Azacitidine for the treatment of myelodysplastic syndromes, chronic myelomonocytic leukaemia and acute myeloid leukaemia

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

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’ (available at www.nice.org.uk).

The key dates for this appraisal are:

Closing date for comments: 24 August 2009

Second Appraisal Committee meeting: 3 September 2009

Details of membership of the Appraisal Committee are given in appendix A, and a list of the sources of evidence used in the preparation of this document is given in appendix B.

1. Appraisal Committee’s preliminary recommendations

1.1 Azacitidine is not recommended as a treatment option for people with myelodysplastic syndromes, chronic myelomonocytic leukaemia or acute myeloid leukaemia.

1.2 People currently receiving azacitidine for myelodysplastic syndrome, chronic myelomonocytic leukaemia or acute myeloid leukaemia should have the option to continue treatment until they and their clinicians consider it appropriate to stop.

2. 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
• acute myeloid leukaemia with 20–30% blasts and multilineage dysplasia, according to World Health Organization classification.

2.2 Azacitidine is contraindicated in people who have known hypersensitivity to azacitidine or to any of its excipients; in women who are breastfeeding; and in people 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 people 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/m² of body surface area. The SPC states that patients should be pre-medicated with anti-emetics for nausea and vomiting. The cost of azacitidine is £321 for a 100-mg vial (excluding VAT; ‘British national formulary’ [BNF] edition 57). Based on a body surface area of 1.7 m²  and  a dose of 75 mg/m², 9 vials would be required for one cycle. 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 azacitidine and a review of this submission by the Evidence Review Group (ERG; appendix B).

3.1 The main evidence for the efficacy of azacitidine in people 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 (RCT) (AZA-001; n = 358). Before randomisation, patients were preselected for treatment with one of three conventional care regimens: best supportive care, low-dose chemotherapy or standard-dose chemotherapy. Patients receiving a particular conventional care regimen were compared with those who had been preselected for the same respective group but were then randomised to treatment with azacitidine. The manufacturer reports 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. 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 were preselected for best supportive care alone, 49 for low-dose chemotherapy and 25 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 with azacitidine compared with 15.0 months for participants receiving conventional care regimens (p = 0.0001, hazard ratio [HR] 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 [IQR] 8.6 to 36.8, 95% CI 13.6 to 23.6) with azacitidine, compared with 11.5 months (IQR 4.9 to not reached, 95% CI 8.3 to14.5) with conventional care regimens (p < 0.0001, HR 0.50, 95% CI 0.35 to 0.70). The manufacturer reported results within each stratification group. Treatment with azacitidine led to statistically significant improvements in overall survival in all stratification groups, except for patients pre-selected for standard-dose chemotherapy. Only patients preselected for best supportive care demonstrated statistically significant improvement in time to transformation to acute myeloid leukaemia. Of the participants who were dependent on red blood cell transfusions at baseline, 45% of those treated with azacitidine became transfusion-independent during treatment, compared with 11.8% of those receiving conventional care regimens (p < 0.0001). The manufacturer reported that in a subgroup analysis of participants with the –7/del(7q) chromosomal abnormality, median overall survival was higher in patients on azacitidine than in those receiving conventional care regimens.

3.4 The ERG considered the results from the AZA-001 trial to be robust and to indicate a clinical benefit for those 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. These factors could reduce the observed effectiveness of azacitidine. In addition, the ERG noted that the results for the comparison with chemotherapy were less robust because of the small numbers included.

3.5 The manufacturer developed its own economic evaluation, comprising a two-arm health-state transition model. The first arm was designed to capture the costs and outcomes associated with treatment with azacitidine; the second arm was designed to capture the costs and outcomes associated with treatment with conventional care regimens, which included best supportive care alone, low-dose chemotherapy (plus best supportive care), and standard-dose chemotherapy (plus best supportive care), as defined in the AZA-001 trial. All modelled patients entered the model in the myelodysplastic syndrome health state at the start of treatment and left the model at death, irrespective of the treatment regimen. The model used a 35-day cycle with a lifetime horizon.

3.6 The manufacturer’s economic model used data from the AZA-001 trial for its estimates of effectiveness. The manufacturer’s base-case analysis employed a log-logistic parametric function to extrapolate the overall survival observed in the trial. In a sensitivity analysis, the use of a Weibull parametric function was explored. To model the time to progression to acute myeloid leukaemia, the model calculated the pooled time in acute myeloid leukaemia across all treatment arms in the AZA-001 trial, and then subtracted this figure from the overall survival estimates.

