Esta es una transcripción del Comité del NICE (National Institute for Health and Care Exellence) Inglés, en el cual analizan las terapias dirigidas en cáncer de colon y su relación con el costo que tienen y los pocos beneficios que se obtienen. Es de hacer notar que no analizan los pacientes que se benefician, ya que esto se sabría si se publicara el NNT (Número de pacientes a tratar, para obtener un resultado). Esta Institución basa sus resultados en comparar los resultados de los grupos de tratamiento en conjunto y los gastos que de ello se derivan.
Si quiere tener una visión más amplia siga el link http://guidance.nice.org.uk
Appraisal title: Aflibercept in combination with irinotecan and fluorouracil-based therapy for treating metastatic colorectal cancer that has progressed following prior oxaliplatin-based chemotherapy
Key conclusion
Aflibercept in combination
with irinotecan and fluorouracil-based therapy is not recommended within its
marketing authorisation for treating metastatic colorectal cancer that is
resistant to or has progressed after an oxaliplatin-containing regimen.
Given the considerable
uncertainty around extrapolating overall survival and its implementation within
the model, and in the absence of other evidence, the Committee was not
satisfied that the estimates from fitting parametric functions to Kaplan–Meier
data or those produced by the model were sufficiently robust to accept that the
3-month life extension criterion is fulfilled.
The Committee concluded
that the most plausible ICER was higher than the normally acceptable maximum
ICER range of £20,000–30,000 per QALY gained
i
En estas diapositivas se muestra el resultado del protocolo VELOSUR, con sus pobrísimos resultados
Current
practice
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Clinical need of patients,
including the availability
of
alternative treatments
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The Committee noted that the current treatment
options for patients with metastatic colorectal cancer are limited, and that
treatment is determined individually. The Committee heard that resecting
tumours surgically may be a treatment option in some patients with metastatic
disease, noting that systemic therapy can make resection possible in some
patients.
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The
technology
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Proposed benefits of the
technology
How innovative is the
technology in its
potential to make
a significant and s
ubstantial impact on
health-related benefits?
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The Committee noted that patients consider biologic
therapies such as aflibercept to improve quality of life compared with
chemotherapy.
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The Committee heard that, because the overall survival curves continued
to separate for both patients who had or had not stopped treatment, the
survival curves might reflect a disease modifying effect in that aflibercept
might have altered the natural course of the disease whereby, despite the
disease progressing, patients lived longer even after treatment stopped. The
Committee agreed that there was no robust evidence to make firm conclusions
about the likely cause of the different shapes of the overall survival and
progression-free survival curves.
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The Committee acknowledged that aflibercept represented a novel
recombinant fusion protein. However, the Committee concluded that all
benefits of a substantial nature relating to treatment with aflibercept plus
FOLFIRI had been captured in the QALY calculation.
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What is the position of the
treatment in
the pathway
of care for the condition?
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Aflibercept in combination with FOLFIRI has a
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Adverse
reactions
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The Committee concluded that treatment with aflibercept plus FOLFIRI
was associated with a considerable burden of adverse effects, but that, being
a new treatment, less is known about its adverse effects profile than for
other available treatments.
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Evidence
for clinical effectiveness
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Availability, nature and
quality of evidence
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The Committee noted that the evidence on the clinical effectiveness of
aflibercept was derived from the VELOUR trial. The Committee agreed that the
VELOUR trial was of good quality and directly relevant to the decision
problem. However, the Committee would have liked the manufacturer to have
collected and presented trial data relating to health-related quality of
life, and would have liked the manufacturer to have followed and presented
event data for all patients after the end of the trial as defined. The
Committee concluded that the results from the VELOUR trial are generalisable
to
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Relevance to general clinical
practice in the NHS
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No specific Committee considerations on the
relevance to general clinical practice in the NHS.
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Uncertainties generated
by the
evidence
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The Committee noted that, to estimate aflibercept's
mean survival benefit of 4.7 months, the manufacturer extrapolated the
survival curves from a trial with a median follow-up of just under
2 years up to 15 years. Although the Committee agreed that a small
proportion of patients, with as yet undefined characteristics, appeared to
derive greater benefit from aflibercept than most patients in the trial, it
considered that the manufacturer's extrapolation of overall survival based on
a population with a very few patients at risk of dying after 30 months'
follow-up over a further 12 years was associated with great uncertainty.
