1 Appraisal Committee's preliminary recommendations

1.1  Abiraterone in combination with prednisone or prednisolone is not recommended for the treatment of castration-resistant metastatic prostate cancer that has progressed on or after a docetaxel-containing regimen.

1.2 People currently receiving abiraterone in combination with prednisone or prednisolone for the treatment of castration-resistant prostate cancer that has progressed on or after a docetaxel-containing regimen should have the option to continue treatment until they and their clinician consider it appropriate to stop.

2 The technology

2.1 Abiraterone acetate (Zytiga, Janssen) is a selective inhibitor of androgen biosynthesis which is taken orally. It irreversibly blocks cytochrome P17 (an enzyme involved in the production of testosterone), thereby stopping androgen synthesis in the adrenals, prostate and the tumour. Abiraterone has a UK marketing authorisation for use ‘with prednisone or prednisolone for the treatment of metastatic castration resistant prostate cancer in adult men whose disease has progressed on or after a docetaxel-based chemotherapy regimen’. For prostate cancer that was previously considered ‘hormone refractory,’ the term ‘castration resistant’ is now used. This is because the cancer still depends on hormones to activate androgen receptors, but no longer responds to androgen-reducing treatments.

2.2 The summary of product characteristics lists the following common adverse reactions to abiraterone: peripheral oedema, hypokalaemia, hypertension and urinary tract infection. For full details of side effects and contraindications, see the summary of product characteristics.

2.3 The cost of abiraterone is £2930 for 120 tablets (excluding VAT; MIMS, December 2011). Abiraterone is administered as a single dose of 1 g per day, taken as four 250-mg tablets. The manufacturer of abiraterone (Janssen) The manufacturer of abiraterone has agreed a patient access scheme with the Department of Health. This involves a single confidential discount applied to the list price of abiraterone. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS. The manufacturer has agreed that the patient access scheme will remain in place until any review of this NICE technology appraisal guidance is published.

3 The manufacturer's submission

The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of abiraterone and a review of this submission by the Evidence Review Group (ERG; appendix B). The decision problem addressed by the manufacturer considered whether treatment with abiraterone plus prednisolone was clinically effective compared with mitoxantrone (with or without prednisolone) or best supportive care for castration-resistant metastatic prostate cancer previously treated with a docetaxel-containing regimen and whether abiraterone treatment reflected a cost-effective use of NHS resources.

3.1 The manufacturer carried out a systematic literature search to identify all relevant trials and studies of abiraterone and potential comparators for the treatment of castration-resistant metastatic prostate cancer. The manufacturer identified four studies of abiraterone following previous chemotherapy: one randomised controlled trial (COU-AA-301) and three single arm trials (COU-AA-304, COU-AA-003, COU-AA-BMA). Four randomised controlled trials comparing mitoxantrone plus prednisolone with other treatments were also identified by the manufacturer, but there were no other trials to link this evidence to the COU-AA-301 trial and enable an indirect comparison of abiraterone and mitoxantrone. The manufacturer’s clinical-effectiveness evidence for abiraterone was derived solely from the COU-AA-301 trial (a phase III, placebo-controlled, randomised, double-blind, multicentre trial carried out across 130 sites in 13 countries, including the UK). In this trial, patients whose disease had progressed on or after docetaxel therapy and who had an Eastern Cooperative Oncology Group (ECOG) performance score of 0–2 were treated with either abiraterone (four 250-mg tablets) in combination with prednisone or prednisolone (n = 797) or with placebo (four tablets) in combination with prednisone or prednisolone (n = 398). Patients in both groups continued treatment until disease progression was documented on the basis of the prostate-specific antigen (PSA), radiographic imaging, and clinical findings. Study follow-up was up to 60 months.

3.2 The baseline demographics and disease characteristics were similar between the two treatment groups in the COU-AA-301 trial: 93% of patients were white, the median age was 69 years and 28% of patients were 75 years or older. Among patients randomised to abiraterone plus prednisone or prednisolone (hereafter the abiraterone group), 70% had previously received docetaxel chemotherapy only (designated as the ‘one prior chemotherapy’ subgroup), compared with 69% of patients randomised to placebo plus prednisone or prednisolone (hereafter the prednisolone group). The proportion of patients with an ECOG performance score of 2 (reflecting worse performance than a score of 0 or 1) was 10% and 11% in the abiraterone and prednisolone groups respectively. The majority of patients in both treatment groups (approximately 70%) had radiographic progression with or without PSA progression at baseline; 89% of patients in the abiraterone group and 90% of patients in the prednisolone group had bone metastasis.

3.3 The primary outcome of the COU-AA-301 trial was overall survival, defined as the time from randomisation to death from any cause. A ‘primary’ analysis was conducted after 552 deaths (12.8 months median follow-up) for the whole (intention-to-treat) population. This was on the basis of a planned interim analysis after 534 deaths (67% of the 797 deaths at the planned final analysis). In the primary analysis, median survival was statistically significantly longer in the abiraterone group than the prednisolone group (14.8 months compared with 10.9 months, hazard ratio [HR] 0.65, 95% confidence interval [CI] 0.54 to 0.77). An ‘updated’ analysis was conducted after 775 deaths (20.2 months median follow-up) for the whole population and the ‘one prior chemotherapy’ subgroup. For the whole population, median survival continued to be statistically significantly longer in the abiraterone group than the prednisolone group (15.8 months compared with 11.2 months, HR 0.74, 95% CI 0.64 to 0.86). Subgroups with an ECOG performance score of 0–1 or 2 and subgroups who had received one or more prior chemotherapy regimens were explored by the manufacturer. For the ‘one prior chemotherapy’ subgroup, median survival was also statistically significantly longer in the abiraterone group than the prednisolone group (17.0 months compared with 11.7 months, HR 0.71, 95% CI 0.60 to 0.86). The manufacturer stated that statistical testing showed that the relative overall survival benefit of abiraterone was not statistically significantly different between the ‘one prior chemotherapy’ subgroup and the subgroup with more than one prior chemotherapy.

3.4 Two secondary outcomes in the COU-AA-301 trial were radiographic progression-free survival (time with no radiographically documented disease progression) and ‘modified’ progression-free survival (based on time to death or one of the following: PSA progression, radiographic progression, increase in glucocorticoid use, pain progression, a skeletal-related event, or initiation of a new cancer therapy). Treatment with abiraterone statistically significantly decreased the risk of radiographically documented disease progression or death compared with prednisolone in the primary analysis (HR 0.67, 95% CI 0.59 to 0.78, p < 0.0001). A significantly decreased risk was also observed in the updated analysis. The median radiographic progression-free survival was identical in the primary and updated analyses: 171 days in the abiraterone group and 110 days in the prednisolone group. Treatment with abiraterone also significantly decreased the risk of disease progression based on the criteria for ‘modified’ progression-free survival compared with prednisolone in the primary analysis (HR 0.63, 95% CI 0.55 to 0.72, p < 0.0001). A significantly decreased risk was also observed in the updated analysis (results provided as academic in confidence).

3.5 The manufacturer indicated that expert opinion had suggested that the endpoints of ‘modified’ progression-free survival and radiographic progression-free survival, as defined in the COU-AA-301 trial, did not necessarily represent the time at which trial participants stopped the study drug because of disease progression. On this basis, the manufacturer argued that treatment discontinuation was the most appropriate proxy for progression-free survival in the economic model. The manufacturer presented rates of time to discontinuation for both the whole population (primary and updated analyses) and the ‘one prior chemotherapy’ subgroup (updated analysis only). For the whole population, the median time to treatment discontinuation for the abiraterone group was significantly longer than in the prednisolone group in the primary analysis (8 months compared with 4 months), which was similar  in the updated analysis. For the ‘one prior chemotherapy’ group, the median time to treatment discontinuation was also significantly longer for the abiraterone group than the prednisolone group and the difference between the two groups was slightly more than observed for the whole population (results provided as academic in confidence).

