Lenalidomide for treating myelodysplastic syndromes associated with a deletion 5q cytogenetic abnormality

 

1   Appraisal Committee’s preliminary recommendations

1.1  Lenalidomide is not recommended within its marketing authorisation, that is, for treating transfusion-dependent anaemia caused by low or intermediate-1 risk myelodysplastic syndromes associated with a deletion 5q cytogenetic abnormality when other therapeutic options are insufficient or inadequate.

1.2  People currently receiving treatment initiated within the NHS with lenalidomide that is not recommended for them by NICE in this guidance should be able to continue treatment until they and their NHS clinician consider it appropriate to stop.

2    The technology

2.1   Lenalidomide (Revlimid, Celgene) is a structural analogue of thalidomide. It has anti‑neoplastic, anti‑angiogenic, pro‑erythropoeitic and immunomodulatory properties. Lenalidomide inhibits the proliferation of certain haematopoietic tumour cells, enhances T cell- and natural killer cell-mediated immunity, increases fetal haemoglobin production by CD34+ haematopoietic stem cells and inhibits production of pro-inflammatory cytokines. Lenalidomide has a marketing authorisation ‘for the treatment of patients with transfusion-dependent anaemia due to low- or intermediate-1-risk myelodysplastic syndromes associated with an isolated deletion 5q cytogenetic abnormality when other therapeutic options are insufficient or inadequate’.

2.2  The summary of product characteristics lists the following adverse reactions for lenalidomide: fatigue, neutropenia, constipation, diarrhoea, muscle cramp, anaemia, thrombocytopenia and rash. The summary of product characteristics recommends a starting dose of 10 mg on days 1 to 21, every 28 days and dose reductions (5.0 mg, 2.5 mg or 2.5 mg every other day) to manage adverse events. Because lenalidomide is structurally related to thalidomide, a known human teratogen that causes severe birth defects, a risk minimisation plan has been developed and agreed with the Medicines and Healthcare products Regulatory Agency to avoid fetal exposure to lenalidomide. For full details of adverse reactions and contraindications, see the summary of product characteristics.

2.3  Lenalidomide is available in 21‑day packs of 10 mg and 5 mg capsules at net prices of £3780 and £3570 respectively (excluding VAT; 'British national formulary' [BNF] edition 67). The recommended starting dose of lenalidomide is 10 mg orally once daily on days 1 to 21 of repeated 28‑day cycles. Dosage is continued or modified based on clinical and laboratory findings. The cost of a 28‑day cycle of treatment with 10 mg of lenalidomide (excluding VAT) is £3780. Costs may vary in different settings because of negotiated procurement discounts. The manufacturer of lenalidomide has agreed a standard patient access scheme with the Department of Health, in which the NHS pays for lenalidomide treatment for all patients up to 26 monthly cycles.  The manufacturer of lenalidomide (Celgene) subsequently provides free of charge lenalidomide for those patients who receive more than 26 monthly cycles. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.

3   The manufacturer’s submission

The Appraisal Committee (section 8) considered evidence submitted by the manufacturer of lenalidomide and a review of this evidence by the Evidence Review Group (ERG; section 9).

Clinical effectiveness

3.1  The manufacturer performed a systematic review of the evidence on the clinical effectiveness of lenalidomide for patients with low- or intermediate-1 risk myelodysplastic syndromes (MDS) associated with a deletion 5q cytogenetic abnormality whose condition is red blood cell transfusion dependent. The review identified a single phase III, randomised, double-blind study (MDS‑004), which compared lenalidomide 10 mg (n=69) and lenalidomide 5 mg (n=69) with placebo (n=67). Treatment was given every day of a 28‑day cycle, except in the lenalidomide 10 mg arm, in which 10 mg lenalidomide was given on days 1–21 only. MDS‑004 was a multinational study that enrolled patients from 37 study sites including the UK, France, Germany, Italy, Spain, Belgium, Netherlands, Sweden and Israel. The study population comprised adults with MDS whose condition was transfusion dependent and who had International Prognostic Scoring System (IPSS) of low-risk (49%) or intermediate-1 risk (51%) MDS with a deletion 5q cytogenetic abnormality. Patients were stratified according to IPSS karyotype score (0 versus >0; that is, isolated deletion 5q cytogenetic abnormality versus isolated deletion 5q cytogenetic abnormality [76.3%] plus 1 or more additional cytogenetic abnormalities [23.7%]). In the MDS-004 study, 51.8% of the total patient population had had previous erythropoietin therapy (58.5% in the 10 mg lenalidomide treatment arm).

3.2   People in MDS‑004 who had at least a minor erythroid response (that is, a 50% decrease in transfusion requirements) by week 16 could continue treatment (double-blind) for up to 52 weeks, or until erythroid relapse, disease progression or unacceptable toxicity. People receiving placebo or lenalidomide 5 mg who didn’t have a minor erythroid response by week 16 could cross over to the lenalidomide 5 mg or 10 mg treatment arms, respectively. Open-label treatment was then continued for up to 156 weeks of total study duration. People with disease progression at any time and those randomly assigned to lenalidomide 10 mg without minor erythroid response by week 16 were withdrawn from the study and were ineligible for open-label treatment. The manufacturer stated that the lenalidomide dose was reduced if dose-limiting toxicities occurred, and complete blood counts were obtained weekly after the development of dose-limiting Grade 3 or 4 neutropenia or thrombocytopenia.

