1 Appraisal Committee's preliminary recommendations

1.1 Erlotinib monotherapy is not recommended for maintenance treatment in people with locally advanced or metastatic non-small-cell lung cancer with stable disease after platinum-based first-line chemotherapy.

2 The technology

2.1 Erlotinib (Tarceva, Roche Products) is an orally active inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase. It has a UK marketing authorisation ‘as monotherapy for maintenance treatment in patients with locally advanced or metastatic non-small cell lung cancer with stable disease after four cycles of standard platinum-based first-line chemotherapy’. For further information see the summary of product characteristics.

2.2 Undesirable effects of erlotinib treatment include diarrhoea, rash, anorexia, gastrointestinal bleeding, liver function test abnormalities and keratitis. For full details of side effects and contraindications, see the summary of product characteristics.

2.3 Erlotinib is given orally at a recommended dose of 150 mg/day. The normal acquisition cost of a pack of 30 tablets (150 mg) is £1631.53 (excluding VAT; ‘British national formulary’ [BNF] 59th edition). The manufacturer of erlotinib agreed a patient access scheme with the Department of Health in which the acquisition cost of erlotinib is reduced by 14.5% (that is, £1394.96 for a pack of 30 tablets [150 mg]). The Department of Health is content for NICE to consider the agreed PAS. 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 erlotinib and a review of this submission by the Evidence Review Group (ERG; appendix B).

3.1 The manufacturer approached the decision problem by providing clinical and cost effectiveness evidence for erlotinib maintenance monotherapy compared with best supportive care in people with stage IIIB or IV squamous or non squamous non-small-cell lung cancer who had stable disease after treatment with standard platinum-based first-line chemotherapy.  Best supportive care included palliative radiotherapy care, corticosteroids (without maintenance therapy) and watchful waiting alone.  In the economic evaluation the manufacturer provided separate analyses for people with squamous and non-squamous disease.  The group with non-squamous disease was further divided into those who were not eligible for pemetrexed maintenance therapy (in whom best supportive care was the comparator) and those who were eligible for pemetrexed maintenance therapy (in whom pemetrexed was the comparator). The manufacturer noted a lack of head to head clinical evidence comparing erlotinib with pemetrexed.   

3.2 At the time the manufacturer's original evidence submission for this appraisal was provided the marketing authorisation for erlotinib had not been granted and the exact population covered by the marketing authorisation was not known. Subsequently, erlotinib received a marketing authorisation for the maintenance treatment of a subgroup of patients with locally advanced or metastatic non-small-cell lung cancer, that is, patients with stable disease after standard platinum-based first-line chemotherapy. In light of this, some of the evidence included in the manufacturer’s original submission was not relevant and further evidence specific to the licensed population became relevant. In response to consultation on the first appraisal consultation document, the manufacturer provided additional clinical and cost-effectiveness evidence relevant to patients with stable disease after first-line chemotherapy, the population covered by the marketing authorisation.

3.3 The key evidence submitted by the manufacturer for the clinical effectiveness of erlotinib came from a randomised double-blind controlled trial comparing erlotinib with placebo in patients with advanced or metastatic non-small-cell lung cancer whose disease had not progressed following platinum-based chemotherapy (SATURN). This population included patients whose disease had responded to first-line chemotherapy and patients whose disease was stable after first-line chemotherapy. Stable disease was defined using the Response Evaluation Criteria in Solid Tumours (RECIST). According to these criteria, stable disease is when tumour shrinkage is not sufficient to be defined as partial response and tumour increase is not sufficient to be defined as progressive disease. The following section describes the clinical-effectiveness evidence for erlotinib in patients with stable disease only. This evidence comes from post hoc subgroup analyses.  

3.4 Patients were included in the SATURN trial if their disease had not progressed after four cycles of a standard, platinum-based chemotherapy doublet (two chemotherapy drugs, one of which is platinum based), if they had an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1 and their life expectancy was at least 12 weeks. The primary outcome of the trial was progression-free survival, defined as the time between randomisation and the date of the first documented disease progression, or death from any cause. Secondary outcomes included overall survival (defined as the time between randomisation and death), time to disease progression, response rates (assessed by the RECIST criteria) and quality of life (assessed by the Functional Assessment of Cancer Therapy – Lung [FACT-L] questionnaire). RECIST criteria were assessed at 6-weekly intervals.

3.5 The SATURN trial included a total of 889 patients of whom 487 (55%) had stable disease after first-line chemotherapy. Of the patients with stable disease, 70%  had an ECOG performance status of 1 at study entry, 20% had never smoked, 71% had tumours with a positive EGFR immunohistochemistry (IHC) status, and 61% had non-squamous disease. The most common first-line treatments for patients in the whole trial population were gemcitabine plus carboplatin (28%), gemcitabine plus cisplatin (26%), and paclitaxel plus carboplatin (19%). No patients with non-squamous disease received combination chemotherapy with cisplatin and pemetrexed. The majority of patients (48%) were from Eastern Europe, 21% were from Southeast Asia and seven patients (1%) were recruited from the UK. The mean age of patients was 60 years. The proportion of patients who had at least one post-study treatment in the placebo and erlotinib groups was 64% and 55% respectively, with 16% of patients in the placebo arm receiving subsequent treatment with erlotinib or gefitinib.

3.6 For patients with stable disease after first-line chemotherapy, median progression-free survival was 12.1 weeks in the erlotinib group compared with 11.3 weeks in the placebo group (hazard ratio [HR] 0.68; 95% confidence interval [CI] 0.56 to 0.83, p < 0.0001). Overall survival was 11.9 months in the erlotinib group compared with 9.6 months in the placebo group (HR 0.72; 95% CI 0.59 to 0.89, p = 0.0019). The increase in progression-free survival associated with erlotinib was similar in patients with squamous and non-squamous disease (HR 0.69; 95% CI 0.51 to 0.93, n = 190 and HR 0.69; 95% CI 0.54 to 0.87, n = 297 in each group respectively). The increase in overall survival associated with erlotinib was higher for patients with squamous disease than for those with non-squamous disease (HR 0.67; 95% CI 0.48 to 0.92 and HR 0.76; 95% CI 0.59 to 1.00 in each group respectively). There were no statistically significant differences between the erlotinib and placebo groups in quality of life measures, including time to symptom progression, time to deterioration in trial outcome index, and time to deterioration in quality of life.

