1 Appraisal Committee’s preliminary recommendations

1.1 Fulvestrant is not recommended as an alternative to aromatase inhibitors for the treatment of oestrogen-receptor-positive, locally advanced or metastatic breast cancer in postmenopausal women whose cancer has relapsed on or after adjuvant anti-oestrogen therapy, or who have disease progression on anti-oestrogen therapy.

2 The technology

2.1 Fulvestrant (Faslodex, AstraZeneca) is an oestrogen antagonist belonging to a class of agents known as selective oestrogen receptor down-regulators (SERDs). Fulvestrant has a UK marketing authorisation for ‘the treatment of postmenopausal women with oestrogen receptor positive, locally advanced or metastatic breast cancer for disease relapse on or after adjuvant anti-oestrogen therapy, or disease progression on therapy with an anti-oestrogen’. The recommended dose is 500 mg (administered as two intramuscular injections of 250 mg) every month, with an additional 500 mg dose given 2 weeks after the initial dose.

2.2 According to the summary of product characteristics, the most common side effects associated with fulvestrant are nausea, vomiting,diarrhoea, venous thromboembolism, anorexia, headache, asthenia, urinary-tract infections, hot flushes, back pain, rash, injection-site reactions and hypersensitivity reactions [‘British national formulary’ [BNF] edition 61]. For full details of side effects and contraindications, see the summary of product characteristics.

2.3 The current NHS list price of fulvestrant is £522.41 for 2 x 5 ml (250 mg) prefilled syringes (excluding VAT; BNF edition 61). The first month of treatment with fulvestrant 500 mg includes an additional loading dose administered 2 weeks after the initial dose, resulting in a cost of £1044.82 for the first month. In subsequent months, the cost of fulvestrant 500 mg is £522.41 per month. Costs may vary in different settings because of negotiated procurement discounts.

3 The manufacturer’s submission

The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of fulvestrant and a review of this submission by the Evidence Review Group (ERG; appendix B).

3.1 The manufacturer’s submission presented clinical effectiveness data derived from one phase III trial (CONFIRM), supported by results from two dose-ranging phase II trials (FINDER-1 and FINDER-2). Women were eligible for these three studies if they were postmenopausal and had oestrogen-receptor-positive breast cancer. Their cancer could have relapsed during or within 12 months of completing adjuvant hormone therapy (with an anti-oestrogen or an aromatase inhibitor) for early breast cancer; or it could have progressed on anti-oestrogen or aromatase inhibitor therapy for advanced breast cancer provided that this hormone therapy was started more than 12 months after completion of adjuvant hormone therapy (anti-oestrogen or aromatase inhibitor); or it could have progressed while they were on first-line hormone therapy (anti-oestrogen or aromatase inhibitor) for advanced breast cancer. All three trials excluded patients who had received two or more lines of previous endocrine therapy for locally advanced or metastatic breast cancer.

3.2 The CONFIRM trial was an international multicentre double-blind parallel-group randomised controlled trial (RCT) that included 736 patients who had previously received an anti-oestrogen or an aromatase inhibitor for the adjuvant treatment of early breast cancer or as palliative therapy for advanced breast cancer. Patients were randomised on a 1:1 basis to receive either fulvestrant 500 mg or fulvestrant 250 mg. The mean age of study participants was 61 years. The baseline characteristics of the groups in the two arms of the trial were generally comparable, although more patients in the fulvestrant 250 mg arm (102 compared with 69) had received radiotherapy as treatment for advanced disease.

3.3 The primary outcome measure used in the CONFIRM study was median time to progression (TTP). Median TTP was statistically significantly longer in the overall mixed population (that is, including both patients who had previously received an anti-oestrogen and patients who had previously received an aromatase inhibitor) for the fulvestrant 500 mg arm compared with the fulvestrant 250 mg arm (6.5 compared with 5.5 months; hazard ratio [HR] 0.80; 95% confidence interval [CI] 0.68 to 0.94; p = 0.006). A pre-planned analysis was done for the subgroups of patients last treated with an anti-oestrogen (58%) or an aromatase inhibitor (42%). The median TTPs for the fulvestrant 500 mg and fulvestrant 250 mg arms were 8.6 and 5.8 months respectively (HR 0.76; 95% CI 0.62 to 0.94; p = 0.013) for the population last treated with an anti-oestrogen, and 5.4 and 4.1 months respectively for the population last treated with an aromatase inhibitor (HR 0.85; 95% CI 0.67 to 1.08; p = 0.195).

3.4 Secondary outcomes reported in the CONFIRM study included objective response rate, clinical benefit rate and overall survival. The results suggested no statistically significant differences between the fulvestrant 500 mg and 250 mg arms for these outcomes, although the median overall survival was numerically greater in the fulvestrant 500 mg group (25.1 compared with 22.8 months). Log-rank tests suggested a trend for improved overall survival in the fulvestrant 500 mg group (HR 0.84; 95% CI 0.69 to 1.03; p = 0.091). Overall survival data from the CONFIRM trial were not mature: 51% of patients had died at the time of primary data cut-off for TTP. The manufacturer stated that it plans to re-analyse the overall survival data when 75% of patients have died.

3.5 A total of 2443 adverse events were reported by 483 (66%) of the 735 patients in the safety analysis set in the CONFIRM trial. A serious adverse event was reported for 54 patients (7%), including 11 patients (1%) who died. Seventeen patients (2%) discontinued fulvestrant treatment because of an adverse event. There were no notable differences in the incidence of adverse events between treatment groups. The most common adverse events were injection-site pain (11.6%), nausea (9.7%) and bone pain (9.4%).

3.6 he manufacturer also provided health-related quality of life data taken from the CONFIRM study for a total of 145 women who completed the Functional Assessment of Cancer Therapy-Breast (FACT-B) questionnaire at baseline. No significant differences were detected between the fulvestrant 500 mg and 250 mg study arms.

3.7 The FINDER-1 study was a multicentre parallel-group double-blind phase II RCT conducted in Japan. A total of 143 patients recruited from 40 centres were randomised on a 1:1:1 basis to receive fulvestrant 500 mg, fulvestrant 250 mg or fulvestrant 250 mg with a loading dose. The FINDER-2 study was a multicentre international double-blind phase II RCT conducted in seven European countries and Canada. A total of 144 patients were recruited from 34 centres and randomised on a 1:1:1 basis to receive fulvestrant 500 mg, fulvestrant 250 mg or fulvestrant 250 mg with a loading dose. The primary outcome in the FINDER-1 and FINDER-2 trials was objective response rate, with secondary outcomes including clinical benefit rate and TTP. The findings from these trials were broadly in favour of fulvestrant 500 mg compared with 250 mg.

