Mesothelioma - pemetrexed disodium: Second appraisal consultation document
NATIONAL INSTITUTE FOR HEALTH AND CLINICAL EXCELLENCE
Appraisal Consultation Document
Pemetrexed disodium for the treatment of malignant pleural mesothelioma
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The Department of Health and the Welsh Assembly Government have asked the National Institute for Health and Clinical Excellence (NICE or the Institute) to conduct an appraisal of pemetrexed disodium for the treatment of malignant pleural mesothelioma and provide guidance on its use to the NHS in England and Wales. The Appraisal Committee has had its first meeting to consider both the evidence submitted and the views put forward by the representatives nominated for this appraisal by professional organisations and patient/carer and service user organisations. The Committee has developed preliminary recommendations on the use of pemetrexed disodium for the treatment of malignant pleural mesothelioma. This document has been prepared for consultation with the formal consultees. It summarises the evidence and views that have been considered and sets out the preliminary recommendations developed by the Committee. The Institute is now inviting comments from the formal consultees in the appraisal process (the consultees for this appraisal are listed on the NICE website, www.nice.org.uk). Note that this document does not constitute the Institute's formal guidance on this technology. The recommendations made in section 1 are preliminary and may change after consultation. The process the Institute will follow after the consultation period is summarised below. For further details, see the ‘Guide to the technology appraisal process’ (this document is available on the Institute’s website, www.nice.org.uk). The Appraisal Committee will meet again to consider the original evidence and this appraisal consultation document in the light of the views of the formal consultees. At that meeting, the Committee will also consider comments made on the document by people who are not formal consultees in the appraisal process. After considering feedback from the consultation process, the Committee will prepare the final appraisal determination (FAD) and submit it to the Institute. Subject to any appeal by consultees, the FAD may be used as the basis for the Institute’s guidance on the use of the appraised technology in the NHS in England and Wales. The key dates for this appraisal are: 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. |
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Note that this document does not constitute the Institute's formal guidance on this technology. The recommendations made in Section 1 are preliminary and may change after consultation. |
| 1 | Appraisal Committee's preliminary recommendations |
| 1.1 | Pemetrexed disodium is not recommended for the treatment of malignant pleural mesothelioma. |
| 1.2 | It is recommended that people currently receiving pemetrexed disodium should have the option to continue therapy until they and their clinicians consider it appropriate to stop. |
| 2 | Clinical need and practice |
| 2.1 | Malignant pleural mesothelioma (MPM) is a type of cancer that occurs in the pleura, the mesothelium (membranous lining) surrounding the lungs. MPM is a rapidly progressive malignancy of insidious onset. |
| 2.2 | Approximately 90% of people diagnosed with MPM have been exposed to asbestos. When asbestos fibres are inhaled or swallowed, they can cause scarring of the lung tissues, cancer of the bronchial tree (lung cancer) and sometimes cancers in the pleura and peritoneum. A wide range of occupations, notably shipbuilding, railway engineering and asbestos product manufacture are associated with an increased risk of MPM. Family members of people whose work clothes were contaminated with asbestos fibres have also developed MPM. The condition is significantly more common in men, with a male to female ratio of 5:1, and typically presents between 60 and 79 years. |
| 2.3 | MPM usually develops 20–50 years after exposure to asbestos. Data from 2004 suggest that about 1700 people in the UK are diagnosed with MPM each year. It is estimated that the number of people diagnosed with MPM in the UK will increase to a peak of more than 2000 each year between 2011 and 2015, reflecting a lag from the highest use of asbestos in the 1970s. An estimated 65,000 people will be diagnosed with MPM between 2002 and 2050. The use of asbestos was banned in the UK in 1999. |
| 2.4 | Most people with MPM present with chest pain and dyspnoea (difficulty breathing) and have pleural effusions (excess fluid in the pleura) on examination. Fatigue, profuse sweating, weight loss, anorexia and difficulty in swallowing become common as the disease progresses. Presentation and diagnosis often occur at an advanced stage, and the prognosis for most people with MPM is extremely poor, with overall median survival ranging from 9-13 months. Age, tumour histology, tumour stage at diagnosis and performance status have been shown to be independent prognostic factors. |