3.7 Additional subgroup analyses were conducted for the following factors in patients with stable disease after first-line chemotherapy: EGFR status, stage of disease, first-line chemotherapy, ECOG performance status, smoking status, geographical region, age, race and gender. Erlotinib was associated with a greater overall survival benefit for patients with EGFR IHC positive tumours (HR 0.65; 95% CI 0.51 to 0.88, p-value not reported), patients who had never smoked (HR 0.56; 95% CI 0.32 to 0.97, p-value not reported), and women (HR 0.55; 95% CI 0.35 to 0.87, p-value not reported) compared with the overall stable disease population.

3.8 The most common adverse events associated with erlotinib for the whole SATURN population were rash (49% in the erlotinib group and 6% in the placebo group) and diarrhoea (20% in the erlotinib group and 5% in the placebo group). In the stable disease subgroup, more patients in the erlotinib group had an adverse event of any kind than in the placebo group (78% compared with 58%). There were 23 deaths in the erlotinib group and 22 in the placebo group during the active treatment phase.

3.9 In the original submission, the manufacturer conducted an indirect analysis of erlotinib and pemetrexed in patients with non-squamous disease using data from a randomised controlled trial of pemetrexed maintenance treatment versus placebo in patients with locally advanced or metastatic non-small-cell lung cancer (JMEN). This analysis included patients with stable disease but also included patients who had responded to first-line treatment. The latter group are not covered by the marketing authorisation for erlotinib. In the additional evidence submission, the manufacturer stated that an indirect comparison of the SATURN and JMEN trials was not possible because there were no data from the JMEN trial in the public domain on the efficacy of pemetrexed in patients with stable, non-squamous disease. The manufacturer also stated that an indirect analysis was not appropriate because of differences in the patient populations in the two trials.  

3.10 In the original submission, the manufacturer submitted economic analyses for three different patient populations, two of which included patients who were not covered by the marketing authorisation, that is, patients whose disease had responded to treatment. The only economic analysis within the marketing authorisation was the comparison of erlotinib with best supportive care in patients with stable disease. In response to consultation, the manufacturer submitted four new economic analyses within the population covered by the marketing authorisation:

• erlotinib compared with best supportive care in all patients with stable disease
• erlotinib compared with best supportive care in patients with stable disease of squamous histology
• erlotinib compared with best supportive care in patients with stable disease of non-squamous histology who are not eligible for pemetrexed maintenance treatment
• erlotinib compared with pemetrexed in patients with stable disease of non-squamous histology who are eligible for pemetrexed maintenance treatment.

3.11 The manufacturer's new models were based on an area under the curve approach with a cycle length of 1 month and a 15-year time horizon. The models included three health states: progression-free survival, progressed (defined as the time from first treatment relapse until death), and death. All patients were assumed to start in the progression-free survival health state (after first-line chemotherapy). At the end of each cycle they could remain in this state, move to the progressed health state or die.

3.12 For the comparisons of erlotinib with best supportive care, the risks of disease progression were taken from the SATURN trial. For the comparison of erlotinib with pemetrexed, the base case assumed equal efficacy of pemetrexed and erlotinib. Additional relative efficacy scenarios were modelled, ranging from assuming greater efficacy of pemetrexed (in progression-free survival and overall survival) to assuming greater efficacy of erlotinib.

3.13 In the new models, the manufacturer used the same utility values as those used in 'Pemetrexed for the maintenance treatment of non-small-cell lung cancer' (NICE technology appraisal guidance 190 [TA190]). The utility values for the progression-free survival health state were 0.6732 for the erlotinib arm and 0.6628 for the placebo arm. The utility value for the progressed health state was 0.53.

3.14 The new models included costs for treatment (erlotinib and pemetrexed), best supportive care, adverse events, and post-progression treatment. Costs for erlotinib were based on a patient access scheme that consisted of a 14.5% discount of the list price (BNF 58) to be deducted at the time of supply to the NHS. The patient access scheme was based on a discount arrangement already in place after 'Erlotinib for the treatment of non-small-cell lung cancer' (NICE technology appraisal guidance 162 [TA162]) was published. Erlotinib doses were based on those given in the SATURN trial. Drug wastage was estimated based on when treatment stopped in the SATURN trial. The average per-patient drug costs for erlotinib were £7148 for the overall stable disease population, £6644 for patients with stable, squamous disease, and £7976 for patients with stable, non-squamous disease. Pemetrexed costs were based on the list price to the NHS (BNF 58) and doses were based on the distribution of body surface area of patients with stable, non-squamous disease in the SATURN trial. The average per-patient drug cost for pemetrexed was £13,062. Costs for best supportive care were based on the average cost of specialist palliative care per cancer death per year reported in a publication by NICE and the University of Sheffield (2004). This is the same methodology used in other NICE technology appraisals of treatments for non-small-cell lung cancer (‘Pemetrexed for the first-line treatment of non-small-cell lung cancer’ [NICE technology appraisal guidance 181; TA181] and in TA190]). The best supportive care costs also included costs of regular monitoring (three-monthly hospital visits consisting of a consultant appointment and an outpatient CT scan). The monthly cost of best supportive care included in the model was £181.46 for the progression-free survival health state and £160.06 for the progressed health state.

3.15 The costs of adverse events associated with erlotinib were based on those used in TA162 (plus inflation). The costs of adverse events associated with pemetrexed were the same as those used in TA181. Post-progression treatment costs were based on various sources including the BNF 58 and other NICE technology appraisal guidance (TA181 and TA190). Data on the number and type of post-progression treatments were collected in the SATURN trial. Because there was a lack of data on post-progression treatment from the JMEN study, the manufacturer assumed that the costs associated with pemetrexed would be the same as those for the placebo group of the SATURN study.