3.8 The manufacturer conducted a network meta-analysis to compare overall survival and TTP for fulvestrant 500 mg and the comparators listed in the scope. Five RCTs that included three of the other comparators (anastrozole, letrozole and exemestane) listed in the scope were identified in the systematic literature review, resulting in eight trials being included in the network meta-analysis. Data from the total population in the fulvestrant trials were included, with the FINDER-1 and FINDER-2 trials contributing only to the TTP network meta-analysis. The manufacturer asserted that inclusion of the group from the CONFIRM trial that had received an aromatase inhibitor as their last treatment did not alter the results in favour of fulvestrant. The manufacturer did not include exemestane as a comparator in the base-case network meta-analysis because of a lack of any relevant trials in which 70% or more patients had documented hormone-receptor-positive advanced breast cancer in a population that had received an anti-oestrogen. Therefore a secondary scenario analysis, as part of the cost-effectiveness analysis comparing fulvestrant 500 mg with exemestane, was undertaken by the manufacturer.

3.9 For the base-case network meta-analysis, data on two outcomes were collected: overall survival and TTP. Data from the eight included trials were pooled and extrapolated. Based on patient-level data from the CONFIRM trial, the Weibull distribution was identified as the best-fitting distribution to estimate overall survival. Because HRs in the CONFIRM trial were constant over time (the shape parameters were very similar for both treatment groups), the relative treatment effects of the alternative treatments were applied to the baseline treatment (fulvestrant 250 mg) using a pooled hazard ratio for overall survival estimated from the network meta-analysis. For TTP, the log-normal distribution was identified by the manufacturer as the best-fitting distribution for data from the CONFIRM trial. Because the log-normal distribution does not have a constant hazard function over time, the relative effects of alternative treatments were applied to the baseline treatment (fulvestrant 250 mg) using the relative pooled shape and scale parameters of the log-normal distribution.

3.10 The results of the network meta-analysis presented by the manufacturer suggested that fulvestrant 500 mg was associated with longer overall survival compared with fulvestrant 250 mg, anastrozole and letrozole, but this finding was not statistically significant. The results of the TTP network meta-analysis suggested that fulvestrant 500 mg is associated with a statistically significantly longer TTP than fulvestrant 250 mg, whereas anastrozole is associated with a statistically significantly shorter TTP than fulvestrant 250 mg. There were no statistically significant differences in TTP between letrozole 2.5 mg and fulvestrant 250 mg.

3.11 The manufacturer developed an Excel-based cost–utility model, based on a time-in-state model structure. The model structure is similar to that of a Markov cohort model with three possible health states: pre-progression, post-progression and dead. However, instead of using transition probabilities to determine movement between health states, the model calculates the proportion of patients in each health state according to the estimated survival functions for TTP and overall survival. All patients are assumed to be in the pre-progression health state at model entry (baseline). The duration of second-line hormonal therapy was assumed to be the same as the amount of time spent in the pre-progression health state. The post-progression health state captures a series of subsequent therapies, including third-line hormonal therapy, up to three sequential lines of chemotherapy, and supportive palliative care. Patients can move to the state of death from either the pre-progression or the post-progression health state, which captures death from any cause. The model uses monthly cycles with a lifetime (13-year) time horizon.

3.12 The results of the base-case network meta-analysis for the clinical effectiveness data on TTP and overall survival were used to populate the economic model. For the base-case analysis, comparator treatments were fulvestrant 250 mg, anastrozole and letrozole. The manufacturer used the overall CONFIRM trial population (that is, a mixed population that had received either an anti-oestrogen or an aromatase inhibitor as their last treatment) in the analysis. The manufacturer reported that it was not feasible to analyse the proportion of patients with grade 3 or grade 4 adverse events because adverse events were not reported consistently across trials included in the network meta-analysis. However, the manufacturer included serious adverse events in the model because sufficient data were available to conduct a network meta-analysis. The serious adverse event data used in the model included both treatment-related and treatment-independent events, because these were available for all relevant RCTs used to derive the estimates of TTP and overall survival in the base-case analysis.

3.13 Health-related quality of life data based on the FACT-B questionnaire were collected at baseline (pre-progression) from a subgroup of patients in the CONFIRM study. However, the model structure required utility values for the pre-progression and post-progression health states that were not collected in the CONFIRM study. Therefore the manufacturer used published pre-progression and post-progression utility values based on a systematic literature review of utility studies for metastatic or locally advanced breast cancer. The manufacturer considered that the study by Lloyd et al. (2006) provided the most appropriate utility values. In this study, utility values were elicited from a relatively small sample of the general public in the UK using the standard gamble technique. The study provided utility values of 0.72 and 0.44 for the pre-progression and post-progression health states respectively. Death was assigned a utility value of zero. Disutilities associated with treatment-related adverse events were not included in the model.

3.14 Resource use and costs in the economic model included those related to each second-line hormonal treatment during the pre-progression phase, subsequent treatments during the post-progression phase including third-line hormonal therapy, supportive palliative care and chemotherapy, and treatment-related adverse events. No treatment-related monitoring costs associated with fulvestrant 500 mg or its comparators were included in the model. An overall average cost per monthly cycle of £1084 per patient was applied to each treatment arm for the proportion of patients in the post-progression health state. For adverse events, the model assumed that each serious adverse event is associated with an average hospital stay of 5 days at a cost of £321.02 per day, which was then weighted by the proportion of serious adverse events estimated in the network meta-analysis for each hormonal treatment considered in the scope. The model assumed that one-third of patients received fulvestrant in primary care and two-thirds in hospital.

3.15 The manufacturer reported the results from the economic model for the two key clinical outcomes, TTP and overall survival. The mean TTP was for 15.0 months for fulvestrant 500 mg compared with 10.8 months for fulvestrant 250 mg, 9.5 months for anastrozole and 9.9 months for letrozole. The mean overall survival was 33.4 months for fulvestrant 500 mg compared with 29.0 months for fulvestrant 250 mg, 28.5 months for anastrozole and 24.9 months for letrozole.

3.16 In the base-case incremental analysis, fulvestrant 500 mg was associated with the highest total quality-adjusted life years (QALYs) (1.487), followed by fulvestrant 250 mg (1.256), anastrozole (1.214) and letrozole (1.105). Based on an incremental analysis ranking of treatments, the base-case results demonstrated that anastrozole and fulvestrant 250 mg were extendedly dominated (that is, dominated by a combination of two other alternative single-agent treatments) by fulvestrant 500 mg and letrozole. The comparison of fulvestrant 500 mg with letrozole gave an incremental cost-effectiveness ratio (ICER) of £31,982 per QALY gained (representing incremental costs of £12,239 and incremental QALYs of 0.383). The manufacturer stated that no patients were assumed to be on an adjuvant switch hormone treatment strategy (that is, sequential treatment with an anti-oestrogen and an aromatase inhibitor).

3.17 The manufacturer conducted deterministic sensitivity analyses by varying key model input parameters. This showed that the key drivers of the cost-effectiveness results were the estimates of TTP and overall survival for all treatments and the utility values assigned to the pre-progression and post-progression health states. The widest range of ICERs were found for the comparison of fulvestrant 500 mg and letrozole, which ranged from £21,894 to £55,160 per QALY gained when the upper and lower 95% credibility interval for the scale and log shape of the estimated TTP for letrozole were used.