| 2.5 | Classifying how far the tumour has spread (staging) provides prognostic information and can help to determine an appropriate treatment strategy. However, staging is complex and can require surgical intervention. There is no universally accepted staging system, but the traditional Butchart staging system is gradually being replaced by a tumour nodes metastases (TNM) system developed by the International Mesothelioma Interest Group. In clinical practice, MPM is generally staged pragmatically based on whether or not surgery is an appropriate option for the person. There is no standard treatment pathway for MPM in the UK. The clinical management of MPM is multimodal and a person may receive a combination of treatments. Surgery (extrapleural pneumonectomy) is an option for the small proportion of people with MPM (1–5%) whose tumours are at stage 1 or 2. |
| 2.6 | For the majority of people with MPM (for whom surgery is not indicated because of advanced disease), treatment is aimed at improving symptoms and maintaining quality of life for as long as possible. Often, this does not involve treating the tumour with chemotherapy. Management of the disease that does not include a specific antitumour therapy is referred to as active symptom control (ASC) or best supportive care (BSC). For people with MPM, this may include interventions to manage pain and dyspnoea, and to address psychosocial problems. Treatments may include draining excess fluid from the pleural cavity and applying a talc pleurodesis (the insertion of talc to prevent further fluid accumulation), palliative radiotherapy, analgesics, steroids, appetite stimulants and bronchodilators |
| 2.7 | There is no standard chemotherapy treatment for MPM in the UK. Pemetrexed disodium in combination with cisplatin is the only chemotherapy regimen that is currently licensed for this indication. However, a variety of combination and single-agent regimens, such as the mitomycin C, vinblastine and cisplatin combination (MVP), or vinorelbine monotherapy, are used. To date there have been no published randomised controlled trials (RCTs) comparing survival and symptom control in people receiving chemotherapy with those receiving ASC/BSC. It is therefore uncertain whether chemotherapy offers any benefit over ASC/BSC in terms of survival and quality of life. |
| 3 | The technology |
| 3.1 | Pemetrexed disodium (Alimta, Eli Lilly and Company Limited) is licensed, in combination with cisplatin, for the treatment of chemotherapy-naive patients with unresectable malignant pleural mesothelioma. The licensed dose is 500 mg/m 2 body surface area, to be administered as a 10-minute intravenous infusion on the first day of a 21-day cycle. It is followed approximately 30 minutes later by cisplatin (recommended dose 75 mg/m 2 body surface area) infused over 2 hours. In order to reduce toxicity, patients treated with pemetrexed disodium must receive folic acid and vitamin B 12 supplementation. To reduce the incidence and severity of skin reactions, patients are pre-medicated with a corticosteroid. |
| 3.2 | Pemetrexed disodium is a multi-targeted folate antagonist that inhibits DNA replication. Cisplatin is a platinum-based chemotherapeutic agent that has antitumour activity, either as a single agent or in combination, for a number of different cancers. |
| 3.3 | Adverse effects commonly associated with pemetrexed disodium include nausea, vomiting, fatigue and neutropenia. Skin rash, mucositis and liver function abnormalities have also been reported. Cisplatin causes nausea and vomiting in the majority of patients. This can be controlled in 50–80% of patients by anti-emetic drugs. Serious toxic effects of cisplatin on the kidneys, bone marrow and ears are common, and serum electrolyte disturbances, hyperuricaemia, allergic reactions and cardiac abnormalities have also been reported. For full details of side effects and contraindications, see the summary of product characteristics. |
| 3.4 | Pemetrexed disodium costs £800 for a 500‑mg vial (excluding VAT; ‘British national formulary’ [BNF] edition 53). The cost per patient, assuming an average of five treatment cycles and a body surface area of 1.8 m 2, is approximately £8000. Costs may vary in different settings because of negotiated procurement discounts. |
| 4 | Evidence and interpretation |
| The Appraisal Committee (appendix A) considered evidence from a number of sources (appendix B). | |
| 4.1 | Clinical effectiveness |