3.16 In the manufacturer's original submission, the incremental cost-effectiveness ratio (ICER) for the comparison of erlotinib with best supportive care in patients with stable disease was £47,743 per quality-adjusted life year (QALY) gained (incremental cost £7747 and incremental benefit 0.162 QALYs; patient access scheme included). In the manufacturer’s new economic analyses, the ICER for this population was £39,936 per QALY gained (incremental cost £7813, incremental benefit 0.196; patient access scheme included). The main reason for the difference in these ICERs was the revised costing of post-progression best supportive care. The ICER for the comparison of erlotinib with best supportive care in patients with stable, squamous disease was £35,491 per QALY gained (incremental cost £7339, incremental benefit 0.207 QALYs) and in patients with stable, non-squamous disease it was £40,020 per QALY gained (incremental cost £8696, incremental benefit 0.218 QALYs; patient access scheme included in all analyses). For the comparison of erlotinib with pemetrexed in patients with stable, non-squamous disease, the cost of erlotinib was £7531 less than pemetrexed (patient access scheme included). Therefore in scenarios where erlotinib was assumed to have equal or better efficacy than pemetrexed, erlotinib dominated pemetrexed (that is, it had lower costs and better efficacy). In the manufacturer’s various relative efficacy scenarios, the ICER for erlotinib compared with pemetrexed ranged from £77,598 (when erlotinib was assumed to have 10% better progression-free survival and 10% worse overall survival) to £511,351 per QALY gained (when erlotinib was assumed to have 10% worse progression-free survival and the same overall survival as pemetrexed; patient access scheme included). In probabilistic sensitivity analyses, the probability that the ICER for erlotinib compared with best supportive care would be less than £50,000 per QALY gained was 97% or higher.  

3.17 The manufacturer conducted a number of deterministic sensitivity analyses. For the overall population of patients with stable disease, in whom pemetrexed is unsuitable, the factors that had the greatest impact on the base-case ICER for erlotinib versus best supportive care were costing erlotinib without the patient access scheme (£46,132 per QALY gained), assuming that a patient spent all their time in the progression-free health state on treatment (£44,942 per QALY gained)  and using the best supportive care costs from TA162, rather than using costs from TA181 and TA190 (£44,745 per QALY gained). The ICERs for the population of patients with stable, squamous disease and for the population with stable, non-squamous disease were sensitive to the same factors, with maximum ICERs of £40,599 per QALY gained (compared with £35,491 in the base case) and £44,589 per QALY gained (compared with £40,020 in the base case) respectively.

3.18 The ERG reviewed the clinical evidence originally submitted by the manufacturer and the additional evidence provided at consultation. It noted that the extent to which patients and investigators were truly blind to treatment allocation throughout the SATURN trial was uncertain because patients in the erlotinib group were significantly more likely to develop a rash and suffer from diarrhoea than patients in the placebo group. The ERG queried whether the results of the SATURN study could be generalised to the UK because the trial included very few UK patients and the population was slightly younger and fitter than would be seen in UK clinical practice. It also commented that a greater proportion of patients had first-line treatment with paclitaxel in the trial than would occur in UK clinical practice and no patients had first-line treatment with pemetrexed, which is becoming a more common first-line treatment for patients with non-squamous disease. The ERG noted there were inconsistencies in the reporting of post-study treatments between the manufacturer’s submission and the SATURN clinical study report. It commented that the patients in the SATURN trial received a variety of post-progression treatments, many of which do not have marketing authorisations in the UK or are not approved by NICE (including pemetrexed, vinorelbine, gemcitabine and paclitaxel). Only docetaxel and erlotinib are recommended by NICE for second-line treatment of non-small-cell lung cancer. The ERG noted that this would affect overall survival results. It commented that the clinical evidence for erlotinib in patients with stable disease was based on a post hoc unstratified subgroup analysis and that the evidence for patients with squamous and non-squamous disease came from further division of this subgroup, again according to an unstratified variable. The ERG considered that the SATURN trial was not designed to perform these types of analyses and therefore the results should be interpreted with caution.

3.19 The ERG identified data on patients with stable, non-squamous disease from the JMEN study. It was therefore able to conduct an indirect comparison of pemetrexed and erlotinib (using data from the SATURN trial) in this patient group. The results indicated a statistically significant progression-free survival benefit for pemetrexed (HR 0.64; 95% CI 0.47 to 0.89) but the difference was not statistically significant for overall survival (HR 0.93; 95% CI 0.66 to 1.3). However, the ERG considered that the results of this analysis should be interpreted with caution because of differences in the patient populations in the JMEN and SATURN studies, the use of post hoc subgroup analyses, and uncertainty about the generalisability of both studies to patients in the UK.

3.20 The ERG reviewed the economic analyses originally submitted by the manufacturer and the additional analyses provided in response to consultation. It considered that the comparison of erlotinib with best supportive care in the total population of patients with stable disease (squamous and non-squamous) could be misleading because it could mask differences in clinical and cost effectiveness between the squamous and non-squamous groups. Therefore, the ERG disregarded this analysis. 

3.21 The ERG's main criticism of the models of erlotinib compared with best supportive care in the subgroups of patients with squamous and non-squamous disease was the method used to extrapolate survival beyond the trial period. It noted that the manufacturer had not modelled post-progression survival directly, and had instead calculated it as the difference between overall survival and progression-free survival. The ERG commented that because all patients in the stable disease population of the SATURN trial had progressed, there is no need to model progression-free survival, it can be based directly on Kaplan-Meier estimates from the trial. With the new data provided by the manufacturer during consultation, the ERG used an alternative approach in which the mean overall survival is estimated by adding progression-free survival to post-progression survival and adjusting the estimate to exclude patients dying at or before disease progression. For post-progression survival in the subgroup of patients with squamous disease, the ERG used Kaplan-Meier estimates up to a 20% survival figure and then modelled the remaining survival. For the subgroup of patients with non-squamous disease, the curves for post-progression survival were identical for the cumulated hazard trends up to 600 days but required modelling after this point for the remaining 7% of patients; a common exponential model was employed for both the intervention and the comparator. The ERG’s preferred approach to modelling survival resulted in mean overall survival gains of 3.3 months (95% CI 1.4 to 5.3 months) in the population of patients with stable, squamous disease and 2.3 months (95% CI 0.9 to 3.5 months) in the population with stable, non-squamous disease (corresponding to a 28% and 75% decrease in QALY gains compared with those in the manufacturer’s base case respectively). Using this modelling approach, the ICER for erlotinib compared with best supportive care in the population of patients with stable, squamous disease increased from £35,491 in the manufacturer’s base case to £44,812 per QALY gained (incremental cost £7129, incremental benefit 0.1591 QALYs; patient access scheme included). For the population of patients with stable, non-squamous disease the manufacturer’s base-case ICER for erlotinib compared with best supportive care increased from £40,020 to £68,120 per QALY gained (incremental cost £8340, incremental benefit 0.1224 QALYs; patient access scheme included).