3.18 The manufacturer also conducted six scenario analyses to assess the impact of key assumptions made in the base-case analysis. These scenarios included: expanding the patient population to enable the inclusion of exemestane into the network meta-analysis (documented hormone-receptor-positive cancer in at least 50% of patients and inclusion of patients that had been last treated with an aromatase inhibitor [because there are no studies comparing fulvestrant with exemestane in patients treated with an anti-oestrogen]); using alternative proportions for the administration of fulvestrant in the primary care setting and in hospital; altering the cost of the post-progression health state by using an alternative mix of chemotherapies; altering the cost of the post-progression health state by eliminating treatment skipping (patients skip further hormonal treatment if the extent and duration of response to a previous hormonal treatment was insufficient); discounting costs and benefits at 0% and 6%; and altering the time horizon. In summary, exemestane, anastrozole and fulvestrant 250 mg were all extendedly dominated. The comparison of fulvestrant 500 mg with letrozole gave a range of ICERs from £29,881 to £38,566 per QALY gained.

3.19 The results of the manufacturer’s probabilistic sensitivity analysis showed that, at a threshold of £20,000 per QALY gained, there is a 2% probability of fulvestrant 500 mg being cost effective. This increased to 20% at a threshold of £30,000 per QALY gained.

ERG comments on the manufacturer’s submission

3.20 The ERG commented that the manufacturer’s systematic review of clinical effectiveness studies was methodologically appropriate and that all relevant studies meeting the inclusion criteria appear to have been identified.

3.21 The ERG commented that the CONFIRM study was well designed and that the clinical outcomes reported in this RCT and the supporting phase II trials (FINDER-1 and FINDER-2) address all the relevant outcomes outlined in the scope. However, it was noted by the ERG that fulvestrant is currently most commonly used in clinical practice in England and Wales after aromatase inhibitors and often after an anti-oestrogen as well, and therefore it is a third or fourth endocrine therapy in the treatment pathway for advanced breast cancer. In the fulvestrant trials used as the basis for direct clinical evidence and in the manufacturer’s submission, fulvestrant was used in the treatment pathway in the position currently occupied by aromatase inhibitors. Therefore, the ERG commented that the generalisability of the patient population and trial results to clinical practice may be questionable, because there is a difference between the licensed indication of fulvestrant and its use in treatment in England and Wales. The ERG also noted that, although the CONFIRM trial was carried out across 17 countries, no patients were recruited in the UK, which may also limit the generalisability of the clinical results.

3.22 The ERG highlighted that the marketing authorisation for fulvestrant 500 mg specifies that the patient has received previous anti-oestrogen therapy, although the ERG noted that it is not clear from the wording of the marketing authorisation that eligibility for treatment depends on the last therapy received. Therefore, the ERG requested that the manufacturer divided the TTP data from CONFIRM in two main ways. First, the data were divided into those patients who had received an anti-oestrogen as their last treatment (58%) and patients who had received an aromatase inhibitor as their last treatment (42%). Second, the data were split into three treatment groups: patients who had received an anti-oestrogen but not an aromatase inhibitor; patients who had received an aromatase inhibitor but not an anti-oestrogen; and patients who had received both an anti-oestrogen and an aromatase inhibitor. This latter set of results was presented as ‘in confidence’ data. The ERG noted from the former division of data that two-thirds of the patients who had received an anti-oestrogen as their last treatment were receiving fulvestrant as a first-line treatment for locally advanced or metastatic breast cancer, whereas two-thirds of the patients who had received an aromatase inhibitor as their last treatment received fulvestrant as second-line therapy for advanced breast cancer. The ERG also demonstrated significant differences between the demography of the two groups: the proportion treated with endocrine therapy for advanced disease was 34% in the anti-oestrogen group compared with 67% for the aromatase inhibitor group; and the proportion who had received two previous hormone therapies was 4% in the anti-oestrogen group compared with 27% in the aromatase inhibitor group. The ERG therefore speculated that the apparent increased benefit for fulvestrant after an anti-oestrogen rather than after an aromatase inhibitor may be influenced by where in the treatment sequence the majority of patients received fulvestrant, rather than by whether the last treatment before fulvestrant was an anti-oestrogen or an aromatase inhibitor.

3.23 The ERG considered that the manufacturer’s base-case economic evaluation was well conducted and closely matched the NICE reference case. The main issue raised by the ERG related to the use of data from the network meta-analysis, which included patients from the CONFIRM trial who had been treated previously with an aromatase inhibitor. The ERG considered it more appropriate to base the model only on patients who had previously received anti-oestrogen therapy, particularly in view of the heterogeneity of the anti-oestrogen and aromatase inhibitor groups. The ERG considered that the advantage of this approach of reducing the heterogeneity of the compared populations outweighed the principal disadvantage of reduced statistical power of the CONFIRM trial.

3.24 In its critique of the network meta-analysis, the ERG noted that in the comparator treatment trials, none of the patients had received a prior aromatase inhibitor. In addition, the ERG noted key differences in the baseline characteristics of the trials included in the network meta-analysis. For example, the percentage of patients whose oestrogen receptor status was not known to be positive ranged from 33.1% (Buzdar 1996/98) to 0% (CONFIRM, FINDER-1 and FINDER-2); the proportion of patients treated previously with chemotherapy ranged from 35.1% (Buzdar 1996/98) to 72.5% (FINDER-1); and the proportion of patients reported with visceral spread was variable, although the ERG noted that the proportion of patients with known visceral spread was high in the fulvestrant trials.

3.25 Overall, the ERG considered that the population in the CONFIRM trial was heterogeneous and that it was not meaningful to regard the group that had received an anti-oestrogen and the group that had received an aromatase inhibitor as similar. The ERG suggested that the network meta-analyses should include data only from patients that had received an anti-oestrogen as their last treatment from the CONFIRM, FINDER-1 and FINDER-2 trials. Therefore the ERG re-ran the analysis using only data from CONFIRM trial patients whose previous endocrine therapy was an anti-oestrogen (n = 423). The results were comparable with those obtained when the whole population of the CONFIRM trial was included in the analysis. All hazard ratios for overall survival still favoured fulvestrant 500 mg over other treatments considered in the scope, although the results were not statistically significant. For the TTP network meta-analysis, the ERG questioned the assumption that the CONFIRM trial results follow a log-normal distribution, because of the higher number of progression events occurring around 90 days, followed by a 90-day period with relatively few new events. From 180 days onwards, there was a clear indication of a linear relationship between time and the cumulative TTP hazard. Therefore the ERG proposed that a more accurate approach would be to split the estimation of TTP into two phases and to include only the anti-oestrogen-treated population from the CONFIRM trial. For the first part of the analysis (0–180 days), the ERG performed a network meta-analysis on the log-hazard ratios at 180 days. For the second part of the analysis (after 180 days), TTP was modelledusing an exponential distribution, which has a constant hazard or linear cumulative hazard, based on a clear indication of a linear relationship between time and cumulative TTP hazard in the CONFIRM trial. The results of this analysis showed no statistically significant differences in TTP between the groups receiving fulvestrant 500 mg and those receiving other treatments for the first 180 days (a period thought to be driven by protocol-activities and short-term events). However, after 180 days (the ERG stated that this period relates to the long-term patient experience) fulvestrant 500 mg was associated with statistically significant improvements in TTP compared with anastrozole and letrozole.

