A systematic review of the effectiveness of adalimumab

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Discussion
Results of modelling
The results of the economic evaluation using
BRAM generally reflect the patterns observed in
the review of clinical effectiveness. The estimated
ICER for etanercept used as third-line treatment
compared with base case, is somewhat more
favourable than the previous estimate (£48,000
per QALY and £83,000 per QALY, respectively).
This is because the model now gives some lasting
benefit to effective treatments after their
withdrawal. The additional evidence available
and improvements in the economic model mean
that the ICER for infliximab as a third-line agent
has changed from £115,000 per QALY to
£139,000 per QALY. In particular, an estimated
mean HAQ improvement of 0.6 (derived from a
personal communication) was used in the first
evaluation, whereas a mean improvement of 0.4,
based on empirical data from ATTRACT, was used
in this evaluation. This outweighs the
incorporation of some lasting benefit to infliximab
treatment.
When used alone as third-line treatment, the
modelling results for adalimumab and etanercept
using ‘early RA’ data are much more favourable
than the results using ‘late RA’ data. The evidence
about whether HAQ improvements tend to be
smaller in patients with longer disease duration
was inconsistent in the trials. Nevertheless, given
equal change in absolute HAQ score on treatment,
the improvement in early RA patients (who tend
to have better HAQ scores to start with) will give a
larger relative improvement. This effect is
reflected in the current version of the BRAM,
which modelled HAQ improvement using a
multiplier for each treatment and the individual
patient’s baseline HAQ score, rather than using a
fixed average HAQ change for all patients.
Compared with etanercept alone, concurrent use
of methotrexate makes little difference in costeffectiveness
when etanercept is used as third-line
treatment. Concurrent use of methotrexate
improved the cost-effectiveness of adalimumab as
third-line treatment.
The modelling results for TNF inhibitors
combined with methotrexate as third-line therapy
using ‘early RA’ data demonstrate that use of
inappropriate estimates of treatment effect
(assuming that the HAQ improvement for
combination therapy in patients who were naïve to
methotrexate or who had not failed methotrexate
can be applied to patients who had failed
methotrexate treatment) can produce ICERs that
are misleadingly low.
The BRAM produces ICERs in the region of
£50,000 per QALY for monotherapy with a TNF
inhibitor as first-line treatment. Combination with
methotrexate makes the results less favourable to
TNF inhibitors in cost-effectiveness terms. This
appears to be because, although the combination
has better effectiveness than monotherapy in itself,
the use of the combination precludes subsequent
use of methotrexate (which is cheap).
The more favourable ICERs for TNF inhibitors
used as last active therapy (compared with
palliation) and less favourable ICERs for TNF
inhibitors used as first-line treatment (compared
with methotrexate) highlight the importance of
using appropriate comparators in economic
evaluation. Such comparators should reflect
treatment options relevant to a patient’s disease
stage.
Assumptions, limitations and
uncertainties
Strengths
Strengths of this review include:
● A comprehensive search strategy to identify all
relevant evidence already within the public
domain was undertaken.
● Additional information, not previously available,
was provided by industry and lead researchers.
● There was a substantial number of trials for
each agent, which generally showed consistent
results.
● Trials were mainly well conducted.
● Clinical expert input at an early stage ensured
that a clinically relevant perspective was
maintained throughout.
● Data were available from the BSRBR and GPRD
that were not available in the first review.
● The BRAM has been in the public domain for
some time and subject to scrutiny and a number
of improvements. A meeting was held with all
three manufacturers before undertaking the
report to ensure that there were no concerns
about fundamental errors within the model and
general agreement about the direction of
proposed further development.
Limitations and uncertainties include:
● There is a potential for bias through unblinding
in TNF inhibitor studies, as infusion and
injection-related adverse events are more
frequent with active therapy. Unblinding of
physician or patient has been demonstrated to