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| Journal of the New Zealand Medical Association,
16-December-2005, Vol 118 No 1227
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PHARMAC responds on TNF inhibitors for inflammatory
arthritis
There are several features in the
Special Series article in October on
the funding of tumour necrosis factor (TNF)-alpha receptor antagonists (TNF
inhibitors) for inflammatory arthritis (http://www.nzma.org.nz/journal/118-1224/1706/)1
that deserve clarification.
TNF inhibitors are now funded for severe treatment-resistant rheumatoid arthritisThe PHARMAC Board decided in October 2005 to list the TNF
inhibitor adalimumab on the Pharmaceutical Schedule under Special Authority for
patients with severe treatment-resistant rheumatoid arthritis (RA).
Implementation of this decision was subject to obtaining specific advice from
the Pharmacology and Therapeutics Advisory Committee (PTAC). This advice has
since been given, and publicly-subsidised adalimumab will be available from 1
January 2006 (http://www.pharmac.govt.nz/pdf/051205.pdf).
Details of eligibility criteria for adalimumab can be found
in the Appendix to this letter. New Zealand’s
criteria will largely align to those of Australia.2
PHARMAC has been running a commercial process with suppliers
since May 2005, and secured a confidential agreement so that a TNF inhibitor
could be listed. The PHARMAC Board resolved to list adalimumab on the basis of
all of PHARMAC’s nine formal decision criteria (http://www.pharmac.govt.nz/operational_policies_and_procedures.asp).3
These included the high health needs and lack of other treatment for patients
with severe treatment-resistant RA, the effectiveness of TNF inhibitors, and
PTAC’s high-priority recommendation for funding TNF inhibitors.
Cost-effectiveness of TNF inhibitors for RAPHARMAC stands behind its previous economic analyses and the
discussion document on TNF inhibitors,4 which was distributed to District Health
Board (DHB) hospitals as part of the Hospital Pharmaceutical Assessment Process
(HPAP)—detailed later.
The initial document and economic analysis underwent a
thorough review process, including internal review of the economic methodology
by PHARMAC staff and external specialist rheumatology input. The draft
discussion document was then circulated to DHB hospitals for comment. PHARMAC
comprehensively considered the responses to this consultation before it made
revisions to arrive at the final document. The key elements of all of the
consultation responses were also considered by PTAC when it reviewed the
economic analysis in August 2004.
Issues raised, and PHARMAC’s responses to these
issues, are detailed in PHARMAC’s Analysis of
consultation responses to the Infliximab and Etanercept Discussion
Document—note that respondents’ identities have been withheld in
this version to maintain privacy.
The authors of the Special
Series article discuss several aspects of the economic analysis,
including the target population, the comparator and outcomes used, and what
savings are included. We respond as follows:
Target populationThe calculations of quality-adjusted life years (QALYs)
gained in the economic analysis were relevant to the likely high-need
high-response target population in New Zealand, and indeed relate closely to the
imminent eligibility (entry and exit) criteria for adalimumab. The calculations
were not based on the whole intention-to-treat population in the ATTRACT trial.5
Rather the analysis was based on unpublished data, sourced from the supplier, on
the subgroup of patients in the trial with severe treatment-resistant
disease.4,6 PHARMAC then calculated the $191,000/QALY for infliximab that was
specific to this more severely-affected subgroup.
Comparator used in analysisMethotrexate was the correct comparator to use in
PHARMAC’s economic analyses. Patients are likely to be on a cocktail of
drugs (which all differ in efficacy and side-effects), but in most cases they
should be co-administered methotrexate (unless methotrexate is contraindicated
or intolerable). Infliximab should be given in combination with
methotrexate7—and concurrent methotrexate improves the long-term
effectiveness of infliximab and etanercept,8,9 and for adalimumab the best
results are obtained with the concurrent methotrexate.10
In addition, since methotrexate was used in both arms of the
economic analysis (either alone or in combination with infliximab), the cost and
benefits occurred in both arms, cancelling out each outer; this in effect was
equivalent to comparing infliximab monotherapy with placebo.
PTAC, when reviewing the economic analysis, considered that
although methotrexate was not the ideal comparator, it was the most appropriate
comparator given currently available data. PTAC members noted that methotrexate
was used as the comparator treatment in the key clinical trial on infliximab
(ATTRACT), and that there were no data available comparing infliximab with
prednisone or leflunomide.
Even if a more expensive agent (e.g. leflunomide) was used
as a comparator, it would make little difference to the results of economic
analysis—because cost-effectiveness was relatively insensitive to the
costs of the comparator treatment (which PHARMAC did vary in sensitivity
analysis).