3.26 Examination of post-progression survival data by the ERG also showed no statistically significant differences between fulvestrant 500 mg and 250 mg, suggesting that any overall survival gains associated with fulvestrant 500 mg were only obtained in the pre-progression phase (TTP). Therefore the ERG estimated a compatible set of survival estimates (TTP, post-progression survival and overall survival) for fulvestrant 250 mg, anastrozole and letrozole by calibrating an HR applied to the overall survival estimated for the fulvestrant 500 mg group, which generated a gain in overall survival equal to the corresponding gain in TTP. The ERG noted that although this is an approximation, it allows the timing of post-progression survival to be calculated without recourse to elaborate additional modelling. This approach appeared fully justified for anastrozole, because key clinical trials comparing anastrozole with fulvestrant 250 mg showed no statistically significant differences in TTP or overall survival. However, this approach was less clearly supported in the case of letrozole, because there are no trials that directly compare letrozole with fulvestrant.

3.27 The ERG noted several criticisms in relation to the design of the manufacturer’s economic model, which was based on separate parametric models of the time from randomisation to TTP and overall survival. The ERG commented that when different statistical functions are used to represent the two sets of data, or when the same function is used for both but does not satisfy proportional hazards criteria (that is, the risk of an event occurring on one treatment relative to another treatment is assumed not to change over time), it is possible for projected estimates of TTP to exceed the corresponding estimates of overall survival. Although the model corrected any negative post-progression survival estimates to zero, it did not compensate for any resultant overestimation of survival.Overall, the ERG concluded that the design of the manufacturer’s economic model is unlikely to provide a robust basis for projecting survival beyond the observed data.

3.28 The ERG identified a few issues in relation to the cost data used in the manufacturer’s model. First, the manufacturer’s model does not account for wastage of part-used dispensed packs at the time of disease progression. The ERG also questioned the use of the two expert opinions for pre-progression and post-progression health state costs, and instead proposed that such costs should be based on treatment pathways described in ‘Advanced breast cancer: diagnosis and treatment’ (NICE clinical guideline 81; 2009). The ERG also commented that the manufacturer’s model limits drug-related adverse events to serious adverse events only. Furthermore, the manufacturer’s approach of applying a single average cost of UK hospital admissions is simplistic and inappropriate for costing of adverse events associated with treatment complications in advanced breast cancer. The ERG calculated an alternative estimate of £3147 per episode, compared with the estimate in the manufacturer’s model of £1605 per episode. Overall, the ERG stated that making all of these modifications to the model increased the ICER in all cases but, because each change represents only a small element of the total cost, the increases were small.

3.29 Finally, the ERG noted an error in the utility values assigned to the pre-progression and post-progression health states in the manufacturer’s economic model. The age parameter used to generate these utility values was based on the age of the participants in the study of Lloyd et al. (2006) and not to the age of patients. The ERG proposed that, to ensure consistency with standard UK EQ-5D tariff scores, the mean age should be set to 47 years (the mean age of the original UK York study sample used). The ERG also accounted for the ‘responder status’ of patients (that is, whether or not their cancer responded to treatment) when estimating new utility values for both health states. In summary, using ERG estimated utility values of 0.7733 for the pre-progression state and 0.4964 for the post-progression state reduced the ICER for fulvestrant by £2700 per QALY gained compared with letrozole.

3.30 The ERG made eight separate modifications to explore the impact of the various issues described in the critique of the manufacturer’s economic model. Seven modifications were made to the economic model logic or parameter values, and the eighth modification involved using effectiveness data from the anti-oestrogen subpopulation in the CONFIRM trial instead of data from the whole trial population. The ERG presented detailed deterministic results separately for the manufacturer’s base-case scenario using the whole CONFIRM population and for the anti-oestrogen subpopulation.

3.31 n summary, based on the full CONFIRM trial population, the calculated deterministic cost-effectiveness results of the ERG’s exploratory analyses showed that fulvestrant 250 mg was extendedly dominated by the other comparators. The ICERs for anastrozole compared with letrozole and for fulvestrant 500 mg compared with anastrozole were both close to £30,000 per QALY gained. The ERG’s preferred exploratory deterministic cost-effectiveness analysis based on the anti-oestrogen subgroup from CONFIRM and an updated network meta-analysis resulted in fulvestrant 250 mg being extendedly dominated by the other comparators. The ICER for anastrozole compared with letrozole was £1162 per QALY gained, and the ICER for fulvestrant 500 mg compared with anastrozole was £34,972 per QALY gained.

3.32 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 fulvestrant, having considered evidence on the nature of locally advanced or metastatic breast cancer and the value placed on the benefits of fulvestrant by women 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 considered the views of the patient experts on their experience of fulvestrant as a treatment for locally advanced or metastatic breast cancer. It heard from a patient expert currently receiving fulvestrant and understood that patients value the availability of a further treatment option after aromatase inhibitors and anti-oestrogen therapies, both in its own value as treatment but also to delay the need for chemotherapy. The Committee also heard from this patient expert that, personally, the disadvantages of having two injections and the associated side effects of fulvestrant were outweighed by the benefits of remaining fit and well on this therapy.

4.3 The Committee considered the licensed indication for fulvestrant. It noted that fulvestrant has a marketing authorisation ‘for the treatment of postmenopausal women with oestrogen receptor positive, locally advanced or metastatic breast cancer for disease relapse on or after adjuvant anti-oestrogen therapy, or disease progression on therapy with an anti-oestrogen’. It noted comments from the ERG that it is not clear from the wording of the marketing authorisation that eligibility for treatment is dependent on the last therapy received and may include women who have received more than one previous line of treatment for metastatic breast cancer. However, the manufacturer confirmed that fulvestrant is licensed as a second-line treatment for metastatic breast cancer in postmenopausal women after adjuvant or first-line treatment of advanced disease with an anti-oestrogen therapy (for most patients this is usually tamoxifen). The Committee was aware that 42% of the patients in the CONFIRM trial had received an aromatase inhibitor as their last treatment before fulvestrant. It also heard from the manufacturer that the European Medicines Agency (EMA) had regarded the results for the aromatase inhibitor group as being inconclusive and had rejected the manufacturer’s request for an extension of the marketing authorisation for fulvestrant to include patients who have experienced treatment failure with an aromatase inhibitor. The Committee was thus aware of the restriction of the marketing authorisation to patients who had been treated previously with an anti-oestrogen, and the manufacturer’s confirmation of the licensed position, which placed fulvestrant as an alternative to aromatase inhibitors following anti-oestrogen treatment.

