Saturday, 8 April 2017

#PoliticalSpeak: catching the British disease

Should neurologists prescribe DMTs based on price? #MSBlog #PolticalSpeak

I heard this week that some German neurologists are behaving like

the British and have taken a stand and will not prescribe alemtuzumab to their patients as it is too expensive. They find the hike in price of alemtuzumab that occurred when Campath-1h was withdrawn from the market and relaunched as Lemtrada unacceptable. Sound familiar? I often refer to this as the British Disease; an infectious meme that infects the minds of some British neurologists. I am surprised by the Germans; as the richest country in Europe, with a high adoption rate of new innovations, I thought they would be resistant to these sorts of infections. I thought this was an old issue that we have previously discussed in some detail and that as a community we had moved on. How wrong!

There is no doubt that on the face of it Lemtrada is a high cost drug (HCD), but it has already been green-lighted by most HTAs (Health Technology Assessments) in Europe. The fact is that alemtuzumab is considered to be cost-effective when used according to its current label in adult people with MS who have active relapsing MS defined clinically or on MRI should be end of the story. In reality the cost-effectiveness of alemtuzumab is very close to natalizumab (Tysabri) in the treatment of active MS. I would really like to know if these same German neurologists have taken the same position in relation to natalizumab prescribing? Or is it related to the fact that alemtuzumab is not a new innovation, but simply a repurposing of an old innovation? 


In essence these neurologists have vetoed the German authorities. This goes a long way to explain the variation in prescribing of DMTs by European neurologists. Another issue that arose on my visit to Germany is the position that some neurologists have taken in view of the their perceived risks of alemtuzumab. Several told me that prescribing alemtuzumab first-line is too risky as a treatment option. Too risky for whom; for them or their patients? Surely it should not be the neurologists who are taking the risks, but the patient themselves, or at least it should be a shared risk?


I have highlighted many times the slow, or poor, adoption of innovations as an unmet need in the management and treatment of MS. Slow adoption of second-line, or more effective, treatments may explain why Germany has fewer people on more-effective treatments as a ratio to first-line or platform therapies. 


In my opinion it is the responsibility of neurologists, and other HCPs, to manage the patient in front of them to the best of their ability given the current evidence-base and tools at their disposable. This includes using tools to encourage shared-decision making. It is not up to them to not offer DMTs because they consider them too expensive. The latter is the job of HTAs, and politicians, and not the practising neurologist. I would argue by not allowing patients a choice of receiving a more active, or aggressive, approach to their initial treatment will cost the country money in the long-term. At the end of the day costs are linked to disability; preventing disability saves money. 

It is very reassuring to note that the HTA commissioned by Norwegian's National system for the introduction of new health technologies to assess the effect and cost-effectiveness of DMTs in Norway found that alemtuzumab was the most cost-effective DMT. The Norwegian findings are similar to NICE. 


In summary to have the greatest impact on MS you have to hit the disease as early and as effectively as possible; based on the current evidence we should be targeting NEDA-3 and if possible NEDA-4 and beyond. With alemtuzumab you get both; some may not like the risks associated with alemtuzumab, but it should be the patient's choice. With alemtuzumab the risks are front-loaded and with time become less of a problem despite the benefit of the treatment remaining in the majority of patients. 







Norwegian Institute of Public Health. Medicines used for Multiple Sclerosis – A Health Technology Assessment. Oslo, February 2016.

Background: Several disease-modifying therapies are available for the treatment of multiple sclerosis, but the comparative clinical effectiveness of these medicines is unclear. Furthermore, the cost-effectiveness of the different treatments has not been investigated in a Norwegian setting. To ensure the most appropriate multiple sclerosis management, it is important to assess effectiveness and cost-effectiveness of disease modifying medicines used for multiple sclerosis.

Objective: The aim of this project was to compare the effect and cost-effectiveness of the disease modifying medicines used for multiple sclerosis in Norway.

Methods: We conducted a systematic review based on the following conditions: Evidence should come from randomised controlled trials (RCTs) with study populations that included men and women aged 18 years or older were eligible. Modifying medicines used for multiple sclerosis were our intervention of interest (dimethyl fumarate, teriflunomide, interferon beta, peg-interferon, glatiramer acetate, natalizumab, fingolimod, and alemtuzumab). We included studies that compared these medicines to placebo or to each other. We examined the following endpoints: annual relapse, disability progression, mortality, serious adverse events, withdrawal from the study due to adverse events, hospitalisations, and health related quality of life.

We systematically searched the literature for previously published health tech-nology assessment reports or systematic reviews that answered our objectives, and met our inclusion criteria. We conducted a systematic review of randomised controlled trials to supplement the evidence of previously published health technology assessments.

Two persons independently examined the risk of bias of included studies using the Norwegian Knowledge Centre for the Health Services methods. These are based on Cochrane methodology.

We summarised the evidence from the randomised clinical trials quantitavely through network meta-analyses of data on direct and indirect evidence on all relevant comparisons.

Two persons independently assessed the quality of the evidence for each selected endpoint. We used GRADE (Grading of recommendations Assessment, De-velopment, and Evaluation) to assess our confidence in the effect estimates.

