Endpoint challenges in ALS clinical trials for approval and market access

I had an interesting conversation with Clinical Trials Arena recently on the development of new treatments for amyotrophic lateral sclerosis (ALS) clinical trials. ALS is a rare, progressive neurodegenerative disease with an average life expectancy of four years after diagnosis.

Although the ALS drug development landscape has historically been sparse, it is expected that there will be a number of clinical trial results forthcoming in 2022. The topic was initially stimulated by the discussion between Harvard University and the US FDA on matters relating to a platform clinical trial for ALS: each party had a different primary endpoint in mind. And yet this is an important consideration for assessing whether a new treatment works or not for it to be approved and accessed by ALS patients.

Development of innovative effective treatments for ALS has been hampered by a limited understanding of the underlying patho-physiology and absence of reliable markers to evaluate treatment effects. Differing endpoint and efficacy expectations can make designing an ALS clinical trial challenging and will have an impact on timely approval and market access to new treatments to benefit patients. 

The debate over primary endpoint reflects many of the broader challenges drug developers face in the research and development of new ALS treatments. All stakeholders want endpoints that are sensitive to subtle changes related to drug treatment, but also correlate with improved quality of life conditions.

In addition, selecting markers predictive of efficacy, stratifying patients according to disease severity, and satisfying regulators and payers in both the US and Europe present further challenges for a global clinical development programme, because ALS affects populations across all parts of the globe.

Some 30 years ago, survival was thought to be the only relevant endpoint. But a survival trial requires hundreds of patients followed over a long period of time. This has been acknowledged by practitioners as not an efficient way to perform new drug development. To successfully convince regulators and payers of the clinical efficacy and therapeutic position of a drug, manufacturers are expected to include a variety of endpoints measuring ALS functionality and quality of life.

Given the increasing pressure on healthcare cost containment, payers are increasingly demanding greater certainty of clinically relevant patient outcomes for a new treatment to be adopted for use in a healthcare system. The process for collecting long-term data in a real-world setting may influence how the terms of the market access agreement are structured.