4.4 The Committee considered the likely position of fulvestrant in the treatment pathway for women with oestrogen-receptor-positive advanced breast cancer in the UK. The Committee also examined the recommendations on the use of endocrine therapy in the NICE clinical guidelines ’Early and locally advanced breast cancer: diagnosis and treatment’ (CG80) and ’Advanced breast cancer: diagnosis and treatment’ (CG81). It observed that aromatase inhibitors were recommended either as the sole, or as a significant part of, adjuvant treatment for most postmenopausal women with oestrogen-receptor-positive early breast cancer. The Committee also understood that aromatase inhibitors were recommended for postmenopausal women with oestrogen-receptor-positive advanced breast cancer who had no history of hormone therapy or who had been treated previously with tamoxifen. It heard from the clinical specialist that clinical practice follows these guidelines, in that most postmenopausal women receive an aromatase inhibitor as adjuvant hormone therapy for early breast cancer or as first-line treatment if presenting with advanced breast cancer. The use of tamoxifen in clinical practice as sole adjuvant treatment or as a first-line treatment for new locally advanced or metastatic breast cancer is diminishing, apart from for the small proportion of women who are unable to tolerate an aromatase inhibitor. The manufacturer stated in its submission that the split is approximately 20:80 between treatment with aromatase inhibitors and treatment with anti-oestrogens for patients whose disease progresses on or after adjuvant therapy. The Committee heard from the clinical specialist that the proportion of patients receiving aromatase inhibitors is increasing, given the changes in clinical practice over the years and therefore this ratio now increasingly favours the use of aromatase inhibitors. The clinical specialist also indicated that there was not thought to be any significant clinical difference between the effectiveness of anastrozole and letrozole for treating advanced disease. The clinical specialist informed the Committee that exemestane or tamoxifen may be given as a second-line treatment to women whose disease has failed to respond to an aromatase inhibitor given as either adjuvant therapy or first-line treatment for advanced disease, with the choice depending on a variety of factors, including an assessment of how well previous treatment had worked. The Committee heard from the clinical specialist that fulvestrant is currently considered to be a third-line or fourth-line treatment for postmenopausal women with metastatic breast cancer in UK clinical practice. It further heard that there is little or no clinical evidence about the optimal treatment sequence for advanced breast cancer beyond first-line treatment. The Committee considered that the most likely position of fulvestrant in UK clinical practice would remain as a third-line or fourth-line treatment after therapy with aromatase inhibitors and/or an anti-oestrogen therapy. The Committee again noted the difference between the manufacturer’s submission and clinical practice, and the restriction placed on the use of fulvestrant by it having a marketing authorisation for use after treatment with an anti-oestrogen. However, on the basis of the manufacturer’s confirmation of the licensed position for fulvestrant (section 4.3) it considered that third-line or fourth-line use was not within the remit of this appraisal.

4.5 The Committee considered the relevant comparator treatments for fulvestrant within its licensed indication. It understood that the scope listed low-dose fulvestrant (250 mg) and aromatase inhibitors (anastrozole, exemestane and letrozole) as the relevant treatment comparators. It heard from the manufacturer that fulvestrant 250 mg has been replaced by 500 mg as the licensed dose. The Committee considered the remaining comparators. It noted that for the positions in the treatment pathway for which the only evidence for fulvestrant was available, non-steroidal aromatase inhibitors such as anastrozole and letrozole are the most likely treatments to be used in clinical practice. It heard from the clinical specialist that, for women who are unable to tolerate non-steroidal aromatase inhibitors, exemestane would be the appropriate comparator if they have been treated previously with an anti-oestrogen. The Committee concluded that the aromatase inhibitors anastrozole, letrozole and exemestane are the most appropriate comparators for the appraisal of fulvestrant.

Clinical effectiveness

4.6 The Committee considered the clinical effectiveness data from the pivotal CONFIRM trial. It noted that the only comparator in CONFIRM was low-dose fulvestrant (250 mg). Relative to this comparator, the Committee noted that fulvestrant 500 mg offered benefits in increasing the TTP, but that the difference between groups was statistically significant only for those patients whose last therapy was an anti-oestrogen, and not for patients whose last therapy was an aromatase inhibitor. The Committee concluded that fulvestrant 500 mg offered some clinical benefit compared to low-dose fulvestrant (250 mg).

4.7 The Committee noted that the results of the network meta-analyses by the manufacturer showed no statistically significant differences in overall survival between fulvestrant and anastrozole and letrozole, although fulvestrant resulted in statistically significantly longer TTP compared with anastrozole but not letrozole. However, the Committee concluded that, because of the issues identified by the ERG around the fit of the parametric survival models used by the manufacturer, there was high uncertainty around the validity of these results.

4.8 The Committee considered the network meta-analysis which included aromatase inhibitors as comparators. It was aware that, although the marketing authorisation for fulvestrant 500 mg is for patients who have received previous anti-oestrogen treatment, the CONFIRM, FINDER-1 and FINDER-2 trial populations included some patients who had last received an aromatase inhibitor, whereas all other trials in the network included only patients who had previously received an anti-oestrogen. It further noted differences in the previous anti-oestrogen and previous aromatase inhibitor groups relating to the position of fulvestrant as a first-line or second-line therapy. Data from CONFIRM showed that, the majority (65.5%) of patients receiving fulvestrant after an anti-oestrogen therapy, received fulvestrant as a first-line treatment for metastatic breast cancer and the remainder (34.5%) received fulvestrant as a second-line treatment for metastatic breast cancer. Conversely, of the patients who received an aromatase inhibitor as their last treatment before fulvestrant, the majority (66%) received fulvestrant as a second-line treatment for advanced breast cancer. The Committee also noted the differences in demography in these anti-oestrogen and aromatase inhibitor populations and agreed with the ERG that these two groups were heterogeneous. Therefore the Committee agreed that only data from the subgroup in the CONFIRM trial that had received an anti-oestrogen as their last treatment before fulvestrant should be included in the network meta-analyses (and this would therefore accord with the marketing authorisation for fulvestrant).

4.9 The Committee considered the eligibility criteria for trials included in the network meta-analysis. It was aware that CONFIRM, FINDER-1 and FINDER-2 were the only trials with an entire patient population documented as having oestrogen-receptor-positive breast cancer. The Committee noted that the manufacturer had sought advice from key opinion leaders about setting firm criteria for the selection of trials for inclusion in the meta-analysis (for example, including only recent trials, or agreeing a stipulated percentage of patients with cancer of unknown oestrogen receptor status). No such criteria could be produced. The main inclusion criterion was relaxed by the manufacturer to include trials with no more than 30% of patients with cancer of unknown oestrogen receptor status. The Committee was aware that, based on this criterion, exemestane was excluded as a comparator owing to the lack of any relevant trials with at least 70% of patients with oestrogen-receptor-positive cancer. The percentage of patients with oestrogen-receptor-negative cancer in the trials included in the network meta-analysis ranged from 0 to 33%. The Committee also highlighted other sources of heterogeneity between the trials included in the network meta-analysis, including inclusion criteria, the median duration of follow-up, the amount of previous chemotherapy given, the types of recurrent and metastatic disease and the wide timespan of the included trials, which were published between 1996 and 2010. The Committee noted that fulvestrant 500 mg was only connected to other treatments in the network through fulvestrant 250 mg, which was used as the baseline comparator in the manufacturer’s network meta-analysis. It was further noted that the baseline characteristics of the patients  enrolled in the CONFIRM, FINDER-1 and FINDER-2 trials may not be directly comparable with patients enrolled in earlier studies, which compared fulvestrant 250 mg with anastrozole. The Committee also commented that the results of the network meta-analyses indicated better outcomes in terms of overall survival and TTP for letrozole 0.5 mg (which is unlicensed for this indication) compared with letrozole 2.5 mg (which is licensed) despite the results of two other trials (Dombernowsky et al. 1998; Gershanovich et al. 1998) that were excluded from the network meta-analyses, which showed superiority of letrozole 2.5 mg over the 0.5 mg dose. The Committee concluded that the results of the manufacturer’s network meta-analysis were subject to bias from the selection of studies included in the network and this therefore increased the uncertainty about the outputs of this analysis.

