The Department of Health has asked the National Institute for Health and Clinical Excellence (NICE) to produce guidance on using bevacizumab in combination with a taxane for the first-line treatment of metastatic breast cancer in the NHS in England and Wales. The Appraisal Committee has considered the evidence submitted by the manufacturer and the views of non‑manufacturer consultees and commentators, and clinical specialists and patient experts.

This document has been prepared for consultation with the consultees. It summarises the evidence and views that have been considered, and sets out the draft recommendations made by the Committee. NICE invites comments from the consultees and commentators for this appraisal (see appendix B) and the public. This document should be read along with the evidence base (the evaluation report), which is available from www.nice.org.uk

The Appraisal Committee is interested in receiving comments on the following:

• Has all of the relevant evidence been taken into account?
• Are the summaries of clinical and cost effectiveness reasonable interpretations of the evidence?
• Are the provisional recommendations sound and a suitable basis for guidance to the NHS?
• Are there any aspects of the recommendations that need particular consideration to ensure we avoid unlawful discrimination against any group of people on the grounds of gender, race, disability, age, sexual orientation, religion or belief?

Note that this document is not NICE's final guidance on this technology. The recommendations in section 1 may change after consultation.

After consultation:

• The Appraisal Committee will meet again to consider the evidence, this appraisal consultation document and comments from the consultees.
• At that meeting, the Committee will also consider comments made by people who are not consultees.
• After considering these comments, the Committee will prepare the final appraisal determination (FAD).
• Subject to any appeal by consultees, the FAD may be used as the basis for NICE’s guidance on using bevacizumab in combination with a taxane for the first-line treatment of metastatic breast cancer in the NHS in England and Wales.

For further details, see the ‘Guide to the technology appraisal process’ (available at www.nice.org.uk).

The key dates for this appraisal are:

Closing date for comments: 30 July 2010

Second Appraisal Committee meeting: 18 August 2010

Details of membership of the Appraisal Committee are given in appendix A, and a list of the sources of evidence used in the preparation of this document is given in appendix B.

1 Appraisal Committee’s preliminary recommendations

1.1 Bevacizumab in combination with a taxane is not recommended for the first-line treatment of metastatic breast cancer.

2 The technology

2.1 Bevacizumab (Avastin, Roche) is a humanised anti-vascular endothelial growth factor (VEGF) monoclonal antibody that inhibits VEGF-induced signalling and inhibits VEGF-driven angiogenesis. This reduces vascularisation of tumours, thereby inhibiting tumour growth. Bevacizumab is administered by intravenous infusion. The recommended dose is 10 mg/kg body weight given once every 2 weeks or 15 mg/kg body weight given once every 3 weeks. Bevacizumab in combination with paclitaxel or docetaxel has a marketing authorisation for ‘first-line treatment of patients with metastatic breast cancer’.

2.2 The summary of product characteristics (SPC) lists the following adverse effects that may be associated with bevacizumab treatment: gastrointestinal perforations, fistulae, wound healing complications, hypertension, proteinuria, arterial and venous thromboembolism, haemorrhage, pulmonary haemorrhage/haemoptysis, congestive heart failure, reversible posterior leucoencephalopathy syndrome and neutropenia. For full details of side effects and contraindications, see the SPC.

2.3 Bevacizumab is available in 100-mg and 400-mg vials at net prices of £242.66 and £924.40, respectively (excluding VAT; ‘British national formulary’ [BNF] edition 59). The acquisition cost of bevacizumab (excluding VAT and assuming wastage) for a patient weighing 70 kg is £1652.38 at a dosage of 10 mg/kg every 2 weeks and £2576.78 at a dosage of 15 mg/kg every 3 weeks. This amounts to a monthly summary cost of £3304.76 at a dosage of 10 mg/kg every 2 weeks and £3435.70 at a dosage of 15 mg/kg every 3 weeks. 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 bevacizumab and a review of this submission by the Evidence Review Group (ERG; appendix B).

Clinical effectiveness

3.1 The manufacturer’s submission presented clinical-effectiveness data from one randomised, open-label, controlled trial (E2100). A total of 722 patients were randomised to either bevacizumab plus weekly paclitaxel (n = 368) or weekly paclitaxel alone (n = 354). All patients were given intravenous weekly paclitaxel (90 mg/m² over 1 hour) once a week for 3 weeks, with no treatment given at week 4. Patients in the bevacizumab plus weekly paclitaxel arm also received intravenous bevacizumab (10 mg/kg) every 2 weeks, until progression of disease or unacceptable toxicity occurred. There was no limit to the number of cycles of therapy allowed. The patients in the trial had locally recurrent or metastatic breast cancer and over 90% had HER2-negative breast cancer. The primary endpoint of the trial was duration of progression-free survival. Secondary endpoints were overall survival, objective response (complete response and partial response) rate, duration of response and health-related quality of life. Health-related quality of life was measured by the Functional Assessment of Cancer Therapy (FACT-B) questionnaire, which is a scale for measuring quality of life among breast cancer patients.

3.2 At the time of the manufacturer’s interim analysis most patients had discontinued randomised therapy; for 360 patients (50%) this was because of disease progression, and 131 patients (18%) withdrew from the study because of unacceptable toxicity. There was a statistically significant increase in median progression-free survival of 5.5 months, from 5.8 months in the paclitaxel alone arm to 11.3 months in the bevacizumab plus paclitaxel arm. The stratified hazard ratio for progression was 0.48 (95% confidence interval [CI] 0.39 to 0.61; p < 0.0001). The median overall survival was increased by 1.7 months, from 24.8 months with paclitaxel alone to 26.5 months with bevacizumab plus paclitaxel. The stratified hazard ratio for death was 0.87 (95% CI 0.72 to 1.05; p = 0.14), indicating a non-statistically significant improvement in overall survival with the combination therapy.