| 4.1.1 | A single RCT of pemetrexed disodium was identified. The EMPHACIS study compared pemetrexed plus cisplatin with cisplatin alone. This was a single-blind, international, multicentre trial in 448 patients. To be eligible, patients were required to be 18 years or older, have a minimum life expectancy of 12 weeks, have uni- or bi-dimensionally measurable disease and a Karnofsky performance status of greater than or equal to 70. Patients who had prior chemotherapy, those with a second primary malignancy or brain metastases, and patients unable to discontinue non-steroidal anti-inflammatory drugs, were excluded. |
| 4.1.2 | Patients in the pemetrexed plus cisplatin arm (n = 226) received 500 mg/m 2 pemetrexed followed 30 minutes later by 75 mg/m2 cisplatin. Patients in the control arm (n = 222) received normal saline followed 30 minutes later by 75 mg/m2 cisplatin. In both arms, treatment was administered on the first day of each 21-day cycle. The median number of cycles given was 6 (range 1–12) in the pemetrexed plus cisplatin arm and 4 (range 1–9) in the cisplatin arm. Median length of follow-up was 10 months. |
| 4.1.3 | During the trial, severe toxicity (including drug-related death, neutropenia, febrile neutropenia and diarrhoea) was reported in the pemetrexed plus cisplatin arm. Therefore, folic acid and vitamin B12 supplementation were added to the trial protocol in both treatment arms to preserve blinding. With effect from the date of the protocol change, all patients received supplementation, resulting in three patient subgroups defined by supplementation status: never supplemented (n = 70), partially supplemented (n = 47) and fully supplemented (n = 331). The primary analysis was performed on all patients who were randomised and treated (intention-to- treat [ITT] population). A subgroup analysis was performed on fully supplemented patients. Further (apparently post-hoc) subgroup analyses were performed on fully supplemented patients with advanced disease (stage 3/4) because it was thought that most patients presenting to clinicians would fall into this category. |
| 4.1.4 | The primary endpoint of the EMPHACIS trial was survival. A statistically significant survival benefit was observed in patients randomised to pemetrexed plus cisplatin versus those receiving cisplatin alone. In the ITT population, median survival was 12.1 months (95% confidence interval [CI], 10.0 to 14.4) in the pemetrexed plus cisplatin arm versus 9.3 months (95% CI, 7.8 to 10.7) in the cisplatin arm (hazard ratio [HR] 0.77; 95% CI, 0.61 to 0.96; log-rank p = 0.02). In fully supplemented patients, median survival was 13.3 months (95% CI, 11.4 to 14.9) in the combination arm versus 10.0 months (95% CI, 8.4 to 11.9) in the cisplatin arm (HR 0.75; 95% CI, 0.57 to 1.00; log-rank p = 0.051). In fully supplemented patients with advanced disease, median survival was 13.2 months (95% CI, 9.3 to 14.9) in the combination arm versus 8.4 months (95% CI, 6.8 to 10.2) in the cisplatin arm (HR 0.63; 95% CI, 0.46 to 0.86; log-rank p = 0.003). |
| 4.1.5 |
Secondary endpoints included 1-year survival, median time to progressive disease and tumour response rate. Pemetrexed plus cisplatin demonstrated statistically significant benefits versus cisplatin alone for all of these outcomes in the ITT population and in the subgroups. The results for these endpoints in the ITT population were as follows:
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| 4.1.6 | Quality of life was evaluated using the Lung Cancer Symptom Scale–Meso instrument. Several aspects of quality of life were evaluated, including pain, dyspnoea, fatigue, anorexia and cough. Over 18 weeks, patients treated with pemetrexed plus cisplatin demonstrated statistically significant symptomatic improvements when compared with those who received cisplatin alone (p < 0.05, ITT population) . For global quality of life, a least squares mean score of 56 out of 100 was reported for patients randomised to pemetrexed plus cisplatin versus a score of 53 out of 100 for patients in the cisplatin only arm in the ITT population (difference between arms: p = 0.012). A similar result was observed in the fully supplemented population. |
| 4.1.7 | Adverse events with a grade of 3 or 4 (serious or life-threatening/disabling), based on National Cancer Institute Common Toxicity Criteria, were statistically significantly more frequent in patients receiving pemetrexed plus cisplatin than in those receiving cisplatin alone (ITT population). The most commonly reported grade 3/4 adverse events in patients receiving pemetrexed plus cisplatin were: neutropenia (27.9%), leukopenia (17.7%), nausea (14.6%) and vomiting (13.3%). In patients receiving pemetrexed plus cisplatin who were fully supplemented with folic acid and vitamin B 12, there was a consistently lower incidence of grade 3/4 adverse events (except for dehydration). The most common grade 3/4 adverse events in this group were: neutropenia (23.2%), leukopenia (14.9%), nausea (11.9%) and vomiting (10.7%). |