In order to assess the cost-effectiveness of disease-modifying therapies in pa-tients diagnosed with relapsing-remitting multiple sclerosis, we developed a decision analytic model. The economic model was developed in the form of a cost-utility analysis and included treatments approved and available in Norway. The model structure and all assumptions were adapted to the Norwegian setting based on Norwegian clinical practice. Efficacy estimates were taken from our network meta-analyses. Transitional probabilities were derived from published sources and clinical experts’ opinions. Quality of life data were extracted from published studies based on a systematic review of the literature. The costs of medications were based on prices obtained through the Drug procurement co-operation (LIS), and other costs were based on official Norwegian unit prices.

We performed probabilistic sensitivity analyses, designed as a Monte Carlo sim-ulation with 10,000 iterations, to explore the uncertainty surrounding our results.

Results: All examined treatments were more effective than placebo against annual relapse. The effect was best for alemtuzumab 12 mg (based on high quality evidence). Fingolimod oral 0.5 mg and dimethyl fumarate 240 mg twice daily were also associated with a reduction in annualised relapse rate. For disability progression, dimethyl fumarate 240 mg twice daily and fingolimod 0.5 mg were more effective than placebo (high quality evidence).

For withdrawal due to adverse events, the conclusion is unclear due to the low quality of the available evidence. However, our results indicate that interferon beta-1a 44 mcg, and peg-interferon beta-1a are associated with more withdrawal due to adverse events than placebo.

For the outcomes change in expanded disability status scale, serious adverse events, and mortality; we did not assess the quality of the available evidence. Our results indicate that interferon beta-1a 30 mcg is associated with a reduction in expanded disability status scale. Interferon beta-1a 30 mcg is associated with fewer serious adverse events. Finally, our results showed that none of the examined treatments increased or decreased mortality compared to placebo.

Our health economic analysis indicated that alemtuzumab dominated all other disease-modifying therapies, as it was more effective in terms of quality-adjusted life-years (QALY) and less costly than the other treatment alternatives.

A scenario analysis that excluded alemtuzumab (the dominant strategy) showed that three treatment alternatives (interferon beta-1b (Extavia), peg-interferon beta-1a and natalizumab) could be cost-effective depending on the willingness-to-pay (WTP) threshold. Interferon beta-1b was likely to be the cost-effective choice for a WTP per QALY below NOK 1,658,000. Peg-interferon was the cost-effective option for a WTP from NOK 1,658,450 to NOK 10,619,960, and natalizumab was the cost-effective alternative for a WTP above NOK 10,619,960. Assuming a WTP below NOK 1,000,000 per QALY, interferon beta-1b (Extavia) was approximately 40% likely to be the most cost-effective treatment, followed by peg-interferon beta-1a (approximately 30% likely).

The results of probabilistic analysis showed that there is some degree of uncertainty regarding the input parameters. More research on efficacy and epidemiologic input parameters would have the greatest impact on reducing decision uncertainty.

We performed several scenario analyses to test the uncertainty around the model assumptions. The results showed that, while there were numerical changes to the incremental cost-effectiveness ratio, the cost-effectiveness results were robust to variations in the model assumptions and the conclusions of the analysis would not change.

Our budget impact analysis based on the results of our cost-effectiveness analysis, the drugs’ adverse events profile, and current clinical practice showed that there is a substantial potential for cost saving.

Discussion: We used a systematic methodology to search for evidence, extract data, and assess the risk of bias of studies and quality of evidence for important outcomes. The systematic review included evidence on both established and emerging treatments. We examined the effect of these treatments on clinical endpoints relevant for patients with multiple sclerosis. We have analysed direct and indi-rect evidence through network meta-analyses. The consistency of results using different methods indicates that our results are robust.

Our systematic review has some limitations, due more to the weakness of the available evidence than to the methods used in this report. These limitations are related to the paucity and quality of the available evidence, and to the methodologies used in the included randomised controlled trials.

We used a probabilistic Markov-model, considered the appropriate approach for simulating the natural history of multiple sclerosis. The model structure and all assumptions have been adapted to the Norwegian setting based on Norwegian clinical practice with close assistance of experts in this Field.

For transitional probabilities, we did not find Norwegian data that were compatible with the developed model, so these were based on estimates reported in the published literature.

Study designs of published trials did not permit separate analyses of first and second line treatments, or conclusions regarding the sequential use of first and second line treatments. Therefore, we did not perform separate cost-effectiveness analyses for first or second line treatments. In addition, based on expert opinion, we did not include combination therapy in our model, as it is not relevant to current Norwegian clinical practice.

Conclusion: Alemtuzumab 12 mg had the best effect against annual relapse. Dimethyl fumarate 240 mg twice daily and fingolimod oral 0.5 mg were the most effective against disability progression. Results indicate that some treatments are associated with more withdrawals due to adverse events than placebo. Our results showed that the examined treatments had no effect on mortality.

