The Department of Health has asked the National Institute for Health and Clinical Excellence (NICE) to produce guidance on using axitinib 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).

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 race, gender, disability, religion or belief, sexual orientation, age, gender reassignment, pregnancy and maternity?

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 axitinib in the NHS in England and Wales.

For further details, see the Guide to the technology appraisal process

The key dates for this appraisal are:

Closing date for comments: 11 January 2013

Second Appraisal Committee meeting: 13 February 2013

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.

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

1  Appraisal Committee’s preliminary recommendations

1.1  Axitinib is not recommended within its marketing authorisation, that is, for the treatment of adults with advanced renal cell carcinoma after failure of prior treatment with sunitinib or a cytokine.

1.2  People currently receiving axitinib that is not recommended according to 1.1 should be able to continue treatment until they and their clinician consider it appropriate to stop.

2  The technology

2.1  Axitinib (Inlyta, Pfizer) is an oral multi-targeted kinase inhibitor with anti-tumour activity. Axitinib selectively inhibits vascular endothelial growth factor receptors 1, 2 and 3, platelet-derived growth factor receptor, and c-kit, which may inhibit angiogenesis in tumours. Axitinib has a marketing authorisation for ‘the treatment of adult patients with advanced renal cell carcinoma, after failure of prior treatment with sunitinib or a cytokine’.

2.2  The summary of product characteristics lists the following adverse reactions for axitinib: diarrhoea, hypertension, fatigue, dysphonia, nausea, decreased appetite, palmar–plantar erythrodysaesthesia (hand–foot syndrome), hypothyroidism, headache, dysgeusia, haemorrhage, vomiting, stomatitis, constipation, rash, dry skin, proteinuria, asthaenia and mucosal inflammation. For full details of adverse reactions and contraindications, see the summary of product characteristics.

2.3  Axitinib is available in 1-mg and 5-mg film-coated tablets at net prices of £703.40 and £3517 per 56-tablet pack respectively (excluding VAT). Axitinib is administered orally at a recommended starting dose of 5 mg twice daily. This dose may be increased to 7 mg and then up to 10 mg, or decreased to 3 mg and then down to 2 mg, depending on individual safety and tolerability. The manufacturer of axitinib (Pfizer) has agreed a patient access scheme with the Department of Health. The size of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.

3  The manufacturer’s submission

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

 Clinical-effectiveness evidence

3.1  The manufacturer conducted a systematic literature search and identified 1 randomised controlled trial (AXIS) that assessed axitinib for the second-line treatment of people with advanced renal cell carcinoma. AXIS was a phase III, international, multicentre, randomised, open-label, active-controlled trial comparing axitinib with sorafenib for the treatment of advanced or metastatic renal cell carcinoma after failure of prior first-line systemic therapy. The trial was undertaken in 175 centres in 22 countries and lasted for 3 years. The clinical-effectiveness evidence presented in the manufacturer’s submission was based mainly on this trial, but because this trial had no best supportive care comparator as defined in the scope, additional studies were used for an indirect comparison of axitinib with best supportive care.

3.2  Patients were eligible to enter the AXIS trial if they had measurable and progressive disease according to the Response Evaluation Criteria in Solid Tumours (RECIST) at least 2 weeks after 1 systemic first-line treatment with sunitinib, temsirolimus or cytokine(s) or at least 4 weeks or more treatment with bevacizumab plus interferon alfa-2a. The trial randomised 723 patients in a 1:1 ratio to receive either 5 mg axitinib twice daily or 400 mg sorafenib twice daily. The dose for axitinib was either maintained, or increased to 7 mg and then up to 10 mg twice daily, or reduced to 3 mg and then down to 2 mg twice daily, depending on individual safety and tolerability and at the discretion of the treating physician. If there were sorafenib-related adverse reactions the dose could be reduced to 400 mg once daily and if necessary further reduced to 400 mg on alternate days. No other chemotherapy or experimental anti-cancer medications were allowed during the on-trial period. Palliative care was allowed for pain control only of bone disease present at baseline and for disease-related symptoms. Baseline patient characteristics were balanced across the 2 treatment groups. The mean age was approximately 60 years (66% of the participants were less than 65 years), 72% were male and approximately 76% were white. The previous systemic therapies used were also similar across the 2 groups (in both groups, 54% of patients had received sunitinib, 35% had received cytokines, 8% had received bevacizumab and 3% had received temsirolimus). There were no notable differences between the treatment groups in terms of disease history.

3.3  The primary outcome in the AXIS trial was progression-free survival as measured by an independent review committee (IRC), and this was defined as the time from randomisation to first disease progression or death from any cause (whichever occurred first). Secondary outcomes included progression-free survival as assessed by the investigator; overall survival, defined as the time from randomisation to the date of death from any cause; objective response rate, defined as the number of patients with complete or partial response according to RECIST criteria; duration of response, defined as the time of the first tumour response to the time of disease progression or death from any cause (whichever occurred first); and patient-reported outcomes (quality of life). Quality of life was assessed using the 15-item Functional Assessment of Cancer Therapy Kidney Symptom Index (FKSI-15), which measures symptoms and quality of life in people with advanced kidney disease; and the FKSI Disease-Related Symptoms subscale (FKSI-DRS), which measures symptoms related to advanced kidney cancer disease. Symptoms measured include lack of energy, pain, weight loss, bone pain, fatigue, shortness of breath, coughing, fevers and haematuria. The EQ-5D was also used to assess generic health status.

3.4  Subgroup analyses of the primary and secondary endpoints were performed for the stratification factors based on Eastern Cooperative Oncology Group (ECOG) performance score (0 and 1) and prior treatment regimen (sunitinib, cytokine, bevacizumab and temsirolimus). The evidence in the manufacturer’s submission was based on the subgroups of patients who were previously treated with sunitinib or a cytokine(such as interferon-alfa or interleukin-2), in line with the marketing authorisation for axitinib. These subgroups are referred to as the prior-sunitinib group and the prior-cytokine group in this document. Subgroups were also predefined for the secondary endpoints based on baseline patient characteristics of age (less than 65 years, 65 years or more); sex (male, female); ethnic origin (white, non-white); geographical region (Asia, Europe, North America, other); and Memorial Sloan-Kettering Cancer Centre (MSKCC) risk groups (favourable, intermediate, poor).

3.5  In the main trial population, there was a statistically significant difference of 2 months in the IRC-assessed median progression-free survival, which was 6.7 months in the axitinib group compared with 4.7 months in the sorafenib group. The hazard ratio (HR) for progression was 0.67 (95% confidence interval [CI] 0.54 to 0.81, p<0.0001), adjusted for the stratification factors (ECOG performance score and prior systemic therapy). However, the improvement in overall survival was not statistically significant (HR 0.97, 95% CI 0.80 to 1.17, p=0.37).

3.6  FKSI-15, FKSI-DRS and EQ-5D quality-of-life data were collected at day 1, every 4 weeks thereafter, at the end of trial treatment or withdrawal, and on day 28 of the follow-up period. Higher FKSI-15, FKSI-DRS and EQ-5D scores indicate better quality of life. A repeated measures mixed-effects model was used to compare differences in quality of life between the 2 treatment groups. There were no statistically significant differences at follow-up between axitinib and sorafenib using the 3 health measures. For FKSI-15, there was no significant difference between axitinib and sorafenib post-treatment (p=0.4833) and no significant interaction between treatment and time (p=0.3943), and quality of life was maintained whilst patients remained on axitinib and sorafenib treatment. The axitinib group had mean FKSI-DRS scores 0.12 higher than the sorafenib group, measured using the FKSI-DRS measure for the main trial population (95% CI –0.45 to 0.69, p=0.67). For EQ-5D, the overall between-treatment comparison for axitinib versus sorafenib was not statistically significant (no p value given); however, quality of life was maintained whilst patients remained on treatment and declined when patients stopped trial medication. The quality of life differences for the prior-cytokine group and the prior-sunitinib group have been marked by the manufacturer as academic in confidence, and therefore cannot be shown here.

3.7  The safety analysis was performed for all patients who received at least 1 dose of axitinib or sorafenib in the AXIS trial (n=714). Diarrhoea was the most common treatment-emergent adverse event, occurring proportionately in both treatment groups (54.9% in the axitinib group and 53.2% in the sorafenib group). The most common additional adverse events in the axitinib group were hypertension, dysphonia, nausea and hypothyroidism. Hand–foot syndrome, rash and alopecia were more common in the sorafenib group than in the axitinib group. The sorafenib group had a higher occurrence of grade 3 (51.3% versus 50.4%) and grade 4 (10.1% versus 5.8%) adverse events compared with axitinib. Serious adverse events resulting in death, hospitalisation, significant disability and congenital abnormalities and/or birth defects in children of trial participants occurred equally in both treatment groups in the full trial population. The sorafenib group was associated with higher proportions of adverse events leading to dose reductions or interruptions (62% versus 55.4%) and permanent discontinuation of trial medication (13% versus 9.2%). The adverse event data for the prior-cytokine and the prior-sunitinib groups are marked academic in confidence by the manufacturer and therefore cannot be shown here.