3.3  Three study populations were defined in MDS‑004: the intention-to-treat (ITT) population, the safety population and the modified-ITT (mITT) population. The ITT population included all randomised patients (n=205). The safety population included all randomised patients who received at least 1 dose of study drug (n=205). The mITT population included patients with low- or intermediate-1 risk MDS with deletion 5q and documented red blood cell transfusion dependence, who received at least 1 dose of study drug (n=139). Confirmation of deletion 5q status (karyotype analysis) and bone marrow morphology was performed by haematological review after randomisation. Therefore some patients not fulfilling the inclusion criteria (that is, people without confirmed deletion 5q status) were included in the ITT population. For the mITT population, 76.3% of patients had an isolated deletion 5q cytogenetic abnormality and 23.7% had deletion 5q plus one or more additional cytogenetic abnormalities. The baseline characteristics of the patients in the treatment arms for the mITT population were similar.

3.4  The primary end point of the MDS‑004 trial was transfusion independence lasting for at least 26 consecutive weeks. Secondary end points included erythroid response at 16 weeks, duration of red blood cell transfusion independence, cytogenetic response at weeks 12, 24 and every 24 weeks thereafter, overall survival, progression to acute myeloid leukaemia (AML) and adverse events. Health-related quality of life was assessed using the Functional Assessment of Cancer Therapy-Anaemia (FACT‑An) questionnaire at weeks 12, 24, 36 and 48.

3.5   For the double-blind phase of MDS‑004, statistically significantly more patients in the mITT population were transfusion independent for at least 26 weeks with lenalidomide 10 mg (56.1%) and 5 mg (42.6%) than with placebo (5.9%; p<0.001 compared with both lenalidomide groups). Using the International Working Group (IWG) 2000 and 2006 criteria for erythroid response, transfusion independence rates for at least 8 weeks in the mITT population were also statistically significantly higher for the lenalidomide 5 mg and 10 mg treatment groups compared with placebo. Similar results were obtained for the ITT population. Median duration of transfusion independence of at least 8 weeks was not reached in the lenalidomide 5 mg or 10 mg treatment groups.

3.6  In the safety population, median time to progression to AML (from date of randomisation to progression to AML, death, or last known contact for people without AML, whichever was earliest) was 30.9 months (range 2.1–56.5 months) in the placebo group, 36.1 months (range 0.4–57.7 months) in the lenalidomide 10 mg group and 31.8 months (range 0.8–59.4 months) in the lenalidomide 5 mg group. Before crossover at 16 weeks, 2 patients (3.0%) in the placebo group, 0 in the lenalidomide 10 mg group and 2 (2.9%) in the lenalidomide 5 mg group had progressed to AML. Overall, 52 patients (25.4%) progressed to AML during the double-blind and open-label phases. The cumulative risk of AML for the lenalidomide 5 mg and 10 mg groups combined was 16.8% (95% CI 9.8–23.7) at 2 years and 25.1% (95% CI 17.1–33.1) at 3 years. Of 11 patients who were randomly assigned to placebo and never received lenalidomide, including 3 patients who completed 52 weeks of the study protocol, 4 (36.4%) progressed to AML. Of the patients who initially received placebo and then crossed over to lenalidomide 5 mg, 30.4% (17 out of 56) progressed to AML, as did 23.2% (16 out of 69) patients in the lenalidomide 5 mg group and 21.7% (15 out of 69) patients in the lenalidomide 10 mg group.

3.7   The median duration of overall survival follow-up in the safety population was 35.9 months (range 2.1–56.5 months) in the placebo group, 36.9 months (range 0.4–57.7 months) in the lenalidomide 10 mg group and 35.5 months (range 1.9–59.4 months) in the lenalidomide 5 mg group. Based on Kaplan-Meier curves, the median length of overall survival was 42.4 months in the lenalidomide 10 mg group (95% CI 31.9 to not reached), 35.5 months in the 5 mg group (95% CI 24.6 to not reached), and 44.5 months (95% CI 35.5 to not reached) in the placebo group. The manufacturer stated that overall survival was similar between patients included in and excluded from the mITT population (p=0.9218).The manufacturer did not adjust the overall survival results using formal statistical methods for any treatment crossover that occurred.

3.8  In MDS‑004, cytogenetic response was assessed using IWG 2000 criteria. Cytogenetic responses help to establish the degree to which the natural history of myelodysplastic syndromes may be affected by therapy. Cytogenetic response (complete plus partial) rates in the mITT population were 50% in the lenalidomide 10 mg group and 25% in the 5 mg group, respectively. No cytogenetic responses occurred in the placebo group (p<0.001 compared with both lenalidomide groups). Cytogenetic progression (development of new independent clones as well as additional aberrations together with deletion 5q) was observed in 23.5% of patients treated with lenalidomide 10 mg (p=0.50 compared with placebo), 31.3% in patients treated with lenalidomide 5 mg (p=0.17 compared with placebo), and 14.3% of patients receiving placebo. Similar results were observed in the ITT population. Median time to cytogenetic progression was 93 days (range 85–170 days) in the lenalidomide 10 mg group, 85 days (range 83–339 days) in the lenalidomide 5 mg group, and 99 days (range 83–172 days) in the placebo group.

3.9  Health-related quality of life data were collected for 167 patients in MDS‑004 using the FACT‑An questionnaire. Baseline and week 12 (that is, before crossover) FACT‑An scores were available for 71% of randomly assigned patients (lenalidomide 10 mg, n=48; 5 mg, n=45; placebo, n=52). Mean change in FACT‑An score from baseline to week 12 was statistically significantly higher in the lenalidomide 10 mg (5.8; p<0.05) and 5 mg (5.9; p<0.05) groups than in the placebo group (−2.5).