3.6 Additional outcomes in the COU-AA-301 trial included PSA response rates, defined as the proportion of patients with a 50% or greater decrease in PSA confirmed by a second measurement at least 4 weeks later, and objective tumour response rates, defined according to Response Evaluation Criteria in Solid Tumours (RECIST). In the primary analysis for the whole population, confirmed PSA response was statistically significantly greater in the abiraterone group than in the prednisolone group (29.1% compared with 5.5%, p < 0.0001).

3.7 The most common adverse reactions (occurring in ≥ 10% of participants in COU-AA-301) reported in both treatment groups were anaemia, vomiting, hot flushes, anorexia, pain in extremities, diarrhoea, musculoskeletal pain, asthenia, dyspnoea, headache, urinary tract infection, weight loss and muscular weakness. For the primary analysis, the most frequently reported grade 3 or 4 adverse reactions in the abiraterone and prednisolone groups were fatigue, anaemia, back pain and bone pain. Adverse reactions relating to mineralocorticoid excess (hypertension, hypokalaemia and oedema), cardiac disorders and hepatotoxicity were more frequent in the abiraterone group than the prednisolone group (55% compared with 44%). Cardiac disorders (primarily grade 1 or 2) were more commonly reported in the abiraterone group than in the prednisolone group (13% compared with 11%, p = 0.14). Adverse reactions resulting in death or the need to discontinue study treatment were lower in the abiraterone group.

3.8 The manufacturer presented updated analyses for three health-related quality of life measures for which data were collected in the COU-AA-301 trial: the brief pain inventory short form (BPI-SF), the brief fatigue inventory short form (BFI-SF), and the functional assessment of cancer therapy-prostate (FACT-P). Neither the EQ-5D, nor any other utility measure was collected in the COU-AA-301 trial. Analyses indicated that a statistically significantly greater proportion of patients in the abiraterone group compared with the prednisolone group experienced an improvement for all three outcome measures (p < 0.001). The manufacturer reported that the proportion of patients who had progression or decline in the outcome measures related to pain, functionality and fatigue did not significantly differ between the two treatment groups. However, patients in the abiraterone group experienced statistically significantly longer time to progression for all three outcome measures compared with the prednisolone group (p < 0.05). The manufacturer concluded that evidence from the COU-AA-301 trial suggests that patients receiving abiraterone are more likely to experience less pain and fatigue, improved functional status, and have a longer time before their pain, functional status and fatigue worsens.

3.9 The manufacturer submitted an economic model to compare the cost effectiveness of the three treatments: abiraterone (plus prednisolone, hereafter abiraterone), prednisolone alone, and mitoxantrone plus prednisolone, (hereafter mitoxantrone). The manufacturer developed a survival-based decision model with three health states: pre-progression, post-progression and dead. People with castration-resistant metastatic prostate cancer were assumed to enter the model in the pre-progression state having already received treatment with docetaxel-based chemotherapy. The manufacturer assumed that people who experienced disease progression would enter the post-progression state. The manufacturer assumed that people who received abiraterone would not take it after their disease had progressed, but would continue taking prednisolone or prednisone. The model assumed that patients in the mitoxantrone and prednisolone treatment groups would continue taking prednisolone or prednisone until death. For the analysis of abiraterone compared with mitoxantrone, the model further assumed a maximum duration of 30 weeks (median duration of 12 weeks) for mitoxantrone treatment in the base-case analysis.

3.10 The manufacturer’s preferred population for its base-case analysis was comprised of people who had received ‘one prior chemotherapy’ only. The number of people remaining in each health state after each cycle of the model (3 weeks, based on the dosing cycle of mitoxantrone) was calculated directly from the overall survival and progression-free survival curves from the ‘one prior chemotherapy’ subgroup of the COU-AA-301 trial. Time in the post-progression state was calculated as the difference between overall survival and progression-free survival. The model used a lifetime horizon of 10 years. The analysis took an NHS and personal social services perspective and discounted costs and benefits at 3.5%.

3.11 The key clinical effectiveness parameters in the model were progression-free and overall survival, which, for the base-case analysis, the manufacturer derived from data from the updated analysis for the ‘one prior chemotherapy’ subgroup of the COU-AA-301 trial. The manufacturer assumed in the base-case analysis that progression-free survival and overall survival did not differ between treatment with mitoxantrone and treatment with prednisolone or prednisone. The manufacturer argued that this assumption was justified because available evidence suggests that mitoxantrone compared with corticosteroids does not extend survival in people without prior chemotherapy, and therefore it would not be expected to extend survival in the people who had received chemotherapy. In the base-case analysis, the manufacturer used data from the abiraterone arm of the COU-AA-301 trial to model overall survival for abiraterone, and data from the prednisolone arm to model overall survival for mitoxantrone or prednisolone.. The manufacturer used data from Kaplan–Meier curves up to the point at which 10% of patients remained in the trial. After this, the manufacturer extrapolated the overall survival curves assuming a constant hazard rate (exponential function).

3.12 In the base case analysis, the manufacturer modelled progression-free survival for patients taking abiraterone who had only one prior chemotherapy. The model assumed that patients moved from the pre-progression to the post-progression health state when they discontinued abiraterone treatment. Treatment discontinuation rates were based on data from the COU-AA-301 trial for patients who had only one prior chemotherapy and were used as a proxy for progression-free survival (see section 3.5). To estimate time spent in the pre-progression state, the manufacturer took Kaplan–Meier (time to treatment discontinuation) survival data directly from the ‘one-prior chemotherapy’ subgroup of the COU-AA-301 trial up to the point at which 5% of participants remained at risk. Beyond this 5% cut-off, the manufacturer extrapolated survival curves assuming a constant hazard rate. The manufacturer used data from Kaplan–Meier curves for patients in the prednisolone group who had received one prior chemotherapy to model progression-free survival for patients taking mitoxantrone or prednisolone. No further extrapolation was applied because just over 2% of patients were still on treatment.

3.13 In the base case analysis, the manufacturer also modelled overall survival based on Kaplan-Meier survival curves for the ‘one prior chemotherapy’ subgroup from the COU-AA-301 trial. As for progression-free survival, the manufacturer extrapolated overall survival using a constant hazard but, because of greater censoring, chose a cut-off of 10%, which was applied to all three treatment groups.

3.14 In the model, the key differences between the mitoxantrone group and the prednisolone group were the treatment durations (maximum duration of mitoxantrone treatment was 30 weeks) and costs (mitoxantrone was associated with more adverse reactions and therefore higher costs). The 30-week maximum duration of mitoxantrone treatment (ten 3-weekly cycles) was taken from the TROPIC trial, which compared cabazitaxel plus prednisolone with mitoxantrone plus prednisolone in patients with metastatic prostate cancer who had received docetaxel chemotherapy. Mitoxantrone was associated with less pain and improved health-related quality of life compared with prednisolone, both of which the manufacturer assumed to be equal to that for abiraterone. However, because more treatment-related adverse reactions with mitoxantrone were observed in the TROPIC trial, mitoxantrone was also associated with a loss in health-related quality of life compared with abiraterone.

3.15 The manufacturer undertook a two-stage analysis to convert FACT-P data from the COU-AA-301 trial into EQ-5D utility values. In the first stage, the manufacturer analysed data from a manufacturer-sponsored cross-sectional study of 291 patients with castration-resistant metastatic prostate cancer who completed FACT-P and EQ-5D questionnaires across five European countries (including the UK). The data were used to develop an algorithm to map data from FACT-P to EQ-5D using an ordinary least squares (OLS) regression model and the UK EQ-5D tariff. In the second stage, the manufacturer converted FACT-P data from patients in both treatment groups in the COU-AA-301 trial who had only one prior chemotherapy regimen to EQ-5D utility values and regression analysis was then applied to derive a treatment effect. The manufacturer did not explicitly model adverse reactions, but instead assumed that any differences in adverse reactions between patients taking abiraterone or prednisolone were reflected in the overall utility values estimated from the FACT-P mapping algorithm.

