A guest post from Dr Emma Tallantyre, Cardiff.
Definition: Clinical equipoise, also known as the principle of equipoise, provides an ethical basis for medical research that involves assigning patients to different treatment arms of a clinical trial. In short, clinical equipoise means that there is genuine uncertainty in the expert medical community over whether a treatment will be beneficial. [Source Wikipedia]
Our view of modern disease-modifying therapies (DMTs) for relapsing MS may depend on whether we like to view our glass as half-empty or half-full. We can look back favourably on the many advances we have seen in the treatment of MS during the last 10 years. But we can also see that much work remains to be done, regarding optimising our therapies for pwMS. When Prof G spoke at ECTRIMS in Stockholm, he warned against complacency when it comes to MS treatment, and summarised some unmet challenges that remain. As always, his speech was passionate and thought-provoking but I was deeply troubled by comments he made, echoing sentiments he recently expressed in a Lancet Neurology editorial, challenging the rationale behind two large, multicentre clinical trials: DELIVER-MS and TREAT-MS. Both trials seek to answer important questions about the optimum treatment approach in MS. Here I want to explain why I think he is wrong to undermine these studies, and to convince you that their results will be important in informing the choices that face people with MS.
Phase 3 clinical trials, which demonstrate how well a drug prevents relapses or delays disability in comparison to either a placebo or another drug, and are hugely helpful, not least in allowing medicines to gain approval for medical use. Monoclonal antibody therapies such as ocrelizumab and alemtuzumab have been shown to be more efficacious than beta interferon in randomised controlled clinical trials.
For that reason, for some people with MS, DMT preference is a “no-brainer”. Why wouldn’t I want the most effective thing available? As Prof G wrote in a letter to the EMA recently: “Many people with MS are willing to take on risks and/or a higher burden of monitoring, in order to be treated with the most effective licensed DMT first-line”. But as Prof G himself said many, but not all people with MS are willing to take on risks and medicine is about offering informed choice. As a neurologist, I believe the key roles I play in helping people with MS to reach a decision about DMT include providing them with good quality information, but also respecting their right to make their own choices about their body and their life.
Despite the evidence from phase 3 clinical trials, some pwMS prefer to choose an injectable or tablet DMT rather than a monoclonal therapy. These DMTs have been shown to be safe and moderately efficacious at reducing the relapse rate in clinical trials. We meet people in the MS clinic who tell us they would prefer to start one of these agents, citing a variety of reasons, including convenience, safety concerns or family planning. Perhaps they are mindful of long-term data showing favourable outcomes in a small minority of pwMS even in the absence of DMT, or they hope they will be among the 20-30% of people who show no evidence of disease activity after 2y of taking an interferon/ tablet DMT.
So how should we counsel those people, who for various reasons when faced with the evidence would prefer to start DMT with something other than a monoclonal? Should we persuade them, or even insist, that taking one of the stronger DMTs will be “better”? Prof G argues there is no equipoise. But I would argue that the findings from clinical trials are difficult to extrapolate to this common, real-life situation. When we look at how DMTs are used in real-world, moderately effective DMTs are not given in a blinded way for 2 years. PwMS commenced with any DMT should expect to have checked for breakthrough disease activity at several time points over the first 2 years, including clinical assessments and MRI scans to check how well the treatment is working. We remain unsure about whether these checks, when performed in a suitably rigorous and responsive manner, could detect “DMT failure” in a timely way, enabling escalation to a stronger DMT for those who need it, before any irreversible disability or consequences occur. Some people with MS would prefer to try this path, to see if they can avoid some of the “burden” of stronger treatments.
For the many people who feel uncertain about starting a monoclonal, I feel equally uncertain about what to advise. I believe they deserve to be better informed about the merits or disadvantages of this alternative approach. The DELIVER-MS and TREAT-MS trials seek to answer precisely this question: Does early treatment with highly effective DMT improve the prognosis for people with MS? Both trials are funded by an organisation called the Patient-Centered Outcome Research Institute (PCORI), which awards research money to answer questions that patients and the public have told them are important. The public asked researchers to design a trial to address whether early highly effective DMT or stepwise “escalation’” therapy is best in the earliest stages of MS. The two trials will recruit people with early MS who are at the point of starting their first DMT. These will be people who have been informed about the pros and cons of different approaches to DMT and yet feel uncertain, as do their neurologists, about which approach to take. Participants will be assigned at random to receive either a monoclonal DMT or to choose one of the non-monoclonal DMTs. But a key difference between these trials and phase 3 trials, is that participants in DELIVER-MS and TREAT-MS will be fully aware of which DMT they are taking, and will be monitored closely to look for signs of breakthrough disease activity, with a view to stepping up to a stronger DMT if they and their neurologist see fit. The DELIVER-MS and TREAT-MS trials will, therefore, tell us for the first time, whether with close monitoring, people who decide to try a moderate efficacy DMT first, can expect to do as well as those who start a monoclonal from the outset.
It is not only pwMS that have uncertain feelings about whether a typical pwMS should start with a monoclonal antibody, but it is also the neurologists. Although Prof G thinks there is no equipoise, many neurologists feel there is a lack of evidence for a benefit of monoclonal DMTs over other DMT types in terms of long-term outcomes, since phase 3 trials last only two years, and yet MS evolves over decades. Indeed over 60 sites in the United States and the United Kingdom have already signed up to be part of the DELIVER-MS and TREAT-MS studies, and several hundreds of patients have chosen to enrol.
Neurologists are a scientific bunch, and will inevitably be heavily influenced by efficacy data. Prof G’s question “If I had multiple sclerosis, how would I want to be treated?” is presumably intended to provoke the response “The highest efficacy drug”. But to imply that decision-making is so one-dimensional fails to acknowledge and respect the influence that a person’s beliefs, lifestyle factors, health considerations and personal experiences will have on their unique decision. I wholeheartedly agree with Prof G’s philosophy that people with MS deserve to be offered the choice to receive the best treatments first-line, but I also strongly believe that we cannot second-guess what will be “best” in a one-size-fits-all manner. The bottom line is we do not have studies comparing monoclonals with an escalation approach, so these studies will provide the necessary data for patients, neurologists, and healthcare agencies to make informed decisions. The public has asked us to answer a question and we owe it to our patients to provide robust evidence that will inform their choice.
Dr Emma Tallantyre, Cardiff
My biography: I graduated from medical school at the University of Nottingham in 2002. I undertook my postgraduate medical and neurological training in Nottingham, Derby, Australia and South Wales. As an MRC research fellow, I completed a PhD investigating imaging (Sir Peter Mansfield MR centre) and neuropathology (Nottingham University) of multiple sclerosis (MS).
I have been involved in the clinical care of people with MS since 2006. I completed my clinical training in 2015 and became a Clinical Senior Lecturer in Neurology in 2018. I hold an honorary contract to work within the Helen Durham Neuroinflammatory Unit of the University Hospital of Wales. As part of this role, I run weekly MS and general neurology clinics and contribute to service development.
My current research interests centre on the outcomes of neuroinflammatory disease. I am involved in clinical trials that investigate the optimum treatment approaches in multiple sclerosis. I have an interest in combining real-world clinical data with associated biological and imaging data to strengthen predictions of outcome and improve trial design. I am also interested in the involvement of patients and the public in the development of clinical research studies.
My conflicts are: I have received honoraria from Novartis, Biogen and Roche. I have received sponsorship to attend educational meetings from Merck and Roche. I have received a salary as an MS Registry Fellow from Biogen. I contribute to investigator-led research funded by Novartis and Genzyme.