The Department of Health has asked the National Institute for Health and Clinical Excellence (NICE) to produce guidance on using trastuzumab in the NHS in England and Wales. The Appraisal Committee has considered the evidence submitted by the manufacturer and the views of non-manufacturer consultees and commentators, and clinical specialists and patient experts.
This document has been prepared for consultation with the consultees. It summarises the evidence and views that have been considered, and sets out the draft recommendations made by the Committee. NICE invites comments from the consultees and commentators for this appraisal (see appendix B) and the public. This document should be read along with the evidence base (the evaluation report), which is available from www.nice.org.uk
The Appraisal Committee is interested in receiving comments on the following:
Has all of the relevant evidence been taken into account?

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

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

• The Appraisal Committee will meet again to consider the evidence, this appraisal consultation document and comments from the consultees.
• At that meeting, the Committee will also consider comments made by people who are not consultees.
• After considering these comments, the Committee will prepare the final appraisal determination (FAD).
• Subject to any appeal by consultees, the FAD may be used as the basis for NICE's guidance on using trastuzumab in the NHS in England and Wales.

For further details, see the 'Guide to the technology appraisal process' (available at www.nice.org.uk).
The key dates for this appraisal are:
Closing date for comments: 27 July 2010
Second Appraisal Committee meeting: 11 August 2010
Details of membership of the Appraisal Committee are given in appendix A, and a list of the sources of evidence used in the preparation of this document is given in appendix B.

1 Appraisal Committee’s preliminary recommendations

1.1 Trastuzumab, in combination with cisplatin and capecitabine or
5-fluorouracil, is not recommended for the treatment of people with human epidermal growth factor receptor (HER) 2-positive, metastatic adenocarcinoma of the stomach or gastro-oesophageal junction who have not received prior treatment for their metastatic disease.

2 The technology

2.1 Trastuzumab (Herceptin, Roche Products) is a recombinant humanised IgG1 monoclonal antibody directed against HER2. Trastuzumab in combination with capecitabine or 5-fluorouracil and cisplatin is indicated for the treatment of patients with HER2-positive metastatic adenocarcinoma of the stomach or gastro-oesophageal junction who have not received prior anticancer treatment for their metastatic disease. Trastuzumab is approved for use only in patients with metastatic gastric cancer whose tumours have HER2 overexpression as defined by immunohistochemistry (IHC)2+ and a confirmatory fluorescence in-situ hybridisation (FISH)+ result, or IHC3+, as determined by an accurate and validated assay'.
2.2 Trastuzumab is associated with cardiotoxicity. The summary of product characteristics states that formal cardiological assessment should be considered in patients in whom there are cardiovascular concerns following baseline screening. Cardiac function should be further monitored during treatment (e.g. every 3 months). The summary of product characteristics also states that caution should be taken in treating people with symptomatic heart failure, a history of hypertension, or documented coronary artery disease. For full details of side effects and contraindications, see the summary of product characteristics.
2.3 Trastuzumab is administered at an initial loading dose of 8 mg/kg body weight, followed by 6 mg/kg body weight 3 weeks later and then 6 mg/kg repeated at 3-weekly intervals. It is given as an intravenous infusion over approximately 90 minutes. If the initial loading dose is well tolerated, the subsequent doses can be administered as a 30-minute infusion. Providing treatment is tolerated, it can be given until disease progression.
2.4 The net price of a 150-mg vial of trastuzumab is £407.40 (excluding VAT; 'British national formulary' [BNF] edition 59). For a patient weighing 62 kg, 4 vials would be required for the first loading dose and 3 vials for each subsequent dose. Assuming that excess trastuzumab is wasted, the drug cost of 8 infusions of trastuzumab (the median number of infusions in the regulatory trial) is £10,185. Costs may vary in different settings because of negotiated procurement discounts.

3 The manufacturer's submission

The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of trastuzumab and a review of this submission by the Evidence Review Group (ERG; appendix B).
3.1 The manufacturer's decision problem compared trastuzumab plus cisplatin and either capecitabine or 5-fluorouracil with:

• epirubicin plus cisplatin and either capecitabine or 5-flourouracil and
• epirubicin plus oxaliplatin and capecitabine.

This was based on the results of a survey of commonly used treatments for gastric cancer in England and Wales. Outcomes were overall survival, progression-free survival, response rate, adverse effects of treatment and health-related quality of life. In the economic evaluation, the incremental cost per quality-adjusted life year (QALY) was presented. A lifetime horizon was used, and costs were considered from the NHS perspective.
Clinical effectiveness
3.2 The manufacturer identified one phase III randomised controlled trial (ToGA) evaluating the efficacy of trastuzumab plus cisplatin and a fluoropyrimidine (that is, capecitabine or 5-fluorouracil) in participants with inoperable locally advanced or recurrent and/or metastatic adenocarcinoma of the stomach or gastro-oesophageal junction. Participants had tumours with high levels of HER2 protein (see section 3.4), and had received no prior treatment for their advanced or metastatic disease.
3.3 The trial randomised 594 people to either a chemotherapy control group (n = 296) or a treatment group in which people received trastuzumab in combination with chemotherapy (n = 298). The chemotherapy group in the ToGA trial received intravenous cisplatin (80 mg/m2) on day one of each cycle with either oral capecitabine (1000 mg/m2) twice daily for 14 days, or an intravenous infusion of 5-fluorouracil (800 mg/m2) on days one to five of each of the six 3-weekly cycles. In addition to six 3-weekly cycles of chemotherapy, the treatment group received trastuzumab (8 mg/kg loading dose on day one, followed by 6 mg/kg intravenous infusion every 3 weeks) until disease progression. In both groups the choice of fluoropyrimidine was at the discretion of the investigator; 87% received capecitabine and 13% received
5-fluorouracil.
3.4 People whose tumours were classed as HER2 positive were included in the ToGA trial. Testing was carried out using IHC and FISH tests. Both tests were carried out at the same time (parallel testing) according to the trial protocol. At the time of randomisation, tumours with an IHC score of IHC3+, or those that tested FISH+ were defined as HER2 positive. Advances in the understanding of HER2 testing during the ToGA trial resulted in HER2 positive being defined as tumours that were IHC2+ and FISH+, or IHC3+. From the full population of 594 in the ToGA trial, 446 people (75%) had tumours that met this narrower definition. The European Medicines Agency (EMA) licence was granted for this population (referred to as the EMA subgroup). Of this subgroup, 218 people received treatment with chemotherapy alone and 228 people received treatment with trastuzumab in combination with chemotherapy.
3.5 At baseline, characteristics in the ToGA trial were balanced between the treatment groups. These characteristics included sex, age, weight, region, and type of tumour (that is, intestinal, diffuse or mixed tumour types). A high proportion of people in the ToGA trial were male (76%) and 55% were from Asian countries. Almost all (97%) people had metastatic gastric cancer and accordingly the licence was granted for the metastatic form of the disease only.
3.6 The primary outcome in the ToGA trial was overall survival. The ToGA trial was terminated early in accordance with a revised stopping rule recommended by the Independent Data Monitoring Committee. At the time of the clinical cut-off, the median duration of survival follow-up was 18.6 months in the trastuzumab plus chemotherapy group and 17.1 months in the chemotherapy alone group. The hazard ratio for overall survival in the EMA subgroup was 0.65 (95% confidence interval [CI] 0.51 to 0.83) corresponding to a median survival for the trastuzumab plus chemotherapy group of 16 months compared with 11.8 months for the chemotherapy alone group (4.2 month improvement in survival). A median survival of 13.8 months was reported for the total trial population receiving trastuzumab plus chemotherapy compared with 11.1 months in the chemotherapy alone group (2.7 month improvement in survival).
3.7 The manufacturer reported the results for secondary outcomes including progression-free survival and overall response rate. For the EMA subgroup the hazard ratio for progression-free survival was 0.64 (95% CI 0.51 to 0.79) corresponding to a median progression-free survival for the trastuzumab plus chemotherapy group of 7.6 months compared with 5.5 months for the chemotherapy alone group (a 2.1-month improvement in progression-free survival). Results for overall response rate were only reported for the total trial population and demonstrated a statistically significantly higher overall response rate in the trastuzumab plus chemotherapy group (47.3%) compared with the chemotherapy alone group (34.5%), odds ratio 1.70, 95% CI 1.22 to 2.38, p = 0.002.
3.8 Quality of life was assessed in the ToGA trial as a secondary objective using the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 (Global Health Status, Functioning and Symptom) and QLQ-ST022 (containing 22 items associated with dysphagia, pain, reflux, eating restrictions, anxiety, dry mouth, body image and hair loss). Both treatment groups in the trial showed improvements in quality of life over the course of treatment. A statistical analysis of differences in quality of life between the treatment groups was not presented. In addition, EQ-5D data were collected at baseline and every 3 weeks until disease progression.
3.9 Slightly more people in the trastuzumab plus chemotherapy group had adverse events than people in the chemotherapy alone group (99% and 98% respectively). In both groups, 68% of participants had grade 3 and 4 adverse events. The most frequent were disorders of the blood and lymphatic system, gastrointestinal disorders, and metabolism and nutritional disorders. More people treated with trastuzumab plus chemotherapy had asymptomatic reductions in left ventricular ejection fraction; this did not translate into a statistically significant difference in any category of symptomatic cardiac events.

