Gemcitabine for the treatment of metastatic breast cancer (appraisal consultation document)
Appraisal Consultation Document
Background
Key dates
Appraisal Committee's preliminary recommendations
The technology
The manufacturer's submission
Consideration of the evidence
Proposed recommendations for further research
Implementation
Related guidance
Proposed date for review of guidance
Appendix A: Appraisal Committee members and NICE project team
Appendix B: Sources of evidence considered by the Committee
Appendix C: List of organisations involved in this appraisal
Background
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 a single technology appraisal (STA) of gemcitabine for the treatment of metastatic breast cancer 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 consultees and by the representatives nominated for this appraisal by healthcare professional and patient/carer groups. The Committee has developed preliminary recommendations on the use of gemcitabine for the treatment of metastatic breast cancer.
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). This document should be read in conjunction with the manufacturer's submission and Evidence Review Group report, which are available from 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 single 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:
Closing date for comments: 6 October 2006
Second Appraisal Committee meeting: 25 October 2006
Details of membership of the Appraisal Committee are given in appendix A, a list of the sources of evidence used in the preparation of this document is given in appendix B, and a list of organisations involved in this appraisal is given in appendix C
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 | Gemcitabine in combination with paclitaxel, within its licensed indication, is not recommended for the treatment of metastatic breast cancer. |
| 2 | The technology |
| 2.1 | Gemcitabine (Gemzar, Eli Lilly and Company) is an anticancer drug that belongs to a class of drugs known as antimetabolites. Gemcitabine in combination with paclitaxel has a UK marketing authorisation for the treatment of patients with metastatic breast cancer who have relapsed following adjuvant/neo-adjuvant chemotherapy. Prior chemotherapy should have included anthracyclines unless clinically contraindicated. For further information see the ‘Summary of product characteristics'. |
| 2.2 | The side-effect profile of gemcitabine plus paclitaxel is similar to that of other chemotherapeutic agents. The most common haematological adverse effect reported is neutropenia and the most common non-haematological adverse effects reported include fatigue and diarrhoea. For full details of side effects and contraindications, see the ‘Summary of product characteristics'. |
| 2.3 | The acquisition cost of gemcitabine is £32.55 for a 200 mg vial and £162.76 for a 1 g vial (excluding VAT; British national formulary, 51st edition). The price for 6 mg/ml branded paclitaxel (Taxol) is £116.05 for a 5 ml vial, £347.82 for 16.7 ml vial, £521.73 for a 25 ml vial, and £1043.46 for a 50 ml vial (excluding VAT; British national formulary, 51st edition). The price for 6 mg/ml non-proprietary paclitaxel is £112.20 for a 5 ml vial, £336.60 for 16.7 ml vial, £561.00 for a 25 ml vial, and £1009.80 for a 50 ml vial (excluding VAT; British national formulary, 51st edition). The recommended dosing regimen is paclitaxel, 175 mg/m2, administered on day 1 over 3 hours as an intravenous infusion, followed by 1250 mg/m2gemcitabine administered as a 30-60 minute infusion on days 1 and 8 of each 21 day treatment cycle. The cost per patient for six treatment cycles of gemcitabine plus paclitaxel will be approximately £9,000 excluding costs of administration. Drug acquisition 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 gemcitabine and a review of this submission by the Evidence Review Group (ERG) (appendix B). | |
| 3.1 | The manufacturer's submission approached the decision problem by comparing gemcitabine plus paclitaxel with licensed taxane-based regimens: docetaxel, paclitaxel, and docetaxel plus capecitabine. The population under consideration consisted of people who had relapsed and developed metastatic breast cancer following anthracycline-based adjuvant or neo-adjuvant chemotherapy, or non-anthracycline-based chemotherapy where anthracyclines are contraindicated. The manufacturer stated that gemcitabine plus paclitaxel will be considered for people who are younger and fitter than the general population of patients with metastatic breast cancer and who are considered suitable for taxane-based therapy. The patients for whom gemcitabine plus paclitaxel is considered also require higher treatment efficacy than can be achieved with single drug therapy for example in the presence of visceral metastasis. The primary outcome measure considered in the decision problem was overall survival. Secondary outcome measures included time to documented progression of disease, progression-free survival, overall response rates, pain and analgesic use, quality of life and incidence of adverse events. |
| 3.2 | The manufacturer's submission presented evidence on the clinical effectiveness of gemcitabine plus paclitaxel based on a single randomised controlled trial (RCT) that compared gemcitabine plus paclitaxel with paclitaxel monotherapy. Final analyses showed that the 266 people in the gemcitabine plus paclitaxel arm of the trial had greater median overall survival (18.6 months versus 15.8 months, p = 0.0489; hazard ratio: 0.82, 95% confidence interval: 0.67 to 1.00, p = 0.0495) and time to documented progression of disease (5.4 months versus 3.5 months, p = 0.0013; hazard ratio: 0.73, 95% confidence interval 0.61 to 0.89, p = 0.0015) than the 263 people in the paclitaxel arm of the trial. |
