Objective: A key goal of the Critical Path for Parkinson’s Consortium (CPP) is to qualify, with regulatory agencies, drug development tools for use in PD clinical trials. CPP’s PD imaging biomarker team aims to achieve regulatory endorsement for the application of reduced dopamine transporter (DAT) binding as a biomarker for PD clinical trial enrichment.

Background: As therapeutic trials aim at earlier stages of Parkinson’s disease (PD), appropriate patient selection based purely on clinical criteria poses significant challenges. Use of biomarkers can be effective in enabling improved accuracy in selecting appropriate subjects for enrollment in clinical trials.

Methods: A team of pharmaceutical companies, academic key opinion leaders, government agencies and advocacy organizations formally submitted to EMA and FDA documentation supporting the use of DAT SPECT imaging in PD. Regulatory documents included a comprehensive literature review, a proposed analysis plan of both observational and clinical trial data, and an assessment of biomarker reproducibility and reliability. The research plan included longitudinal analysis of the Parkinson Research Examination of CEP-1347 Trial (PRECEPT) and the PPMI study to estimate the degree of enrichment and impact on future trials in subjects with early motor PD.

Results: The presence of reduced striatal DAT binding based on visual reads of SPECT scans in PD subjects within 2 years of diagnosis is associated with decline in UPDRS part II and III as compared to subjects without evidence of dopamine deficiency (SWEDD) who show minimal decline. The FDA (March 2015) and EMA (October 2016) have issued publically posted letters of support to encourage collection and sharing of relevant data supporting the use of DAT at baseline as an enrichment biomarker.

Conclusions: Exclusion of SWEDD subjects in future clinical trials targeting early motor PD subjects aims to enrich clinical trial populations with idiopathic PD patients, improve statistical power, and spare subjects who are unlikely to have PD from being exposed to novel test therapeutics. Publically posted letters of support by FDA and EMA encourage broader use of this biomarker by trial sponsors.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/global-regulatory-agencies-support-the-use-of-dopamine-transporter-neuroimaging-for-subject-selection-in-clinical-trials-targeting-early-stage-parkinsons-disease-on-behalf-of-critical-path/