OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is an adult-onset, fatal disease, in which the degeneration of motor neurons located in the brain and spinal cord affects voluntary muscle movement. The etiology of ALS is highly complex, and, when compounded by the disease’s intrinsic heterogeneity, imposes considerable challenges to the selection of valid and clinically meaningful efficacy endpoints within clinical trials. This review aims to evaluate trends in the selection of efficacy endpoints and corresponding definitions in trials of ALS and superoxide dismutase 1 (SOD1) ALS across a targeted range of interventions. METHODS: Relevant studies were identified by searching the following databases: MEDLINE^®, Embase, and the Cochrane Central Register of Controlled Trials. A mini-review was conducted to supplement the existing evidence base with trials specifically targeting the ALS SOD1 subpopulation. RESULTS: A total of 22 studies met inclusion criteria. In general, trials evaluated efficacy endpoints across similar domains, although heterogeneity existed in outcome definitions and measurement parameters. High variability was observed in event-free survival definitions, and methods for quantifying a clinically meaningful change in disease progression were inconsistent across trials. A few innovative approaches to outcome assessment were identified within one recent trial of SOD1 patients. These included use of remote outcome assessment methods to mitigate participation bias, and the use of a combined efficacy endpoint of function and survival to mitigate the confounding effect of mortality. CONCLUSIONS: The clinical evidence base for ALS is highly heterogeneous with respect to outcome definitions and measurement parameters, mirroring the challenges to effective clinical trial design within this disease area. Future studies of ALS may benefit from a) the application of greater scrutiny when operationalizing outcome definitions, including more judicious selection of clinically meaningful assessment scales and measurement time points and b) the incorporation of remote assessment methods in an effort to alleviate participant burden.