| 3.3 | The manufacturer's submission presented a series of pairwise economic analyses comparing gemcitabine plus paclitaxel with docetaxel monotherapy, paclitaxel monotherapy and docetaxel plus capecitabine. The economic analyses were based on a state-transition Markov model with a 3-year horizon equivalent to the life expectancy of people diagnosed with metastatic breast cancer. All these analyses were based on an indirect comparison in which weighted absolute treatment outcomes (including survival data) were pooled from single arms of different trials in published literature. No assessment of heterogeneity between the characteristics of the patients in the different study populations was performed, nor was there any adjustment for differences in the baseline characteristics. The median overall survival estimate for gemcitabine plus paclitaxel was taken from the RCT comparing gemcitabine plus paclitaxel with paclitaxel monotherapy. However, the manufacturer did not use overall survival estimates for paclitaxel from this comparative study and used the average of the pooled, weighted absolute survival data from single arms of different studies instead. |
| 3.4 | The base-case analysis compared gemcitabine plus paclitaxel with docetaxel monotherapy and resulted in an incremental cost-effectiveness ratio (ICER) of £17,200 per quality-adjusted life year (QALY). A comparison of gemcitabine plus paclitaxel with paclitaxel monotherapy resulted in an ICER of £30,100 per QALY, and against docetaxel plus capecitabine, the ICER was £23,200 per QALY. The manufacturer presented a scenario analysis for gemcitabine plus paclitaxel against docetaxel monotherapy where the price of non-proprietary paclitaxel is assumed to be 55% less than that of branded paclitaxel. The ICER in this case fell from £17,200 per QALY to £4,700 per QALY. |
| 3.5 | The Evidence Review Group (ERG) reviewed the evidence submitted for clinical and cost effectiveness. The ERG judged that the manufacturer's submission contained a reasonable estimate of the clinical effectiveness of gemcitabine plus paclitaxel when compared with paclitaxel monotherapy. It was noted that the overall survival benefits of gemcitabine plus paclitaxel may have been diluted by a number of patients in the paclitaxel arm of the trial receiving second-line treatments that included gemcitabine, docetaxel, vinorelbine and capecitabine. The use of second-line treatments was similar in both arms of the trial except for a four-fold greater use of gemcitabine in the paclitaxel arm. |
| 3.6 | The ERG reviewed the economic model and judged its structure to be reasonable and based on previous economic studies. The main drivers of cost effectiveness are the estimates of overall survival, the cost of paclitaxel, and the utilities assigned to the health states in the model. The ERG's main source of concern was the indirect comparison method used by the manufacturer to generate the survival estimates for the economic model which involved pooling absolute treatment efficacy data from single arms of different trials. The ERG described this approach as 'naïve' when evaluated against an NHS R&D HTA methodological review of indirect comparisons. |
| 3.7 | The ERG specifically commented that method used by the manufacturer ignores the fact that RCTs are designed to measure relative treatment effects. The indirect comparison method used does not preserve the benefits of randomisation and it is at best equivalent to observational studies. The ERG also raised concerns about the comparability between the trials from which the data were pooled. In particular the ERG highlighted underlying differences in the patient characteristics in the trials, notably the lines of prior therapies received. Finally the ERG noted that the manufacturer's indirect comparison estimated survival with paclitaxel monotherapy to be longer than that with docetaxel monotherapy, which contradicts the results of a head-to-head trial in which patients randomised to docetaxel monotherapy had greater median overall survival than those randomised to paclitaxel monotherapy. |
| 3.8 | By using the treatment efficacy data from both arms of the RCT comparing gemcitabine plus paclitaxel with paclitaxel monotherapy in place of the pooled estimates from the manufacturer's indirect comparisons, the ERG estimated the ICER for a comparison between gemcitabine plus paclitaxel and paclitaxel to be £42,800 per QALY. In an illustrative analysis, the ERG found that using relative treatment effects to estimate overall survival for docetaxel resulted in an ICER of £45,800 per QALY for a comparison of gemcitabine plus paclitaxel against docetaxel monotherapy. 3.9 Full details of the trial are in the manufacturer's submission and the Evidence Review Group report, both of which are available from www.nice.org.uk/page.aspx?o=260234 |
| 4 | Consideration of the evidence |
| 4.1 | The Appraisal Committee (appendix A) reviewed the data available on the clinical and cost effectiveness of gemcitabine for the treatment of metastatic breast cancer, having considered evidence (appendix B) on the nature of the condition and the value placed on the benefits of gemcitabine by people with metastatic breast cancer, those who represent them, and clinical experts. It was also mindful of the need to take account of the effective use of NHS resources. |