| 4.1.8 | Supplementary documentation provided by the manufacturer of pemetrexed indicated that, in the ITT population, 42% (94 of 226) of patients randomised to pemetrexed plus cisplatin responded to treatment. Of those who experienced a response, 87% (82 of 94) did so within four cycles. |
| Summary of the evidence on clinical effectiveness | |
| 4.1.9 | The results of the EMPHACIS trial suggest that pemetrexed plus cisplatin confers a survival benefit of approximately 3 months, compared with cisplatin alone. The combination treatment also appears to demonstrate advantages in terms of 1-year survival, time to progressive disease, tumour response rate and quality of life. Pemetrexed plus cisplatin appears to offer a greater benefit in comparison with cisplatin alone but causes increased side effects. |
| 4.2 | Cost effectiveness |
| 4.2.1 | Estimates of cost effectiveness were provided by the manufacturer and by the Assessment Group. A review of the published literature identified a single cost-effectiveness study. This was a conference presentation/abstract that was a forerunner of the manufacturer’s submission. |
| 4.2.2 | Two cost-effectiveness models were submitted by the manufacturer. Model 1 compared pemetrexed plus cisplatin with cisplatin alone. Model 2 compared pemetrexed plus cisplatin with standard care (as defined by the manufacturer on the basis of a market research survey). Both models had a 29-month time horizon (reflecting the trial follow-up period) and took a health service perspective. Both considered outcomes in terms of life years gained (LYGs) and quality-adjusted life years (QALYs). No discounting was applied to costs, because they were all incurred within 1 year. Outcomes were discounted at 3.5%. |
| 4.2.3 | Model 1 was based on individual patient data from the EMPHACIS trial. The model considered four subgroups: fully supplemented patients; fully supplemented patients with advanced disease; fully supplemented patients with good performance status; and fully supplemented patients with advanced disease and good performance status. Resource use was taken from the trial and unit costs were taken from Department of Health reference costs, the BNF 50 th edition and Monthly Index of Medical Specialities (MIMS) 2005. Mean survival was estimated from the area under Kaplan-Meier curves reported over the follow-up period of the EMPHACIS trial. Utility scores were taken from an ongoing observational study in patients with non-small-cell lung cancer (NSCLC) who completed the EQ-5D health-related quality of life questionnaire before chemotherapy. The base-case utility scores in the manufacturer’s economic models 1 and 2 were similar for both treatment arms (0.68 for the pemetrexed plus cisplatin arm and 0.69 for the cisplatin arm) and did not take account of loss of quality of life in people with MPM as their disease progresses. A range of one-way and two-way sensitivity analyses was performed. No probabilistic sensitivity analysis was performed. |
| 4.2.4 | The incremental cost-effectiveness ratio (ICER) was £68,598 per QALY (£44,264 per LYG) in the fully supplemented population. The ICER was more favourable in fully supplemented patients with advanced disease (£53,314 per QALY, £35,065 per LYG), fully supplemented patients with good performance status (£48,099 per QALY, £31,688 per LYG), and fully supplemented patients with advanced disease and good performance status (£47,567 per QALY, £31,337 per LYG). |
| 4.2.5 | Model 2 indirectly compared pemetrexed plus cisplatin with MVP, vinorelbine regimens (with or without platinum compounds) and ASC/BSC. Costs and outcomes for pemetrexed plus cisplatin were taken from the fully supplemented population in model 1. For the comparators, resource use data were gathered from market research surveys of oncologists, commissioned by the manufacturer. Zero cost was assumed for ASC/BSC, because it was reasoned that participants in chemotherapy trials would have received a similar level of ASC/BSC to patients receiving ASC/BSC alone. Median survival estimates were taken from a review of the published literature. Mean survival estimates for use in the cost-effectiveness analysis were derived by calculating a weighted average of reported medians and assuming the same mean to median ratio as that observed in the cisplatin arm of the EMPHACIS trial. The same utility values were used as in model 1, with the utility for cisplatin (0.69) being applied to all comparators in model 2. A range of one-way and two-way sensitivity analyses was performed. The incremental cost per QALY for pemetrexed plus cisplatin was calculated to be £21,731 versus MVP, £28,391 versus vinorelbine regimens (with or without platinum compounds), and £32,066 versus ASC/BSC. |
