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PHARMAC not funding some treatments for rare,
life-threatening diseases: bosentan as an example
Ken Whyte
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Abstract
Pulmonary arterial hypertension is a devastating and fatal
disease for which effective therapies have been developed over the last 10
years. Unfortunately these therapies are expensive. The New Zealand health
system which has no discernible strategy to deal with the issue of high-cost
treatments has, through its agent, PHARMAC, failed to either clearly state that
they recognise the need to fund treatment for this condition or to refuse all
effective treatments and defend such a decision in the public arena. Bosentan,
an endothelin antagonist, improves symptoms and extends life substantially in
this condition, but access has been near impossible as it is expensive. PHARMAC
have for the last 18 months refused to fund any effective therapy through the
Community Exceptional Circumstances Panel. However, clinicians can approach the
patient’s DHB to fund treatment and yet the treatment offered and the
duration is decided by the Hospital Exceptional Circumstances Panel of PHARMAC.
Power without either clinical or fiscal responsibility?
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Drug
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Bosentan (Tracleer)
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Indication
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Treatment of Pulmonary Arterial Hypertension (PAH):
- Idiopathic
(primary).
- Related
to collagen vascular disease.
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Recommended
dose and duration
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Bosentan: 125 mg twice daily as open-ended treatment
(62.5 mg twice daily for first month of treatment)
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Clinical
efficacy
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Bosentan is an endothelin A & B receptor antagonist with
a proven role in the treatment of patients with severe PAH (NYHA/WHO grade
III/IV exertional dyspnoea). PAH is a progressive disease leading to
increasingly severe pulmonary hypertension and death, usually as a result of
right heart failure.
The majority of patients commenced on treatment with
bosentan will either report stability in exercise tolerance or an improvement in
exercise tolerance (usually one NYHA grade) with treatment.
The RCT evidence confirms short-term efficacy (12–16
weeks) with improvements in 6-minute walking distance,1,2 haemodynamics1 and
delay in time to clinical deterioration1,2 compared to placebo.
A long-term open-label extension trial demonstrated
persistent improvement in functional class for up to 1 year3 and more recently
the patients in these original RCT studies4 were shown to have survival benefits
at 24 months (89% survival compared to 57% predicted based on historical
controls from the NIH PPH database5).
Chronic treatment with bosentan will delay progression of
this disease to a variable extent ranging from months to years thus extending
life and delaying the need for pulmonary transplantation in the sub-group of
patients suitable for transplantation.
Idiopathic PAH patients tend to have a more prolonged
response than patients with PAH related to collagen vascular disease.
A transient rise in transaminase levels is common, with a
proportion of patients (5%) having a severe and prolonged rise in transaminases
as a result of a drug induced hepatitis requiring withdrawal of therapy.
The European Drug Agency in conjunction with the
manufacturer has had a rigorous surveillance programme in place; and to date in
over 10,000 patients there has been a 6% incidence of events including deaths.
Most deaths appear to be due to progressive right heart
failure, though distinguishing between hepatic congestion secondary to right
heart failure and a drug reaction is not always simple. Thus the possibility of
drug-induced hepatic disease resulting in fatalities remains. It is important to
realise that this is a therapy for a progressive and fatal disease.
Teratogenicity has not been excluded but all PAH patients
are advised to use two methods of contraception, as pregnancy has such a high
fatality rate (both for the mother and foetus) that it is generally considered
too dangerous.
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Background
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Although rare, PAH is an increasingly recognised condition,
and in almost all cases leads to death as a result of right heart failure.
Proliferation of all the layers of small muscular pulmonary arteries leads to
progressive obliteration of these vessels. This can be regarded as a form of
dysfunctional angioneogenesis.6
As a result of the destruction of these vessels, pulmonary
arterial pressure rises progressively. Endothelin antagonists have an
antiproliferative action in these vessels by halting or significantly slowing
down the progression of the disease-process in destroying the vessels.
The cause of PAH is not understood though cases can be
familial (linked to mutations in the bone morphometric protein receptor in
70+%), idiopathic (previously called Primary Pulmonary Hypertension) and related
to an increasingly wide range of other diseases. The commonest related diseases
being collagen vascular disease, most frequently limited variant
scleroderma.