3.10   The manufacturer reported adverse event rates for the double-blind safety population in MDS‑004. A higher proportion of patients in the lenalidomide 10 mg (95.7%) and 5 mg groups (98.6%) had at least 1 drug-related adverse event compared with the placebo group (49.3%). The most frequently reported drug-related adverse events were neutropenia (14.9% in the placebo group, and 75.4% in each of the lenalidomide groups) and thrombocytopenia (3.0% in the placebo group, 39.1% in the lenalidomide 5 mg group and 47.8% in the lenalidomide 10 mg group). For serious infections, only rates of grade 3 or 4 pneumonia were reported by the manufacturer (1.5% in the placebo group, 1.4% in the lenalidomide 5 mg group and 4.3% in the lenalidomide 10 mg group).

Cost effectiveness

3.11  The manufacturer developed a de novo Markov model that simulated cohorts of people with low- to intermediate-1 risk MDS with deletion 5q receiving lenalidomide 10 mg or best supportive care. The model cycle length was 4 weeks to reflect the dosing interval for lenalidomide treatment and a half-cycle correction was not applied. The time horizon of the model was 20 years based on an average age of 67 years in the MDS‑004 study. An NHS and personal social services perspective was taken and costs and benefits were discounted at 3.5%. The manufacturer provided 4 models in total, the first being the original base-case (model 1), model 2 was provided in response to the first appraisal consultation document, models 3 and 4 were submitted to incorporate the patient access scheme and further revisions to address some concerns raised by the Committee. Sections 3.12 to 3.26 below discuss model 1. Models 2, 3 and 4 are discussed in sections 3.42 to 3.49.

3.12  The model included 13 health states and a death state. The structure was developed to reflect 3 key features of MDS deletion 5q treatment:

·      transfusion dependence or independence

·      need for iron chelation after a certain number of red blood cell transfusions

·      AML progression.

After starting treatment, people move to 3 possible health states relating to transfusion status: transfusion independent and transfusion dependent with or without chelation. Additional states were defined to reflect response to iron chelation, potential hepatic and diabetic complications, and increased risk of cardiac disease caused by red blood cell transfusion. In addition, people who were transfusion dependent or independent with or without complications could develop AML.

3.13  Clinical-effectiveness data from the ITT population in the MDS‑004 study were used in the model. The manufacturer stated that this population more closely matched the NICE scope than the mITT population. It also stated that using the mITT population substantially reduced the amount of available data and that, in this population, no statistically significant differences were observed in key end points between trial arms in MDS‑004. The manufacturer assumed that patients in the lenalidomide group remained on treatment (10 mg per day for 21 days of a 28‑day cycle) until their condition stopped responding to treatment, that is, they became transfusion dependent. Best supportive care was based on the placebo arm of the MDS‑004 study, which included blood transfusions for transfusion-dependent patients. The manufacturer stated that, in UK clinical practice, best supportive care may also include an erythropoiesis stimulating agent (ESA). Therefore, the manufacturer assumed that 28% of patients in the best supportive care group received an ESA for 3 cycles based on the proportion of people in the UK in MDS‑004 who received an ESA before the trial started. In addition, it was assumed that granulocyte colony-stimulating factor (G-CSF) for 3 cycles would be used as part of best supportive care when the condition did not respond to an ESA.

3.14    In the model, treatment response was defined as becoming transfusion independent. The proportion of patients who became transfusion independent for 56 consecutive days (based on IWG 2000 criteria) was 60.9% for the lenalidomide group and 7.5% for the best supportive care group. The response rates for people who received an ESA and a G‑CSF in the best supportive care group (21.7%) were taken from a separate study that reported response rates after combination therapy (Jadersten et al. 2005). However, the manufacturer stated that this was unlikely to be representative of ESA and G‑CSF use in the UK because combination therapy is started after the failure of ESA monotherapy. On the basis of a separate study by Balleari et al. (2006), the manufacturer assumed that response rates to monotherapy with either ESA or a G‑CSF would be half of those to combination therapy (10.8%).

3.15   The duration of response to treatment with lenalidomide and best supportive care in the model was based on patient-level data taken from the MDS‑004 ITT population. Because of patient crossover in MDS‑004, the manufacturer used log-rank tests to determine whether there was a significant difference in response duration according to whether a treatment was provided as first- or second-line treatment in the study. The results showed that the order in which patients received treatment in MDS‑004 did not have a significant impact on duration of response. Parametric response duration curves were fitted to patients in the lenalidomide 10 mg treatment arm in MDS‑004 to estimate response duration in the lenalidomide group. The manufacturer stated that response duration curves could not be estimated for people in the placebo arm because of insufficient numbers of people whose condition responded to treatment (n=5). Therefore, the manufacturer used data from the lenalidomide 5 mg treatment arm in MDS‑004 to approximate duration of response to best supportive care. Based on goodness-of-fit tests using the Integrated Brier Score and Akaike Information Criterion, the log-normal distribution was fitted to both response duration curves.