Cost effectiveness

3.10 The manufacturer developed a Markov economic model to assess the cost effectiveness of trastuzumab plus chemotherapy to treat people with HER2-positive metastatic gastric cancer. The model had three distinct health states: progression-free survival, disease progression and death. The model had a cycle length of 1 month and an 8-year time horizon (considered to be a lifetime horizon). Both costs and benefits were discounted at a rate of 3.5%. One-way sensitivity analyses were undertaken on utility values, survival analysis, unit costs and various resource use assumptions. Probabilistic sensitivity analysis was also undertaken to explore parameter uncertainty in the model.
3.11 The treatment regimens included in the manufacturer's economic evaluation were:

• trastuzumab plus cisplatin and capecitabine
• trastuzumab plus cisplatin and 5-fluorouracil
• epirubicin plus cisplatin and capecitabine
• epirubicin plus cisplatin and 5-fluorouracil
• epirubicin plus oxaliplatin and capecitabine.

3.12 The clinical estimates (transition probabilities) in the model were derived from the progression-free and overall survival estimates from the trastuzumab plus chemotherapy group in the ToGA trial (EMA subgroup).
3.13 The manufacturer's literature search for comparator data did not find trials in which triple regimens including epirubicin had been directly compared with triple regimens including trastuzumab. However, four studies were identified that evaluated one of the regimens of interest:

• Tobe (1992) and Kim (2001), which compared epirubicin, cisplatin and 5-fluorouracil with cisplatin and
  5-fluorouracil;
• Yun (2010), which compared epirubicin, cisplatin and capecitabine with cisplatin and capecitabine;
• REAL-2 (2008), which compared the non-inferiority of capecitabine with 5-fluorouracil in triple chemotherapy regimens including epirubicin.