3.3 At baseline, 302 (87.3%) patients in the paclitaxel alone arm and 317 (88.8%) patients in the bevacizumab plus paclitaxel arm completed the FACT-B questionnaire. At week 33, 205 patients in the bevacizumab plus paclitaxel arm and 163 patients in the paclitaxel arm completed the questionnaire. If scores were missing at week 17 or week 33, the patient was not included in the analysis for that respective time point – except when disease progression or death was recorded earlier. For those patients who died or had disease progression, a value of zero (that is, the worst score) for each of the five subscales in the FACT-B questionnaire was imputed (rather than the patient being excluded from the analysis). With imputed values, the difference in total FACT-B score between the two treatment arms was statistically significant (p = 0.0046) in favour of the bevacizumab plus paclitaxel arm at week 33. There were no statistically significant differences between treatment arms at week 17, or at week 33 if imputed values were not used. The manufacturer stated that, taken together, these results demonstrated that the addition of bevacizumab to paclitaxel led to a relative improvement in health-related quality of life.

3.4 The safety analyses from the E2100 trial reported that the addition of bevacizumab to paclitaxel resulted in a 20% overall increase in the incidence of grade 3–5 adverse events. These included hypertension (16%), neuropathy (25.3%), proteinuria (3%), arterial thromboembolic events (3.6%), bleeding (2.2%) and congestive heart failure (2.2%). In addition, adverse event data from a non‑randomised single-arm, open-label study (ATHENA, n = 2251) were presented. The most frequent serious adverse events (grade 3–5) were febrile neutropenia (5.1%), neutropenia (3.6%) and pyrexia (1.5%).

3.5 The manufacturer carried out indirect comparisons for bevacizumab plus paclitaxel compared with docetaxel alone and gemcitabine plus paclitaxel. The comparisons were carried out by an indirect method using a common comparator (that is, 3-weekly paclitaxel). The manufacturer noted that studies conducted only in patients having first-line treatment for metastatic breast cancer were not always available, so the exclusion criteria specified that trials in which the majority of patients (more than 60%) were receiving second or later lines of treatment would be excluded. The manufacturer noted that one study used a higher docetaxel dose (100 mg/m² 3-weekly) and a longer duration of treatment (maximum 32 cycles) compared with standard UK practice (considered by the manufacturer to be 75 mg/m² 3-weekly; maximum 6–8 cycles). However, based on the similar populations, baseline characteristics and exclusion/inclusion criteria, the manufacturer assumed that heterogeneity would not be significant.

3.6 The hazard ratio for progression with bevacizumab plus weekly paclitaxel compared with docetaxel alone was estimated to be 0.56 (95% CI 0.39 to 0.78) and 0.46 (95% CI 0.34 to 0.64) compared with gemcitabine plus 3-weekly paclitaxel. For weekly paclitaxel compared with 3-weekly docetaxel the hazard ratio for progression was 1.15 (95% CI 0.89 to 1.48) and for weekly paclitaxel compared with gemcitabine plus 3-weekly paclitaxel the hazard ratio for progression was 0.96 (95% CI 0.76 to 1.21).

Cost effectiveness

3.7 The manufacturer’s model was a 3-state Markov model with a cycle length of 1 month. Patients in the model received treatment with either bevacizumab plus weekly paclitaxel or the comparator treatment, that is:

• weekly paclitaxel or
• docetaxel or
• gemcitabine plus 3-weekly paclitaxel.

Although bevacizumab plus docetaxel was included in the scope it was not formally evaluated in the manufacturer’s economic analysis.

3.8 Patients were assumed to be in one of three possible discrete health states at any given time: ‘progression-free survival’, ‘progressed’ or ‘death’. It was assumed that patients would have the same risk of dying after disease progression regardless of the first-line treatment they had received. In addition, the model assumed that patients would have the same sequence of further treatment and resource use after disease progression, regardless of their initial treatment. The number of patients who died while in the ‘progression-free survival’ state was determined either by background mortality or by the monthly rate at which patients died (from any cause) while progression‑free in the E2100 trial. In the base-case model, the progression-free mortality rates for weekly paclitaxel alone were used as a proxy for the mortality rates for docetaxel and gemcitabine plus paclitaxel.

3.9 The manufacturer provided two base-case analyses, both incorporating a 10-year time horizon:

• The first used the list prices in accordance with the NICE reference case. The prices for bevacizumab (total average cost per patient, £25,929) and paclitaxel (total average cost per patient, £7720) were taken from the BNF, edition 58.
• The second used an average NHS cost for paclitaxel (total average cost per patient, £649) based on the average price paid by NHS trusts over a 4‑month period and a patient access scheme whereby the NHS covers the cost of the first 10 g bevacizumab needed for each patient. Sensitivity analyses were only provided for this case. The patient access scheme (10-g cap) for bevacizumab has not currently been approved by the Department of Health.

3.10 The base-case utility values were taken from one study that derived utility values from oncology nurses, using the standard gamble technique. The values were 0.73 for progression-free survival (this was an average of values of 0.81 for response and 0.65 for stable disease), 0.45 for progressive disease, −0.21 for disutility from febrile neutropenia and for peripheral sensory neuropathy (both applied only in month 1 of experiencing the event). It was assumed that the remaining adverse events (hypersensitivity, infection and hypertension) would not have a notable impact on health-related quality of life.

3.11 The results based on the NHS list prices indicated incremental costs of £30,469, £31,416 and £27,358 and incremental quality‑adjusted life years (QALYs) of 0.259, 0.273 and 0.259 for bevacizumab plus weekly paclitaxel therapy relative to weekly paclitaxel, docetaxel and gemcitabine plus paclitaxel therapy respectively. The cost per QALY was £117,803, £115,059 and £105,777 for bevacizumab plus weekly paclitaxel therapy relative to weekly paclitaxel, docetaxel and gemcitabine plus paclitaxel therapy respectively. The results based on average prices paid by NHS trusts over a 4-month period for paclitaxel and the patient access scheme (not currently approved by the Department of Health) for bevacizumab indicated a cost per QALY of £77,314, £57,753 and £60,101 for bevacizumab plus weekly paclitaxel therapy relative to weekly paclitaxel, docetaxel and gemcitabine plus paclitaxel therapy respectively. The manufacturer stated that it can be inferred from the high incremental cost-effectiveness ratios (ICERs) in the model that bevacizumab plus docetaxel (the more expensive taxane) is unlikely to provide a more cost-effective outcome than the analysis presented in the submission and, hence, a full economic analysis of bevacizumab plus docetaxel was not presented.

