The Department of Health has asked the National Institute for Health and Clinical Excellence (NICE) to produce guidance on using azacitidine in the NHS in England and Wales. The Appraisal Committee has considered the evidence submitted by the manufacturer and the views of non-manufacturer consultees and commentators, and clinical specialists and patient experts.

This document has been prepared for consultation with the consultees. It summarises the evidence and views that have been considered, and sets out the draft recommendations made by the Committee. NICE invites comments from the consultees and commentators for this appraisal (see appendix B) and the public. This document should be read along with the evidence base (the evaluation report), which is available from www.nice.org.uk

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

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

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

After consultation:

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

For further details, see the 'Guide to the technology appraisal process'.

The key dates for this appraisal are:

Closing date for comments: 25 November 2010

Second Appraisal Committee meeting: 06 January 2011

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.

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

Appraisal Committee’s preliminary recommendations

1.1 Azacitidine is not recommended within its marketing authorisation as a treatment option for adults with the following conditions who are not eligible for haematopoietic stem cell transplantation:

• intermediate-2 and high-risk myelodysplastic syndromes according to the International Prognostic Scoring System (IPSS)
• chronic myelomonocytic leukaemia with 10–29% marrow blasts without myeloproliferative disorder or
• acute myeloid leukaemia with 20–30% blasts and multilineage dysplasia, according to the World Health Organization classification.

Adults with the conditions stated in section 1.1 who are currently receiving azacitidine for myelodysplastic syndromes, chronic myelomonocytic leukaemia or acute myeloid leukaemia should have the option to continue treatment until they and their clinicians consider it appropriate to stop.

The technology

2.1 Azacitidine (Vidaza, Celgene) is an anticancer drug that is thought to work by re-establishing cells’ natural mechanisms to control abnormal growth. Azacitidine has a UK marketing authorisation for the treatment of adult patients who are not eligible for haematopoietic stem cell transplantation with:

• intermediate-2 and high-risk myelodysplastic syndromes according to the International Prognostic Scoring System (IPSS)
• chronic myelomonocytic leukaemia with 10–29% marrow blasts without myeloproliferative disorder or
• acute myeloid leukaemia with 20–30% blasts and multilineage dysplasia, according to World Health Organization classification.

2.2 Azacitidine is contraindicated in patients who have known hypersensitivity to azacitidine or to any of its excipients; in women who are breastfeeding; and in patients with advanced malignant hepatic tumours. The summary of product characteristics (SPC) states that complete blood counts should be performed before starting therapy, and as often as needed, to monitor response and toxicity. The SPC lists precautions for use in patients with liver or kidney impairment, and cardiac or pulmonary disease. The SPC reports that the most common adverse reactions are thrombocytopenia, neutropenia, leukopenia, nausea, vomiting and injection site reactions. For full details of side effects and contraindications, see the SPC.

2.3 Azacitidine is injected subcutaneously daily for 7 days, followed by a rest period of 21 days. The SPC states that patients should be treated for a minimum of six cycles. The recommended dose is 75 mg/m 2 of body surface area. The SPC states that patients should be pre-medicated with anti-emetics to prevent nausea and vomiting. The cost of azacitidine is £321 for a 100-mg vial (excluding VAT; ‘British national formulary’ [BNF] edition 60). Based on a body surface area of 1.7 m 2 and a dose of 75 mg/m 2, fourteen vials would be required for one cycle (two vials for each day of treatment), and the cost of azacitidine would be £4494 per cycle (excluding the costs associated with administration). Costs may vary in different settings because of negotiated procurement discounts.

2.4 The manufacturer has agreed a patient access scheme with the Department of Health, in which azacitidine for the treatment of myelodysplastic syndromes, chronic myelomonocytic leukaemia and acute myeloid leukaemia will be available with a 7% reduction in the acquisition cost. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.

The manufacturer's submission

The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of azacitidine, a further submission after an appeal, and a review of these submissions by the Evidence Review Group (ERG) and the Decision Support Unit (DSU; appendix B).

3.1 The main evidence for the efficacy of azacitidine in patients with higher-risk myelodysplastic syndromes, chronic myelomonocytic leukaemia or acute myeloid leukaemia in the manufacturer’s submission was obtained from a phase III, open-label, multicentre, randomised controlled trial (AZA-001; n = 358). Supplementary data from an open-label extension trial of AZA-001 were also provided. Before randomisation, patients were preselected by the investigator (on the basis of age, general condition, comorbidities and patient preference) for treatment with one of three conventional care regimens: best supportive care alone, low-dose chemotherapy plus best supportive care or standard-dose chemotherapy plus best supportive care. Patients were then randomised to receive either azacitidine or the preselected conventional care regimen. Patients receiving a particular conventional care regimen were compared with patients who had been preselected for the same care regimen but were then randomised to treatment with azacitidine. The manufacturer reported that patients randomised to either azacitidine or one of the conventional care regimens were comparable in terms of age, baseline severity of myelodysplastic syndrome, Eastern Cooperative Oncology Group (ECOG) performance status and time since original diagnosis. However, within the conventional care regimens, patients preselected to receive low- or standard-dose chemotherapy tended to be younger and have a higher ECOG performance status than patients preselected to receive best supportive care alone. Randomisation and subsequent analyses were stratified according to the French–American–British classification (FAB) subtype and IPSS group. Of the 179 patients receiving a conventional care regimen, 105 (59%) were preselected for best supportive care alone, 49 (27%) for low-dose chemotherapy and 25 (14%) for standard-dose chemotherapy. Of the 179 patients receiving azacitidine, 117 (65%) had been preselected for best supportive care, 45 (25%) for low-dose chemotherapy and 17 (9%; percentages do not add to 100% due to rounding) for standard-dose chemotherapy.

3.2 The primary endpoint in AZA-001 was overall survival. Secondary endpoints included time to transformation to acute myeloid leukaemia, haematological response, independence from red blood cell transfusions for 56 consecutive days or more, number of infections needing intravenous antibiotics and occurrence of adverse events.

3.3 The manufacturer’s submission states that the intention-to-treat median overall survival was 24.5 months for patients receiving azacitidine compared with 15.0 months for patients receiving conventional care regimens (p = 0.0001, hazard ratio 0.58, 95% confidence interval [CI] 0.43 to 0.77). The median time to transformation to acute myeloid leukaemia was 17.8 months (interquartile range 8.6 to 36.8, 95% CI 13.6 to 23.6) with azacitidine compared with 11.5 months (interquartile range 4.9 to not reached, 95% CI 8.3 to 14.5) with conventional care regimens (p < 0.0001, hazard ratio 0.50, 95% CI 0.35 to 0.70). The manufacturer also reported results within each of the preselection groups (that is, best supportive care alone, low-dose chemotherapy plus best supportive care, and standard-dose chemotherapy plus best supportive care). Treatment with azacitidine led to statistically significant improvements in overall survival in all preselection groups, except for the group preselected for standard-dose chemotherapy. Only patients preselected for best supportive care had statistically significant improvement in time to transformation to acute myeloid leukaemia. Of the patients who were dependent on red blood cell transfusions at baseline, 45% of patients treated with azacitidine became transfusion independent during treatment compared with 11.8% of patients receiving conventional care regimens (p < 0.0001). The manufacturer reported that in a subgroup analysis of patients with the –7/del(7q) chromosomal abnormality, median overall survival was higher in patients receiving azacitidine than in patients receiving conventional care regimens.