In addition, a meta-analysis (Wagner) evaluating the efficacy of a triple regimen including an anthracycline (epirubicin) compared with a regimen that did not include an anthracycline was identified. However, the results of this analysis were not used in the economic model because the largest trial assessed a comparison between epirubicin, cisplatin and 5-fluorouracil and cisplatin and 5-fluorouracil plus mitomycin (Ross), and the other trials were presented in abstract form (Kim) or only included a small population and had more severe disease (Tobe).
3.14 The manufacturer explored the possibility of conducting a network meta-analysis between the three comparator triple regimens identified as UK practice (that is, epirubicin with cisplatin and capecitabine, epirubicin with cisplatin and 5-fluorouracil and epirubicin with oxaliplatin and capecitabine) and the chemotherapy comparator group from the ToGA trial to obtain the comparator effectiveness data for the model. However, the manufacturer concluded that the results of a network meta-analysis would not produce reliable or meaningful results because the only study to evaluate epirubicin, cisplatin and capecitabine compared with cisplatin and capecitabine (Yun) did not report the primary outcome of the ToGA trial (overall survival). In addition, the studies that compared cisplatin and 5-fluorouracil with epirubicin, cisplatin and 5-fluorouracil (Tobe and Kim) did not have comparable patient populations. Therefore, the manufacturer presented a narrative summary of the results from the Yun, Tobe, Kim and REAL-2 trials.
3.15 For epirubicin, cisplatin and capecitabine, the manufacturer concluded that the estimates of overall survival and progression-free survival could be assumed equivalent to those from the chemotherapy comparator group in the ToGA trial because of no evidence of a significant difference in the Yun study (hazard ratio of progression-free survival of epirubicin, cisplatin and capecitabine compared with cisplatin and capecitabine 0.96, 95% CI 0.58 to 1.57). It was also considered that the dose of cisplatin in the ToGA trial was higher than would be the case in UK clinical practice when added to a triple regimen including epirubicin, and that the two regimens could therefore be regarded as equivalent.
3.16 The manufacturer also made an assumption of no difference in effectiveness from the addition of epirubicin to cisplatin and
5-fluorouracil based on the study by Tobe (hazard ratio of overall survival for epirubicin, cisplatin and 5-fluorouracil compared with cisplatin and 5-fluorouracil 0.57, 95% CI 0.27 to 1.2) and the study by Kim (hazard ratio of overall survival for epirubicin, cisplatin and 5-fluorouracil compared with cisplatin and 5-fluorouracil 0.83, 95% CI 0.42 to 1.61). The estimate of progression-free survival for epirubicin, cisplatin and 5-fluorouracil was assumed to be equivalent to the chemotherapy comparator group in the ToGA trial. For overall survival for epirubicin, cisplatin and 5-fluorouracil, the manufacturer used an overall survival benefit of capecitabine over 5-fluorouracil from a meta-analysis (Okines) that found a benefit of capecitabine over 5-fluorouracil to justify a hazard ratio of 1.15 for epirubicin, cisplatin and 5-fluorouracil compared with epirubicin, cisplatin and capecitabine.
3.17 For the third comparator regimen (epirubicin, oxaliplatin and capecitabine), the manufacturer assumed epirubicin, oxaliplatin and capecitabine were equivalent to epirubicin, cisplatin and capecitabine in effectiveness. This was based on the REAL-2 trial. The manufacturer stated that the results of this study indicated that oxaliplatin was as effective as cisplatin (hazard ratio of overall survival for oxaliplatin arms compared with cisplatin arms 0.92, 95% CI 0.80 to 1.10). Overall survival and progression-free survival estimates for epirubicin, oxaliplatin and capecitabine were therefore considered equivalent to those for epirubicin, cisplatin and capecitabine.
3.18 Health-related quality of life was estimated for progression-free survival and progressive disease health states. Utility values were applied to the population in each health state during each cycle to determine the overall QALY estimates for each regimen. A utility value for the progression-free survival health state was calculated using results from the EQ-5D data collected at baseline and then every 3 weeks until progression in the ToGA trial. The manufacturer estimated a baseline utility value of 0.7292, which increased daily by 0.000142 during progression-free survival. For the progressive disease health state, an estimate from the literature was used because EQ-5D was not collected after disease progression in the ToGA trial. The utility value of 0.577 for progressive disease was taken from 'Sunitinib for the treatment of gastrointestinal stromal tumours' (NICE technology appraisal guidance 179). Utility values associated with adverse events were not included in the model.
3.19 The model included costs for HER2 testing, drug acquisition, drug administration, monitoring during progression-free survival, treating adverse events, care costs in progression-free survival after chemotherapy treatment was stopped, and supportive care costs after progression of disease. The cost of HER2 testing was based on a sequential testing strategy in which only people who tested IHC2+ received a FISH test. Total drug costs included an amount for wastage based on an assumption that 80% of centres would administer trastuzumab for breast cancer and would vial share, thereby implying no wastage. Cardiac monitoring was assumed to be done using a multiple-gated acquisition (MUGA) scan or an echocardiogram and to take place once every cycle for people treated with epirubicin and once every 3 months for people treated with trastuzumab in accordance with the summaries of product characteristics. The costs of grade 3 or 4 adverse events were included if there was an incidence of at least 5% in any of the treatment groups.
3.20 The model suggested that trastuzumab with cisplatin and capecitabine compared with epirubicin with cisplatin and capecitabine and epirubicin with oxaliplatin and capecitabine produced a mean gain of 4.8 months of life. Trastuzumab with cisplatin and 5-fluorouracil compared with epirubicin with cisplatin and 5-fluorouracil produced a mean gain of 4.3 months of life. In the manufacturer's incremental cost-effectiveness analysis of all five regimens, epirubicin plus cisplatin and 5-fluorouracil and epirubicin plus oxaliplatin and capecitabine were both less effective and more expensive (that is, they were dominated) than the other regimens. In addition, although the total cost of the trastuzumab plus cisplatin and 5-fluorouracil regimen was lower than that of trastuzumab plus cisplatin and capecitabine, it was also less effective than trastuzumab, cisplatin and capecitabine and had a higher ICER than trastuzumab, cisplatin and capecitabine. Therefore this strategy was extendedly dominated. For the two remaining regimens, trastuzumab plus cisplatin and capecitabine had an additional cost of £13,064 and produced an additional 0.25 QALYs over epirubicin plus cisplatin and capecitabine. The incremental cost-effectiveness ratio (ICER) was £51,927 per QALY gained. The manufacturer examined other scenarios in a probabilistic sensitivity analysis. Distributions were applied to utilities, unit costs, monthly supportive care costs, adverse event probabilities, survival curves, parametric parameters, and progression-free survival monthly Kaplan-Maier estimates. This resulted in ICERs that ranged from £37,180 to £95,238 per QALY gained. The probability that trastuzumab with cisplatin and capecitabine was cost effective at £30,000 was 0%.
3.21 Additionally, the manufacturer presented the results of pair-wise comparisons between trastuzumab plus cisplatin and 5-fluorouracil and epirubicin plus cisplatin and 5-fluorouracil, and between trastuzumab plus cisplatin and capecitabine and epirubicin plus oxaliplatin and capecitabine. The ICERs for these comparisons were £50,838 and £40,711 per QALY gained respectively.

Evidence review group comments

3.22 The ERG stated that the manufacturer identified the only trial evaluating trastuzumab in the treatment of HER2-positive metastatic gastric cancer (the ToGA trial). This trial was a well-conducted phase III randomised controlled trial with appropriate validity assessment. The ERG considered that the ToGA trial demonstrated improved overall survival of people treated with trastuzumab when added to cisplatin plus either capecitabine or
5-fluorouracil. The economic model was considered appropriate for the decision problem and the general approach employed by the manufacturer to estimate lifetime cost-effectiveness met the requirements of the NICE reference case.
3.23 The ERG identified a number of small errors in the manufacturer's model related to inconsistent assumptions about adverse events, distributions of survival data and resource use. Correcting these errors reduced the ICER from £51,927 per QALY gained to £49,005 per QALY gained. This ICER represented an additional cost of £12,332 and an additional 0.251 QALYs from treatment with trastuzumab plus cisplatin and capecitabine over epirubicin plus cisplatin and capecitabine.
3.24 The ERG highlighted the following main areas of concern in the manufacturer's submission:

• The relevance of the trial data to a UK population.
• The comparator data considered for network meta-analysis.
• The relative effectiveness estimates of comparators in the model.
• The utility values applied during progression-free survival.
• The frequency of cardiac monitoring with trastuzumab and epirubicin.
• The uncertainty of using a sequential HER2 testing strategy.