3.12 The manufacturer carried out sensitivity analyses only on the second base-case scenario in which the average price of paclitaxel paid by NHS trusts over a 4-month period and the patient access scheme for bevacizumab were used. Using different parametric functions for survival extrapolation and alternative assumptions on treatment duration had the largest impact on the ICERs.

3.13 The manufacturer conducted further analyses in response to points of clarification from the ERG, incorporating a comparison of bevacizumab plus weekly paclitaxel with 3-weekly paclitaxel alone into the model. The ICER of bevacizumab plus weekly paclitaxel compared with 3-weekly paclitaxel was £59,339 per QALY gained using average prices paid by NHS trusts and incorporating the patient access scheme for bevacizumab. The manufacturer also incorporated the results of the evidence synthesis into the economic model as opposed to assuming that all comparators were equally effective. This was also based on the average price of paclitaxel paid by NHS trusts and the patient access scheme for bevacizumab. This resulted in an ICER for bevacizumab plus weekly paclitaxel compared with docetaxel and gemcitabine plus 3‑weekly paclitaxel of £59,310 and £51,795 per QALY gained respectively.

ERG comments

3.14 The ERG had several concerns about the selection and quality of the evidence presented in the manufacturer’s submission. The evaluation of the clinical effectiveness of bevacizumab was based primarily on a single trial comparing bevacizumab plus weekly paclitaxel with weekly paclitaxel alone. The ERG highlighted limitations in the methodological quality of the study, for example, lack of blinding and lack of data collection about treatments given after disease progression. The ERG noted concerns that as the conclusions about health-related quality of life were based primarily on the analyses using extreme imputed values for patients who had died or whose disease had progressed, the significant improvement in the FACT-B score stated by the manufacturer may not be reliable. The ERG noted that the results reported in the manufacturer’s submission were derived from interim analyses and that more recent follow-up data would be valuable, particularly for survival outcomes. The ERG also noted that the E2100 trial suggested that overall survival was not statistically significantly different between the treatment arms. However, the ERG was unable to establish whether or not the lack of overall survival difference was due to crossover between treatment groups or any other post‑progression events, because these data were not collected in the trial.

3.15 The ERG noted that the manufacturer had not presented any data on the clinical effectiveness of bevacizumab plus docetaxel. The ERG noted that a trial of bevacizumab plus docetaxel compared with docetaxel plus placebo (the AVADO trial) had not been included. In the AVADO study the intended dose of docetaxel was 100 mg/m² 3-weekly (that is, once every 3 weeks) for up to 9 cycles. The manufacturer stated that this dosing regimen was not considered representative of routine NHS clinical practice. However, clinical advice to the ERG indicated that the dose of docetaxel used in AVADO is used in routine clinical practice. Results from the AVADO study indicated a median progression‑free survival of 8.2 months in the docetaxel plus placebo arm, 9.0 months in the bevacizumab (7.5 mg/kg every 3 weeks) plus docetaxel arm (hazard ratio for progression compared with placebo, 0.86; p = 0.12) and 10.1 months in the bevacizumab (15 mg/kg every 3 weeks) plus docetaxel arm (hazard ratio for progression compared with placebo, 0.77; p = 0.006). Because of the lack of other data for comparison of effectiveness of bevacizumab plus docetaxel, the ERG also considered that data from the RIBBON-1 trial could have been included. In the RIBBON-1 study, patients were randomised to receive treatment with capecitabine, a taxane or anthracyclines plus bevacizumab or placebo. This study was excluded by the manufacturer because of insufficient statistical power for the relevant docetaxel comparison.

3.16 The ERG also highlighted a number of concerns about the indirect comparison conducted by the manufacturer. The ERG noted that an additional study (the Will Weekly Win study comparing weekly paclitaxel with 3-weekly paclitaxel, for which there were some data reported in an abstract) had not been identified and included by the manufacturer. The ERG noted that the inclusion criteria specified that studies could be included as long as fewer than 60% (rather than a strict majority of 50%) of patients were receiving second-line treatments for metastatic breast cancer. The ERG highlighted that the validity of the studies included in the indirect comparison had not been adequately assessed. The ERG also reported concerns about the methods of the indirect comparison, noting differences between patient populations and potentially important methodological limitations among the trials included in this comparison. In addition, the ERG considered that the statistical method used had been applied beyond its intended use in the submitted indirect comparison network. Given these methodological limitations, the ERG did not consider the findings of the indirect comparison to be reliable.

3.17 The ERG had a number of concerns about the economic model submitted by the manufacturer. The ERG considered that the series of pair wise comparisons for bevacizumab plus paclitaxel relative to each separate comparator regimen were inappropriate. They stated that, to establish the correct estimate of the ICER for bevacizumab plus paclitaxel, a fully incremental analysis should have been conducted, comparing all the regimens simultaneously. In addition, the ERG noted that the model assumed that mortality after disease progression was independent of initial treatment. It assumed that the rate of death after progression was constant over time and the same for all initial treatments. This meant that the differences in mean progression-free survival between treatments were maintained in the estimates of mean overall survival. The ERG stated that this was likely to have led to overestimates of overall survival for bevacizumab plus paclitaxel versus paclitaxel alone compared with the results of the E2100 trial.

3.18 The ERG highlighted that the base-case model did not include the results from the indirect comparison and made the assumption that all included comparators (docetaxel alone, paclitaxel alone and gemcitabine plus paclitaxel) were equally effective in terms of progression-free survival and overall survival. Additionally, in the second base case, the cost of bevacizumab was based on the NHS paying for a maximum dose of 10 g per patient and this patient access scheme had not been agreed with the Department of Health. The cost of paclitaxel used in the second base case was based on the average price by NHS trusts over a 4-month period, whereas other proprietary prices were taken from the BNF 58. The ERG also reported that the utility values were taken from a non-systematic review of the literature and that the reasoning for the choice of the study used to inform the utility values was not explained. In addition, the ERG noted that the manufacturer had not attempted to map health-related quality of life data from the E2100 study (measured by the FACT-B instrument) to a preference-based measure or collate alternative values.