3.4 The ERG considered the results from AZA-001 to be robust and to show clinical benefit for patients treated with azacitidine. The ERG noted that the open-label design of the study meant that the results could be subject to bias and that there was an imbalance in the numbers lost to follow-up. This means that the effectiveness in clinical practice could be lower than that seen in AZA-001. In addition, the ERG noted that the results for the comparison with low- and standard-dose chemotherapy were less robust because of the small numbers of patients included.

3.5 The manufacturer developed an economic evaluation, comprising a two-arm health-state transition model. One arm estimated the costs and outcomes associated with treatment with azacitidine; the other arm estimated the costs and outcomes associated with treatment with the conventional care regimens in AZA-001 (see section 3.1). All modelled patients entered the model in the myelodysplastic syndromes health state at the start of treatment and left the model at death. The model used a 35-day cycle with a lifetime horizon.

3.6 The manufacturer’s economic model used data from AZA-001 and its open-label extension trial to estimate effectiveness. The economic model underwent a number of iterations after clarification requests from the Committee, the ERG and the DSU. The manufacturer’s base-case analysis used a lognormal parametric function to extrapolate the overall survival from the data observed in the trial. Survival data from a myelodysplastic syndromes registry in Düsseldorf were presented in support of the selection of the lognormal function. Sensitivity analyses explored the use of alternative parametric functions. Time to progression was modelled in such a way that progression to the acute myeloid leukaemia health state occurred eight cycles before death to reflect the mean length of time patients had acute myeloid leukaemia in AZA-001.

3.7 The manufacturer reported that no quality of life data were collected in AZA-001 that could be used to populate the economic model. Utility value estimates for patients treated with azacitidine and best supportive care were taken from the prospective, open-label, multicentre randomised controlled trial CALGB 9221 (n = 191). In this trial, patients with myelodysplastic syndromes were treated with either azacitidine or best supportive care, and European Organisation for Research and Treatment of Cancer (EORTC) quality of life data were collected. This trial was excluded from the clinical-effectiveness analysis because the patient population was of a lower IPSS risk category than the population specified in the marketing authorisation for azacitidine. The manufacturer converted the EORTC quality of life data into EQ-5D values using an algorithm developed using data from a study in patients with oesophageal cancer. Utility value estimates for patients treated with chemotherapy were mapped to EQ-5D from SF-12 scores published in a report about patients receiving low-dose and standard-dose chemotherapy.

3.8 The manufacturer reported that, when possible, healthcare resource use was determined from AZA-001 protocol regimens. When data were not available from the trial, resource use estimates were based on expert opinion obtained through a questionnaire. Drug costs were taken from the BNF (edition 57). The majority of treatment costs were determined using the NHS 2009/10 tariff. Personal and Social Services Research Unit costs and NHS reference costs (2006/07) were used for resources if a tariff cost was not available. Because azacitidine requires a 7-day continuous treatment cycle, the additional cost of weekend administration was modelled as a two-fold increase in administration cost for 2 days of each treatment cycle. The manufacturer estimated that vial sharing, which involves treating multiple patients on the same day, could be used for 49% of patients. The reduction in unused vials and consequent savings in drug costs resulting from vial sharing were explored in a scenario analysis.

3.9 The manufacturer’s base-case results (using the lognormal parametric function to extrapolate overall survival; see section 3.6) gave incremental cost-effectiveness ratios (ICERs) for treatment with azacitidine of £47,432 per quality-adjusted life year (QALY) gained for patients in the best supportive care group, £40,754 per QALY gained for patients in the low-dose chemotherapy group, and £37,105 for patients in the standard-dose chemotherapy group. The scenario analysis that explored vial sharing decreased the base-case ICERs to £44,440, £37,929 and £34,366 per QALY gained for the best supportive care, low-dose chemotherapy and standard-dose chemotherapy groups respectively. Incorporating the patient access scheme reduced the base-case ICERs (and those with vial sharing) to £45,538 (£42,756), £38,966 (£36,399) and £35,371 (£32,823) per QALY gained for the best supportive care, low-dose chemotherapy and standard-dose chemotherapy groups respectively.

3.10 The manufacturer provided cost-effectiveness analyses for each of the parametric survival functions explored. The ICERs referred to below incorporate the patient access scheme. For the analyses using the Weibull survival function, the ICERs were £63,177 per QALY gained for the best supportive care group, £49,030 per QALY gained for the low-dose chemotherapy group, and £51,252 per QALY gained for the standard-dose chemotherapy group. For the analyses using the exponential survival function, the ICERs were £67,203 per QALY gained for the best supportive care group, £58,418 per QALY gained for the low-dose chemotherapy group, and £60,097 per QALY gained for the standard-dose chemotherapy group. For the analyses using the lognormal survival function, the ICERs were £45,538 per QALY gained for the best supportive care group, £38,996 per QALY gained for the low-dose chemotherapy group, and £35,371 per QALY gained for the standard-dose chemotherapy group. For analyses using the baseline survival from the Düsseldorf registry data and applying the respective hazard ratios associated with treatment, the ICERs were £71,522 per QALY gained for the best supportive care group, £58,282 per QALY gained for the low-dose chemotherapy group, and £85,790 per QALY gained for the standard-dose chemotherapy group .

3.11 The ERG expressed concerns about the analyses of the preselected conventional care groups in AZA-001. It noted that two of the groups, particularly the standard-dose chemotherapy group, consisted of very small numbers of patients, and that to consider the arms of the trial in isolation effectively breaks randomisation.

3.12 The ERG raised concerns about the parametric function selected to model overall survival. It noted that the selection of the lognormal function was not strongly supported by evidence from AZA-001, its open-label extension trial or the Düsseldorf registry data. The ERG reported that when various parametric functions were compared with the individual patient data from the Düsseldorf registry, an exponential survival function underestimated long-term survival, while log-logistic and lognormal survival functions overestimated long-term survival. The ERG noted that the use of log-logistic and lognormal functions estimated a percentage of patients would survive into their nineties, which the ERG considered unrealistic, given the nature of the condition. The ERG reported that of the functions explored, the Weibull survival function provided the best fit to the Düsseldorf registry data.

3.13 The ERG commented that the time to transformation to acute myeloid leukaemia in AZA-001 was subject to considerable censoring from loss of patients to follow-up. It therefore considered that the modelled time to transformation was subject to uncertainty.

3.14 The ERG noted several issues with the conversion of EORTC quality of life data into utility values. The ERG reported that the algorithm used to derive the utility values was considered by its developers to be less reliable for patients in more severe health states than alternative algorithms that were explored and rejected by the manufacturer. The ERG noted that this could bias the results. It also reported that the algorithm had been developed using data from patients with oesophageal cancer, and that patients eligible for azacitidine were of a similar age to these patients. However, the underlying conditions and comorbidities were potentially very different. The ERG stated that the utility values resulting from the algorithm should be treated with caution.