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The Committee was aware that the manufacturer
estimated the mean survival benefit of 4.7 months by fitting the
log-logistic function to the observed data, and extrapolating the survival
curves over 15 years. The Committee noted that the estimates using other
parametric functions ranged from 3.0–5.3 months. The Committee was aware
that a longer than 5-year survival for patients with metastatic colorectal
cancer is very unusual. Having considered the estimates obtained using
different parametric functions and extrapolation periods, the Committee was
concerned that the log-logistic function had a very 'heavy tail', and that
this is likely to have overestimated the survival benefit of aflibercept. The
Committee was also concerned that the manufacturer did not characterise the
uncertainty around any of the estimates. The Committee concluded that
extrapolating overall survival with the log-logistic function over
15 years did not provide a plausible mean overall survival benefit.
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Are there any clinically
relevant subgroups for
which there
is evidence
of differential effectiveness?
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The Committee agreed that there was no evidence to
suggest that aflibercept would be more effective in patients with liver
metastases only than in patients with metastases confined to other organs.
The Committee was not presented with evidence about rates of resection and
cure with aflibercept in the subgroup of patients with liver metastases only.
The Committee therefore agreed that aflibercept cannot be considered an
effective treatment option to make liver metastases resectable, concluding
that this subgroup should not be considered further.
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The Committee heard from the clinical specialists
that, in clinical practice, patients who had received oxaliplatin-based
therapy in the adjuvant setting and relapsed within the following
6 months would not be treated differently to the overall trial
population. In addition, the Committee noted that the analysis for this
subgroup was planned after the trial results had been compiled (post hoc),
and that the test for interaction did not show that the treatment effect in
this subgroup differed from the effect in the rest of the trial population.
The Committee therefore concluded that it did not need to consider further
the subgroup that excluded patients whose disease had relapsed 6 months
or less after starting oxaliplatin-based adjuvant therapy.
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Estimate of the size of the
clinical
effectiveness
including strength of
supporting evidence
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The Committee agreed that the difference in median
overall survival of 1.44 months reflects a statistically significant but
clinically small benefit.
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The Committee considered that the manufacturer's
extrapolation of overall survival from a population with very few patients at
risk of dying after 30 months' follow-up, over a further 12 years,
was associated with great uncertainty.
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Availability and nature
of evidence
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The Committee concluded that overall the
manufacturer's model adhered to the NICE reference case for assessing cost
effectiveness.
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Uncertainties around and
plausibility of assumptions
and inputs in the economic
model
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The Committee considered that the manufacturer's
assumption that the treatment benefit continues beyond the trial period and
until 15 years is highly uncertain given that most patients had died
during the 3-year follow-up period of the trial. The Committee considered
that the ERG's analysis that allows the hazard ratio to become greater
than 1.0 could be considered implausible. The Committee agreed that the
ERG's scenario, which assumes equal risk of death for all patients beyond the
trial period (hazard ratio equals 1.0), represents an acceptable
compromise between the 2 extremes of assuming continuing treatment
effect (manufacturer's base case) and allowing for a reversed treatment
effect (ERG's second scenario). The Committee noted that, in response to consultation,
the manufacturer implemented a new scenario in its revised base case in which
the hazard ratio begins to taper to 1.0 36 months after starting
treatment, over a 12‑month period. The Committee agreed that as a means to
extrapolate overall survival both its preferred scenario (that is, the ERG's
first scenario) and the manufacturer's new scenario were associated with some
degree of uncertainty. In the absence of further evidence to validate the
manufacturer's new approach, the Committee maintained its preference for the
ERG's first scenario.
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Incorporation of health-related
quality-of-life benefits and
utility values
Have any potential significant
and
substantial health-related
benefits been identified that
were not
included in the
economic model,
and how have
they been
considered?
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The Committee was aware that the manufacturer got
the utility value for the stable-disease state from the 'mCRC utilities
study' and revised it after consultation to a value derived from the ASQoP.
The Committee noted that the ERG preferred another value from the ASQoP study
for the stable-disease state. The Committee concluded that either value could
be considered appropriate.