As the symptoms are insidious and non-specific, patients are
rarely diagnosed until the disease is severe, and average survival from
diagnosis to death is 2.8 years.5 Idiopathic PAH is commonest in young women but
it can present in both sexes and all ages including childhood.
Occasional patients who are diagnosed with relatively early
disease and who have a brisk pulmonary vasodilator response to NO or prostanoids
in the catheter laboratory will have a sustained response to high-dose calcium
channel blocker therapy (270 mg of nifedipine/720 mg of diltiazem).6
Less than 7% of patients with this disease will respond long
term (>1 year) to this therapy. Anticoagulation appears to slow progression
of disease and is thought to decrease in
situ thrombosis in the pulmonary circulation caused by shear force injury
to the remaining vessel walls as a result of high pulmonary vascular
pressures.6
Alternative therapies used to treat this condition include
continuous intravenous prostacyclin (a prostanoid) which has been shown to be
effective with decreased mortality at 12 weeks.7 However, the treatment is
costly both in terms of pharmaceutical budgets (>USD$100,000) and the
provision of nursing support to maintain lifelong continuous IV infusion with
significant complications resulting from catheter infections and IV access
problems. Prostacyclin is not registered in New Zealand.
Iloprost, a prostacylcin analogue with a longer half-life,
is registered for intravenous use in New Zealand and has also been shown to be
effective in PAH as a chronic therapy given by nebulisation three-hourly night
and day.8 It is a feasible therapy (though demanding), and currently is cheaper
than IV prostacyclin but more expensive than bosentan based on a dose of 15
μg per nebulisation three-hourly.
Increasingly it would seem that there is a potential role
for the PDE5 antagonist, sildenafil (Viagra), in treating pulmonary arterial
hypertension. To date, other than case reports and small series, the only fully
published RCT of short-term therapy (22 patients in a 6-week crossover study
against placebo) was positive.9
A larger apparently positive study (SUPER study sponsored by
Pfizer) has been presented at a meeting but has not been published either in
abstract or in a peer-reviewed publication, and details of the protocol remain
incomplete. Full publication* is awaited.
The optimal dosing strategy is unclear (previous reports
have used 20–100mg tds or qds) and the incidence of toxicity of these high
doses are unknown at this time. Original human toxicology data for sildenafil
prior to its launch as a treatment for erectile dysfunction was based on
intermittent use in males and did not examine the toxicity of high-dose chronic
therapy in humans.
*Whilst this paper was in press, the SUPER study was
published earlier this month.14
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Government
policy
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The New Zealand Health Strategy has no clear policy on
access to funding for rare or “orphan” diseases. Patients with rare
and rapidly fatal diseases have no advocates in the NZ Health System and there
are no powerful patient groups able to advocate for a realistic appraisal of the
cost benefit of such treatments and to resolve funding issues centrally. Thus
access to treatment is a ‘lottery’ based on the patient’s
physician’s willingness to advocate; their local DHB willingness to fund
therapy; and the decision of the HEC panel as to what therapy should be funded,
if any.
These treatments are expensive. Bosentan will be
NZ$40,000–50,000 per annum; if the quality of evidence for sildenafil
improves, it will be cheaper, though until we know what dose is appropriate the
final cost is unclear. It could be anywhere from NZ$10–30,000 per annum.
Clearly a case can be made that such costs represent an inappropriate use of
health resources in a resource-limited system.
Such an argument would have some validity if there was
consistency in the system. However these treatments are at least as cheap as a
year of chronic haemodialysis (NZD$40,000+ per year). In diabetic renal failure,
chronic haemodialysis is a life-extending therapy. As dialysis is not a
pharmaceutical intervention it does not fall under the PHARMAC umbrella and is
funded directly from DHB budgets.
One of the goals of the MOH is “to reduce inequalities
in health outcomes” but no attempt is made to address inequalities in
access to high-cost treatments. Indeed, access varies depending on the type of
treatment rather than efficacy or cost-effectiveness of the treatments.
