Heterogeneity, urgency, generalizability, and enrollment

Most clinical trials in people with amyotrophic lateral sclerosis (ALS) have not produced successful new drugs.¹ Putative new therapies may not work to slow ALS for a number of reasons: perhaps the target is not pertinent or the drug characteristics are unacceptable (e.g., inadequate CNS penetration). If a drug is ineffective in treating ALS, it is best to declare this quickly and move on. If it looks promising, it is best to hasten development. Thus, conducting high-quality, rapid trials is a meaningful goal for ALS trialists. Yet, there are numerous challenges in ALS drug development. Perhaps chief among them is that ALS is a heterogeneous disorder.² This heterogeneity is most obvious to clinicians and clinical researchers as differences in location of onset, duration of diagnostic delay, and rate of ALS progression.³ This phenotypic heterogeneity can also be threatening: it reduces statistical power, resulting in larger, longer ALS trials. Participant selection criteria are 1 trial design tool that ALS trialists use to try to manage this challenge.