Prior-cytokine group

3.8  For the prior-cytokine group in the AXIS trial, the axitinib group had a statistically significant IRC-assessed median progression-free survival of 12.1 months compared with 6.5 months in the sorafenib group (HR 0.46, 95% CI 0.32 to 0.68, p<0.0001). There was also a statistically significant 3.7-month higher investigator-assessed progression-free survival in the axitinib group (HR 0.64, 95% CI 0.45 to 0.90, p=0.0049). However, there was no statistically significant improvement in overall survival, which was 29.4 months in the axitinib group and 27.8 months in the sorafenib group (HR 0.81, 95% CI 0.56 to 1.19, p=0.14).

Indirect treatment comparison

3.9  In a systematic review of the literature, the manufacturer identified 1 relevant trial, known as TARGET (Treatment Approaches in Renal Cancer Global Evaluation Trial), that was considered suitable for an indirect comparison of axitinib versus best supportive care. For the purpose of this appraisal, the manufacturer used placebo from the TARGET and RECORD-1 trials (see section 3.14) as a proxy for best supportive care. TARGET was a phase III, multicentre,randomised, double-blind, placebo-controlled trial comparing sorafenib with placebo for people with metastatic renal cell carcinoma who had received 1 prior systemic therapy. However, TARGET was made up mostly of patients that had received first-line cytokine therapy only (interferon-alfa or interleukin-2), and had no prior-sunitinib group. Therefore, an indirect comparison of axitinib versus best supportive care was possible only for the cytokine-refractory subgroup. The patients in TARGET were similar to the patients in the AXIS trial in terms of age, sex and nephrectomy status. However, only 2 metastatic sites (lung and liver) were reported in TARGET, while AXIS reported more than 8 sites. MSKCC risk scores and prior treatments also differed between the 2 trials, with TARGET patients having predominantly received prior cytokines. Median progression-free survival was 5.5 months for sorafenib compared with 2.8 months for placebo using the intention to treat (ITT) population, and mean overall survival was 17.8 months for sorafenib compared with 14.3 months for placebo in the ITT population censored for crossover.

3.10  The indirect comparison was performed using Bayesian Markov-chain Monte Carlo sampling to determine the relative efficacy of the treatments. Sampling was performed using WinBugs. The hazard ratios from AXIS (median progression-free survival [HR 0.46, 95% CI 0.32 to 0.68, p<0.0001] and overall survival median [HR 0.81, 95% CI 0.56 to 1.19, p=0.14]) and TARGET (median progression-free survival [HR 0.54, 95% CI 0.45 to 0.64, p<0.001], and median overall survival censored for crossover [HR 0.78, 95% CI 0.62 to 0.97, p=0.029]) were used in a fixed effects model with an assumption of proportional hazards. Point estimates of the hazard ratio for each pair of treatments and 95% credible intervals were calculated. The result of the indirect comparison showed a 75% reduction in disease progression (median HR 0.25, 95% credible intervals 0.17 to 0.38) for axitinib compared with placebo (assumed here to be equivalent to best supportive care). For overall survival, the median hazard ratio for death censored for crossover was 0.63 (95% credible intervals 0.41 to 0.99).

3.11  The manufacturer identified some limitations in the evidence networks from the AXIS and TARGET trials that had an impact on the indirect comparison. The manufacturer stated that in the AXIS trial the relative efficacy as measured by overall survival (which was not statistically significant) may have been diluted because an active comparator (sorafenib) was used in the trial. The overall survival results may also have been confounded because of the subsequent treatments received after progression. In the prior-cytokine subgroup, 46.4% of patients in both the axitinib and sorafenib groups received subsequent treatments after progression. In the prior-sunitinib subgroup, 60% of patients in the axitinib group and 65.2% of patients in the sorafenib group received subsequent treatments. The manufacturer also stated that the overall survival analysis may have been affected by the relatively long survival post progression because of the patient heterogeneity usually seen in advanced renal cell carcinoma, the likelihood of receiving subsequent therapy, and the variability in treatment decisions made after progression.

3.12  The manufacturer stated that in the TARGET trial, the overall survival result may have been confounded by crossover from the placebo arm to the sorafenib treatment arm. It said that the method of adjusting for crossover (censoring of the patients) was not appropriate because it could lead to selection bias. The manufacturer stated that the rank-preserving structural failure time (RPSFT) method used in previous NICE appraisals of everolimus and sunitinib would have been more appropriate, and that the methodusually improves the hazard ratio in favour of the active treatment. Another limitation with the evidence from TARGET was the absence of a prior-sunitinib group. The manufacturer stated that the prior-cytokine group (who have never received a tyrosine kinase inhibitor such as sunitinib) and prior-sunitinib group were considered to be clinically different populations that were not interchangeable. First-line therapy was considered to have failed more rapidly in the prior-cytokine group than in the prior-sunitinib group. Therefore, the prior-cytokine group may benefit more from second-line treatment, as shown by the higher median progression-free survival. Because of this, separate evidence was presented for the prior-sunitinib subgroup.

Prior-sunitinib group

3.13  For the subgroup of patients who were previously treated with sunitinib in the AXIS trial, there was a statistically significant difference in the IRC-assessed median progression-free survival of 1.4 months (4.8 months in the axitinib group compared with 3.4 months in the sorafenib group, HR 0.74, 95% CI 0.57 to 0.96, p=0.0107), adjusted for performance status. The axitinib group also had a 2-month longer investigator-assessed progression-free survival than the sorafenib group (HR 0.64, 95% CI 0.49 to 0.82, p=0.0002). The hazard ratio for median overall survival was 0.997 (95% CI 0.78 to 1.27, p=0.49), based on 15.2 months median overall survival in the axitinib group and 16.5 months in the sorafenib group.

Simulated treatment comparison

3.14  The manufacturer identified 1 trial in an additional systematic review of the literature where sunitinib-refractory patients received best supportive care after disease progression. This was used to provide a link between axitinib and best supportive care in a prior-sunitinib population. This trial is known as the RECORD-1 trial (Renal Cell Cancer Treatment With Oral RAD001 Given Daily), and compared everolimus plus best supportive care with placebo plus best supportive care in patients with metastatic renal cell carcinoma that progressed after treatment with a tyrosine kinase inhibitor. As there was no direct link between the treatments used in the AXIS trial and those used in RECORD-1, the manufacturer performed a simulated treatment comparison to create an adjusted indirect comparison between the axitinib prior-sunitinib group from AXIS and the best supportive care prior-sunitinib group from RECORD-1. The aim of the comparison was to estimate how the prior-sunitinib group from the AXIS trial would have performed if they had been treated with placebo, using data from RECORD-1. Patients in RECORD-1 were allowed to cross over to the everolimus arm, although the impact of the crossover was adjusted for using the RPSFT method, which the manufacturer considered to be valid. The manufacturer stated that 2 different figures for median progression-free survival for the everolimus arm of the prior-sunitinib group were published by 2 different authors (5.6 months and 3.9 months). The manufacturer chose the 3.9-month figure and this resulted in a hazard ratio of 0.34 (95% CI 0.23 to 0.51) when compared with 1.8 months for placebo in the prior-sunitinib group. The median overall survival was 14.8 months for everolimus in the prior-sunitinib group compared with 10.0 months for placebo in the ITT population (HR 0.53, CIs not reported).

3.15  There were several differences highlighted between the AXIS and RECORD-1 trials. First, 14% of patients in RECORD-1 had discontinued prior treatment because of intolerance, rather than progressing from prior treatment as in the AXIS trial. Secondly, only 43 patients in the everolimus arm of RECORD-1 had received prior sunitinibonly, in contrast to the 194 prior-sunitinib patients in the axitinib arm of the AXIS trial. The manufacturer noted that some of the 43 patients in RECORD-1 may have had sunitinib intolerance rather than sunitinib-refractory disease, which may have led to potential bias because sunitinib-intolerant patients would be expected to respond better to subsequent treatment than patients with sunitinib-refractory disease. Thirdly, patients in RECORD-1 had received 1 or more prior treatments, while patients in AXIS had received just 1 first-line treatment. In RECORD-1, median progression-free survival was assessed in a prior-sunitinib only subgroup (n=56). However, the overall survival and patient characteristics for this subgroup were not assessed. As a result, 2 approaches were taken in the simulated treatment comparison to compare axitinib with best supportive care in a prior-sunitinib population. The first compared the axitinib prior-sunitinib group in AXIS with the best supportive care intention-to-treat (ITT) group in RECORD-1, and assumed that the ITT group would have the same overall survival and patient characteristics as the prior-sunitinib group in RECORD-1. The second approach compared the axitinib prior-sunitinib group with the everolimus prior-sunitinib group, and then applied the RPSFT-adjusted hazard ratio for everolimus to best supportive care to create a modelled prior-sunitinib group.