3.16  The manufacturer assumed that people in the transfusion-dependent states in the model received red blood cell and platelet transfusions. On the basis of data from MDS‑004, it was assumed that people needed an average of 1.89 red blood cell transfusions to provide 4.57 red blood cell units and an average of 0.02 platelet transfusions to provide 0.06 platelet units per 28‑day cycle. The manufacturer also assumed that people who were transfusion dependent had an increased risk of cardiac disease, based on the findings of a study by Malcovati et al. (2011). A Gompertz curve was fitted to data from this study to estimate the probability of being transfusion dependent and progressing to cardiac disease.

3.17 The manufacturer assumed that people who were transfusion dependent started iron chelation therapy to avoid complications associated with iron overload. It was assumed that patients started iron chelation therapy when they reached a threshold of 25 red blood cell units. The manufacturer also assumed that people had already received 9.15 red blood cell units per 8 weeks based on the average number of units that people had received before entering the MDS‑004 study. A response rate for iron chelation of 66% was taken from a study by Kontoghiorges et al. (2000) and was assumed to occur in the first cycle of treatment. People who needed iron chelation moved to either the chelation or chelation failure state. The manufacturer assumed that people whose disease responded to treatment continued to receive iron chelation until progression to AML or death. People in the model whose disease did not respond to iron chelation therapy were assumed to be at risk of iron overload complications, including diabetes mellitus and hepatic complications. The probabilities of developing diabetes mellitus (0.21%) and hepatic complications (0.66%) per 28–day cycle on iron chelation were taken from a study by Jaeger et al. (2008).

3.18  The manufacturer stated that survival with MDS is strongly related to transfusion dependence. Data from the MDS‑004 study were used to estimate separate mortality curves for patients who were transfusion dependent or independent at 8 weeks. Based on goodness-of-fit, the Weibull distribution was fitted to data from MDS‑004. The manufacturer stated that crossover of patients in the MDS‑004 study at week 16 precluded any long-term assessment of the impact of lenalidomide on survival and, as a result, using only MDS‑004 study data was likely to result in an underestimate of overall survival. Therefore, the median survival for best supportive care in the model was adjusted to match the combined median survival data reported from a phase II trial, MDS‑003, and the phase III MDS‑004 study, resulting in a figure of 3.8 years.

3.19  The time to progression to AML in the model was taken from an individual patient-level analysis from the MDS‑004 study and was estimated separately for transfusion dependence and independence. On the basis of goodness-of-fit, the Weibull distribution was chosen to estimate time to AML progression curves. AML-related mortality could not be estimated from the MDS‑004 study because the number of people who died from AML was too low. Therefore, the manufacturer used data from a study by Wahlin et al. (2001) of older people with AML, including 113 people with MDS caused by deletion 5q. Although the log-normal function provided the best fit to the data from this study, it also resulted in a 'long tail' whereby some people remained alive for an unrealistically long time. A Weibull distribution was therefore chosen to estimate the survival time for people who developed AML in the model because it did not result in such a 'long tail'.

3.20  The manufacturer included grade 3 or 4 neutropenia and thrombocytopenia episodes in the model, because of differences in these adverse events between the placebo and lenalidomide treatment arms in MDS‑004. The manufacturer stated that it was unlikely that all neutropenia and thrombocytopenia events could be attributed to lenalidomide treatment because MDS is characterised by these peripheral cytopenias. Therefore, the number of people who had neutropenia and thrombocytopenia in the lenalidomide group was adjusted by subtracting those who had these events in the placebo group. The manufacturer assumed that any adverse events in the lenalidomide group occurred only in the first 4 cycles of the model. Based on data from MDS‑004, the manufacturer assumed that only a proportion of patients who had neutropenia (27.7%) and thrombocytopenia (6%) needed additional treatment. The manufacturer did not include other adverse events such as deep vein thrombosis or pulmonary embolism in the model because of the low incidence of these events in MDS‑004.

3.21  The model accounted for 2 periods of treatment interruption during which people in the lenalidomide group did not receive treatment. Based on data from the MDS‑004 ITT population, it was assumed that 68.7% of patients in the lenalidomide group had a first dose interruption and 73.8% had a second dose interruption. The mean time to first treatment interruption was 54.2 days and the length of treatment interruption was 17.5 days. After the first dose interruption, people in the lenalidomide group resumed treatment at a lower dose of 5 mg for 28 days per cycle. The mean time to second treatment interruption (from the start of the first interruption) was 72.1 days and the length of interruption was 13.9 days. After the second dose interruption, people in the lenalidomide group resumed treatment at a lower dose of 5 mg for 14 days per cycle. The cost of lenalidomide treatment was adjusted to take these treatment interruptions into consideration but the manufacturer stated that there was no need for clinical outcomes to be adjusted in a similar way, because the efficacy data for the ITT population used in the model already accounted for these interruptions. The manufacturer presented further analyses on treatment interruptions which is discussed in sections 3.47 and 3.50.

