disorders and Stroke (NINDS) organized the Committee to Identify Neuroprotective Agents for Parkinson's (CINAPS). CINAPS broadly solicited suggestions for agents and evaluated these agents using rigorous criteria. NINDS also created the NIH Exploratory Trials in PD program (NET-PD), a clinical network where CINAPS recommendations could be tested. Given multiple recommended agents, NET-PD investigators used Phase II futility designs with calibration controls, tested against an historical standard, to screen agents for testing in Phase III trials. Investigators also used the Phase II trial to assess ancillary outcome measures for use in Phase III. The observed value for the calibration controls in the first NET-PD Phase II trial was outside the 95% CI for the historical standard. Using bootstrap methodology it appeared unlikely this outcome happened by chance. The historical standard was updated using more contemporaneous data than were available at the start of the futility trials and a re-evaluation using the new threshold was conducted. Assessment of ancillary outcome measures led to a reduced set of outcome measures for use in Phase III. The CINAPS process, and lessons learned from NET-PD futility studies, particularly with respect to calibration controls and assessment of outcome measures, could enhance the choice and testing of new agents for stroke treatment.