Objective:
The Clinical Trial Endpoints Initiative seeks to align the Parkinson’s community, researchers and regulators on what constitutes meaningful and acceptable regulatory endpoints to improve clinical trials of promising therapies for Parkinson’s disease (PD).
Background on Clinical Outcome Assessments and Trial Endpoints
Nearly all primary endpoints used for approval of current PD therapies have been defined by clinical outcome assessments (COAs). Thus, The Michael J. Fox Foundation (MJFF) sees COAs as a crucial part of accelerating the therapeutic pipeline and bringing new treatments to market. Clinical outcome assessments measure how patients feel and function and are used to quantify specific outcomes being studied in a clinical trial. Endpoints are events or outcomes that are measurable (such as with a COA) to determine if a therapy is having a beneficial effect. For example, Unified Parkinson’s Disease Rating Scale (UPDRS) Part 3 is a clinician-rated COA that assesses motor severity, while a change in UPDRS Part 3 from baseline to some follow-up point is an endpoint.
Developing Fit-for-Purpose Clinical Outcome Assessments
Aligning the Parkinson’s community, researchers and regulators on what constitutes a meaningful endpoint goes a long way toward improving trials, while also attracting new interest and investment by ensuring drug developers have an agreed-upon way to prove their treatment’s efficacy.
One important focus of our Clinical Trial Endpoints Initiative is to accurately capture and measure the experiences and perspectives of people living with PD, which is central to advancing next-generation endpoints. With assistance from the MJFF community, including clinical trial participants and members of our Patient Council, we capture insights from their lived experiences that can inform trial design and endpoint selection. This helps ensure that clinical endpoints and the tools that help measure these concepts are meaningful and reflective of real patient needs related to quality-of-life issues as well as improved symptom control.
Another focus is the optimization of existing COAs and development of novel instruments, including clinical measures that leverage digital health technology. The Foundation works closely with a multi-disciplinary group of experts to identify gaps in today’s COA landscape and opportunities for collaboration and funding. Perspectives from the PD community are deeply integrated into these research projects. Areas we have prioritized for funding based on the current COA landscape include cognitive impairment, early stages of clinical PD, and freezing of gait and mobility. Ensuring that these tools are sensitive to change and measure disease concepts that are meaningful to people with Parkinson’s will give researchers greater confidence to use them to define clinical trial endpoints.
The relevance of measures, no matter how well developed, must be fit for use in clinical trials. Regulators, researchers and drug developers must agree that an endpoint represents an important measure of efficacy for it to be used most effectively. To drive the adoption and utilization of improved endpoints, the Foundation also fosters collaboration and alignment among key stakeholders, including researchers, regulatory authorities, pharmaceutical companies, and advocacy groups. Through convening stakeholder roundtables and engaging in various pre-competitive partnerships, the Foundation aims to facilitate dialogue and consensus-building to ensure that these stakeholders are aligned on the value, application, and regulatory acceptance of new and refined endpoints, ultimately speeding up the path to effective treatment options by allowing us to prioritize investments and further their impact. Reports of stakeholder meetings co-hosted by the Foundation can be found in the Resources section below.
On the Horizon: Surrogate Endpoints
Beyond COAs, biomarkers can also be used to define an endpoint as a substitute for a direct measure of a clinical outcome (functioning as a surrogate endpoint). Substantial evidence linking biomarker levels to clinical outcomes is necessary for the biomarker to be considered a “reasonably likely” surrogate endpoint and acceptable to regulators as a primary endpoint. Because current Parkinson’s biomarkers have not garnered sufficient data to support their use as surrogate endpoints, COAs continue to be used to evaluate treatment efficacy in pivotal studies. As tools to biologically measure, track, and predict progression of PD advance closer to use in clinical trials, including work supported through MJFF’s Biomarker Advancement Programs, we will work with our advisors to lay out roadmaps for establishing surrogate biomarkers.
Available Resources
To Learn More
If you have questions about the Clinical Trial Endpoints Initiative or are interested in contributing, please email us at researchpartnerships@michaeljfox.org.