3.16  The simulated treatment comparison was performed by analysing patient-level data from the axitinib arm of the AXIS trial to derive parametric failure-time (survival) equations incorporating baseline predictors of the endpoints (progression-free survival and overall survival). Five distributions were examined, but only the 2 best fitting (log-normal and Weibull) were used in the comparison, and an assumption of proportional hazardswas applied. The results of the comparison suggested a progression-free survival and overall survival benefit from axitinib treatment compared with best supportive care and everolimus treatment when the log-normal and Weibull distributionswere used. The estimated increase in mean progression-free survival and overall survival for the best supportive care ITT and everolimus prior-sunitinib simulated treatment comparison curves are marked as commercial in confidence by the manufacturer and therefore cannot be shown here. The progression-free survival hazard ratio (0.34) for the prior-sunitinib group and adjusted overall survival hazard ratio (0.53) for the ITT group of RECORD-1 were applied to the everolimus simulated treatment comparison curves to generate modelled AXIS-like, prior-sunitinib progression-free survival and overall survival curves for best supportive care. This resulted in an estimated median progression-free survival of 1.7 months for the group of patients referred to in the manufacturer’s submission as ‘axitinib-like patients’ if they had received placebo compared to 6.3 months if they had receivedaxitinib (HR not reported), a difference of 4.6 months. The median overall survival estimated for these patients was 8.3 months for placebo compared with 16.6 months for axitinib(HR not reported).

Indirect treatment comparison

3.17  The manufacturer also provided an additional analysis, using retrospective observational data from a Swedish database (Renal Comparison; RENCOMP) to estimate the overall survival hazard ratio forpeople who received sorafenib or best supportive care after first-line treatment with sunitinib. Patient characteristics such as age, sex and nephrectomy status were similar across the 2 treatment groups (sorafenib and best supportive care). However, the sorafenib and best supportive care groups differed in terms of year of diagnosis, lead time between metastatic disease and first prescription of sunitinib, diagnosis of primary metastatic disease and place of treatment. A multivariate Cox proportional regression analysis was performed using variables with significance at the 5% level to adjust for uncertainty resulting from confounding, and an assumption of proportional hazards was applied. This resulted in a median overall survival hazard ratio of 0.62 (95% CI 0.41 to 0.94, p=0.023). The results from RENCOMP were used in an indirect comparison with the results from the prior-sunitinib group in the AXIS trial (median progression-free survival HR 0.74 [95% CI 0.57 to 0.96] and median overall survival HR 0.997 [95% CI 0.78 to 1.27]) in order to generate indirect hazard ratios for axitinib and best supportive care in the prior-sunitinib group. The results showed that axitinib was associated with an improvement in overall survival compared with best supportive care in a sunitinib-refractory population (HR 0.62, 95% credible interval 0.38 to 0.997).

 Evidence Review Group comments

3.18  The ERG stated that there were a few limitations with the literature search conducted by the manufacturer, some of which were addressed by the manufacturer after clarification. Despite these limitations, the ERG considered that the search was adequate and accurately reflected the research question. The ERG was satisfied that the clinical-effectiveness evidence for axitinib was based on the subgroups of patients who were previously treated with sunitinib and cytokines only, in line with the marketing authorisation for axitinib. It stated that AXIS, TARGET and RECORD-1 were good-quality clinical trials with sound methodologies, except for the method used to adjust for crossover in TARGET (censoring of patients). The ERG considered that censoring often introduces bias and they agreed that the method used in RECORD-1 (RPSFT) was more appropriate for adjusting for crossover. The ERG noted that although the outcomes reported in the AXIS trial corresponded with those in the final scope, only progression-free survival and overall survival outcomes were presented for the comparison of axitinib with best supportive care.

3.19  The ERG noted that baseline patient characteristics were not reported separately for the prior-cytokine groups in either the AXIS or the TARGET trial. Therefore, the indirect comparison of the trial populations was based on the ITT groups in the 2 trials. The ERG noted that the patient characteristics of the ITT groups in the AXIS and TARGET trials were reasonably similar, with slight differences observed only in the MSKCC scores and the number of metastatic sites. The ERG considered that the potential bias associated with the hazard ratio for overall survival in TARGET may limit the robustness of the indirect comparison in the prior-cytokine group.

3.20  The ERG noted that the comparison of patient characteristics in the AXIS and RECORD-1 trials for the prior-sunitinib group was based on the ITT group of the RECORD-1 placebo arm, in the absence of any data on patient characteristics in the prior-sunitinib group for the placebo group. The ERG also noted the differences between the AXIS and RECORD-1 trials that were highlighted by the manufacturer (see section 3.15), which could limit the evidence available for comparing axitinib with best supportive care in a prior-sunitinib group. The ERG was uncertain whether a simulated treatment comparison presents a valid and reliable estimate of the clinical effectiveness of axitinib compared with best supportive care in this group of patients. The ERG considered that there could be potential bias associated with the simulated treatment comparison because it involves a comparison of 2 single treatment arms and not a comparison of randomised treatment allocation. The ERG also stated that the results of the comparison could not be verified because individual patient data from the AXIS trial were used; and the uncertainties around the results could not be assessed because standard errors and 95% confidence intervals were not presented. However, the ERG indicated that the analysis seemed to have been performed correctly and the reporting of methods, results and limitations was clear despite the issues identified. The ERG agreed with the manufacturer that combiningobservational data (a lower level of evidence) from the RENCOMP database with the data from the AXIS trial was a potential source of uncertainty because patients were not randomly allocated to receive the second-line treatments and the reasons for discontinuing first-line treatments were not known.

 Cost-effectiveness evidence

3.21  The manufacturer conducted a systematic review of the literature and identified 3 studies on the cost effectiveness of active treatments compared with best supportive care for advanced and metastatic renal cell carcinoma after failure of a systemic therapy. None of the studies identified included axitinib, so the manufacturer carried out a de novo analysis on the cost effectiveness of axitinib compared with best supportive care for treating advanced renal cell carcinoma after failure of prior treatment with sunitinib or a cytokine. The economic evaluation was based on the 2 separate populations specified in the marketing authorisation for axitinib (the groups of people in whom prior treatment with sunitinib or cytokines has failed, also referred to as the prior-sunitinib and the prior-cytokine groups).

3.22  A 3-state Markov cohort model was developed, based on previous modelling of metastatic cancer using Microsoft Excel. All patients enter the model in the ‘progression-free’ health state and in each cycle can progress to the ‘progressed disease’ health state, progress from either of these health states to ‘death’, or remain in their current health state. The model had a lifetime horizon of 10 years consisting of 4-weekly cycles, included a half-cycle correction, and both costs and benefits were discounted at 3.5%. The analysis was performed from the perspective of the NHS and personal social services.

3.23  The proportion of patients in each health state at each point in time was calculated directly from parametric survival function equations. For the axitinib, prior-cytokine group, the Weibull distribution was used to extrapolate the overall survival and progression-free survival data because it was considered to provide the best model fit. Survival models based on log-logistic and Gompertz parametric distributions were used in a sensitivity analysis for overall survival, as of the 5 parametric distributions tested by the manufacturer, they provided the next-best model fit. However, the log-normal and Gompertz distributions were used in the sensitivity analysis to extrapolate progression-free survival. For the best supportive care group, parametric survival curves were generated by applying the hazard ratios from the indirect comparison (see section 3.10) to the parametric survival functions used to model the axitinib treatment group.

3.24  For the axitinib, prior-sunitinib group, the log-normal distribution was used in the base case to extrapolate overall survival data because it provided the best model fit. The Weibull and Gompertz distributions provided the next-best fits, so these were explored in a sensitivity analysis. The Weibull distribution was used for progression-free survival data in the base-case analysis, while the log-normal and Gompertz distributions were explored in the sensitivity analysis. For the best supportive care group, the prior-sunitinib progression-free survival and the ITT population-adjusted hazard ratios (see section 4.18) were applied to the everolimus simulated treatment comparison curves to generate a modelled AXIS-like, prior-sunitinib progression-free survival and overall curves. Only the Weibull option was used in the economic model for the survival curves, because the log-normal distribution did not support the use of hazard ratios. In a sensitivity analysis, the overall survival hazard ratio generated from the indirect comparison of the RENCOMP analysis and the prior-sunitinib overall survival analysis from the AXIS trial was applied to the axitinib parametric survival functions to generate parametric survival curves for the best supportive care group.

3.25  The utility values used in the model were derived from the AXIS trial using the EQ-5D questionnaire. The analysis was based on the full AXIS population because the p values indicated no statistically significant difference between the prior-sunitinib and prior-cytokine subgroups. The baseline mean utility value for the axitinib group was 0.73. The mean utility value for the progression-free health state was 0.69, based on the average of the EQ-5D index value at each time point in the AXIS trial and weighted by the number of patients still on treatment at that time point. The utility value for the progressed disease health state was 0.61, based on the weighted average of the mean utility at the end of treatment. The utility values used in the model were assumed to reflect the adverse event profile of the treatment from the AXIS trial. In a systematic review of the literature, the manufacturer did not identify any sources reporting utility values for people with advanced renal cell carcinoma receiving best supportive care after sunitinib treatment has failed. Therefore, the manufacturer assumed that people receiving best supportive care would have the same utility value as people receiving axitinib in the model. Utility values from previous NICE technology appraisals, derived from a phase II study of sunitinib in a cytokine-refractory population, were explored in a sensitivity analysis. Quality of life was assumed to remain constant for each health state in the post-trial period.