3.7 The manufacturer reported that no usable utility data were collected in the AZA-001 trial. For estimates of utility for patients treated with azacitidine, the manufacturer reported that data were acquired from the prospective, open-label, multicentre RCT CALGB 9221 (n = 191), in which patients with myelodysplastic syndromes were treated with either azacitidine or best supportive careand in which European Organisation for Research and Treatment of Cancer (EORTC) scores were collected. This trial was excluded from the clinical effectiveness analysis because the patient population was of a lower-risk category than the population licensed for treatment with azacitidine. The manufacturer transformed the EORTC quality of life data into EQ-5D values by using an algorithm developed using data from patients with oesophageal cancer. For those patients treated with chemotherapy, utility estimates were taken from a publication reporting scores for 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 clinical trial, estimates of resource use were based on expert opinion elicited though a resource use questionnaire. Drug costs were taken from the BNF. NHS costs were taken from the NHS Reference Costs 2006–07 and indexed to 2008 prices using the 2008 pay and price index from the Personal Social Services Research Unit. The cost of treatment using the NHS 2009–10 tariff was presented as a sensitivity analysis. As azacitidine requires a 7-day continuous treatment cycle, which means that patients need treatment over a weekend, the manufacturer stated that additional infrastructure may be required. However, it was assumed in the model that no additional costs would be incurred above the cost of normal administration.

3.9 The manufacturer’s base-case results gave incremental cost-effectiveness ratios (ICERs) for treatment with azacitidine of £51,139 per quality-adjusted life year (QALY) gained for those in the best supportive care group, £47,178 per QALY gained for those in the low-dose chemotherapy group, and £34,207 for those in the standard-dose chemotherapy group. The manufacturer explored uncertainty in a series of one-way and probabilistic sensitivity analyses. The manufacturer explored the effect of using the Weibull distribution to extrapolate survival, which increased the ICERs to £66,209, £63,429 and £45,179 for the best supportive care, low-dose chemotherapy and standard-dose chemotherapy groups respectively. In a sensitivity analysis using the NHS 2009–10 tariff, the ICERs increased to £63,372, £48,658 and £39,510 for the best supportive care, low-dose chemotherapy and standard-dose chemotherapy groups respectively.

3.10 The ERG raised considerable concerns about the face validity of the results of the model relative to the results of the main source of evidence on clinical effectiveness. The overall survival gains attributable to azacitidine observed in the trial were 9.6 months, 9.2 months and 9.4 months for the best supportive care, low-dose chemotherapy and standard-dose chemotherapy groups respectively. For the same respective groups, the model estimated overall survival gains of 33.9 months, 32.3 months and 32.2 months. They explored the effect of the use of alternative parametric distributions in the extrapolation of overall survival data using the Akaike’s Information Criterion (which assesses the goodness of fit of curves). The ERG reported that both the Weibull and exponential distributions provided better fits to the trial data, with the exponential distribution providing the best fit. In no instance did the log-logistic distribution provide the best fit. Therefore, the ERG expressed the view that the use of the log-logistic function in the base case was inappropriate.

3.11 The ERG commented that the modelled time to transformation to acute myeloid leukaemia was different from that observed in AZA-001. They commented that, in order to calculate a reliable estimate of the median time in acute myeloid leukaemia, reliable identification of patients whose cells underwent transformation, and reliable estimates of their time to transformation, were needed. The ERG noted that the observed time to transformation was subject to considerable censoring from loss of patients to follow-up, and considered that the back-calculation performed by the manufacturer did not resolve the problem associated with excessive censoring.

3.12 The ERG noted that the overall mortality rate in the model was derived from the overall survival curves. For health-state-specific mortality, the per-cycle rate for the acute myeloid leukaemia health state was defined by a constant parameter based on the pooled acute myeloid leukaemia mortality rate across all treatment arms. The difference between this and the overall mortality rate was used as the mortality rate in the myelodysplastic syndromes health state. For cycles when the overall mortality was lower than the pre-defined rate used in the acute myeloid leukaemia state, the myelodysplastic syndromes state rate was reduced to zero, and the acute myeloid leukaemia state rate was reduced to match the overall mortality rate. This equated to a 0% probability of death in the myelodysplastic syndromes health state in these cycles. The ERG noted that this occurred in the vast majority of cycles. It noted that this was likely to result in an overestimate of survival in the model.