Outcomes considered in analysisPHARMAC’s economic analysis was based on the Health
Assessment Questionnaire (HAQ) index scores.11–13 HAQ scores are
considered to be sensitive measures of DMARD effectiveness14 and correlate with
disease severity (ACR scores15).16 HAQ scores were also a pre-specified primary
endpoint of the ATTRACT trial.5
The use of HAQ scores in the analysis indirectly accounted
for empirical reductions in joint damage, as radiological joint destruction
strongly correlates with HAQ scores.17–21 Therefore, any reductions in
joint erosions with TNF inhibitor treatment were reflected in the decrease in
HAQ scores and hence the QALY gains measured in PHARMAC’s analysis.
The long-term benefits of reducing joint erosion were not
measured in the relevant clinical trials. Hence it is difficult to conclusively
predict the effects of TNF inhibitors on erosive effects in economic models,
other than by using proxy but relevant measures such as HAQ scores.
Savings beyond the health sectorAlthough there may be non-health sector savings from using
TNF inhibitors, there are both philosophical and pragmatic reasons for limiting
analyses to health sector costs alone, as outlined by PHARMAC previously in the
Journal22 and in its Prescription for
Pharmacoeconomics.23
Discussion documents sent to DHB hospitalsPHARMAC did not publish the summary discussion document on
TNF inhibitors.4 The document was written in response to a request from DHB
hospitals, and made available to all DHBs as part of the HPAP—see http://www.pharmac.govt.nz/hospital_strategy.asp.24
These documents are circulated to DHBs as confidential documents, at the request
of and agreement with the pharmaceutical industry.
The advice in the discussion document4 should not in itself
have been a barrier to DHB hospitals’ funding of medicines such as TNF
inhibitors. Cost-effectiveness is only one of a number of factors considered by
DHBs when making funding decisions about such medicines.
We are interested that concerns with the methods and
assumptions used by the economic analysis have been highlighted by international
commentators. We would be keen to see the nature or source of these concerns,
although we haven’t been able to identify them yet in the literature.
Being confidential to DHBs, we are unsure how the TNF inhibitors discussion
document has gained international readership—beyond overseas
rheumatologists working for DHBs on fixed term contracts, whose comments were
part of the responses considered by PHARMAC.
Other inflammatory arthropathiesPTAC in November 2004 recommended listing etanercept for
ankylosing spondylitis, but with low priority. PTAC did note however that it
should reconsider that priority rating once longer-term data become available.
In general, applications with low-priority PTAC recommendations are treated with
less urgency than higher priority recommendations.25
PHARMAC has yet to receive any applications for TNF
inhibitors for psoriatic arthritis or other inflammatory arthropathies.
Scott Metcalfe
Public Health Physician Wellington Peter Moodie
Medical Director PHARMAC Wellington Rachel Grocott
Senior Analyst, Hospital Pharmaceuticals Assessment PHARMAC Wellington Tommy
Wilkinson
Therapeutic Group Intern PHARMAC Wellington Conflict
of interest: Scott Metcalfe is externally
contracted to work with PHARMAC for public health advice. Peter Moodie, Rachel
Grocott, and Tommy Wilkinson declare no conflicts.
References and
endnotes:
PHARMAC. A
prescription for pharmacoeconomic analysis (version 1.1). September 2004. URL:
http://www.pharmac.govt.nz/pdf/pfpa.pdf
The perspective taken by
PHARMAC when conducting cost effectiveness analyses is that of the health
sector. This relates to PHARMAC’s primary objective of achieving the best
health outcomes possible from pharmaceutical treatment within the funding
available (New Zealand Public Health and Disability Act 2000 [NZPHDA], Section
47 Objectives of Pharmac). This implies that any patient benefits and/or costs
that accrue beyond being either healthy or unhealthy are outside the scope of
PHARMAC analysis (where “health” is defined by default in the NZPHDA
as amenable to health services interventions).
This means that extra
economic production stemming from an individual being healthier is outside the
scope of PHARMAC’s analyses. Including indirect costs, such as loss of
earnings, may prejudice decisions against issues affecting the young, elderly,
and less economically productive groups. This conflicts with the public
priorities as stated by the Government under the New Zealand Health Strategy (http://www.moh.govt.nz/nzhs.html).
In addition, indirect costs
such as patient travelling times and productivity losses are not easily
measured. There is usually little available data on these issues or how to cost
them across patient sub-groups. Consequently, incorporating these into analyses
would mean using significant and untestable assumptions. Given the large
uncertainties involved, PHARMAC has felt it best to avoid incorporating these
estimates into its base case analyses.
Further
information on the purpose of HPAP and PHARMAC’s role in the distribution
of discussion documents can be found on the PHARMAC website—http://www.pharmac.govt.nz/hospital_strategy.asp
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