3.26  The average cycle (4 weeks/28 days) costs of axitinib were estimated applying the proposed patient access scheme, which is commercial in confidence and so cannot be shown here. This was based on the recommended dosing schedule of 5 mg twice daily until disease progression. The cost was adjusted for the relative dosing intensity observed in the AXIS trial, which was 102%. A dosing intensity of 80% was assumed in a scenario analysis to reflect the lower intensities observed in clinical practice and previous NICE technology appraisals. Drug discontinuation occurred because of disease progression or adverse events. The probabilities of discontinuation per cycle applied in the model were 0.80% and 1.26% for the prior-cytokine and prior-sunitinib groups respectively, although the discontinuation rates from adverse events alone were assumed to be the same. No administration cost was included in the manufacturer’s model because axitinib is taken orally and the patient access scheme is a flat net discount applied at the point of invoice. No drug costs were assumed for best supportive care.

3.27  The manufacturer stated that the costs associated with routine medical monitoring were based on those used in ‘Bevacizumab (first-line), sorafenib (first- and second-line), sunitinib (second-line) and temsirolimus (first-line) for the treatment of advanced and/or metastatic renal cell carcinoma’ (NICE technology appraisal guidance 178) and ‘Everolimus for the second-line treatment of advanced renal cell carcinoma’ (NICE technology appraisal guidance 219). The manufacturer also stated that this assumption was validated with expert clinical opinion to ensure consistency with current clinical practice in the UK. These costs were applied equally to the axitinib and best supportive care groups in the manufacturer’s model because patients were assumed to receive the same management regardless of their treatment. For the progression-free state, the total cost per cycle (£109.69) was based on 1 GP visit per cycle, 1 tumour scan per 3 cycles and 1 blood test per cycle. The total cost per cycle for the progressed disease state was £319, and this included 1 GP visit per cycle, 3 visits by a specialist community nurse every 2 cycles, and 28 vials of pain medication per cycle. A scenario analysis was explored where patients visited an oncologist rather than their GP. This resulted in a total management cost per cycle of £176.69 for the progression-free state and £386 for the progressed disease state. Costs associated with adverse events were included in the model for the progression-free state only, and were assumed by the manufacturer to be similar for the prior-sunitinib and prior-cytokine groups. Only the costs for grade 3 and 4 adverse events (which occurred in over 5% of the patient population) were included. For the axitinib group the included adverse events were hypertension (£424 per episode) and diarrhoea (£544 per episode), and the cost of anaemia (£2068.47 per episode) was applied to the best supportive care group in a sensitivity analysis.

Prior-cytokine group

3.28  The results of the economic analysis showed that the additional quality-adjusted life year (QALY) gains from axitinib treatment were observed in the progression-free state. The base-case assumptions resulted in an incremental cost effectiveness ratio (ICER) of £65,326 per QALY gained (with the patient access scheme applied) for axitinib compared with best supportive care after failure of a prior cytokine. All the incremental costs and QALYs gained in the manufacture’s submission are marked as commercial in confidence and so cannot be shown here.

3.29  The manufacturer performed a univariate deterministic sensitivity analysis by varying some of the model input parameters by ±20% of their base-case value. The cost-effectiveness result for the prior-cytokine group was most sensitive to changes in the progressed disease utility values for the axitinib and best supportive care groups and the progression-free utility value for the axitinib group, with ICERs ranging from £46,402 to £110,317 per QALY gained (with the patient access scheme applied). The base-case ICER was also sensitive to changes in the values of the survival parameters for the axitinib group, the overall survival hazard ratio for axitinib compared with best supportive care, and the relative dose intensity of axitinib. Changes in the cost estimates (such as GP visits, specialist nurse visits and tumour scans), discontinuation because of adverse events, changes in the progression-free utility for the best supportive care group, and changes in the IRC-assessed progression-free survival hazard ratio from the AXIS trial had very little effect on the base-case results. The ICERs ranged from £59,530 to £72,373 per QALY gained (with the patient access scheme applied).

3.30  The probabilistic sensitivity analysis indicated that axitinib would have a 31% chance of being cost effective compared with best supportive care, if the maximum acceptable ICER was £50,000 per QALY gained with the patient access scheme applied to the prior-cytokine group.

3.31  The manufacturer also explored various scenario analyses to account for the uncertainties associated with some of the assumptions in the base-case model. All results are inclusive of the patient access scheme. The scenario analyses explored the effect on the ICER of:

• using alternative parametric distributions (log-normal, log-logistic and Gompertz) to extrapolate survival
• using external data to estimate utility values
• reducing the dosing intensity of axitinib to 80%
• assuming an oncologist visit instead of a GP visit for estimating costs in the progression-free state
• assuming time horizons of 5 and 15 years and
• using alternative discount rates of 0% and 6%.

The scenario analyses all resulted in ICERs ranging from £51,546 to £84,255 per QALY gained. The ICER was most sensitive to the use of the Gompertz distribution for extrapolating overall survival (£84,255 per QALY gained), use of a 5-year time horizon (£83,752 per QALY gained), and reduction in the dosing intensity of axitinib (£51,546 per QALY gained). It was least sensitive to the use of a 15-year time horizon and costing based on oncologist visit (ICERs of £64,359 and £66,410 per QALY gained respectively).

Prior-sunitinib group

3.32  The results of the economic analysis showed that there were additional QALY gains with axitinib before and after progression, although the majority of the additional QALYs gained were observed before progression. The base-case analysis resulted in an ICER of £40,933 per QALY gained (with the patient access scheme applied) for axitinib compared with best supportive care for the prior-sunitinib group. All the incremental costs and QALYs gained are marked by the manufacturer as commercial in confidence and so cannot be shown here.

3.33  The univariate sensitivity analysis performed for the prior-sunitinib group showed that the ICER was most sensitive to changes in the survival parameter values for the axitinib group, with ICERs ranging from £31,271 to £59,373 per QALY gained (with the patient access scheme applied). The base-case ICER was also sensitive to changes in the progressed disease utility values for the axitinib and best supportive care groups and progression-free utility value for the axitinib group, the resulting ICERs ranging from £31,324 to £59,044 per QALY gained (with the patient access scheme applied). Changes in the relative dosing intensity of axitinib also showed some sensitivity to the base-case results (£33,434 to £48,432 per QALY gained with the patient access scheme applied). Changes in the cost estimates (such as GP visits, specialist nurse visits and tumour scans), discontinuation because of adverse events, and changes in the progression-free utility for the best supportive care group showed very little sensitivity to the base-case results. The ICERs ranged from £38,927 to £43,157 per QALY gained(with the patient access scheme applied).

3.34  The probabilistic sensitivity analysis showed that axitinib would have a 67% chance of being cost effective compared with best supportive care if the maximum acceptable ICER was £50,000 per QALY gained for the prior-sunitinib group (applying the patient access scheme).

3.35  Several scenario analyses were also performed by the manufacturer to explore the effect on the ICER of:

• using alternative parametric distributions (Weibull, log-normal and Gompertz) to extrapolate survival
• using alternative methods of comparison with best supportive care
• using external data to estimate utility values
• reducing the dosing intensity of axitinib to 80%
• assuming an oncologist visit instead of a GP visit for estimating costs in the progression-free state
• using time horizons of 5 and 10 years, and
• using alternative discount rates of 0% and 6%.

The scenario analyses all resulted in ICERs ranging from £32,846 to £56,113 per QALY gained (with the patient access scheme applied). The ICER was most sensitive to the use of the Weibull and Gompertz distributions to extrapolate overall survival using the RENCOMP method of comparison (£56,113 and £54,851 per QALY gained respectively), use of a 5-year time horizon (£48,283 per QALY gained) and reducing the dosing intensity of axitinib (£32,846). It was least sensitive to the use of alternative distributions to extrapolate progression-free survival using the simulated treatment method of comparison, use of a 15-year time horizon, use of a 6% discount rate, and costing based on oncologist visit (ICERs ranged from £39,207 to £42,806 per QALY gained).

3.36  In response to clarification questions from the ERG and NICE, the manufacturer provided the results of a univariate sensitivity analysis, where the model input parameters for the prior-cytokine and prior-sunitinib groups were varied using the 95% confidence interval. The results showed that the base-case results were most sensitive to the utility values, with some of the scenarios resulting in negative ICERs. However, the manufacturer stated that the results should be interpreted with caution because some of the univariate scenarios could be clinically implausible. No further subgroup analysis was performed by the manufacturer because the economic evaluation was based on 2 subgroups from the main AXIS trial.

 Evidence Review Group comments

3.37  The ERG was satisfied with the manufacturer’s modelling approach, which was consistent with other published economic studies of advanced renal cell carcinoma and used a population that was reflective of the actual clinical population. It re-emphasised that approximately 94% of the renal cell carcinoma population will receive sunitinib for first-line treatment, and 6% will receive cytokines. The ERG was satisfied that the best supportive care comparator used in the model reflected recommended UK clinical practice and was in line with the final scope for this appraisal. The ERG was concerned that the lifetime time horizon of 10 years used in the base-case model may not be in line with real life expectancy. Nevertheless, it considered the time horizon to be acceptable because the sensitivity analysis performed by the manufacturer showed that increasing the time horizon to 15 years had minimal impact on the base-case results (see sections 3.31 and 3.35).

