Development of effective treatment for amyotrophic lateral sclerosis (ALS) has been hampered by disease heterogeneity, a limited understanding of underlying pathophysiology and methodological design challenges. Here we have evaluated two major themes in the design of pivotal, phase 3 clinical trials for ALS: (1) patient selection and (2) analytical strategy, and discussed potential solutions with the European Medicines Agency (EMA). Several design considerations were assessed using data from five placebo-controlled clinical trials (N = 988), four population-based cohorts (N = 5,100), and 2,436 placebo-allocated patients from the PRO-ACT database. The validity of each proposed design modification was confirmed by means of simulation and illustrated for a hypothetical setting. Compared to classical trial design, the proposed design modifications reduce the sample size by 30.5% and placebo exposure time by 35.4%. By making use of prognostic survival models, one creates a potential to include a larger proportion of the population and maximize generalizability. We propose a flexible design framework which naturally adapts the trial duration when inaccurate assumptions are made at the design stage such as the enrollment or survival rate. In case of futility, the follow-up time is shortened and patient exposure to ineffective treatments or placebo is minimized. For diseases such as ALS, optimizing the use of resources, widening eligibility criteria and minimizing the exposure to futile treatments and placebo is critical to the development of effective treatments. Our proposed design modifications could circumvent important pitfalls and may serve a blueprint for future clinical trials in this population.