Saturday, 12 March 2016

PoliticalSpeak: What is the most cost-effective DMT?

Are you surprised with the Norwegian view of DMTs? The most cost-effective treatment for MS is alemtuzumab #MSBlog #MSResearch #PoliticalSpeak

"The HTA (Health Technology Assessment) below was commissioned by Norwegian's National system for the introduction of new health technologies. The aim of the report was to assess the effect and cost-effectiveness of DMTs in Norway. The analysis included dimethyl fumarate, teriflunomide, interferon beta, peg-interferon, glatiramer acetate, natalizumab, fingolimod, and alemtuzumab. The key results are summarised here in bullet point: 

37 randomised clinical trials were analysed. The quality of the available evidence ranged from very low to high.
  1. Alemtuzumab 12 mg had the best effect on annual relapse (for DMTs for which they had high quality evidence). 
  2. Dimethyl fumarate 240 mg twice daily and fingolimod oral 0.5 mg were the most effective against disability progression (for DMTs for which they had high quality evidence). 
  3. Their results indicate that interferon beta-1a 44 mcg and peg-interferon beta-1a were associated with more withdrawal due to adverse events than placebo. 
  4. The examined treatments had no effect on mortality compared to placebo.
  5. Their health economic analysis, examining all DMTs indicate that alemtuzumab was more effective (in terms of quality-adjusted life-years (QALY)) and less costly than the other treatment alternatives. 
  6. The results of a scenario analysis that excluded alemtuzumab (the dominant strategy), showed that three treatments alternatives (interferon beta-1b (Extavia), peg-interferon beta-1a and natalizumab) could be cost-effective depending on the willingness-to-pay (WTP) per QALY. Assuming a WTP below NOK 1,000,000 (£84,000) per annum, interferon beta-1b (Extavia) was 40% likely to be the most cost-effective treatment, followed by peginterferon beta-1a (30% likely). 
  7. The results of their model showed that there is some degree of uncertainty regarding the input parameters. More research on efficacy and epidemiological data would have the greatest impact on reducing decision uncertainty.
  8. Their 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.
This HTA demonstrates several points. Firstly, that MS is a very expensive disease to treat and based on my knowledge of prices in the UK costs are much higher in Norway than England. It is not surprising that Alemtuzumab, one of our most effective DMTs, comes out on top in their analysis. Although Alemtuzumab costs are front-loaded and paid in year 1 & 2 the benefits of the drug are long-term in the majority of treated subjects. Based on the fact that NICE and NHS England have greenlighted Alemtuzumab as a first-line treatment, despite its adverse event profile, suggest they are on the same page as the Norwegians regarding the cost-effectiveness of the drug. What surprised me was that DMF and fingolimod were the most effective against disability progression; both these DMTs failed to hit a significant disability endpoints in one of their phase 3 trials; interestingly the same thing happened with alemtuzumab. In comparison, Teriflunomide hit a significant disability endpoint is both of its phase 3 trials; the only drug to do so. I am surprised that natalizumab didn't get more attention in the headline findings; in my opinion it bats in the same zone as alemtuzumab when it comes to efficacy. I suspect Natalizumab does less well as it it is a maintenance treatment and hence the costs are cumulative, i.e. they are there every year."

"The report is very long and technical and looks quite turgid so I doubt I am going to read the whole document; not because I am not interested, but I have other priorities. I have little doubt, however, that the Pharma companies who drew the short straws in this report will have their health economics teams pouring over the report to discredit it. That's the way big business works."

"My superficial take on this HTA is that to have the greatest impact on MS you have to hit the disease as early as possible and effectively as possible; based on the current evidence which should be targeting NEDA-3 and if possible NEDA-4. With alemtuzumab you get both; some may not like the risks associated with alemtuzumab but at least they are front-loaded and with time become less of a problem despite the benefit of the treatment remaining. I predict this report is going to stimulate a massive debate in the MS community, which is long overdue don't you think?"


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 bugdet 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

14 comments:

  1. This surely can't be a surprise to anyone who has taken a basic econ course. Alemtuzumab is a sunk cost, very effective and the side effects are managed cheaply. (Neither CBC nor thyroid drugs are very expensive.) A two year course that allows 25-40 year olds to stay in the tax paying employment brackets helps a lot if you're paying into socialized medical care. The cost of MS drugs and care is not actually high compared to many drugs, it's the actuary table with cost accumulation over a lifetime that does you in, same with HIV.

    The problem is that no drug companies want this and I'm increasingly convinced most neurologists don't want it either. Better to keep those Tysabri infusions flowing...

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  2. Yes, intuitively it would seem alemtuzumab would be the most cost effective treatment.

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    1. Generic cladribine (£1000 verses about £100000 plus. For drug costs monitoring costs and costs of dealing with automatically immunities :-)

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  3. What happens if you stop taking your claribidine? theres rebound effect? if so... its jus another of what i call ¨duct tape¨ DMTs, a more long term solution seems better if you dont look at the price, still based on cost-effectiveness Claribidine is way ahead of any other DMT.

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    1. Sorry to burst your bubble but it is an induction therapy like alemtuzumab, and so there is no evidence of rebound...so no...not duct. tape and 50% NEDA for a few years at least. So for some take it and thenforget about MS and get on with your life.

      I suspect we will see the follow-up CLARITY data published soon as Merck reawaken there interest and then if the regulators approve Movectro, it will be alot less cost -effective. Let's see what the regulators do.

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  4. over nine years since my first alemtuzumab infusion - no relapses, stable EDSS, no activity on MRI. I know several others in the same situation. I work fulltime. There's been too much scaremongering among some neuros. It may not work as effectively for everyone, but I wake up everyday and thank my lucky stars that I had the choice. Another who has done well - http://www.davidscampathstory.org/

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    1. Thanks 50% like you are NEDA. This is exactly what we should aim for everyone.

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    2. Thanks 50% like you are NEDA. This is exactly what we should aim for everyone.

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  5. Cladribine widely available & prescribed at current prices would greatly upset the MS drug market. Be interesting to see what intended & unintended consequences arise.

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    1. Sadly no-one wants this to become a reality so we won't have to worry about the consequences.

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  6. If Cladribine had indeed been approved it would be the most effective and most profitable drug...
    Data DMF and Fingolimod surprised me also about the progression of disability as well as the teriflunomide.
    I think this means that as soon as they start treatment with higher chances of not converting to SPMS ... Hence also perhaps why the answers Fingolimod did not work in the PPMS ...

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    1. but G may work if you have SPMS with high disability: https://actrims.confex.com/actrims/2016/meetingapp.cgi/Paper/1484

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  7. It is common for health technology assessments to be made on clinical trial data, but they're not a substitute for real life experience - more work should be done on MS registries to answer these questions instead.

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  8. "The results of a scenario analysis that excluded alemtuzumab (the dominant strategy), showed that three treatments alternatives (interferon beta-1b (Extavia), peg-interferon beta-1a and natalizumab) could be cost-effective depending on the willingness-to-pay (WTP) per QALY."

    So excluding the most effective therapy they conclude interferon is the next best. This doesn't bode well for the 25 years of MS drug research. Given the high drug costs that is required to stimulate "innovation" it seems the cat is out of the bag as it is nothing more than a racket.

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