The Department of Health has asked the National Institute for Health and Care Excellence (NICE) to produce guidance on using pertuzumab 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 section 10) and the public. This document should be read along with the evidence base (the evaluation report) www.nice.org.uk.

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

• Has all of the relevant evidence been taken into account?
• Are the summaries of clinical and cost effectiveness reasonable interpretations of the evidence?
• Are the provisional recommendations sound and a suitable basis for guidance to the NHS?
• Are there any aspects of the recommendations that need particular consideration to ensure we avoid unlawful discrimination against any group of people on the grounds of 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 pertuzumab in the NHS in England and Wales.

For further details, see the Guides to the technology appraisal process.

The key dates for this appraisal are:

Closing date for comments: 28 August 2013

Second Appraisal Committee meeting: 4 September 2013

Details of membership of the Appraisal Committee are given in section 9, and a list of the sources of evidence used in the preparation of this document is given in section 10.

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   Pertuzumab in combination with trastuzumab and docetaxel is not recommended within its marketing authorisation, that is, for treating people with human epidermal growth factor receptor 2 (HER2)-positive metastatic or locally recurrent unresectable breast cancer who have not received previous anti-HER2 therapy or chemotherapy for their metastatic disease.

1.2   People currently receiving pertuzumab 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  Pertuzumab (Perjeta, Roche Products) is a monoclonal antibody targeting HER2. Pertuzumab binds to the HER2 receptor and inhibits intracellular signalling. It is administered by intravenous infusion. Pertuzumab has a UK marketing authorisation for use ‘in combination with trastuzumab and docetaxel in adult patients with HER2-positive metastatic or locally recurrent unresectable breast cancer, who have not received previous anti-HER2 therapy or chemotherapy for their metastatic disease’. The recommended dose of pertuzumab is an initial loading dose of 840 mg followed every 3 weeks by a maintenance dose of 420 mg in combination with trastuzumab and docetaxel. Treatment with pertuzumab should be continued until disease progression or unmanageable toxicity.

2.2   The summary of product characteristics lists the following adverse reactions for pertuzumab in combination with docetaxel and trastuzumab: left ventricular dysfunction (including congestive heart failure), infusion reactions, hypersensitivity reactions (including anaphylaxis), neutropenia, febrile neutropenia, leukopenia, diarrhoea, alopecia and rash. For full details of adverse reactions and contraindications, see the summary of product characteristics.

2.3   The manufacturer’s submission states that the list price of pertuzumab is £2395 per 420 mg vial (excluding VAT; Roche Products). Therefore the cost of pertuzumab (excluding VAT) is estimated to be £4790 for the initial dose, followed by £2395 for subsequent doses. Costs may vary in different settings because of negotiated procurement discounts.

3   The manufacturer’s submission

The Appraisal Committee (section 9) considered evidence submitted by the manufacturer of pertuzumab and a review of this submission by the Evidence Review Group (ERG; section 10).

3.1   The key evidence for the clinical effectiveness of pertuzumab plus trastuzumab and docetaxel came from 1 randomised controlled trial, the CLEOPATRA trial. This double-blind, randomised, placebo-controlled trial assessed the efficacy and safety of pertuzumab plus trastuzumab and docetaxel in 808 adults with HER2-positive metastatic breast cancer in 204 centres, in 25 countries including the UK. Randomisation was stratified by geographic region (Asia, Europe, North America and South America) and prior treatment status (de novo and prior adjuvant or neoadjuvant chemotherapy). Investigators randomised patients in a 1:1 ratio to either pertuzumab plus trastuzumab and docetaxel (n=406) or placebo plus trastuzumab and docetaxel (n=404). Patients received either pertuzumab at a loading dose of 840 mg followed by 420 mg every 3 weeks or placebo every 3 weeks until disease progression or unacceptable toxicity occurred. All patients received a trastuzumab loading dose of 8 mg/kg body weight followed by 6 mg/kg body weight every 3 weeks, and docetaxel 75–100 mg/m² (at investigator discretion) every 3 weeks for at least 6 cycles.

3.2   The primary end point in the CLEOPATRA trial was progression-free survival (PFS), defined as the time from randomisation to the first documented progressive disease based on a review of radiographic, cytological and photographic data, as determined by the independent review facility, according to Response Evaluation Criteria for Solid Tumours (RECIST) criteria, or death from any cause (within 18 weeks of last tumour assessment), whichever occurred first. Secondary end points were:

• investigator-assessed PFS (defined as the time from randomisation to the first documented radiographic progression based on RECIST criteria or death from any cause)
• overall survival (defined as the time from randomisation to death from any cause)
• overall response rate (defined as a complete response or partial response determined by the independent review facility based on RECIST criteria on 2 consecutive occasions more than 4 weeks apart)
• duration of objective response (defined as the time from initial confirmed partial or complete response to progression or death from any cause)
• health-related quality of life.

Exploratory end points included time to response, clinical benefit response rate (defined as the percentage with an objective response or stable disease maintained for at least 180 days) and safety parameters.

3.3  The manufacturer conducted 2 interim analyses for PFS with data cut offs of May 2011 and May 2012 respectively. The first interim analysis of the independent review facility PFS assessment in the intention-to-treat population was based on a cut-off date of May 2011 when 191 (48%) patients in the pertuzumab arm and 242 (60%) patients in the placebo arm had experienced disease progression or death. The median follow-up was 19 months for this analysis. The results reported a statistically significant gain in median PFS of 6.1 months in the pertuzumab arm (median PFS of 18.5 and 12.4 months in the pertuzumab and placebo arms respectively; hazard ratio [HR] 0.62, 95% confidence interval [CI] 0.51 to 0.75, p<0.0001). The manufacturer also carried out an analysis of investigator-assessed PFS based on the data cut off of May 2012, when 1553 (68%) patients had disease progression or had died (64% and 73% of the patients in the pertuzumab and in the placebo arm respectively), for a median follow-up of 30 months. Results showed that there was a statistically significant gain in median PFS of 6.3 months (18.7 months in the pertuzumab arm compared with 12.4 months in the placebo arm; HR 0.69, 95% CI 0.58 to 0.81).

3.4   The manufacturer also conducted subgroup analyses of PFS for the predefined stratification and baseline factors based on independent review facility assessment (data cut off May 2011). Results were generally consistent with those seen in the whole study population. For the subgroup based on disease type (visceral and non-visceral disease) the HR for PFS was 0.55 (95% CI 0.45 to 0.68) for patients with visceral disease (n=630) and 0.96 (95% CI 0.61 to 1.52) in patients with non-visceral disease (statistical test for interaction p=0.0332).