| 4.2.6 | When the Assessment Group corrected the survival estimate for MVP, by adjusting for the influence of performance status on median survival, an ICER of £47,972 was obtained for pemetrexed plus cisplatin versus MVP. Using more favourable survival estimates and taking the number of cycles of chemotherapy from the literature rather than the manufacturer’s market research survey, the ICERs versus MVP and vinorelbine were both above £60,000. Using survival estimates for ASC/BSC taken from a meta-analysis designed to consider prognostic factors in MPM, resulted in an ICER of £48,779 for pemetrexed plus cisplatin versus ASC/BSC. |
| 4.2.7 | The Assessment Group also carried out its own economic analysis of pemetrexed plus cisplatin compared with cisplatin alone. The four subgroups considered in the manufacturer’s model 1 were analysed. Mean costs were derived from the individual patient data in model 1. Costs were not discounted. To derive mean effectiveness estimates, Weibull distributions were fitted to the Kaplan‑Meier survival curves from the EMPHACIS trial, in order to model the survival distribution of people with MPM beyond the end of the follow-up period of the EMPHACIS trial. Mean survival was estimated from the Weibull model parameters and a discount rate of 3.5% was applied. In both arms, the Assessment Group used mean utility values of 0.51–0.54 for each subgroup. These values were calculated based on an initial utility of 0.65, falling to 0.40 during a 100-day terminal period to account for lower quality of life in people with MPM as they approach death. A probabilistic sensitivity analysis was carried out. |
| 4.2.8 | The Assessment Group’s analysis resulted in an ICER of £60,561 per QALY in the fully supplemented population. The results were more favourable in fully supplemented patients with advanced disease (£49,051), fully supplemented patients with good performance status (£50,357) and fully supplemented patients with advanced disease and good performance status (£37,664). The probability that pemetrexed plus cisplatin is cost effective at a maximum acceptable ICER of £30,000 per QALY was less than 20% for all subgroups. |
| 4.2.9 | In a later document, the manufacturer suggested that pemetrexed plus cisplatin might be more cost effective if no further cycles were given to patients who had not experienced a tumour response after their fourth cycle of treatment. It was suggested that this would lower overall costs without reducing aggregate health benefit, because only those who respond to treatment would experience survival gains. No clinical evidence or economic analysis to support this proposal was submitted. |
| Summary of the evidence on cost effectiveness | |
| 4.2.10 | The economic analyses carried out by the manufacturer and the Assessment Group both indicate a cost per QALY of greater than £60,000 when pemetrexed plus cisplatin is compared with cisplatin alone in the fully supplemented population. Pemetrexed plus cisplatin appears to be more cost effective in patients with advanced disease and/or good performance status, but the cost per QALY versus cisplatin remains above £30,000 in all subgroups. An indirect comparison submitted by the manufacturer indicates more favourable cost effectiveness of pemetrexed plus cisplatin versus MVP, vinorelbine and ASC/BSC. However, the assumptions underpinning this model are subject to high levels of uncertainty. When the assumptions were modified to reflect performance-status-adjusted survival, and resource use based on published data, the ICERs were in line with those of pemetrexed plus cisplatin versus cisplatin alone. |
| 4.3 | Consideration of the evidence |
| 4.3.1 | The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of pemetrexed disodium for the treatment of MPM, having considered evidence on the nature of the condition and the value placed on the benefits of pemetrexed disodium by patient representatives and clinical experts. It was also mindful of the need to take account of the effective use of NHS resources. |
| 4.3.2 | The Committee heard from clinical and patient experts that pemetrexed disodium plus cisplatin is valued as a potential treatment option in a disease area in which it has demonstrated survival and quality of life advantages in an RCT and in which there is incomplete evidence on the efficacy of alternative treatments. |
| 4.3.3 | The Committee discussed the relevant comparator for pemetrexed plus cisplatin in terms of clinical and cost effectiveness. Clinical experts advised that cisplatin monotherapy would not normally be used to treat MPM in clinical practice in England and Wales because of a lack of evidence for its effectiveness and its relatively unfavourable adverse-effect profile. The Committee heard that there is no nationally agreed standard care pathway for MPM. Although some patients receive chemotherapy treatment, notably with MVP or vinorelbine, many patients receive ASC/BSC only. However, the Committee was also aware that there have been no published RCTs of MVP or vinorelbine in MPM, either versus ASC/BSC or against each other. The Committee noted that the results of a meta-analysis investigating prognostic factors for MPM suggest that survival benefits in people receiving ASC/BSC alone are no different from survival benefits in people receiving chemotherapy. The Committee agreed that a direct RCT comparison of the efficacy of pemetrexed versus other chemotherapy treatments and ASC/BSC would be a highly informative addition to the evidence base. |