3.19 The ERG conducted two sets of exploratory incremental analyses, both including 3‑weekly paclitaxel as a comparator. One was based on the revised results, that incorporated the indirect comparison undertaken by the manufacturer rather than assuming that all comparators were equally effective. The second analysis was based on the original approach employed by the manufacturer where all comparators were assumed to be equally effective. These analyses used the following drug acquisition costs:

• Case 1 (ERG re-analysis) – NHS list prices from BNF 58 excluding the patient access scheme for bevacizumab.
• Case 2 (manufacturer re-analysis) – average prices paid by NHS trusts over a 4-month period for paclitaxel including the patient access scheme for bevacizumab.
• Case 3 (ERG re-analysis) – average prices paid by NHS trusts for paclitaxel over a 4-month period excluding the patient access scheme for bevacizumab.

In both analyses, gemcitabine plus paclitaxel was dominated, in all cases, by weekly paclitaxel. In the first analysis for Case 1, weekly paclitaxel was extendedly dominated by docetaxel and therefore the relevant comparison was bevacizumab plus paclitaxel versus docetaxel. The ICER for this comparison was £118,362 per QALY gained (incremental cost of £31,362 and incremental QALY of 0.265). In the second analysis, docetaxel was the cheapest and least effective regimen. Therefore the relevant comparison in the second analysis was always bevacizumab plus paclitaxel versus weekly paclitaxel. For case 1, the ICER for bevacizumab plus paclitaxel versus weekly paclitaxel was £117,641 per QALY gained (incremental cost of £30,469 and incremental QALY of 0.259). For case 3 (not including the patient access scheme for bevacizumab) the ICER was £110,475 (incremental cost of £28,574 and incremental QALY of 0.259) per QALY gained.

3.20 The ERG agreed with the manufacturer’s conclusion that bevacizumab plus paclitaxel and bevacizumab plus docetaxel would be expected to be of similar effectiveness. Therefore the inclusion and exclusion of studies in the indirect comparison would not have a major effect. The analyses by the ERG found that the acquisition cost of docetaxel had very little effect on the ICER of bevacizumab plus paclitaxel compared with docetaxel. Alternative assumptions about utility values for the health states did not markedly affect the results. The ERG also evaluated bevacizumab plus docetaxel versus docetaxel based on the results of the AVADO trial. The pair wise ICER for this comparison was £254,530 per QALY gained (incremental cost of £34,712 and incremental QALY of 0.136).

3.21 The ERG conducted further exploratory analyses and calibrated the model to the E2100 trial results for overall survival. This was considered important to test the internal validity of the model by comparing the median progression-free survival and overall survival found by the E2100 trial with the model predictions. The pair wise ICER of bevacizumab plus paclitaxel versus weekly paclitaxel was £259,267 per QALY gained (incremental cost of £29,675 and incremental QALY of 0.114) in the exploratory analyses.

3.22 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 bevacizumab in combination with a taxane, having considered evidence on the nature of metastatic breast cancer and the value placed on the benefits of bevacizumab in combination with a taxane by people with metastatic breast cancer, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.

Clinical effectiveness

4.2 The Committee considered current clinical practice for the treatment of metastatic breast cancer. The Committee noted the manufacturer’s clarification response which stated that approximately 30% of patients receive a taxane as first-line treatment for metastatic disease. The clinical specialist stated that in current practice, taxanes (that is, weekly paclitaxel or 3-weekly docetaxel) are offered as first-line treatment for the majority of people with metastatic breast cancer in England and Wales. The Committee also heard from clinical specialists that 3-weekly paclitaxel is no longer routinely used in clinical practice, having been largely replaced by weekly dosing schedules. The Committee heard that the choice between the two taxanes is made locally and that weekly paclitaxel and 3-weekly docetaxel are considered to have comparable efficacy. The Committee concluded that the relevant comparators for bevacizumab in combination with a taxane for the first-line treatment of metastatic breast cancer are weekly paclitaxel and 3‑weekly docetaxel.

4.3 The Committee discussed the clinical effectiveness of bevacizumab in combination with a taxane. It heard that bevacizumab is the first VEGF-targeted therapy for this indication. The Committee considered the clinical effectiveness evidence presented by the manufacturer. It noted that the submission was based on one trial (E2100), which compared bevacizumab plus paclitaxel with weekly paclitaxel. The trial demonstrated a statistically significant increase in median progression-free survival of 5.5 months, from 5.8 months in the paclitaxel alone arm to 11.3 months in the bevacizumab plus paclitaxel arm. The Committee explored the value of an increase in progression-free survival with the clinical specialist and patient expert. It heard about the importance and significance of progression-free survival for patients in terms of being able to carry out normal daily activities, as well as being a therapeutic aim of treatment for clinicians. However, the Committee noted that the trial did not produce similar results for overall survival, with a non‑statistically significant increase in median survival of 1.7 months, from 24.8 months with paclitaxel alone to 26.5 months with bevacizumab plus paclitaxel. The Committee discussed the possible reasons for the increase in progression-free survival not being reflected in overall survival in the trial. It acknowledged that although it was possible that the relative treatment effect may have been confounded by crossover or other treatments received after disease progression, no data on this had been collected. In addition, the Committee heard from the ERG that the trial had several limitations, such as the lack of blinding and the absence of a placebo in the paclitaxel alone arm. The Committee heard from the clinical specialist that the response in E2100 to paclitaxel alone was lower than demonstrated in previous studies. The Committee concluded that it was likely that bevacizumab plus paclitaxel improved progression-free survival relative to weekly paclitaxel, but that there was no robust evidence that bevacizumab plus paclitaxel improved overall survival compared with weekly paclitaxel alone.

4.4 The Committee discussed the health-related quality of life data for bevacizumab plus paclitaxel compared with weekly paclitaxel. The Committee heard from the Primary Care Trust expert that robust data on the magnitude of quality of life improvements were important. The Committee noted concerns about the data presented by the manufacturer. It was aware that a statistically significant improvement in health-related quality of life at 33 weeks was only demonstrated when extreme values were imputed. The Committee also heard from the clinical specialist that the measures of psychological elements and emotional wellbeing were not provided by the manufacturer. The Committee concluded that the magnitude of health-related quality of life benefits with bevacizumab plus paclitaxel compared with paclitaxel alone was uncertain.

