Author Topic: Dimethyl fumarate for RRMS (Lancet Neurology)  (Read 135 times)

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Offline agate

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Dimethyl fumarate for RRMS (Lancet Neurology)
« on: October 14, 2014, 02:11:11 pm »
From Lancet Neurology, November 2014:

Quote
Dimethyl fumarate for relapsing-remitting multiple sclerosis

Martyn J Burke a, Joanna Richardson a, Elisabeth George a, Amanda I Adler a

On August 27, 2014, the National Institute for Health and Care Excellence (NICE) published guidance recommending dimethyl fumarate as an option for the treatment of active relapsing-remitting multiple sclerosis (RRMS) that is neither highly active nor rapidly evolving severe RRMS.

NICE appraised dimethyl fumarate under the Single Technology Appraisal process. Biogen Idec, the manufacturer of dimethyl fumarate, under the brand name Tecfidera, submitted clinical evidence and a health-economics model, which were critiqued by an independent Evidence Review Group from the University of York. Furthermore, an independent NICE Appraisal Committee met twice on August 21, 2013 and May 21, 2014 to develop guidance on the use of dimethyl fumarate. Clinical specialists and a patient expert attended the first meeting, and Biogen Idec representatives attended both meetings.
The clinical evidence focused on two randomised controlled trials, DEFINE and CONFIRM. In DEFINE, 1237 adults with RRMS were randomly assigned to 240 mg dimethyl fumarate taken orally, twice daily (n=410) or three times daily (n=416), or to placebo (n=408). In CONFIRM, 1430 adults with RRMS were randomly assigned to 240 mg dimethyl fumarate twice daily (n=359) or three times daily (n=345), to 20 mg glatiramer acetate once daily (n=350; open-label), or to placebo (n=363). In both trials, patients were treated for up to 96 weeks. Patients stopped treatment if they did not tolerate the study drug or withdrew consent.

The primary outcome measure was the proportion of patients with a relapse at 2 years in DEFINE, and the annualised relapse rate at 2 years in CONFIRM. In DEFINE, the proportion of patients with a relapse was lower in the group treated with dimethyl fumarate than in the group that was given placebo (27% vs 46%; hazard ratio
051, 95% CI 040066). In CONFIRM, the annualised relapse rate was 022 in patients treated with dimethyl fumarate and 040 in patients given placebo (relative risk 056, 95% CI 042074).

Secondary outcomes in both trials included progression of disability on the Expanded Disability Status Scale (EDSS) from 0 to 10, with high scores indicating high levels of disability. Patients in DEFINE who were randomly assigned to dimethyl fumarate were less likely to have disability progression sustained for 3 months than were patients randomly assigned to placebo (16% vs 27%; HR 062, 95% CI 044087). In CONFIRM, any benefit in terms of disability progression was not significant (13% vs 17%; HR 079, 95% CI 052119). Biogen Idec also analysed disability progression sustained for 6 months in patients given dimethyl fumarate or placebo in DEFINE (HR 077, 95% CI 052114) and CONFIRM (HR 062, 95% CI 037103). Although DEFINE and CONFIRM both included MRI assessments of the brain, these outcomes were not included in the appraisal because stakeholders agreed during the scoping stage at the start of the appraisal that the outcomes of primary importance to patients with RRMS were relapse rate, relapse severity, and disability.
Biogen Idec did a mixed treatment comparison unadjusted for relapse rates to estimate the effectiveness of dimethyl fumarate compared with disease-modifying therapies including beta interferon-1a (Avonex, Rebif-22, and Rebif-44), beta interferon-1b (Betaferon), glatiramer acetate, fingolimod, natalizumab, and placebo in people with active RRMS. Biogen Idec's mixed treatment comparison showed the annualised relapse rate and proportion of patients with relapses were significantly lower in patients treated with dimethyl fumarate than patients given placebo, glatiramer acetate, or all beta interferon treatments, and disability progression sustained for 3 months was decreased in patients treated with dimethyl fumarate compared with placebo. Biogen Idec did not estimate the effectiveness of dimethyl fumarate in highly active or rapidly evolving severe RRMS, stating that most trials included in its mixed treatment comparison excluded these subgroups.

To determine the cost effectiveness of dimethyl fumarate compared with other disease-modifying therapies, Biogen Idec used a Markov model to estimate disease progression through 21 health states defined by EDSS, progression to secondary progressive multiple sclerosis, and death. In each cycle, a patient with RRMS could move to a lower or higher score on EDSS, remain stable, or could progress from RRMS to secondary progressive multiple sclerosis. Biogen Idec assumed, in the absence of evidence to the contrary, that the treatment effect of dimethyl fumarate decreases over time.