3.25 The ERG stated that the efficacy of standard triple regimens in people with HER2-positive gastric cancer was unknown. It was assumed that the HER2-positive population is equivalent to a mixed-HER2 population containing an unknown proportion of HER2-positive people. The ERG noted that the trial population in the ToGA trial was substantially younger than the UK population of people with gastric cancer, only 17% of whom are aged under 65 at death. The population of the ToGA trial also differed substantially from the UK clinical population, which is predominantly white in that over 50% of trial participants were from Asian countries.
3.26 The ERG considered that the most relevant comparators in the context of current clinical practice were epirubicin plus cisplatin and capecitabine, epirubicin plus cisplatin and 5-fluorouracil, epirubicin plus oxaliplatin and capecitabine and epirubicin plus oxaliplatin and 5-fluorouracil. However, it stated that epirubicin plus oxaliplatin and capecitabine was likely to form a larger part of routine clinical practice in England and Wales than the 6% suggested in the manufacturer's submission. Following clarification by the manufacturer, the ERG concluded that all relevant trials had been identified for inclusion in a possible network meta-analysis to establish a link between the triple regimens with the chemotherapy comparator group of the ToGA trial. The ERG considered that the manufacturer's decision not to attempt a network meta-analysis using these trials was justified, mainly because of differences in the trial populations.
3.27 The ERG stated that the manufacturer's conclusion of no difference in effect between the chemotherapy comparator regimen in the ToGA trial and the comparator regimens in the economic evaluation largely rested on the critique of the meta-analysis by Wagner. This study found a benefit for triple regimens including an anthracycline over regimens that did not include an anthracycline. The ERG stated that the manufacturer's decision to exclude the meta-analysis on the basis that it contained a trial that had only been published in abstract form (Kim) and a trial with a small population of people with more severe disease (Tobe) was inconsistent with the decision to include these studies individually. As a result of dismissing the meta-analysis, the small phase II Kim, Tobe and Yun trials were used to infer evidence of no effect between double and triple regimens, and the ERG stated that these were underpowered to detect a statistically significant benefit of treatment. The ERG therefore considered that the manufacturer's conclusion of no difference in effectiveness between the chemotherapy comparator group in the ToGA trial and triple regimens including epirubicin was not justified. The ERG noted that the balance of evidence suggested that there may be an advantage in adding epirubicin to a double regimen.
3.28 The ERG explored the effect on the ICER using the hazard ratio from the Yun study (0.96), which indicated a small benefit in adding epirubicin to a double regimen. When applied to progression-free survival only, the ICER increased from the revised base case of £49,005 per QALY gained to £49,754 per QALY gained. When applied to progression-free survival and overall survival, the ICER increased from £49,005 per QALY gained to £52,709 per QALY gained.
3.29 The ERG also explored the effect of the manufacturer's assumption of no difference between triple regimens including oxaliplatin and triple regimens including cisplatin. From the REAL-2 trial, a hazard ratio for overall survival and progression free survival (0.87) was derived that suggested a benefit of oxaliplatin regimens over cisplatin regimens. As a result, the cisplatin regimen was no longer dominant over the oxaliplatin regimen in the incremental analysis and this had the effect of increasing the ICER for trastuzumab plus cisplatin and capecitabine. When applied to overall survival alone, the ICER increased from £49,005 per QALY gained to £50,745 per QALY gained. When applied to overall survival and progression-free survival, the ICER increased from £49,005 per QALY gained to £54,114 per QALY gained.
3.30 The ERG stated that the manufacturer's base-case approach was relatively optimistic because utility was assumed to increase by 0.000142 for each day in progression-free survival. The ERG suggested that it would be more appropriate to apply a small decrease in utility over time to reflect the change in utility over time for an equivalent group of people from UK general population norms for EQ-5D. The ERG calculated this utility decrement to be 0.003502 per year. The ERG explored the impact of applying this assumption to the corrected manufacturer's base case and reported an increase from £49,005 per QALY gained to £51,309 per QALY gained.
3.31 The ERG highlighted the manufacturer's base-case assumption that cardiac monitoring took place once every cycle with epirubicin and once every 3 months with trastuzumab. Although the summary of product characteristics for epirubicin recommends that an echocardiogram be carried out before and after each treatment cycle, the ERG's clinical advisers considered that in the UK cardiac monitoring is not carried out as often as this. The ERG carried out an exploratory analysis assuming that cardiac monitoring was carried out at the same level for epirubicin as for trastuzumab. This resulted in the ICER increasing from the corrected base-case estimate of £49,005 per QALY gained to £50,816 per QALY gained.
3.32 The ERG raised a number of issues relating to HER2 testing in the manufacturer's base case. These included the potential costs of repeat tests needed because of test failures and that the effectiveness estimates in the model were derived from the ToGA trial, which used a parallel testing strategy rather than a sequential testing strategy. The ERG also noted the assumption that 17.8% of people with metastatic gastric cancer were eligible for trastuzumab came from the full trial population; however, in the UK subgroup of people in the ToGA trial, this was 26%. To explore the impact of variations in the HER2-positive rate, the ERG undertook an exploratory analysis in which the HER2 rate was varied between 5% and 30%. The resulting ICER from this analysis ranged from £52,866 per QALY gained for the lower assumption of 5% to £48,395 per QALY gained for the higher assumption of 30%.
3.33 To consider the combined potential impact of some of the uncertainties raised, the ERG undertook two alternative exploratory analyses in which the following key assumptions were considered to be equally plausible:

• The hazard ratio of epirubicin plus oxaliplatin and capecitabine compared with epirubicin plus cisplatin and capecitabine was changed to 0.87.
• The hazard ratio of epirubicin, cisplatin and capecitabine compared with cisplatin and capecitabine was changed to 0.96 for progression-free survival and overall survival (indicating a survival benefit for epirubicin, cisplatin and capecitabine compared with cisplatin and capecitabine alone).
• Utility during progression-free survival was changed to incorporate an expected decrease in utility in line with the general population over time.
• The frequency of cardiac monitoring for epirubicin was changed to be the same as trastuzumab.