4.5 The Committee noted the safety results and the side-effect profile from the E2100 trial as well as a large uncontrolled study (ATHENA). The Committee noted that the frequency of grade 3–5 adverse events was slightly higher with the addition of bevacizumab to paclitaxel. However, the Committee heard from the clinical specialist that many of the adverse events were those expected in cytotoxic regimens, and could be attributed to the taxane. Increased treatment duration would also lead to an increase in the incidence of adverse events. The Committee understood that most adverse events could be satisfactorily managed (for example with dose reductions). Specific adverse events associated with bevacizumab, notably hypertension, were also readily treatable. The Committee concluded that the addition of bevacizumab did not lead to unacceptable toxicity compared with paclitaxel alone, and that adverse effects were manageable.

4.6 The Committee noted that no clinical evidence of the effectiveness of bevacizumab plus docetaxel was presented by the manufacturer. The Committee heard from the ERG that a trial comparing bevacizumab plus docetaxel with 3-weekly docetaxel alone (AVADO) was potentially relevant, and has recently been published. The Committee understood that the manufacturer had not considered the trial in its submission because the dose of docetaxel (100 mg/m²) was considered to be higher than that used in clinical practice. The Committee heard from the clinical specialist that 100 mg/m² was the standard dose used in the absence of contraindications, and that therefore the trial data were relevant to UK clinical practice. The clinical specialist also highlighted the high methodological quality of the AVADO trial and its placebo‑controlled design. The Committee noted the publically available results from this study that demonstrated an approximate 2-month, statistically significant, improvement in progression-free survival for bevacizumab at a dose of 15 mg/m² plus docetaxel, and non-statistically significant 0.8 months for bevacizumab 7.5 mg/m² plus docetaxel compared with docetaxel alone. The Committee concluded that bevacizumab plus docetaxel was modestly clinically effective compared with docetaxel alone in terms of progression-free survival.

4.7 The Committee discussed the indirect comparison presented by the manufacturer. The Committee noted the ERG’s comments related to the reliability of the indirect comparison. The quality of the included studies was variable, and the trials included variable numbers of patients receiving second-line treatment, where the prognosis is likely be worse than for first-line chemotherapy. Also, it was not clear that the selection criteria for included studies had been consistently applied, with the AVADO trial being excluded on the grounds of the docetaxel dose used, while another study using the same dose of docetaxel was included. The Committee concluded that the results from the indirect comparison were not robust.

4.8 The Committee discussed whether there were any equality and diversity issues relating to population groups protected by equality legislation. It noted information from the manufacturer’s submission relating to the potential for worse outcomes in lower socioeconomic groups or by ethnicity. The Committee heard from clinical specialists that there may be differences in overall treatment outcomes between these groups, but that they are likely to result from factors such as lower uptake of screening or later presentation of disease rather than differences in treatment. The Committee concluded that there was no evidence of differences in access to treatment or response to treatment by socioeconomic status or ethnicity in patients with disease at the metastatic stage.

4.9 The Committee explored whether there were any specific subgroups of patients for whom bevacizumab might be more clinically effective. The Committee heard from the clinical specialist that it was plausible that bevacizumab would be more effective in some tumour types than others, but that currently there is no robust evidence of any differential benefit. The Committee noted that the subgroup of triple negative cancers, that is cancers that do not have receptors for oestrogen, progesterone or HER2, have worse outcomes and that this subgroup may be over-represented in some ethnic groups. The Committee noted the clinical specialist’s comment that further research into whether there are any clinical or biological subgroups (such as subgroups by biological markers) for whom bevacizumab is particularly beneficial would be useful but concluded that no robust evidence on subgroups was currently available.

Cost effectiveness

4.10 The Committee discussed the pair wise cost-effectiveness estimates of bevacizumab plus paclitaxel as presented by the manufacturer. The Committee noted that the manufacturer had provided two base cases, one of which was based on average prices paid by NHS trusts for paclitaxel over a 4-month period and a patient access scheme for bevacizumab. The Committee was aware that no patient access scheme had been approved by the Department of Health and therefore the scheme could not be taken into account in the consideration of cost effectiveness. The Committee was also aware that the manufacturer had used average prices paid by NHS trusts over a 4-month period rather than a nationally agreed discounted price that is consistently available to the NHS and that this was not in accordance with the NICE methods guide. In addition, the Committee considered that if the average prices paid by NHS trusts were used for paclitaxel then they should also be used for other treatments in the model. Although the Committee noted comments from the ERG that the inclusion of average prices over a 4-month period rather than NHS list prices did not have a large impact on the cost-effectiveness results, the Committee concluded that the analyses which incorporated the NHS list prices for all drug treatments were the most appropriate for consideration.

4.11 The Committee was aware that the manufacturer’s analysis used a series of pair wise comparisons for bevacizumab plus paclitaxel relative to each separate comparator regimen. The Committee accepted comments from the ERG that the correct methodological approach would be a fully incremental analysis. The Committee noted that the incremental analysis carried out by the ERG resulted in ICERs that were similar to the pair wise ICERs. The Committee therefore concluded that, taking this into account, together with the fact that the ERG’s exploratory analyses had been conducted using the pair wise ICERs, these were appropriate for consideration in this instance.

4.12 The Committee noted that the manufacturer’s base case assumed that the clinical effectiveness of all comparators (that is 3-weekly docetaxel, gemcitabine plus paclitaxel and 3-weekly paclitaxel) was the same as weekly paclitaxel. The manufacturer subsequently conducted revised analyses substituting the clinical effectiveness results from the indirect comparison. The Committee noted its earlier conclusions that the results of the indirect comparison were not reliable and that there were only two relevant comparators. In addition, the Committee heard from the clinical specialist that weekly paclitaxel and 3-weekly docetaxel were not considered to demonstrate clinically meaningful differences in effectiveness. The Committee concluded that the cost-effectiveness estimates derived from assuming comparators had equivalent effectiveness to weekly paclitaxel were acceptable.