3.15 The manufacturer explored the impact of adjusting the utility values to account for the differences in the baseline patient characteristics. This was shown to have little impact on the ICERs.

3.16 After the appeal, the manufacturer submitted information on the proportions of patients with high-risk myelodysplastic syndromes, chronic myelomonocytic leukaemia or acute myeloid leukaemia receiving low-dose chemotherapy plus best supportive care and patients receiving best supportive care alone. This information included:

• a survey of 72 UK haematologists, with the proportions of patients treated between 2008 and 2010 for each conventional care regimen who met the eligibility criteria for azacitidine specified in the marketing authorisation
• a survey of 23 UK hospitals, with the proportions of patients treated for each conventional care regimen and
• data from the Haematological Malignancy Research Network registry (HMRN; collecting data from 22 hospitals in the Yorkshire and Humber and Yorkshire Coast cancer networks) on the first-line treatment of patients with myelodysplastic syndromes, chronic myelomonocytic leukaemia or acute myeloid leukaemia between September 2004 and August 2009.

The hospital survey and HMRN registry data included all patients with higher-risk myelodysplastic syndromes, chronic myelomonocytic leukaemia or acute myeloid leukaemia, not just patients who would meet the eligibility criteria for azacitidine. The haematologist survey data and hospital survey data were presented graphically and indicate that the majority of patients receive best supportive care alone, although this proportion appears lower among the haematologists identified as specialist consultants and among the hospitals identified as specialist centres. The audit of the HMRN registry data showed that of those patients considered as IPSS intermediate-2 and as IPSS high risk, 58% received best supportive care alone (including observation only), 12% received low-dose chemotherapy and 28% received standard-dose chemotherapy (2% of patients died before treatment). Of the patients considered to have refractory anaemia with excess blasts (WHO subtype RAEB), 69% received best supportive care alone, 13% received low-dose chemotherapy and 18% received standard-dose chemotherapy.

3.17 The DSU provided a critique of the three sources of information. The survey of 72 UK haematologists was based on clinicians’ estimates of patients receiving each conventional care regimen, rather than the proportions of patients who were eligible for each regimen. Because it was not clear whether the data provided were from case note review or from clinician self-reporting, the DSU considered that the survey was subject to a high risk of bias. For these reasons the DSU considered that this survey did not provide reliable data to inform the Committee’s considerations about the conventional care regimens. Regarding the survey from 23 UK hospitals, the DSU commented that because the data had been presented graphically it was difficult to estimate the exact proportions of patients for each care regimen. The survey was considered to offer limited information because:

• patients who would not be eligible to receive azacitidine were included and
• there was a lack of information about whether the sample of hospitals was representative of all UK hospitals and about the methods of data collection.

In the DSU’s view, the HMRN registry provided the most objective and reliable data for the numbers of patients receiving conventional care regimens. In summary, the DSU expressed the view that the three sources of information provided only a limited evidence base for the use of low-dose chemotherapy and confirmed the current variation in clinical practice.

3.18 After the appeal, the manufacturer also submitted information about the clinical characteristics of patients receiving each of the conventional care regimens in routine clinical practice. This included the results of an ‘informal literature review’ by the manufacturer and the results of the survey of UK haematologists about the clinical characteristics of patients receiving low-dose chemotherapy. The manufacturer reported that among patients who met the eligibility criteria for azacitidine as specified in the marketing authorisation, low-dose chemotherapy was most widely used in the UK in patients with the following characteristics:

• symptomatic cytopenias:
  • anaemia requiring transfusion
  • neutropenia 0.5–1.0  × 10 9/l (with or without infectious episodes)
  • thrombocytopenia 30–100  × 10 9/l
• normal karyotype (or one cytogenetic abnormality)
• limited comorbidities, with Haematopoietic Cell Transplantation-specific Comorbidity Index (HCTCI) score 0–2
• ECOG performance status 0–2
• logistically able to undergo treatment.

3.19 The DSU commented that only two of the eleven studies provided by the manufacturer after the appeal were conducted in the UK and only one had been published since 1991. It was not clear how the characteristics had been selected from these studies; in particular toxicity and administration had been identified in the literature review but did not appear in the final list of characteristics. However, the HCTCI score, which the manufacturer previously considered to not be in routine clinical use in the UK, was included in the list. In summary the DSU considered that the literature review offered limited evidence on eligibility criteria for patients receiving the conventional care regimens.

3.20 After the appeal, the manufacturer also submitted additional cost-effectiveness analyses incorporating health-related quality of life data from the patient group MDS UK. The manufacturer provided analyses:

• separately comparing azacitidine with each conventional care regimen specified by the Appeal Panel (that is, compared with best supportive care alone and compared with low-dose chemotherapy plus best supportive care) and
• comparing azacitidine with usual care (that is, a single estimate representing a weighted average of all the conventional care regimens together).

Each analysis used a Weibull parametric function to extrapolate overall survival, assumed no vial sharing, and included the patient access scheme.

3.21 The manufacturer’s new analyses indicated that azacitidine compared with best supportive care alone was associated with an incremental cost of £63,756 and an incremental QALY gain of 1.01, producing an ICER of £63,177 per QALY gained. Azacitidine compared with low-dose chemotherapy was associated with an incremental cost of £65,671 and an incremental QALY gain of 1.34, giving an ICER of £49,030 per QALY gained. Azacitidine compared with a weighted average of all the conventional care regimens together was associated with an incremental cost of £61,801 and an incremental QALY gain of 1.09, giving an ICER of £56,945 per QALY gained. The manufacturer’s submission stated that this weighted average was calculated using the proportion of patients receiving each of the conventional care regimens in AZA-001 (that is, 62% for best supportive care alone, 26% for low-dose chemotherapy plus best supportive care and 12% for standard-dose chemotherapy plus best supportive care).

3.22 The DSU commented that the utility values used in the revised economic evaluation were based on descriptions of health states that included transfusion dependence or independence as a feature and did not separate the specific utility value of transfusion dependence or independence from that of associated symptoms. It noted the small sample size of patients in the study (n = 47) and the low number of people from the UK (n = 21). The DSU further noted that the data did not capture adverse events, in contrast with the utility value estimates used in the manufacturer’s original base case. The DSU commented that constant utility values had been applied over the time horizon of the model, assuming that a patient’s dependence on transfusion would remain constant throughout their treatment period. It considered that this was an unreasonable assumption. The DSU concluded that the MDS utility data did not provide more appropriate information for the economic evaluation than that used in the manufacturer’s base case. However, the DSU ran exploratory analyses using data from all patients in the MDS UK study and then with only data from the UK patients. None of these exploratory analyses resulted in significant changes to the cost-effectiveness estimate provided by the manufacturer.

3.23 The DSU considered that the analysis using a weighted average (see section 3.21) was not an appropriate measure of the cost effectiveness of azacitidine. The DSU took the view that the appropriate approach would be to consider all treatment options in a single incremental analysis, comparing each treatment to the next most effective alternative, and excluding any dominated (that is, more costly and less effective) treatments from the analysis.