3.5  The manufacturer conducted 2 interim overall survival analyses each for data cut offs of May 2011 and May 2012. The manufacturer stated that the final overall survival data will be presented after approximately 385 deaths. Results for the first interim analysis (May 2011) showed an increase in overall survival for the pertuzumab group compared with the placebo group, however this difference did not meet the criteria to be considered statistically significant (HR 0.64, 95% CI 0.47 to 0.8). At the time of the second interim analysis (May 2012), 267 deaths had occurred (113 deaths [28%] in the pertuzumab arm and 154 deaths [38%] in the placebo arm) with a median follow-up of 30 months in both arms. Results for the second analysis (May 2012) reported a median overall survival of 37.6 months in the placebo arm; the median overall survival had not been reached in the pertuzumab arm. The overall survival increase for pertuzumab compared with placebo was statistically significant (HR 0.66, 95% CI 0.52 to 0.84, p=0.0008).

3.6   The manufacturer also reported subgroup analyses of overall survival based on predefined stratification and baseline factors. The majority of these results were consistent with the results seen in the overall survival analysis for the whole study population. For the subgroup of patients with non-visceral disease the HR for overall survival was 1.42 (95% CI 0.71 to 2.84). The manufacturer noted the variability around this estimate in this subgroup (demonstrated in its wide confidence interval), and that the sample size and the number of patients who died in this subgroup were low (33 of 178 patients died [19%]). Subgroup analyses for prior treatment status were consistent with the results seen in the study population.

3.7  Objective response (data cut off May 2011) was based on the best overall response (complete response or partial response) recorded from the start of trial treatment until independent review facility assessed progression, death or first administration of next-line anticancer therapy. A higher percentage of patients had an objective response in the pertuzumab arm (275 patients [80%]) compared with the placebo arm (233 patients [69%], p=0.0011). The median duration of objective response was longer in the pertuzumab arm (87.6 weeks) compared with the placebo arm (54.1 weeks) (HR 0.66, 95% CI 0.51 to 0.85). Sensitivity analyses of objective response and duration of objective response based on investigator assessment in the intention-to-treat population with investigator-determined measurable disease (n=367 in the pertuzumab arm, n=371 in the placebo arm) were consistent with the independent review facility analysis.

3.8 Health-related quality of life was measured with the Functional Assessment of Cancer Therapy-Breast (FACT-B) version 4 questionnaire, which provides a total quality of life score and information about physical wellbeing, social/family wellbeing, functional wellbeing, and disease-specific concerns (data cut off May 2011). This questionnaire was completed at each scheduled visit every 9 weeks for female patients (806 patients). No differences between treatment arms in terms of health-related quality of life were reported. The number of patients experiencing symptom progression was similar in the 2 treatment arms (239 [60%] in the pertuzumab arm and 229 [57%] in the placebo arm). The median time to symptom progression was 18.4 weeks in the pertuzumab arm compared with 18.3 weeks in the placebo arm (HR 0.97, 95% CI 0.81 to 1.16).

3.9   The manufacturer presented adverse event data for both data cut off dates in the CLEOPATRA trial and stated that overall the results were similar between the 2 analyses. The incidence of serious adverse events (data cut off May 2012) was higher in the pertuzumab arm (36%) compared with the placebo arm (29%) and the incidence of adverse events leading to dose interruption or modification was also higher in the pertuzumab arm (62%) compared with the placebo arm (54%). The incidence of diarrhoea, rash, mucosal inflammation, febrile neutropenia, dry skin and pruritus was at least 5% higher in the pertuzumab arm compared with the placebo arm, whereas peripheral oedema and constipation were more common in the placebo arm. The manufacturer noted that the incidence of febrile neutropenia was likely to be associated with docetaxel treatment and that no febrile neutropenia events occurred after docetaxel was stopped in the trial. The manufacturer also noted that patients of Asian family origin experienced more febrile neutropenia events (possibly related to the fact that docetaxel clearance is reduced in people with low body surface area to volume ratio) and concluded that the incidence of febrile neutropenia in CLEOPATRA was likely to be greater than the expected incidence for the UK population. The incidence of left ventricular dysfunction and heart failure was similar in both treatment arms, although more serious cardiac adverse events occurred in the placebo arm (3.5%) compared with the pertuzumab arm (1.7%).

3.10   The manufacturer noted that there are 2 taxanes (paclitaxel and docetaxel) that are used routinely in clinical practice with trastuzumab for treating HER2-positive metastatic breast cancer. In the absence of direct evidence on the relative efficacy of pertuzumab with trastuzumab and docetaxel or paclitaxel, and given the conclusions of the Appraisal Committee in NICE technology appraisal guidance 214 (Bevacizumab in combination with a taxane for the first-line treatment of metastatic breast cancer), the manufacturer stated that it considered the taxane regimens of 3 weekly docetaxel and weekly paclitaxel to be clinically equivalent. The manufacturer referred to the rationale of the discussion in NICE technology appraisal guidance 214 where, based on a naive indirect comparison of 2 different trials, it was shown that docetaxel had a comparable efficacy and safety profile when compared with paclitaxel when used in combination with trastuzumab for the treatment of HER2-positive disease (Slamon et al. 2011; Marty et al. 2005). The manufacturer also cited a study (Sparano et al. 2008) that provided head to head evidence on the relative efficacy of different taxanes regimens in the adjuvant treatment of HER2-negative early disease and that showed that 3 weekly docetaxel and weekly paclitaxel were the most effective taxane regimens, with similar 5-year disease free survival and overall survival results. The manufacturer concluded that the outcomes for people treated with trastuzumab in combination with weekly paclitaxel would be similar to the outcomes observed for the placebo arm in the CLEOPATRA trial.

3.11 The manufacturer submitted a de novo economic analysis that assessed the cost effectiveness of pertuzumab plus trastuzumab and docetaxel compared with placebo plus trastuzumab and docetaxel, and with placebo plus trastuzumab and paclitaxel, for treating people with HER2-positive metastatic breast cancer who have not previously received chemotherapy or anti-HER2 therapy in the metastatic setting. The model was a partitioned survival model with 3 states consisting of PFS, progressed disease and death. The manufacturer used clinical efficacy inputs based on data from the CLEOPATRA trial in the model. The cost-effectiveness analysis was conducted from an NHS and personal social services perspective, costs and outcomes were discounted at 3.5% per year and a lifetime time horizon that equated to 25 years was used. The cycle length was 1 week.