4.13 The Committee discussed the way in which the manufacturer had modelled overall survival in the economic model. It noted that a key assumption made by the manufacturer was that patients would have the same risk of dying per unit time once disease progressed, regardless of the first-line treatment they had received. This resulted in improvements in observed progression-free survival being carried over to projected improvements in overall survival. The Committee was aware that there are various ways of modelling which would result in different estimates of overall survival. The Committee noted that the manufacturer’s model (whereby overall survival was independent of previous treatments received) resulted in mean life years of 2.68 years in the bevacizumab plus paclitaxel arm and 2.33 years in the paclitaxel alone arm (incremental benefit of 0.35 years) and a pair wise ICER of £118,000 per QALY gained. The manufacturer indicated that this represented an optimistic scenario compared with the trial data. The Committee also examined the exploratory analyses carried out by the ERG that attempted to calibrate the overall survival in the model with that directly observed in the E2100 trial by using an area under the curve method. These analyses resulted in mean life years of 2.17 years in the bevacizumab plus paclitaxel arm and 2.13 years in the paclitaxel alone arm (incremental benefit of 0.03 years) and a pair wise ICER of £259,000 per QALY gained. The ERG acknowledged that this represented a pessimistic scenario. The Committee therefore concluded that the true ICER for bevacizumab plus paclitaxel compared with weekly paclitaxel probably lay between £118,000 and £259,000 per QALY gained. The Committee noted that the ICER for bevacizumab plus paclitaxel versus docetaxel alone presented by the manufacturer was £115,000 per QALY gained. Although the ERG did not conduct a further exploratory analysis for this comparison, the Committee considered that it would also have resulted in a substantially higher ICER. The Committee concluded that the true pair wise ICER for bevacizumab plus paclitaxel compared with 3‑weekly docetaxel was over £115,000 per QALY gained.

4.14 The Committee noted that the manufacturer did not provide any clinical or cost-effectiveness data related to bevacizumab plus docetaxel, even though it was specified in the scope. The Committee considered the manufacturer’s statement that it can be inferred from the high ICERs in the model that bevacizumab plus docetaxel (the more expensive taxane) is unlikely to provide a more cost‑effective outcome than the analysis presented in the submission and, hence, a full economic analysis of bevacizumab plus docetaxel was not warranted. The Committee agreed with this statement and considered that the ICER for bevacizumab plus docetaxel would be higher than the ICER for bevacizumab plus paclitaxel compared with weekly paclitaxel and 3-weekly docetaxel.

4.15 The Committee considered supplementary advice from NICE that should be taken into account when appraising treatments that may extend the life of people 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 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 the assumptions used in the reference case economic modelling are plausible, objective and robust.

4.16 The Committee discussed whether bevacizumab in combination with a taxane for the first-line treatment of metastatic breast cancer fulfilled the criteria for a life-extending, end-of-life treatment. The Committee noted that the E2100 trial data indicated that median overall survival in the paclitaxel alone arm was 24.8 months. The Committee considered that bevacizumab would be used in a clinical situation in which the life expectancy was just above the defined limit of life expectancy of less than 24 months in the end-of-life criteria. The Committee also noted that there was a median increase of 1.7 months in overall survival with bevacizumab plus paclitaxel compared with paclitaxel alone. The Committee accepted that, although it was possible that this increase had been underestimated (because of the possibility of crossover or additional treatments), there was no robust evidence that bevacizumab plus paclitaxel offers an extension to life of an additional 3 months, compared with paclitaxel alone. The Committee also noted that bevacizumab is licensed for a relatively large population across a range of indications such as colorectal cancer, non-small cell lung cancer and renal cell carcinoma, and hence does not meet the third criterion that the treatment should be licensed for small populations. The Committee concluded that bevacizumab in combination with a taxane did not fulfil the criteria for being a life‑extending, end-of-life treatment.

4.17 In summary, the Committee concluded that the most plausible ICER for bevacizumab plus paclitaxel versus weekly paclitaxel was between £118,000 and £259,000 per QALY gained and that the ICER for bevacizumab plus paclitaxel versus docetaxel would be greater than £115,000 per QALY gained. The Committee accepted the manufacturer’s statement that the ICER for bevacizumab plus docetaxel would be higher than that for bevacizumab plus paclitaxel since docetaxel is the more expensive taxane. The Committee concluded that bevacizumab in combination with a taxane as a first-line treatment for metastatic breast cancer was not a cost-effective use of NHS resources.