3.22 The ERG commented on the manufacturer’s economic analysis of erlotinib compared with pemetrexed in the population of patients with stable, non-squamous disease. It noted that the manufacturer’s estimate of pemetrexed costs did not account for gender differences in body surface area distribution. It also noted that a modifying factor that reduced pemetrexed costs by 5% had been used and that no evidence had been provided to support this method. The ERG revised the manufacturer’s model using their own estimation of pemetrexed costs, and used the hazard ratios from its indirect analysis (noting the previously mentioned caution about this analysis). The resulting ICER of £84,029 per QALY gained was based on the lower costs (–£8460) and lower efficacy (‑0.1007 QALYs) of erlotinib compared with pemetrexed.

3.23 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 maintenance treatment with erlotinib, having considered evidence on the nature of non-small-cell lung cancer and the value placed on the benefits of erlotinib by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources and comments received during consultation on the first appraisal consultation document.

4.2 The Committee considered current UK practice for the treatment of patients with locally advanced or metastatic non-small-cell lung cancer. It heard from clinical specialists that first-line treatment in the UK is usually with a platinum doublet of carboplatin or cisplatin plus gemcitabine or vinorelbine, or cisplatin plus pemetrexed for patients with non-squamous disease. If disease progresses, patients have the option of receiving second-line systemic treatment if they have a good performance status. In the UK, second-line treatment is normally docetaxel or erlotinib. The Committee was aware that maintenance treatment after first-line treatment is still a relatively new concept in lung cancer and that its aim is to prolong the benefits of treatment and to maximise quality of life for as long as possible. It noted that pemetrexed is recommended in TA190 as an option for the maintenance treatment of people with locally advanced or metastatic non-small-cell lung cancer other than predominantly squamous cell histology if disease has not progressed immediately following platinum-based chemotherapy in combination with gemcitabine, paclitaxel or docetaxel. The Committee noted that patients are only eligible for maintenance treatment with pemetrexed if they have not received it as part of first-line treatment in combination with cisplatin. It heard from clinical specialists that the number of patients who would be eligible for maintenance treatment with pemetrexed is already small and would progressively decrease as more patients receive first-line treatment with pemetrexed.

4.3 The Committee noted that the decision problem is different for patients with squamous and non-squamous disease because pemetrexed is an option for some patients with non-squamous disease but best supportive care is currently the only option for patients with squamous disease. It considered that the additional evidence provided by the manufacturer during consultation was in accordance with this decision problem.

4.4 The Committee noted views from clinical specialists that erlotinib is an oral drug with adverse effects that are well known and relatively well tolerated. The clinical specialists stated that a potential benefit of maintenance treatment is that it may increase the proportion of patients who receive subsequent treatment after first-line treatment. This is because some patients treated with first-line therapy are too unwell at relapse to receive subsequent treatment. The clinical specialists also commented that erlotinib may provide a maintenance treatment option for patients who are not suitable for pemetrexed maintenance treatment because they have squamous disease and/or they have had pemetrexed as a first-line treatment. The Committee noted that no statements were received from patient experts.

 Clinical effectiveness

4.5 The Committee discussed the evidence on the clinical effectiveness of erlotinib for the maintenance treatment of patients with stable disease. It noted that one randomised trial, the SATURN trial, was presented, which showed that maintenance treatment with erlotinib was associated with a statistically significant improvement in progression-free survival and overall survival compared with placebo for the overall population of patients with stable disease. It noted that the improvement in progression-free survival with erlotinib was similar for patients in the squamous and non-squamous disease subgroups, but that a statistically significant improvement in overall survival was not demonstrated in the subgroup of patients with non-squamous disease. However, the Committee was aware that the results for patients with stable disease were based on a post hoc subgroup analysis of 55% of the SATURN trial population. Furthermore, the results for the subgroups of patients with squamous and non-squamous disease were also post hoc analyses based on a disaggregation of the stable disease population and there were relatively small numbers of patients in each subgroup (190 and 297 respectively). The Committee was aware that the SATURN trial had not been designed for such analyses. It therefore regarded the apparent benefits of erlotinib with caution. The Committee considered that the adverse events associated with erlotinib (most commonly, rash and diarrhoea) were well known and noted that most patients in the SATURN trial did not require their treatment to be changed or stopped because of adverse events.

4.6 The Committee discussed whether the results of the SATURN trial could be generalised to UK clinical practice, noting that there were few UK patients in the trial. It considered that in the trial there was a high proportion of patients from Southeast Asia and a high proportion of patients who had never smoked. The Committee was aware that these two patient groups are known to respond better to lung cancer treatments than patients of other races and patients who had a history of smoking. It noted that in covariate analyses of the SATURN population as a whole, Southeast Asian patients had a greater progression-free survival benefit from erlotinib than white patients (covariate effect HR 0.78; p-value 0.0214), as did patients who had never smoked compared with current smokers (covariate effect for current smokers versus people who had never smoked HR 1.46; p = 0.0003). It noted that in the SATURN trial 30% of patients with stable disease had a performance status of 0 after four cycles of chemotherapy and this was likely to reflect a fitter group of patients than the UK population who would be considered for maintenance treatment with erlotinib.

4.7 The Committee also noted that a small proportion of patients in the SATURN trial had EGFR mutations. It heard from clinical specialists that these patients have a better prognosis with treatment than other patients with non-small-cell lung cancer. It was aware that 49 patients (10%) in the SATURN trial who were tested had an EGFR mutation and that despite the limitations of small numbers, this subgroup gained substantially more benefit from erlotinib than the trial population as whole (HR for progression-free survival 0.23; 95% CI 0.12 to 0.45). Furthermore, in the SATURN population as a whole (n = 887), the hazard ratio for progression-free survival increased from 0.71 to 0.76 when the small proportion of patients with EGFR mutations were excluded from the analysis. The Committee was also aware that EGFR mutation status was not recorded in half of the SATURN patients. It considered that patients with EGFR mutations would not receive maintenance treatment with erlotinib in UK clinical practice because NICE recommends gefitinib as a first-line treatment in this group rather than chemotherapy. The Committee was concerned that some of the survival benefit of maintenance treatment with erlotinib demonstrated in the SATURN trial would not be observed in clinical practice because patients with EGFR mutations would be excluded from treatment with chemotherapy and therefore from maintenance treatment with erlotinib.

