Amyotrophic Lateral Sclerosis Clinical Trials and Interpretation of Functional End Points and Fluid Biomarkers: A Review

Document Type

Article

Abstract

IMPORTANCE: Clinical trial activity in amyotrophic lateral sclerosis (ALS) is dramatically increasing; as a result, trial modifications have been introduced to improve efficiency, outcome measures have been reassessed, and considerable discussion about the level of data necessary to advance a drug to approval has occurred. This review discusses what recent pivotal studies can teach the community about these topics. OBSERVATIONS: By restricting inclusion and exclusion criteria, recent trials have enrolled populations distinct from previous studies. This has led to efficacy signals being observed in studies that are smaller and shorter than was thought feasible previously. However, such trials raise questions about generalizability of results. Small trials with equivocal clinical results also raise questions about the data necessary to lead to regulatory approval. The ALS Functional Rating Scale-Revised remains the most commonly used primary outcome measure; this review discusses innovations in its use. Blood neurofilament levels can predict prognosis in ALS and may be a sensitive indicator of biologic effect; current knowledge does not yet support its use as a primary outcome. CONCLUSIONS AND RELEVANCE: It is now possible to use specific inclusion criteria to recruit a homogeneous patient population progressing at a specific rate; this will likely impact trials in the future. Generalizability of results on limited populations remains a concern. Although clinical outcomes remain the most appropriate primary outcome measures, fluid markers reflecting biologically important processes will assume more importance as more is learned about the association between such markers and clinical end points. The benefit of use of analytic strategies, such as responder analyses, is still uncertain.

Medical Subject Headings

Humans; Amyotrophic Lateral Sclerosis (diagnosis, drug therapy); Outcome Assessment, Health Care; Biomarkers; Prognosis

Publication Date

12-1-2022

Publication Title

JAMA neurology

E-ISSN

2168-6157

Volume

79

Issue

12

First Page

1312

Last Page

1318

PubMed ID

36251310

Digital Object Identifier (DOI)

10.1001/jamaneurol.2022.3282

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