3.38  The ERG accepted the manufacturer’s choice of the distributions used in the base-case and scenario analysis. However, it noted that in some cases, the method of selection of the distributions (based on the Akaike and Bayesian information criteria, visual inspection and anchoring) was unclear, with expert opinion always dominating the reason for selection, and in one instance the decision was based on expert opinion of clinical plausibility. The ERG also noted the manufacturer’s clarification that patients who withdrew from treatment prematurely because of adverse events were still followed up in the trial, and were included in the estimation of progression-free survival and overall survival curves for the axitinib arm rather than the best supportive care arm. The ERG stated that this approach would only be valid if the patients were followed up for progression as well, and not for survival only. The ERG considered that the estimate of the QALYs in the axitinib group may have been affected if they were not followed up for progression, because these patients are expected to progress earlier once they stop treatment. It also noted that, because of earlier progression to the progressed disease state, the overall costs would be higher for the axitinib group compared with the cost in the model, which was set at ‘zero’ for these patients. The ERG indicated that making this adjustment in the model would increase the base-case ICERs, although the impact would be limited by the relatively small group of patients withdrawing from the treatment prematurely.

3.39  The ERG was satisfied with the manufacturer’s assumption that the utility value was the same for people receiving axitinib and those receiving best supportive care. They agreed that while people on axitinib may experience utility decreases from adverse events, those receiving best supportive care would experience utility decreases from actively progressing uncontrolled disease. The ERG was concerned that the utility value applied in the progressed disease state remained constant after entry into that state, when it should actually decline as patients near the end of life. It noted that applying declining utility values would increase the ICER slightly if axitinib patients stay in the progressed disease state for longer than best supportive care patients (prior-sunitinib group), but no impact would be observed if the time spent in the progressed disease state is the same for both treatment arms (prior-cytokine group). The ERG noted from the AXIS clinical trial report that health states were based on the US valuation. It stated that the utilities used in the model appear to be too high because studies have shown that US valuations are consistently higher than UK valuations. The ERG noted that standard errors should have been used with the utility values in the analysis instead of standard deviation because the reported utility values were sample means. The ERG stated that it could not reproduce the original utility for the progression-free state; a higher utility value of 0.73 was produced instead using the method described in the manufacturer’s submission.

3.40  The ERG noted that the percentage of people with hypertension was less than 1% in the TARGET trial, whereas a value of 2% was applied in the manufacturer’s model. However, the impact on the base-case ICER was negligible given the small costs associated with treating this adverse event. The ERG also noted that the relative dosing intensity of axitinib was based on a sample mean from the AXIS trial, so standard error should have been used rather than standard deviation. The ERG considered that the assumption that the cost of death is a fixed cost in the model underestimates the uncertainty associated with the cost in the model. Therefore, it calculated the standard error for the cost of death (104.43) from the reference provided by the manufacturer and conducted an exploratory analysis.

3.41  The ERG concluded given the result of the sensitivity analyses that the model for the prior-cytokine group was not very robust to most of the structural assumptions. However, the ERG agreed that the manufacturer’s model for the prior-sunitinib group was robust to the majority of the assumptions, with most of the scenarios producing ICERs below £50,000 per QALY gained with the patient access scheme applied (see section 3.35). It noted, however, that the evidence for this population was derived from a simulated treatment comparison which was not based on randomised treatment allocation, so there is potential bias in the evidence.

ERG’s exploratory analyses

3.42  The ERG undertook exploratory analyses within which adjustments were made to some of the parameters used in the manufacturer’s base-case sensitivity analysis. It varied the model input parameters using the 95% confidence intervals provided by the manufacturer in response to the ERG and NICE clarificationquestions. The most obvious difference from the manufacturer’s analysis was observed when the overall survival hazard ratio for the prior-cytokine group was varied. The manufacturer’s base-case result of £65,326 per QALY gained was very sensitive to this change, which resulted in an ICER range of £42,647 to £423,083 per QALY gained (with the patient access scheme applied). The manufacturer’s base-case ICER for the prior-sunitinib group remained relatively stable to the ERG’s changes to the input parameters.

3.43  The ERG replaced the standard deviations used for the utilities and relative dosing intensity of axitinib with standard errors in the probabilistic sensitivity analysis. The standard errors used (0.0035, 0.0175 and 1.86%) reduced the uncertainty in the ERG’s progression-free utility (section 3.39), the progressed disease utility and the dosing intensity of axitinib. The ERG also specified the cost of death as an uncertain parameter by providing a standard error of 104.43 in the probabilistic sensitivity analysis (section 3.40). The revised results showed that axitinib has a 19% and 83% chance of being cost effective for the prior-cytokine and prior-sunitinib groups respectively, if the maximum acceptable ICER is £50,000 per QALY gained (applying the patient access scheme). The ERG emphasised that the results for the prior-sunitinib group should be interpreted with a degree of caution because the assumptions for the simulated treatment comparison estimates could not be quantified (that is, no measures of uncertainty were provided for the adjustment factor for the best supportive care arm). In addition, the evidence for the prior-sunitinib group was limited compared with the prior-cytokine group.

3.44  The ERG further explored several scenarios using different assumptions for the utility estimates (with the patient access scheme applied). Firstly, the ERG used separate utility values for the prior-cytokine and prior-sunitinib groups based on the data provided by the manufacturer during clarification. This resulted in a slightly lower ICER than the base-case ICER of £65,326 per QALY gained for the prior-cytokine group (£62,885 per QALY gained) and a slightly higher ICER than the base-case ICER of £40,933 per QALY gained for the prior-sunitinib group (£42,095 per QALY gained). Secondly, lower utility values were applied for progression-free disease (0.66) and progressed disease (0.54) based on the assumption of lower UK valuation. The ICERs increased slightly to £68,433 and £44,125 per QALY gained for the prior-cytokine and prior-sunitinib groups respectively. Finally, a higher utility value of 0.72 was assumed for the best supportive care group in order to test the impact of treatment-specific utility estimates before progression (that is, the progression-free health state). This also had very minimal impact on the ICERs: £66,639 and £41,363 per QALY gained for the prior-cytokine group and the prior-sunitinib group respectively, with the patient access scheme applied.

3.45  The ERG performed an exploratory analysis to test the impact of assuming no difference in the QALY gains or the costs for the prior-sunitinib group. This was done because the manufacturer’s results showed that a considerable proportion of the QALY gains in the prior-sunitinib group occurred in the progressed disease state, while almost all the QALY gains in the prior-cytokine group occurred in the progression-free survival state. The incremental QALYs and costs are marked by the manufacturer as commercial in confidence and so cannot be shown here. Assuming no difference after progression in the prior-sunitinib group resulted in a total QALY gain and total cost which were both less than the manufacturer’s estimate. These assumptions resulted in an ICER increase from £40,933 per QALY gained to £62,108 per QALY gained (with the patient access scheme applied) for the prior-sunitinib group.

3.46  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 axitinib, having considered evidence on the nature of advanced renal cell carcinoma and the value placed on the benefits of axitinib by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.

4.2  The Committee considered the clinical need for treatment in people with advanced renal cell carcinoma in whom previous treatments with sunitinib or cytokines have failed. The Committee heard from the clinical specialists that there was a need for more drugs for people whose disease has become resistant to first-line treatment. It noted the comment from the patient experts that there was an unmet clinical need in this group of people because there are currently no second-line drugs approved by NICE, although it was noted that the Cancer Drugs Fund funds requests for everolimus. The patient experts also stated that availability of another treatment would offer a sense of hope to patients and their families or carers and also reduce the mental burden associated with the lack of treatment options. The patient experts indicated that patients were aware of the adverse events associated with axitinib and were prepared to cope with them.

4.3  The Committee considered the relevance of the populations covered by the marketing authorisation of axitinib, that is, the prior-cytokine group and the prior-sunitinib group. It heard from the clinical specialists that the use of cytokines is rapidly decreasing in clinical practice and only a few people currently receive them because the majority of patients begin treatment with sunitinib or pazopanib. The Committee was also aware that there was a difference of opinion among the Committee for Medicinal Products for Human Use members regarding the rationale for a prior-sunitinib group, given that sunitinib and axitinib have the same mechanism of action. The Committee concluded that although both groups are relevant populations for treatment with axitinib, there are fewer patients in the prior-cytokine group and other treatments such as pazopanib and sunitinib are available for use inthis prior-cytokine population.

4.4  The Committee discussed the population for whom axitinib would be prescribed in clinical practice, bearing in mind that of the 2 anti-vascular endothelial growth factor first-line treatments recommended by NICE (sunitinib and pazopanib), only sunitinib had been specified in the marketing authorisation for axitinib. The clinical specialists further stated that although both sunitinib and pazopanib are used interchangeably in clinical practice, patients are increasingly treated with pazopanib. The Committee noted this and was concerned that the exclusion of the prior-pazopanib group from the AXIS trial and the axitinib marketing authorisation could affect choice of first-line therapy in clinical practice, given that a large number of people currently receive pazopanib. The Committee heard from the clinical specialists that in practice axitinib would be used in the prior-pazopanib group as well, since pazopanib and sunitinib are both tyrosine kinase inhibitors with similar biochemical activities. The Committee concluded that the prior-pazopanib group would be a relevant population for treatment with axitinib in current clinical practice in addition to the prior-sunitinib group.