The ERG presented the results of these exploratory analyses separately for sequential and parallel HER2 testing strategies. In both analyses, epirubicin plus cisplatin and capecitabine was no longer the dominant comparator regimen and the relevant comparator for trastuzumab plus cisplatin and capecitabine was epirubicin plus oxaliplatin and capecitabine. When trastuzumab plus cisplatin and capecitabine was compared with epirubicin plus oxaliplatin and capecitabine, the QALY gain was 0.149 at an incremental cost of £9,987, giving an ICER of £66,982 per QALY gained using a sequential testing strategy. When a parallel testing strategy was assumed, the QALY gain was the same, however the incremental costs increased to £10,681, giving an ICER of £71,637 per QALY.
3.34 Finally, the ERG undertook a separate exploratory analysis in which the hazard ratio was 0.77 (indicating a survival benefit) for epirubicin plus cisplatin and capecitabine, and epirubicin plus oxaliplatin and capecitabine compared with cisplatin and capecitabine alone. This estimate of effectiveness was inferred from the Wagner meta-analysis in which a triple regimen including an anthracycline therapy had been compared with a regimen without an anthracycline. When applied to overall survival only, the QALY gain was approximately 0.13 at an incremental cost of £10,993, giving an ICER increased of £84,373 per QALY gained. When applied to overall survival and progression-free survival, the QALY gain was approximately 0.13 at an incremental cost of £11,226, giving an ICER of £99,797 per QALY gained.
3.35 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 trastuzumab when given in combination with cisplatin and either capecitabine or 5-fluorouracil, having considered evidence on the nature of metastatic gastric cancer and the value placed on the benefits of trastuzumab by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.
Clinical effectiveness
4.2 The Committee discussed current clinical practice in the UK. The Committee heard from clinical specialists that this is normally a triple regimen that includes an anthracycline, a platinum agent, and a fluoropyrimidine. It understood that epirubicin, cisplatin and capecitabine are the standard anthracycline, platinum agent and fluoropyrimidine therapies used. It also understood that oxaliplatin is sometimes used in place of cisplatin and that 5-fluorouracil is sometimes used in place of capecitabine. The Committee considered this in the context of the regimen given in the ToGA trial, which was a double regimen including a platinum agent and a fluoropyrimidine therapy, but not an anthracycline. The Committee discussed the manufacturer's data showing that double regimens were not often used in UK clinical practice. The Committee concluded that the comparator in the ToGA trial did not represent current practice in the UK.
4.3 The Committee discussed the clinical effectiveness of the trastuzumab regimens presented in the ToGA trial. It noted that, compared with cisplatin plus either capecitabine or 5-fluorouracil alone, trastuzumab plus cisplatin and either capecitabine or
5-fluorouracil reported gains in progression free survival and overall survival. The Committee considered whether the outcomes in the trial, in which most of the participants were from Asia, would apply to the population of people with HER2-positive metastatic gastric cancer in England in Wales. It noted that a subgroup analysis appeared to confirm a similar overall survival benefit for the group of European people in the trial. The Committee was persuaded that the population in the ToGA trial could be considered applicable to the UK population. However, because of the comparator in the trial the gains observed for trastuzumab could not be considered directly applicable to the UK.
4.4 The Committee discussed the likely clinical effectiveness of the current UK triple regimens, that is, when epirubicin is added to cisplatin and fluoropyrimidine. It heard from clinical specialists that adding epirubicin to cisplatin and a fluoropyrimidine provides sufficient additional benefit to be standard practice. However, clinical specialists underlined that this had not been subject to rigorous evaluation. The Committee discussed the evidence identified by the manufacturer and the ERG, recognising that none of the studies had been completed in a HER2-positive population. The Committee acknowledged the lack of ideal evidence for this comparison. However, it considered, on the basis of the evidence and clinical specialist testimony, that epirubicin provided some additional benefit when added to a cisplatin and fluoropyrimidine combination.
4.5 The Committee discussed whether the results of the ToGA trial could be applied to the comparison between a trastuzumab plus chemotherapy regimen and an epirubicin plus chemotherapy regimen. It was aware of the manufacturer's view that the ToGA trial had used a higher dose of cisplatin than would be used as part of a triple regimen in UK clinical practice. However, it heard from clinical specialists that people in the UK would receive up to eight cycles of treatment, whereas only six cycles had been provided in the ToGA trial. Therefore, the total quantity of cisplatin provided was similar in the trial and in UK practice. The Committee was not therefore persuaded that the outcomes for the chemotherapy comparator group in the ToGA trial were representative of the outcomes of triple regimens in the UK. It did accept that trastuzumab plus cisplatin and either capecitabine or 5-fluorouracil was likely to offer a survival benefit over treatment with epirubicin plus cisplatin and either capecitabine or 5-fluorouracil. However, the Committee considered that they could not know the size of this benefit because there were no trial data for the HER2-positive population comparing trastuzumab regimens with the standard triple regimens used in the UK.
4.6 The Committee discussed the quality-of-life data from the ToGA trial. It noted that there was no difference in quality-of-life scores between the two treatment groups and that there was no statistical analysis of these data. It heard from clinical specialists that treatment could bring about some improvement in quality of life, because gastric cancer had serious disease symptoms, which chemotherapy reduced. They considered that the reduced symptoms outweighed the side effects of chemotherapy. The Committee noted that the data appeared to show improving quality of life during progression-free survival beyond the trial period. It considered that continuing, progressive improvement in quality of life was not plausible and that the appearance of improving quality of life was more likely to be explained by survivor bias (that is, including only data for people who had survived and not taking into account the people who had not survived). The Committee concluded that it was not possible to assess whether the trastuzumab regimen progressively improved the quality of life for people who survived progression free.
4.7 The Committee discussed the adverse event data provided by the manufacturer. The Committee heard from clinical specialists that they considered that the adverse effects of trastuzumab are known and manageable in clinical practice because of its use in breast cancer. It further heard that epirubicin was associated with adverse effects and that there may be benefits in providing trastuzumab as an alternative to epirubicin. It understood that trastuzumab is associated with cardiotoxicity, but noted that the incidence of cardiac failure in the trial was low and was similar in both treatment groups in the ToGA trial (two in the chemotherapy alone group and one in the trastuzumab plus chemotherapy group). The Committee also noted commercial-in-confidence information relating to infusion-related reactions.
4.8 The Committee considered the proposed benefits of the technology, that is, how innovative it is in its potential to make a significant and substantial impact on health-related benefits. It noted that trastuzumab has been used for treating breast cancer since 2002. It accepted that targeting HER2 represented a change in the management of gastric cancer. However, the Committee considered that, because of the uncertainties in the evidence, together with several years of established use in a relatively large population there were no additional potential significant health-related benefits to take into consideration.
Cost effectiveness
4.9 The Committee considered the estimates of cost effectiveness in the manufacturer's model. It noted that the base-case ICER of £51,900 per QALY gained represented the manufacturer's estimated additional cost per QALY gained of trastuzumab plus cisplatin and capecitabine compared with the most cost-effective comparator regimen (that is, epirubicin plus cisplatin and capecitabine). It noted that this had subsequently been corrected by the ERG to £49,000 per QALY gained. The Committee was aware that the base-case ICER assumed the same clinical effectiveness for the triple comparator regimen as for the chemotherapy comparator group in the ToGA trial (in which people only received two therapies, a platinum agent and a fluoropyrimidine). In view of previous discussions in which the Committee agreed that the benefit of triple regimens would be greater than double regimens (see section 4.4), the Committee considered the manufacturer's base case to be favourable to trastuzumab. It further noted that probabilistic sensitivity analysis did not incorporate uncertainty in the clinical-effectiveness estimates, and that these appeared to be a key driver of cost effectiveness from the ERG's exploratory analysis. The Committee concluded that the manufacturer's base-case ICER was likely to be an underestimate.
4.10 The Committee discussed the ERG's exploratory analyses. It recognised that the impact of individual parameter changes on the ICER was small but that the effect of combining changes to the estimates of comparator effectiveness, utility during progression-free survival, and the frequency of cardiac monitoring was that the ICER increased to £67,000 per QALY gained with a sequential HER2 testing strategy and £71,600 per QALY gained with a parallel testing strategy. It understood that the parameter assumptions in the combined analysis represented those that the ERG considered to be as plausible as those in the manufacturer's base case. The Committee also noted the ERG's exploratory analysis in which a hazard ratio of 0.77 from the meta-analysis by Wagner (see section 3.34) was used to reduce the efficacy of cisplatin and capecitabine in comparison with the capecitabine triple regimens in the manufacturer's model. The Committee noted that when this hazard ratio was applied to both progression-free survival and overall survival, the ICER was £99,800 per QALY gained, and £84,400 per QALY gained when the hazard ratio was only applied to overall survival. The Committee recognised that the only change to the assumptions was to the effectiveness estimate of comparator regimens. The Committee concluded that the ICERs were sensitive to combinations of changes, and to the clinical estimates of effectiveness. However, the ICERs were not as sensitive to other individual parameter changes.
4.11 The Committee considered the following issues arising from the manufacturer's submission, the ERG report and the evidence given by the clinical specialists:

