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| Journal of the New Zealand Medical Association,
07-June-2002, Vol 115 No 1155
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PHARMAC and availability of pharmaceuticals - and
response
In his editorial,1
Professor Menkes makes a number of points to which we would like to respond. We
support the principle of obtaining pharmaceuticals at the best possible price
and of prescribing in a way to get the best health outcome for the money
available. We agree that it is in nobody's interest for expensive but
ineffective treatments to be sanctioned. However, we question whether PHARMAC
adopts a systematic unbiased approach to reckoning cost effectiveness in
pharmaceuticals. There is evidence that a number of pharmacological agents,
discussed in the article,2 which are available
in most other countries, are useful in depression when treatment resistance or
side effects occur and it is the fact that these data seem to be selectively
noted or ignored by PHARMAC that we have difficulty with. There are also some
specific points to which we would like to respond.
Firstly, on the basis of other studies of drug treatment
data which apparently show that drug sponsorship has affected the interpretation
and also in some cases the data, Professor Menkes casts doubt on company
sponsored trial data and presumably, by implication, the meta-analysis of
Thase.3 However, he finds no fault in this
particular meta-analysis and does not criticise interpretation of the data.
Since there are no other data available on this subject, for reasons which we
discussed in our article, we find this approach unhelpful.
Secondly, Professor Menkes specifically criticises the study
by Poirier and Boyer4 of venlafaxine versus
paroxetine in treatment resistant depression stating that it "unfortunately does
not specify what proportion of patients failed to respond to SSRIs during the
index episode". In fact, the paper quite clearly specifies that in the
venlafaxine group 66% of patients previously failed to respond to an SSRI and in
the paroxetine group 65% had failed to respond to an SSRO. This is comparable
with the number of patients that have previously failed to respond to a
tricyclic antidepressant in each group. His assertion that it would be
unsurprising that SSRI non-responders tend not to respond when challenged with
another SSRI is not supported by the data or our clinical experience. Open
trials quite clearly show that the response rate to a second SSRI in the
presence of non-response to a first SSRI is approximately
50%3 and the strategy of switching from one
SSRI to another is commonly clinically used.
Furthermore the pharmacological profile of venlafaxine is
similar to that of some tricylic antidepressants, making this, in our opinion, a
very fair comparison. Indeed, this is a trial of a novel strategy (venlafaxine)
versus a commonly used strategy (switching to a second SSRI). The suggestion
that venlafaxine be compared with the novel strategy of augmentation of SSRI
with reboxetine (which is not funded in New Zealand) seems to us to be far more
open to methodological criticism.
Finally we would like to draw the attention of readers to a
forthcoming meta-analysis of venlafaxine5 which
adds to the data suggesting that this may be more effective than SSRIs in the
treatment of depression. Once again this is drug company sponsored. Readers,
PHARMAC and Professor Menkes can decide whether to evaluate the data critically
or simply to dismiss it on the grounds that it may be affected by this
sponsorship.
Dr Richard Porter
Senior Lecturer in Psychological Medicine. Roger T Mulder
Associate Professor in Psychological Medicine, Christchurch.
ResponseI am pleased that Porter and Mulder
agree that pharmaceuticals be obtained at the best possible price and used in a
way which maximizes health outcomes -- this is entirely in line with PHARMAC's
operating principles.1 However, they question
whether PHARMAC adopts a systematic unbiased approach in reckoning cost
effectiveness, based on the agency's decision not to purchase certain drugs
available in other countries. Of course in themselves such decisions can hardly
be taken to indicate bias. The real issue is whether these decisions are
reasonable given the evident cost-effectiveness of venlafaxine and the other
drugs in question. Since a drug's cost-effectiveness is calculated as a ratio of
benefit to cost, any treatment can become 'not worth it' if the supplier demands
too high a price.
The argument boils down to a simple question: are new drugs
such as venlafaxine worth what the companies want to charge, given the existing
drugs budget and the competing priorities both within and without psychiatry?
Thus far, it would seem that PHARMAC's calculations have yet to justify purchase
of venlafaxine, but the potential usefulness of this and other agents in
treatment of resistant mental disorders has left them on an 'investment list'
prompting continuing negotiations with suppliers. Looking back over PHARMAC's
history, the same arguments previously unfolded with regard to purchase of
branded SSRIs and atypical antipsychotics. In both cases, good evidence has
become available vindicating PHARMAC's hard-nosed purchasing policy. In both
cases, enormous price differentials (one to two orders of magnitude) relative to
conventional treatments effectively prohibited the unrestricted availability of
the branded drugs -- the additional benefits simply were not worth it. In both
cases, targetting the new drugs' availability to those most likely to benefit
was both clinically and fiscally sensible. Unfortunately, awareness of this
simple point was obscured, inter alia,
the very effective lobbying and marketing strategies of the pharmaceutical
companies concerned, and by the rhetoric of a number of indignant
prescribers.
Because PHARMAC has been given responsibility for
judiciously allocating scarce resourcing it is inevitable that hard decisions
will need to be made, and that some prescribers and their patients will be
frustrated. If Porter and Mulder have constructive suggestions for affordable
improvements to PHARMAC's methods of economic
analysis,2 or ways to make ends meet such as
how to increase revenue or to reduce the prices demanded by suppliers, then
their suggestions will be welcome. Meanwhile they should not be surprised if
PHARMAC's efforts to avoid bias lead to an apparent, often frustrating,
resistance to focused lobbying. Such lobbying reflects both dedication and the
individualism which is part of our clinical medical
culture,3 and which inevitably collides with
the utilitarian ethos of government agencies.
Just because a study is funded by a drug company does not
make it worthless but is cause for healthy scepticism. Thus I seem to be
somewhat more sceptical than Porter and Mulder regarding the RCT of venlafaxine
versus paroxetine in refractory depression.4 I
am grateful to my Canterbury colleagues for bringing to my attention the
proportion of patients who failed to respond to SSRIs during the index episode
in that study. However, concern remains when a single sponsored RCT is relied
upon to make important funding decisions. This is particularly true given very
recent evidence from a large (n=168) RCT confirming that more than 50% of
chronically depressed SSRI or tricyclic non-responders improve significantly
when crossed over to the alternate antidepressant
class,5 suggesting a cheap alternative for many
patients who might otherwise receive vanlafaxine.
Porter and Mulder also take issue with my 'implied'
scepticism about sponsored metaanalysis, such as the one by Thase et
al,6 and find my approach unhelpful since
"there are no other data available on this subject." I am indeed sceptical about
that meta-analysis, specifically because other data apparently do exist and have
been excluded from the analysis, probably on the basis of publication
bias.7 As Porter and Mulder note in their
original article8 "...Reputable journals are
extremely careful about the review and publication of studies with possible
conflicts of interest and we have no reason to suppose that the British Journal
of Psychiatry is any different in this regard." Exactly so, and it is
fascinating to note recent concerns about the links between Wyeth (the
manufacturer of venlafaxine) and the editor of the British Journal of
Psychiatry, in which the aforementioned meta-analysis
appeared.9
Venlafaxine will, I predict, shortly become available in New
Zealand, but since the price demanded by Wyeth is many times that of the generic
SSRI and tricyclic alternatives, its availability may sensibly be restricted to
use in a specific population of patients refractory to both conventional
antidepressant classes. The net economic impact of venlafaxine is difficult to
anticipate, partly due to externalized costs of depression and its treatment,
but also because the majority of pharmacoeconomic analyses may suffer from
sponsorship bias, sometimes with embarrassing
transparency.10
David Menkes
Professor of Psychological Medicine, University of Wales.
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