3.24 During the Committee meeting, the Committee requested that the DSU estimate the ICER for azacitidine compared with a weighted average of the conventional care regimens, using the manufacturer’s model. To calculate the weighted average of the conventional care regimens, the proportions of patients reported in the manufacturer’s audit of the HMRN registry (see section 3.16) classified as having WHO subtype RAEB were used; in this patient population 69% received best supportive care alone, 13% received low-dose chemotherapy and 18% received standard-dose chemotherapy. Using these proportions, the DSU estimated that the ICER for azacitidine compared with a weighted average of the conventional care regimens was £58,900 per QALY gained.

3.25 Full details of all the evidence are in the manufacturer’s submission and the ERG report, which are available from www.nice.org.uk/TA XXX.

Consideration of the evidence

4.1 The Appraisal Committee (appendix A) reviewed the data available on the clinical and cost effectiveness of azacitidine, having considered evidence on the nature of myelodysplastic syndromes, chronic myelomonocytic leukaemia and acute myeloid leukaemia and the value placed on the benefits of azacitidine by patients with the conditions, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.

4.2 The Committee heard from the clinical specialists that current practice includes the use of best supportive care and, for some patients who are able to tolerate it, low- or standard-dose chemotherapy. However, the Committee heard from the clinical specialists that there was no nationally recognised standard of care for patients with myelodysplastic syndromes, chronic myelomonocytic leukaemia or acute myeloid leukaemia, particularly regarding patients’ eligibility for chemotherapy. The Committee noted survey and HMRN registry data provided by the manufacturer, which, taken together, showed variations in treatment patterns among UK haematologists. The survey data demonstrated a wide variation in clinicians’ views about what determines a patient’s eligibility for chemotherapy. The Committee noted the list of patient characteristics proposed by the manufacturer to define the subset of patients who would be eligible for chemotherapy. However, the Committee heard from the clinical specialists that the group of patients eligible for chemotherapy could only be broadly described because of the current lack of consensus among UK haematologists about whether chemotherapy is appropriate for patients with certain comorbidities or disease-specific characteristics, and because of the inability to quantify clinician and patient preference for treatment. The Committee concluded that while best supportive care, low-dose and standard-dose chemotherapy were currently being used to treat patients with myelodysplastic syndromes, chronic myelomonocytic leukaemia or acute myeloid leukaemia, there was no consensus amongst clinicians on the set of clinical characteristics which could identify patients for whom chemotherapy should be a treatment option.

4.3 The Committee considered the quality of life of patients with myelodysplastic syndromes, chronic myelomonocytic leukaemia and acute myeloid leukaemia. The Committee understood from the evidence submitted, and from the evidence of clinical specialists and patient experts, that fatigue and a reduced ability to perform normal activities of daily living are common in these conditions and have a negative impact on patients’ quality of life. The Committee noted information from patient groups, who reported that dependence on blood transfusions is an important aspect of these conditions and also has a negative impact on quality of life. The Committee concluded that having myelodysplastic syndromes decreases quality of life, and that aspects of current conventional care (such as the need for blood transfusions) have a further negative impact on quality of life.

Clinical effectiveness

4.4 The Committee considered the clinical-effectiveness evidence presented by the manufacturer from AZA-001. The Committee understood that patients were preselected for treatment with one of the conventional care regimens before randomisation, and this was based on age, ECOG performance status and the presence of comorbidities. It also understood that patients randomised to treatment with azacitidine were compared with those in their respective pre-randomisation regimen. The Committee also heard from the clinical specialists that the proportion of patients in each preselection group in AZA-001 broadly represented the treatment patients with these conditions receive in the UK (that is, treatment with chemotherapy plus best supportive care is appropriate for considerably fewer patients than treatment with best supportive care alone).

4.5 The Committee noted that the median overall survival for patients receiving azacitidine was longer than for patients receiving the conventional care regimens. The Committee further noted that median time to transformation to acute myeloid leukaemia was longer for patients receiving azacitidine and the percentage of patients becoming independent of blood transfusions was higher for patients receiving azacitidine than for patients receiving the conventional care regimens. The Committee noted that when outcomes were analysed separately for each conventional care regimen, the difference in overall survival between the treatment arms in the standard-dose chemotherapy group was not statistically significant, nor were the differences between the treatment arms in the estimates of time to transformation to acute myeloid leukaemia for either the low-dose or standard-dose chemotherapy groups. The Committee was aware that the small patient numbers limited the precision and certainty of the outcome estimates in these groups, but concluded that the estimates of total overall survival against conventional care appeared robust. The Committee noted that the problems relating to loss of patients to follow-up, as described by the ERG (see section 3.13), may have introduced bias into estimates of relative effectiveness, but concluded that this effect was likely to be minimal.

4.6 The Committee considered the role of patient preference in the design and analysis of AZA-001. The Committee heard from the manufacturer and the DSU that the term ‘patient preference trial’ is used to describe trial designs which take account of a patient’s preference to receive either the study treatment (for example, azacitidine) or the comparator (for example, conventional care). It noted that in AZA-001, patient preference informed preselection to one of the conventional care regimens before randomisation, but did not inform randomisation to either azacitidine or conventional care. The Committee concluded that the role of patient preference in AZA-001 did not affect the way in which the trial results or subsequent analyses should be considered.

4.7 The Committee considered adverse events of treatments for myelodysplastic syndromes, chronic myelomonocytic leukaemia or acute myeloid leukaemia. It heard from the patient experts that compared with other treatment options, azacitidine was associated with relief from fatigue, fewer hospitalisations because of infections, decreased need for blood and platelet transfusion, and increased ability to perform normal activities of daily living. The Committee heard from the clinical specialists that common adverse events include peripheral blood cytopenias, myelosuppression, nausea, vomiting and injection site reactions. The patient experts and clinical specialists agreed that these adverse events are generally well tolerated. The Committee noted that no quality of life data were collected in AZA-001, although EORTC data collected in CALGB 9221 suggested improvements in overall health with azacitidine.

4.8 The Committee concluded on the basis of the clinical-effectiveness evidence and the evidence from the clinical specialists and patient experts that azacitidine is a clinically effective treatment for myelodysplastic syndromes, chronic myelomonocytic leukaemia and acute myeloid leukaemia.

Cost effectiveness

4.9 The Committee considered evidence on the cost effectiveness of azacitidine for the treatment of myelodysplastic syndromes, chronic myelomonocytic leukaemia and acute myeloid leukaemia. It discussed the likelihood of vial sharing, noting that because of the small number of patients, it may be difficult to implement a vial-sharing scheme efficiently. It concluded that the estimate of 49% of patients being able to receive treatment at the same time (and therefore suitable for vial sharing) seemed optimistic. The Committee concluded that the analyses incorporating estimated vial sharing did not produce plausible results and therefore would not form the basis for its decision on the use of azacitidine in the NHS.

4.10 The Committee noted the ERG’s concerns about the manufacturer’s model, mainly relating to the selection of the parametric function to model overall survival. The ERG stated that the most important influence on the model’s outputs was overall survival, and that the choice of parametric distribution used to extrapolate estimates of overall survival from AZA-001 greatly influenced the results. The Committee noted that the manufacturer’s base case used the lognormal function to extrapolate overall survival from the trial data, which the manufacturer justified with supporting data from a Düsseldorf myelodysplastic syndromes registry. The Committee understood that the use of the lognormal distribution modelled survival in such a way that some patients were predicted to live to an unrealistic age given the nature of the condition (see section 3.12), that is the use of lognormal distribution lead to an overestimation of survival. The Committee concluded that the Weibull distribution generally provided the best overall fit to the Düsseldorf registry long-term survival data, and that modelling that incorporated the Weibull distribution should be used to inform decision on the use of azacitidine in the NHS.