3.22   The MDS‑004 trial assessed health-related quality of life using the EQ-5D at baseline, and the FACT‑An questionnaire at baseline and at weeks 12, 24, 36 and 48. The manufacturer conducted preliminary analyses to explore any relationship between EQ-5D utility values and the FACT‑An. However, regression models to map FACT‑An scores from MDS‑004 to EQ-5D utility values resulted in an unacceptable level of error. Therefore, the manufacturer performed a systematic literature search to identify relevant health-related quality of life data for patients with MDS. Four potentially relevant studies were identified (Buckstein et al. 2009 and 2011, Goss et al. 2006 and Szende et al. 2009). The manufacturer chose to use Szende et al. (2009). In this study, utility data were collected from 47 MDS patients of mean age 67 years (including 21 from the UK) using visual analogue scale and time trade-off methods. People were interviewed to elicit utility values for 3 health states: transfusion independence, reduced transfusion and transfusion dependence. The resulting mean utility values for the UK sample using the time trade-off method were 0.85 for transfusion independence and 0.65 for transfusion dependence. The study did not estimate utility values for the AML state, so the manufacturer assumed that people in the AML state had the same utility value as for transfusion dependence (0.65). Utility values in the model were adjusted by an age-dependent factor taken from Kind et al. (1999). The studies by Buckstein et al. reported EQ-5D utility values for 69 Canadian patients (mean age 73 years) with MDS, resulting in utility values of 0.80 for transfusion independence and 0.63 for transfusion dependence. The study by Goss et al. (2006) reported utility values estimated using the time trade-off technique in 8 US patients with low- and intermediate-1 risk MDS, resulting in utility values of 0.91 for transfusion independence and 0.50 for transfusion dependence. The utility values from both of these studies were used in additional scenario analyses conducted by the manufacturer.

3.23   Utility decrements associated with iron chelation therapy (21% for intravenous iron chelation and 0% for oral chelation) were obtained from a study by McLeod (2009). Utility decrements for adverse events, including cardiac disease (17.9%), diabetes (12.3%) and hepatic complications (8.0%) were obtained from studies by Fryback (1993) and Wong (1995). The model did not incorporate utility decrements for people who had neutropenia and thrombocytopenia episodes. The manufacturer's justification was that these adverse events were likely to have a short-term effect on quality of life.

3.24  The manufacturer’s model (model 1) included drug acquisition, monitoring costs and costs of adverse events. The acquisition costs of lenalidomide were based on the dosing observed in the MDS‑004 trial, which included dose interruption because of adverse events. The costs of ESA (£885 per cycle) and G‑CSF (£633 per cycle) were also included for 28% of patients in the best supportive care group. Drug acquisition prices were obtained from the BNF edition 64. In addition, monitoring costs (including GP visits and blood tests) and transfusion costs (including administration and acquisition of red blood cell and platelet units) were included. The costs of treating AML (£1919.40 per cycle) were taken from Azacitidine for the treatment of myelodysplastic syndromes, chronic myelomonocytic leukaemia and acute myeloid leukaemia (NICE technology appraisal guidance 218). The costs of thrombocytopenia and neutropenia episodes of £1636.38 were taken from NHS reference costs 2011/12. The model also included the annual costs of iron chelation and transfusion-dependent complications, which were taken from the literature. To estimate the costs of iron chelation therapy, the manufacturer assumed that people had either intravenous desferrioxamine (29%) or oral deferasirox (71%) based on prescription cost analysis data for England (2010), resulting in a total cost of £1383.39 per cycle. The frequency of monitoring associated with lenalidomide treatment was taken directly from the summary of product characteristics: GP visits (and blood counts) occurred weekly for the first 8 weeks, bi-weekly for the next 4 weeks and then 4‑weekly thereafter. For best supportive care, monitoring was assumed to occur once every 4 weeks throughout treatment.

3.25    The manufacturer’s model (model 1) estimated 5.69 and 4.53 total undiscounted life years gained with lenalidomide and best supportive care, respectively. The manufacturer's base-case deterministic cost-effectiveness analysis resulted in an incremental cost-effectiveness ratio (ICER) of £56,965 per quality-adjusted life year (QALY) gained for lenalidomide compared with best supportive care (incremental costs £50,582 and incremental QALYs 0.89). The probabilistic cost-effectiveness analysis estimated an ICER of £58,178 per QALY gained. Results of the probabilistic sensitivity analysis showed that at £30,000 per QALY gained, lenalidomide had a 0% probability of being cost effective.

3.26   The manufacturer undertook a series of deterministic sensitivity analyses. The cost-effectiveness estimate of lenalidomide compared with best supportive care was most sensitive to the utility value for the transfusion-independent state. The ICER was also sensitive to the utility value for the transfusion-dependent state. The manufacturer also conducted further scenario analyses, which included altering the population used to estimate the model parameters, altering the proportion in the best supportive care group who received an ESA, altering the number of red blood cell units people received before iron chelation therapy was started, using alternative utility values from the studies by Goss and Buckstein and using alternative methods of extrapolating response duration, AML progression and overall survival. The ICERs were robust to nearly all of the scenarios explored. However, when the manufacturer applied alternative utility values for the transfusion-independent (0.91), transfusion-dependent (0.5) and AML (0.5) states taken from the study by Goss et al. (2006), the ICER reduced to £47,621 per QALY gained.

Evidence Review Group comments

3.27   The ERG considered that the manufacturer had identified all the available evidence on the clinical effectiveness of lenalidomide for treating myelodysplastic syndromes associated with the deletion 5q cytogenetic abnormality. The ERG noted that a significant proportion of the lenalidomide 5 mg and 10 mg groups had an adverse event resulting in dose interruption or reduction. It also noted that dose reductions made it difficult to distinguish between the 5 mg and 10 mg lenalidomide treatment groups. It noted that because of crossover, only 1 patient in the placebo group completed the 52‑week double-blind phase. The ERG suggested that one of the main concerns for people receiving lenalidomide is the incidence of increased clonal evolution and progression to AML. The ERG was concerned that because people could switch from placebo to active drug treatment in MDS‑004, the chances of detecting prolonged survival or acceleration of leukaemia progression were limited. Overall, the ERG considered that that assessment of the long-term effectiveness of lenalidomide was compromised because patients in the MDS‑004 study were allowed to switch treatment after 16 weeks.

