LAUSR

In this issue of Annals of Neurology, Pittock and colleagues report the primary outcome of a phase 3 clinical trial of ravulizumab for aquaporin-4-positive neuromyelitis optica spectrum disorder (NMOSD). Ravulizumab is a second-in-class terminal complement inhibitor; like the firstgeneration medication eculizumab, it effectively prevented clinical relapses of NMOSD. No confirmed relapses were observed in this study of 58 patients followed for at least 50 weeks. Because ravulizumab is infused only once every 8 weeks, this medication is far more convenient for patients than eculizumab, which required infusions every 2 weeks, and no new safety concerns arose during the trial. This study is impactful, not so much for the efficacy of ravulizumab (which was unsurprising, given the potency of complement inhibition for preventing NMOSD relapses), but for the innovation in clinical trial design that is highlighted by the study. For decades, placebo-controlled, double-blinded clinical trials have been the gold standard for biomedical research. The use of placebo ensures that any observed clinical effect can be attributed to the pharmacology of the agent being tested, and blinding avoids bias caused by expectations of either participants or researchers. In most cases, data derived from randomized, double-blinded clinical trials (RCTs) are considered necessary for the US Food and Drug Administration (FDA) to approve a new pharmacologic agent for consumer use. Nevertheless, as medical science has progressed, questions of ethics and fiscal responsibility challenge the notion that traditional RCTs hold the unassailable high ground. Rather than clinging to this tried-and-true methodology, it is increasingly necessary for researchers to creatively consider evidence drawn from alternative clinical trial designs and observational, realworld data that have been examined using modern computational techniques. Regulatory bodies, in turn, must shift away from strict reliance on a traditional RCT design. The FDA acknowledges that for certain diseases an internal control (eg, placebo) may not be appropriate, and in these instances, external controls (eg, historical) may be acceptable. Despite this official guidance, when products approved between 2000 and 2019 were examined, only 45 products had been supported by external controls, and of these, only 4 were for neurologic indications. Many neurologic diseases, including relapsing multiple sclerosis (MS) and NMOSD, are now treatable, and thus alternatives to traditional placebo-controlled trials must be sought. For MS, recent phase 3 trials have adopted a superiority approach, comparing an experimental agent to an already-approved medication. The comparator is almost inevitably a medication considered “low efficacy” or “modest efficacy” within the pantheon of MS disease-modifying therapies. This raises thorny ethical issues, as many treatment centers in Western nations forego participation in late stage trials, believing that the chance of being on a low-efficacy comparator is not in their patients’ best interest. Instead, clinical trial recruitment is outsourced to less advantaged nations, where access to care and resources is limited and where the outcome of the trial may not directly benefit those who took part. Many of the MS studies are now performed in Eastern Europe, with nearly all white participants and unknown applicability to more diverse populations. Two ongoing pragmatic clinical trials, TREAT-MS (NCT03500328) and DELIVER-MS (NCT03535298), are examining equipoise between early intensive/highefficacy therapies and the less aggressive, escalation approaches to treatment. Should these find, as several observational studies have, that early use of highly effective therapies leads to improved outcomes relative to first-line use of modestly effective medications, this may once again force re-evaluation of ethical clinical trial design in MS. NMOSD causes destructive central nervous system lesions and not infrequently leads to lasting physical disability with each relapse. Three agents were FDAapproved for treatment between 2019 and 2020, and data also support the efficacy of several nonapproved immunomodulators. Placebo-controlled studies are now clearly unethical, remanding the question of how future trials in this space should be conducted. Some have suggested either superiority or noninferiority studies, comparing novel agents with a previously approved agent, but to appropriately power either of these designs may require