MOH in a number of areas has stated that it will “give
substantial weight to interventions for which there is strong scientific
evidence of effectiveness”. Despite an increasing body of good quality
evidence that pulmonary vasodilator therapy is effective in this fatal disease
(most commonly seen in young people), the NZ health system via its agent PHARMAC
refuses to consider funding (from the pharmaceutical budget) any effective
therapy for the 90+% who will not respond to calcium channel blockers.
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Current
situation
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New Zealand
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Bosentan is registered in New Zealand for the treatment of
PAH in idiopathic cases and in cases related to collagen vascular disease. PTAC
have advised that funding would be appropriate but “low priority”.
As there are increasing numbers of requests for funding for
pulmonary “vasodilator” therapy, the PHARMAC Community Exceptional
Circumstances Committee has decided that demand means the use of these agents is
“no longer exceptional” and will not accept requests for funding any
of the effective agents discussed above. Thus, PHARMAC have (financially)
abandoned these patients by offering no access to treatment from the
pharmaceutical budget.
However, individual patient’s clinicians can make an
application to the Hospital Exceptional Circumstances (HEC) Panel if they have
agreement for funding of therapy from the relevant authority of the
patient’s local DHB hospital.
Even if there is agreement by the DHB to fund therapy, the
HEC have the right to refuse such funding as “inappropriate”. The
current situation is that applications for bosentan are being refused but it is
being suggested that sildenafil might be appropriate to be funded.
The rational offered by the HEC Committee10 for this
suggestion is that there is concern over the toxicity of bosentan, though FDA
and EDA have not been concerned to the extent of hinting at any withdrawal of
this potentially life saving therapy.
The Panel have also expressed concerns regarding
teratogenicity, presumably unaware that pulmonary vascular diseases clinics go
to great lengths to counsel patients regarding pregnancy and would strongly
advise termination in the event of an unplanned pregnancy. Moreover, the Panel
have suggested sildenafil is a more efficacious therapy though published
evidence is limited and there has been no systematic drug toxicity monitoring of
sildenafil in this condition.
Effectively the unfortunate HEC Committee are in the
situation of influencing the spending of a DHB hospital budget without any
insight or knowledge of that DHB’s budgetary constraints. Thus it is not
surprising that they will tend to favour the cheaper if less well-proven
alternative.
In addition, they are put in the invidious position of
determining the therapy for patients in a difficult and challenging clinical
area without intimate knowledge of each individual patient’s situation or
the financial constraints of the organisation that will have to fund the
therapy. Surely, an impossible dilemma for this PHARMAC panel?
The physician applying in desperation on behalf of their
patient is put in the dilemma of applying for the more expensive but currently
better proven therapy (bosentan) or do they take the view that any therapy is
better than none?
Do they enter into complicity with this flawed and illogical
system to enhance the patient’s chance of having access to a therapy for
this devastating disease?
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International
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Bosentan is registered in the USA, Canada, Europe, and
Australia and is funded fully in the latter three areas and by most HMOs in the
US.
Control of access varies in each system, with some European
countries restricting access to a handful of units running a dedicated pulmonary
vascular disease service to ensure appropriate use and equity of access (e.g.
the UK has 8 designated centres) and others allowing even GPs to prescribe (e.g.
Republic of Ireland).
Pfizer have just had approval by both the FDA and EDA to
expand the indications for sildenafil to the treatment of PAH based on the SUPER
trial,14 and thus possibly extend its patent on the compound.
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Access/supply
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Supplies of bosentan can be arranged through a NZ
distributor to the funding DHB pharmacy.
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Economic
analysis
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To the author’s knowledge, there is only one paper
that has examined the cost benefit analysis of treatments for PAH in the
literature.11 This paper suggested that bosentan was a efficacious intervention.
In the application for funding for bosentan to PBAC in Australia, the
manufacturers submitted cost-benefit data which presumably was to some extent
convincing as the decision of the Australian funding agency was to fund
bosentan. The data used in that analysis is not in the public domain.
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Other
issues
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Why recommend bosentan rather than sildenafil?
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In 2004, there have been two excellent reviews of the
evidence which differ on the levels of evidence for bosentan and sildenafil.