 Clinical effectiveness

4.5  The Committee examined the clinical evidence from the AXIS trial, which compared axitinib with sorafenib, noting that the scope for this appraisal had specified a comparison with best supportive care. The Committee noted that the trial was well conducted and the relevant outcomes were assessed in line with the scope of the appraisal. However, the Committee noted the difficulties in interpreting the AXIS trial in this appraisal because of the lack of a best supportive care comparison. The Committee noted that the better progression-free survival results for axitinib patients (HR 0.67, 95% CI 0.54 to 0.81, p<0.0001) did not translate into statistically significant overall survival benefits (HR 0.97, 95% CI 0.80 to 1.17, p=0.37) for the full trial population. The Committee also noted the comment from the Committee for Medicinal Products for Human Use members that there were uncertainties over the therapeutic value of using axitinib after failure of prior sunitinib and the rationale for preferring axitinib over everolimus in this group of people. The Committee heard the manufacturer’s explanation that this could be a result of the use of subsequent cancer treatments after progression. The Committee was satisfied with the health-related quality-of-life data collected and assessed in the AXIS trial using both generic and disease-specific instruments, and it concluded that AXIS was a well-conducted trial, although the comparator was not relevant for this appraisal. Because there was no relevant comparator in the AXIS trial, the Committee concluded that its discussion of the efficacy of axitinib would need to be based on the results of the indirect and the simulated treatment comparisons performed by the manufacturer. It also concluded that it was reasonable to separate out the results for patients who had received only prior cytokines from those who had received prior sunitinib as specified in the marketing authorisation for axitinib.

4.6  The Committee noted, however, that the prior-cytokine population has been diminishing since the introduction of sunitinib and pazopanib and their approval by NICE as first-line treatments. It considered that prior-cytokine patients would, in practice, be given sunitinib and pazopanib notwithstanding previous treatment with cytokines. Nevertheless the Committee examined the indirect comparison performed to generate a best supportive care comparison for axitinib in the prior-cytokine group. It noted that the evidence for the indirect comparison was based on the AXIS trial (which compared axitinib with sorafenib) and the TARGET trial (which compared sorafenib with placebo). The Committee accepted the manufacturer’s use of placebo as a proxy for best supportive care in the indirect and simulated treatment comparisons. The Committee was aware that patient baseline characteristics were not presented separately for the prior-cytokine subgroups in the 2 trials. It noted that the 2 trials were not fully comparable in terms of MSKCC scores, prior treatments and number of metastatic sites reported. The Committee noted that crossover in the TARGET trial was adjusted by censoring the patients who crossed over and considered that this could have resulted in bias and ultimately affected the robustness of the results of the indirect comparison (progression-free survival [HR 0.25, 95% credible intervals 0.17 to 0.38] overall survival, [HR 0.63 95% credible intervals 0.41 to 0.99]). The Committee also noted that an assumption of proportional hazards, which assumes a constant treatment effect over a lifetime, had been used to derive the survival estimates and had not been tested. Therefore, the Committee concluded that although the indirect comparison was adequately performed, the results might not be robust given these problems with the data.

4.7  The Committee considered the simulated treatment comparison performed for the prior-sunitinib subgroup using evidence from the AXIS trial (which compared axitinib with sorafenib) and RECORD-1 trial (which compared everolimus with placebo). The Committee noted that this method of comparison was used to create an adjusted indirect comparison of axitinib with best supportive care in the prior-sunitinib group. The Committee discussed whether the use of the simulated treatment comparison method could be considered reliable and valid. It noted the ERG’s comment that it was based on a comparison of 2 single treatment arms without random allocations to treatment. It was aware that no confidence intervals or standard errors were provided to assess the uncertainties. The Committee was aware that crossover also occurred in the RECORD-1 trial, although this was adjusted using the RPSFT method which both the manufacturer and the ERG considered to be appropriate. The Committee was also aware that there were key differences between the RECORD-1 trial population and that of AXIS which could bias the results of the simulated treatment comparison, such as the higher number of prior therapies allowed, the small number of people in the prior-sunitinib group, the inclusion of sunitinib-intolerant patients who had discontinued sunitinib treatment, and the use of the ITT (rather than the prior-sunitinib) population to estimate overall survival in the placebo arm. The Committee was therefore concerned about the validity of the simulated treatment comparison analysis. However, the Committee also noted that the manufacturer performed an alternative indirect comparison for the prior-sunitinib group using evidence from AXIS and the Swedish database (RENCOMP) analyses of sorafenib compared with best supportive care, but noted that the RENCOMP analysis was based on observational data without random allocation to treatments and also needed cautious interpretation. The Committee also noted that an assumption of proportional hazards had again been used in the simulated treatment and RENCOMP analyses to derive the survival estimates and had not been tested. The Committee concluded that there were serious limitations with the indirect comparisons performed for theprior-sunitinib group,and the outcomes from the simulated treatment comparison (progression-free survival [4.6 months for axitinib compared with 1.7 months for placebo], overall survival [16.6 months for axitinib compared with 8.3 months for placebo]) and indirect comparison (overall survival [HR 0.62, 95% credible interval 0.38 to 0.997]) should be interpreted with caution, especially as the uncertainties were not fully considered in the analyses.

4.8  The Committee considered the adverse event profile associated with axitinib which was observed in the AXIS trial. The Committee noted that diarrhoea, which was the most common adverse event, occurred with similar frequencyin the axitinib and sorafenib groups. It was aware that hypertension, dysphonia, nausea and hypothyroidism occurred more frequently in the axitinib group, although hand–foot syndrome, rash and alopecia occurred more frequently in the sorafenib group. The Committee also noted the comment from the clinical specialists that axitinib was a well-tolerated drug except for the high occurrence rate of hypertension which is common with all tyrosine kinase inhibitors. The patient experts commented that patients would be willing to accept these adverse events, and so the Committee concluded that axitinib had a manageable adverse event profile compared with other advanced renal cell carcinoma treatments.

 Cost effectiveness

4.9  The Committee considered the manufacturer’s economic model and the ERG’s critique of the model. The Committee was aware that the economic evaluation considered 2 separate populations based on the subgroups of patients previously treated with sunitinib or a cytokine. It noted that these were the subgroups for whom axitinib has a marketing authorisation. The Committee was satisfied that the best supportive care comparator used reflected UK clinical practice, although it recognised that everolimus is also available through the Cancer Drugs Fund as a second-line treatment for advanced renal cell carcinoma. However, it considered that everolimus cannot be considered as a comparator for axitinib because it was not recommended by NICE for use in the NHS and was not specified in the scope for this appraisal. It was also satisfied with the manufacturer’s use of placebo as a proxy for best supportive care given the lack of any other relevant data. The Committee concluded that the appropriate populations and comparator for the economic evaluation had been captured in the model.

4.10  The Committee discussed the assumptions made by the manufacturer in developing the economic model. The Committee noted the ERG’s comment that the method used by the manufacturer for selecting the distributions for extrapolating survival was unclear and sometimes contradictory. The Committee also noted that when alternative distributions were tested in the scenario analysis, it resulted in sizeable changes to the base-case result for the prior-cytokine population and moderate changes for the prior-sunitinib population. The Committee concluded that the rationale forselecting the distributions for extrapolating survival was unclear and that the model results were sensitive to the method used.

4.11  The Committee was satisfied that the utility values applied in the model were derived from AXIS, which was the main trial used in the economic analysis, and considered the assumptions made around the utility estimates to be robust. The Committee was satisfied with the assumptions made for the costs used in the model. The Committee concluded that the appropriate utilities and costs for the economic evaluation had been applied in the model.

4.12  The Committee discussed the plausibility of the survival gains estimated for the prior-cytokine group from the economic model. The Committee heard from the clinical specialists and patient experts that the overall survival gain of approximately 24 months in the best supportive care group of the prior-cytokine group is not seen clinically. It noted the manufacturer’s comment that the implausibility observed may have resulted from the overall survival of 14 months in the placebo arm of TARGET which was not properly adjusted for crossover. The Committee considered that this possible over-estimation of the overall survival in TARGET was carried over into the overall survival results in the indirect comparison and ultimately affected the model results for the best supportive care group. The Committee also noted that the ICER was sensitive to some of the parameters and assumptions (such as the utility values, the value of the survival parameters and the type of distribution used to extrapolate survival) used in the model. The Committee concluded that the ICER of approximately £65,000 per QALY gained (with the patient access scheme applied) may have been over-estimated based on the unlikely overall survival gains with best supportive care in the prior-cytokine population, but that there were other uncertainties that might push the ICER higher.

