Do we really have equipoise about DMTs?

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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. 

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39 comments

  • Hey thanks for your retort to prof G.
    I had to look up equipoise as most will!
    All treatment has to be patient centered and don’t think prof G is arguing for a one cap fits all approach.
    Personally I was dianised in 2015 with rr me started on tecfidera and Had to change from tecfidera to plegridy as low white blood count. So a drop of roughly 17 % efficacy by ms society info on DMT.
    4 year follow up shows no progression on mri or edss. So technically I should be ecstatic! However I was gutted I had to change u see I didn’t want give any ground to the disease by lose of efficacy, it is like a knock on in rugby!
    An unforced error!

    The problem the ms world will have is the massive backlog of people who will want HSCT if it passes the next phase in testing!
    Out of interest how would u treat yourself?
    In a world where u had access to HCST?
    Thanks in advance!
    Robbie

    • Thanks Robbie.
      I agree it’s really tricky because the decision hinges on so many things – how active your MS is at the time you make the decision to start DMT, how you tolerate it, how it suits your lifestyle etc. Often people want to try with the high efficacy stuff but then sometime, like you, they run into problems and decide to switch onto lower efficacy- even if it wasn’t what they’d intended. But I think you also make a good point that some people do have adequate control of relapses/ MRI activity using interferon alone – it’s just not easy to predict which people.

      I think it’s very reasonable of people with MS to ask their neurologist “what would you do?” but I’m being honest when I say I am really not sure. That’s the reason I became involved in the DELIVER-MS trial. The neurologists involved are all people who genuinely feel there are pros and cons to both escalation and early highly intensive treatment approaches.

      • The only predictable thing about MS is how unpredictable it is. MRI burden of disease does not accurately predict progression and reliable biomarkers are lacking. Sure, a lower efficacy drug may hold the “beast at bay” for a period…or, that could just be the natural disease course for that particular individual. I think people need to think longer term when deciding on treatment options given MS is a disease that can take 30 years for risks to be realised. Hitting it hard and early seems like the sensible approach in my opinion. Preserve as much brain as possible for as long as possible. With that said, treatment decisions are multifactorial as this post highlights and people’s tolerance of treatment risks plays a huge role in decision making.

  • I am iterested in comparison across other chronic diseases.

    I appreciate this may be an over-simplification, however, it is my impression that if I turned up to an oncology specialist they would have no hesitation in steering me very positively towards the latest treatments and not the 20-30y old ones because I was scared.

    MS is bloody terrifying at first, it is entirely logical to fear data sheets and find Internet stories completely off-putting if you are unaccustomed to interpreting data. And very few of us are. It is not a general life requirement.

    Isn’t it the role of the medical team to ease these concerns and show an absolutely (evidence based) bias towards the most efficacious treatments? This hands off the tiller patient led approach to treating an incurable and disabling condition seems to me to be side-stepping professional responsibility to instead avoid could conflict at all costs.

    MSologists are professionals who have much experience in treating the disease. Because a patient heard from someone who read something about MS and – insert ill-informed information here – has decided for themselves that drug X is too dangerous (something else addressed in large scale RCTs) that shouldn’t constitute a reason not to press the patient to do the best thing medically.

    To psychologically assauge someone in the short-term at the proven expense of life long-term disease outcomes doesn’t seem right.

  • I don’t think Prof G was arguing for a one size fits all approach.
    I was diagnosed last year and went for the most aggressive treatment that I could get which at the time was Lemtrada although now I wouldn’t be able to because of the EMA review. I felt that I was given exceptionally limited information from the hospital about the DMT choices available to me so I did my own extensive research. I was therefore a frustrated patient feeling that the MS team sat on the fence although when I asked for Lemtrada my neurologist was in full agreement and said that would be his recommendation for me. I don’t think there is anywhere near enough awareness of brain volume loss and DMTs when patients are asked to pick their treatment. I think the focus is purely on relapse rate and feel this is misleading to people who haven’t done their own research. I also think the true extent of accruing disability needs to be balanced against side effects of DMTs and that it is the responsibility of the MS team to ensure that patients have an accurate understanding of this.

