Challenging the established order: innovating clinical trials for amyotrophic lateral sclerosis

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.