3.16 As a result of these analyses, the manufacturer applied separate pre-progression (baseline) utility values for both treatment groups (utility values provided as academic in confidence). The manufacturer also applied the utility value for abiraterone to the mitoxantrone group in the base-case analysis. In order to estimate the impact of grade 3 or 4 adverse reactions to mitoxantrone on the utility of the pre-progression state, the manufacturer conducted a separate, parallel regression, which estimated an average utility decrement for the ‘one prior chemotherapy’ subgroup. The manufacturer estimated that, based on the average number of grade 3 or 4 adverse reactions reported for abiraterone (from the COU-AA-301 trial) and mitoxantrone (from the TROPIC trial), mitoxantrone resulted in a net increase of 32% in grade 3 or 4 adverse reactions compared with abiraterone. This resulted in a small utility decrement for mitoxantrone compared with abiraterone (utility values provided as academic in confidence).

3.17 The manufacturer noted that the COU-AA-301 trial did not collect FACT-P data beyond the point of disease progression (treatment discontinuation). Based on a systematic literature review, the manufacturer identified a study that estimated EQ-5D utility values in the year before death in Swedish men with prostate cancer (metastatic or non-metastatic) (Sandblom et al. 2004). In this study, utility values ranged from 0.58 in men with 8–12 months to live to 0.46 in those with less than 4 months to live. Based on the average utility observed for men in the last 8 months of life, the manufacturer used a utility value of 0.50 for the post-progression state in the economic model. This post-progression utility value was applied for all three treatment groups.

3.18 The manufacturer included the costs of drug treatment as costs of drug acquisition, administration and monitoring. Under the terms of the patient access scheme approved by the Department of Health, the cost of a 3-week cycle of abiraterone, based on a daily dose of 1 g, is commercial in confidence and not reported here. Dosing of mitoxantrone is determined by body surface area. The manufacturer assumed a value of 2.02 m², based on the average body surface area observed in the TROPIC trial. Based on a cost of £100 per 20-mg vial, and assuming a patient needs two vials, the cost of mitoxantrone used in the model was £200 per 3-week cycle. The model also assumed that a person receiving treatment with mitoxantrone would need one outpatient visit per 3-week cycle, resulting in a total cost of £448.45 per 3-week cycle. The cost of prednisolone was £1.03 for a 28-tablet (5 mg) pack (£1.55 per 3-week cycle at 10 mg daily). Because patients were taking prednisolone with abiraterone and with mitoxantrone, this cost was included for all three treatments and was assumed to continue after treatment with abiraterone and with mitoxantrone was discontinued until death. The costs of mitoxantrone and prednisolone were taken from the ‘British national formulary’ (BNF; edition 61).

3.19 The model also included the costs of scheduled follow-up consisting of clinical visits, diagnostic imaging and clinical laboratory tests to monitor the status of the disease. To estimate scheduled UK medical resource utilisation in each treatment group, the manufacturer conducted a clinical consensus panel meeting, consisting of five oncologists and three oncology nurse specialists. Based on statistical analysis of data from the COU-AA-301 trial, the manufacturer estimated that unscheduled medical resource utilisation (because of unplanned clinical events) would be similar for patients whether taking abiraterone or prednisolone alone. Therefore, the manufacturer applied a one-off fixed cost of unplanned, event-related resource utilisation in the pre- and post-progression states to patients taking abiraterone or prednisolone alone. For patients receiving mitoxantrone, the manufacturer assigned the extra costs of treating grade 3 or 4 adverse reactions based on data from the TROPIC trial. The costs of other drugs (including bisphosphonates in the pre- and post-progression states for people taking any of the three treatments, and granulocyte colony-stimulating factor [G-CSF] to treat febrile neutropenia in the abiraterone and mitoxantrone groups) were also included in the model. Based on results from the UK subpopulation of the COU-AA-301 trial, in which a small proportion of patients received subsequent chemotherapy treatments, including taxanes and anthracenediones, the manufacturer assumed that a proportion of people in each treatment group would receive three cycles of cabazitaxel (currently being appraised by NICE) in the post-progression state. The manufacturer also estimated resource utilisation and costs for end-of-life care based on clinical expert opinion. These costs were applied for the last 3 months of life for patients taking any of the three treatment regimens.

3.20 The manufacturer’s base-case deterministic cost-effectiveness results for the ‘one prior chemotherapy’ subgroup showed that mitoxantrone resulted in higher costs and lower quality-adjusted life years (QALYs) than a combination of abiraterone and predinisolone alone (extendedly dominated). The comparison between abiraterone and prednisolone alone resulted in an incremental cost-effectiveness ratio (ICER) of £52,851 per QALY gained (incremental costs and incremental QALYs provided as commercial in confidence). The manufacturer’s base-case probabilistic cost-effectiveness results were similar. The manufacturer’s base-case deterministic cost-effectiveness results for the whole trial population showed that mitoxantrone was extendedly dominated by abiraterone and prednisolone alone whereas the comparison between abiraterone plus prednisolone and placebo plus prednisolone resulted in an ICER of £63,233 per QALY gained (incremental costs and incremental QALYs provided as commercial in confidence).

3.21 The manufacturer conducted a number of one-way sensitivity analyses on various model parameters which included: altering the time horizon from 10 years to 4, 6, or 8 years, varying the discount rates for costs and benefits from 3.5% each to 0% and 6%, using a Weibull instead of an exponential parametric approach to extrapolate survival beyond the cut-off point of the Kaplan–Meier curve for both progression-free and overall survival, using alternative estimates of utility for pre- and post-progression health states and for the effect on utility of treatment with abiraterone, and varying a number of cost input parameters (±50%). The results of these one-way sensitivity analyses indicated that the ICERs were fairly insensitive to changes in most, but not all, of the input parameters. Decreasing the baseline utility value for the pre-progression state to 0.538 increased the ICER significantly, resulting in an ICER for treatment with abiraterone compared with prednisolone of £77,000 per QALY gained. In one scenario analysis, the manufacturer assumed that patients taking mitoxantrone remained in the pre-progression state for longer than patients taking prednisolone only (HR 0.77). This scenario resulted in an ICER of £21,038 per QALY gained for mitoxantrone compared with prednisolone and an ICER of £62,843 per QALY gained for abiraterone compared with mitoxantrone. Results of the probabilistic sensitivity analysis showed that prednisolone had the highest probability (100%) of being cost effective at a level of £20,000 to £30,000 per QALY gained, whereas abiraterone had the highest probability of being cost effective at over £50,000 per QALY gained.  

3.22 The ERG was satisfied with the methodological quality of the COU-AA-301 trial and considered that it provided persuasive evidence that abiraterone offers a survival advantage in patients with castration-resistant metastatic prostate cancer. However, the ERG stated that the ‘one prior chemotherapy’ subgroup differed from the COU-AA-301 trial population and, because it was smaller, it had reduced statistical power for comparison of outcomes between the treatment arms. The ERG commented that the manufacturer submitted a relatively straightforward economic model comparing the relevant comparators following docetaxel chemotherapy, and closely adhered to the NICE reference case requirements for economic analysis.