During its first meeting, the Committee heard that most patients with active disease, defined as two relapses in the previous 2 years, would be offered a disease-modifying therapy in current clinical practice. Based on the evidence, the Committee concluded that dimethyl fumarate decreases relapses compared with placebo in patients with RRMS. The Committee understood from clinical specialists that although most trials do not assess disability progression sustained for 6 months the assessment of disability progression sustained for 3 months provides a more robust indication of the treatment effect given that patients may recover from relapse. The Committee recognised that to model the natural history of RRMS with low EDSS scores, Biogen Idec used placebo data from DEFINE and CONFIRM, which reflected the population in UK clinical practice more closely than the population in the older London Ontario data used in previous NICE appraisals of treatments for RRMS. However, the Committee agreed that uncertainty remained in estimates of the incremental cost-effectiveness ratios. The Committee was concerned about the economic model's prediction that the sooner a patient stops treatment, the more cost effective the treatment. The Committee, therefore, requested that Biogen Idec clarify several issues and undertake further analyses. Among other requests, the Committee asked Biogen Idec to revise the probabilistic incremental cost-effectiveness ratios incorporating mixed treatment comparison results adjusted for relapse rates of patients entering the trials, to revise resource use and cost estimates, and exclude non-health-care costs. The Committee also requested that Biogen Idec externally validate its incremental cost-effectiveness ratio and compare estimates of cost-effectiveness of current treatments with treatments in the NHS risk-sharing scheme for multiple sclerosis (a scheme to ensure that patients with multiple sclerosis can access Avonex, Betaferon, Copaxone, and Rebif-22).


At the second meeting, the Committee considered the additional analyses from Biogen Idec, a critique of the additional analyses from the independent Evidence Review Group; and responses to the Committee's preliminary guidance from consultees, commentators, and the general public. The Committee noted that uncertainty remained about whether Biogen Idec had adjusted appropriately for the relapse rate of patients entering the trials, and therefore, agreed that the unadjusted mixed treatment comparison was preferable because it provided a better statistical fit. The Committee concluded that dimethyl fumarate decreases relapse rates more effectively than beta interferons or glatiramer acetate, and decreases the progression of disability as effectively as beta interferons or glatiramer acetate. The Committee noted that it had insufficient evidence to recommend dimethyl fumarate for people with highly active or rapidly evolving severe RRMS, for whom fingolimod and natalizumab, respectively, have been recommended by NICE.

The Committee was satisfied that the Biogen Idec economic model was robust for decision-making after considering the results from the external validation. The Committee noted that Biogen Idec also provided incremental cost-effectiveness ratios for a scenario using its preferred assumptions, in which it incorporated estimates from the unadjusted mixed treatment comparison and monitoring requirements based on its summary of product characteristics. The Committee acknowledged that Biogen Idec had appropriately modelled health-related quality of life using EQ-5D (a measure of health outcome) data and had included a decrease in treatment effect over time. The Committee acknowledged that Rebif-22 appeared to be the most cost-effective comparator, but that Rebif-22 is a step-down therapy for patients who cannot tolerate the recommended high dose (ie, Rebif-44). The Committee, therefore, disregarded Rebif-22, and based the most plausible incremental cost-effectiveness ratio on a comparison of dimethyl fumarate with glatiramer acetate (the next most cost-effective comparator after Rebif-22) using Biogen Idec's preferred model. This analysis showed an incremental cost-effectiveness ratio of about 27 700 per quality-adjusted life year (QALY) gained based on drug costs including a patient access scheme agreed with the Department of Health, UK. The Committee agreed that if Biogen Idec's model had overestimated the drug's decreased treatment effect over time, and had included the non-medical costs covered by Personal Social Services, the incremental cost-effectiveness ratio of dimethyl fumarate compared with glatiramer acetate would decrease. The Committee noted that benefits not reflected in QALYs, such as taking dimethyl fumarate orally compared with injections of glatiramer acetate, and its shorter washout period, could further decrease the incremental cost-effectiveness ratio. In conclusion, the Committee deemed dimethyl fumarate to be a cost-effective use of NHS resources in the treatment of adults who have active RRMS, but who have neither highly active nor rapidly evolving severe RRMS, only if the manufacturer provides dimethyl fumarate with the discount agreed in the patient access scheme.

NICE issued a final appraisal determination stating the Committee's decision. NICE offered stakeholders the opportunity to appeal against the recommendations, but no appeals were received.
__________________
We declare no competing interests.

a National Institute for Health and Care Excellence, City Tower, Piccadilly Plaza, Manchester, M1 4BT, UK
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SPMS, diagnosed 1980. Avonex 2001-2004. Copaxone 2007-2010.