3.12 PFS in the model was derived using Kaplan-Meier estimates from the CLEOPATRA trial (data cut off May 2012). The manufacturer presented Kaplan-Meier plots and cumulative hazard plots to investigate the change in the hazard of progression over time. The manufacturer noted that for the placebo arm there were 2 distinct periods of time with different associated constant linear hazards, these being associated with a higher hazard of progression up to week 86 and then a lower hazard of progression from week 87 onwards. The hazard of progression in the pertuzumab arm also seemed to be constant and linear over time and lower than in the placebo arm, potentially with a period with a lower hazard from week 117 onwards. The manufacturer provided different scenarios to explain the reason for the different hazards before and after week 87 in the placebo arm and used different methods of exponentially extrapolating these data in the model. The manufacturer considered, based on its clinical experts’ advice, that there was a group of people that had a long-term response to treatment with trastuzumab in clinical practice, and that it was clinically plausible that the addition of pertuzumab resulted in a longer duration of response. The manufacturer assumed in its base case that if patients in the pertuzumab arm were followed up over a longer period of time, the hazard of progression would become similar to that seen in the placebo arm. This would represent a clinically distinct cohort of patients in both treatment arms whose condition responds better to treatment than those associated with the higher hazard of progression. The manufacturer noted that week 117 was considered as a transition point from using Kaplan-Meier data and the exponential tail in the pertuzumab arm because this was the point at which the observed Kaplan-Meier data flattened slightly before rising sharply, and that this would be expected to be seen if there were 2 clinically distinct cohorts of patients in the arm. This scenario applied the same weekly transition probability used to extrapolate the part of the curve of the placebo arm associated with the lower hazard of progression to the pertuzumab curve from week 117 onwards. The manufacturer explored the other scenarios and alternative extrapolation approaches in its sensitivity analyses.

3.13   Overall survival in the model was derived using the Kaplan-Meier estimates observed in both treatment arms in the CLEOPATRA trial (data cut off May 2012). The manufacturer incorporated the hazards of death in both treatment arms in the model using Kaplan-Meier data up to month 35 followed by a constant hazard. The manufacturer assessed the external validity of the Kaplan-Meier estimates and their extrapolation using register data of 523 patients with HER2-positive metastatic breast cancer between 2002 and 2009 in Munich (Germany). The manufacturer stated that this indicated a constant linear hazard that supported the use of the exponential distribution for extrapolating the data.

3.14  Utility values applied in the model were obtained from a regression analysis detailed in a study (Lloyd et al. 2006) which had been used in NICE technology appraisal guidance 263 (Bevacizumab in combination with capecitabine for the first-line treatment of metastatic breast cancer). This study reported utility values obtained from 100 people from the general population who were asked to value different health states and adverse events associated with metastatic breast cancer using the standard gamble technique. The manufacturer calculated a treatment-specific weighted average for stable disease and treatment response based on the overall response rate, and applied it to the PFS state in the model. The utility values used in the model were 0.772 and 0.769 in the pertuzumab and the placebo arms respectively for patients receiving docetaxel (0.785 and 0.777 after docetaxel treatment for the pertuzumab and the placebo arms respectively) in the PFS state; and 0.496 in the progressed disease state in both arms. The manufacturer included disutilities of adverse events with grade 3, 4 and 5 severity that affected more than 2% of patients in either treatment arm in the CLEOPATRA trial and which were deemed to affect quality of life according to clinical opinion. The manufacturer highlighted that the adverse events that had a significant impact on quality of life were: febrile neutropenia, diarrhoea and vomiting, fatigue, anaemia and peripheral neuropathy. The utility decrement associated with febrile neutropenia was applied only during treatment with docetaxel or paclitaxel. The manufacturer mentioned that clinical specialists indicated that the utility values used in the model were conservative and that they would expect to see a higher quality of life in the progressed disease state.

3.15   The manufacturer used the distribution of body weight of patients in the CLEOPATRA trial to derive the dosage of trastuzumab, docetaxel and paclitaxel. Drug prices were taken from the ‘British national formulary’ (BNF 65th edition) and the Commercial Medicines Unit 2012 electronic Market Information Tool (CMU eMIT database). The manufacturer assumed in its base case that any unused drug in a vial was wasted. Administration costs were obtained from NHS Reference costs 2011/12 and the associated pharmacy time was assumed to be 12 minutes. The weekly costs of second-line treatment with vinorelbine and capecitabine were applied to the progressed disease state in the model for 4.3 months based on a study (Cameron et al. 2008) in which patients with metastatic breast cancer whose disease had progressed after treatment with trastuzumab were treated with capecitabine. The weekly costs of supporting patients in the PFS and progressed health states and costs of palliative care were also included. Costs associated with adverse events that occurred at grade 3, 4 or 5 severity in more than 2% of patients from the CLEOPATRA trial were incorporated into the analysis. All adverse events were assumed to occur in week 1 of the model and so were not discounted.

3.16  The manufacturer presented its base-case results in an incremental analysis of the cost effectiveness of pertuzumab plus trastuzumab and docetaxel, trastuzumab plus docetaxel, and trastuzumab plus paclitaxel, the results of which were provided as commercial in confidence and therefore are not presented. The base-case results estimated that adding pertuzumab to trastuzumab and docetaxel provided an additional 0.83 quality-adjusted life years (QALYs) compared with trastuzumab and docetaxel alone. The manufacturer’s sensitivity analyses suggested that the model was most sensitive to assumptions around the extrapolations of PFS and overall survival. The model was also sensitive to the assumption of first-line treatment duration, the utility values in PFS (after docetaxel treatment) and progressed disease states, and health and costs discount rates. The manufacturer also investigated the different assumptions for extrapolating PFS data in different scenario analyses (see section 3.12) the results of which were similar to the manufacturer’s base-case results. The manufacturer’s probabilistic sensitivity analyses showed a 0% probability of pertuzumab plus trastuzumab and docetaxel being cost effective compared with trastuzumab and docetaxel alone at £30,000 per QALY gained. The manufacturer concluded that the cost-effectiveness results were most sensitive to the cost of pertuzumab, the long-term projection of PFS and overall survival data, and the utility values used.

3.17  The ERG considered the CLEOPATRA trial to be of good methodological quality with a minimum risk of bias. It further noted that the manufacturer did not include information on therapy received after disease progression but identified 1 publication (published after the manufacturer’s search was carried out) that included these data (Swain et al. 2013). The ERG considered that the course of treatment with docetaxel assumed in the CLEOPATRA trial (in which patients received a median of 8 cycles of docetaxel therapy) may not fully represent clinical practice in the UK (where a maximum of 6 cycles of docetaxel therapy is administered). The ERG also noted that a minority of patients in the CLEOPATRA trial (n=88 [11%]) had received prior adjuvant or neoadjuvant treatment with trastuzumab, which is standard care in the UK, and stated that it was unclear if the results observed in the CLEOPATRA trial would be observed in clinical practice. The results of a post-hoc analysis of patients who had previously received trastuzumab (requested by the Committee for Medicinal Products for Human Use) were consistent with the results observed for the whole patient population in the CLEOPATRA trial.