Our health economic analysis indicated that alemtuzumab was more effective and less costly than the other treatment alternatives. A scenario analysis that excluded alemtuzumab indicated that three treatment alternatives (interferon beta-1b (Extavia), peg-interferon beta-1a and natalizumab) could be cost-effective depending on the WTP. For a WTP below NOK 1,000,000 per QALY, interferon beta-1b (Extavia) was approximately 40% likely to be the most cost-effective treatment, followed by peg-interferon beta-1a (approximately 30% likely).

The results of probabilistic analysis showed that there is some degree of uncertainty regarding the input parameters. More research on efficacy and epidemiologic input parameters would have the greatest impact on reducing decision uncertainty.

Our budget impact analysis showed that there is a substantial potential for cost saving.

CoI: multiple

20 comments:

  1. Cost. Generic cladribine...:-).

    I'll stop soon, once its back it will sound like marketing..Maybe that's why Merck is bringin it back..to shut me up:-)

    However, will keep it in the spot light as our papers are accepted and coming soon.

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    1. The more I have read in this blog about generic cladribine the more I am so grateful for the work that has been put into it and the more disappointed that neuros are not picking up on it yet it seems. Why not? Ok, understand not appropriate when there are licensed effective affordable alternatives available. But when there aren't? Eg anyone with progressive / worsening MS, self-payers and under-resourced countries.
      If it wasn't for this blog I'd never have heard of cladribine. Pretty gutted when neuro said no :-( however I'm lucky to live in UK as I know where to turn up should my lymphocyte count ever allow it ;-)

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    2. Pharma cladribine will be back on..... Gagged...I have found the count down clock..Can you?

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    3. Movectro? For progressive / worsening MS? Affordable?

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    4. I don't think it will be called movectro as that is tarred with the cancer brush (we we have questeioned)...I think I know what it will be called. I found it on a Norwegian website...new name sounds like a bit of roofing.

      It will be for RRMS because that was the trial data.
      The cost will be what mErck Charge

      For progressive MS and affordable, you would have to consider using off-label, like we have done/do. First paper accepted will be available open access soon.

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    5. Norway, roofing?... I give up ;-)
      Off-label fine for me if can get past haematologist.
      Look forward to new paper.

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    6. Should have said wall covering think... cladding.

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  2. I don't trust this drug. We deserve something better and safer.

    I don't blame Germany.

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  3. I guess this Norwegian assessment does not take any anti-CD20 therapies into consideration?

    Anyway, before Norwegian neurologists start prescribing alemtuzumab en masse, they should get a briefing of how to prevent opportunistic infections. The first case of Listeria in MSer in a hospital near Oslo has recently been reported. Wake up, people, Genzyme is not interested in advertising problems.

    And as for the German neurologists... I do not think the cost explains it all, but alemtuzumab is a heavy drug on the prescriber - with monthly monitoring for at least five years. I do not know how the German system works, but here a patient who just comes to take blood tests at a hospital lab does not exist as an "activity" on a doctors list. The more patients on alemtuzumab a neurologist has, the heavier the load after a while.

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    1. You are correct they don't advertise problems...should they be exposed?

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    2. Yes, German neurologists are like everyone else and respond to incentives and disincentives. They don't get reimbursed for the majority of monitoring visits.

      Please note this post is not about this issue, but the decision not of offer alemtuzumab as a treatment option because of the price hike from Campath to Lemtrada. I thought this was a UK issue, but I was surprised to find-out that some German neurologists are doing the same.

      The other issues in relation to alemtuzumab are no different in Germany as compared to other countries, which is why oral cladribine and ocrelizumab are likely to have a massive effect on the market.

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  4. Just noticed that MD thought the same thought about the workload yesterday :-)

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  5. My sister has MS with posterior fossal lesions! She took fingo from 02/16. Her Qol improves dramatically but She has permanent brainstem and cerebellar sympthoms. Before G She took copax, and tec without any effect. She was cognitively and phisically detoriated but her neuro did not want to change. We fight for Natalizumab (my sister JC-) but her neuro denied it so fingo will be the result of the consensus. Now my sister walking speed is normal and she could run again but her symptoms growing while she active so she could able to run really. Her neuro found last Oct, that her EDSS improved from 3 to 2.5. My sister have had cognitive and behavioral changes from the beginning, but the big brain fog hide it. Now she is more impulsive, loud, speaks more, so her behave changes come along. Her neuro noticed it, but found she is currently stable and finally added plus 1 point her EDSS so now she is 3.5. I talked about it with my sister and she told her state is much more better with G, that is the cause of that her behave changes come along. Her memory improved dramatically with G.
    The neurologist here and actually Germany live in the past. They are side effect 'fetishists'. I am so-so angry and hope fingo works for a long-long time because I think the possible med-change, gonna be so-so long and so risky!

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    1. One senses that you really love your sister. That is brilliant. It's better than any DMT her neurologist can prescribe.

      Hope she gets better.

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    2. Thank you! I hope her MS will be very-very stable! (further improvement would be a Qol gift)
      And finally I hope we can change to a PIRT (like alemtuzumab,OCR or oral cladribine.

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  6. What will be the place of Lemtrada after Ocrevus approval?
    Could OCR cannibalize Lem, Nat, and other highly effective ones?

    ReplyDelete

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