| 4.3.4 | The Committee discussed whether pemetrexed should be recommended over the treatments for MPM that the clinical experts advised were the most commonly used in the UK. It therefore first considered the indirect comparisons submitted by the manufacturer. It discussed the plausibility of the result that pemetrexed plus cisplatin was more cost effective when compared with MVP, vinorelbine and ASC/BSC than when it was compared with cisplatin alone. The Committee noted the high degree of uncertainty surrounding the assumptions underpinning the model and observed that the survival estimates had been taken from relatively small, non-comparative and observational studies. It also noted that the study populations were unlikely to be comparable with the population of the EMPHACIS trial, particularly in terms of performance status, a key independent predictor of survival in people with MPM. |
| 4.3.5 | The Committee also noted that resource-use estimates for MVP and vinorelbine (based on the number of cycles of chemotherapy derived from the manufacturer’s market research surveys) were higher than those reported in the studies from which the effectiveness estimates were taken, and it considered the possibility that comparator costs may have been overestimated. The Committee saw that when the model assumptions were amended to incorporate more favourable survival estimates and resource use taken from the literature, ICERs for comparisons of pemetrexed plus cisplatin with MVP, vinorelbine or ASC/ BSC were significantly higher. On balance, the Committee concluded that the evidence base underlying the economic comparisons of pemetrexed plus cisplatin with MVP, vinorelbine or ASC/BSC was too weak to use as a basis for decision making, and, in any case, did not indicate that pemetrexed plus cisplatin could be considered cost effective. |
| 4.3.6 | The Committee heard from clinical experts that cisplatin could be considered a valid chemotherapeutic agent even though it is not favoured in the UK. The Committee discussed what inferences could be made when the comparative evidence was limited to pemetrexed and cisplatin. The Committee concluded that the survival benefit demonstrated by pemetrexed plus cisplatin in the EMPHACIS trial was likely to be robust because cisplatin was likely to be at least as effective as placebo or ASC/BSC, although, in terms of quality of life, cisplatin is likely to have relevant adverse effects. The Committee also noted that cisplatin was likely to have higher costs than placebo or ASC/BSC and that this would affect the results of cost-effectiveness analysis. |
| 4.3.7 | The Committee discussed the estimates of the cost effectiveness of pemetrexed plus cisplatin versus cisplatin alone produced by the manufacturer and the Assessment Group. The Committee discussed the possibility of making subgroup recommendations for patients with both advanced disease and good performance status, because the most favourable cost effectiveness, £37,000 per QALY, versus cisplatin alone had been calculated for this group. However, the Committee considered that this was unreliable, having been based on a post-hoc subgroup analysis. The Committee heard from the experts that most people with MPM present with advanced disease judged on the basis of pragmatic staging criteria using non-invasive imaging techniques. The Committee was not persuaded that subgroups with advanced and non-advanced disease could be clearly defined in clinical practice and that a recommendation for the use of pemetrexed based on differential stages of disease was likely to be unworkable in practice. Therefore, the calculation of £50,357 per QALY, for the fully supplemented group with good performance status, was considered to be a more reliable estimate. The Committee discussed whether a subgroup recommendation should be made based on good performance status alone, because this was better grounded and more easily measurable in clinical practice. However, the Committee concluded that the evidence from the economic analyses did not support such a recommendation. |
| 4.3.8 | The Committee explored a number of scenarios in order to ascertain whether there were any circumstances in which pemetrexed plus cisplatin could be considered cost effective. |
