Noting that Aubagio (teriflunomide) continues to have "a robust impact on disability progression" in multiple sclerosis (MS) despite being eclipsed by newer MS treatments in trials, an international team of researchers are now arguing that it is, in fact, still ethical to use the older therapy as a comparator in clinical studies. That's the case the researchers make in a new paper, titled "Is it ethical to use teriflunomide as an active comparator in phase 3 trials?" and published in Multiple Sclerosis and Related Disorders. The team acknowledged that Aubagio is an older drug with a modest impact on relapses and MRI activity. But they say that, if scientists "look beyond" acute inflammation, the drug has a "similar effect to [newer] antibody therapies on slowing down the accelerated brain volume loss [shrinkage] associated with MS." Thus, their answer to the question posed in the title of their paper is a definitive "Yes." "We think we still have equipoise [sufficient equivalency between therapies], and that [Aubagio] comparator trials are ethical," the researchers wrote. Aubagio was approved in U.S. more than a decade ago. Aubagio is an oral therapy that's been approved in the U.S. for more than a decade as a treatment for relapsing types of MS. It works to reduce disease-driving inflammation by lowering the activity of certain immune cells. The name-brand therapy Aubagio is sold by Sanofi; generic forms of the drug also are available. Given that there are many approved treatments for MS, scientists generally agree that it's morally dubious to run a placebo-controlled clinical trial in which some patients would get a placebo that is known to be ineffective. Instead, many modern clinical trials use an active comparator — essentially, testing an experimental therapy against one that is already approved. Aubagio has been a popular choice for use as a comparator in MS drug trials. The approvals of Ponvory (ponesimod), Kesimpta (ofatumumab), and Briumvi (ublituximab) all were supported by clinical trials showing that these newer therapies were superior to Aubagio at reducing relapse rates and disease activity on MRI scans. In several ongoing studies, Aubagio also is being used as a comparator for testing new experimental treatments. However, with several approved treatments having already bested Aubagio in clinical trials, some MS experts have argued that it's no longer ethical to use it as a comparator in future trials. In this paper, scientists from Australia, Canada, the U.K., and the U.S. argued against this idea. "There is a rising chorus of voices calling for teriflunomide to be replaced as the go-to comparator because (1) it is being used less often and (2) because it is perceived to be a low-efficacy [therapy] relative to the newer licensed [treatments]. Several MS experts are therefore claiming that any Phase 3 trial using teriflunomide as an active comparator should be considered unethical," the researchers wrote. The team countered that, so long as parameters are in place, this is not the case. "We are not sure it is unethical, provided specific provisions are implemented to address [such] ethical concerns," they wrote, adding, "The premise that we have lost equipoise [equivalency] is based on a misinterpretation of how [Aubagio] works as a disease-modifying therapy." Data show older therapy still works well to prevent disability. The researchers argued that, although Aubagio has shown to be less effective than some newer therapies at preventing relapses, data still demonstrate that Aubagio is comparable at preventing worsening disability. Trials generally have showed no significant difference in disability progression and in the rate of brain volume loss between Aubagio and newer therapies, the team noted. And even when there have been statistically significant differences, "the differences are very small and are unlikely to be clinically significant." Economic factors also may make Aubagio a useful comparator, the team noted, pointing out that generic versions of the therapy — which cost as little as $32.40 for a 30-day supply — are increasingly available. Because newer MS therapies are typically very expensive, using a cheaper comparator may make it easier to run trials, they said. Another argument in favor of Aubagio as a comparator is that other approved MS therapies aren't as well suited to the job. The researchers noted that many newer therapies require monitoring to reduce the risk from potential side effects, which adds logistical complications to trials that are already complex and expensive to run. This also makes it more likely that patients know which drug they're getting, removing the blinding from the trial. Plus, as newer therapies are so good at reducing relapses, a trial that aims to show that an experimental therapy is better would need to be very large and run for a very long time, further adding to the expense and logistical burden. Trials that aim to show an experimental therapy is equivalent to newer high-efficacy therapies would have similar issues, the researchers argued. The team also noted that making trials cheaper and easier to run means more trials are likely to be launched, which offers the possibility of more approved treatments and wider ability for people with MS to participate, especially for individuals who may not otherwise be able to afford treatment. "It is our impression that [people with] MS want action, i.e. innovative trials to address the unmet need, rather than academic discussions about whether or not we should do the trials," the scientists wrote. Overall, the researchers concluded that Aubagio still has a place as a comparator in MS clinical trials, arguing that it's too early to say that doing so is unethical. "A wider discussion is needed to explore these issues with PwMS [people with MS], organisations representing PwMS, statisticians, ethicists, ethics committees and the wider MS community before we take the moral high ground that teriflunomide comparator trials are unethical," they wrote, ultimately concluding the use of Aubagio is ethical. No funding was obtained for the study and Sanofi was not directly involved in it. One of the study's co-authors disclosed having previously received compensation from Sanofi as well as many other pharmaceutical companies.