4.8 The Committee discussed the RECIST criteria for determining disease response in the SATURN trial, taking into account the marketing authorisation for erlotinib, which includes patients with stable disease only. It heard from clinical specialists that some centres, particularly those involved in clinical trials, use the RECIST criteria routinely but that centres less involved in research may not use RECIST criteria on a day-to-day basis. The Committee noted that the RECIST criteria in the SATURN trial were based on 6-weekly scans and considered that such frequent scans were not likely in the routine care of lung cancer patients in the UK.

4.9 The Committee discussed the first-line treatments received by patients in the SATURN trial. It considered that about 64% of patients received first-line chemotherapy regimens that are commonly used in the UK. The Committee noted that no one in the SATURN trial had received first-line treatment with pemetrexed and cisplatin, a regimen that is now commonly used as combination chemotherapy for patients with non-squamous disease because of its superiority to the regimens used in the SATURN trial. It therefore concluded that there was uncertainty about the clinical benefit of erlotinib in patients who had previously received pemetrexed and cisplatin. The Committee also noted that a high proportion of patients (60%) in the SATURN trial received a range of post-progression treatments, some of which would not be routinely used in the UK. It also observed that only a small proportion of patients in the placebo group had received erlotinib after progression. It considered that the post-progression treatments and the small proportion of patients in the placebo group who had received erlotinib after progression would affect the estimates of overall survival in the erlotinib and placebo groups. The Committee was aware that it is unclear whether patients would benefit more from receiving erlotinib as maintenance treatment or for treatment of relapsed disease. It was also aware that the small number of patients in the placebo group receiving erlotinib after progression could favour the erlotinib maintenance arm. The Committee noted that patients in the SATURN trial were younger, had a better performance status and a longer duration of overall survival than would be seen in routine clinical practice in the UK. The Committee concluded that the relative effectiveness of erlotinib for maintenance treatment reported in the SATURN trial may be seen in clinical practice in the UK, but there was considerable uncertainty that the absolute gains of treatment seen in the trial would be translated into routine practice.

Cost effectiveness

4.10 The Committee was aware that a patient access scheme had been agreed by the manufacturer. It noted that this is a simple scheme in which erlotinib is supplied to the NHS at a discount of 14.5% of the list price. The Committee concluded that it was appropriate to appraise the cost effectiveness of erlotinib maintenance treatment on the basis of ICERs that include this discount.

4.11 The Committee discussed the evidence for the cost effectiveness of erlotinib compared with best supportive care and noted that this was based on the manufacturer’s new economic evaluation. In the new evaluation the ICERs for erlotinib compared with best supportive care were £39,900 per QALY gained for all patients with stable disease, £35,500 per QALY gained for patients with stable, squamous disease and £40,000 per QALY gained for patients with stable, non-squamous disease (patient access scheme included). The Committee was aware that the main reason for the new ICER for the overall stable disease population being lower than that in the original submission (£47,700 per QALY gained) was the manufacturer’s revised costing of post-progression best supportive care. The Committee noted that the new costs were based on those used in previous NICE appraisals of treatments for non-small-cell lung cancer and considered them to be appropriate. The Committee noted that the factors that had the greatest effect on the new ICERs were assumptions about how much time a patient spent on treatment in the progression-free health state, and the costs attributed to best supportive care.

4.12 The Committee considered the ERG's critique of the new economic analysis. It noted the ERG’s comment that it was more appropriate to consider the cost effectiveness of erlotinib in the subgroups of patients with squamous disease and non-squamous disease separately, rather than in the stable disease population as a whole, because of heterogeneity between the subgroups. Nevertheless, the Committee was concerned about the subgroup analyses because two major variables were used for which the trial had not been stratified. Therefore the trial had not been designed to examine the effect of erlotinib maintenance treatment in these groups. The Committee also noted the ERG’s criticism of the manufacturer’s calculation of pemetrexed costs and accepted the ERG’s revised costing, which was consistent with previous NICE appraisals of treatments for non-small-cell lung cancer.

4.13 The Committee discussed the ERG’s comments on the methods used by the manufacturer to model progression-free survival and overall survival, in particular that post-progression survival had been calculated as the difference between overall survival and progression-free survival. The Committee preferred the ERG’s approach to estimating survival because it was based as much as possible on data directly from the trial and used modelling only where necessary. It noted that the ERG’s modelling approach resulted in lower estimates of overall survival benefit than the manufacturer’s method and that there were wide confidence intervals around these estimates, indicating a high degree of uncertainty. In addition, the Committee noted that there was a survival benefit in the ERG’s exploratory analysis for erlotinib in the post-progression phase for patients with squamous disease, but not non-squamous disease and found this difficult to interpret. The Committee considered that the overall survival benefit of erlotinib in clinical practice was likely to be even lower than that estimated by the ERG because of the nature of the SATURN trial population, in particular the high proportion of Southeast Asian patients and patients who had never smoked, as well as the inclusion of patients with EGFR mutations and patients with stable disease and a relatively good performance status despite having had four cycles of platinum-based chemotherapy.

4.14 The Committee noted that the ERG’s revisions to the manufacturer’s model (including correcting the pemetrexed costs and using an alternative survival modelling method) increased the ICERs for erlotinib compared with best supportive care to £44,800 per QALY gained for patients with stable, squamous disease and £68,100 per QALY gained for patients with stable, non-squamous disease (patient access scheme included). However, the Committee considered that the most plausible ICERs would be higher than those estimated by the ERG, and were all likely to be above £50,000 per QALY gained, because of uncertainties about the overall survival benefit associated with erlotinib. The Committee noted that the ERG had not provided a revised ICER for the whole stable disease population. However, in light of the differences between the ERG’s ICERs for the subgroups of patients with squamous and non-squamous disease and those of the manufacturer, the greater proportion of patients with non-squamous disease than with squamous disease in the stable disease population, and uncertainties about the overall survival benefit of erlotinib, the Committee considered that the ICER for the whole stable disease population would be above £50,000 per QALY gained.

