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DIR Return to: TECFIDERA (dimethyl fumarate, BG-12, Fumaderm)
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#Post#: 516--------------------------------------------------
Dimethyl fumarate for RRMS (Lancet Neurology)
By: agate Date: October 14, 2014, 6:11 pm
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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 [HR] 0·51, 95% CI 0·40—0·66). In CONFIRM, the
annualised relapse rate was 0·22 in patients treated with
dimethyl fumarate and 0·40 in patients given placebo (relative
risk 0·56, 95% CI 0·42—0·74).
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 0·62, 95% CI 0·44—0·87). In CONFIRM, any
benefit in terms of disability progression was not significant
(13% vs 17%; HR 0·79, 95% CI 0·52—1·19). Biogen Idec also
analysed disability progression sustained for 6 months in
patients given dimethyl fumarate or placebo in DEFINE (HR 0·77,
95% CI 0·52—1·14) and CONFIRM (HR 0·62, 95% CI 0·37—1·03).
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[/quote]
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