3.28  The ERG noted that data were reported separately for 2 populations in the MDS‑004 study: the ITT and mITT population, although not all results were reported for both populations. The ERG also noted that confirmation of deletion 5q status (by karyotype analysis) and bone marrow morphology were performed by central haematological review after randomisation, resulting in people whose disease did not meet the study inclusion criteria being included in the ITT population. The ERG noted that it was not clear how differences between these 2 populations could influence the results.

3.29  The ERG stated that the manufacturer's economic model (model 1) was generally well presented and reported. However, the ERG noted that the model described in the manufacturer's submission did not fully correspond with the model structure in the electronic model provided. It also noted that the manufacturer did not consider progression to intermediate-2 or high-risk MDS in the model because these data were not collected in MDS‑004. The ERG considered that it would have been more reasonable for a lifetime model to incorporate all future costs and effects, including the possibility of disease progression and reduced transfusion burden. The ERG disagreed with the manufacturer's decision not to apply a half-cycle correction in the model because of the short cycle length of 28 days. The ERG considered that short cycles would involve small changes between 2 consecutive cycles, because cycle length depends on the changes observed in patient distribution from one cycle to another. The ERG noted that the cycles at the start of the model showed a significant redistribution between the various health states, suggesting that a cycle of 28 days was rather long during this phase of the model.

3.30  The ERG noted that in the manufacturer's economic model, best supportive care was defined as blood transfusions for transfusion dependence. No changes to best supportive care (in terms of transfusion frequency or iron chelation therapy) were assumed when cardiac conditions, diabetes, or hepatic conditions occurred. The ERG considered that it was unclear whether best supportive care as represented in the model was similar enough to clinical practice in England.

3.31   The ERG considered the response rates used in the manufacturer’s model, which were based on the MDS‑004 ITT population. The ERG noted that the manufacturer’s description of the model stated that response to treatment was assumed to occur within the first cycle, so that all patients spent the first cycle in the transfusion-dependent state. However, the ERG noted that the model started with the results of the treatment initiation and that people moved immediately from the first cycle onwards to the transfusion-independent state. The ERG considered that this assumption may have been optimistic because the overall response rate also included people whose condition did not respond immediately to treatment. In response to clarification, the manufacturer provided data on the proportion of patients responding to treatment according to 28‑day cycles in the MDS‑004 study, which showed that the lenalidomide 10 mg arm had a response rate of 60.9% after 112 days and the placebo arm had a response rate of 7.5% after 182 days. The ERG considered that it would have been more appropriate to use these data rather than assuming that all patients whose condition responded to treatment were transfusion independent from cycle 1 onwards.

3.32   The ERG noted that neither the proportion of patients receiving ESA as part of best supportive care nor the response rate to ESA could be obtained from the MDS‑004 trial, which introduced additional uncertainty in the model. It noted that, according to expert opinion given to the ERG, there is some uncertainty about the effect of providing ESA to patients with MDS with deletion 5q. The ERG also noted that the initial response rates to best supportive care in the model were weighted twice by the proportion of patients (28%) who received ESA and G‑CSF therapy. In response to clarification, the manufacturer confirmed that these were programming errors. The ERG considered that, in the absence of other available data, it was appropriate for the manufacturer to assume that response duration for the best supportive care group could be estimated from the lenalidomide 5 mg treatment arm in MDS‑004. However, it also considered that the manufacturer's rationale for using response duration estimates from the lenalidomide 5 mg arm rather than the 10 mg arm seemed arbitrary.

3.33  The ERG noted that the cost effectiveness of lenalidomide was sensitive to the proportion of patients in the lenalidomide treatment group who had a second dose interruption in the model. The ERG noted that these values were directly obtained from the MDS‑004 trial, but that only cost estimates were assumed to be affected by treatment interruptions in the model, and the clinical effectiveness of lenalidomide was unaffected. The ERG suggested that, in clinical practice, treatment interruptions would affect the response rates to lenalidomide treatment. The ERG also noted that the programming of dose interruptions in the electronic model contained errors.

3.34   The ERG noted that people in the transfusion-dependent state in the model started iron chelation therapy after receiving 25 units of red blood cells and that at the start of the model they were assumed to have already received an average of 9.15 red blood cell units over 8 weeks, based on data from MDS‑004. However, the ERG noted that the manufacturer had multiplied the number of red blood cell units that patients had received at the start of the model by 2, which resulted in patients in the transfusion-dependent state needing iron chelation therapy after 8 weeks in the model instead of 16 weeks. The ERG therefore conducted an exploratory scenario analysis assuming that people in the transfusion-dependent state would start iron chelation therapy after 8 weeks.

3.35  The ERG noted that all people in the model would be monitored by a GP. In response to clarification, the manufacturer stated that the cost of haematology visits were included in the costs of transfusion dependence and associated adverse events and that, as a result, haematology visits were not included as part of monitoring in the model. However, the ERG considered that because most people in the model were not treated for adverse events, it would be more reasonable for them to be monitored by a haematologist rather than a GP. The ERG therefore conducted an exploratory scenario analysis assuming that all monitoring would take place at a haematologist visit.

3.36   The ERG noted that the utility values (that is, the measure of health) were taken from a study by Szende et al. (2009). This provided evidence that transfusion independence is associated with significantly better quality of life scores (p < 0.001) compared to fewer transfusions and transfusion dependence. The ERG highlighted some concerns with the values applied in the model.