4.13  The Committee considered the uncertainty around the base-case estimates in the prior-sunitinib group. The Committee recognised that the use of the simulated treatment comparison method to derive a best supportive care comparison for axitinib in the group was the greatest source of uncertainty. It noted that the absence of confidence intervals or standard errors indicated that a proper probabilistic sensitivity analysis had not been performed and that the ICERs were likely to be high if uncertainty was fully incorporated into a probabilistic sensitivity analysis. It discussed the plausibility of the survival gains estimated for the prior-sunitinib group (figures marked as confidential by the manufacturer). It noted that the median survival gain difference between axitinib and best supportive care patients estimated directly from the trials was increased by 63% when modelled, although no such modelling increase was estimated in the prior-cytokine group. Furthermore the Committee noted that an implausibly high proportion of the total QALY gains with axitinib (versus best supportive care) in the prior-sunitinib group were observed after progression when active treatment with axitinib has ceased. It noted that this was not a feature in either the prior-cytokine analysis or the AXIS trial results. The Committee examined the exploratory analysis performed by the ERG where it was assumed that there was no QALY difference between axitinib and best supportive care in the prior-sunitinib group after progression. When it was also assumed that there was no cost difference after progression the resultant ICER was approximately £62,000 per QALY gained (with the patient access scheme applied). The Committee concluded that the results from the simulated treatment comparison and the post-progression model outputs for the prior-sunitinib group should be interpreted with caution because they lacked clinical plausibility.

4.14  The Committee also noted that the results of the RENCOMP indirect comparison of axitinib and best supportive caredid not support the manufacturer’s base case. When the RENCOMP method was used rather than the simulated treatment comparison, the ICER increased to over £50,000 per QALY gained (with the patient access scheme applied) using the Weibull and Gompertz distributions, suggesting that this was a key driver of the results in this population. The Committee concluded that the results for the prior-sunitinib group should be interpreted with caution because the uncertainties had not been fully considered.

4.15  The Committee considered whether axitinib reflected a cost-effective use of NHS resources. The Committee noted that the manufacturer’s base-case ICER of £65,000 per QALY gained (with the patient access scheme applied) generated for the prior-cytokine group may have been over-estimated considering the discussions in section 4.12, but there were uncertainties in both directions and the most plausible ICER was likely to still be above £50,000 per QALY gained (with the patient access scheme applied) for this group of people. For the prior-sunitinib population, the Committee noted the uncertainty in the simulated treatment comparison method and the clinical implausibility of the QALY gains accumulated after progression in this group of people (section 4.13). The Committee considered that the ICER of approximately £62,000 per QALY gained estimated by the ERG represented a more plausible (although still uncertain) ICER for the prior-sunitinib group. The Committee concluded therefore that axitinib could not be considered to be a cost-effective use of NHS resources.

4.16  The Committee discussed whether axitinib for advanced renal cell carcinoma fulfilled the criteria for a life-extending, end-of-life treatment, which are that:

• 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 and
• 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 agreed that the life expectancy of people with advanced renal cell carcinoma in whom prior cytokines and sunitinib have failed was less than 24 months. The Committee also agreed that there was sufficient evidence to indicate that the treatment offers an extension to life of at least an additional 3 months in the case of the prior-sunitinib population, compared with current NHS treatment which is best supportive care. However in the case of the prior-cytokine group the Committee considered that these were people who could receive sunitinib or pazopanib but no comparison had been available. The Committee noted that the manufacturer’s estimation of the eligible population for whom axitinib is licensed (the majority being in the prior-sunitinib group), that is, 1580 people in year 1 and up to 1743 people in year 5, represented a small patient population. The Committee concluded that axitinib represented a life-extending, end-of-life treatment for the prior-sunitinib population, based on these 3 criteria. However it concluded that the value of the ICERs and the uncertainty around the ICERs meant that axitinib still could not be considered a good use of NHS resources for this population.

4.18  The Committee noted the comments made by the manufacturer and patient organisations regarding the ‘innovativeness’ of axitinib. They stated that the availability of axitinib was expected to offer a step-change in the second-line management of advanced renal cell carcinoma by improving survival beyond what is expected with best supportive care, while maintaining health-related quality of life. The Committee understood this but considered that there were no additional gains in health-related quality of life over those already included in the QALY calculations. Therefore the Committee concluded that the innovative aspects of axitinib were already incorporated in the economic model and analyses.

4.19  The Committee discussed potential equality issues and gave particular consideration to avoid unlawful discrimination against any group of people on the grounds of race, gender, disability, religion or belief, sexual orientation, age, gender reassignment, pregnancy and maternity. The Committee noted the following potential equality issues raised by the patient experts, patient organisations and NHS organisations:

• Older patients with additional health issues may find the adverse effects more difficult to tolerate.
• People with rare cancers such as kidney cancer have inequity of access to NHS-funded treatments.
• The scope does not consider axitinib for people who are unsuitable for first-line immunotherapy.

The Committee considered that these were not equality issues under the legislation. The Committee therefore concluded that its preliminary recommendations did not have a particular impact on any of the groups whose interests are protected by the legislation and that there was no need to alter or add to its preliminary recommendations.

Summary of Appraisal Committee’s key conclusions

TAXXX	Appraisal title: Axitinib for treating advanced renal cell carcinoma after failure of prior systemic treatment		Section
Key conclusion
The Committee does not recommend axitinib for the treatment of adults with advanced renal cell carcinoma after failure of prior treatment with sunitinib or a cytokine. The Committee concluded that the ICER of approximately £65,000 per QALY gained (with the patient access scheme applied) may have been over-estimated based on the unlikely overall survival gains with best supportive care in the prior-cytokine population, but that there were other uncertainties that might push the ICER higher. The Committee concluded that the results from the simulated treatment comparison and the post-progression model outputs for the prior-sunitinib group should be interpreted with caution because they lacked clinical plausibility. The Committee concluded that the value of the ICERs and the uncertainty around the ICERs meant that axitinib still could not be considered a good use of NHS resources for this population.			1.1 4.12 4.13 4.17
Current practice
Clinical need of patients, including the availability of alternative treatments		The patient experts stated that there was an unmet clinical need for people whose disease has become resistant to first-line treatment. This is because there are currently no second-line drugs for renal cell carcinoma approved by NICE.	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 understood that the availability of axitinib was expected to improve survival beyond what is currently expected with best supportive care in the second-line management of advanced renal cell carcinoma, but considered that there were no additional gains in health-related quality of life over those already included in the QALY calculations.	4.18
What is the position of the treatment in the pathway of care for the condition?		Axitinib has a marketing authorisation for ‘the treatment of adult patients with advanced renal cell carcinoma, after failure of prior treatment with sunitinib or a cytokine’. However, the Committee concluded that the prior-pazopanib group would be a relevant population for treatment with axitinib in current clinical practice in addition to the prior-sunitinib group.	2.1 4.4
Adverse reactions		The Committee noted that diarrhoea, which was the most common adverse event, occurred with similar frequency in the axitinib and sorafenib groups. It was aware that hypertension, dysphonia, nausea and hypothyroidism occurred more frequently in the axitinib group. It concluded that axitinib had a manageable adverse event profile compared with other advanced renal cell carcinoma treatments.	4.8
Evidence for clinical effectiveness
Availability, nature and quality of evidence		The Committee noted that the AXIS trial was well conducted and the relevant outcomes were assessed in line with the scope of the appraisal. However, it noted the difficulties in interpreting the AXIS trial in this appraisal because of the lack of a best supportive care comparison. The Committee concluded that the indirect comparison used to generate a best supportive care comparison for the prior-cytokine group based on the AXIS trial (which compared axitinib with sorafenib) and the TARGET trial (which compared sorafenib with placebo) was adequately performed. However, the Committee considered that there were serious limitations with the simulated treatment comparison performed for the prior-sunitinib group using evidence from the AXIS and RECORD-1 trials and the indirect comparison using evidence from AXIS and the Swedish database (RENCOMP).	4.5 4.6, 4.7
Relevance to general clinical practice in the NHS		The Committee concluded that although both groups are relevant populations for treatment with axitinib, there are fewer patients in the prior-cytokine group and other treatments such as pazopanib and sunitinib are available for use in this prior-cytokine population. However, the Committee concluded that the prior-pazopanib group would be a relevant population for treatment with axitinib in current clinical practice in addition to the prior-sunitinib group.	4.3, 4.4
Uncertainties generated by the evidence		The Committee noted that crossover in the TARGET trial was adjusted by censoring the patients who crossed over and considered that this could have resulted in bias and ultimately affected the robustness of the indirect comparison. The Committee was concerned about the validity and reliability of the simulated treatment comparison because no confidence intervals or standard errors were provided to assess the uncertainties and because it was based on a comparison of 2 single treatment arms without random allocations to treatment. The RENCOMP analysis was based on observational data without random allocation to treatments and also needed cautious interpretation. An assumption of proportional hazards had been used in the indirect comparisons and simulated treatment comparison to derive the survival estimates and had not been tested.	4.6 4.7
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?		The Committee concluded that although both groups are relevant populations for treatment with axitinib, there are fewer patients in the prior-cytokine group and other treatments such as pazopanib and sunitinib are available for use in this prior-cytokine population. The Committee concluded that the prior-pazopanib group would be a relevant population for treatment with axitinib in current clinical practice.	4.3 4.4
Estimate of the size of the clinical effectiveness including strength of supporting evidence		The Committee noted that the better progression-free survival results for axitinib patients (HR 0.67, 95% CI 0.54 to 0.81, p<0.0001) did not translate into statistically significant overall survival benefits (HR 0.97, 95% CI 0.80 to 1.17, p=0.37) for the full trial population. The Committee noted that crossover in the TARGET trial was adjusted by censoring the patients who crossed over and considered that this could have resulted in bias and ultimately affected the robustness of the results of the indirect comparison (progression-free survival [HR 0.25, 95% credible intervals 0.17 to 0.38] overall survival, [HR 0.63 95% credible intervals 0.41 to 0.99]) The Committee concluded that there were serious limitations with the indirect comparisons performed for the prior-sunitinib group, and the outcomes from the simulated treatment comparison (progression-free survival [4.6 months for axitinib compared with 1.7 months for placebo], overall survival [16.6 months for axitinib compared with 8.3 months for placebo]) and indirect comparison (overall survival [HR 0.62, 95% credible interval 0.38 to 0.997]) should be interpreted with caution	4.5 4.6 4.7
Evidence for cost effectiveness
Availability and nature of evidence		The economic evaluation was based on the 2 separate populations specified in the marketing authorisation for axitinib (the groups of people in whom prior treatment with sunitinib or cytokines has failed, also referred to as the prior-sunitinib and the prior-cytokine groups). A 3-state Markov cohort model was developed based on previous modelling of metastatic cancer using Microsoft Excel.	3.21 3.22
Uncertainties around and plausibility of assumptions and inputs in the economic model		The Committee noted that when alternative survival distributions were tested in the scenario analysis, it resulted in sizeable changes to the base-case result for the prior-cytokine population and moderate changes for the prior-sunitinib population. The Committee considered that the possible over-estimation of the overall survival in the TARGET trial was carried over into the overall survival results in the indirect comparison and ultimately affected the model results for the best supportive care group. The Committee recognised that the results of the simulated treatment comparison method used to derive a best supportive care comparison for axitinib in the prior-sunitinib group should be interpreted with caution.	4.10 4.12 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 was satisfied that the utility values applied in the model were derived from AXIS, which was the main trial used in the economic analysis, and considered the assumptions made around the utility estimates to be robust. The Committee considered that there were no additional gains in health-related quality of life over those already included in the QALY calculations.	4.11 4.18
Are there specific groups of people for whom the technology is particularly cost effective?		None identified.	−
What are the key drivers of cost effectiveness?		When the RENCOMP method was used rather than the simulated treatment comparison, the ICER increased to over £50,000 per QALY gained (with the patient access scheme applied) using the Weibull and Gompertz distributions, suggesting that this was a key driver of the results in the prior-sunitinib group.	4.14
Most likely cost-effectiveness estimate (given as an ICER)		The Committee noted that the manufacturer’s base-case ICER of £65,000 per QALY gained may have been over-estimated for the prior-cytokine group, but it noted that the most plausible ICER was likely to still be above £50,000 per QALY gained. The Committee considered that the ICER of approximately £62,000 per QALY gained estimated by the ERG represented a more plausible (although still uncertain) ICER for the prior-sunitinib group.	4.15
Additional factors taken into account
Patient access schemes (PPRS)		The manufacturer of axitinib has agreed a patient access scheme with the Department of Health. The size of the discount is commercial in confidence.	2.3
End-of-life considerations		The Committee concluded that axitinib fulfilled the 3 criteria for a life-extending, end-of-life treatment for the prior-sunitinib population. However, it concluded that the value of the ICERs and the uncertainty around the ICERs meant that axitinib still could not be considered a good use of NHS resources for this population. For the prior-cytokine group, the Committee considered that these were people who could receive sunitinib or pazopanib but no comparison had been available.	4.17
Equalities considerations and social value judgements		The Committee noted the potential equality issues raised by the patient experts, patient organisations and NHS organisations, but concluded that its preliminary recommendations did not have a particular impact on any of the groups whose interests are protected by the legislation and that there was no need to alter or add to its preliminary recommendations.	4.19