4.15 The Committee discussed the evidence for the cost effectiveness of erlotinib compared with pemetrexed. It noted that this was based on the manufacturer’s new economic evaluation in which various relative efficacy scenarios were modelled because of the lack of comparative data for erlotinib and pemetrexed. The Committee was aware that erlotinib was less costly than pemetrexed. It noted the ERG’s indirect analysis of the JMEN and SATURN trials, indicating that erlotinib was less effective than pemetrexed. It also noted that the ICER based on this analysis was £84,000 per QALY gained (with erlotinib being both less costly with patient access scheme included, and less effective than pemetrexed). However the Committee considered that the JMEN and SATURN trials were not directly comparable and that there was no way to robustly estimate the relative efficacy of erlotinib and pemetrexed. The Committee therefore concluded that it had not been presented with a plausible estimate of the cost effectiveness of erlotinib compared with pemetrexed.  

4.16 The Committee considered supplementary advice from NICE that should be taken into account when appraising treatments that may extend the life of patients with a short life expectancy and that are licensed for indications that affect small numbers of people with incurable illnesses. For this advice to be applied, all 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 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.

4.17 The Committee considered that the life expectancy of patients in the UK with non-small-cell lung cancer who receive first-line chemotherapy is between 7 and 11 months. The Committee discussed the size of the patient population and was aware that the erlotinib marketing authorisation includes monotherapy for maintenance treatment of patients with locally advanced or metastatic non-small-cell lung cancer with stable disease after four cycles of standard platinum-based first-line chemotherapy, but also the treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of at least one prior chemotherapy regimen. In its new evidence provided at consultation, the manufacturer estimated that about 4100 patients would be eligible for treatment with erlotinib according to its current marketing authorisations. The Committee noted that the manufacturer had indicated that 6700 patients receive first-line chemotherapy in the UK. Some of these patients would receive erlotinib as maintenance treatment rather than as a second-line therapy. The Committee also noted that the erlotinib marketing authorisation includes the treatment of patients with metastatic pancreatic cancer in combination with gemcitabine. Most of the 7000 patients with pancreatic cancer present with metastatic disease and erlotinib would potentially be indicated for this population. The Committee therefore considered that the true size of the cumulative population potentially eligible for treatment with erlotinib according to its marketing authorisation was not small and was considerably higher than the manufacturer’s estimate.

4.18 The Committee then discussed the extension to life offered by erlotinib for patients in the stable disease population. It also considered whether mean or median survival was a more appropriate measure for evaluating the end-of-life criteria. The Committee agreed with comments from the ERG that the mean survival figures were more informative because they were based on all available data for all patients across the whole trial period. . The Committee also heard from the clinical specialists that some patients have significantly longer responses to treatment with erlotinib, which was another reason to consider the mean rather than the median values. It noted that in the new analyses provided during consultation, the manufacturer estimated the mean overall survival benefit of erlotinib compared with best supportive care to be 3.3 months in the whole stable disease population, 4.2 months in the stable, squamous disease population and 4.5 months in the stable, non-squamous disease population. It also noted that the ERG estimated the mean overall survival benefit to be 3.2 months and 2.2 months in the populations of patients with squamous and non-squamous disease respectively. The Committee was concerned that no rationale could be provided to explain why the manufacturer’s survival estimates for each population were greater than for the whole population, which cast further uncertainty over the validity of the analysis. Although the ERG had not provided an overall survival estimate for the whole stable disease population, the Committee heard from the ERG that this figure was likely to be closer to the mean overall survival estimate for patients in the non-squamous group than the mean overall survival estimate for patients in the squamous group. The Committee had previously concluded that the overall survival benefit of erlotinib in clinical practice was uncertain and likely to be less than the ERG’s estimates. The Committee did not consider that robust evidence had been provided to demonstrate an extension to life of at least three months and therefore concluded that the end-of-life considerations did not apply to this appraisal.

4.19 The Committee considered that the most plausible ICERs for erlotinib compared with best supportive care would be higher than those estimated by the ERG (£44,800 and £68,100 per QALY gained for the populations of patients with stable, squamous disease and with stable, non-squamous disease respectively) and considerably higher than £50,000 per QALY gained for the whole stable disease population (with patient access scheme included). The Committee agreed that the end-of-life considerations did not apply to this appraisal, but it noted that even if they were taken into account, the most plausible ICERs were higher than that normally considered to be cost effective. The Committee considered that cost effectiveness had not been demonstrated for erlotinib compared with pemetrexed in patients with stable, non-squamous disease.  It was also mindful that the proportion of patients who would be eligible to receive pemetrexed for maintenance treatment was declining quickly over time and therefore the relevance of pemetrexed as a comparator to erlotinib was also declining. Therefore, the Committee concluded that erlotinib could not be considered a cost-effective use of NHS resources when used as monotherapy for maintenance treatment in patients with locally advanced or metastatic non-small-cell lung cancer who have stable disease following platinum-based first-line chemotherapy.

