Sunday, 5 November 2017

Guest post: will the COMBAT-MS study disrupt the MS market?

You may be aware that people living with MS in resource-poor environments are often not treated with disease-modifying therapies. To address this we have been promoting a Barts-MS Essential Off-label list of DMTsThe problem with this list is that it is often not backed by a so-called 'class 1 evidence'. 

To address this lack of evidence, trials such as COMBAT-MS are being performed to provide data from real-life practice to support off-label prescribing. We are therefore privileged to have a guest post from the team running the COMBAT-MS trial explaining what the trial is about.





COMBAT-MS STUDY

We keep getting at least one new approved MS disease-modifying drug per year. You might think this would help tailor therapy to individual needs. Unfortunately, this doesn't really seem to be the case. Patients are switching therapies now more than ever. MS experts can't seem to agree which drug is the best even for the same types of patients. Treatment practices vary widely, not only across countries but all the way down to regions, clinics and even individual doctors. Perhaps the most important cause of these wide variations in care is the lack of long-term real-world data. 


Loads of money has been invested into randomized clinical trials and they are really important. However, randomized controlled trials don't give the whole picture. These trials are conducted over a relatively short period of time, in mostly treatment-naive patients who are otherwise healthy and do not want to get pregnant. The drugs are usually compared only to placebo rather than to the other drugs patients have to choose from. These studies also do not consider patient-reported outcomes like quality of life. 

In the real world, many patients don't fit this picture. They may have tried other therapies before, have health issues other than MS, want to get pregnant soon and/or (of course) value the impact the drug may have on their quality of life (QoL). Short of a cure, they desire a highly effective treatment, that is reasonably safe and well-tolerated even if they need to take it for decades. Unfortunately, we can´t rely on the pharmaceutical industry to support us in answering these questions. And academic registry-based studies have inherent weaknesses that prevent them from satisfactorily addressing these issues. 

Aside from a prohibitively expense and complex randomized controlled trial, is there a middle way? Yes, perhaps. The US federally-funded Patient-Centered Outcomes Research Institute (PCORI) last year gave a big award to a US-Swedish initiative for a hybrid study between a traditional retrospective cohort and a structured, prospective cohort study. Sweden has a nationwide MS registry which includes >90% of patients and nearly complete information on MS drugs used, physical disability outcomes and the ability to link to national health registries to detect major safety signals. However, much of the other key variables like patient-reported outcomes and MRI data have over 20% missing data, which would make effects of treatments on these outcomes difficult to interpret. Therefore, a prospective trial (COMBAT-MS; clinicaltrials.gov NCT03193866) has recently launched. 

We aim to recruit up to 3,700 MS patients at all of Sweden´s seven university clinics (serving about 50% of the total population) who are starting their first MS therapy or switching therapies. By doing the same structured follow-ups with annual disability scorings, MRIs and patient-reported QoL outcomes the study will generate high quality, real-world long-term efficacy outcomes. This will help us sort out which drugs work or don’t work so well in real-world MS patients. To address safety concerns, we will obtain data from Swedish national healthcare registries, as well as from Kaiser Permanente Southern California. By combining these resources, we will be able to address major risks, such as cancer, as well as transient treatable concerns like recurring bladder infections and bothersome skin rashes. So, which of the approved MS drugs will be the winner? Perhaps none! 

Over the last few years, there has been a dramatic shift in Sweden and Kaiser Permanente toward rituximab. One in two MS patients in Sweden now chooses to start rituximab. The data produced so far show that rituximab beats all approved MS drugs in terms of providing MS patients with an effective, safe and tolerable drug. The fact that rituximab is much cheaper than other MS drugs also makes it an attractive option in resource-limited countries, where access to brand name MS drugs is out of reach for most patients. 

Fredrik Piehl, Annette Langer-Gould, Jessica Smith and Anna Fogdell Hahn on behalf of the COMBAT-MS investigators and steering committee



ProfG    

19 comments:

  1. What about off label cladribine? Why not include it as well?

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  2. Any idea why Ocrelizumab has still not been licensed in the UK? Do you think the delay is due to any new safety concerns? Also, wondering your thoughts on the recent approval of oral Cladribine - from what I have read on this blog it would appear that this particular treatment will be safer and almost as effective as Ocrelizumab. Is this thinking correct?

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    1. We have no idea. I suspect the EMA is doing due diligence on ocrelizumab and are making sure they get the decision right. I am sure we will hear shortly. My concern is for the PPMS indication. If we don't get access to ocrelizumab for pwMPPMS it would be a travesty.