• The most plausible estimate of comparator effectiveness.
• The frequency of cardiac monitoring for epirubicin.
• The most relevant HER2 testing strategy.
• The change in utility during progression-free survival.
• The assumption that 80% of centres would share vials of trastuzumab.

4.12 The Committee discussed the most plausible estimate of comparator effectiveness. It first considered the ERG's exploratory analysis in which a hazard ratio of 0.96 had been used to estimate overall survival and progression-free survival of people treated with epirubicin plus cisplatin and capecitabine compared with cisplatin plus capecitabine. It noted that when this parameter change was applied to both overall survival and progression-free survival, the ICER increased by less than £1000. The Committee heard from the ERG that they had chosen to use this estimate in their revised base-case analysis because it was drawn from a study that compared cisplatin plus capecitabine with epirubicin plus cisplatin and capecitabine. In the absence of any evidence specifically for the HER2-positive group, this study best represented the decision problem in the appraisal. The Committee also considered the hazard ratio of 0.77 (indicating a more favourable benefit of treatment with epirubicin) from the Wagner meta-analysis. It acknowledged concerns raised by the ERG that this study was not directly applicable to the estimates of effectiveness of the regimens including capecitabine, because two of the studies used 5-fluorouracil regimens and the third study compared two triple therapies. The Committee heard from clinical specialists that they considered that the meta-analysis may have overestimated the survival benefit of adding epirubicin to cisplatin and fluoropyrimidine. The Committee noted that, although the effect of changing the hazard ratio to 0.96 had been relatively minor, the effect of changing the hazard ratio to 0.77 resulted in large changes to the ICERs. The Committee concluded that the survival benefit of a triple regimen including epirubicin compared with that of a double regimen without epirubicin was unlikely to be represented by a hazard ratio of 0.96 but that a hazard ratio of 0.77 (that is, a more favourable estimate of the clinical effectiveness of epirubicin) represented the upper end of a plausible range. The most likely estimate would lie somewhere in between the two.
4.13 The Committee understood that the ERG's estimate of the ICER in the alternative base-case scenario assumed that people would receive cardiac monitoring every 3 months whether they were treated with epirubicin or trastuzumab. However, it heard from the clinical specialists that people on epirubicin treatment were not necessarily given cardiac monitoring this often in the UK. It heard that in current practice people were tested before starting epirubicin treatment and this was only repeated when treatment levels made it necessary or if cardiac toxicity was suspected during treatment. The Committee therefore concluded that the ERG's alternative base-case scenarios may still slightly overestimate the cost of the comparator strategies. However, the Committee accepted that the ICER calculated by the ERG in their alternative base-case scenario was likely to more closely represent the true estimate of cost-effectiveness than the manufacturer's base-case estimate, which assumed that cardiac monitoring for people treated with epirubicin was once every cycle (21 days).
4.14 The Committee heard from the clinical specialists that people with gastric cancer were not routinely tested for their HER2 status. However, for people with breast cancer in the UK, testing is sequential and only people with a score of IHC2+ have a confirmatory FISH test. The clinical specialists considered that there were no reasons to assume a different testing strategy for metastatic gastric cancer. The Committee therefore considered that sequential testing would be most relevant in assessing HER2 status in people with metastatic gastric cancer. The Committee concluded that the ERG's estimate of the alternative base-case ICER for sequential HER2 testing was the most appropriate.
4.15 The Committee discussed the manufacturer's assumption of a daily rise in utility during progression-free survival. It was aware that this assumption was based on data only for people in the clinical trial surviving without progression and was not adjusted for those who had died or had otherwise left the trial during treatment. It therefore considered that assuming a rise in utility was not plausible. The Committee discussed the ERG's alternative assumption of a very slow decrease in utility calculated from those of a similar age group based on UK general population norms for EQ-5D. The Committee concluded that a rise in utility for people in progression-free survival had not been robustly demonstrated and a more likely estimate was that utility would decrease, as modelled by the ERG.
4.16 The Committee noted the manufacturer's assumption that sharing vials between patients to minimise wastage would occur in 80% of centres. It considered that this might be an overestimate and that in some centres, particularly smaller centres, sharing vials may not be possible, and therefore there was likely to be large variation in the practice of vial sharing. The Committee concluded that there was not enough evidence to estimate the proportion of centres that would vial share in clinical practice, but that 80% could be an overestimate.
4.17 The Committee considered supplementary advice from NICE that should be taken into account when appraising treatments that may extend the life of patients with a short life expectancy and that are licensed for indications that affect small numbers of people with incurable illnesses. For this advice to be applied, the following criteria must be met:

