Rethinking phase 2 trials in amyotrophic lateral sclerosis

There is a long history in amyotrophic lateral sclerosis (ALS) of promoting therapies based on phase 2 data, which then fail in phase 3 trials. Experience suggests that studies of 6 months in duration are too short, especially with function-based outcome measures. Multiplicity poses a serious threat to data interpretation, and strategies to impute missing data may not be appropriate for ALS where progression is always expected. Emerging surrogate markers of clinical benefit such as reduction of neurofilament light chain levels may be better suited to phase 2 go/no-go decisions. Over-interpretation of phase 2 data, and overly optimistic communication of exploratory analyses must be avoided to ensure optimal prioritization for the investment needed for definitive phase 3 trials and to minimize the harm of false hope for people living with ALS. Delivering on advances in understanding of the neurobiology of ALS requires urgent attention to phase 2 design and implementation.