| Clinical effectiveness | |
| 4.2 | The Committee considered the decision problem in the manufacturer's submission to be reasonable and appropriate. |
| 4.3 | The Committee considered current clinical practice in the treatment of metastatic breast cancer following relapse after anthracycline-based regimens in adjuvant and neo-adjuvant settings. The Committee heard from the clinical specialists that gemcitabine plus paclitaxel would be valued as an option in a group of patients who required higher efficacy than could be achieved with a single taxane agent (for example in patients with visceral metastasis) and who were also considered fit enough to receive combination therapy. The Committee heard from the clinical specialists that gemcitabine plus paclitaxel would probably be used as an alternative option to the combination of docetaxel plus capecitabine because it is considered to be equally effective, but with less toxicity. Finally, the Committee heard from the clinical specialists that as capecitabine can be an important option in later lines of therapy for metastatic breast cancer, the use of docetaxel plus capecitabine as a first-line choice would reduce the possibility of using capecitabine in later lines of therapy. The patient representatives confirmed that for patients whose condition required an alternative to single agent taxanes, gemcitabine plus paclitaxel was a useful option because of its efficacy and low level of toxicity. |
| 4.4 | The Committee considered the evidence on the clinical effectiveness of gemcitabine plus paclitaxel for the treatment of metastatic breast cancer. The Committee noted that there is only one RCT comparing gemcitabine plus paclitaxel with paclitaxel monotherapy, the final results of which have not yet been published in a peer-reviewed journal. The Committee considered the uncertainty surrounding the clinical effectiveness data relating to the borderline statistical significance of median overall survival, the fact that the 95% confidence interval for the hazard ratio for median overall survival includes 1.00 and the possibility that the four-fold greater use of gemcitabine as second line treatment in the paclitaxel arm of the trial may have influenced the results. On balance, the Committee concluded that gemcitabine plus paclitaxel is likely to be more clinically effective than paclitaxel monotherapy, but recognised significant uncertainties surrounding the trial results. |
Cost effectiveness |
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| 4.5 | The Committee considered the evidence on the cost effectiveness of gemcitabine plus paclitaxel when compared with all relevant UK comparators as presented in the manufacturer's submission. The Committee noted that the manufacturer provided estimates of the cost effectiveness of gemcitabine plus paclitaxel versus paclitaxel monotherapy using only data from the indirect comparisons. The Committee also noted the ERG's view that using the actual data from the trial that directly compared gemcitabine plus paclitaxel with paclitaxel monotherapy provided an ICER of £42,800 per QALY. The Committee understood that given the lack of head-to-head trials, indirect comparison methods are necessary in order to compare gemcitabine plus paclitaxel with docetaxel monotherapy. The Committee discussed the indirect comparisons method used by the manufacturer, and expressed concerns about the pooling of absolute treatment effects from single arms of different trials. The Committee considered that this indirect comparison method may be subject to greater bias than is associated with observational studies, in which confounding factors are appropriately assessed and adjusted for. The Committee noted that the failure to address the comparability and heterogeneity between trials from which the manufacturer pooled data for the economic model added to the uncertainties in the indirect comparisons method used. |
| 4.6 | The Committee noted that the manufacturer's economic analysis suggested that gemcitabine plus paclitaxel was more cost effective when compared with docetaxel monotherapy than with paclitaxel monotherapy. The Committee noted that the survival estimates from the manufacturer's indirect comparisons appeared to contradict the results from a study that directly compared docetaxel monotherapy with paclitaxel monotherapy. The indirect comparison suggested that overall survival with paclitaxel monotherapy was superior to docetaxel monotherapy, but the clinical study suggested the opposite. Given that overall survival is a key driver of cost effectiveness in the manufacturer's economic model, the manufacturer's indirect survival estimates have the effect of producing cost effectiveness ratios in favour of gemcitabine plus paclitaxel when compared with docetaxel monotherapy. The Committee also discussed the ERG's survival estimates from an indirect comparison method, based on relative treatment efficacy data, that maintained the randomised structure of clinical trials. The Committee considered the ICER of £45,800 per QALY obtained using the ERG's indirect estimates for a comparison of gemcitabine plus paclitaxel with docetaxel monotherapy. Although the ERG's analyses were indicative and for illustrative purposes only, the ERG's indirect survival estimates were more consistent with, and closer to, the results from the head-to-head trial between docetaxel monotherapy and paclitaxel monotherapy. The Committee considered that the manufacturer's indirect estimates were inconsistent with published evidence, and subject to substantial uncertainty. On balance, the Committee concluded that the ICERs presented in the manufacturer's submission were likely to be substantial underestimates of the ICERs for the gemcitabine plus paclitaxel combination regimen. |
