Heterogeneity, urgency, generalizability, and enrollment
The HUGE balance in ALS trials
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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.
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