3.13 The ERG noted several issues with the mapping exercise used to calculate the utilities in the model. The ERG reported that the algorithm used in the mapping exercise was considered by its developers to be less reliable for predicting utility values for patients in more severe health states than alternative algorithms that were explored and rejected by the manufacturer. The ERG noted that this could lead to bias in the results. It also reported that the algorithm had been developed using data from patients with oesophageal cancer. The ERG noted that patients eligible for azacitidine are of a similar age to the patients on whom the algorithm was based. However, the underlying conditions and comorbidities were potentially very different. The ERG stated that the results of the mapping algorithm should be treated with caution.

3.14 The ERG reported that the model included no estimate of age-dependent mortality. It commented that, given the age of the relevant patient population, it would be reasonable to expect that the underlying mortality varies among patients (for example, between people aged 70 years and those aged 90 years). The ERG reported that survival was therefore overestimated in the manufacturer’s model.

3.15 The ERG reported a number of other problems with the model, only some of which it was able to correct. The corrections included the inclusion of per-cycle discount rates (as opposed to yearly rates) and the incorporation of parameter covariance within the model. The ERG was unable to correct for the underestimates of mortality (including the problems related to health-state-specific mortality, the extrapolation of overall mortality and the lack of age-specific mortality), or to explore the impact of alternative assumptions about adverse events and the modelled time horizon. The ERG reported corrected results for the manufacturer’s base case similar to those provided by the manufacturer, but it noted that, because of the problems remaining with the model, there was large uncertainty around the results of the manufacturer’s economic submission.

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

4. Consideration of the evidence

4.1 The Appraisal Committee 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 people with the conditions, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.

Clinical effectiveness

4.2 The Committee considered the treatment pathway in the UK for patients with myelodysplastic syndrome, chronic myelomonocytic leukaemia or acute myeloid leukaemia. The Committee heard from the clinical specialists that current treatment for this group of patients most often consists of best supportive care, with approximately only 10% patients able to tolerate chemotherapy.  

4.3 The Committee considered the clinical effectiveness evidence presented by the manufacturer from the pivotal AZA-001 trial. The Committee understood that in AZA-001 patients were selected for treatment with one of the conventional care regimens based on age, Eastern Cooperative Oncology Group (ECOG) performance status and the presence of comorbidities prior to randomisation, and that patients randomised to treatment with azacitidine were stratified according to their pre-randomisation regimen. The Committee noted that this method of randomisation resulted in low patient numbers in the low-dose chemotherapy and standard-dose chemotherapy stratification groups. The Committee heard from the clinical specialists that the design of the AZA-001 trial reflects standard practice in the UK with regard to determining patient eligibility for chemotherapy, and that the proportion of patients in each stratification group broadly represents the spectrum of patients with these conditions treated in the UK. The Committee understood that the small patient numbers in the chemotherapy stratification groups introduced a degree of uncertainty into the estimates of overall survival within each group, but concluded that the trial results could be generalised to UK clinical practice.

4.4 The Committee noted that the median overall survival for patients receiving azacitidine was longer than for those receiving the conventional care regimens. The Committee further noted that median time to transformation to acute myeloid leukaemia and the percentage of patients becoming independent of blood transfusions were greater for patients receiving azacitidine than for those receiving the conventional care regimens. The Committee noted that when outcomes were analysed by stratification group, the difference in overall survival between the treatment arms in the standard-dose chemotherapy stratification group favouring azacitidine was not statistically significant, nor were the differences between the treatment arms in the estimates of time to transformation to acute myeloid leukaemia in the low-dose and standard-dose chemotherapy groups. The Committee was mindful that the small patient numbers limited the precision of the outcome estimates by stratification group, but concluded that the estimates of total overall survival appeared robust. The Committee noted that the problems relating to loss to follow-up, as described by the ERG (see section 3.4), may have introduced bias into estimates of relative effectiveness, but concluded that this effect was likely to be minimal.

4.5 The patient experts stated that treatment with 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 included 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 the AZA-001 trial, although such data collected in CALGB 9221 suggested improvements in overall health with azacitidine.