The WHO-sponsored group12 summarised the bosentan data
as:
- Level
of evidence:
good
- Benefit:
substantial
- Grade
of recommendation:
A
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The same group for sildenafil rated it as:
- Level
of evidence:
low
- Benefit:
intermediate
- Grade
of recommendation:
C
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The European Cardiology Society Group gave similar grading
to the bosentan evidence, but (with the preliminary data from the large
unpublished sildenafil RCT study available) it suggested:
- Grade
of recommendation:
1
- Level
of evidence:
A
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The European Cardiology Society Group did, however, added
the statement “that it should be considered in patients with PAH, who have
failed or are not candidates for other approved therapies”.13
Once the sildenafil study (SUPER)* has been published after
peer review then the balance may change in favour of sildenafil especially in
view of the fact it is likely to be cheaper. Clearly the final recommended dose
of sildenafil from that study will influence the cost-benefit analysis
significantly. However in addition there will be a significant time lag to build
up enough patient treatment years to be able to determine the safety profile of
sildenafil at these doses.
*Whilst this paper was in press, the SUPER study was
published earlier this month.14
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Combination therapy for PAH?
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PAH is due to dysfunctional angiogenesis and the triggers to
this may involve different or multiple pathways. The three groups of drugs
discussed above (prostanoids, endothelin antagonists, and PDE5 inhibitors) all
inhibit vessel wall proliferation by different mechanisms.
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Thus there is the potential for the effect of these agents
to be additive and for combination therapy to offer considerably better outcomes
than monotherapy.
To date, though there is some supportive data for
combination therapy from acute challenge studies in the catheter laboratory,
there are no outcome RCT studies demonstrating benefit available though several
are underway.
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If such studies show significant benefit, then these
clinical and funding dilemmas will increase and our health system is clearly
neither willing or able to deal with these issues as the actions of PHARMAC so
clearly demonstrate.
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Comment
The current approach whereby PHARMAC is not responsible for
funding the therapy—yet is responsible for determining the use of a
DHB’s funds for a pharmaceutical therapy for a life-threatening illness,
but not responsible for use of that DHB’s funds in other life-threatening
conditions that do not require pharmaceutical treatment such as
dialysis—is a nonsense. The system is failing these patients, and PHARMAC
has allowed itself to be a willing agent in this treatment
“lottery”.
The issue for the NZ Health System and PHARMAC is not which
is the best agent but its lack of transparency regarding the availability and
funding of any treatment for this condition.
The current situation is akin to “smoke and
mirrors” and is clearly neither evidence based nor a rational use of
resource in a transparent system. The system is failing patients and their
families in many respects but adds insult to injury by nature of the
“lottery” of therapy that they are sucked into in the current
system.
The Ministry show no interest in solving such conundrums. No
one in PHARMAC appears to be empowered or willing in this system of “pass
the buck” to make it clear to the Ministry and the DHBs that the system is
a nonsense. The failure to fund such pharmaceutical therapies raises major
issues of equity of access and highlights the difficulties that high cost
treatments impose on our system. It seems in no one’s interest in these
agencies to initiate rational and open debate around high cost treatments.
Instead it is swept under the carpet or put in the “too hard
basket”. The result is “ad hoc” and irrational decisions that
vary from condition to condition, therapy to therapy and DHB to DHB.
PHARMAC and/or the MOH could decide that there will be no
access to pulmonary vasodilator therapy in this country. By making such a
decision they would then have to justify their actions and come under public
scrutiny explaining why the dollar resource threshold for treatments varies
arbitrarily from one treatment (haemodialysis) to another (pharmaceutical
treatment with pulmonary vasodilator therapy).
Alternatively they could elect to fund such therapy with
clearly stated limits of therapy giving patients and their clinicians both
clarity and the ability to argue the merits of any such choice that PHARMAC
make.
In this devastating disease there is a strong case for
PHARMAC to think “out of the box” and share the “grief”
with the development of a pulmonary vasodilator fund with a committee of
interested and experienced clinicians working in tandem with the funders to
allow equitable and rational access to such therapy whilst also working within
agreed resource constraints. Such a system would not be easy for those involved
with hard decisions necessary to achieve maximum benefit from scarce resources
but would offer transparency and consistency to patients and clinicians. Surely
this would be an improvement on the current “system” which
represents irrational rationing and is indefensible in this day and age?