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

In addition, when taking these criteria into account the Committee must be persuaded that the estimates of the extension to life are robust and the assumptions used in the reference-case economic modelling are plausible, objective and robust.
4.18 The Committee considered the criteria that needed to be met to consider trastuzumab as a life-extending, end-of-life treatment. First, the Committee considered the life expectancy of people with HER2-positive metastatic gastric cancer. It understood that the ToGA trial reported a median 11.8 months overall survival for people receiving cisplatin plus either capecitabine or 5-fluorouracil. The study by Wagner also suggested survival below 24 months. Therefore, the Committee was persuaded that trastuzumab plus cisplatin and either capecitabine or 5-fluorouracil met the criterion of short life expectancy.
4.19 The Committee then considered the survival data provided by the manufacturer. It noted that the overall survival gain from the ToGA trial was 4.2 months for trastuzumab plus cisplatin and capecitabine or 5-fluorouracil compared with cisplatin and capecitabine or 5-fluorouracil alone. This produced a modelled median overall survival gain of 4.8 months for people treated with trastuzumab plus cisplatin and capecitabine compared with people treated with epirubicin plus cisplatin and capecitabine. The Committee considered that this was subject to uncertainty because of the absence of appropriate UK practice comparator data. However, on balance the Committee was persuaded that the addition of trastuzumab to chemotherapy would result in an extension to life of more than 3 months. The Committee therefore considered that trastuzumab plus cisplatin and capecitabine or
5-fluorouracil met this criterion, although they were concerned about the robustness of this estimate.
4.20 The Committee considered the size of the patient population. Treatment with trastuzumab would be suitable for an estimated 7144 people with one of the diseases for which trastuzumab is licensed (that is, HER2-positive metastatic gastric cancer, HER2-positive early and locally advanced breast cancer or HER2-positive metastatic breast cancer). The Committee was not satisfied that the population for whom trastuzumab is licensed met the criterion of a small patient population.
4.21 The Committee discussed the range of cost-effectiveness estimates for trastuzumab plus cisplatin and capecitabine. It agreed that the estimate was at least £67,000 per QALY gained (using the ERG's alternative base case with sequential HER2 testing) and could be more than £99,800 per QALY gained (using an estimate of the hazard ratio for overall survival of 0.77 for epirubicin plus cisplatin and capecitabine and epirubicin plus oxaliplatin and capecitabine compared with cisplatin plus capecitabine). The Committee considered that £99,800 per QALY gained could be an underestimate of the upper range because this only included changes to the effectiveness of the comparator. These estimates exceed what can be considered a reasonable use of NHS resources, with or without end-of-life considerations. Therefore the Committee concluded that trastuzumab plus cisplatin and capecitabine or 5-fluorouracil could not be recommended as an appropriate use of NHS resources.

Summary of Appraisal Committee’s key conclusions

TAXXX (MTA Part-Review)		Appraisal title: Trastuzumab for the treatment of HER2-positive metastatic gastric cancer	ACD section
Key conclusions
Trastuzumab, in combination with cisplatin and capecitabine or 5-fluorouracil, is not recommended for the treatment of people with human epidermal growth factor receptor (HER)2-positive, metastatic adenocarcinoma of the stomach or gastro-oesophageal junction who have not received prior treatment for their metastatic disease. The Committee was persuaded that the most plausible ICER would be at least £67,000 per QALY gained and could be in excess of £99,800 per QALY gained because of the uncertainty around the additional clinical effectiveness of the trastuzumab regimen compared with the comparator triple regimen in the manufacturer's model. Therefore the Committee concluded that trastuzumab plus cisplatin and capecitabine or 5-fluorouracil could not be recommended as an appropriate use of NHS resources.			1.1 4.21
Current practice
Clinical need of patients including the availability of alternative treatments	Current NHS treatment for metastatic gastric cancer is a triple regimen comprising an anthracycline, a platinum agent and a fluoropyrimidine. Chemotherapy is associated with overall survival of 11.8 months (based on the chemotherapy alone group in the ToGA trial) and reduces disease symptoms. There are side effects of treatments with anthracyclines such as epirubicin.		4.21 4.18 4.7
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 considered that, because of the uncertainties in the evidence, together with several years of established use in a relatively large population there were no additional potential significant health-related benefits to take into consideration.		4.8
What is the position of the treatment in the pathway of care for the condition?	No issues were raised by the Committee concerning the position of the treatment in the pathway of care.		N/A
Adverse effects	The Committee noted that the adverse effects of trastuzumab are known through its use in breast cancer treatment. It noted that trastuzumab is associated with cardiotoxicity and that there was a similar incidence of cardiac incidence between the trastuzumab and comparator groups and that this incidence was low.		4.7
Evidence for clinical effectiveness
Availability, nature and quality of evidence	No issues were raised about the quality of the evidence by the Committee. See Relevance to general clinical practice in the NHS.		N/A
Relevance to general clinical practice in the NHS	The Committee was persuaded that the population in the ToGA trial could be considered applicable to the UK population. However, because of the comparator in the trial the gains observed for trastuzumab could not be considered directly applicable to the UK. UK clinical practice is normally a triplet regimen that includes an anthracycline, a platinum agent and a fluoropyrimidine. The regimen given in the ToGA trial was a double regimen of a platinum agent and a fluoropyrimidine therapy. Double regimens are not often used in UK clinical practice. The Committee concluded that the comparator in the ToGA trial did not represent current practice in the UK.		4.3 4.2
Uncertainties generated by the evidence	The Committee heard from clinical specialists that adding epirubicin to cisplatin and a fluoropyrimidine provides sufficient additional benefit to be standard practice. However, this had not been subject to rigorous evaluation. The Committee was aware that only the ToGA trial had been conducted in a HER2-positive population of people with metastatic gastric cancer. The assumptions for the clinical effectiveness of comparators in the analysis were based on trials in a population of people with metastatic gastric cancer whose HER2 status was unknown.		4.4
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?	There were no subgroups to be discussed, other than the licensed subgroup.		N/A
Estimate of the size of the clinical effectiveness including strength of supporting evidence	The Committee accepted that there was evidence of an overall survival gain of trastuzumab in combination with cisplatin and capecitabine or 5-fluorouracil compared with cisplatin plus capecitabine or 5-fluorouracil alone from the ToGA trial. The Committee was less certain regarding the modelled median overall survival gain of 4.8 months from treatment with a trastuzumab regimen compared with the standard triple regimen comparator in UK clinical practice. It accepted that a trastuzumab regimen was likely to offer a survival benefit when compared with UK triple comparator regimens; however, the Committee concluded there was uncertainty regarding the size of the benefit.		4.3 4.19
Evidence for cost effectiveness
Availability and nature of evidence	The assumption of no difference in effectiveness between double and triple regimens was central to the estimates of cost effectiveness. The Committee recognised that there was a lack of evidence to estimate the benefit of comparator effectiveness estimates for people with HER2-positive metastatic gastric cancer.		4.9 4.4
Uncertainties around and plausibility of assumptions and inputs in the economic model	The Committee concluded that the survival benefit of a triple regimen including epirubicin compared with that of a double regimen without epirubicin was unlikely to be represented by a hazard ratio of 0.96 but that a hazard ratio of 0.77 (that is, a more favourable estimate of the clinical effectiveness of epirubicin) represented the upper end of a plausible range. The most likely estimate would lie somewhere in between the two. There remained some uncertainty regarding the frequency of cardiac monitoring for epirubicin. The Committee concluded that it was likely to be closer to every 3 months, as modelled by the Evidence Review Group (ERG), than every cycle (21 days), as modelled in the manufacturer's base case. However, the Committee heard from clinical specialists that every 3 months may also be more frequent than in reality. The Committee concluded that there was not enough evidence to estimate the proportion of centres that would vial share in clinical practice.		4.12 4.13 4.16
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 manufacturer assumed an increase in utility over time for people in progression-free survival. The Committee concluded that a rise in utility for people in progression-free survival had not been robustly demonstrated and that the more conservative assumption of a decrease in utility as modelled by the ERG was more likely.		4.15
Are there specific groups of people for whom the technology is particularly cost effective?	No subgroups were considered.		N/A
What are the key drivers of cost effectiveness?	The Committee considered that the assumptions regarding the clinical effectiveness of triple regimens in the model compared with the double comparator regimen in the ToGA trial were key drivers of cost effectiveness, based on the ERG's exploratory analyses.		4.9
Most likely cost-effectiveness estimate (given as an ICER)	The Committee agreed that the range was between £67,000 per QALY gained (using the ERG's alternative base case with sequential HER2 testing) and more than £99,800 per QALY gained (using an estimate of the hazard ratio for overall survival of 0.77 for epirubicin plus cisplatin and capecitabine and epirubicin plus oxaliplatin and capecitabine compared with cisplatin plus capecitabine). The Committee considered that £99,800 per QALY gained could be an underestimate of the upper range because this only included changes to the effectiveness of the comparator.		4.21
Additional factors taken into account
Patient Access Schemes (PPRS)	The manufacturer did not submit a Patient Access Scheme.		N/A
End-of-life considerations	The Committee was persuaded that the criterion of short life expectancy was met. On balance the Committee was persuaded that the addition of trastuzumab would provide an extension to life of more than 3 months. It is estimated that approximately 7140 patients with one of the diseases for which trastuzumab is licensed (that is, HER2-positive metastatic gastric cancer, HER2-positive early and locally advanced breast cancer and HER2-positive metastatic breast cancer) may be offered treatment with trastuzumab. Therefore the Committee was not satisfied that the population for whom trastuzumab is licensed met the criterion of small patient population.		4.18 4.19 4.20
Equalities considerations, social value judgements	No equalities and diversities issues affecting access to treatments were raised in the submissions for this appraisal.		N/A

