Table 1.

Summary of the main reasons for clinical trials failure in ALS and proposal of possible solutions

Reasons of failure of ALS clinical trials	Proposed solutions to be developed:
Incomplete knowledge of pathogenic pathways and limited disease models of the disease	-Novel disease models encompassing the complexity of the human disease and its key pathology (i.e. cytoplasmic accumulation of TDP-43);
	-Specific models to demonstrate target engagement of different treatment strategies;
	-Preclinical pharmacodynamics biomarkers for therapeutic candidates;
	-Multidrug approaches to affect different pathogenic cascades.
Phenotypic and biological heterogeneity and rarity of the disease.	-Organization of multicentric clinical trials and collaboration with patients’ associations and caregivers to facilitate recruitment and reduce the drop-out rate;
	-Effective stratification of the patients to improve statistical power according to disease phenotype and stage;
	-Extended genetic screening of the ALS population with the aim of improving stratification, treating pre-symptomatic subjects and developing targeted gene therapies.
Limitations in clinical trials design, outcome measures and patient’s stratification.	-Development of sensitive outcome measures to be adapted to the specific clinical trial with standardized operating procedures;
	-Implementation of predictive, prognostic and pharmacodynamic biomarkers including combined scores and multimodal composed outcome measures;
	-Development of innovative predictive models to demonstrate treatment efficacy and to take into account pharmacological interactions;
	-Implementation of alternative study designs such as adaptive designs, platform trials, enrichment design, multistage sequential design, futility design.