3.23 The ERG commented that the factors with the most influence on the cost effectiveness of abiraterone compared with prednisolone and mitoxantrone were the differences in the EQ-5D utility values attached to the pre- and post-progression health states for all three treatments, which the manufacturer had derived from different sources. The ERG noted that the manufacturer’s mapping function, which was developed and used to determine pre-progression utility values, had yet to appear in a peer-reviewed publication. The ERG noted that the pre-progression utility value for patients taking abiraterone, which was estimated from a function mapping FACT-P to EQ-5D, was similar to or higher than EQ-5D utility values for men of similar age taken from a survey of the general UK population living in the community (Kind et al. 1998). This survey reported average EQ-5D visual analogue scores of between 0.800 and 0.750 for men aged between 60 and 79 years. The ERG’s clinical advisers suggested that, because the COU-AA-301 trial may have been oversubscribed, the population selected could have been fitter than generally seen in clinical practice.

3.24 The ERG noted that because most patients in the cross-sectional study used to derive the mapping function were receiving chemotherapy, both their FACT-P scores and EQ-5D utilities would likely be lower than patients in the COU-AA-301 trial. The ERG argued that this could have resulted in the FACT-P mapping function being used to convert FACT-P values outside the reliable range of the mapping function, which would increase the uncertainty around the manufacturer’s derived EQ-5D utility values.   The ERG noted that the manufacturer derived the mapping function from a restricted set of patients who provided FACT-P scores both at baseline and over the course of the trial, but that over time, a declining proportion of trial participants remaining on treatment provided FACT-P scores. The ERG further noted that the manufacturer’s regression analysis is based on changes from baseline scores rather than absolute values and that the baseline scores among those reporting FACT-P scores subsequent to baseline may have been higher in the prednisolone group than in the abiraterone group. The ERG suggested that patients receiving prednisolone who reported FACT-P scores subsequent to baseline may have shown a smaller change in their scores compared with patients receiving abiraterone because they had less severe disease at baseline.

3.25 The ERG had some concerns about the manufacturer’s approach to the regression analysis used to estimate separate pre-progression utility values for treatment with abiraterone and prednisolone. The ERG noted that the utility values used in the manufacturer’s model implied that utility dropped when a patient discontinued treatment (disease progressed) but that a larger utility decrement for discontinuing abiraterone treatment was assumed than for discontinuing prednisolone. The ERG considered this pre-progression utility value to be an overestimate, which, by increasing the utility decrement when moving from the pre-progression to post progression state, would exaggerate the benefit of remaining on abiraterone treatment. The ERG also noted that the utility decrement applied when moving from stable to progressive disease in the ongoing NICE appraisal of cabazitaxel was lower than that used in this appraisal.

3.26 The ERG explored the manufacturer’s methods for extrapolating overall survival and suggested that the manufacturer’s decision to extrapolate beyond a cut-off of 10% of trial participants at-risk was arbitrary. However, the ERG was aware that when the manufacturer applied a cut-off of 5% in sensitivity analyses there was little impact on the ICERs for abiraterone compared with prednisolone.  In contrast, the ERG’s exploratory analyses using cut-offs ranging from 0% to 20% showed that the cut-off of 10% used by the manufacturer resulted in a relatively low ICER compared with other cut-off points. The ERG noted that when extrapolating progression-free survival, the manufacturer chose different cut-off points (or none at all) depending on the treatment. The ERG noted that when data from Kaplan–Meier survival plots of the prednisolone group were used in the economic model, 2% of patients remained in the pre-progression state, which may have slightly underestimated progression-free survival for the mitoxantrone and prednsiolone treatment groups compared with abiraterone. The ERG also noted that the Kaplan–Meier curve for treatment discontinuation had an unusual shape, with many patients discontinuing treatment over a period of a few weeks at approximately 60 days into treatment. In the ERG’s view, this was unlikely to represent actual disease progression which would be better represented by fitting a parametric distribution.

3.27 The ERG noted that there was uncertainty around the most appropriate functions for extrapolating overall survival and progression-free survival in the manufacturer’s model. The ERG commented that by using patient-level trial data to generate Kaplan–Meier curves for overall survival (up to the cut-off) the manufacturer considered all time points whereas when extrapolating overall survival using a constant hazard, the manufacturer used only two time points (baseline and cut-off hazards). The ERG considered that this approach was less reasonable than applying a parametric distribution to the data representing all time points. The ERG further argued that the use of patient-level Kaplan–Meier data may lead to over-fitting of the model and may be less generalisable to patients outside the COU-AA-301 trial than employing well-fitting parametric distributions.

3.28 The ERG and manufacturer conducted exploratory analyses to assess the impact of fitting alternative parametric functions to data reflecting overall survival and progression-free survival from the COU-AA-301 trial. In response to requests from the ERG for clarification, the manufacturer indicated that the best-fitting parametric distributions were: a Weibull distribution for overall survival in the abiraterone group, a log-normal distribution for overall survival in the prednisolone group, and a log-logistic distribution for progression-free survival for both abiraterone and prednisolone. The ERG and the manufacturer agreed that the log-normal distribution should not be used to extrapolate overall survival because its long tail resulted in patients surviving implausibly long. The ERG also noted that when the log-logistic distribution was fitted to time to treatment discontinuation data, the resulting curve crossed the extrapolated part of the Kaplan–Meier overall survival curve from the manufacturer’s base case so that some patients appeared to remain in the pre-progression state after death, which is clinically implausible. In the ERG’s view, a Weibull distribution should be used to estimate overall and progression-free survival for abiraterone and for prednislone alone at all time points rather than using extrapolated Kaplan–Meier curves. The ERG acknowledged that both approaches were associated with uncertainty. When the ERG fitted the Weibull parametric distribution to overall survival in both the abiraterone and prednisolone groups and an extrapolated (constant hazard) Kaplan–Meier curve for progression-free survival, the ICER for abiraterone compared with prednisolone was £56,339 per QALY gained. When the ERG fitted its preferred distribution, that is, a Weibull parametric distribution to overall survival and progression-free survival in both the abiraterone and prednisolone groups, the ICER for abiraterone compared with prednisolone increased to £58,116 per QALY gained.

3.29 In addition to fitting the Weibull distribution to estimate overall survival and progression-free survival, the ERG made changes to cost and utility parameters in the economic model. The ERG revised administration costs to reflect the costs of oncology outpatient visits and of administering mitoxantrone, and varied the proportion of patients receiving biphosphonates following progression. The ERG corrected the manufacturer’s regression analysis of utility for progression-free survival for patients who take prednisolone only. With these changes, mitoxantrone continued to be extendedly dominated and the ERG’s revised base-case ICER for abiraterone compared with prednisolone was £60,084 per QALY gained.

3.30 The ERG conducted additional one-way sensitivity analyses for its revised base-case analysis. The ERG varied the costs for unplanned medical resource use resulting in ICERs for abiraterone compared with prednisolone ranging from £60,492 to £67,554 per QALY gained. The ERG varied utility estimates (provided as academic in confidence) and this resulted in ICERs for abiraterone compared with prednisolone ranging from £63,281 to £72,469 per QALY gained. When the ERG extrapolated overall survival for prednisolone using the truncated log-normal distribution, the ICER for abiraterone compared with prednisolone was £70,217 per QALY gained. Mitoxantrone continued to be extendedly dominated in all sensitivity analyses.

3.31 Full details of all the evidence are in the manufacturer’s submission and the ERG report, which are available from www.nice.org.uk/guidance/TAXXX

4 Consideration of the evidence

4.1 The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of abiraterone, having considered evidence on the nature of castration-resistant metastatic prostate cancer and the value placed on the benefits of abiraterone by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.