Summary of Appraisal Committee's key conclusions

TAXXX	Appraisal title: Erlotinib monotherapy for the maintenance treatment of non-small-cell lung cancer	Section
Key conclusion
Erlotinib monotherapy is not recommended for maintenance treatment in people with locally advanced or metastatic non-small-cell lung cancer with stable disease after platinum-based first-line chemotherapy. The Committee concluded that the relative efficacy of erlotinib maintenance treatment reported in the SATURN trial may be seen in clinical practice in the UK, but there was considerable uncertainty that the absolute gains of treatment seen in the trial would be translated into routine practice. The Committee considered that the most plausible ICER for erlotinib compared with best supportive care would be considerably higher than £50,000 per QALY gained for the whole stable disease population. It concluded that erlotinib could not be considered a cost-effective use of NHS resources compared with best supportive care or pemetrexed when used as monotherapy for maintenance treatment in patients with locally advanced or metastatic non-small-cell lung cancer who have stable disease following platinum-based first-line chemotherapy.		1.1 4.9 4.19, 4.20
Current practice
Clinical need of patients, including the availability of alternative treatments	The Committee noted that pemetrexed is recommended in TA190 as an option for the maintenance treatment of people with locally advanced or metastatic non-small-cell lung cancer other than predominantly squamous cell histology if disease has not progressed immediately following platinum-based chemotherapy in combination with gemcitabine, paclitaxel or docetaxel. The Committee noted that patients are only eligible for maintenance treatment with this drug if they have not received it as part of first-line treatment in combination with cisplatin. Therefore the number of patients who would be eligible for maintenance treatment would progressively decrease as more patients receive first-line treatment with pemetrexed.	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 was aware that maintenance treatment after first-line treatment is still a relatively new concept in lung cancer and that its aim is to prolong the benefits of treatment and to maximise quality of life for as long as possible. The Committee noted that pemetrexed is an option for the maintenance treatment of people with non-squamous disease but best supportive care is currently the only option for patients with squamous disease.	4.2 4.3
What is the position of the treatment in the pathway of care for the condition?	The Committee considered current UK practice for the treatment of patients with locally advanced or metastatic non-small-cell lung cancer. It heard from clinical specialists that first-line treatment in the UK is usually with a platinum doublet of carboplatin or cisplatin plus gemcitabine or vinorelbine, or cisplatin plus pemetrexed for patients with non-squamous disease. If disease progresses, patients have the option of receiving second-line systemic treatment if they have a good performance status. In the UK, second-line treatment is normally docetaxel or erlotinib.	4.2
Adverse effects	The Committee noted views from clinical specialists that erlotinib is an oral drug with adverse events that are relatively well tolerated. The Committee considered that the adverse events associated with erlotinib (most commonly rash and diarrhoea) were well known and that most patients in the SATURN trial did not require their treatment to be changed or stopped because of adverse events.	4.4 4.5
Evidence for clinical effectiveness
Availability, nature and quality of evidence	The Committee noted that the only evidence for maintenance treatment with erlotinib in patients with stable disease came from one randomised controlled trial (SATURN).	4.5
Relevance to general clinical practice in the NHS	The Committee discussed whether the results of the SATURN trial could be generalised to UK clinical practice. It considered that in the trial there was a high proportion of patients from Southeast Asia and a high proportion of patients who had never smoked. The Committee was aware that these two patient groups are known to respond better to lung cancer treatments than patients of other races and patients who had a history of smoking. The Committee also noted that a small proportion of patients in the trial had EGFR mutations and these patients are likely to have better prognosis with treatment than other patients with non-small-cell lung cancer. In addition, the Committee considered that patients with EGFR mutations would not receive maintenance treatment with erlotinib in UK clinical practice because NICE recommends gefitinib as a first-line treatment in this group rather than chemotherapy. The Committee noted that in the key clinical trial of erlotinib, the RECIST criteria were based on 6-weekly scans and considered that such frequent scans were not likely in the routine care of lung cancer patients in the UK. The Committee noted that no one in the SATURN trial had received first-line treatment with pemetrexed and cisplatin, which is now commonly used as combination chemotherapy for patients with non-squamous disease because of its superiority to the regimens used in the SATURN trial. It concluded that there was uncertainty about the clinical benefit of erlotinib in patients who had received this combination. The Committee noted that patients in the SATURN trial were younger, had a better performance status and a longer duration of overall survival than would be seen in routine clinical practice in the UK. It concluded that the relative efficacy of erlotinib reported in the SATURN trial may be seen in clinical practice in the UK, but there was considerable uncertainty that the absolute gains of treatment seen in the trial would be translated into routine practice.	4.6,4.7 4.8 4.9 4.9
Uncertainties generated by the evidence	See ‘Relevance to general clinical practice in the NHS’.
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?	None considered.
Estimate of the size of the clinical effectiveness including strength of supporting evidence	The Committee noted that the SATURN trial showed that erlotinib was associated with a statistically significant improvement in progression-free survival and overall survival compared with placebo for the overall population of patients with stable disease.	4.5
Evidence for cost effectiveness
Availability and nature of evidence	The Committee noted the evidence for the cost effectiveness of erlotinib compared with best supportive care in patients with stable disease was based on the manufacturer’s new economic evaluation in which the ICERs were £39,900 per QALY gained for all patients with stable disease, £35,500 per QALY gained for patients with stable, squamous disease and £40,000 per QALY gained for patients with stable, non-squamous disease. The Committee was aware that the new ICER for the overall stable disease population was lower than that in the original submission (that is, £47,700 per QALY gained).	4.11
Uncertainties around and plausibility of assumptions and inputs in the economic model	The Committee noted the ERG’s criticism of the manufacturer’s calculation of the pemetrexed costs and accepted the ERG’s revised costing, which was consistent with previous NICE appraisals of treatments for non-small-cell lung cancer. The Committee noted that the ERG’s approach to modelling progression-free survival and overall survival resulted in lower estimates of overall survival benefit than the manufacturer’s method and that there were wide confidence intervals around these estimates, indicating a high degree of uncertainty. The Committee considered that the overall survival benefit of erlotinib in clinical practice was likely to be even lower than that estimated by the ERG because of the nature of the SATURN trial population, in particular the high proportion of Southeast Asian patients, and of patients who had never smoked, as well as the inclusion of patients with EGFR mutations and patients with relatively good performance status.	4.12 4.13
Incorporation of health-related quality-of-life benefits and utility values Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?	None considered.
Are there specific groups of people for whom the technology is particularly cost effective?	None considered.
What are the key drivers of cost effectiveness?	The Committee noted that the factors that had the greatest effect on the new ICERs from the manufacturer were assumptions about drug wastage (in particular, how much time a patient spent on treatment in the progression-free health state), and the costs attributed to best supportive care.	4.11
Most likely cost-effectiveness estimate (given as an ICER)	The Committee considered that the most plausible ICERs for erlotinib compared with best supportive care would be above £50,000 per QALY gained because of uncertainties about the overall survival benefit associated with erlotinib. The Committee discussed evidence for the cost effectiveness of erlotinib compared with pemetrexed. It noted that this was based on the manufacturer’s new economic evaluation in which various relative effectiveness scenarios were modelled because of the lack of comparative data for erlotinib and pemetrexed. The Committee considered that  the cost effectiveness had not been demonstrated for  erlotinib compared with pemetrexed in patients with stable, non-squamous disease.	4.14, 4.19 4.15, 4.19
Additional factors taken into account
Patient access schemes (PPRS)	The Committee noted that a patient access scheme was agreed by the manufacturer, in which erlotinib is supplied to the NHS at a discount of 14.5% of the list price.	4.10
End-of-life considerations	The Committee considered that the true size of the population potentially eligible for treatment with erlotinib according to its marketing authorisation was considerably higher than the manufacturer’s estimate. The Committee did not consider that robust evidence had been provided to demonstrate an extension to life of at least three months and therefore concluded that the end-of-life considerations did not apply to this appraisal.	4.17 4.18
Equalities considerations and social value judgements	No equalities issues were raised during the scoping exercise or the course of the appraisal.	-