4.6 The Committee concluded on the basis of the clinical-effectiveness evidence and the testimony 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

4.7 The Committee considered evidence on the cost effectiveness of azacitidine for the treatment of myelodysplastic syndrome, chronic myelomonocytic leukaemia, and acute myeloid leukaemia. It understood that, given the patient distribution in the UK, best supportive care was the most appropriate comparator. The Committee considered that chemotherapy was not an appropriate comparator since there was limited evidence of statistically significant clinical effectiveness. In addition, the Committee noted that chemotherapy was only used in a minority of patients and the clinical specialists stated that most of these patients go on to receive stem cell transplantation and are therefore not eligible to receive azacitidine. The Committee was mindful of difficulties with identifying patients eligible for chemotherapy in clinical practice. It also noted that no cost-effectiveness evidence was presented for the subgroup of patients with chromosome 7 abnormalities.

4.8 The Committee noted the ERG’s considerable concerns about the manufacturer’s model, principally relating to the validity of its prediction of clinical events compared with the data available from AZA-001, and to the course of the condition. 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 model used the log-logistic distribution to extrapolate overall survival from the trial data. It noted that better fits to the trial data were provided by the exponential or Weibull distributions, with the exponential distribution generally providing the best fit. The clinical specialists stated that the modelled survival times using either the exponential or the Weibull distributions appeared to better represent clinical reality than those suggested in the manufacturer’s base case using the log-logistic distribution. The Committee understood that both the Weibull and exponential distributions produced lower estimates of overall survival than the log-logistic, and noted that the use of the log-logistic function predicted that an appreciable number of patients would live into their tenth decade. The Committee concluded that the model probably overestimated the gain in overall survival attributable to treatment with azacitidine. It noted that the degree of overestimation was not known. The Committee further concluded that the manufacturer’s sensitivity analysis, in which it used the Weibull distribution, produced a more plausible estimate of the ICER of approximately £66,000 per QALY gained for the comparison with best supportive care.

4.9 The Committee considered the ERG’s concerns that the manufacturer’s estimate of patients’ quality of life included in the model lacked face validity. The patient experts and clinical specialists stated that treatment with azacitidine reduces symptoms (such as fatigue) and the need for blood transfusions, both of which are probably associated with a degree of disutility. The Committee noted that the manufacturer’s model produced small gains in health-related quality of life as a result of treatment with azacitidine, and that greater independence from blood transfusions was not included in the utility estimate. It noted that the manufacturer had estimated utility by mapping to the EQ-5D, and that the EQ-5D does not include fatigue as a dimension, although some effects of this symptom on ability to undertake normal activities would be captured. The Committee considered that reduced fatigue resulting from treatment with azacitidine may not have been completely captured in the modelled utility values. The Committee was mindful of the ERG’s concerns over the mapping of EORTC values to EQ-5D. The Committee was aware that mapping is associated with greater uncertainty than directly elicited values. Additionally, the Committee considered that because the mapping algorithm had been developed using data from patients with oesophageal cancer, the resultant values would be associated with greater uncertainty than would those derived from a validated algorithm based on patients with myelodysplastic syndrome. The Committee concluded that the manufacturer’s model may have underestimated the gains in health-related quality of life resulting from treatment with azacitidine, but noted that the degree of underestimation was not known. It also concluded that because the estimation of the ICER is largely driven by the incremental life years gained and is only minimally affected by the changes in health-related quality of life, the impact of this underestimation is likely to be small, and would not offset the overestimation of overall survival.

4.10 The Committee noted the ERG’s concerns over the modelling of time to transformation to acute myeloid leukaemia. The Committee noted that the modelled time to transformation was shorter than that observed in the clinical trial. The Committee considered that this could impact on total treatment costs as 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 noted that the use of the NHS 2009–10 tariff in sensitivity analyses increased the manufacturer’s base-case estimate of the ICER by approximately £12,000. The Committee noted that, in this case, the tariff was potentially more appropriate to use than reference costs, as it could provide a more precise estimate of hospital costs by breaking down those costs attributable to adverse events. The Committee considered that, together, these issues raised further concerns about the validity of the model, and that the ICERs for azacitidine are probably underestimated.

4.11 The Committee decided that it could not conclude on a final cost-effectiveness estimate. However, the Committee considered that the combination of the issues surrounding the extrapolation of overall survival, the estimation of time to progression and the assumed NHS costs would result in an ICER significantly higher than the manufacturer’s base case of £66,000 per QALY. The Committee considered it unlikely that such an increase would be offset by any potential decrease resulting from a resolution of the problems with estimating quality of life.

4.12 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.
• No alternative treatment with comparable benefits is available through the NHS.
• 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.

