Amyotrophic Lateral Sclerosis (ALS) is a rapidly progressive neurodegenerative disorder leading to muscle weakness and respiratory failure, with death following, on average, within three years after symptom onset. Currently, there is no effective therapy and the mainstay of care for patients with ALS aims at improving the quality of life and at the management of symptoms. Therefore, there is a pressing unmet need for effective therapy. Despite the conduct of dozens of clinical trials and promising preclinical results, none of the evaluated drugs obtained global market authorization. This thesis, therefore, aims to identify and address the main bottlenecks of the clinical drug development for ALS.
Clinical trials for ALS are complicated by the unpredictable and variable course of the disease, the insensitivity of clinical outcome measures and by suboptimal or unrealistic design assumptions. These bottlenecks are further aggravated by the absence of clear data-driven guidance for the design of clinical trials, and the limited availability of resources. This leads to suboptimal studies that could miss crucial treatment clues or needlessly expose patients to potentially harmful experiments. This thesis describes that large efficiency gains can be obtained by innovating eligibility criteria, efficacy outcomes, design settings and analytical strategies of clinical trials. This reduces the size and duration of clinical trials, which lowers the burden for patients and optimizes the use of the available resources. Ultimately, these innovations could circumvent important pitfalls encountered by classical trial design and accelerate the development of effective therapy against this debilitating disease.