4.10 The Committee discussed the parametric survival models used to project TTP and overall survival. The Committee understood that the manufacturer had chosen a log-normal distribution and a Weibull distribution to model TTP and overall survival respectively for fulvestrant. The Committee heard from the ERG that fitting a log-normal distribution to TTP was not appropriate owing to a poor fit with the underlying data from the CONFIRM trial, and this resulted in a small number of patients with very long TTP influencing the results. It further heard from the ERG that using a parametric survival model to estimate overall survival may result in overestimation or underestimation of mean overall survival benefit. Instead, the ERG suggested in their exploratory analysis that the best estimate of overall survival is obtained from modelling post-progression on the basis of trial data and combining pre-progression and post-progression estimates. Overall, the Committee concluded that the manufacturer did not provide sufficient commentary or analysis of uncertainty around the fit of alternative parametric survival models and concluded that the estimates of TTP and overall survival based on the ERG’s exploratory analysis were more appropriate and were therefore preferred.

Cost effectiveness

4.11 The Committee considered the manufacturer’s economic model and the ERG’s critique of the model. The Committee agreed with the ERG that because two different statistical probability distributions were fitted to the two sets of data, it is possible for projected estimates of TTP to exceed the corresponding estimates of overall survival, which can lead to negative values for the number of patients alive in the post-progression state in the economic model. Although the model corrected any negative post-progression survival estimates to zero, it did not compensate for any resultant overestimation of survival. The Committee concluded that the manufacturer’s economic model is unlikely to provide a robust basis for projecting survival data beyond the observed data from the CONFIRM trial.

4.12 The Committee discussed the utility values applied to the pre-progression and post-progression health states by the manufacturer. The Committee agreed that, although the utility values (taken from Lloyd et al. 2006) were not generated in accordance with the NICE reference case, they probably represent the best published estimates available, although methodological uncertainty remains. However, it was agreed that the age parameter used to generate these utility values, which was based on the age of the participants in the study of Lloyd et al. (2006), should have been adjusted to the mean age of participants used to estimate UK EQ-5D tariff scores. The Committee also agreed with the ERG that the ‘responder status’ of patients should have been incorporated in the estimation of utility values for these two health states. The Committee concluded that the ERG’s adjusted utility values used in their exploratory analysis were preferable to those used by the manufacturer.

4.13 The Committee discussed the validity of the cost inputs used in the manufacturer’s economic model. The Committee agreed with the ERG in relation to the cost data used and that modifications to these parameters resulted in small increases in the ICER. The Committee also noted that the list price of anastrozole reported in the manufacturer’s submission may not be what the NHS usually pays. Therefore the Committee concluded that it is likely that the ICERs for fulvestrant compared with anastrozole would be an underestimate.

4.14 The Committee noted that the key drivers of the cost-effectiveness results in the manufacturer’s model were the estimates of TTP and overall survival for all treatments and the utility values assigned to the pre-progression and post-progression health states. The Committee highlighted the results of the manufacturer’s probabilistic sensitivity analysis, which indicated that fulvestrant 500 mg had a low probability of being cost effective (2%) at a threshold of £20,000 per QALY gained. The Committee also considered that the ICERs generated using the manufacturer’s model were not reliable owing to problems with the design of the model and the inclusion of the mixed patient population from the CONFIRM trial. The Committee agreed that the ICERs generated by the ERG’s exploratory analysis, which used different estimates of TTP and overall survival, included only the population from the CONFIRM trial whose last treatment had been an anti-oestrogen, revised cost inputs and adjusted the utility estimates, would be more reliable. However, the Committee noted that the ERG’s exploratory analysis was based on the same trials in the network meta-analysis as those used in the manufacturer’s network meta-analysis. The Committee considered that the network meta-analysis represented considerable uncertainty, which was unaccounted for in the ICERs. Overall, the Committee concluded that the ERG’s ICER of £35,000 per QALY gained for fulvestrant 500 mg compared with anastrozole was more plausible than the manufacturer’s base case estimate but there remained considerable uncertainty around this estimate.

4.15 The Committee noted that no comparison with exemestane could be made in the manufacturer’s base case cost-effectiveness analysis because of a lack of any relevant trials in which 70% or more of patients had oestrogen-receptor-positive advanced breast cancer in a population that had an anti-oestrogen as their last treatment. The Committee noted that, as a result, the cost effectiveness of exemestane compared with fulvestrant in this patient population remains unknown. The Committee further concluded that a cost-effectiveness analysis for a subgroup of people who are contraindicated to non-steroidal aromatase inhibitors would be desirable, but because the comparator treatment in such an analysis would be exemestane, this could not be undertaken. The Committee concluded that it was unable to recommend fulvestrant as an alternative to exemestane in postmenopausal women with oestrogen-receptor-positive, locally advanced or metastatic breast cancer, or disease progression on therapy with an anti-oestrogen who are contraindicated to non-steroidal aromatase inhibitors.

4.16 The Committee considered supplementary advice from NICE that should be taken into account when appraising treatments that may extend the life of patients with a 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 of 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.

4.17 The Committee discussed whether fulvestrant fulfilled the criteria for a life-extending, end-of-life treatment. The Committee was aware that fulvestrant was associated with an extension of life of at least an additional 3 months compared with anastrozole and letrozole, although these were based on the overall survival results obtained in the manufacturer’s economic model, which were associated with considerable uncertainty (section 4.9). The Committee considered that it was likely that fulvestrant is licensed for a small population (given the licence restriction to patients who have had previously received an anti-oestrogen, the declining use of tamoxifen and the increasing use of aromatase inhibitors) but that the precise population size is uncertain. The Committee agreed that, based on the results of the CONFIRM trial, fulvestrant is indicated for patients with a life expectancy of more than 24 months (the ERG’s estimate of mean overall survival for patients on fulvestrant 500 mg was 36.33 months, for anastrozole it was 32.31 months and for letrozole it was 31). Considering all the criteria, the Committee concluded that fulvestrant did not fulfil all of the end-of-life criteria.