4.13 The Committee discussed whether the benefit provided by azacitidine for the treatment of myelodysplastic syndromes, chronic myelomonocytic leukaemia, or acute myeloid leukaemia fulfilled the criteria for consideration as a life-extending, end-of-life treatment. The Committee understood that the total number of people with IPSS intermediate-II and high-risk myelodysplastic syndromes in England and Wales was approximately 700. The Committee considered that life expectancy with best supportive care alone was likely to be approximately 11.5 months. It considered the evidence from the AZA-001 trial and noted that the median overall survival for patients treated with azacitidine in the best supportive care stratification group was 21.1 months. The Committee agreed that azacitidine provided an improvement in 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. However, the Committee remained concerned about the uncertainty in the manufacturer’s estimates of cost effectiveness. It concluded that the estimates of the ICER were not sufficiently robust to meet the criteria needed for a life-extending, end-of-life treatment. It further concluded that even if the problems with the manufacturer’s model were corrected so as to improve the robustness of the estimates, any potential decreases in the ICER would probably not be large enough to sufficiently offset the likely increase resulting from the specification of the appropriate parametric distribution for estimating overall survival. The Committee therefore concluded that, with a likely ICER exceeding £66,000 per QALY gained, azacitidine for the treatment of myelodysplastic syndromes, chronic myelomonocytic leukaemia and acute myeloid leukaemia would not be a cost-effective use of NHS resources.

4.14 The Committee considered whether there were any subgroups of patients for whom azacitidine would be considered a cost-effective use of NHS resources, and 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 those 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 those treated with best supportive care. However, the Committee noted that no representations had been made or evidence received regarding the pathway of care for people with myelodysplastic syndromes, chronic myelomonocytic leukaemia or acute myeloid leukaemia who are unable to receive blood transfusions, or regarding the effectiveness of azacitidine in this patient population. The Committee considered that since the most plausible ICER for azacitidine in the general patient population was above £66,000 per QALY gained, it would be inappropriate to make any recommendations for specific subgroups without any evidence on how the characteristics of those subgroups affect the estimates of azacitidine’s cost effectiveness. The Committee therefore concluded that it could not recommend the use of azacitidine in specific subgroups of patients with myelodysplastic syndromes, chronic myelomonocytic leukaemia, or acute myeloid leukaemia.

5. Implementation

5.1 The Secretary of State and the Welsh Assembly Minister for Health and Social Services have issued directions to the NHS on implementing NICE technology appraisal guidance. When a NICE technology appraisal recommends use of a drug or treatment, or other technology, the NHS must provide funding and resources for it within 3 months of the guidance being published. If the Department of Health issues a variation to the 3-month funding direction, details will be available on the NICE website. The NHS is not required to fund treatments that are not recommended by NICE.

5.2 NICE has developed tools to help organisations put this guidance into practice (listed below). These are available on our website (www.nice.org.uk/TAXXX).

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

6. Proposed recommendations for further research

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

7. Related NICE guidance

Published

• Improving outcomes in haematological cancers. Cancer service guidance (2003). Available from: guidance.nice.org.uk/CSGHO

8. 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 November 2012. 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.

David Barnett
Chair, Appraisal Committee
July 2009

Appendix A: Appraisal Committee members and NICE project team

A. Appraisal Committee members

The Appraisal Committee is one of NICE’s standing advisory committees. Its members are appointed for a 3-year term. A list of the Committee members who took part in the discussions for this appraisal appears below. The Appraisal Committee meets three times a month except in December, when there are no meetings. The Committee membership is split into three branches, each with a chair and vice chair. Each branch considers its own list of technologies, and ongoing topics are not moved between the branches.

Committee members are asked to declare any interests in the technology to be appraised. If it is considered there is a conflict of interest, the member is excluded from participating further in that appraisal.

The minutes of each Appraisal Committee meeting, which include the names of the members who attended and their declarations of interests, are posted on the NICE website.

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)
Professor of Clinical Pharmacology, University of Leicester

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

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

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

Dr Martin Duerden
Medical Director, Conwy Local Health Board

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

Mr Terence Lewis
Lay Member, Mental Health Consultant, National Institute for Mental Health in England

Professor Gary McVeigh
Professor of Cardiovascular Medicine, Queens 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 Neil Milner
General Practitioner, Tramways Medical Centre, Sheffield

Dr John Pounsford
Consultant Physician, Frenchay  Hospital, Bristol

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

Mr Tom Wilson
Director of Contracts and Information Management and Technology, Milton Keynes PCT

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

Prashanth Kandaswamy
Technical Adviser

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

B. The following organisations accepted the invitation to participate in this appraisal. 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 advocate 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 are 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