4.11 The Committee considered the estimates of quality of life included in the model (see also sections 4.12 and 4.13). The Committee first considered the derivation of the utility values. It was aware of the ERG’s concerns about the mapping of EORTC values to the EQ‑5D (see section 3.14). The Committee concluded that because the algorithm had been developed using data from patients with oesophageal cancer, the values would be associated with greater uncertainty than if a validated algorithm based on patients with myelodysplastic syndromes, chronic myelomonocytic leukaemia and acute myeloid leukaemia had been used.

4.12 The Committee then considered the face validity of the quality of life gains attributed to azacitidine in the model. The patient experts and clinical specialists stated that treatment with azacitidine reduces symptoms (such as fatigue) and the need for blood transfusions. The Committee agreed that the associated utility value gains of these should ideally be reflected in the model. The Committee noted that greater independence from blood transfusions was not explicitly included in the utility value estimate. It was aware that the manufacturer estimated the utility value by mapping to the EQ-5D. The Committee understood that EQ-5D does not include fatigue as a dimension, although it would capture some of the effects of fatigue on the patient’s ability to undertake normal activities. The Committee also understood that the EORTC measure includes a domain that captures the impact of treatment on quality of life, and that dependence on transfusion could be expected to affect this. It considered that reduced fatigue after azacitidine treatment may not have been completely captured in the modelled utility values. The Committee noted the alternative utility values provided by MDS UK after the appeal, which were meant to better reflect the utility values associated with dependence on or independence from blood transfusions. However, the Committee noted the DSU’s concern that the alternative utility values did not separate transfusion dependence or independence from associated symptoms (see section 3.22). The Committee also noted that the mean utility value submitted by MDS UK for patients who were transfusion independent was 0.85. The Committee understood that this estimate is slightly higher than the age-matched utility score for the general population at age 65 (0.844, as estimated in the Health Survey for England 2006). The Committee noted that a patient with myelodysplastic syndromes was modelled as having a slightly higher quality of life than someone aged 65 without myelodysplastic syndromes and that this limited the face validity of the quality of life estimates included in the model. It further noted that the age-matched utility values of the general population for the median age in the trial (67 years) and in the HMRN registry (70 years) were lower, at 0.821 and 0.819 respectively. The Committee noted that the model applied constant utility values within each health state. It heard from the DSU that this assumes that patients in the ‘myelodysplastic syndromes’ health state remain either transfusion dependent or independent until either they die or progress to the ‘acute myeloid leukaemia’ health state, and that the quality of life gains from becoming transfusion independent apply from the first day of treatment. The Committee also noted clinical expert opinion that utility gain would not be expected on the first day of treatment, but after the first or second treatment cycle. It agreed that an assumption of constant utility from the first day of treatment was unrealistic. Taking all these points into account, the Committee concluded that it was uncertain whether the utility values used in the model under- or over-estimated the true utility values associated with myelodysplastic syndromes.

4.13 The Committee considered the uncertainty around the quality of life estimates included in the model (see sections 4.11 and 4.12). The Committee noted that sensitivity analyses carried out by the manufacturer showed that variations in the utility values had relatively little impact on the ICERs. The Committee agreed that the alternative utility values provided by MDS UK did not provide better estimates of the gains in health-related quality of life than the manufacturer’s previous estimates. It concluded that because the ICER estimate was largely driven by the incremental life years gained and the acquisition cost of azacitidine, and was only minimally affected by the changes in health-related quality of life, the impact of any over- or underestimation of quality of life gains was likely to be small.

4.14 The Committee noted the ERG’s concerns about the modelling of time to transformation to acute myeloid leukaemia. The Committee noted that the modelled time to transformation was shorter than observed in AZA-001. The Committee considered that this could affect total treatment costs because it would affect the proportion of patients remaining on treatment and how much treatment was received. The Committee further considered the use of costs in the model. It considered that the use of the NHS 2009/10 tariff was appropriate because it could provide a more precise estimate of hospital costs by breaking down costs attributable to adverse events. The Committee concluded that the modelled increased costs of weekend administration were reasonable; noting that the associated impact on the ICERs was relatively small.

4.15 The Committee considered the estimated cost effectiveness of azacitidine. The Committee noted that the manufacturer had submitted the results of two analyses estimating the ICERs for azacitidine:

• one analysis comparing azacitidine separately with each of the conventional care regimens specified by the Appeal Panel (that is, compared with best supportive care alone and compared with low-dose chemotherapy plus best supportive care) and
• one analysis comparing azacitidine with usual care (that is, a single estimate representing a weighted average of all the conventional care regimens together).

The Committee discussed which of these estimates was most appropriate. It also noted that no cost-effectiveness evidence was presented for the subgroup of patients with the –7/del(7q) chromosomal abnormality.

4.16 The Committee considered the two ways in which the cost effectiveness of azacitidine had been presented. The Committee first considered the separate conventional care regimen analyses. The Committee noted that the total costs in the azacitidine arm incurred in the comparison with low-dose chemotherapy (£101,000) were higher than those in the comparison with best-supportive care (£91,800). It further noted that the number of QALYs (that is, not the incremental QALY gain) in the azacitidine arm was greater in the comparison with low-dose chemotherapy (2.44) than in the comparison with best supportive care (2.04). The Committee also noted that in the analyses presented before the appeal, when azacitidine was compared with standard-dose chemotherapy the number of QALYs in the azacitidine arm was 1.91. The Committee considered there appeared to be no reason why the azacitidine group should have done better in the low-dose chemotherapy comparison than in the best supportive care or standard-dose chemotherapy comparisons. The Committee agreed that this uncertainty should be noted when considering whether recommendations could be based on the separate estimates for each of the conventional care regimen groups.

4.17 The Committee then considered the analysis of azacitidine compared with the weighted average of usual care (see section 4.12). The Committee understood that the weighted ICER had been calculated by combining the ICERs for the respective conventional care regimens, each weighted by the proportion of patients receiving each of these regimens in AZA-001. The Committee understood the significant methodological limitations associated with analyses involving the use of such a weighted average, in particular the need for equivalent patient characteristics (such as age or disease severity) at baseline among any of the groups being combined. It also acknowledged the importance of ensuring that the full range of appropriate comparators was considered within these groups. It noted that because of differences in the baseline patient characteristics of the conventional care regimen subgroups (see section 3.1) the patient populations and associated population-specific results may not necessarily be appropriate for statistical analysis, which combines estimates across the groups using a simple weighted average.

4.18 The Committee then considered which of the two analytical approaches to considering cost effectiveness provided the most appropriate basis for its decision. It agreed that the most important consideration in whether a decision should be based on the separate comparisons with the different conventional care regimens was the need for a clear a priori definition of the groups of patients eligible to receive each of the conventional care regimens. The Committee agreed that because a set of clear and objective clinical characteristics defining the eligibility of patients to receive chemotherapy had not been agreed among haematologists, it could not make recommendations based on any of the separate conventional care regimen groups (see section 4.2).