  • It was way back in 2014 when Barts-MS proposed a trial to test treating-2-target of NEDA vs. conventional step-care approach (see blog post 9th January 2014). Prof K and I hosted a UK meeting in May 2014 to get the trial off the ground. We subsequently handed the trial over to the MS Society Clinical Trial Group and Nikos Evangelou and Matt Craner developed and NIHR application that was not successful. Eventually, PCORI picked-up the baton and funded the trial. However, in the intervening 5-6 years, the treatment of MS had advanced so much and our practice had changed that we felt we couldn’t participate. At Barts-MS we treat-2-target of NEDA and practice a zero-tolerance strategy and we also offer patients a choice between rapid-escalation and flipping the pyramid as part of routine care. Hence at Barts-MS, we don’t have equipoise. I do agree however it should be based on informed decision-making and personal choice.

    • I find this response confusing. In many instances you argue that gold standard evidence must prevail (e.g. randomised controlled trials). Yet here you appear to be questioning equipoise when the “gold standard” study hasn’t been conducted. If there is uncertainty then there is equipoise. There seems to be much uncertainty amongst neurologists about treatment regimes. Surely the outcome of these studies will provide the evidence to facilitate better treatment decisions?

  • Patients can be a ‘scientific bunch’ too. A quick a dirty search of the literature will reveal some work that has been done on patient tx decisions and concordance with MS drugs. Would love to look at the protocols for these trials to see what stuff is being collected – some good opportunities. FWIW, I believe in a zero tolerance r.e. disease activity, total abrogation of inflammation being the only way. The pt should be at the centre of decision making, like with any chronic and progressive condition.
    There are sometimes written pieces that say a lot about not very much at all. This is one such example. It’s quite a skill.

    • Thanks F. I agree that understanding treatment decisions is really important. Aside from all the complexities of MS and DMTs, we have to accept that we all make decisions quite differently from each other. Even simple things like what we eat or how we spend/ invest our money. I love the work being done in the CRIMSON project by Ana Manzano, Helen Ford and others. They have interviewed many people with MS about treatment decisions to try to develop decision-aids that are informed by genuine lived experience. I think this will be a really welcome.

  • The MRI of the brain in MS and Neuroborreliosis is indistinguishable.
    I found this FACT very compelling.
    I began testing every MS patient I encountered for Neuroborreliosis.
    All MS patients I have encountered are positive for Neuroborreliosi when PROPERLY tested.
    Every pathological microscopic finding in MS and Neuroborreliosis is indistinguishable.
    Conclusion: The etiology of MS is Neuroborreliosis,
    The inflammatory findings are not autoimmune but rather are due to an infection.
    The treatment is with antibiotics to eradicate this infection.
    Alfred Miller,M.D.
    Mayo Clinic trained physician.
    Full Professor, Clinical Faculty, Univ. of Texas Med School, San Antonio, Tx.
    Private practice – Int. Med/Rheumatology 1968-2008.
    Now retired

      • The facts speak for themselves.
        The test results are objective, reproducible, and non-negotiable.
        I am as amazed as you !
        Intellectual Honesty must prevail.
        I am not selling anything – I am not affiliated with any organization or laboratory – I am retired and not seeking any patients.
        Alfred Miller,M.D.

          • Why did they look at death rates as the surrogate? Not all people with MS etc. die due to the disease just like not all people with Lyme’s die.

        • “The test results are objective, reproducible, and non-negotiable.”
          For those who might read this, the test for neuroborreliosis (or Lymes) is non specific and not always accurate. Many false-positive, false-negaive results. There is no reliable test for this disease yet. There is research on a more accurate test though.
          The “objectivity” of the test is ludicrous.

          Brain lesions are not typical for neuroborreliosis (or Lymes) and can rarely show up only later in the disease. Immunesuppresion like the one MS drugs develop would have a negative and not positive effect on the disease.

          So, no cure here :_(

  • Hmm, a lot of Big Pharma subsidies going on in Dr Tallantyre’s pay package. Government ought fund education, training and academic career development but they don’t. It wasn’t like this fifty years ago. The state used to pay for one’s PhD back then.