4.2 The Committee discussed the place of abiraterone in the clinical pathway of care for people with castration-resistant metastatic prostate cancer. The Committee noted that the main treatment options for patients whose disease progresses after first-line docetaxel include mitoxantrone, best supportive care, and re-treatment with docetaxel (which is not recommended by current NICE guidance). The Committee heard from clinical specialists that mitoxantrone is used rarely in UK clinical practice because there is little evidence that people who take it live longer, but the commissioning expert informed the Committee that 20%–30% of patients at this stage of the disease are treated with mitoxantrone. The Committee also heard from the clinical specialists that they would be unlikely to offer abiraterone to patients with an ECOG performance score of 2.

4.3 The Committee heard from the patient experts that the most important benefits of abiraterone were extension to life and improved quality of life, including less pain and improved mental and physical health.. The Committee also heard that patient experts believed that adverse reactions to abiraterone treatment were tolerable and comparable to those associated with hormone treatment. The patient experts also commented that another advantage of abiraterone is that patients can take it orally at home.

Clinical effectiveness

4.4 The Committee considered the evidence submitted by the manufacturer on the clinical effectiveness of abiraterone. The Committee agreed with the manufacturer and the ERG that, although mitoxantrone was listed as a comparator in the scope, differences in the COU-AA-301 and the TROPIC trials made it difficult to indirectly compare mitoxantrone with abiraterone. The Committee heard from clinical specialists that participants in the COU-AA-301 trial were likely to be healthier than those who would receive abiraterone treatment in UK clinical practice.  

4.5 The Committee considered the different ways that progression-free survival was defined in the COU-AA-301 trial: radiographic evidence of progression-free survival, ‘modified’ progression-free survival, and time to treatment discontinuation. The Committee noted that determining progression-free survival from radiographic evidence was difficult because patients entered the study with metastatic disease and they could also die of prostate cancer without any evidence of radiological progression. The Committee heard from the clinical specialists that disease progression is not determined with a single measure and that they would also consider progression of a patient’s symptoms. The Committee discussed whether discontinuing abiraterone treatment was an adequate proxy for progression of disease. The Committee heard from clinical specialists that in general patients stop treatment at approximately the same time as their disease progresses, but noted that some patients in the COU-AA-301 trial continued to take abiraterone after their disease had progressed. The Committee also noted that most patients in the COU-AA-301 trial discontinued abiraterone treatment for reasons other than disease progression. The Committee acknowledged uncertainty around this measure, but agreed that of the measures of disease progression in the COU-AA-301 trial, time to treatment discontinuation was the most reasonable indicator of disease progression.

4.6 The Committee discussed the results for the COU-AA-301 trial and noted that abiraterone is associated with a statistically significant improvement in overall survival and progression-free survival compared with prednisolone for both the whole (intention-to-treat) population and the manufacturer’s base-case population (‘one prior chemotherapy’ subgroup). The Committee also noted that patients receiving abiraterone were more likely to experience an improvement in symptoms, including pain, functional status and fatigue.. The Committee therefore concluded that the evidence demonstrated that abiraterone was an effective second-line treatment for castration-resistant metastatic prostate cancer.

4.7 The Committee considered the manufacturer’s base-case population of patients who received only one prior docetaxel-containing chemotherapy regimen (‘one prior chemotherapy’) in the COU-AA-301 trial. The Committee noted that this subgroup did not match the population for which abiraterone is licensed (the license does not stipulate only one prior chemotherapy) but likely reflected the population in England and Wales for whom abiraterone would be considered. The Committee noted that in the COU-AA-301 trial the relative overall survival benefit for abiraterone was numerically different, but not statistically significantly different, between the ‘one prior chemotherapy’ subgroup and the subgroup with more than one prior chemotherapy. The Committee did not consider there to be any evidence suggesting a difference in the effectiveness of abiraterone treatment between the whole trial population and the ‘one prior chemotherapy’ subgroup and therefore concluded that it is unnecessary for the manufacturer to restrict the base-case population to this patient subgroup.

4.8 The Committee considered the evidence on adverse reactions associated with abiraterone. The Committee was aware that abiraterone may cause hypertension, hypokalaemia and fluid retention as a consequence of an increased mineralocorticoid level. The Committee noted that adherence to abiraterone in the COU-AA-301 trial was generally high and reflective of abiraterone use in clinical practice, and that adverse reactions were generally manageable and reversible. The Committee also noted that abiraterone is not associated with the more severe adverse reactions that can occur with cytotoxic drugs such as mitoxantrone. The Committee heard from the clinical specialists that abiraterone is a well tolerated oral medication. The Committee concluded that abiraterone is generally safe and that any associated adverse reactions are tolerable.

Cost effectiveness

4.9 The Committee considered the manufacturer’s economic model, the assumptions on which the parameters were based, and the critique and exploratory analyses conducted by the ERG. The Committee considered that the model closely adhered to the NICE reference case for economic analysis.

4.10 The Committee considered the comparator treatments (placebo plus prednsiolone and mitoxantrone with or without prednisolone) and the population included in the economic model. The Committee noted that in the base-case analysis the manufacturer assumed that overall survival and progression-free survival were the same for patients taking mitoxantrone and patients taking prednisolone. The Committee agreed that, in the absence of any direct or indirect comparative data and the absence of published evidence showing any survival benefit for mitoxantrone in a population without prior chemotherapy, this assumption was reasonable. The Committee also noted that the manufacturer’s base-case analysis used clinical effectiveness estimates from the COU-AA-301 trial for the ‘one prior chemotherapy’ subgroup. The Committee was aware that the point estimates for this subgroup were more favourable, although not statistically different, from those of patients who received more than one prior chemotherapy. The Committee concluded that it was not appropriate to restrict the population considered in the base-case economic analysis to the subgroup with one prior chemotherapy.

4.11 The Committee considered the overall survival curve used in the manufacturer’s economic model. The Committee noted that estimates related to overall survival were taken from the ‘updated’ analyses, which the Committee preferred to the ‘primary’ analyses. The Committee also noted that the manufacturer modelled overall survival using Kaplan–Meier survival analysis of patient-level data from the COU-AA-301 trial up to a cut-off point at which a small proportion (10%) of patients remained at risk. Beyond this, the manufacturer extrapolated overall survival using a constant hazard. The Committee considered that the Kaplan–Meier survival curves specifically reflect the COU-AA-301 trial population and that a well-fitting parametric distribution would be more generalisable to all patients for whom abiraterone may be a potential therapy. The Committee noted that the 10% cut-off chosen by the manufacturer for overall survival was arbitrary and produced a relatively favourable ICER compared with other possible cut-off points. The Committee considered the ERG’s concerns that extrapolating overall survival using a constant hazard resulted in abiraterone continuing to deliver a clinically implausible survival gain relative to prednisolone for up to 10 years. The Committee noted that when the ERG used a Weibull parametric distribution to extrapolate overall survival beyond the 10% cut-off, the manufacturer’s base-case ICER for abiraterone compared with prednisolone increased from £52,900 to £56,300 per QALY gained. The Committee concluded that it is more appropriate to use a well-fitting parametric curve to extrapolate overall survival in the economic model.

4.12 The Committee considered the modelling of progression-free survival in the manufacturer’s base-case analysis. The Committee noted that time to treatment discontinuation was used as a proxy for disease progression in the economic model. The Committee was aware that the manufacturer was unable to determine the proportion of patients among those who discontinued therapy who met criteria for disease progression. The Committee agreed with the ERG that using time to treatment discontinuation as a proxy for disease progression was not unreasonable because of concerns about using radiographic imaging to monitor disease progression in prostate cancer. However, the Committee considered that, although time to treatment discontinuation may provide a reliable estimate of treatment costs in the model, it was less clear whether it provided a reliable estimate of the QALY gains associated with being in the pre-progression state. The Committee was also aware that disease is likely to progress before patients stop abiraterone. However, the Committee concluded that changing the duration of progression-free survival did not significantly alter the ICERs associated with treatment with abiraterone relative to treatment with prednisolone.