As for the MOH it must finally grasp the nettle of how to
fund equitably and openly high cost treatments across the board from dialysis
through expensive pharmaceuticals to surgical interventions – is there any
leadership left in these agencies or has the ability of independent thought been
eviscerated from the publicly funded health service?
Disclosures:
Dr Whyte has received sponsorship for attendance at two pulmonary vascular
disease meetings each from Actelion (manufacturers of bosentan) and Schering
(manufacturers of iloprost) over the last 8 years. He has a long standing
interest in pulmonary vascular disease and set up the Pulmonary Vascular Clinic
at Greenlane Hospital in 1997 along with Dr Coverdale. He is also involved in
the NZ Cardiac and Pulmonary Transplant Programme.
Author information:
Ken F Whyte, Respiratory Physician, Respiratory Medicine Service, Auckland City
Hospital and Greenlane Clinical Centre, Auckland
Correspondence: Dr
Ken Whyte, Respiratory Services, Auckland City Hospital, Grafton Road, Private
Bag, Auckland. Fax: (09) 631 0712; email: kenw@adhb.govt.nz
- Channick
RN, Simmoneau G, Sitbon O, et al. Effects of the dual endothelin-receptor
antagonist bosentan in patients with pulmonary hypertension: a randomised
placebo-controlled study. Lancet. 2001;358:1119–23.
- Rubin
LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial
hypertension. N Engl J Med. 2002;346:896–903.
- Sitbon
O, Badesch DB, Channick RN, et al. Effects of the dual endothelin receptor
antagonist bosentan in patients with pulmonary arterial hypertension. A 1 year
follow up study. Chest. 2003;124:247–54.
- McLaughlin
VV, Sitbon O, Badesch DB, et al. Survival with first-line bosentan in patients
with primary pulmonary hypertension. Eur Respir J. 2005;25:244–9.
- D’Alonzo
GE, Barst RJ, Ayres SM, et al. Survival in patients with primary pulmonary
hypertension. Results from a national prospective registry. Ann Intern Med.
1991;115:343–9.
- Galie
N, Rubin LJ. Pulmonary Arterial Hypertension: Epidemiology, Pathobiology,
Assessment and Therapy. J Am Coll Cardiol. 2004;43 (Supplement):12.
- Barst
RJ, Rubin LJ, Long WA, et al. A comparision of continuous intravenous
epoprostenol (prostacyclin) with conventional therapy for primary pulmonary
hypertension. The Primary Pulmonary Hypertension Study Group. N Engl J Med.
1996;334:296–302.
- Olschewski
H, Simmonneau G, Galie N, et al. Inhaled iloprost for severe pulmonary
hypertension. N Engl J Med. 2002;347:322–9.
- Sastry
BKD, Narasimhan C, Reddy NK, et al. Clinical efficacy of sildenafil in primary
pulmonary hypertension: A randomised placebo-controlled, double-blind, crossover
study. J Am Coll Cardiol. 2004;43:1149–53.
- Personal
communication: HEC Panel, PHARMAC; 2005.
- Highland
KB, Strange C, Mazur J, Simpson KN. Treatment of pulmonary arterial
hypertension: A preliminary decision analysis. Chest.
2003;124:2087–92.
- Badesch
DB, Abman SH, Ahearn GS, et al. Medical therapy for pulmonary arterial
hypertension: American College of Chest Physicians Evidence-based clinical
practice Guidelines. Chest 2004; 126:35S–62S.
- Task
Force on diagnosis and treatment of PAH of the European Society of Cardiology.
Guidelines on diagnosis and treatment of pulmonary arterial hypertension. Eur
Heart J. 2004;25:2243–78.
- Galie
N, Ghofrani HA, Trobicki A, et al. Sildenafil citrate therapy for pulmonary
arterial hypertension. N Engl J Med 2005;353:2148–57. Abstract available
online. URL: http://content.nejm.org/cgi/content/abstract/353/20/2148
Accessed November 2005.
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