    The devaluing of education is horrendous. Dr Tallantyre ought to be completely sponsored by the state. I bet that she’s had to incur massive debt just to get so throughly educated.

    • The doctor graduated in 2002, this is before student paid university tuition fees in England, for undergraduate degrees came in.

        • The doctor graduated from medical school in 2002, as stated by the doctor.

          So the doctor would of began the first year at medical school before 2000.
          The year students start university dictate the fees they need to pay.

    • Dear ‘Mad For IT’,

      Mentioning en passant that a Doctor does work for the Pharmaceutical Industry and is renumerated for doing so comes across as a thinly veiled swipe at their credibility. Additionally, using the slang ‘Big Pharma’ with the connotations that that moniker has attached to it serves to just cheapen the shot.

      Why doesn’t one research exactly what the Doctor did for the money before just leaving the implication hanging that there is possibly a whiff of intellectual corruption present by the mere association?

      If the intention is to use an association with the pharmaceutical industry to discredit it then why not just come out and be specific?

  • Dear Emma,

    I happen to be a patient of Profs Giovannoni and Robertson simultaneously. In the sense that I see both of them for advice. I am lucky to have first hand experience of the Heath modus operandi as well as Barts – what I thought was a philosophical approach to medicine may simply be a cultural gap after all. MS is mostly theoretical after all. We don’t really know where it is coming from, how it evolves an how to stop it. I would like to thank you for your work in helping us understand optimal treatment choice.

    Now a question comes to mind that I would like to challenge you with if OK:

    A patient of yours is responding well to treatment. Their annual routine MRI in that mobile truck parked next to A&E shows a couple of new T2 lesions. Their EDSS is stable nontheless. What would you advise them to do?

    What if it was a new (or enlarging) T1?

    What if they have acute brain atrophy despite being relapse free?

    Many thanks

    Tony Fonda
    (not my real name, but I am very real MSer)

    • Thanks Tony. Yes when to switch treatments is another whole discussion, I agree. And there are many schools of thought. As Prof G says some neurologists strive for NEDA, others accept 2 (or even more) new lesions annually if other things are stable. It may surprise you to know but not all centres use MRI surveillance. But many neurologists (myself included) would take into account several other factors, including things you have mentioned, and also how long the period of stability has been, how satisfied they are with their current treatment etc. I think the first thing would be to discuss with the person with MS and try to help them understand pros and cons of switching. As I say, that is a whole other topic of discussion.

      • I am certainly keen to pop-in for a cup of coffee at some point and discuss further if convenient to you. We may perceive the risk/benefit curve very differently – but I am certainly interested in hearing your thought.

        Tony, Penarth

  • Emma,

    Thanks for you post.

    Given that relapses can cause irreversible disability (by destroying axons and neurones) surely its the role / duty of a neuro to recommend the treatment that reduces the frequency and impact of relapses / inflammatory activity?

    If a bedroom was on fire with a baby inside would you grab a pint glass of water or the flower vase containing three pints before heading upstairs?

    Neuros shouldn’t hide their responsibilities behind patient choice. Patients haven’t gone through medical school / neurology training / experience in the clinic seeing 100s of MS patients.

    I like the comparison with oncology – would an oncologist offer a moderately effective treatment licensed 25 years ago or the latest highly effective treatment? Patients need to be told the real impact of MS if not treated or treated with a moderately effective treatment. Injectables were introduced 25 years ago, Tysabri c.15 years ago, there is Alemtuzumab data for the last 10-12 years. Is it really that difficult for a bunch of MSologists to get together for a day to share their experiences of how their patients are doing in real life? The two trials you mention will take some time to complete / report.

    Unfortunately I suspect the outcome of the trials may well turn out to be not so useful once the researchers prove that MS is caused by a virus or is primarily neurodegenerative (relapses and MRI aren’t the real disease).

    What MSologists really need are additional treatments to protect nerves and encourage repair.

    • Sometimes it takes time for clinicians to change their behaviour when it comes to new treatments or new treatment strategies. May be the data from these trials will help them change how they manage MS?