4.13 The Committee noted the manufacturer’s inconsistent approach for extrapolating progression-free survival beyond the data observed in the trial, with extrapolation beyond the time at which 5% of the population remained for abiraterone, and no extrapolation for prednisolone. The Committee also considered the ERG’s concerns that the shape of the Kaplan–Meier survival curve for treatment discontinuation in the prednisolone group was unusual, with a high proportion of patients discontinuing treatment over a narrow time period after approximately 60 days of treatment. The Committee agreed that this was unlikely to represent actual disease progression and that a well-fitting parametric distribution should have been used. The Committee noted that when the ERG used a Weibull parametric distribution to extrapolate both overall survival and progression-free survival, the manufacturer’s base-case ICER increased to £58,100 per QALY gained. The Committee concluded that a well-fitting parametric curve should also have been used to extrapolate progression-free survival in the economic model.

4.14 The Committee considered the health state utility values used in the economic model. The Committee was aware that utility values for the pre-progression state differed according to treatment, and were derived from an algorithm that mapped FACT-P scores to EQ-5D utility values from a separate cross-sectional dataset of patients with castration-resistant metastatic prostate cancer. The Committee was aware that patients contributing to the cross-sectional dataset may have differed from the population in the COU-AA-301 trial as well as from patients who might receive abiraterone in the UK. The Committee heard from the manufacturer that its mapping algorithm had not been externally validated or subject to peer review. The Committee also noted that the mapping algorithm resulted in pre-progression utility values which were similar to or higher than utility values observed in the age-matched general population. The Committee agreed that this may not be reasonable because people with metastatic prostate cancer would be expected to have a poorer quality of life than people without prostate cancer. The Committee heard from the clinical specialists that patients recruited to the COU-AA-301 trial were healthier than other patients for whom abiraterone would be considered in clinical practice. It also heard from one clinical specialist  that the utility gain estimated for abiraterone compared with prednisolone may have been an underestimate of the improvement in health-related quality of life associated with abiraterone and, as a result, that the ICER may have been overestimated.  However, the clinical specialists acknowledged that more reliable estimates of the utility gain associated with abiraterone treatment may not be available. The Committee noted that the utility values for the pre-progression state were higher than those used in the ongoing technology appraisal of cabizataxel for metastatic hormone-refractory prostate cancer. Overall, the Committee concluded that there was considerable uncertainty about the validity of the pre-progression utility values derived from the manufacturer’s FACT-P mapping algorithm.

4.15 The Committee considered the differences in utility values between the pre- and post-progression health states. The Committee noted that the COU-AA-310 trial did not collect FACT-P data after patients stopped treatment and therefore the manufacturer identified a utility value for the post-progression state from the literature (see section 3.17). This value was lower than that estimated by the ERG from the manufacturer’s FACT-P mapping algorithm for patients at the end of treatment. The Committee noted that a smaller utility decrement when moving from pre-progression to post-progression would increase the ICER. The Committee acknowledged that it may be difficult to determine the true difference in quality of life between the two health states. The Committee acknowledged that although patients were considered to be in the pre-progression state for the purposes of the model, the patients already have metastatic disease and further progression to the post-progression state (defined only by stopping medication) would unlikely be associated with the drop in utility modelled by the manufacturer. The Committee concluded that it was inappropriate for the manufacturer to use utility values for the pre- and post-progression states derived from separate sources, that the difference in utility values between the two states was unreasonably large and consequently the ICER for abiraterone compared with prednisolone was likely to be underestimated.

4.16 The Committee considered the assumptions related to resource use in the manufacturer’s economic model. The Committee noted that the ERG was generally satisfied with the assumptions made. The Committee also noted that the ERG made further corrections to resource use including: revising the duration and cost of mitoxantrone treatment, using monthly administration and monitoring costs based on an oncology outpatient consultation, and assuming that the proportion of people receiving bisphosphonates would remain the same when their disease progressed. The Committee agreed that these changes to the resource use would increase the ICER marginally.

4.17 The Committee considered the most plausible ICERs presented by the manufacturer and also by the ERG in their exploratory analyses. The Committee agreed that, for nearly all analyses presented, mitoxantrone was extendedly dominated by abiraterone. In the Committee’s view the ICER should be based on data from the whole trial population. However, the Committee concluded that the manufacturer’s ICER of £63,200 per QALY gained for this population would increase when the following factors were taken into consideration:

• assuming a smaller difference in utility between the pre-progression and post-progression health states (section 4.15)
• applying a Weibull distribution to the curves for overall survival and progression-free survival throughout the course of follow-up, and not only beyond a given time point (sections 4.11 and 4.13)
• assuming a population more reflective of UK practice than seen in the COU-AA-301 trial, with lower baseline utility (section 4.14)
• applying corrections to resource use estimates (section 4.16)

4.18 The Committee considered supplementary advice from NICE that should be taken into account when appraising treatments that may extend the life of patients with short life expectancy and that are licensed for indications that affect small numbers of people with incurable illnesses. For this advice to be applied, all the following criteria must be met:

• The treatment is indicated for patients with a short life expectancy, normally less than 24 months.
• There is sufficient evidence to indicate that the treatment offers an extension to life, normally of at least an additional 3 months, compared with current NHS treatment.
• The treatment is licensed or otherwise indicated for small patient populations.

In addition, when taking these criteria into account, the Committee must be persuaded that the estimates of the extension to life are robust and that the assumptions used in the reference case of the economic modelling are plausible, objective and robust.

4.19 The Committee discussed whether abiraterone fulfilled the criteria for consideration as a life-extending, end-of-life treatment. For castration-resistant metastatic prostate cancer that has progressed after first-line chemotherapy, the Committee agreed that the first criterion related to life expectancy was fulfilled, because estimates of life expectancy from trials with best supportive care were less than 15 months. The Committee considered the degree to which abiraterone extended life. It noted that in the manufacturer’s base-case economic analysis the estimated mean overall survival gain for abiraterone was greater than 3 months (median overall survival gain 4.6 months; mean overall survival gain commercial in confidence). The Committee concluded that a mean improvement of greater than 3 months in mean overall survival had been robustly demonstrated. The Committee was aware that the population included in the marketing authorisation was likely to be larger than that for cabazitaxel given that abiraterone can be administered at home, and that some patients who would be unlikely to tolerate chemotherapy might take abiraterone. The Committee understood from the estimates provided by the manufacturer that approximately 4300 people with metastatic castration-resistant metastatic prostate cancer were receiving docetaxel in England and Wales in 2011, and that approximately 75% of these (n = 3300) would be eligible for abiraterone. The Committee also noted that the manufacturer estimated that the number of people with castration-resistant metastatic prostate cancer receiving docetaxel in England and Wales would rise to approximately 5500 in 2013. The Committee heard from the commissioning expert that these were underestimates of the number of patients who would receive abiraterone in clinical practice. The Committee concluded that abiraterone was not licensed for a small population, and therefore considered that it does not meet the criteria for an end-of-life treatment. The Committee also concluded that, even if abiraterone did meet the end-of-life criteria, the additional weight that would need to be assigned to the QALY benefits would be too great to justify abiraterone as an appropriate use of limited NHS resources.

4.20 The Committee considered whether abiraterone is an innovative technology. It noted that abiraterone may offer a step change in treatment because it is life-extending rather than simply palliative. The Committee was aware that because patients take abiraterone orally it would provide a benefit for those patients who would otherwise have intravenous mitoxantrone. However when queried, the manufacturer did not provide the Committee with evidence that abiraterone adds substantial benefits other than those captured in the QALY calculation. The Committee concluded that there was no justification for accepting an ICER that was at least £60,000 per QALY gained.