Summary of Appraisal Committee’s key conclusions

TAXXX (STA)	Appraisal title: Bevacizumab in combination with a taxane for the first-line treatment of metastatic breast cancer	ACD section
Key conclusion
Bevacizumab in combination with a taxane is not recommended for the first-line treatment of metastatic breast cancer. The Committee concluded that bevacizumab in combination with a taxane as a first-line treatment for metastatic breast cancer was not a cost-effective use of NHS resources.		1.1, 4.17
Current practice
Clinical need of patients including the availability of alternative treatments	The clinical specialist stated that in current practice, taxanes (that is, weekly paclitaxel or 3-weekly docetaxel) are offered as first-line treatment for the majority of people with metastatic breast cancer in England and Wales.	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 that bevacizumab is the first VEGF-targeted therapy for this indication. The Committee heard about the importance and significance of progression-free survival for patients in terms of being able to carry out normal daily activities, as well as being a therapeutic aim of treatment for clinicians. The Committee concluded that it was likely that bevacizumab plus paclitaxel improved progression-free survival, but that there was no robust evidence that bevacizumab plus paclitaxel improved overall survival compared with weekly paclitaxel alone. The Committee concluded that the magnitude of health-related quality of life benefits with bevacizumab plus paclitaxel compared with paclitaxel alone was uncertain.	4.3, 4.4
What is the position of the treatment in the pathway of care for the condition?	Bevacizumab in combination with paclitaxel or docetaxel has a marketing authorisation for ‘first-line treatment of patients with metastatic breast cancer’.	2.1
Adverse events	The Committee understood that most adverse events could be satisfactorily managed (for example with dose reductions). Specific adverse events associated with bevacizumab, notably hypertension, were also readily treatable. The Committee concluded that the addition of bevacizumab did not lead to any unacceptable toxicity compared with paclitaxel alone, and that adverse effects were manageable.	4.5
Evidence for clinical effectiveness
Quality, availability and nature of evidence	The Committee noted that the submission was based on one trial (E2100) which compared bevacizumab plus paclitaxel with weekly paclitaxel. The Committee heard from the ERG that the trial had several limitations, such as the lack of blinding, and the absence of a placebo in the paclitaxel alone arm. The Committee heard from the clinical specialist that the response in E2100 to paclitaxel alone was lower than demonstrated in previous studies. The Committee concluded that it was likely that bevacizumab plus paclitaxel improved progression-free survival relative to weekly paclitaxel, but that there was no robust evidence that bevacizumab plus paclitaxel improved overall survival compared with weekly paclitaxel alone. The Committee noted that no clinical evidence of the effectiveness of bevacizumab plus docetaxel was presented by the manufacturer, even though a trial comparing bevacizumab plus docetaxel with 3-weekly docetaxel alone (AVADO) has recently been published. The Committee noted the ERG’s comments related to the reliability of the indirect comparison. The quality of the included studies was variable, and the trials included variable numbers of patients receiving second-line treatment, where the prognosis is likely be worse than for first-line chemotherapy. Also, it was not clear that the selection criteria for included studies had been consistently applied, with the AVADO trial being excluded on the grounds of the docetaxel dose used, while another study using the same dose of docetaxel was included. The Committee concluded that the results from the indirect comparison were not robust.	4.3, 4.6, 4.7
Relevance to general clinical practice in the NHS	The Committee concluded that the relevant comparators for bevacizumab in combination with a taxane for the first-line treatment of metastatic breast cancer are weekly paclitaxel and 3-weekly docetaxel. The Committee noted that the submission was based on one trial (E2100) which compared bevacizumab plus paclitaxel with weekly paclitaxel. The Committee understood that the manufacturer had not considered the AVADO trial in its submission because the dose of docetaxel (100 mg/m2) was considered to be higher than that used in clinical practice. The Committee heard from the clinical specialist that the dose used in the trial was standard for 3-weekly docetaxel in the absence of contraindications and therefore the trial data were relevant to UK clinical practice. The Committee noted that no clinical evidence of the effectiveness of bevacizumab plus docetaxel was presented by the manufacturer, even though a trial comparing bevacizumab plus docetaxel with 3-weekly docetaxel alone (AVADO) has recently been published.	4.2, 4.6, 4.7
Uncertainties generated by the evidence	The Committee concluded that it was likely that bevacizumab plus paclitaxel improved progression-free survival relative to weekly paclitaxel, but that there was no robust evidence that bevacizumab plus paclitaxel improved overall survival compared with weekly paclitaxel alone. The Committee was aware that a statistically significant improvement in health-related quality of life at 33 weeks was only demonstrated when extreme values were imputed. The Committee also heard from the clinical specialist that the measures of psychological elements and emotional wellbeing were not provided by the manufacturer. The Committee concluded that the magnitude of health-related quality of life benefits with bevacizumab plus paclitaxel compared with paclitaxel alone was uncertain.	4.3, 4.4.
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?	The Committee heard from the clinical specialist that it was plausible that bevacizumab would be more effective in some tumour types than others, but that currently there is no robust evidence of any differential benefit.	4.9
Estimate of the size of the clinical effectiveness including strength of supporting evidence	The Committee noted that the submission was based on one trial (E2100), which compared bevacizumab plus paclitaxel with weekly paclitaxel. The trial demonstrated a statistically significant increase in median progression-free survival of 5.5 months, from 5.8 months in the paclitaxel alone arm to 11.3 months in the bevacizumab plus paclitaxel arm. However, the Committee noted that the trial did not produce similar results for overall survival, with a non-statistically significant increase in median survival of 1.7 months, from 24.8 months with paclitaxel alone to 26.5 months with bevacizumab plus paclitaxel. The Committee noted that no clinical evidence of the effectiveness of bevacizumab plus docetaxel was presented by the manufacturer. The Committee heard from the ERG that a trial comparing bevacizumab plus docetaxel with 3-weekly docetaxel alone (AVADO) was potentially relevant, and has recently been published. The Committee noted the publically available results from this study that demonstrated an approximate 2-month, statistically significant, improvement in progression-free survival for bevacizumab at a dose of 15 mg/m2 plus docetaxel, and non-statistically significant 0.8 months for bevacizumab 7.5 mg/m2 plus docetaxel compared with docetaxel alone.	4.3, 4.6
Evidence for cost effectiveness
Availability and nature of evidence	The manufacturer used a Markov model to evaluate the cost effectiveness of bevacizumab plus paclitaxel compared with weekly paclitaxel, 3-weekly docetaxel and gemcitabine plus paclitaxel, using pair wise comparison for bevacizumab plus paclitaxel with each separate comparator regimen. As an additional analysis, the manufacturer presented a comparison with 3-weekly paclitaxel. Bevacizumab plus docetaxel was not formally evaluated.	4.11, 4.14
Uncertainties around and plausibility of assumptions and inputs in the economic model	A key assumption made by the manufacturer was that patients would have the same risk of dying per unit time once disease progressed, regardless of the first-line treatment they had received. This resulted in improvements in observed progression-free survival being carried over to projected improvements in overall survival, resulting in an incremental benefit of 0.35 years between the paclitaxel alone arm and the bevacizumab plus paclitaxel arm and a pair wise ICER of £118,000 per QALY gained. The manufacturer indicated that this represented an optimistic scenario. The Committee also examined the exploratory analyses carried out by the ERG that attempted to calibrate the overall survival in the model with that directly observed in the E2100 trial by using an area under the curve method. These analyses resulted in mean life years of 2.17 years in the bevacizumab plus paclitaxel arm and 2.13 years in the paclitaxel alone arm (incremental benefit of 0.03 years) and a pair wise ICER of £259,000 per QALY gained. The ERG acknowledged that this represented a pessimistic scenario.	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?	No health-related benefits were identified that were not included in the economic models	N.A.
Most likely cost-effectiveness estimate (given as an ICER)	The Committee concluded that the most plausible ICER for bevacizumab plus paclitaxel versus weekly paclitaxel was between £118,000 and £259,000 per QALY gained and that the ICER for bevacizumab plus paclitaxel versus docetaxel would be greater than £115,000 per QALY gained. The Committee accepted the manufacturer’s statement that the ICER for bevacizumab plus docetaxel would be higher than that for bevacizumab plus paclitaxel since docetaxel is the more expensive taxane.	4.17
Additional factors taken into account
Patient access scheme	The Committee noted that the manufacturer had provided two base cases, one of which was based on average prices for paclitaxel paid by NHS trusts over a 4-month period and included a patient access scheme for bevacizumab. The Committee was aware that no patient access scheme had been approved by the Department of Health and therefore the scheme could not be taken into account in the consideration of cost effectiveness.	4.10
End-of-life considerations	The Committee concluded that bevacizumab in combination with a taxane did not fulfil the criteria for being a life-extending, end-of-life treatment.	4.16
Equalities considerations, Social value judgements	The Committee concluded that there was no evidence of differences in access to treatment or response to treatment by socioeconomic status or ethnicity in patients with disease at the metastatic stage.	4.8

