Datos personales

sábado, 3 de mayo de 2014

OTRA MIRADA DE LAS TERAPIAS DIRIGIDAS EN CÁNCER COLORRECTAL METASTÁTICO: AFLIBERCEPT

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


Current practice
Clinical need of patients,
including the availability
 of alternative treatments
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.
The technology
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?
The Committee noted that patients consider biologic therapies such as aflibercept to improve quality of life compared with chemotherapy.
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.
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.
What is the position of the
 treatment in the pathway
of care for the condition?
Aflibercept in combination with FOLFIRI has a UK marketing authorisation 'for the treatment of adults with metastatic colorectal cancer that is resistant to or has progressed after an oxaliplatin-containing regimen'.
Adverse reactions
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.
Evidence for clinical effectiveness
Availability, nature and
quality of evidence
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 UK clinical practice.
Relevance to general clinical
practice in the NHS
No specific Committee considerations on the relevance to general clinical practice in the NHS.
Uncertainties generated
 by the evidence
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.
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.
Are there any clinically
relevant subgroups for
 which there is evidence
of differential effectiveness?
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.
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.
Estimate of the size of the
 clinical effectiveness
including strength of
supporting evidence
The Committee agreed that the difference in median overall survival of 1.44 months reflects a statistically significant but clinically small benefit.
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.

Availability and nature
of evidence
The Committee concluded that overall the manufacturer's model adhered to the NICE reference case for assessing cost effectiveness.
Uncertainties around and
plausibility of assumptions
and inputs in the economic
 model
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.
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?
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.
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.
The Committee concluded that all benefits of a substantial nature relating to treatment with aflibercept plus FOLFIRI had been captured in the QALY calculation.
Are there specific groups
 of people for whom the
 technology is particularly cost effective?
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.
What are the key drivers
 of cost effectiveness?
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.
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.
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.
Most likely cost-
effectiveness estimate
(given as an ICER)
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.
Additional factors taken into account
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.
i
Additional factors taken into account
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.

En estas diapositivas se muestra el resultado del protocolo VELOSUR, con sus pobrísimos resultados


No hay comentarios:

Publicar un comentario