3.18  The ERG noted that the overall survival data from the CLEOPATRA trial were immature (because median overall survival had not been reached in the pertuzumab arm) and that it was not possible to estimate the absolute difference in median overall survival between the pertuzumab arm and the placebo arm. The ERG hypothesised that apparent improvements in overall survival observed for the pertuzumab arm may arise from subsequent lines of treatment rather from pertuzumab. It however noted that Swain et al. (2013) showed that treatments received by patients who stopped study treatment were similar in both treatment arms and that pertuzumab was not provided as a subsequent line of treatment minimising the risk of bias in the overall survival results.

3.19   The ERG critiqued the indirect evidence provided by the manufacturer in its submission for the comparison between docetaxel and paclitaxel. The ERG noted that the manufacturer concluded that docetaxel has been shown to have a comparable efficacy and safety profile when compared with paclitaxel but noted that the manufacturer did not conduct any formal statistical analyses to support this statement and that it based its conclusion on a descriptive indirect comparison of 2 trials comparing trastuzumab plus a taxane in the metastatic setting (Marty et al. 2005; Slamon et al. 2001), and a head to head comparison of 3 weekly docetaxel and weekly paclitaxel regimens in the adjuvant setting (Sparano et al. 2008). The ERG considered that extreme caution should be taken because there were differences in terms of the patient populations in the trials and because in the head to head comparison conducted in the adjuvant setting, patients did not receive trastuzumab. The ERG further noted safety data from Sparano et al. (2008) showed that paclitaxel has a generally more favourable safety profile than docetaxel in patients with early breast cancer who received treatment in the adjuvant setting. The ERG considered that naive indirect comparisons such as these havebeen criticised for discarding the within-trial comparison, increasing the risk of bias and presenting estimates without a measure of the degree of uncertainty (such as confidence intervals).

3.20   The ERG considered that the manufacturer’s model structure was appropriate to describe the decision problem and was easy to understand. It identified and corrected a number of minor errors in the model and concluded that the impact of these corrections on the ICER was limited. The ERG highlighted that during clarification the manufacturer did not provide the requested alternative survival analyses from the CLEOPATRA trial censoring for the data cut-off date, and that the available data appeared to suffer from systematic bias because of censoring at the last trial observation date. The ERG considered that when censoring time-to-event data it is usual to base it on the last trial observation and that this has the effect of underestimating the time many patients are at risk in the latter stages of the trial while still counting deaths right up to the termination date, so that the mortality rate (deaths/time at risk) is artificially exaggerated. The ERG used the overall survival data observed in the Munich register to support this assumption. It compared the overall survival data from the CLEOPATRA trial and from the Munich register and found that from approximately 1000 days onwards the CLEOPATRA trial data showed a sudden increase in the hazard of death and that the placebo arm crossed the Munich registry data. The ERG believed that for this reason, these survival analyses based on data censored for the last trial observation date should not be used for extrapolating the data in the model. The ERG stated that in the absence of the requested alternative survival analyses it had been unable to offer alternative interpretations of the PFS, overall survival, time to off-treatment and post-progression survival results in relation to long-term projection of survival gains.

3.21  The ERG considered the manufacturer’s approach for projecting long-term survival assuming a higher risk of death in the placebo arm compared with the pertuzumab arm to be inappropriate, and assumed that there was no evidence of any difference in survival between treatment arms after progression. The ERG applied the mortality trend from the Munich register in both arms in the model, which substantially reduced the post-progression survival gain estimated by the manufacturer. The ERG also estimated overall survival using the PFS estimates, adjusting them for any difference in the proportion of patients dying before disease progression. Specifically, it used the estimated PFS gain and added to it the additional benefit after progression due to the small difference between the 2 treatment arms in the proportion of patients still alive after disease progression and assumed that the long-term post-progression hazard was the same in both arms. This approach reduced the overall survival gain to a similar magnitude as when using the Munich register data and the discounted QALY gain from 0.83 to 0.43. Both approaches gave similar incremental cost-effectiveness ratios (ICERs), both being higher than the manufacturer’s base-case.

3.22  The ERG noted that the manufacturer did not include any subgroup analyses in the model despite the differences in the clinical results for some subgroups. However, it provided in its clarification response its discussion with the Committee for Medicinal Products for Human Use and additional time-to-event analyses for subgroups (although not using the censoring rule requested by the ERG), the results of which are commercial in confidence.

3.23  The ERG agreed with the manufacturer that adding pertuzumab to trastuzumab and docetaxel resulted in an increase in PFS but considered that there was uncertainty around the size of this gain because of the impact of censoring in the final part of the PFS curve. The ERG conducted an exploratory analysis applying long-term linear hazard trends to both arms in the model from day 600 onwards. This analysis slightly reduced the mean undiscounted PFS gain calculated by the manufacturer.

3.24  Full details of all the evidence are in the manufacturer’s submission and the ERG report.

4   Consideration of the evidence

The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of pertuzumab plus trastuzumab and docetaxel, having considered evidence on the nature of HER2-positive metastatic or locally recurrent unresectable breast cancer and the value placed on the benefits of pertuzumab plus trastuzumab and docetaxel by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.

4.1   The Committee discussed the current management of HER2-positive metastatic or locally recurrent unresectable breast cancer. The Committee noted comments received from the professional groups that over 90% of people in the UK with HER2-positive breast cancer receive treatment with trastuzumab, usually in combination with docetaxel, in the neoadjuvant or adjuvant setting. The clinical specialist highlighted that the introduction of neoadjuvant or adjuvant trastuzumab for early breast cancer had dramatically changed the disease course and prognosis of people with HER2-positive breast cancer. Trastuzumab in combination with chemotherapy is currently considered the standard treatment when people develop metastatic disease. The Committee further heard from the clinical specialist that although the marketing authorisation for pertuzumab is for use in combination with trastuzumab and docetaxel, it may be more likely to be used in combination with trastuzumab and paclitaxel in clinical practice as the large majority of people would have had prior treatment with docetaxel in the adjuvant setting and a different taxane might be preferred. The Committee concluded that in clinical practice pertuzumab would be used in combination with trastuzumab and docetaxel or paclitaxel for treating HER2-positive metastatic or locally recurrent unresectable breast cancer in people who have not received previous anti-HER2 therapy or chemotherapy for their metastatic disease.