• The Szende study did not conform to the NICE reference case because it was obtained from a sample of UK patients with MDS rather than a sample of the general UK population without the condition.
• The ERG noted that the model included transfusion dependent and transfusion independent health states. It commented that in clinical practice, people may lie between these states, that is, they are neither completely dependent on transfusion nor completely independent, they need a few transfusions. The ERG noted than the transfusion dependent health state included all those that were not transfusion independent, that is, it would include those who were completely dependent on transfusion and those who weren't completely dependent, but were not independent either.  The ERG commented that the value of 0.65 was elicited for people who were completely transfusion dependent (requiring a lot of transfusions) and therefore may under estimate the utility value of the transfusion dependent health state, as it also included people who only need a few transfusions.
• The ERG highlighted that the health state description for transfusion dependence in the Szende et al. (2009) study was very broad in that it covered a range of health problems and the level of transfusion dependence was not the only difference between the health states being compared for the elicitation. This meant that the transfusion-dependent state may have already incorporated some of the adverse events associated with transfusion and chelation therapy, or complications such as cardiac disease, diabetes or hepatic complications. The ERG considered it likely that some double counting was included in the model by also using utility decrements, such as for chelation therapy and complications (see section 3.23).
• The ERG considered that the utility value of 0.65 from the Szende et al. (2009) study for people in the transfusion-dependent state may underestimate utility for the reasons described above. The ERG commented that this would favour lenalidomide because people in the best supportive care group spent a much longer time in this health state compared with the lenalidomide group, thus increasing the QALY difference between lenalidomide and best supportive care in the model.
• The ERG questioned whether it was appropriate to use the same utility values for the AML state as the transfusion-dependent state because this implied that being partly or completely transfusion dependent had the same impact on quality of life as having AML. However, the ERG noted that because there was no difference between the 2 treatment groups in the time spent in the AML state in the model, the impact of the utility value for the AML state was negligible.
• The ERG noted that the manufacturer did not apply utility decrements for neutropenia and thrombocytopenia events associated with lenalidomide treatment, although it accepted that the impact of these events on health-related quality of life was likely to be small.

3.37  The ERG identified several issues in relation to the resource use and cost estimates used in the manufacturer's model. The ERG noted that people receiving iron chelation therapy in the model either had intravenous desferrioxamine or oral deferasirox treatment based on prescription cost analysis data in England from 2010. The ERG considered that deferiprone, which is a third possible iron chelation therapy listed in the prescription cost analysis, should also have been included. When the ERG included deferiprone and adjusted the proportion of people who were treated with the 3 iron chelation therapies based on 2011 prescription cost analysis data, this reduced the total cost of iron chelation therapy from £1383 to £1332 per 28‑day cycle. The ERG noted that the manufacturer's estimated cost of AML treatment of £1919.40 was based on a 5‑week cycle rather than a 4‑week cycle used in the model. The ERG also identified alternative cost estimates for episodes of neutropenia (£1045) and thrombocytopenia (£1768) from the NHS reference costs (2011/12). The ERG considered that the manufacturer's assumption of standard errors of 10% of the mean cost estimates for complications and adverse events used in the probabilistic sensitivity analysis were too small and that standard errors of 20% of the mean estimate would be more reasonable. Similarly, the ERG noted that the manufacturer’s probabilistic sensitivity analysis did not account for uncertainty around the number of monitoring visits in both treatment groups.

3.38   The ERG ran the manufacturer's model incorporating the following adjustments:

• Programming errors confirmed by the manufacturer were removed.
• Programming errors for dose interruptions and days on active treatment in the model were removed.
• A half-cycle correction was included.
• Costs of iron chelation therapy were updated to £1332 per cycle to include deferiprone.
• Treatment costs of AML were amended to £1451 per 28 day cycle.
• Response was distributed over time according to the trial instead of all patients from cycle 1 onwards.
• Costs of neutropenia and thrombocytopenia were amended to £1045 and £1768 respectively.
• Uncertainty around the number of monitoring visits, and increased uncertainty around cost estimates, complications and adverse events were incorporated into the model.

3.39   When the ERG included all of these changes in the manufacturer's model (model 1) the deterministic ICER without PAS increased from £56,965 to £62,674 per QALY gained for lenalidomide compared with best supportive care (incremental costs £50,898 and incremental QALYs 0.81). The probabilistic ICER was £65,052 per QALY gained.

3.40  The ERG reproduced the manufacturer's sensitivity and scenario analyses in the amended model (model 1). The sensitivity analyses found that the cost effectiveness of lenalidomide compared with best supportive care was most sensitive to the utility values for the transfusion-independent state and the response rate for the lenalidomide treatment group. When the ERG re-ran the manufacturer’s scenario analyses, the ICERs changed little when nearly all of the scenarios were explored (see 3.26) except when alternative utility values taken from the study by Goss et al. (2006) were used, which reduced the ICER to £51,956 per QALY gained.