4.19 The Committee was aware of significant methodological limitations with using weighted averages. The Committee understood that weighted averages can mask differences in the incremental costs and/or QALYs of the technologies being combined. The Committee was aware that the NICE ‘Guide to the methods of technology appraisal’ states that best practice should be considered as a comparator for appraisal of health technologies. If best practice is defined as a cost-effective treatment option, the standard approach to assessing the cost effectiveness of azacitidine in this context would be to consider all treatment options (that is, each of the conventional care regimens) in an iterative incremental analysis (that is, assessing the ratio of the additional cost and benefit of each technology compared with the next best alternative). This would compare the costs and health effects of all potential technologies so that the most cost-effective treatment strategy can be identified. The Committee was aware that any evaluation of the cost effectiveness of low-dose chemotherapy was not within the remit of this appraisal and therefore had not been presented. However, the Committee noted that the modelling data available suggested that low-dose chemotherapy may not be cost effective compared with best supportive care. In such a case, low-dose chemotherapy would be removed from an incremental analysis, and the remaining comparison would be azacitidine compared with best supportive care alone. However, the Committee understood that because the populations eligible for each of the conventional care regimens are probably not mutually exclusive (see section 4.2) such an incremental analysis may not be possible in this case. Taking into account the limitations of the available evidence and in the absence of a satisfactory alternative, and the fact that the evidence for the weighted average came from one clinical trial that reflected to a large extend physician and patient choice, the Committee hesitantly concluded that any decision on the cost effectiveness of azacitidine would need to be made using the weighted average (see section 4.12) in this situation.

4.20 The Committee noted that the manufacturer’s ICER for azacitidine compared with the weighted average of usual care was £57,000 per QALY gained. It understood that this figure was based on the proportions of patients stratified to each of the conventional care regimens in AZA-001 (see section 3.1). The Committee was aware that because of the variation in the use of chemotherapy treatment (see section 4.2) these proportions may not represent the proportions of patients receiving each treatment in current routine clinical practice in the UK.

4.21 The Committee considered the survey data submitted by the manufacturer regarding the proportions of patients with high-risk myelodysplastic syndromes, chronic myelomonocytic leukaemia or acute myeloid leukaemia (see sections 3.16 and 3.17). The Committee heard from the clinical specialists that the HMRN registry contained data that provided the most representative estimates for people with IPSS intermediate-2 or high risk myelodysplastic syndromes. The Committee noted that these data indicated that approximately 69% of patients received best supportive care alone, 13% received low-dose chemotherapy plus best supportive care and 18% received standard-dose chemotherapy plus best supportive care. The Committee heard from the DSU that using these proportions in the calculations increased the deterministic estimate of the ICER to £58,900 per QALY gained. The Committee noted that because of the inclusion of a potentially cost-ineffective technology (that is, low-dose chemotherapy) in the weighted average (see section 4.19) the true ICER of azacitidine compared with usual care was probably higher than £58,900 per QALY gained. Taking into account the limitations associated with the use of a weighted average and the uncertainty associated with the proportions reported, the Committee concluded that £58,900 per QALY gained represented the lower limit of the most plausible estimate of the cost effectiveness of azacitidine.

4.22 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 criteria into account, the Committee must be persuaded that the estimates of the extension to life are robust and that the assumptions used in the reference case economic modelling are plausible, objective and robust.

4.23 The Committee discussed whether the benefit provided by azacitidine for the treatment of myelodysplastic syndromes, chronic myelomonocytic leukaemia and acute myeloid leukaemia fulfilled the criteria for consideration as a life-extending, end-of-life treatment. The Committee understood that there were approximately 700 patients with IPSS intermediate-2 and high-risk myelodysplastic syndromes in England and Wales. The Committee considered that life expectancy with best supportive care alone was likely to be approximately 11.5 months. It considered the evidence from AZA-001 and noted that the median overall survival for patients treated with azacitidine in the best supportive care preselection group was 21.1 months. The Committee agreed that azacitidine would improve the treatment of myelodysplastic syndromes, chronic myelomonocytic leukaemia and acute myeloid leukaemia and that it was likely that azacitidine would increase overall survival by approximately 9.6 months. The Committee agreed that the estimates of clinical effectiveness informing the best available estimate of the ICER were sufficiently robust and concluded that azacitidine meets the criteria for being a life-extending, end-of-life treatment.

4.24 The Committee then considered the ICER taking into account the end-of-life considerations. It considered the best available estimate of the base-case ICER to be approximately £59,000 per QALY gained (see section 4.15). It considered that the additional weight that would need to be assigned to the original QALY benefits in this patient group for the cost effectiveness of the drug to fall within the current threshold range would be too great. Therefore the Committee concluded that azacitidine would not be a cost-effective use of NHS resources as a treatment for patients with myelodysplastic syndromes, chronic myelomonocytic leukaemia or acute myeloid leukaemia (see section 2.1).

4.25 The Committee considered whether NICE’s duties under the equalities legislation required it to alter or to add to its recommendations in any way. The Committee noted that azacitidine may be of specific benefit to patients who are unable to receive blood transfusions for clinical or religious reasons. The Committee noted that patients treated with azacitidine required fewer blood transfusions than patients treated with best supportive care. However, the Committee noted that no representations had been made or evidence received about the pathway of care for patients with myelodysplastic syndromes, chronic myelomonocytic leukaemia or acute myeloid leukaemia who are unable to receive blood transfusions, or about the effectiveness of azacitidine in this patient population. The Committee considered that because the most plausible ICER for azacitidine in the general patient population was approximately £59,000 per QALY gained, it would be inappropriate to make recommendations for a subgroup of patients unable to receive blood transfusions without any evidence of azacitidine’s cost effectiveness in that subgroup of patients.