  • Dear Dr. Tallantyre,

    I find your outlook very disturbing for both current and future MS patients. I really wish you would start laying your weight behind research that actually matters. Neither escalation therapy approach vs. most efficacious immunosuppressant therapy is addressing the real or progressive MS.

    In other words, relapses and Gd+ MRI changes do not equal progression of MS. Yes, some fortunate MS patients will be lucky enough with these immunosuppressant DMDs, like alemtuzumab and HSCT, to slow conversion to progressive stage of MS. However, many, if not most, will progress independent of relapse activity despite highly efficacious therapy or escalation DMD therapy.

    As we continue to focus on our current model that treats a downstream reaction with immunosuppressants (adaptive peripheral immunity) addressing relapses and Gd+MRI changes and not addressing the progression caused by innate changes in immunity (hot microglia, A1 astrocytes, oligodendrocyte changes and neuron death likely caused by a virus, like EBV), we will continue to produce underwhelming clinical outcomes.

    Placing your support behind these immunosuppressant trials is an utter waste of precious time and absolute insanity. The only one further ahead will be the stockholders of of each Pharma company involved.

    • Dr Hartt, I think you have been consuming too much of Prof G’s comments and thoughts on the smouldering MS, EBV, etc. He may yet be proved to be wrong. Or not?

      • Anonymous 7:44:

        Ask the 1 million wheelchair users & patients progressing despite taking the approved DMDs which, together, make up the majority of the 2.5 million MS patients, if there is one effective immunosuppressant treatment for non-active/smouldering/PIRA MS?

        If you think there is an effective treatment for progression of MS then you are naive. Dr. G is just pointing out the obvious. Take away the “active” patients in the siponimod trial and ocrezulimab trials and you are left with zero effective treatments above placebo for progressive disease.

        Treatment of relapses and Gd MRI clearly do not translate into stopping progression. A revolution in current thinking in MS research needs to happen as immunosuppressants treating a downstream reaction is clearly not the answer for curing or stopping progression of MS, let alone improve a progressive patient’s QOL..

    • Thanks DJ. You raise an important issue by highlighting the urgent need for effective treatments for progressive MS. I have been delighted to see a shift in focus of research into slowing MS progression in recent years, and am currently a strong supporter and active contributor to that field too. Nevertheless, you can see from the blog comments that the question of which DMT to choose is still highly emotive for people with relapsing MS and the DELIVER-MS trial was born out of patient and stakeholder engagement that asked for this specific question to be addressed.

      • Emma, thanks for your post and all your replies.

        The idea of choice sounds great if simply available to everyone ie give every pwMS the choice then monitor real world data. None of this having to jump through EMA hoops to qualify for the most effective treatments (for those who want them) but let everyone (in conjunction with their neurologist) choose.

        DJ above has indeed drawn us back to the importance of underlying progression. Re

        Take away the “active” patients in the siponimod trial and ocrezulimab trials and you are left with zero effective treatments above placebo for progressive disease.

        Not sure this is true? Less effective
        but not ineffective. As comments keep saying time over active spells carry on right to the end…. but agree we desperately need neuroprotective, remyelination treatments.

        • “Not sure this is true? Less effective
          but not ineffective”

          FDA and EMA both agree that ocrelizumab and siponimod have no place (ie. no effect above placebo) in treating non-active progressive MS (ie. anyone without documented relapses or Gd+MRI activity)

          Researchers will argue trials were not powered to answer the question of efficacy on non active progressive MS, which begs the question why for this highly unmet need in progressive MS? Answer=Money.

  • At diagnosis I had highly active MS, now I have what Prof G calls smouldering MS. I’ve recently has my first relapse for 24 years, I would say every pwMS is has a different experience of the disease. What is highly effective, if there is breakthrough disease? Is it that sometimes it works and sometimes the epidemiology naturally stops relapses?

    • Anon 4:38
      I’ve recently has my first relapse for 24 years

      Any dmt may I ask?

      As a person with SPMS I consider myself very lucky to have eventually been treated (off-label) when I had my first relapse for 5 years. Always feel a bit guilty about this having friends with no treatment.

      Following this blog has opened my eyes as to how variable things are across different centres in the UK let alone around the world.

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