Sunday, 12 April 2015

ClinicSpeak: did you know interferon-beta and glatiramer acetate are actually effective?

The Risk Sharing Scheme 6-years on: time for the nihilists to capitulate? #ClinicSpeak #MSBlog #MSResearch

"One of the most damaging things to happen to the treatment of RRMS is NICE stating that the injectable therapies (interferon-beta and glatiramer acetate) were not cost-effective. This created the perception amongst neurologists that these drugs did not work, despite a wealth of  evidence to the contrary. This is a common problem with NICE when it says 'NO' to new drugs. It's not NICE's role to assess efficacy of drugs this is done by the EMA and MHRA. All NICE do is state that the drug is too expensive given the established benefits to be prescribed under the NHS. It is therefore reassuring that after 13 years we have the results of the NHS's Risk Sharing Scheme (RSS) that finally show that these drugs do what they say they do on the tin and they are cost effective. The comparator used in this study was the Canadian British Columbian database that is a bit of an outlier in its own right; compared to other registries MSers in this database do much better than expected. This means that despite a relatively benign comparator IFNbeta & GA do okay. I suspect when compared against other natural history cohorts they would do even better. I really hope these results change prescribing behavior and finally slay therapeutic nihilism that is so prevalent in the UK. A large number of neurologists have always been of the opinion IFNbeta and GA don't work and that it is a waste NHS resources to be prescribing them."

"Since the launch of the RSS things have moved on with the licensing of more effective DMTs and oral DMTs. In addition, or therapeutic target has moved on from simply reducing the frequency of clinical attacks with a modest effect on disability progression, to treating-2-target of NEDA (no evident disease activity). Some of us are beginning to move beyond NEDA to try and prevent end-organ damage to maintain brain health. Some of us are even daring to ask about what a MS cure looks like."

Epub: Palace et al. Effectiveness and cost-effectiveness of interferon beta and glatiramer acetate in the UK Multiple Sclerosis Risk Sharing Scheme at 6 years: a clinical cohort study with natural history comparator. Lancet Neurol. 2015 Apr 1. pii: S1474-4422(15)00018-6.

Background: In 2002 the National Institute for Clinical Excellence (NICE) concluded that interferon beta and glatiramer acetate would be cost effective as disease-modifying therapies (DMTs) for multiple sclerosis only if the short-term disability benefits reported in clinical trials were maintained. The UK Multiple Sclerosis Risk Sharing Scheme (RSS) was established to assess whether disability progression was consistent with a cost-effectiveness target of £36,000 per quality-adjusted life-year projected over 20 years. 

Aims: We aimed to evaluate the long-term effectiveness and cost-effectiveness of these DMTs by comparing a cohort of MSers with relapsing-remitting multiple sclerosis enrolled in the UK RSS with a natural history cohort from British Columbia, Canada.
Methods: In our clinical cohort we included MSers starting a DMT who were enrolled in the UK RSS who had relapsing multiple sclerosis at baseline and had at least one further clinical assessment. In our control cohort we included MSers in the British Columbia multiple sclerosis database (BCMS; data collection 1980–96) who met the same eligibility criteria as for the RSS cohort. We compared disability progression at 6 years for RSS MSers with untreated progression modelled from BCMS MSers. The primary outcomes were the progression ratio (treated vs untreated) measured both in Expanded Disability Status Scale (EDSS) score and utility. A ratio of less than 100% for EDSS implied slower than expected progression on treatment compared with off treatment; a utility ratio of 62% or less implied that the DMTs were cost effective.

Findings: 5610 MSers starting a DMT were enrolled in the UK RSS between Jan 14, 2002, and July 13, 2005 (72 sites), of whom 4137 were included in our clinical cohort. We included 898 BCMS MSers in the control cohort who met the RSS inclusion criteria and had at least one EDSS score after baseline. RSS MSers had a mean follow-up of 5·1 years (SD 1·4). Both models showed slower EDSS progression than predicted for untreated controls (Markov model, 75·8% [95% CI 71·4–80·2]; multilevel model, 60·0% [56·6–63·4]). Utility ratios were consistent with cost-effectiveness (Markov model, 58·5% [95% CI 54·2–62·8]; multilevel model, 57·1% [53·0–61·2]).

Interpretation: Findings from this large observational study of treatment with interferon beta or glatiramer acetate provide evidence that their effects on disability in MSers with relapsing-remitting multiple sclerosis are maintained and cost effective over 6 years. Similar modelling approaches could be applied to other chronic diseases for which long-term controlled trials are not feasible.