4.18 The Committee considered the most plausible ICER for fulvestrant compared with anastrozole, which it had previously agreed was likely to be at least £35,000 per QALY gained (section 4.14). The Committee also noted the considerable uncertainty associated with this estimate. The Committee concluded that fulvestrant could not be considered a cost-effective use of NHS resources as an alternative to aromatase inhibitors for the treatment of oestrogen-receptor-positive, locally advanced or metastatic breast cancer in post-menopausal women whose cancer has relapsed on or after adjuvant anti-oestrogen therapy, or who have disease progression on anti-oestrogen therapy. 

Summary of Appraisal Committee’s key conclusions

TAXXX	Appraisal title: Fulvestrant for the treatment of locally advanced or metastatic breast cancer		Section
Key conclusion
Fulvestrant is not recommended as an alternative to aromatase inhibitors for the treatment of oestrogen-receptor-positive, locally advanced or metastatic breast cancer in postmenopausal women whose cancer has relapsed on or after adjuvant anti-oestrogen therapy, or who have disease progression on anti-oestrogen therapy.			1.1
Current practice
Clinical need of patients, including the availability of alternative treatments		The Committee heard from the clinical specialist and patient expert of the importance of having a further treatment option after aromatase inhibitors and anti-oestrogen therapies.	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 noted that although fulvestrant 500 mg offered benefits in terms of increased TTP compared with low-dose fulvestrant (250 mg) in the CONFIRM trial, this difference was statistically significant only for patients whose last therapy was an anti-oestrogen, and not for patients whose last therapy was an aromatase inhibitor. The Committee noted that the results of the network meta-analyses by the manufacturer showed no statistically significant differences in overall survival between fulvestrant and anastrozole and letrozole, although fulvestrant resulted in statistically significantly longer TTP compared with anastrozole but not letrozole. However, the Committee concluded there was high uncertainty around the validity of these results due to the parametric survival models used. No specific claim for innovation was made.	4.4, 4.6, 4.7
What is the position of the treatment in the pathway of care for the condition?		The Committee heard from the clinical specialist that, in clinical practice, most postmenopausal women receive an aromatase inhibitor as adjuvant hormone therapy for early breast cancer or as first-line treatment for advanced breast cancer. The Committee was aware that the use of tamoxifen for locally advanced or metastatic breast cancer is diminishing and the clinical specialist stated that the proportion of patients receiving aromatase inhibitors is increasing. The Committee concluded that the most likely position of fulvestrant in UK clinical practice would be as third-line or fourth-line treatment after therapy with aromatase inhibitors and/or an anti-oestrogen therapy. However, on the basis of the manufacturer’s confirmation of the licensed position for fulvestrant (section 4.3) it considered that third-line or fourth-line use was not within the remit of this appraisal.	4.4
Adverse effects		The Committee heard from the patient expert that, despite the disadvantages of having two intramuscular injections and associated side effects, these are outweighed by the benefits of remaining fit and well on this therapy.	4.2
Evidence for clinical effectiveness
Availability, nature and quality of evidence		The Committee was aware that the only treatment comparator in the CONFIRM trial was low-dose fulvestrant (250 mg). The Committee noted that although the marketing authorisation for fulvestrant 500 mg is for patients who have received previous anti-oestrogen therapy, the CONFIRM trial population consisted of a mixture of patients who had last received either an anti-oestrogen or an aromatase inhibitor. The Committee noted significant heterogeneity between these two subgroups in terms of previous treatment and patient characteristics. The Committee therefore concluded that only data from the subgroup in the CONFIRM trial that had received an anti-oestrogen as their last treatment should be included in the network meta-analyses. The Committee noted that CONFIRM, FINDER-1 and FINDER-2 trials, which compared fulvestrant 500 mg and 250 mg, were the only trials with an entire patient population documented as having oestrogen-receptor-positive breast cancer. The Committee was also aware that no firm eligibility criteria for trials included in the network meta-analyses could be produced by the manufacturer. The Committee noted that this inclusion criterion was relaxed to include trials with at least 70% of patients with oestrogen-receptor-positive cancer, which resulted in exemestane being excluded as a comparator. The Committee also noted other sources of heterogeneity between the trials included in the network meta-analysis. The Committee concluded that the results of the manufacturer’s network meta-analysis were subject to bias from the selection of studies included in the network. The Committee discussed the parametric survival models used by the manufacturer to project TTP and overall survival. The Committee agreed that fitting a log-normal distribution to TTP was not appropriate owing to a poor fit with the underlying data from the CONFIRM trial, which resulted in a small number of patients with a very long TTP influencing the results. The Committee also noted that using a separate parametric survival model to estimate overall survival may result in overestimation or underestimation of mean overall survival benefit. The Committee agreed with the ERG that the best estimate of overall survival is obtained from modelling post-progression on the basis of trial data and combining pre-progression and post-progression estimates.	4.6, 4.8, 4.9
Relevance to general clinical practice in the NHS		The Committee concluded that the most likely position of fulvestrant in UK clinical practice would remain as a third-line or fourth-line treatment after therapy with aromatase inhibitors and/or an anti-oestrogen therapy. However, on the basis of the manufacturer’s confirmation of the licensed position for fulvestrant (section 4.3) it considered that third-line or fourth-line use was not within the remit of this appraisal.	4.4
Uncertainties generated by the evidence		The Committee concluded that there was high uncertainty around the results of the manufacturer’s network meta-analysis because of heterogeneity between the studies selected and the parametric survival models used to project TTP and overall survival.	4.9, 4.10
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?		The Committee noted that the CONFIRM trial population consisted of a mixture of patients who had last received either an anti-oestrogen or an aromatase inhibitor. The Committee noted significant heterogeneity between these two subgroups in terms of previous treatment and patient characteristics. The Committee therefore concluded that only data from the subgroup in the CONFIRM trial that had received an anti-oestrogen as their last treatment should be included in the network meta-analyses.	4.8
Estimate of the size of the clinical effectiveness including strength of supporting evidence		The Committee noted that the results of the network meta-analyses by the manufacturer showed no significant differences in overall survival between fulvestrant and anastrozole and letrozole, although fulvestrant resulted in significantly longer TTP compared with anastrozole but not letrozole. However, the Committee concluded that, because of the issues identified by the ERG around the fit of the parametric survival models used by the manufacturer, there was high uncertainty around these results.	4.7
Evidence for cost effectiveness
Availability and nature of evidence		The Committee agreed with the ERG that, when different statistical probability distributions are fitted to the two sets of data, it is possible for projected estimates of TTP to exceed the corresponding estimates of overall survival, which can lead to negative values for the number of patients alive in the post-progression state in the economic model. The Committee concluded that the manufacturer’s model is unlikely to provide a robust basis for projecting survival data beyond the observed data from the CONFIRM trial.	4.11
Uncertainties around and plausibility of assumptions and inputs in the economic model		The Committee discussed the validity of the cost inputs used in the manufacturer’s economic model. The Committee agreed with the ERG in relation to the cost data used and that modifications to these parameters resulted in small changes in the calculated ICERs for fulvestrant.	4.13
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 discussed the utility values applied to the pre-progression and post-progression health states by the manufacturer. The Committee agreed that although the utility values were not generated in accordance with the NICE reference case, they probably represent the best published estimates available. However, the Committee agreed with the ERG that the utility values should have been adjusted for the age and responder status of the patients.	4.12
Are there specific groups of people for whom the technology is particularly cost effective?		The Committee noted that, as a result, the cost effectiveness of exemestane compared with fulvestrant in this patient population remains unknown. The Committee thought that a cost-effectiveness analysis for a subgroup of people who are contraindicated to non-steroidal aromatase inhibitors would be desirable, but the cost effectiveness was unknown. The Committee concluded that it was unable to recommend fulvestrant as an alternative to exemestane in postmenopausal women with oestrogen-receptor-positive, locally advanced or metastatic breast cancer, or disease progression on therapy with an anti-oestrogen who are contraindicated to non-steroidal aromatase inhibitors.	4.15
What are the key drivers of cost effectiveness?		The Committee noted that the key drivers of the cost-effectiveness results in the manufacturer’s model were the estimates of TTP and overall survival for all treatments and the utility values assigned to the pre-progression and post-progression health states.	4.14
Most likely cost-effectiveness estimate (given as an ICER)		The Committee agreed that the ICERs generated by the ERG’s analysis, which used different estimates of TTP and overall survival, included only the population from the CONFIRM trial whose last treatment had been an anti-oestrogen and adjusted the utility estimates, would be more reliable than the ICERs generated in the manufacturer’s model. Therefore, the Committee concluded that the ICER of £35,000 per QALY gained for fulvestrant 500 mg compared with anastrozole was the most reliable estimate of the relative cost effectiveness of fulvestrant.	4.14
Additional factors taken into account
Patient access schemes (PPRS)		No approved patient access scheme was submitted for the technology being appraised.
End-of-life considerations		The Committee concluded that fulvestrant did not fulfil all of the end-of-life criteria because, based on the results of the CONFIRM trial, fulvestrant is indicated for patient with a life expectancy of more than 24 months. The Committee also noted that, although fulvestrant was associated with an extension of life of at least an additional 3 months compared with anastrozole and letrozole, these results were based on the overall survival results obtained in the manufacturer’s economic model, which were associated with considerable uncertainty	4.17
Equalities considerations and social value judgements		No equality issues were identified during the scoping process or the appraisal.