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The Committee considered that the utility value
chosen by the manufacturer for the progressed-disease state did not reflect
the entire duration of progressed disease but only early progressed disease,
and so was likely to be an overestimate. The Committee was aware that, in its
base case, the ERG used an alternative lower value of 0.60, which had been
used in NICE technology appraisal guidance 118. The Committee agreed that no utility values for
progressed disease were universally accepted as valid, but that it would be
important that the utility value reflected the entire progressed-disease
state. The Committee also agreed that adjusting the utility values for age
was appropriate. The Committee concluded that the most plausible utility
value for the progressed-disease health state would lie between the
manufacturer's and the ERG's estimate.
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The Committee concluded that all benefits of a
substantial nature relating to treatment with aflibercept plus FOLFIRI had
been captured in the QALY calculation.
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Are there specific groups
of people for
whom the
technology is
particularly cost effective?
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Having considered the clinical evidence presented by
the manufacturer for the 2 subgroups, the Committee concluded that it
did not need to consider the cost effectiveness of the technology for any of
the subgroups.
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What are the key drivers
of cost
effectiveness?
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The Committee considered the robustness of the mean
overall survival benefit, obtained using the log-logistic function, of
3 months (5 years extrapolation time), 4.7 months
(15 years extrapolation time) and 6.6 months (without truncating
the survival curves.
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The Committee was aware that the longer the time
horizon, the greater the influence of the 'tails' of the extrapolation
curves, which define the difference in mean overall survival between the
treatment arms, and to which the model is highly sensitive.
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The Committee noted that, because approximately
three-quarters of the QALY gain in the model was accrued after disease
progression, the model is highly sensitive to utility value for the
progressed-disease state in the model.
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Most likely cost-
effectiveness estimate
(given as an ICER)
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The Committee noted that the manufacturer's ICER
closest to its preferred assumptions was £44,000 per QALY gained (for
age 60), but would increase for the higher age bracket, if the mean
value was used from the manufacturer's survey of clinical oncologists after
removing the outlier and if an extrapolation function with a less heavy tail
had been used. Because the manufacturer's ICERs incorporated a utility value
for progressed disease deemed by the Committee to be high, the Committee
considered the ICER produced by the ERG using the Committee's preferred
assumptions, but which used a utility value for progressed disease of 0.6.
The Committee noted that this was approximately £51,000 per QALY gained and
would be higher if an extrapolation function with a less heavy tail had been
used. The Committee therefore concluded that the most plausible ICER was
higher than the normally acceptable maximum ICER range of £20,000–30,000 per
QALY gained.
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Additional factors taken
into account
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Patient
access schemes
(PPRS)
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The manufacturer of aflibercept (Sanofi) has agreed
a patient access scheme with the Department of Health that makes aflibercept
available with a discount. The
size of the discount is commercial in confidence.
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End-of-life
considerations
|
The Committee agreed that, given the considerable
uncertainty around extrapolating overall survival and its implementation
within the model, it is important to take into account what has actually been
observed in the trial and, in the absence of other evidence, the Committee
was not satisfied that the estimates from fitting parametric functions to
Kaplan–Meier data or those produced by the model were sufficiently robust to
accept that the 3-month life extension criterion is fulfilled. The Committee
therefore concluded that aflibercept did not meet the criteria for an
end-of-life therapy as defined by NICE.
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Equalities
considerations and
social value judgements
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No equality issues relevant to the Committee's recommendations were
raised.
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Additional factors taken
into account
|
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Patient
access schemes
(PPRS)
|
The manufacturer of aflibercept (Sanofi) has agreed
a patient access scheme with the Department of Health that makes aflibercept
available with a discount. The
size of the discount is commercial in confidence.
|
End-of-life
considerations
|
The Committee agreed that, given the considerable
uncertainty around extrapolating overall survival and its implementation
within the model, it is important to take into account what has actually been
observed in the trial and, in the absence of other evidence, the Committee
was not satisfied that the estimates from fitting parametric functions to
Kaplan–Meier data or those produced by the model were sufficiently robust to
accept that the 3-month life extension criterion is fulfilled. The Committee
therefore concluded that aflibercept did not meet the criteria for an
end-of-life therapy as defined by NICE.
|
Equalities
considerations and
social value judgements
|
No equality issues relevant to the Committee's recommendations were
raised.
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En estas diapositivas se muestra el resultado del protocolo VELOSUR, con sus pobrísimos resultados
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