| 4.3.9 | The Committee noted that several consultees and commentators had indicated that, in clinical practice in England and Wales, people with MPM might routinely receive fewer cycles of pemetrexed plus cisplatin than the mean of six cycles reported in the EMPHACIS trial. The Committee discussed the possibility that this might lower the costs of pemetrexed plus cisplatin and consequently improve the cost effectiveness. However, it agreed that there was no evidence that the survival benefit demonstrated in the EMPHACIS trial could be achieved with fewer cycles of treatment. |
| 4.3.10 | The Committee noted that not all patients respond to treatment with pemetrexed plus cisplatin. In the EMPHACIS trial, 87% of those who responded had done so within four cycles. The Committee discussed the possibility that the cost effectiveness of pemetrexed plus cisplatin might be improved if treatment were to be discontinued in patients who had not responded to treatment after four cycles. However, it was not persuaded that the savings that might be made employing this ‘stopping rule’ would be sufficient to render the technology cost effective in comparison with the other treatments for MPM. The Committee noted that there was no evidence of what impact a stopping rule at four cycles in non-responders would have on overall survival, and there was insufficient evidence that the survival benefit achieved in the EMPHACIS trial could be maintained under this stopping rule. In addition, the Committee was aware that there are inconsistencies in assessments of response and times to disease progression that made differentiation of responders from non-responders very unreliable. |
| 4.3.11 | The Committee considered whether it was appropriate to accept economic results expressed in incremental costs per LYG. The Committee noted that the ’Guide to the methods of technology appraisal’ advises that the reference case measure of health benefits is the QALY and that ’where health gain is expressed in terms of life-years gained, the range of most plausible ICERs that are acceptable will be substantially lower...’ In other words, the fact that the estimates for LYGs are shown to be numerically more acceptable on a QALY scale does not suggest that they are acceptable on a life-year scale, unless it is likely that a patient with mesothelioma on chemotherapy will have a full quality of life. The Committee noted on the basis of the testimony from the clinical experts that this was far from the case. Furthermore, the Committee heard from clinical experts that symptom burden (especially pain and dyspnoea) was greater for people with MPM than for people with NSCLC. However, the clinical experts stated that utility values derived from studies in NSCLC are a fair approximation of the utility values for people with MPM. |
| 4.3.12 | The Committee noted that, as long as parameter uncertainty surrounding these surrogate utility values was adequately assessed, there were no reasons for the Committee to change their preference for QALYs. The Committee noted the Assessment Group carried out a probabilistic sensitivity analysis on parameters that included utility gain. In addition, the Committee noted that one- and two-way sensitivity analyses presented by the manufacturer indicated the key drivers of the ICERs to be treatment costs and survival estimates. The Committee agreed the economic analyses presented dealt appropriately with uncertainty surrounding utility values and concluded that there are no reasons for the Committee to change its preference for QALYs. |
| 4.3.13 | The Committee noted that MPM is a rare and aggressive malignancy caused by occupational exposure to asbestos and for which limited treatment options are available. However, the Committee was not persuaded that the evidence provided a robust demonstration of both clinical and cost effectiveness of pemetrexed plus cisplatin in comparison to the other treatment regimens for MPM. The Committee, therefore, could not recommend pemetrexed disodium as a treatment option for malignant pleural mesothelioma. |
| 5 | Implementation |
| 5.1 | The Healthcare Commission assesses the performance of NHS organisations in meeting core and developmental standards set by the Department of Health in ‘Standards for better health’ issued in July 2004. The Secretary of State has directed that the NHS provides funding and resources for medicines and treatments that have been recommended by NICE technology appraisals normally within 3 months from the date that NICE publishes the guidance. Core standard C5 states that healthcare organisations should ensure they conform to NICE technology appraisals. |
| 5.2 | 'Healthcare Standards for Wales’ was issued by the Welsh Assembly Government in May 2005 and provides a framework both for self-assessment by healthcare organisations and for external review and investigation by Healthcare Inspectorate Wales. Standard 12a requires healthcare organisations to ensure that patients and service users are provided with effective treatment and care that conforms to NICE technology appraisal guidance. The Assembly Minister for Health and Social Services issued a Direction in October 2003 which requires Local Health Boards and NHS Trusts to make funding available to enable the implementation of NICE technology appraisal guidance, normally within 3 months. |
