A systematic review of the effectiveness of adalimumab

introduce bias which generally exaggerates the
treatment effect.
● This review primarily focuses on evidence from
RCTs, which, so far, have insufficient numbers
of patients and follow-up time to detect rare but
potentially SAEs. Some of the non-statistically
significant trends in adverse events identified in
this review therefore warrant close monitoring
when new trial evidence becomes available. For
example, for all three TNF inhibitors, a similar
non-significant trend for increased SAEs was
found for TNF inhibitors combined with
methotrexate compared with methotrexate
alone in patients who were naïve to
methotrexate. Pooling the data for all three
agents showed that SAEs just approached
statistical significance (RR [Commercial-inconfidence
information removed]). Using
methods specific for analysing data of sparse
events, Bongartz and colleagues demonstrated a
statistically significant increase in the risk of
malignancies associated with higher doses of
adalimumab and infliximab. 202 The analysis was
based on similar (but fewer) trials to those
included in this review. Data from adalimumab
and infliximab trials in both early and late RA
patients were combined in this analysis.
● It is commendable that all the manufacturers
made available the clinical study reports of their
major trials in the technology appraisal process.
This allowed the reviewers to include
unpublished data. Substantial information from
adalimumab trials and some information from
infliximab trials, however, was regarded by
manufacturers as confidential, despite repeated
requests to reconsider. Therefore, important
data on SAEs had to be removed from this
report, and readers are urged to interpret data
in the relevant sections with care.
Assumptions relating to the economic analyses are
described in detail in the section ‘Economic
analysis used in this report’ (p. 86). However, key
limitations include:
● The BRAM assumes that if patients continue on
a DMARD it remains effective. Patients and
clinicians are aware of the limitations and flaws
of such an assumption. 203
● The evidence concerning how long patients
remain on treatment is uncertain and data were
used from observational cohorts studying drug
survival with particular DMARDs to determine
when lack of effectiveness or toxicity causes a
change in treatment.
● The evidence about how long patients remain
on TNF inhibitors is also uncertain. Data from
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Health Technology Assessment 2006; Vol. 10: No. 42
the BSRBR about drug-survival for the different
TNF inhibitors were not used because of
uncertainty about their validity: constraints
imposed by national guidance on the use of
TNF inhibitors mean that data may not be
accurately recorded and there has been no audit
or validation of the registry data.
● The drug survival curves for 6, 12 and
18 months in the BSRBR show different
patterns of patients remaining on each TNF
inhibitor during the first 6 months of treatment,
suggesting a cohort effect, possibly caused by
changing use of these drugs, which needs to be
investigated and explained and which adds to
the uncertainty about how long patients will
remain on treatment.
● This report explored the strategies of using
either TNF inhibitor alone or combination
therapy (TNF inhibitor plus methotrexate) as
the first-line treatment for early RA patients
and incorporated data on HAQ improvement
from relevant clinical trials. There were
insufficient data to distinguish survival on
treatment between these two strategies and thus
a common data set for withdrawal was used.
This may potentially underestimate the
treatment benefit of combination therapy, if the
combination therapy is better than
monotherapy. The impact is probably greater
for adalimumab than for etanercept: in the
PREMIER trial the combination therapy was
better than adalimumab alone, whereas in
TEMPO continuation on the drug appeared to
be similar between these two strategies.
● Adalimumab was only modelled at 40 mg every
other week using associated costs. In the
PREMIER trial the dose could be increased
(dosing interval reduced) to 40 mg weekly.
Since the data from PREMIER were used in the
‘early RA’ scenario in the model, the treatment
benefit may have been overestimated and the
costs underestimated.
● By using an NHS and PSS perspective, as
required by NICE, the BRAM significantly
underestimates the potential economic
advantages of effective disease control since
costs incurred by families and carers are
substantial.
● Strategies for treating RA are potentially very
complex. For reasons of feasibility only the most
common strategies were modelled. The model
is based on the saw-tooth strategy, in which
there is continued or serial use of one or
multiple DMARDs. While this approach appears
to reflect and be effective in clinical practice, 38
there are limited long-term data on optimum
strategies for treating RA, although recent data,
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