4.2  The Committee was aware that people with metastatic breast cancer understand that they have a life-limiting incurable disease that will eventually progress. The Committee heard from patient experts that although extension to life is important to patients, the benefits of progression-free survival (PFS) should not be underestimated because it allows them to maintain a good quality of life during this period. The patient experts also stated that treatments that extend life, even for a few weeks or months, are important to people, and that they may be willing to accept the side effects associated with such treatments. The Committee also heard from the patient experts that they considered pertuzumab to be an innovative technology because of the benefits shown in terms of PFS and overall survival. The Committee concluded that the availability of new treatments such as pertuzumab is important to people with HER2-positive metastatic or locally recurrent unresectable breast cancer.

Clinical effectiveness

4.3  The Committee noted that the main source of evidence for the clinical effectiveness of pertuzumab plus trastuzumab and docetaxel was the CLEOPATRA trial. It agreed with the ERG’s comments that overall this was a well-designed, double-blind, randomised, placebo-controlled trial and that the prevention of crossover between arms before the May 2012 data cut off minimised the risk of bias. However, the Committee heard from the clinical specialist that the protocol and inclusion criteria of the CLEOPATRA trial did not reflect current clinical practice in the UK. The clinical specialist highlighted that only 11% of the randomised population in the CLEOPATRA trial received previous treatment with trastuzumab in the adjuvant setting and therefore it represented a different population compared with patients in clinical practice in the UK where trastuzumab in the neoadjuvant or adjuvant setting is standard treatment. The Committee heard from the manufacturer that although trastuzumab was available in the UK from 2006, it was not a standard adjuvant therapy in all 25 different countries where the CLEOPATRA trial was conducted. The Committee was aware that the results of the additional subgroup analysis on the clinical effectiveness of pertuzumab in patients who had received previous treatment with trastuzumab in the adjuvant setting (requested by the Committee for Medicinal Products for Human Use) were consistent with the results found for the whole trial population. It noted, however, the clinical specialist’s comment about the small number of patients in this subgroup. The Committee also considered comments received from professional groups that the inclusion criteria of the CLEOPATRA trial specified disease progression occurring at least 12 months after neoadjuvant or adjuvant therapy. It heard from the clinical specialist that people who had experienced a 12 month disease-free interval might be expected to have a better prognosis than the whole population with HER2-positive metastatic breast cancer. The Committee considered that there were considerable differences between the population in the CLEOPATRA trial and people currently receiving treatment for HER2-positive metastatic breast cancer in the NHS, and expressed reservations about the applicability and generalisability of the CLEOPATRA trial to UK clinical practice. It concluded that there was considerable uncertainty as to whether the clinical effectiveness of pertuzumab in clinical practice in the UK would be the same as demonstrated in the CLEOPATRA trial because of the inclusion of patients with better prognosis and the inclusion of only small numbers of people previously treated with HER2-targeted therapies, which might affect their subsequent response.

4.4   The Committee discussed the end points in the CLEOPATRA trial. It noted that pertuzumab plus trastuzumab and docetaxel was associated with a statistically significant gain in median PFS of 6.1 months at the first data cut off (assessed by the independent review facility) and 6.3 months at the second data cut off (assessed by the investigators) compared with trastuzumab and docetaxel alone. It also noted that at the time of the second data cut off, the hazard ratio for overall survival showed a statistically significant benefit for the combination therapy compared with trastuzumab and docetaxel alone. The Committee concluded that pertuzumab plus trastuzumab and docetaxel offered a benefit in PFS and overall survival, although because of the immaturity of the overall survival data, the magnitude of the overall survival benefit was uncertain.

4.5  The Committee discussed the relationship between PFS and overall survival gain in the CLEOPATRA trial. It heard from the clinical specialist that the PFS gain as measured in a trial is a good indicator of the overall efficacy and the potential effect on overall survival. This is particularly the case in a well-designed trial such as CLEOPATRA, where switching to pertuzumab after disease progression was not allowed in the placebo arm and post-progression treatments were similar in both treatment arms. The clinical specialist considered that the statistically significant benefit of pertuzumab on PFS would be expected to be translated into a similar, if not greater gain in overall survival. The Committee considered that if overall survival gain exceeded the PFS gain this implied a continuing beneficial drug effect in the disease progression phase, after the drug had been stopped. The Committee acknowledged that the relationship between overall survival and PFS is very complex and discussed the biological plausibility of pertuzumab having a carry-over effect after treatment has been stopped. It heard from the clinical specialist that this carry-over effect has been seen with the use of tamoxifen in the adjuvant setting, in which the treatment benefit was maintained after disease progression. The clinical specialist noted, however, that this carry-over effect of tamoxifen is seen with adjuvant therapy and it would not necessarily be seen with HER2-targeted treatments in metastatic disease. The Committee heard from the manufacturer that the median 18 day half-life of pertuzumab could provide a rationale for a carry-over effect after progression. The Committee further discussed whether any post-progression survival benefit could be attributed to differences in subsequent post-progression treatments, for example with trastuzumab. The Committee heard from the manufacturer that in the CLEOPATRA trial treatment with trastuzumab was stopped once the disease progressed. The Committee also heard from the manufacturer that there have been other clinical trials with HER2-targeted therapies that showed an overall survival gain exceeding the PFS gain. The Committee noted that these trials compared treatment with trastuzumab plus a taxane against a taxane alone, or trastuzumab and an aromatase inhibitor against an aromatase inhibitor alone for metastatic disease. The Committee considered that it did not necessarily imply that the same effect would also be seen with the addition of pertuzumab to trastuzumab and docetaxel compared with trastuzumab and a taxane alone in metastatic disease. The Committee concluded that there were various hypothetical explanations for the presence of a carry-over effect with pertuzumab after stopping the drug at disease progression. However, it considered that the immature overall survival data in the trial did not allow a robust assessment of any post-progression benefit, and the relationship between PFS gain and overall survival gain remained uncertain.

4.6 The Committee discussed the subgroup analyses for people with visceral and non-visceral disease from the CLEOPATRA trial. It noted that there was no difference in survival between treatment arms in the subgroup with non-visceral disease and heard from the clinical specialist that people with metastatic disease confined to bone usually have a better prognosis. The Committee considered that the results could be affected by the small number of patients and events in this subgroup and noted the wide confidence intervals. The Committee concluded that there was insufficient evidence on which to base specific recommendations for people with visceral and non-visceral disease.