| 5.3 | NICE has developed tools to help organisations implement this guidance (listed below). These are available on our website (www.nice.org.uk/TAXXX). |
| 6 |
Proposed recommendations for further research |
| 6.1 | The Committee identified a need for RCTs comparing alternative treatment regimens in MPM. The Committee recommended that trials be conducted in which pemetrexed is compared with treatments that are currently commonly used in clinical practice in England and Wales (notably MVP, ASC and vinorelbine) in order to determine its relative effectiveness. The Committee also recommended that comparative trials of pemetrexed versus other promising treatments be conducted. |
| 7 | Related NICE guidance |
| 7.1 | There is no related guidance for this technology. |
| 8 | Proposed date for review of guidance |
| 8.1 | The review date for a technology appraisal refers to the month and year in which the Guidance Executive will consider whether the technology should be reviewed. This decision will be taken in the light of information gathered by the Institute, and in consultation with consultees and commentators. |
| 8.2 | It is proposed that the guidance on this technology is considered for review in March 2008. The Institute would particularly welcome comment on this proposed date. |
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Andrew Stevens |
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Chair, Appraisal Committee |
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March 2007 |
| Appendix A. Appraisal Committee members |
| The Appraisal Committee is a standing advisory committee of the Institute. Its 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. The Appraisal Committee meets three times a month except in December, when there are no meetings. The Committee membership is split into three branches, each with a chair and vice-chair. Each branch considers its own list of technologies and ongoing topics are not moved between the branches. |
| 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. |
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Professor Keith Abrams Dr Jeff Aronson Dr Darren Ashcroft Professor David Barnett Dr Peter Barry Professor Stirling Bryan Mr Brian Buckley Professor John Cairns Professor Mike Campbell Professor David Chadwick Dr Mark Chakravarty Dr Peter I Clark Dr Mike Davies Mr Richard Devereaux-Phillips Professor Jack Dowie Lynn Field Professor Christopher Fowler Dr Fergus Gleeson Ms Sally Gooch Mrs Barbara Greggains Mr Sanjay Gupta Professor Philip Home Dr Peter Jackson Professor Peter Jones Dr Mike Laker Dr George Levvy Ms Rachel Lewis Mr Terence Lewis Professor Gary McVeigh Professor Jonathan Michaels Dr Neil Milner Dr Ruairidh Milne Dr Rubin Minhas Dr John Pounsford Dr Rosalind Ramsay Dr Christa Roberts Dr Stephen Saltissi Mr Miles Scott Dr Lindsay Smith Mr Cliff Snelling Dr Ken Stein Professor of Public Health, University of Birmingham |
| B. NICE Project Team |
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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. Ebenezer Tetteh Janet Robertson Reetan Patel |
| Appendix B. Sources of evidence considered by the Committee | |
| A |
The assessment report for this appraisal was prepared by The Liverpool Reviews and Implementation Group (LRiG), Department of Pharmacology and Therapeutics, University of Liverpool:
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| B | The following organisations accepted the invitation to participate in this appraisal. They were invited to make submissions and comment on the draft scope, and assessment report. They are also invited to comment on the ACD and consultee organisations are provided with the opportunity to appeal against the FAD. |
| I | Manufacturers/sponsors:
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| II |
Professional/specialist and patient/carer groups:
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| III |
Commentator organisations (without the right of appeal):
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| C |
The following individuals were selected from clinical expert and patient advocate nominations from the professional/specialist and patient/carer groups. They participated in the Appraisal Committee discussions and provided evidence to inform the Appraisal Committee’s deliberations. They gave their expert personal view on pemetrexed disodium for malignant pleural mesothelioma by attending the initial Committee discussion and/or providing written evidence to the Committee. They are invited to comment on the ACD.
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This page was last updated: 30 March 2010