5 Implementation

5.1 The Secretary of State and the Welsh Assembly Minister for Health and Social Services have issued directions to the NHS 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

Published

• Pemetrexed for the maintenance treatment of non-small-cell lung cancer. NICE technology appraisal guidance 190 (2010). Available from www.nice.org.uk/guidance/TA190
• Gefitinib for the first-line treatment of locally advanced or metastatic non-small-cell lung cancer. NICE technology appraisal guidance 192 (2010). Available from www.nice.org.uk/guidance/TA192
• Pemetrexed for the first-line treatment of non-small-cell lung cancer. NICE technology appraisal guidance 181 (2009). Available from www.nice.org.uk/guidance/TA181
• Gefitinib for the second-line treatment of locally advanced or metastatic non-small-cell lung cancer (terminated appraisal). NICE technology appraisal guidance 175 (2009). Available from www.nice.org.uk/guidance/TA175
• Erlotinib for the treatment of non-small-cell lung cancer. NICE technology appraisal guidance 162 (2008). Available from www.nice.org.uk/guidance/TA162
• Bevacizumab for the treatment of non-small-cell lung cancer (terminated appraisal). NICE technology appraisal 148 (2008). Available from www.nice.org.uk/guidance/TA148
• Pemetrexed for the treatment of non-small-cell lung cancer. NICE technology appraisal guidance 124 (2007). Available from www.nice.org.uk/guidance/TA124
• Lung cancer: the diagnosis and treatment of lung cancer. NICE clinical guideline 24 (2005). Available from www.nice.org.uk/guidance/CG24

Under development

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

• The diagnosis and treatment of lung cancer (update). NICE clinical guideline (publication expected March 2011).
• Erlotinib (in combination with bevacizumab) for the maintenance treatment of advanced or metastatic non-small-cell lung cancer. NICE technology appraisal guidance (publication expected June 2011).

7 Proposed date for review of guidance

7.1 NICE proposes that the guidance on this technology is considered for review by the Guidance Executive in November 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.

Peter Clark
Chair, Appraisal Committee
October 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 Darren Ashcroft
Senior Clinical Lecturer, School of Pharmacy and Pharmaceutical Sciences, University of Manchester

Dr Matthew Bradley
Value Demonstration Director, AstraZeneca

Dr Brian Buckley
Lay Member

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

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

Dr Ian Davidson
Lecturer in Rehabilitation, The University of Manchester

Professor Simon Dixon
Professor of Health Economics, University of Sheffield

Dr Martin Duerden
Medical Director, Conwy Local Health Board

Dr Alexander Dyker
Consultant Physician, Wolfson Unit of Clinical Pharmacology

Gillian Ells
Prescribing Advisor, NHS Sussex Downs and Weald

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

Paula Ghaneh
Senior Lecturer and Honorary Consultant, University of Liverpool

Niru Goenka
Consultant Physician, Countess of Chester NHS Foundation Trust

Professor Carol Haigh
Professor in Nursing, Manchester Metropolitan University

Alison Hawdale
Lay Member

Professor John Hutton
Professor of Health Economics, University of York

Professor Peter Jones
Pro Vice Chancellor for Research and Enterprise, Keele University
Professor of Statistics, Keele University

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

Dr Vincent Kirkbride
Consultant Neonatologist, Regional Neonatal Intensive Care Unit, Sheffield

Dr Anne McCune
Consultant Hepatologist, University Hospitals Bristol NHS Foundation Trust

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

Dr Neil Milner
General Medical Practitioner, Tramways Medical Centre

Professor Oluwafemi Oyebode
Professor of Psychiatry and Consultant Psychiatrist, The National Centre for Mental Health

Mr Mike Pinkerton
Chief of Business Development, The Rotherham NHS Foundation Trust

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

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

Dr Brian Shine
Consultant Chemical Pathologist, John Radcliffe Hospital

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

Mr Paddy Storrie
Lay Member

Dr Cathryn Patricia Thomas
GP and Associate Professor, The University of Birmingham

Charles Waddicor
Chief Executive, NHS Berkshire

Mr Mike Wallace
Health Economics and Reimbursement Director, Johnson and Johnson Medical Ltd

Dr Lok Yap
Consultant in Acute Medicine and Clinical Pharmacology, Whittington Hospitals NHS Trust

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.

Sally Gallaugher
Technical Lead

Fiona Rinaldi
Technical Adviser

Kate Moore
Project Manager

 Appendix B: Sources of evidence considered by the Committee

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

• Bagust A, Boland A, Blundell M et al. Erlotinib monotherapy for the maintenance treatment of non-small cell lung cancer after previous platinum-containing therapy. March 2010.

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

I Manufacturer/sponsor:

• Roche Products

II Professional/specialist and patient/carer groups:

• Macmillan Cancer Support
• Roy Castle Lung Cancer Foundation
• British Thoracic Society
• National Lung Cancer Forum for Nurses
• Royal College of Nursing
• Royal College of Physicians’ Intercollegiate Lung Cancer Group
• United Kingdom Oncology Nursing Society

III Other consultees:

• NHS Cornwall and the Isles of Scilly
• Department of Health
• NHS Dudley
• Welsh Assembly Government

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

• NHS Quality Improvement Scotland
• Eli Lilly and Company
• British Thoracic Oncology Group
• Liverpool Reviews and Implementation Group (LRIG)
• National Institute for Health Research Health Technology Assessment Programme
• National Collaborating Centre for Cancer

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

• Professor David Ferry, Consultant Medical Oncologist, nominated by Eli Lilly and Company – clinical specialist
• Dr Diane Parry, Consultant Physician and Lung Cancer Lead, nominated by Welsh Assembly Government – clinical specialist
• Dr Yvonne Summers, Honorary Lecturer, nominated by Royal College of Physicians – clinical specialist
• Dr Clive Mulatero, Senior Lecturer in Medical Oncology, nominated by Royal College of Physicians – clinical specialist

D The following individuals were nominated as NHS Commissioning experts by the selected PCT allocated to this appraisal. They gave their expert/NHS commissioning personal view on erlotinib by attending the initial Committee discussion and providing written evidence to the Committee. They are invited to comment on the ACD.

• Dr Caroline Court, Consultant in Public Health Medicine and Public Health Lead for Cancer, NHS Cornwall, selected by NHS Cornwall and Isles Of Scilly – NHS Commissioning expert

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

• Roche Products