Funding: Health Departments of England, Wales, Scotland, and Northern Ireland, Biogen Idec, Merck Serono, Bayer Schering Pharmaceuticals, Teva Pharmaceuticals Industries, UK National Institute of Health Research's Health Technology Assessment Programme.

Background to the Risk-sharing Scheme (RSS): The Risk-sharing Scheme was that NICE (National Institute for Health and Care Excellence) had considered the clinical and cost-effectiveness of the disease modifying therapies for MS - beta interferon and glatiramer acetate - in a technology appraisal (TA32). At that time NICE concluded that it was not appropriate to recommend use of the treatments on the NHS because there was insufficient evidence to show their cost effectiveness over a twenty year time horizon. However, NICE invited the UK Health Departments to enter into a discussion with the license holders of the four products to see whether there was a possible basis on which they could be cost-effectively used in the NHS.

Subsequently, the four UK health administrations reached agreement with the manufacturers of the MS drugs to make the treatments available on the NHS and the Risk-sharing Scheme was enshrined within Health Service Circular 2002/004. Prior to entering the Scheme the manufacturers reduced the prices of the drugs to ensure they were cost effective using the NICE model.
Previous data analysis

Data from the first two years of follow-up were collected, analysed and interpreted by an independent group who concluded that it was premature to reach any conclusion about the cost-effectiveness of the drugs used to treat relapsing remitting multiple sclerosis from the first interim analysis.

The two year data showed a number of issues with the methodology being used. Firstly, the natural history database used to compare disease progression on treatment with expected disease progression off treatment as part of the NICE review did not allow improvement and yet circa 40% of patients treated with drug therapy in the RSS cohort showed improvements. Secondly, the statistical assumptions underlying the model were uncertain.

Benefits of the Scheme: The Department of Health and the Health Departments across the UK remain committed to the Scheme. It has realised many benefits for all 100,000 people with MS, including infrastructure development of services, consistent access for thousands of patients to drug treatments, and the development of the specialist centres across the UK. The support has been provided under the auspices of the Scheme by the pharmaceutical companies engaged in the Scheme (Bayer, Biogen Idec, Merck Serono and Teva). In addition the longer term findings of the Risk-sharing Scheme have the potential to genuinely inform and change the way in which MS is treated. This new information may allow the manufacturers to put up their costs.


  1. Guess what after this result a certain company put up its price of drug. Got to wring out that last bit of profit.

  2. These DMTs are a waste of money. If they worked they'd benefit all MSers, which they don't.

    The NHS shouldn't be strong-armed into funding these drugs while social care funding for disabled people is cut.

    1. You have to remember if the scheme had not been started people with MS would have had nothing for another ten years and there would be a dirth of MS nurses.

      Interferons work in progressive MSers if they have active lesions they work in RRMSers if they have active lesions.

      Not sure the cost of drugs is dictating social care cost

  3. ".....provide evidence that their effects on disability in MSers with relapsing-remitting multiple sclerosis are maintained and cost effective over 6 years." The use of these "old guard" DMTs in the early RRMS inflammatory stage maybe of limited value unless reliable biomarkers such as NFL are used instead of EDSS. Measure of EDSS early in the disease seems to be an unreliable marker of future MS progression due to neurological reserve. Neuroprotective drugs plus these immunomodulators are needed.

  4. Good news. There should be a registry in this country (UK) of MS patients, their doctor, and treatment history. Start shaming the docs who trash people's health by telling them to "wait and see" without drugs after diagnosis.

    I don't mean that in a vindictive way, but when I was dx'd my neuro was a nice guy, but took this wait and see approach with no drugs and I went from optic neuritis to one lesion, to five lesions, to eight lesions and still no drugs.

    This blog definitely helps to give patients the knowledge/power to challenge it but really you shouldn't have to and should be able to trust the advice of a so-called specialist.

    So I think a registry of some kind would help to drive change in this area by showing up the nice but numpty docs who are costing their patients quality of life - potentially irreversibly - with outdated or ill-informed decisions around the need for early effective treatments.

    I harp in about this a lot, I know, but in any other area of life, if something was on fire you'd not think about letting it burn on whilst you wait and see what happens. Yet when it's my brain that's burning down, that's exactly what my specialist thought best to do. Pretty ridiculous, and really at the heart of why I prefer the opinion of haemo's to neuro's when seeking MS care. They have a more aggressive treatment mindset in my experience, whereas neuro's are generally more risk averse and settle for less.

    Prof G I'm sure is different, but that's the exception rather than the norm - at least in my experience.


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