Is it ethical to use teriflunomide as an active comparator in phase 3 trials?

Ethical concerns have been raised about the practice of using teriflunomide, an oral licensed disease-modifying therapy, as an active comparator in phase 3 multiple sclerosis (MS) trials. The assumption is based on the perceived low efficacy of teriflunomide as judged by its effect on relapses and focal MRI activity. However, when you look beyond focal inflammation, teriflunomide has a robust impact on disability progression and a similar effect to the anti-CD20 monoclonal antibody therapies on slowing down the accelerated brain volume loss associated with MS. Teriflunomide is also more effective when used second or third line. The other classes of disease-modifying therapies have problems with their use as active comparators in clinical trials. Using a non-inferiority or equivalence trial design has its own unique set of regulatory and ethical challenges and is not necessarily a solution. There are also economic, altruistic and pragmatic reasons for continuing to use teriflunomide as an active comparator in MS clinical trials. An online survey indicates that the majority of the MS community feels it is still ethical to randomise subjects to teriflunomide and that procedures can be put in place to protect trial subjects randomised to teriflunomide. Therefore, we still have equipoise, and teriflunomide comparator trials are ethical.