5 Implementation

5.1 The Secretary of State and the Welsh Assembly Minister for Health and Social Services have issued directions to the NHS on implementing NICE technology appraisal guidance. When a NICE technology appraisal recommends use of a drug or treatment, or other technology, the NHS must 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. The NHS is not required to fund treatments that are not recommended by NICE.

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 report and costing template to estimate the 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 Proposed recommendations for further research

6.1 Further research into whether there are any clinical or biological subgroups (such as subgroups by biological markers) for whom bevacizumab is particularly beneficial would be useful.

7 Related NICE guidance

Published

• Advanced breast cancer: diagnosis and treatment. NICE clinical guideline 81 (2009). Available from www.nice.org.uk/guidance/CG81
• Bevacizumab for the first-line treatment of metastatic breast cancer (terminated appraisal). NICE technology appraisal guidance 147 (2008). Available from www.nice.org.uk/guidance/TA147
• Gemcitabine for the treatment of metastatic breast cancer. NICE technology appraisal guidance 116 (2007). Available from www.nice.org.uk/guidance/TA116

8 Proposed date for review of guidance

8.1 NICE proposes that the guidance on this technology is considered for review by the Guidance Executive in July 2013. 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.

Jane Adam
Chair, Appraisal Committee
July 2010

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 Jane Adam (Chair)
Department of Diagnostic Radiology, St George’s Hospital

Professor Philip Home (Vice Chair)
Professor of Diabetes Medicine, Newcastle University

Professor A E Ades
Professor of Public Health Science, Department of Community Based Medicine, University of Bristol

Dr Fiona Duncan
Clinical Nurse Specialist, Anaesthetic Department, Blackpool Victoria Hospital, Blackpool

Dr Paul Ewings
Statistician, Taunton & Somerset NHS Trust, Taunton

Mr John Goulston
Chief Executive, Barking, Havering and Redbridge Hospitals NHS Trust

Mr Adrian Griffin
VP Strategic Affairs, LifeScan, Johnson & Johnson

Dr Ann Richardson
Lay Member

Mr David Thomson
Lay Member

Dr Luke Twelves
General Practitioner, Ramsey Health Centre, Cambridgeshire

Mr Mike Spencer
Assistant Director Patient Experience, Cardiff and Vale University Health Board

Dr David Newsham
Lecturer (Orthoptics), University of Liverpool

Professor Iain Squire
Consultant Physician, University Hospitals of Leicester

Dr Peter Heywood
Consultant Neurologist, Frenchay Hospital

Dr Ian Lewin
Consultant Endocrinologist, North Devon District Hospital

Dr Louise Longworth
Reader in Health Economics, HERG, Brunel University

Dr Anthony S Wierzbicki
Consultant in Metabolic Medicine/Chemical Pathology, Guy’s and St Thomas’ Hospitals NHS Trust

Professor Jonathan Grigg
Professor of Paediatric Respiratory and Environmental Medicine, Barts and the London School of Medicine and Dentistry, Queen Mary University London

Dr John Watkins
Clinical Senior Lecturer/Consultant in Public Health Medicine, Cardiff University and National Public Health Service Wales

Dr Olivia Wu
Reader in Health Economics, University of Glasgow

Dr Paul Robinson
Medical Director, Merck Sharp & Dohme

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.

Raisa Sidhu
Technical Lead

Rebecca Trowman
Technical Adviser

Bijal Joshi
Project Manager

Appendix B: Sources of evidence considered by the Committee

A The Evidence Review Group (ERG) report for this appraisal was prepared by The CRD and CHE Technology Assessment Group, University of York:

• Rodgers M, et al., Bevacizumab in combination with a taxane for the first-line treatment of HER2-negative metastatic breast cancer, May 2010

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:

• Roche Products

II Professional/specialist and patient/carer groups:

• Breakthrough Breast Cancer
• Breast Cancer Care
• Royal College of Nursing
• Royal College of Physicians (NCRI Breast Clinical Studies Group/RCP/RCR/ACP/JCCO)

III Other consultees:

• NHS Kensington and Chelsea
• NHS Milton Keynes

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 bevacizumab in combination with a taxane for the first-line treatment of metastatic breast cancer by attending the initial Committee discussion and providing written evidence to the Committee. They are invited to comment on the ACD.

• Dr Paul Ellis, Senior Medical Oncologist, Guys Hospital, nominated by The Royal College of Physicians (NCRI/RCP/RCR/ACP/JCCO) – clinical specialist
• Ms Maria Leadbeater, nominated by Breast Cancer Care – patient expert

D The following individuals were nominated as NHS Commissioning experts by the selected PCT allocated to this appraisal. They gave their expert/NHS commissioning personal view on bevacizumab in combination with a taxane for the first-line treatment of metastatic breast cancer by attending the initial Committee discussion and providing written evidence to the Committee. They are invited to comment on the ACD.

• Dr Don Sinclair, Public Health Consultant, nominated by NHS Milton Keynes – 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.

• Roche Products