Challenges in randomized controlled trials and emerging multiple sclerosis therapeutics

Abstract

The remarkable global development of disease-modifying therapies (DMTs) specific for multiple sclerosis (MS) has signifi cantly reduced the frequency of relapse, slowed the progression of disability, and improved the quality of life in patients with MS. With increasing numbers of approved DMTs, neurologists in North America and Europe are able to present multiple treatment options to their patients to achieve a better therapeutic outcome, and in many cases, no evidence of disease activity. MS patients have improved accessibility to various DMTs at no or minimal out-of-pocket cost. The ethical guidelines defi ned by the Edinburgh revision of the Declaration of Helsinki strongly discourage the use of placebo control groups in modern MS clinical trials. The use of an active comparator control group increases the number of participants in each group that is essential to achieve statistical signifi cance, thus further increasing the diffi culty of completing randomized controlled trials (RCTs) for the development of new MS therapies. There is evidence of a high prevalence of MS and a large number of patients in Asia. The belief of the existence of Asian types of MS that are distinct from Western types, and regulatory policies are among the reasons why DMTs are limited in most Asian countries. Lack of access to approved DMTs provides a good opportunity for clinical trials that are designed for the development of new MS therapies. Recently, data from RCTs have demonstrated excellent recruitment of participants and the completion of multi-nation and single-nation MS trials within this region. Recent studies using the McDonald MS diagnostic criteria carefully excluded patients with neuromyelitis optica (NMO) and NMO spectrum disorder, and demonstrated that patients with MS in Asia have clinical characteristics and treatment responses similar to those in Western countries.

Multiple Sclerosis: Immunopathology and Treatment Update

“…In the last 20 years there has been an evolving trend in novel treatments for MS and the global progress of therapies for MS has been quite promising. In general treatments consist of Ampyra ® , Aubagio ® , Avonex ® , Betaseron ® , Copaxone ® , Extavia ® , Gilenya ® , Lemtrada ® , Novantrone ® , Plegridy ® , Rebif ® , Tecfidera ® and Tysabri ® [100]. Such treatment options consist of alemtuzumab (depletes lymphocytes), daclizumab (blocks the cytokine receptor IL-2), dimethylfumarate (combines features of immunomodulatory and immunosuppressive actions), fingolimod (modulates the sphingosine-receptor system), natalizumab (inhibits the migration of lymphocytes) and teriflunomide (inhibits activated T and B cells) [9,27,50].…”

Should MRI be the primary endpoint of phase 3 trials in multiple sclerosis?

“…With effective therapies now widely available for relapsing MS, using placebo controls in MS clinical trials is becoming increasingly difficult due to ethical and practical constraints [3]. In lieu of placebo, recent trials increasingly use existing DMTs as active comparators against which the new therapy's effects on clinical disease activity are measured [4]. This design requires even larger sample sizes and longer study durations to provide adequate statistical power.…”

Genetic prediction of the causal relationship between schizophrenia and tumors: a Mendelian randomized study

“…In addition, for rare and life-threatening diseases that lack effective treatments, routine RCTS may be difficult to implement, require high time costs, or may raise ethical concerns. Therefore, randomized controlled trials face various challenges in clinical practice (28)(29)(30). Mendelian randomization (MR) is a statistical method for evaluating etiological inferences in epidemiological studies.…”