 

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  The technology in this appraisal may not be the only treatment for advanced renal cell carcinoma. If a NICE technology appraisal recommends use of a technology, it is as an option for the treatment of a disease or condition. This means that the technology should be available for a patient who meets the clinical criteria set out in the guidance, subject to the clinical judgement of the treating clinician. The NHS must provide funding and resources (in line with section 5.1) when the clinician concludes and the patient agrees that the recommended technology is the most appropriate to use, based on a discussion of all available treatments.

5.3  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

• Everolimus for the second-line treatment of renal cell carcinoma. NICE technology appraisal guidance 219 (2011).
• Bevacizumab (first-line), sorafenib (first- and second-line), sunitinib (second-line) and temsirolimus (first-line) for the treatment of advanced and/or metastatic renal cell carcinoma. NICE technology appraisal guidance 178 (2009).

Under development

There is no related guidance under development for this technology.

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 May 2016. 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.

Professor Andrew Stevens
Chair, Appraisal Committee
November 2012

Appendix A: Appraisal Committee members and NICE project team

A  Appraisal Committee members

The Appraisal Committees are standing advisory committees of NICE. Members are appointed for a 3-year term. A list of the Committee members who took part in the discussions for this appraisal appears below. There are 4 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 Andrew Stevens

Chair of Appraisal Committee C, Professor of Public Health, University of Birmingham

Professor Gary McVeigh

Vice Chair of Appraisal Committee C, Professor of Cardiovascular Medicine, Queens University Belfast and Consultant Physician, Belfast City Hospital

Dr David Black

Medical Director, NHS South Yorkshire and Bassetlaw

Dr Daniele Bryden

Consultant in Intensive Care Medicine and Anaesthesia, Sheffield Teaching Hospitals NHS Trust

Dr Andrew Burnett

Director for Health Improvement and Medical Director, NHS Barnet, London

David Chandler

Lay Member

Dr Mary Cooke

Lecturer, School of Nursing, Midwifery and Social Work, University of Manchester

Professor Peter Crome

Honorary Professor, Dept of Primary Care and Population Health, University College London

Professor Rachel A Elliott

Lord Trent Professor of Medicines and Health, University of Nottingham

Dr Greg Fell

Consultant in Public Health, Bradford and Airedale Primary Care Trust

Dr Peter Jackson

Clinical Pharmacologist, University of Sheffield

Dr Janice Kohler

Senior Lecturer and Consultant in Paediatric Oncology, Southampton University Hospital Trust

Emily Lam

Lay Member

Dr Grant Maclaine

Director, Health Economics & Outcomes Research, BD, Oxford

Dr Andrea Manca

Health Economist and Senior Research Fellow, University of York

Henry Marsh

Consultant Neurosurgeon, St George's Hospital, London

Professor Stephen O’Brien

Professor of Haematology, Newcastle University

Dr Anna O’Neill

Deputy Head of Nursing & Healthcare School/Senior Clinical University Teacher, University of Glasgow

Professor Katherine Payne

Professor of Health Economics, University of Manchester

Dr Martin Price

Head of Outcomes Research, Janssen-Cilag, Buckinghamshire

Dr Surinder Sethi

Consultant in Public Health Medicine, North West Specialised Services Commissioning Team, Warrington

Dr John Stevens

Lecturer in Bayesian Statistics in Health Economics, School of Health and Related Research, Sheffield

Prof Matt Stevenson

Technical Director, School of Health and Related Research, University of Sheffield

Dr Judith Wardle

Lay Member

C  NICE project team

Each technology appraisal is assigned to a team consisting of 1 or more health technology analysts (who act as technical leads for the appraisal), a technical adviser and a project manager.

Nwamaka Umeweni

Technical Lead

Dr Bhash Naidoo

Technical Adviser

Lori Farrar

Project Manager

 Appendix B: Sources of evidence considered by the Committee

A  The Evidence Review Group (ERG) report for this appraisal was prepared by Kleijnen Systematic Reviews Ltd:

• Riemsma R, Al M, Corro Ramos I et al. Axitinib for the treatment of advanced renal cell carcinoma after failure of prior systematic treatment, October 2012.

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:

• Pfizer

II.  Professional/specialist and patient/carer groups:

• Cancer Research UK
• James Whale Fund for Kidney Cancer
• Kidney Cancer UK
• Royal College of Nursing
• Royal College of Physicians

III.  Other consultees:

• Department of Health
• NHS Devon
• NHS Norfolk
• 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 for Northern Ireland
• Healthcare Improvement Scotland
• Kleijnen Systematic Reviews Ltd
• National Cancer Research Institute
• National Collaborating Centre for Cancer
• National Institute for Health Research Health Technology Assessment Programme

C  The following individuals were selected from clinical specialist and patient expert nominations from the consultees and commentators. They gave their expert personal view on axitinib for the treatment of advanced renal cell carcinoma after failure of prior systemic treatment by attending the initial Committee discussion and providing written evidence to the Committee. They are invited to comment on the ACD.

• Dr Janet Brown, Senior Lecturer, Honorary Consultant Medical Oncology, nominated by the Royal College of Physicians – clinical specialist
• Professor Robert Hawkins, Director of Medical Oncology, nominated by the Royal College of Physicians – clinical specialist
• Dr Pat Hanlon, nominated by Kidney Cancer UK – patient expert
• Jacqueline Lowe, nominated by Kidney Cancer UK – 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.

• Pfizer