4.7  The Committee discussed the comparison of pertuzumab plus trastuzumab and docetaxel with trastuzumab plus paclitaxel. It noted that there was no head to head evidence available that compared these treatments and that the manufacturer presented a naive indirect comparison based on 2 trials that compared trastuzumab plus a taxane for metastatic disease, and 1 clinical trial that compared different taxane regimens in adjuvant therapy. The Committee agreed with the ERG’s comments that comparisons such as these should be viewed with caution. The Committee heard from the clinical specialist that in clinical practice 3 weekly docetaxel and weekly paclitaxel are regarded as clinically similar and noted that the similar clinical effectiveness of these 2 regimens had been previously accepted by the Appraisal Committee in a previous technology appraisal (Bevacizumab in combination with a taxane for the first-line treatment of metastatic breast cancer). The Committee concluded that it was reasonable to assume similar clinical effectiveness between 3 weekly docetaxel and weekly paclitaxel when used in combination with pertuzumab and trastuzumab.

Cost effectiveness

4.8   The Committee considered the structure, assumptions and results of the manufacturer’s economic model, which was based on data from the CLEOPATRA trial. The Committee noted that the ERG considered the manufacturer’s model structure to be appropriate to describe the decision problem, easy to understand and correctly implemented. The Committee was aware that the model structure had been used in other appraisals of metastatic breast cancer and concluded that the model adhered to the NICE reference case for economic analysis and was acceptable for assessing the cost effectiveness of pertuzumab plus trastuzumab and docetaxel for treating HER2-positive metastatic breast cancer.

4.9  The Committee considered the way in which PFS and overall survival data had been extrapolated in the manufacturer’s model. The Committee noted from the manufacturer’s submission that pertuzumab in combination with trastuzumab and docetaxel is associated with a 0% probability of being cost effective at £30,000 per QALY gained. The Committee further considered the deterministic sensitivity analysis and the ERG’s exploratory analysis which demonstrated that the model was sensitive to the long-term projection of overall survival.

4.10  The Committee considered the magnitude of PFS gain associated with pertuzumab estimated in the manufacturer’s model and the ERG’s exploratory analysis. It agreed with the manufacturer and the ERG that there was a statistically significant PFS gain from pertuzumab compared with placebo and considered that this benefit was appropriately captured in the model. The Committee noted that the difference between the 2 estimates was relatively minor and concluded that the magnitude of PFS gain was less critical than overall survival for the cost-effectiveness calculation and therefore for decision-making.

4.11 The Committee considered the magnitude of overall survival gain associated with pertuzumab estimated in the manufacturer’s model and the ERG’s exploratory analysis. The Committee noted that the manufacturer assumed that there was a prolonged treatment benefit from pertuzumab which was carried over into the post-progression state. In contrast, the ERG’s exploratory analysis of post-progression survival assumed that there was no additional benefit of pertuzumab after disease progression. The Committee heard from the manufacturer that there is evidence from trials with other agents that show a carry-over benefit from PFS to the post-progression state, leading to an overall survival gain that exceeds the PFS gain. The manufacturer suggested that this might also apply to pertuzumab. The Committee considered that although some post-progression benefit might be present as a carry-over effect, the manufacturer’s calculation that the gain was more than twice as great in the post-progression phase after pertuzumab had been stopped as when the patients were receiving the drug in the pre-progression state was likely to be an over-optimistic estimate. The Committee further noted that when the ERG used the assumption that there was no additional post-progression survival gain with pertuzumab, this approximately halved the incremental QALYs gained with pertuzumab and almost doubled the manufacturer’s base-case incremental cost effectiveness estimate. The Committee stated that it would have liked to receive further information from the manufacturer about post-progression survival in the trial, and modelling in which PFS and post-progression survival were estimated separately. This might have produced a more reliable estimate of overall survival. The Committee concluded that given the immature overall survival data, there remained considerable uncertainty around the presence, or magnitude of any post-progression benefit from the addition of pertuzumab to trastuzumab and docetaxel.

4.12 The Committee considered the method for censoring survival data in the CLEOPATRA trial. The Committee noted the ERG’s comment that the manufacturer’s censoring rules might have affected the results of the extrapolation in the model. It noted the ERG’s preferred method to censor data at the last data cut-off date instead of censoring at the last trial observation date. The Committee was aware that censoring at the last trial observation date is frequently done in clinical trials and that this was not an isolated issue for this appraisal. However, it acknowledged that it does add additional uncertainty to the manufacturer’s survival estimates because it could underestimate the time many patients were at risk in the latter stages of the trial while still counting deaths up to the termination date. This could have the effect of artificially exaggerating the mortality rate (deaths/time at risk).

4.13 The Committee discussed whether pertuzumab should be considered an innovative treatment. It noted that the clinical specialist emphasised the benefits of HER2 therapies in changing the prognosis of people with this disease and the significant PFS benefit observed with this new HER2-targeted therapy. Patient experts regarded it as an innovative treatment because it significantly increases the duration of PFS, thereby maintaining a good quality of life for patients. The Committee considered that the innovative nature of pertuzumab had been demonstrated in the statistically significant PFS gain in the CLEOPATRA trial and had been incorporated in the economic model. The Committee concluded that all relevant health related benefits of pertuzumab had been captured in the QALY calculation.

4.14 The Committee considered the most plausible incremental cost-effectiveness ratio (ICER) for pertuzumab plus trastuzumab and docetaxel compared with trastuzumab and docetaxel presented by the manufacturer and by the ERG in its exploratory analyses. The Committee noted that the manufacturer’s estimate of overall survival resulted in an ICER (which was provided as commercial in confidence) that was outside the range normally considered as a cost-effective use of NHS resources and that the Committee considered this ICER reflected a very optimistic scenario. The Committee noted that the ERG’s assumption of no benefit from pertuzumab in the post-progression state reflected the worst case scenario, and this yielded an ICER which was approximately double the manufacturer’s base-case result. The Committee noted the lack of direct evidence for, and considerable uncertainty around, any benefit from pertuzumab in the post-progression state when treatment had been stopped. It further noted that the manufacturer’s base-case ICER showed a 0% probability for pertuzumab plus trastuzumab and docetaxel to be considered cost effective at £30,000 per QALY gained. The Committee concluded that pertuzumab plus trastuzumab and docetaxel would not be a cost-effective use of NHS resources for treating HER2-positive metastatic or locally recurrent unresectable breast cancer compared with trastuzumab and docetaxel alone.

