Ethics of placebo-controlled clinical trials in multiple sclerosis

Abstract

The increasing number of established effective therapies for relapsing multiple sclerosis (MS) and emerging consensus for early treatment raise practical concerns and ethical dilemmas for placebo-controlled clinical trials in this disease. An international group of clinicians, ethicists, statisticians, regulators, and representatives from the pharmaceutical industry convened to reconsider prior recommendations regarding the ethics of placebo-controlled trials in MS. The group concluded that placebo-controlled trials can still be done ethically, with restrictions. For patients with relapsing MS for which established effective therapies exist, placebo-controlled trials should only be offered with rigorous informed consent if the subjects refuse to use these treatments, have not responded to them, or if these treatments are not available to them for other reasons (e.g., economics). Suggestions are provided to protect subject autonomy and improve informed consent procedures. Recommendations are tighter than previously suggested for placebo-controlled trials in "resource-restricted" environments where established therapies may not be available. Guidance is also provided on the ethics of alternative trial designs and the balance between study subject burden and risk, scientific rationale and interpretability of trial outcomes.

Trends in annualized relapse rates in relapsing–remitting multiple sclerosis and consequences for clinical trial design

“…23 As the MS environment changes, active controlled trials might become more common. 24 Although not considered in this paper, the statistical procedures underlying the BSSR procedure are also applicable to active control trials planned to demonstrate superiority or non-inferiority. 7 …”

Evolving landscapes in multiple sclerosis research: adaptive designs and novel endpoints

“…One standard option has been to increase the sample size and the number of subjects on placebo, introducing potential ethical issues [19]. Alternatively, use of a head-to-head comparative or add-on treatment study designs, both designs with active treatment groups, addresses the ethical issue of exposure to placebo, but adds further challenges due to the expected small difference in efficacy between two active treatments using traditional measures.…”

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

“…However, clinical end points are relatively insensitive for detecting therapeutic benefits of new agents compared to placebo in relapsing MS. As a result, to ensure adequate statistical power, trials with clinical end points require sample sizes of at least several hundred patients and study durations of 2-3 years. 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].…”