Donepezil, rivastigmine, galantamine and memantine for ...

Reisberg and colleagues. 72 These probabilities are
reported in the industry submission but do not
form part of the published papers. The LASER-
AD Study is a 6-month observational study, funded
by the manufacturer of memantine, and may be
subject to bias from a number of sources such as
selection bias and reporting bias. The authors of
the LASER-AD Study note that it was made up of
volunteers who may have been particularly
motivated, and therefore unrepresentative. Transit
probabilities by dependency and location from the
RCT show distinct differences (between
memantine and usual care), and the derivation of
probabilities and their generalisability to the UK
population raise some concerns. Furthermore, the
validity of applying a derived OR to adjust
probabilities according to memantine treatment
versus usual care introduces further uncertainty,
and we have concerns over the methods used to
derive ORs. For example, an OR of 0.147 was
calculated to adjust transition probabilities for
location (probability of institutionalisation) using
data on a subset (a treated per protocol subset) of
patients from a clinical trial, 75 using 6-month data
on institutionalisation rate (with 6/66 placebo and
1/84 memantine patients institutionalised,
respectively). The industry submission cites a
resource utilisation study by Wimo and
colleagues 147 as the source for these data, yet
SHTAC have not found these data in the
published study, or in the associated published
RCT by Reisberg and colleagues; 72 furthermore,
rate of/time to institutionalisation is not stated as a
prespecified outcome in the trial.
Cost data used in the industry submission are also
from the LASER-AD study, and they seem high
compared with other published data on AD. We
discuss the study in outline in the section ‘Costing
considerations in the treatment of AD’ (p. 108),
but again highlight that the study is open to bias
and the sample may have been unrepresentative.
The cost estimates are based on a 3-month period
of patient recall, which may introduce recall bias
and measurement error. Furthermore, the
submission does not take into account that not all
costs are met by the NHS and 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 pension payments,
these will be used as a transfer payment to offset
funding in an institutional setting (further discussion
of this issue can be found in the section referred to
above). The published resource utilisation study by
Wimo and colleagues 147 reporting resource costs
for patients in the placebo and memantine arms
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Health Technology Assessment 2006; Vol. 10: No. 1
of the RCT by Reisberg and colleagues, 72 present
estimates of US$8194 and US$7104 per month,
respectively (1999$), but these estimates are from
a societal perspective and contain caregiver time
costs and productivity losses which account for
over 90% of these cost estimates.
We have serious concerns over the use of health
state utilities/values in the model for the calculation
of QALYs. As stated above, health state utility
values used in the industry submission are 0.65 (SD
0.20) for independent AD health states and 0.32
(SD 0.31) for dependent health states. These values
are cited from an unpublished Danish study by
Kronborg Andersen and colleagues, and the
respective sample sizes for these estimates were 131
independent patients and seven dependent
patients (although the authors do offer support for
the dependent values from a further small sample
of 18 dependent demential patients). The data
used to derive health state values are from a crosssectional
study reporting data from a Danish cohort
of patients aged 65–84 years living in Odense,
Denmark. 148 In this study a total of 244 patients
with mild to severe dementia were interviewed.
Data have subsequently been mapped (by Kronborg
Andersen and colleagues) across to EQ-5D health
states and values derived using Danish EQ-5D
population values (tariffs). The study included 164
patients with AD, 132 of whom were living in the
community. Data on health state values are from a
total group of 138 patients, whereas the authors
report that 164 AD patients were interviewed, with
no explanation offered on the exclusion of patients.
The mean MMSE score for the 164 AD patients
was 20.6. Of the 164 AD patients interviewed only
22 were classed as severe (MMSE < 10), 91 (55.5%)
were classed as mild (MMSE 20–30) and 140 were
classed as independent. Therefore, the majority of
patients may be regarded as mild and independent,
and the generalisability of data from these patients
to the more severe (moderately severe to severe)
patient group eligible for memantine treatment is
dubious. In the initial patient distribution used for
the industry model, over 70% of patients start in a
dependent state, with 60% classified as severe and
dependent. Supplementary data presented in the
industry submission report a mean health state
value of 0.486 for a sample of 12 patients with
severe dementia. It also reports only a small
difference between those patients in the community
(n = 191) and those in an institution (n = 20), with
health state values of 0.62 and 0.56, respectively.
The process of mapping from interview data to
EQ-5D health state values (tariffs) introduces
potential for misrepresenting the EQ-5D
107