4.21 The Committee discussed whether there are any equality issues that required consideration in this appraisal. The Committee was aware that people who have proposed, started or completed male to female gender reassignment can develop prostate cancer. The Committee therefore concluded that this appraisal should refer to people rather than to men. Furthermore, the Committee had been made aware that people with prostate cancer who have proposed, started or completed male to female gender reassignment may find it uncomfortable to attend male urology clinics. However, the Committee agreed that the treatment of prostate cancer would be likely to be provided in oncology clinics.

Summary of Appraisal Committee’s key conclusions

TAXXX	Appraisal title: Abiraterone for castration-resistant metastatic prostate cancer previously treated with a docetaxel-containing regimen		Section
Key conclusion
Abiraterone in combination with prednisone or prednisolone is not recommended for the treatment of castration-resistant metastatic prostate cancer that has progressed on or after a docetaxel-containing regimen. This is because the manufacturer’s ICER of £63,200 per QALY gained for the whole population would increase when a smaller difference in utility between the pre-progression and post-progression health states is assumed, a Weibull distribution is fitted to the curves for overall survival and progression-free survival throughout the course of follow-up, and not only beyond a given time point,  a population more reflective of UK practice than seen in the COU-AA-301 trial, with lower baseline utility is modelled, and when corrections to resource use were made.			1.1, 4.19
Current practice
Clinical need of patients, including the availability of alternative treatments		The main treatment options for patients whose disease progresses after first-line docetaxel include mitoxantrone, best supportive care, and re-treatment with docetaxel (which is not recommended by current NICE guidance). The Committee heard from clinical specialists that mitoxantrone is used rarely in UK clinical practice. The Committee also heard from the clinical specialists that they would be unlikely to offer abiraterone to patients with an ECOG performance score of 2.	4.2
The technology
Proposed benefits of the technology How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?		The Committee heard from the patient experts that the most important benefits of abiraterone were extension to life and improved quality of life, including less pain and improved mental and physical health. The Committee also heard that patient experts believed that adverse reactions to abiraterone treatment were tolerable and comparable to those associated with hormone treatment. The patient experts also commented that another advantage of abiraterone is that patients can take it orally at home. The Committee noted that abiraterone may offer a step change in treatment because it is life-extending rather than simply palliative. The Committee was aware that because patients take abiraterone orally it would provide a benefit for those patients who would otherwise have intravenous mitoxantrone. However the manufacturer did not provide the Committee with evidence that abiraterone adds substantial benefits other than those captured in the QALY calculation.	4.3 4.20
What is the position of the treatment in the pathway of care for the condition?		Abiraterone has a UK marketing authorisation for use ‘with prednisone or prednisolone for the treatment of metastatic castration resistant prostate cancer in adult men whose disease has progressed on or after a docetaxel-based chemotherapy regimen’.	2.1
Adverse reactions		The Committee was aware that abiraterone may cause hypertension, hypokalaemia and fluid retention as a consequence of an increased mineralocorticoid effect. The Committee noted that adverse reactions were generally manageable and reversible. The Committee concluded that abiraterone is generally safe and that any associated adverse reactions are tolerable.	4.8
Evidence for clinical effectiveness
Availability, nature and quality of evidence		The manufacturer’s clinical-effectiveness evidence was derived solely from the COU-AA-301 trial (a phase III, placebo-controlled, randomised, double-blind, multicentre trial carried out across 130 sites in 13 countries, including the UK).	3.1
Relevance to general clinical practice in the NHS		The Committee heard from clinical specialists that participants in the COU-AA-301 trial were likely to be healthier than those who would receive abiraterone treatment in UK clinical practice.	4.4
Uncertainties generated by the evidence		The Committee acknowledged uncertainty around measure of disease progression in the COU-AA-301 trial. However, they agreed that of the measures of disease progression in the COU-AA-301 trial, time to treatment discontinuation was the most reasonable indicator of disease progression.	4.5
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?		In the base case the manufacturer included a subgroup of the COU-AA-301 trial who had received one prior chemotherapy. The Committee did not consider there to be any evidence suggesting a difference in the effectiveness of abiraterone treatment between the whole trial population and the ‘one prior chemotherapy’ subgroup and therefore concluded that it is not appropriate for the manufacturer to restrict the base-case population to this patient subgroup.	4.7
Estimate of the size of the clinical effectiveness including strength of supporting evidence		The primary analysis of the whole (intention-to-treat) population of the COU-AA-301 trial reported that median survival was statistically significantly longer in the abiraterone group than the prednisolone group (14.8 months compared with 10.9 months, hazard ratio [HR] 0.65, 95% confidence interval [CI] 0.54 to 0.77). The median time to treatment discontinuation in both the primary and updated analyses for the abiraterone group was statistically significantly longer than in the prednsiolone group (8months compared with 4 months). The Committee concluded that the evidence demonstrated that abiraterone was an effective second-line treatment for castration-resistant metastatic prostate cancer.	3.3 3.6 4.6
Evidence for cost effectiveness
Availability and nature of evidence		The manufacturer submitted an economic model comparing three treatments: abiraterone (plus prednisolone), prednisolone alone, and mitoxantrone (plus prednisolone). The manufacturer developed a survival-based decision model with three health states: pre-progression, post-progression and dead. The model used a lifetime horizon of 10 years. The Committee concluded that the model closely adhered to the NICE reference case for economic analysis.	3.9, 3.10 4.9
Uncertainties around and plausibility of assumptions and inputs in the economic model		The Committee concluded that it was not appropriate to restrict the population considered in the base-case economic analysis to the subgroup with one prior chemotherapy. The Committee concluded that the manufacturer should have used a well-fitting parametric curve to extrapolate overall survival and progression-free survival in the economic model.	4.10 4.11, 4.13
Incorporation of health-related quality-of-life benefits and utility valuesHave 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 concluded that there was considerable uncertainty about the validity of the pre-progression utility values derived from the manufacturer’s FACT-P mapping algorithm. The Committee concluded that it was inappropriate for the manufacturer to use utility values for the pre- and post-progression states derived from separate sources, that the difference in utility values between the two states was unreasonably large and consequently the ICER for abiraterone compared with prednisolone was likely to be underestimated. None identified.	4.14, 4.15
Are there specific groups of people for whom the technology is particularly cost effective?		Not applicable	-
What are the key drivers of cost effectiveness?		The Committee noted that a smaller utility decrement when moving from pre-progression to post-progression would increase the ICER.	4.15
Most likely cost-effectiveness estimate (given as an ICER)		The Committee considered the most plausible ICERs presented by the manufacturer and also by the ERG in their exploratory analyses. The Committee agreed that, for nearly all analyses presented, mitoxantrone was extendedly dominated by abiraterone. In the Committee’s view the ICER should be based on data from the whole trial population. However, the Committee concluded that the manufacturer’s ICER of £63,200 per QALY gained for this population would increase when the following factors were taken into consideration: ·           assuming a smaller difference in utility between the pre-progression and post-progression health states (section 4.15) ·           applying a Weibull distribution to the curves for overall survival and progression-free survival throughout the course of follow-up, and not only beyond a given time point (sections 4.11 and 4.13) ·           assuming a population more reflective of UK practice than seen in the COU-AA-301 trial, with lower baseline utility and shorter life expectancy (section 4.14) ·           applying corrections to resource use estimates (section 4.16)	4.17
Additional factors taken into account
Patient access schemes (PPRS)		The manufacturer of abiraterone has agreed a patient access scheme with the Department of Health. This involves a single confidential discount applied to the list price of abiraterone.	2.3,
End-of-life considerations		The Committee agreed that the criteria related to short life expectancy (less than 24 months) without treatment and extension to life (at least 3 months) with treatment were met. However, the Committee concluded that abiraterone was not licensed for a small population, and therefore considered that it does not meet the criteria for an end-of-life treatment.	4.19
Equalities considerations and social value judgements		The Committee were aware that people who have proposed, started or completed male to female gender reassignment can develop prostate cancer. The Committee therefore concluded that this appraisal should refer to people rather than to men.	4.21

 

5 Implementation

5.1 The Secretary of State and the Welsh Assembly Minister for Health and Social Services have issued directions to the NHS in England and Wales on implementing NICE technology appraisal guidance. When a NICE technology appraisal recommends use of a drug or treatment, or other technology, the NHS must usually provide funding and resources for it within 3 months of the guidance being published. If the Department of Health issues a variation to the 3-month funding direction, details will be available on the NICE website. When there is no NICE technology appraisal guidance on a drug, treatment or other technology, decisions on funding should be made locally.