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  3. It's funny because we were talking just a few days ago at Doc Gnanapavan's post about how awesome Sweden is for running this trial and recognizing HSCT as a second line treatment! We salute Sweden!
    Thanks ProfG!

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    1. This post is very timely. In the latest issue of the BMJ there is an article debates the off-label prescribing issue in the NHS. It looks as if the NHS' position is not clear. There is a legal battle going at the moment about whether, or not, it is illegal to prescribe off-label therapies in Europe for an indication with licensed therapy. We, and the Swedes, may yet have to eat humble pie.

      http://www.bmj.com/content/359/bmj.j5016

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    2. Surely it is legal? I thought the that the government had even supported you on this issue.

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    3. Doctors should primarily consider their patients' needs and prescribe the most effective and safest treatment available. Nobody disputes this and Sweden have been allowing doctors to do exactly that. Add Mavenclad and Ocrevus into the mix and difficult to justify so I concede that for patients who qualify then these licensed products should be used. Meanwhile, for everyone not qualifying for most effective treatments ie PPMS (ignoring ocrelizumab for now), SPMS and many RRMS I believe we should all be offered off-label cladribine injections or rituximab first line. 'Because it's better and safer' should be sufficient reason to justify. End of, black and white. I get R&D costs but I'm out of sympathy. If pharma feel aggrieved they need to find better drugs and stop relying on their older, less effective or riskier ones.

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  4. This drug is class one evidence

    https://onlinelibrary.ectrims-congress.eu/ectrims/2016/32nd/147064/rebecca.spain.lipoic.acid.for.neuroprotection.in.secondary.progressive.html?f=m3

    Classification of evidence: This study provides Class I evidence that for patients with SPMS, LA
    reduces the rate of brain atrophy.

    Why dont you include it in your list?

    Obrigado

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  5. Thanks for this fascinating guest post. Sweden sounds incredibly ahead of the game, organised and not afraid to do the right thing for people with MS.

    Disrupt the market? The Girl who Kicked the Hornets' Nest

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    1. I agree. The reason why they are ahead of the game is that the neurologists are given control over the DMT budget. They therefore have the incentive to maximise the use of their budgets. How do you treat the majority of pwMS for the least amount of money with a high efficacy therapy? I am told that close to 50% of pwMS are now being treated with rituximab in Sweden. This is an incredible story.

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    2. and who will fund new MS therapies if pharma are kicked out of the room?

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    3. Pharma is incredibly important to bring new drugs to the market. Still, health care/academia should carefully evaluate if these new drugs are more effective, safer etc. We have seen that before with novel drugs for hypertension not reducing mortality as much as older, cheaper drugs. So every now and then it is good to exercise some caution; newer, more expansive is not always an improvement. So there is a need for checks and balances.

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    4. The thing is that the deal with the pharma industry is not based on what is the benefit of patients or in a ethical agreement. It is based on what can bring profit to the industry. And all is well when the benefit of patients and the profit of the business agree, but often enough this is not the case.
      As with every other business in economy, when pharma is left without any pressure and regulations, it brings an uncontroled chaos that remindes of mafia. There is no "invisible hand" that makes economy self-regulated.
      Drug overpricing, fake drug "revolutions" and denial in access to non (enough) profitable old ones is only a few of the consequenses of unregulated pharma practice. And they have enough power to be the ones who put pressure (on goverments) instead of being pressed.

      But no need to worry about the pharma profits, there is a long way till cures are found and the game is over. Till then, it is a lot of money not to play the game.

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  6. Very interesting guest post. That also raises the question, again, why is not rituximab with that winning profile towards the other available treatments more used in the other countries? One in two choose to be treated with it. And it's cheaper for their national healthcare system. Definitely in Sweden doctors have the guts to choose what it best for their patients!

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  7. If these results are positive will it lead to rituximab being licensed for MS?

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    1. This is a very good question. I am not aware of if we had this type of situation before, so maybe we also have to drive this part as pioneers. And we might then need all the support we can get from all of our stakeholders and all of you.
      Does anyone have any experience of similar cases where a drug has been licensed without having a pharma sponsored phase III trial?

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  8. You want to read ' the shameful story of rituximab in multiple sclerosis' printed in NeuroImmunology in 2011. You can google it

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    1. Article here.
      https://neuroimmunology.wordpress.com/2011/03/27/the-shameful-story-of-rituximab-in-multiple-sclerosis/

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