Summary of Appraisal Committee’s key conclusions

TAXXX (STA)	Azacitidine for the treatment of myelodysplastic syndromes, chronic myelomonocytic leukaemia and acute myeloid leukaemia	ACD section
Key conclusion
Azacitidine is not recommended within its marketing authorisation as a treatment option for adults with the following conditions who are not eligible for haematopoietic stem cell transplantation: intermediate-2 and high-risk myelodysplastic syndromes according to the International Prognostic Scoring System (IPSS) chronic myelomonocytic leukaemia with 10–29% marrow blasts without myeloproliferative disorder or acute myeloid leukaemia with 20–30% blasts and multilineage dysplasia, according to the World Health Organization classification. The key drivers for this recommendation were as follows: A set of clear and objective clinical characteristics defining the eligibility of patients to receive chemotherapy had not been agreed among haematologists. Therefore, the Committee could not make recommendations based on any of the separate conventional care regimen groups. The ICER for azacitidine compared with a weighted average of the conventional care regimens was too high, even taking into account end of life considerations.		1.1 -1.2
Current practice
Clinical need of patients, including the availability of alternative treatments	Best supportive care, low-dose and standard-dose chemotherapy are currently being used to treat patients with myelodysplastic syndromes, chronic myelomonocytic leukaemia or acute myeloid leukaemia who cannot receive stem cell transplantation.	4.2
	However, a set of clear and objective clinical characteristics defining the eligibility of patients to receive chemotherapy had not been agreed among haematologists.	4.2
	Fatigue and a reduced ability to perform normal activities of daily living are common in these conditions and have a negative impact on patients’ quality of life. Dependence on blood transfusions is an important aspect of these conditions and also has a negative impact on quality of life.	4.3
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 and how it might improve the way that current need is met (is this a ‘step-change’ in the management of the condition)	The Committee concluded on the basis of the clinical-effectiveness evidence and the evidence from the clinical specialists and patient experts that azacitidine is a clinically effective treatment for myelodysplastic syndromes, chronic myelomonocytic leukaemia and acute myeloid leukaemia.	4.8
	Compared with other treatment options, azacitidine is associated with relief from fatigue, fewer hospitalisations because of infections, decreased need for blood and platelet transfusion, and increased ability to perform normal activities of daily living.	4.7
What is the position of the treatment in the pathway of care for the condition	Azacitidine is licensed as first line treatment for myelodysplastic syndromes, chronic myelomonocytic leukaemia or acute myeloid leukaemia and would replace best supportive care, low-dose and standard-dose chemotherapy.	4.2
Adverse effects	Common adverse events associated include peripheral blood cytopenias, myelosuppression, nausea, vomiting and injection site reactions. The patient experts and clinical specialists agreed that these adverse events are generally well tolerated.	4.7
Evidence for clinical effectiveness
Availability, nature and quality of evidence	The Committee concluded that problems created by loss of patients to follow-up in the pivotal trial may have introduced bias into the estimates of relative effectiveness, but that this effect was likely to be minimal.	4.5
	The Committee concluded that the estimates of total overall survival against conventional care appeared robust.	4.5
	The role of patient preference in the pivotal trial did not affect the way in which the trial results or subsequent analyses should be considered.	4.6
Relevance to general  clinical practice in the NHS	The comparator therapies used in the pivotal trial broadly represented the treatment patients with these conditions receive in the UK	4.4
Uncertainties generated by the evidence	The small patient numbers limited the precision of the outcome estimates in the low-dose and standard-dose chemotherapy groups.	4.5
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness	The manufacturer reported that in a subgroup analysis of patients with the –7/del(7q) chromosomal abnormality, median overall survival was higher in patients receiving azacitidine than in patients receiving conventional care regimens.	3.3
Estimate of the size of the clinical effectiveness including strength of supporting evidence	The Committee concluded on the basis of the clinical-effectiveness evidence and the evidence from the clinical specialists and patient experts that azacitidine is a clinically effective treatment for myelodysplastic syndromes, chronic myelomonocytic leukaemia and acute myeloid leukaemia.	4.8
Evidence for cost effectiveness
Availability and nature of evidence	No quality of life data were collected in the pivotal trial, although EORTC data collected in the CALGB 9221 trial suggested improvements in overall health with azacitidine.	4.7
	The use of a weighted average for the comparator was associated with significant methodological limitations. However, taking into account the limitations of the available evidence and in the absence of a satisfactory alternative, the Committee hesitantly concluded that any decision on the cost effectiveness of azacitidine would need to be made using the weighted average.	4.19
	The data from the HMRN registry contained data that provided the most representative estimates of the proportions of patients receiving each of the comparator treatment regimens to use in the calculation of the weighted average.	4.21
Uncertainties around and plausibility of assumptions and inputs in the economic model	The Committee concluded that the analyses incorporating estimated vial sharing did not produce plausible results and therefore would not form the basis for its decision on the use of azacitidine in the NHS.	4.9
	The Committee concluded that the Weibull distribution generally provided the best overall fit to the Düsseldorf registry long-term survival data.	4.10
	The Committee concluded that it was uncertain if the utility values used in the model under- or over-estimated the true utility values associated with myelodysplastic syndromes.	4.12
	The Committee noted that both the total costs and total QALY gain for azacitidine differed dependent on which care regimen it was being compared with. It considered that this variation added to the uncertainty in the model.	4.16
Incorporation of health-related quality of life benefits and utility values Have any potential significant and substantial health-related benefits been identified that were not included in the QALY calculation, and how have these been separately evaluated and what is the impact (if any) on the judgement of the most plausible ICER.	The Committee concluded that because the algorithm had been developed using data from patients with oesophageal cancer, the values would be associated with greater uncertainty than if a validated algorithm based on patients with myelodysplastic syndromes, chronic myelomonocytic leukaemia and acute myeloid leukaemia had been used.	4.11
	The Committee concluded that the utility values used in manufacturer’s base case may not have captured the effects of transfusion dependence and fatigue. However, the ICER was only minimally affected by changes in the utility values.	4.13
	The Committee agreed that the utility values provided by MDS UK following the appeal did not provide better estimates of the gains in health-related quality of life than the manufacturer’s previous estimates.	4.13
Are there specific groups of people for whom the technology is particularly cost-effective?	No cost-effectiveness evidence was presented for the subgroup of patients with the –7/del(7q) chromosomal abnormality.	4.15
What are the key drivers of cost effectiveness?	The ICER estimate was only minimally affected by the changes in health-related quality of life.	4.13
Most likely cost-effectiveness estimate (given as an ICER)	Taking into account the limitations associated with the use of a weighted average and the uncertainty associated with the proportions reported, the Committee concluded that £58,900 per QALY gained represented the lower limit of the most plausible estimate of the cost effectiveness of azacitidine.	4.21
Additional factors taken into account
Patient Access Schemes (PPRS)	The manufacturer has agreed a patient access scheme with the Department of Health, in which azacitidine for the treatment of myelodysplastic syndromes, chronic myelomonocytic leukaemia and acute myeloid leukaemia will be available with a 7% reduction in the acquisition cost.	2.4
End of life considerations	The Committee concluded that azacitidine meets the criteria for being a life-extending, end-of-life treatment, but it considered that the additional weight that would need to be assigned to the original QALY benefits in this patient group for the cost effectiveness of the drug to fall within the current threshold range would be too great.	4.24
Equalities considerations	The Committee noted that azacitidine may be of specific benefit to those who, for clinical or religious reasons, are unable to receive blood transfusions, because patients treated with azacitidine required fewer blood transfusions than patients treated with best supportive care. However, the Committee noted that no representations had been made or evidence received about the pathway of care for the particular group of patients, or about the effectiveness of azacitidine in this patient population. The Committee considered that because the most plausible ICER for azacitidine in the general patient population was approximately £59,000 per QALY gained, it would be inappropriate to make recommendations for a subgroup of patients unable to receive blood transfusions without any evidence of azacitidine’s cost effectiveness in that subgroup of patients.	4.25

Implementation

5.1 The Secretary of State and the Welsh Assembly Minister for Health and Social Services have issued directions to the NHS in England and Wales on implementing NICE technology appraisal guidance. When a NICE technology appraisal recommends use of a drug or treatment, or other technology, the NHS must usually 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. When there is no NICE technology appraisal guidance on a drug, treatment or other technology, decisions on funding should be made locally.