5 Implementation

5.1 The Secretary of State and the Welsh Assembly Minister for Health and Social Services have issued directions to the NHS on implementing NICE technology appraisal guidance. When a NICE technology appraisal recommends use of a drug or treatment, or other technology, the NHS must provide funding and resources for it within 3 months of the guidance being published. If the Department of Health issues a variation to the 3-month funding direction, details will be available on the NICE website. The NHS is not required to fund treatments that are not recommended by NICE.
5.2 NICE has developed tools to help organisations put this guidance into practice (listed below). These are available on our website (www.nice.org.uk/guidance/TAXXX). [NICE to amend list as needed at time of publication]

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

6 Related NICE guidance

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

• Capecitabine for the treatment of advanced gastric cancer. NICE technology appraisal guidance (publication expected July 2010).

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 June 2013. NICE welcomes comment on this proposed date. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.
Andrew Stevens
Chair, Appraisal Committee
June 2010

Appendix A: Appraisal Committee members and NICE project team

A Appraisal Committee members

The Appraisal Committees are standing advisory committees of NICE. Members are appointed for a 3-year term. A list of the Committee members who took part in the discussions for this appraisal appears below. There are four Appraisal Committees, each with a chair and vice chair. Each Appraisal Committee meets once a month, except in December when there are no meetings. Each Committee considers its own list of technologies, and ongoing topics are not moved between Committees.
Committee members are asked to declare any interests in the technology to be appraised. If it is considered there is a conflict of interest, the member is excluded from participating further in that appraisal.
The minutes of each Appraisal Committee meeting, which include the names of the members who attended and their declarations of interests, are posted on the NICE website.
Dr Kathryn Abel
Reader and Consultant Psychiatrist/Director of Centre for Women's Mental Health, University of Manchester
Professor Mike Campbell
Statistician, Institute of Primary Care and General Practice, University of Sheffield
David Chandler
Lay member
Dr Mary Cooke
Lecturer School of Nursing, Midwifery & Social Work, University of Manchester
Dr Chris Cooper
General Practitioner, St John's Way Medical Centre, London
Professor Peter Crome
Consultant Physician, Bucknall Hospital
Dr Christine Davey
Senior Researcher, North Yorkshire Alliance R & D Unit
Richard Devereaux-Phillips
Public Affairs and Reimbursement Manager UK & Ireland, Medtronic
Dr Rachel A Elliott
Lord Trent Professor of Medicines and Health, University of Nottingham
Dr Wasim Hanif MD FRCP
Consultant Physician & Honorary Senior Lecturer University Hospital Birmingham
Dr Alan Haycox
Reader in Health Economics, University of Liverpool Management School
Professor Catherine Jackson
Professor of Primary Care Medicine, University of St Andrews
Dr Peter Jackson
Clinical Pharmacologist, University of Sheffield
Henry Marsh
Consultant Neurosurgeon, St George's Hospital
Dr Eugene Milne
Deputy Medical Director, North East Strategic Health Authority
Dr Neil Myers
General Practitioner
Dr Richard Nakielny
Consultant Radiologist, Sheffield Teaching Hospitals Foundation Trust
Dr Martin J Price
Head of Outcomes Research, Janssen-Cilag
Dr Peter Selby
Consultant Physician, Central Manchester University Hospitals NHS Foundation Trust
Professor Andrew Stevens
Chair of Appraisal Committee C, Professor of Public Health, University of Birmingham
John Stevens
Director, Centre for Bayesian Statistics in Health Economics University of Sheffield
Dr Matt Stevenson
Technical Director, School of Health and Related Research, University of Sheffield
Professor Paul Trueman
Health Economics Research Group, Brunel University
Dr Judith Wardle
Lay member

C NICE project team

Each technology appraisal is assigned to a team consisting of one or more health technology analysts (who act as technical leads for the appraisal), a technical adviser and a project manager.
Joanne Holden
Technical Lead
Zoe Garrett
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 Centre for Reviews and Dissemination, University of York:

• CRD and CHE Technology Assessment Group. Trastuzumab for the treatment of HER2 positive metastatic adenocarcinoma of the stomach or gastro-oesophageal junction, May 2010

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

• Roche Products (trastuzumab)

II Professional/specialist and patient/carer groups:

• Cancer Research UK
• Royal College of Nursing
• Royal College of Pathologists
• Royal College of Physicians
• United Kingdom Oncology Nursing Society

III Other consultees:

• Department of Health
• Welsh Assembly 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
  
• NHS Quality Improvement Scotland
  
• National Institute for Health Research Health Technology Assessment Programme
• NHS Centre for Reviews & Dissemination and Centre for Health Economics - York

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

• Dr David Watkins, Clinical Research Fellow, nominated by NCRI/RCP/RCR/ACP/JCCO - clinical specialist
• Professor Marco Novelli, Consultant Pathologist, nominated by Royal College of Pathologists - clinical specialist

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