Donepezil, rivastigmine, galantamine and memantine for ...

Cost-effectiveness acceptability curves (CEACs)
indicate (reading from figures only) that the
probability that the ICER for donepezil at base
case would be dominant in favour of donepezil is
37%, and where half-cycle corrections are applied
the probability of a dominant ICER is around
15%. However, these data are not specified, and
we are unsure how the analyst has interpreted
ICERs to determine the CEACs (i.e. a negative
ICER can have different interpretations – negative
benefits and additional costs gives an ICER below
zero).
The CEAC with half-cycle correction indicates a
probability of around 55% of getting an ICER at
£15,000 per year of non-severe AD (we would
suggest that with an incremental utility of 0.30
between severe and non-severe AD this is
interpreted as somewhere in the region of £50,000
per QALY).
One-way sensitivity analyses are reported against
discount rate, disease progression, source of cost
data and mortality rate. Results were sensitive to
assumptions made about disease progression,
source of cost data and mortality rate. The ICER
increased significantly assuming that benefits of
drug treatment were reflected in transit
probabilities for the first 12-months only [scenario
(a)] (ICER £23,162) and ICERs also increased with
alternative cost sources. Using higher mortality
rates resulted in cost dominant ICERs (–£1324 to
–£2208). (Sensitivity analysis not reported for halfcycle
correction scenario.)
Comments on industry submission
The CEA in the industry submission for donepezil
is based on a model that is solely structured
around cognitive function using the MMSE (see
Appendix 15 for an outline appraisal of the
model). Health states for stages of disease severity
are described using categories of MMSE, and
transitions between these health states are based
on patient level MMSE data from one clinical trial:
the RCT reported by Winblad and colleagues 47
with 286 patients randomised to either donepezil
or placebo (across 28 treatment centres). The
authors do not provide a rationale for the model
structure. The transit probabilities used remain
unpublished (presented in industry submission),
and the data used to derive them have not been
published. Winblad and colleagues report a
statistically significant difference in MMSE over
52 weeks (–0.46 donepezil versus –2.18 placebo);
however, analysis is not based on ITT and MMSE
is a secondary outcome measure. Primary
outcomes were GBS (not statistically significant)
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Health Technology Assessment 2006; Vol. 10: No. 1
and GDS (where a statistically significant
improvement was shown).
Although accepting that there are currently few
alternatives to the use of cognitive function when
considering AD progression, we believe that it is
important to state that the use of cognitive
function alone (i.e. MMSE in this model) is likely
to misrepresent disease progression over time. In
this instance the use of transit probabilities from
this one clinical trial introduces added uncertainty
over the methods used to model disease transition
over time (by defined health states), given the
documented concerns over the use of the
MMSE. 43,123–125
When comparing the transit probabilities used to
predict disease progression in donepezil-treated
patients versus placebo, we note that there are a
number of instances where large differences occur
in the probabilities associated with moves between
health states, for example, the probability of
patients remaining in a minimal severity AD state
(82% donepezil versus 69% placebo per year), the
predicted move from mild AD back to minimal AD
(26 versus 2%) and the predicted move from mild
AD to severe AD (2 versus 17%). Given that the
mean difference between donepezil and placebo in
MMSE score per year is 1.72 points in the clinical
trial, and that there are no data published
presenting the numbers of patients involved in
transits between health states, we would raise
concerns over the use of the data to predict
disease progression in a broader treatment eligible
population, that is, numbers may be small and
differences may be statistically insignificant, and
thereafter is the common issue of transferring
findings from a clinical trial setting to general
practice.
Furthermore, we have concerns over the endpoint
used in the model, namely time in years spent in
an AD health state that is non-severe (i.e.