5.2 NICE has developed tools to help organisations put this guidance into practice (listed below). These are available on our website (www.nice.org.uk/guidance/TAXXX). [NICE to amend list as needed at time of publication]

• Slides highlighting key messages for local discussion.
• Costing template and report to estimate the national and local savings and costs associated with implementation.
• Implementation advice on how to put the guidance into practice and national initiatives that support this locally.
• A costing statement explaining the resource impact of this guidance.
• Audit support for monitoring local practice.

6 Related NICE guidance

Published

• Prostate cancer: diagnosis and treatment. NICE clinical guideline 58 (2008). Available from www.nice.org.uk/guidance/CG58
• Docetaxel for the treatment of hormone refractory prostate cancer. NICE technology appraisal guidance 101 (2006). Available from www.nice.org.uk/guidance/TA101
• Improving outcomes in urogenital cancers: the manual. NICE cancer service guidance (2002). Available from www.nice.org.uk/guidance/CSGUC

Under development

NICE is developing the following guidance (details available from www.nice.org.uk):

• Cabazitaxel for hormone-refractory metastatic prostate cancer previously treated with a docetaxel-containing regimen. Technology appraisal in preparation. Earliest anticipated date of publication February 2012.

7 Proposed date for review of guidance

7.1 NICE proposes that the guidance on this technology is considered for review by the Guidance Executive in April 2015. NICE welcomes comment on this proposed date. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.

Amanda Adler
Chair, Appraisal Committee
January 2012

Appendix A: Appraisal Committee members, and NICE project team

A Appraisal Committee members

The Appraisal Committees are standing advisory committees of NICE. Members are appointed for a 3-year term. A list of the Committee members who took part in the discussions for this appraisal appears below. There are four Appraisal Committees, each with a chair and vice chair. Each Appraisal Committee meets once a month, except in December when there are no meetings. Each Committee considers its own list of technologies, and ongoing topics are not moved between Committees.

Committee members are asked to declare any interests in the technology to be appraised. If it is considered there is a conflict of interest, the member is excluded from participating further in that appraisal.

The minutes of each Appraisal Committee meeting, which include the names of the members who attended and their declarations of interests, are posted on the NICE website.

Dr Amanda Adler (Chair)
Consultant Physician, Addenbrooke's Hospital

Dr Mark Chakravarty
External Relations Director - Pharmaceuticals & Personal Health, Oral Care Europe

Mark Chapman
Health Economics and Market Access Manager, Medtronic UK

Professor Fergus Gleeson
Consultant Radiologist, Churchill Hospital, Oxford

Eleanor Grey
Lay member

Dr Neil Iosson
General Practitioner

Terence Lewis
Lay Member

Dr Rubin Minhas
General Practitioner and Clinical Director, BMJ Evidence Centre

Dr Peter Norrie
Principal Lecturer in Nursing, DeMontfort University

Dr Sanjeev Patel
Consultant Physician & Senior Lecturer in Rheumatology, St Helier University Hospital

Dr John Pounsford
Consultant Physician, Frenchay Hospital, Bristol

Dr John Rodriguez
Assistant Director of Public Health, NHS Eastern and Coastal Kent

Dr Florian Alexander Ruths
Consultant Psychiatrist & Cognitive Therapist at the Maudsley Hospital, London

Navin Sewak
Primary Care Pharmacist, NHS Hammersmith and Fulham

Cliff Snelling
Lay Member

Marta Soares
Research Fellow, Centre for Health Economics, University of York

Professor Andrew Stevens
Professor of Public Health, Department of Public Health and Epidemiology, University of Birmingham

Tom Wilson
Director of Contracting & Performance, NHS Tameside & Glossop

Dr Nerys Woolacott
Senior Research Fellow, Centre for Health Economics, University of York

B NICE project team

Each technology appraisal is assigned to a team consisting of one or more health technology analysts (who act as technical leads for the appraisal), a technical adviser and a project manager.

Matthew Dyer
Technical Lead

Fiona Rinaldi
Technical Adviser

Jeremy Powell
Project Manager

Appendix B: Sources of evidence considered by the Committee

A The Evidence Review Group (ERG) report for this appraisal was prepared by Warwick Evidence:

• Connock M, Cummins E, Shyangdan D et al. Abiraterone acetate for the treatment of metastatic, castrate-resistant prostate cancer following previous cytotoxic chemotherapy. Warwick Evidence, University of Warwick (December 2011)

B The following organisations accepted the invitation to participate in this appraisal as consultees and commentators. They were invited to comment on the draft scope, the ERG report and the appraisal consultation document (ACD). Organisations listed in I were also invited to make written submissions. Organisations listed in II and III had the opportunity to give their expert views. Organisations listed in I, II and III also have the opportunity to appeal against the final appraisal determination.

I  Manufacturer/sponsor:

• Janssen

II  Professional/specialist and patient/carer groups:

• British Association of Urological Surgeons
• British Uro-Oncology Group
• Cancer Research UK
• Macmillan Cancer Support
• PCaSO – Prostate Cancer Network
• Prostate Cancer Charity
• Prostate Cancer Support Federation
• Royal College of General Practitioners
• Royal College of Nursing
• Royal College of Physicians
• United Kingdom Clinical Pharmacy Association
• United Kingdom Oncology Nursing Society

III Other consultees:

• Department of Health
• NHS Hertfordshire
• NHS Bradford and Airedale
• Welsh Government

IV Commentator organisations (did not provide written evidence and without the right of appeal):

• British National Formulary
• Commissioning Support Appraisals Service
• Department of Health, Social Services and Public Safety for Northern Ireland
• Healthcare Improvement Scotland
• MRC Clinical Trials Unit
• Prostate Action

C The following individuals were selected from clinical specialist and patient expert nominations from the non-manufacturer/sponsor consultees and commentators. They gave their expert personal view on abiraterone by attending the initial Committee discussion and providing written evidence to the Committee. They are invited to comment on the ACD.

• Dr John Staffurth, , nominated by the RCP on behalf of the NCRI/RCP/RCR/ACP/JCCO and the British Uro-Oncology Group – clinical specialist
• Dr Isabel Syndikus clinical expert, nominated by the RCP on behalf of the NCRI/RCP/RCR/ACP/JCCO – clinical specialist
• Mr Hugh Gunn, nominated by the Prostate Cancer Federation – patient expert
• Mr Stuart Watson, nominated by the Prostate Cancer Charity – patient expert

D The following individuals were nominated as NHS Commissioning experts by the selected NHS Trust allocated to this appraisal. They gave their expert/NHS commissioning personal view on abiraterone by attending the initial Committee discussion and providing written evidence to the Committee. They are invited to comment on the ACD.

• Mrs Rasila Shah, nominated by NHS Hertfordshire - NHS Commissioning expert – NHS Commissioning expert

E Representatives from the following manufacturer/sponsor attended Committee meetings. They contributed only when asked by the Committee chair to clarify specific issues and comment on factual accuracy.

• Janssen