Summary of Appraisal Committee’s key conclusions

TAXXX	Appraisal title: Pertuzumab in combination with trastuzumab and docetaxel for treating HER2-positive metastatic or locally recurrent unresectable breast cancer		Section
Key conclusion
Pertuzumab in combination with trastuzumab and docetaxel is not recommended within its marketing authorisation, that is, for treating people with human epidermal growth factor receptor 2 (HER2)-positive metastatic or locally recurrent unresectable breast cancer who have not received previous anti-HER2 therapy or chemotherapy for their metastatic disease. The Committee concluded that pertuzumab plus trastuzumab and docetaxel offered a benefit in progression-free survival (PFS) and overall survival, although because of the immaturity of the overall survival data, the magnitude of the overall survival benefit was uncertain. The Committee noted that the manufacturer’s cost-effectiveness estimates for pertuzumab plus trastuzumab and docetaxel were outside the range normally considered to be cost-effective use of NHS resources. It concluded that pertuzumab plus trastuzumab and docetaxel would not be a cost-effective use of NHS resources for treating HER2-positive metastatic or locally recurrent unresectable breast cancer compared with trastuzumab and docetaxel alone			1.1 4.4 4.14
Current practice
Clinical need of patients, including the availability of alternative treatments		The Committee noted comments received from the professional groups that over 90% of people in the UK with HER2-positive breast cancer receive treatment with trastuzumab, usually in combination with docetaxel, in the neoadjuvant or adjuvant setting. Trastuzumab in combination with chemotherapy is currently considered the standard treatment when patients develop metastatic disease. The Committee was aware that people with metastatic breast cancer understand that they have a life-limiting incurable disease that will eventually progress. The Committee concluded that the availability of new treatments such as pertuzumab is important to patients with HER2-positive metastatic or locally recurrent unresectable breast cancer.	4.1 4.2
The technology
Proposed benefits of the technology How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?		The Committee heard from patient experts that they considered pertuzumab to be an innovative technology because of the benefits shown in terms of PFS and overall survival. The Committee noted that the clinical specialist emphasised the benefits of HER2 therapies in changing the prognosis of people with this disease and the significant PFS benefit observed with this new HER2-targeted therapy. The Committee considered that the innovative nature of pertuzumab had been demonstrated in the statistically significant PFS gain in the CLEOPATRA trial and had been incorporated in the economic model. The Committee concluded that all relevant health related benefits of pertuzumab had been captured in the QALY calculation.	4.2, 4.13
What is the position of the treatment in the pathway of care for the condition?		The Committee concluded that in clinical practice pertuzumab would be used in combination with trastuzumab and docetaxel or paclitaxel for treating HER2-positive metastatic or locally recurrent unresectable breast cancer in people who have not received previous anti-HER2 therapy or chemotherapy for their metastatic disease. For patients who have had prior treatment with docetaxel in the adjuvant setting paclitaxel might be preferred.	4.1
Adverse reactions		The incidence of serious adverse events in the CLEOPATRA trial was higher in the pertuzumab arm compared with the placebo arm and the incidence of adverse events leading to dose interruption or modification was also higher in the pertuzumab arm compared with the placebo arm.	3.9
Evidence for clinical effectiveness
Availability, nature and quality of evidence		The main source of evidence for the clinical effectiveness of pertuzumab plus trastuzumab and docetaxel was the CLEOPATRA trial. This was a well-designed, double-blind, randomised, placebo-controlled trial. The Committee noted that there was no head to head evidence available to compare the clinical effectiveness of pertuzumab plus trastuzumab and docetaxel with trastuzumab plus paclitaxel. The Committee considered the naive indirect comparison presented by the manufacturer based on 2 trials that compared trastuzumab plus a taxane for metastatic disease, and 1 clinical trial that compared different taxane regimens in adjuvant therapy, and the assumption of the similar clinical effectiveness of the 2 taxane regimens which was accepted in a previous technology appraisal. The Committee concluded that it was reasonable to assume similar clinical effectiveness between 3 weekly docetaxel and weekly paclitaxel when used in combination with pertuzumab and trastuzumab.	4.3 4.7
Relevance to general clinical practice in the NHS		The Committee considered that there were considerable differences between the population in the CLEOPATRA trial and people currently receiving treatment for HER2-positive metastatic breast cancer in the NHS, and expressed reservations about the applicability and generalisability of the CLEOPATRA trial to UK clinical practice.	4.3
Uncertainties generated by the evidence		The Committee concluded that there was considerable uncertainty as to whether the clinical effectiveness of pertuzumab in clinical practice in the UK would be the same as demonstrated in the CLEOPATRA trial because of the inclusion of patients with better prognosis and the inclusion of only small numbers of people previously treated with HER2-targeted therapies, which might affect their subsequent response. The Committee concluded that because of the immaturity of the overall survival data, the magnitude of the overall survival benefit was uncertain. The Committee concluded that there were various hypothetical explanations for the presence of a carry-over effect with pertuzumab after stopping the drug at disease progression. However, it considered that the immature overall survival data in the trial did not allow a robust assessment of any post-progression benefit, and the relationship between PFS gain and overall survival gain remained uncertain.	4.3 4.4 4.5
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?		The Committee noted that there was no difference in survival between treatment arms in the subgroup with non-visceral disease and heard from the clinical specialist that people with metastatic disease confined to bone usually have a better prognosis. The Committee considered that the results could be affected by the small number of patients and events in this subgroup and noted the wide confidence intervals. The Committee concluded that there was insufficient evidence on which to base specific recommendations for people with visceral and non-visceral disease.	4.6
Estimate of the size of the clinical effectiveness including strength of supporting evidence		The Committee noted that pertuzumab plus trastuzumab and docetaxel was associated with a statistically significant gain in median PFS of 6.1 months at the first data cut off (assessed by the independent review facility) and 6.3 months at the second data cut off (assessed by the investigators) compared with trastuzumab and docetaxel alone. It also noted the hazard ratio for overall survival showed a statistically significant benefit for the combination therapy compared with trastuzumab and docetaxel alone. The Committee concluded that pertuzumab plus trastuzumab and docetaxel offered a benefit in PFS and overall survival, although because of the immaturity of the overall survival data, the magnitude of the overall survival benefit was uncertain.	4.4
Evidence for cost effectiveness
Availability and nature of evidence		The Committee considered the structure, assumptions and results of the manufacturer’s economic model, which was based on data from the CLEOPATRA trial. The Committee was aware that the model structure had been used in other appraisals of metastatic breast cancer and concluded that the model adhered to the NICE reference case for economic analysis and was acceptable for assessing the cost effectiveness of pertuzumab plus trastuzumab and docetaxel for treating HER2-positive metastatic breast cancer.	4.8
Uncertainties around and plausibility of assumptions and inputs in the economic model		The Committee concluded that given the immature overall survival data, there remained considerable uncertainty around the presence, or magnitude of any post-progression benefit from the addition of pertuzumab to trastuzumab and docetaxel. The Committee acknowledged that censoring at the last trial observation date added additional uncertainty to the manufacturer’s survival estimates because it could have underestimated the time many patients were at risk in the latter stages of the trial while still counting deaths up to the termination date. This could have the effect of artificially exaggerating the mortality rate (deaths/time at risk).	4.11 4.12
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?		Utility values applied in the model were obtained from a regression analysis detailed in a study (Lloyd et al. 2006) which had been used in NICE technology appraisal guidance 263. The Committee concluded that all relevant health related benefits of pertuzumab had been captured in the QALY calculation.	3.14 4.13
Are there specific groups of people for whom the technology is particularly cost effective?		None.
What are the key drivers of cost effectiveness?		The deterministic sensitivity analysis and the ERG’s exploratory analysis demonstrated that the model was sensitive to the long-term projection of overall survival.	4.9
Most likely cost-effectiveness estimate (given as an ICER)		The Committee noted that the manufacturer’s estimate of overall survival resulted in an ICER that was outside the range normally considered as a cost-effective use of NHS resources and that the Committee considered this ICER reflected a very optimistic scenario. The Committee noted that the ERG’s assumption of no benefit from pertuzumab in the post-progression state reflected the worst case scenario, and this yielded an ICER which was approximately double the manufacturer’s base-case result. It further noted that the manufacturer’s base-case ICER showed a 0% probability for pertuzumab plus trastuzumab and docetaxel to be considered cost effective at £30,000 per QALY gained.	4.14
Additional factors taken into account
Patient access schemes (PPRS)		Not applicable.
End-of-life considerations		Not applicable.
Equalities considerations and social value judgements		No issues relating to equality considerations were raised in the submissions or the Committee meeting.

