Suggestions for improving the design of clinical trials in multiple sclerosis—results of a systematic analysis of completed phase III trials

Abstract

This manuscript reviews the primary and secondary endpoints of pivotal phase III trials with immunomodulatory drugs in multiple sclerosis (MS). Considering the limitations of previous trial designs, we propose new standards for the planning of clinical trials, taking into account latest insights into MS pathophysiology and patient-relevant aspects. Using a systematic overview of published phase III (pivotal) trials performed as part of application for drug market approval, we evaluate the following characteristics: trial duration, number of trial participants, comparators, and endpoints (primary, secondary, magnetic resonance imaging outcome, and patient-reported outcomes). From a patient perspective, the primary and secondary endpoints of clinical trials are only partially relevant. High-quality trial data pertaining to efficacy and safety that stretch beyond the time frame of pivotal trials are almost non-existent. Understanding of long-term benefits and risks of disease-modifying MS therapy is largely lacking. Concrete proposals for the trial designs of relapsing (remitting) multiple sclerosis/clinically isolated syndrome, primary progressive multiple sclerosis, and secondary progressive multiple sclerosis (e.g., study duration, mechanism of action, and choice of endpoints) are presented based on the results of the systematic overview. Given the increasing number of available immunotherapies, the therapeutic strategy in MS has shifted from a mere "relapse-prevention" approach to a personalized provision of medical care as to the choice of the appropriate drugs and their sequential application over the course of the disease. This personalized provision takes patient preferences as well as disease-related factors into consideration such as objective clinical and radiographic findings but also very burdensome symptoms such as fatigue, depression, and cognitive impairment. Future trial designs in MS will have to assign higher relevance to these patient-reported outcomes and will also have to implement surrogate measures that can serve as predictive markers for individual treatment response to new and investigational immunotherapies. This is an indispensable prerequisite to maximize the benefit of individual patients when participating in clinical trials. Moreover, such appropriate trial designs and suitable enrolment criteria that correspond to the mode of action of the study drug will facilitate targeted prevention of adverse events, thus mitigating risks for individual study participants.

Treatment patterns and comorbid burden of patients newly diagnosed with multiple sclerosis in the United States

“…The disease is typically divided into two partially overlapping phases. After an initial phase of relapsing-remitting multiple sclerosis (RRMS) patients may transition to secondary progressive MS (SPMS), characterized by continuous worsening of symptoms, such as fatigue or cognitive impairment [ 5 ]. Currently available disease-modifying therapies (DMTs) address the RRMS phase of MS and are less efficacious in the progressive phase.…”

Predictors of Health Utility in Relapsing–Remitting and Secondary-Progressive Multiple Sclerosis: Implications for Future Economic Models of Disease-Modifying Therapies

“…Scores of 0-4.5 represent normal ambulation and measure disability based on neurological examination, while scores of 5.0 and above represent progressive loss of walking ability [20]. The EDSS has been the most commonly used endpoint to measure disability progression in randomized clinical trials (RCTs) of RRMS, [21,22] and it is well understood and accepted by the neurology and regulatory communities [23][24][25][26]. However, the EDSS has several limitations, including: high intra-and inter-observer variability, [27] it is an ordinal scale and the differences between contiguous scores are variable, [27,28] it is nonlinear and the time spent in the middle scores is shortest, with peaks at EDSS 1.0-3.0 and 6.0-7.0, [27] EDSS levels of 4.0-7.5 are primarily determined based on the distance people can walk and the need for an assistive device, [20] and it cannot detect changes in people with severe disability and in various domains relevant in MS (e.g., upper extremity function, cognition) [27,28].…”

“…Although the MSFC covers multiple major MS domains and has been reported to be highly reliable and correlated with the EDSS, health-related quality of life (HRQoL), and other important clinical and economic indicators, its responsiveness is not always better than the EDSS and also has several limitations [25,28,29,[33][34][35][36][37]. To address the individual limitations with the EDSS and the MSFC, endpoints combining the EDSS with the MSFC, or the MSFC individual components, have been proposed and used to assess the efficacy of DMTs in clinical trials of RRMS [24,38,39].…”

Targeting Endocannabinoid Metabolism: an Arrow with Multiple Tips Against Multiple Sclerosis

“…In this context, new preclinical models accurately recapitulating disease features would be extremely beneficial for predictive, preventive and prognostic purposes. Future trials of therapeutics against MS, including trials with cannabinoid derivatives, should take into consideration predictive markers for individual response to new treatment strategies [191] . In order to enlarge the armamentarium of therapeutic options against MS, the expanded signaling related to ECS has growingly gained interest over years.…”