| 4.7 | The Committee also considered the impact and relevance of discounted pricing of non-proprietary paclitaxel, and accepted that using discounted non-proprietary paclitaxel prices could lower the ICERs for gemcitabine plus paclitaxel (when compared with docetaxel monotherapy or docetaxel plus capecitabine) to within conventional cost effectiveness thresholds. However, the duration of any procurement discounts is unknown and the Committee was not persuaded that negotiated procurement discounts would be universally available within the NHS in England and Wales. |
| Summary of the considerations | |
| 4.8 | The Committee was not persuaded that the evidence presented by the manufacturer provided a robust demonstration of the clinical and cost effectiveness of gemcitabine plus paclitaxel compared with the other licensed taxane-based treatments. The Committee concluded that gemcitabine plus paclitaxel within its licensed indication could not be recommended for the treatment of metastatic breast cancer in the NHS. |
| 5 | Proposed recommendations for further research |
| 5.1 | The Committee recommended that head-to-head trials of gemcitabine plus paclitaxel versus docetaxel, and docetaxel plus capecitabine be conducted. |
| 6 | Implementation |
| 6.1 | 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. |
| 6.2 | '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 |
| 6.3 | NICE has developed tools to help organisations implement this guidance (listed below). These are available on our website (www.nice.org.uk/TAXXX). [Note: tools will be available when the final guidance is issued] |
| 7 | Related guidance |
| 7.1 |
NICE has issued the following related technology appraisals.
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7.2 NICE is in the process of producing the following clinical guideline.
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| 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 September 2009. The Institute would particularly welcome comment on this proposed date. |
| David Barnett Chair, Appraisal Committee September 2006 |
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Appendix A. Appraisal Committee members and NICE project team |
A. Appraisal Committee members |
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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 twice a month except in December, when there are no meetings. The Committee membership is split into two branches, with the chair, vice chair and a number of other members attending meetings of both branches. 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. Dr Jane Adam Professor A E Ades Dr Amanda Adler Dr Tom Aslan Professor David Barnett (Chair) Mrs Elizabeth Brain Dr Karl Claxton Dr Richard Cookson Mrs Fiona Duncan Dr Paul Ewings Professor John Geddes Mr John Goulston Mr Adrian Griffin Ms Linda Hands Dr Elizabeth Haxby Dr Rowan Hillson Dr Catherine Jackson Professor Richard Lilford Dr Simon Mitchell Ms Judith Paget Dr Katherine Payne Dr Ann Richardson Dr Stephen Saltissi Mr Mike Spencer Professor Andrew Stevens (Vice Chair) Dr Cathryn Thomas Simon Thomas Dr Norman Vetter Professor Mary Watkins Dr Paul Watson The following individuals, representing the National Collaborating Centre responsible for developing the Institute's clinical guideline related to this topic, attended the meeting to observe and to contribute as advisors to the Committee.
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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 advisor and a project manager. Ebenezer Tetteh and Kate Burslem Janet Robertson Christopher Feinmann |
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Appendix B. Sources of evidence considered by the Committee |
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| A |
The following manufacturer/sponsor provided a submission for this appraisal:
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| B | The evidence review group (ERG) report for this appraisal was prepared by Southampton Health Technology Assessment Centre: J Jones, A Takeda, SC Tan, K Cooper, E Loveman, A Clegg, N Murray (July 2006). Gemcitabine for metastatic breast cancer. |
| C |
The following individuals were selected from clinical specialist and patient advocate nominations from the professional/specialist and patient/carer groups. They gave their expert personal view on Gemcitabine by providing written evidence to the Committee. They are invited to comment on the Appraisal Consultation Document (ACD).
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Appendix C. List of organisations involved in this appraisal |
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The following organisations accepted the invitation to participate in this appraisal. They are also invited to comment on the Appraisal Consultation Document (ACD) and supporting evidence. Consultee organisations have the opportunity to appeal against the Final Appraisal Determination.
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This page was last updated: 30 March 2010