Donepezil, rivastigmine, galantamine and memantine for ...

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Economic analysis
term). Where we see no mortality effect in the
model of disease progression we are in effect
seeing a greater number of years lived in a nonsevere
AD state than would actually be expected.
However, we are concerned that where mortality is
introduced to the model it has a perverse effect on
the endpoint used (i.e. sensitivity analysis shows an
incremental cost saving and slight change in
incremental benefits compared with base case,
although absolute data are not presented). Where
Stewart and colleagues 82 used a similar
modelling approach they report that increasing
mortality results in a higher cost per year of
non-severe AD.
Within the model (and base-case results) presented
we are concerned at the use of a 12-month cycle
(to fit with data from the 1-year trial) given the
differences presented in the industry submission
when half-cycle correction has been employed. In
a Markov model using a 12-month cycle, events
(transits between states of disease severity) are
assumed to occur at the end (or start) of the 12month
cycle. Where a half-cycle-correction is
applied, there is an allowance for events occurring
mid-cycle, and this can impact on the expected
value for costs and benefits. The industry
submission reports findings to indicate that the
impact of the half-cycle correction in this model is
very significant, yet the base-case results presented
and the presentation of most findings in the
sensitivity analysis are not calculated using the
half-cycle correction. We believe the appropriate
findings are those that make some allowance for
events within the 12-month cycle period. This
alters the base-case ICER from £1206 per year in
a non-severe AD state to £7449 per year (£3278
and £10,826, respectively, for probabilistic
analysis). Results reported using half-cycle
correction show an increase in incremental costs
incurred and a reduction in incremental benefits
gained (years in non-severe state), compared with
base-case analysis. The authors of the industry
submission attribute these marked differences to
entry and exit rates (transit probabilities) from the
health state ‘minimal AD’, where data predictions
are very different for the donepezil and placebo
cohorts.
Where the industry submission examines
sensitivity analysis, it notes a large impact on costeffectiveness
where assumptions on effectiveness
are relaxed (i.e. where effect is assumed to last for
1 year only [scenario (b)] the ICER increases to
over £23,000 per year in a non-severe state).
Scenario (a), where probabilities are different for
the first 12 months, and thereafter patients transit
by the same transit probability matrix, is presented
as a cost-saving scenario.
Within the industry model, we have concerns over
the mortality data used. As discussed above, the
transition probability matrix in the model makes
minimal allowance for transit to death from AD
states. In the donepezil treated cohort the
probability of moving to death from the minimal
and mild AD states is zero and from moderate AD
the probability of death is 5% per year. In the
usual care cohort, the probability of death from
minimal AD is zero, from mild AD it is 2% per
year and from moderate AD it is zero. These data
highlight concerns with generalisability from the
trial data used in the model. Sensitivity analysis is
reported for mortality rates included, with
increases in mortality resulting in a more attractive
profile for donepezil treatment, and we have
raised concerns over this above.
Cost estimates used in the model are from data
derived and presented by Wolstenholme and
colleagues 122 [discussed in the section ‘Costing
considerations in the treatment of AD’ (p. 108)],
and although these may reflect resource use in the
sample studied by those authors, the study does
not take into account that not all costs are met by
the NHS and Personal Social Services (PSS), with
many patients in an institutional setting being
privately funded (or at least partially funded from
private sources). Furthermore, where publicly
funded patients are also in receipt of state pension
payments, these will be used as a transfer payment
to offset funding in an institutional setting [for
further discussion of this issue, see the section
‘Costing considerations in the treatment of AD’
(p. 108)]. The study by Wolstenholme and
colleagues, used in the base-case analysis, is
unclear as to where the costs for private
accommodation are factored into analysis. If costs
for personal accommodation are included in the
analysis the perspective of the study is not that of
the NHS and PSS, and the cost data will be
incorrect for the analysis in the donepezil model.
The executive summary in the industry submission
states that “Donepezil costs can be fully offset (i.e.
cost saving), generally after two years of treatment”,
but this result is not presented in the report and
the scenarios tested by the model indicate that
many of the 5-year outcomes are cost incurring.
See our adjustments to the industry model in the
section ‘SHTAC analysis of cost-effectiveness of
donepezil, rivastigmine and galantamine using the
industry models submitted to NICE (p. 131).