5  Implementation

5.1  NICE has developed tools [link to www.nice.org.uk/guidance/TAXXX] to help organisations put this guidance into practice (listed below). [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

Details are correct at the time of consultation. Further information is available on the NICE website.

Published

• Advanced breast cancer: diagnosis and treatment. NICE clinical guideline 81 (2009).
• Trastuzumab for the treatment of advanced breast cancer. NICE technology appraisal guidance 34 (2002).
• Bevacizumab in combination with a taxane for the first-line treatment of metastatic breast cancer. NICE technology appraisal guidance 214 (2011).
• Lapatinib or trastuzumab in combination with an aromatase inhibitor for the first-line treatment of metastatic hormone-receptor-positive breast cancer that overexpresses HER2. NICE technology appraisal guidance 257 (2012).
• Bevacizumab in combination with capecitabine for the first line treatment of metastatic breast cancer. NICE technology appraisal guidance 263 (2012).

Under development

• Trastuzumab emtansine for treating unresectable metastatic HER2-positive breast cancer after treatment with trastuzumab and a taxane. NICE technology appraisal. August 2014

NICE pathways

• There is a NICE pathway on advanced breast cancer.

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 September 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.

Jane Adam
Chair, Appraisal Committee
July 2013

8  Appraisal Committee members, guideline representatives and NICE project team

8.1   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.

Dr Jane Adam (Chair)

Department of Diagnostic Radiology, St George’s Hospital, London

Professor Iain Squire (Vice-Chair)

Consultant Physician, University Hospitals of Leicester

Professor A E Ades

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

Professor Thanos Athanasiou

Professor of Cardiovascular Sciences and Cardiac Surgery, Imperial College London; Consultant Cardiothoracic Surgeon, Imperial College Healthcare NHS Trust

Dr Jeremy Braybrooke

Consultant Medical Oncologist, University Hospitals Bristol NHS Foundation Trust

Professor Aileen Clarke

Professor of Public Health & Health Services Research, University of Warwick

Dr Fiona Duncan

Clinical Nurse Specialist, Anaesthetic Department, Blackpool Victoria Hospital

Mr Andrew England

Lecturer in Medical Imaging, NIHR Fellow, University of Liverpool

Mr Adrian Griffin

Vice President, HTA & International Policy, Johnson & Johnson

Professor Jonathan Grigg

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

Dr Brian Hawkins

Chief Pharmacist, Cwm Taf Health Board, South Wales

Dr Sharon Saint Lamont

Head of Quality and Innovation, North East Strategic Health Authority

Dr Ian Lewin

Consultant Endocrinologist, North Devon District Hospital

Dr Anne McCune

Consultant Hepatologist, University Hospitals Bristol NHS Foundation Trust

Ms Sarah Parry

CNS Paediatric Pain Management, Bristol Royal Hospital for Children

Dr Ann Richardson

Lay Member

Dr Paul Robinson

Medical Director, Merck Sharp & Dohme

Mr Stephen Sharp

Senior Statistician, MRC Epidemiology Unit

Dr Peter Sims

GP, Devon

Dr Eldon Spackman

Research Fellow, Centre for Health Economics, University of York

Mr David Thomson

Lay Member

Dr Olivia Wu

Reader in Health Economics, University of Glasgow

8.2   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.

Pilar Pinilla-Dominguez
Technical Lead

Eleanor Donegan
Technical Adviser

Bijal Joshi
Project Manager

9  Sources of evidence considered by the Committee

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

• Fleeman N, Bagust A, Beale S et al. Pertuzumab in combination with trastuzumab and docetaxel for the treatment of HER2 positive metastatic or locally recurrent unresectable breast cancer: A Single Technology Appraisal. June 2013.

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

I. Manufacturer/sponsor:

• Roche Products

II. Professional/specialist and patient/carer groups:

• Breakthrough Breast Cancer
• Breast Cancer Campaign
• Breast Cancer Care
• Cancer Research UK
• Royal College of Nursing
• Royal College of Pathologists
• Royal College of Physicians
• United Kingdom Clinical Pharmacy Association
• United Kingdom Oncology Nursing Society

III. Other consultees:

• Department of Health
• NHS England
• Pan-Lancashire PCT Cluster
• 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
• Liverpool Reviews & Implementation Group, University of Liverpool
• 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 pertuzumab by attending the initial Committee discussion and providing written evidence to the Committee. They are invited to comment on the ACD.

• Dr Helena Earl, Reader in Clinical Cancer Medicine and Hon Consultant in Medical Oncology, nominated by organisation representing Royal College of Physicians – clinical specialist
• Dr Caroline Dalton, Senior Policy Officer, nominated by organisation representing Breakthrough Breast Cancer – patient expert
• Tara Beaumont, Clinical nurse specialist-metastatic breast cancer, nominated by organisation representing Breast Cancer Care – patient expert

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

• Roche Products