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

• Advanced breast cancer: diagnosis and treatment. NICE clinical guideline 81 (2009). Available from www.nice.org.uk/guidance/CG81
• Early and locally advanced breast cancer: diagnosis and treatment. NICE clinical guideline 80 (2009). Available from www.nice.org.uk/guidance/CG80
• Gemcitabine for the treatment of metastatic breast cancer. NICE technology appraisal guidance 116 (2007). Available from www.nice.org.uk/guidance/TA116

Under development

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

• Eribulin for the treatment of locally advanced or metastatic breast cancer. NICE technology appraisal guidance (publication expected December 2011).

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 August 2014. 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.

Peter Clark
Chair, Appraisal Committee
August 2011

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.

Professor Usha Chakravarthy
Professor of Ophthalmology and Vision Sciences, The Queen’s University of Belfast

Professor Peter Clark (Chair)
Consultant Medical Oncologist, Clatterbridge Centre for Oncology

Dr Ian Davidson
Lecturer in Rehabilitation, University of Manchester

Professor Simon Dixon
Professor in Health Economics, University of Sheffield

Dr Martin Duerden
Assistant Medical Director, Betsi Cadwaladr University Health Board

Dr Alexander Dyker
Consultant Physician, Wolfson Unit of Clinical Pharmacology, University of Newcastle

Gillian Ells
Prescribing Advisor, NHS Sussex Downs and Weald

Dr Jon Fear
Consultant in Public Health Medicine, Head of Healthcare Effectiveness NHS Leeds

Paula Ghaneh
Senior Lecturer and Honorary Consultant, University of Liverpool

Niru Goenka
Consultant Physician, Countess of Chester NHS Foundation Trust

Dr Susan Griffin
Research Fellow, Centre for Health Economics, University of York

Professor Carol Haigh
Professor in Nursing, Manchester Metropolitan University

Alison Hawdale
Lay member

Professor John Hutton
Professor of Health Economics, University of York

Professor Peter Jones
Emeritus Professor of Statistics, Keele University

Dr Steven Julious
Senior Lecturer in Medical Statistics, University of Sheffield

Dr Rachel Lewis
Doctoral Researcher, Manchester Business School

Professor Jonathan Michaels (Vice Chair)
Professor of Vascular Surgery, University of Sheffield

Professor Femi Oyebode
Professor of Psychiatry & Consultant Psychiatrist, The National Centre for Mental Health

Dr John Radford
Director of Public Health, Rotherham Primary Care Trust

Dr Phillip Rutledge
GP and Consultant in Medicines Management, NHS Lothian

Dr Brian Shine
Consultant Chemical Pathologist, John Radcliffe Hospital, Oxford

Dr Murray D. Smith
Associate Professor in Social Research in Medicines and Health, University of Nottingham

Cliff Snelling
Lay member

Charles Waddicor
Chief Executive, NHS Berkshire

Mike Wallace
Health Economics & Reimbursement Director, Johnson & Johnson Medical Ltd

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

Joanne Holden
Technical Adviser

Kate Moore
Project Manager

Appendix B: Sources of evidence considered by the Committee

A. The Evidence Review Group (ERG) report for this appraisal was prepared by Liverpool Reviews and Implementation Group:

• Fleeman N, Bagust A, Boland A et al. (2011) Fulvestrant for the treatment of locally advanced or metastatic breast cancer. Liverpool Reviews and Implementation Group, The University of Liverpool

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:

• AstraZeneca

II Professional/specialist and patient/carer groups:

• Breakthrough Breast Cancer
• Breast Cancer Campaign
• Breast Cancer Care
• Cancer Research UK
• Macmillan Cancer Support
• Royal College of Nursing
• Royal College of Pathologists
• Royal College of Physicians

III Other consultees:

• Department of Health
• Welsh Government

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

• Commissioning Support Appraisals Service
• Department of Health, Social Services and Public Safety, Northern Ireland
• Healthcare Improvement Scotland
• AstraZeneca
• Pfizer
• Liverpool Reviews and Implementation Group
• National Institute for Health Research Technology Assessment Programme

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 fulvestrant by attending the initial Committee discussion and providing written evidence to the Committee. They are invited to comment on the ACD.

• Dr Andreas Makris, Consultant Clinical Oncologist, nominated by Royal College of Physicians – clinical specialist
• Tara Beaumont, Clinical Nurse Specialist, nominated by Breast Cancer Care – patient expert
• Marie Hecht, nominated by Breast Cancer Care – patient expert

D. 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.

• AstraZeneca