Regulatory bodies consider use of a placebo control essential in evaluating safety and efficacy of new drugs. However, randomization to placebo in disease states where there are approved treatments raises ethical concerns in light of the Declaration of Helsinki statement that “every patient should be assured the best proven therapeutic method.”¹ Patients are becoming increasingly reluctant to participate in studies where they might be blindly randomized to placebo, and local ethical committees often refuse to approve such trials.² On the other hand, the idea that it is unethical to test a new treatment when a proven effective treatment exists has been called into question on the basis that there is an ethical distinction between clinical trials and treatment in the context of clinical medicine.³ Use of an active comparator may be an alternative, but because the number of patients needed will increase with the magnitude of effect of the active drug, it is costly and can cause problems with respect to adequate blinding as well as sample size.² So-called noninferiority, or equivalence trials using active controls have been criticized as having limited ability to establish the efficacy of new therapies in many medical contexts.⁴

In considering these issues, the National Multiple Sclerosis Society Task Force on Placebo-Controlled Trials in MS arrived at a consensus that placebo-controlled trials in forms of the disease for which partially effective therapies exist would be ethical, “so long as study subjects were fully apprised of the availability of such therapies and were encouraged to pursue them [when not taking part in] a clinical trial.”⁵

One common challenge in clinical trials is the ability to recruit adequate numbers of patients representing various minority groups.⁶ This problem does not appear to stem from a lesser degree of willingness to participate on the part of minorities.⁷ Indeed, a study of enrollment decisions by more than 70,000 individuals considering participation in 20 studies found few differences in consent rates by race or ethnicity.⁷ This observation suggests that efforts to increase the participation of minority groups in clinical trials should, in the words of one commentator,⁷ “focus on ensuring access to health research for all groups, rather than changing minority attitudes.”

Several different outcome measures have been used in clinical trials for MS (Table), and many studies have used multiple outcome measures.⁸ Observers have pointed out, however, that it is vital to identify the most important (primary) outcome and to enroll a sufficiently large enough number of patients to yield the statistical power needed to demonstrate an effect.⁸ Relapse rate has been the primary outcome in most trials of drugs eventually approved for the treatment of relapsing–remitting MS. This endpoint offers several advantages: relapse prevention translates into an immediate benefit to patients, relapses may be associated with significant residual deficits, and the relapse rate early in the disease course is an important predictor of accumulated disability at later time points.

Although the Expanded Disability Status Scale has also been used as an outcome measure in most pivotal trials, it has been the subject of controversy because of its limitations.⁹ Debate has centered on the difficulties associated with the scale itself, problems interpreting the conventional endpoints for disease progression, poor sensitivity, and the clinical applicability of such endpoints in relatively short studies.^2,9 Studies have suggested that measurement of the area under the EDSS/time curve is more clinically meaningful.⁹ The Multiple Sclerosis Functional Composite, which has greater sensitivity and reproducibility, has also been suggested as an alternative, and has been successfully used to measure reductions in disability accumulation rate.^2,10,11