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/TAXXX). [NICE to amend list as needed at time of publication]

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

Proposed recommendations for further research

6.1 The Committee recommends that a study estimating utility values using directly observed health-related quality of life values (such as EQ‑5D scores) in patients with myelodysplastic syndromes, chronic myelomonocytic leukaemia or acute myeloid leukaemia is conducted.

Related NICE guidance

Published:

• Improving outcomes in haematological cancers. NICE cancer service guidance (2003). Available from csgho

Proposed date for review of guidance

8.1 NICE proposes that the guidance on this technology is considered for review by the Guidance Executive in February 2014. 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.

Ken Stein
Vice 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.

Professor Keith Abrams
Professor of Medical Statistics, University of Leicester

Dr Amanda Adler (Chair from September 2009)
Consultant Physician, Addenbrooke's Hospital, Cambridge

Dr Ray Armstrong
Consultant Rheumatologist, Southampton General Hospital

Dr Jeff Aronson
Reader in Clinical Pharmacology, University Department of Primary Health Care, University of Oxford

Dr Darren Ashcroft
Reader in Medicines Usage and Safety, School of Pharmacy and Pharmaceutical Sciences, University of Manchester

Professor David Barnett (Chair until September 2009)
Professor of Clinical Pharmacology, University of Leicester

Dr Peter Barry
Consultant in Paediatric Intensive Care, Leicester Royal Infirmary

Dr Michael Boscoe
Consultant Cardiothoracic Anaesthetist, Royal Brompton and Harefield NHS Foundation Trust

Professor John Cairns
Professor of Public Health and Policy, London School of Hygiene and Tropical Medicine

Dr Mark Chakravarty
External Relations Director, Pharmaceuticals and Personal Health, Oral Care Europe

Dr Martin Duerden
Medical Director, Conwy Local Health Board

Dr Fergus Gleeson
Consultant Radiologist, Churchill Hospital, Oxford

Ms Sally Gooch
Independent Nursing and Healthcare Consultant

Mrs Eleanor Grey
Lay member

Mr Sanjay Gupta
Former Service Manager in Stroke, Gastroenterology, Diabetes and Endocrinology, Basildon and Thurrock University Hospitals Foundation NHS Trust

Dr Neil Iosson
General Practitioner

Dr Rosa Legood
Lecturer, London School of Hygiene and Tropical Medicine

Mr Terence Lewis
Lay member

Professor Gary McVeigh
Professor of Cardiovascular Medicine, Queen’s University, Belfast

Dr Ruairidh Milne
Director of Strategy and Development and Director for Public Health Research at the NIHR Evaluation, Trials and Studies Coordinating Centre at the University of Southampton

Dr Rubin Minhas
General Practitioner and Clinical Director, BMJ Evidence Centre

Dr Peter Norrie
Principal Lecturer in Nursing, DeMontfort University

Mr Stephen Palmer
Senior Research Fellow, Centre for Health Economics, University of York

Dr Sanjeev Patel
Consultant Physician and Senior Lecturer in Rheumatology, St Helier University Hospital

Dr John Pounsford
Consultant Physician, Frenchay Hospital, Bristol

Mr Philip Pugh
Strategic Development Lead for Healthcare Associated Infection and Antimicrobial Resistance, Health Protection Agency

Dr Casey Quinn
Lecturer in Health Economics, Division of Primary Care, University of Nottingham

Dr John Rodriguez
Assistant Director of Public Health, NHS Eastern and Coastal Kent

Mr Alun Roebuck
Consultant Nurse in Critical and Acute Care, United Lincolnshire NHS Trust

Dr Florian Alexander Ruths
Consultant Psychiatrist and Cognitive Therapist at the Maudsley Hospital, London

Mr Navin Sewak
Primary Care Pharmacist, NHS Hammersmith and Fulham

Dr Stephen Saltissi
Consultant Cardiologist, Royal Liverpool University Hospital

Dr Lindsay Smith
General Practitioner, East Somerset Research Consortium

Mr Roderick Smith
Finance Director, West Kent Primary Care Trust

Mr Cliff Snelling
Lay member

Professor Ken Stein (Vice Chair)
Professor of Public Health, Peninsula Technology Assessment Group (PenTAG), University of Exeter

Professor Andrew Stevens
Professor of Public Health, Department of Public Health and Epidemiology, University of Birmingham

Dr Rod Taylor
Associate Professor in Health Services Research, Peninsula Medical School, Universities of Exeter and Plymouth

Ms Nathalie Verin
Health Economics Manager, Boston Scientific UK and Ireland

Dr Colin Watts
Consultant Neurosurgeon, Addenbrooke’s Hospital, Cambridge

Mr Tom Wilson
Director of Contracts and Information Management and Technology, Milton Keynes Primary Care Trust

B 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.

Whitney Miller
Technical Lead

Joanne Holden, Bhash Naidoo and Prashanth Kandaswamy
Technical Advisers

Jeremy Powell
Project Manager

Appendix B: Sources of evidence considered by the Committee

A The Evidence Review Group (ERG) report for this appraisal was prepared by the West Midlands Health Technology Assessment Collaboration:

• Edlin R, Connock M, Round J et al. Azacitidine for the treatment of myelodysplastic syndrome, chronic myelomonocytic leukaemia, and acute myeloid leukaemia, April 2009

The Decision Support Unit (DSU) prepared two reports for this appraisal:

• Miners A. DSU report for NICE – Azacitidine STA economic model 09/12/09, December 2009
• Davis S, Wailoo A and Carroll C. Myelodysplastic syndromes – Azacitidine: A critical appraisal of additional evidence submitted by Celgene and the MDS Foundation, September 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:

• Celgene

II Professional/specialist and patient/carer groups:

• British Committee for Standardisation in Haematology
• British Society for Haematology
• Cancer Research UK
• Leukaemia CARE
• Leukaemia Research Fund
• Leukaemia Society ( UK)
• Macmillan Cancer Support
• MDS Patient Support Group
• Rarer Cancers Forum
• Royal College of Nursing
• Royal College of Pathologists
• Royal College of Physicians, Medical Oncology Joint Special Committee
• United Kingdom Oncology Nursing Society

III Other consultees:

• Department of Health
• Harrow PCT
• Stockton-On-Tees PCT
• Welsh Assembly Government

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

• Department of Health, Social Services and Public Safety for Northern Ireland
• National Collaborating Centre for Cancer
• NHS Quality Improvement Scotland
• Pharmacia
• West Midlands Health Technology Assessment Collaboration
• Winthrop Pharmaceuticals UK

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 azacitidine by attending the initial Committee discussion and providing written evidence to the Committee. They were also invited to comment on the ACD.

• Dr David T Bowen, Consultant Haematologist, nominated by the NCRI Haematological Oncology Clinical Studies Group/RCP/RCR/ACP/JCCO – clinical specialist
• Dr Dominic J Culligan, Consultant Haematologist, nominated by the Royal College of Pathologists and British Committee for Standardisation in Haematology – clinical specialist
• Mr Paul Harford, nominated by MDS UK – patient expert
• Ms Stella Pendleton, nominated by the Rarer Cancers Forum – patient expert
• Professor Rodney Taylor, nominated by the MDS UK Patient Support Group – patient expert
• Ms Sophie Wintrich, nominated by the MDS UK Patient Support Group – patient expert

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

• Celgene