3.41    The ERG undertook additional scenario analyses. The scenarios that had the most substantial effect on the ICER were the utility value for transition dependence and the proportion of patients who received intravenous iron chelation therapy. When the utility value for transfusion dependence was increased from 0.65 to 0.77 (the value for reduced transfusion burden taken from Szende et al. [2009]), the ICER for lenalidomide compared with best supportive care increased to £68,357 per QALY gained compared with the manufacturer’s base-case ICER of £56,965 per QALY gained. When the proportion of patients who received intravenous iron chelation therapy was increased from 5.7% to 100%, the ICER reduced to £56,750 per QALY gained. Assuming that people in the transfusion-dependent state would start iron chelation therapy after 4 cycles increased the ICER to £67,428 per QALY gained. Assuming that all monitoring would take place at a haematologist visit increased the ICER to £64,079 per QALY gained.

Manufacturer’s response to the appraisal consultation document

3.42  To support transfusion dependence as a prognostic factor for overall survival and rate of progression to AML, the manufacturer submitted the results of a systematic literature review. Sixteen of the 17 studies (mainly retrospective case series or register populations) meeting the inclusion criteria reported statistically significant associations between transfusion status and overall survival. This association was explained by:

• transfusion dependence and anaemia leading to increased death from causes other than leukaemia (particularly cardiac death)
• transfusion dependence and anaemia leading to increased risk of AML and death caused by leukaemia
• transfusion independence after dependency at baseline improving overall survival because of reduced complications from chronic anaemia.

The manufacturer also cited literature that examined the relationship between AML and both transfusion status and erythroid response, arguing that lenalidomide triggers programmed cell death in the deletion (5q) clone, and that the MDS‑004 trial showed significant reductions in progression to AML for people whose condition responded to lenalidomide.

3.43   In response to the appraisal consultation document, the manufacturer revised the economic model (model 2). It accepted the adjustments described in sections 3.38 and 3.39, which increased the base-case ICER (model 2) from £56,965 to £62,674 per QALY gained. It also accepted that monitoring would be undertaken by a haematologist rather than a GP, increasing the ICER (model 2) to £64,079 per QALY gained. A model scenario was explored in which the progression to AML was the same for the lenalidomide and best supportive care arms and increased the ICER (model 2) to £68,125 per QALY gained. The manufacturer also provided further information to explain a labelling error in its model about iron chelation. It outlined that the underlying model was accurate for the assumption of when iron chelation started, despite this labelling error, and that no adjustments in the base-case ICER were needed. Finally, the manufacturer submitted its methods for attempting to map FACT‑An scores to EQ-5D and the way it accounted for crossover in the trial arms.

3.44  The ERG considered the additional information submitted by the manufacturer, and the updated model (model 2). It agreed that this information, combined with the results of the MDS‑004 trial, suggested that it was reasonable to assume a 2‑step relationship: first between lenalidomide response and transfusion independence, and then between transfusion independence and overall survival. However, there was uncertainty in the strength of the relationship between transfusion independence and overall survival beyond 5 years. For AML progression, the ERG outlined differing evidence from the MDS‑004 trial. While Kaplan Meier survival curves showed significant differences in progression to AML in favour of those whose disease responded to lenalidomide, a univariate Cox-regression of time to AML showed that response status was not a significant variable in relation to the association between lenalidomide and reduced rate of progression to AML.

Manufacturer’s patient access scheme and further revisions to the manufacturer’s model

3.45  The manufacturer has agreed a patient access scheme for lenalidomide with the Department of Health. The manufacturer requested permission to submit the patient access scheme as part of the technology appraisal, which was agreed by NICE as an exceptional circumstance. It is a standard scheme, with the NHS paying for up to 26 cycles of treatment with lenalidomide for each patient. The company will then provide free-of-charge lenalidomide for patients needing treatment beyond 26 cycles, which could take the form of a rebate, vouchers or free stock of the drug. The manufacturer provided updated analyses (model 3) that:

• incorporated the patient access scheme – the manufacturer assumed that 31.9% of patients would have 26 cycles of treatment and would therefore be eligible for the rebate of free subsequent treatment to the NHS as outlined in the patient access scheme, based on the MDS-004 trial
• included the adjustments stated in section 3.38, including a half-cycle correction
• amended the rate of progression to AML in the lenalidomide arm to be the same as in the best supportive care arm
• assumed routine monitoring by a haematologist rather than a GP.

3.46   The manufacturer presented revised analyses (model 3) with and without the patient access scheme. The resulting deterministic ICERs for lenalidomide compared with best supportive care were £68,125 per QALY gained (without the patient access scheme; model 3) and £24,544 per QALY gained (with the patient access scheme). The mean probabilistic ICER including the patient access scheme was £25,468 per QALY gained. Sensitivity analyses showed that the ICER was most sensitive to median survival from the MDS-003 and MDS-004 trials, with a maximum deterministic ICER of £33,309 per QALY gained. The manufacturer presented scenario analyses, including varying utilities, where the ICERs ranged from £19,135 to £25,861 per QALY gained when alternative utility sources were used (Goss and Buckstein, respectively), and varying the selection of survival curves where ICERs ranged from £24,776 to £30,022 per QALY gained.

Committee request for additional cost-effectiveness analysis

3.47 The Committee were unable to make a decision based on the evidence submitted with the patient access scheme and requested further cost-effectiveness analysis with the patient access scheme as it would apply in clinical practice. The Committee noted that dose interruptions had not appropriately been taken into account when the patient access scheme was incorporated into the model, and that interruptions would delay when the patient access scheme would take effect for people who have dose-interruptions. That is, cycles may be missed to manage toxicity which would delay when a patient reached 26 cycles, beyond which the patient access scheme allowed free lenalidomide. The manufacturer therefore updated the base case to account for 16 days of treatment interruptions and explored the impact of longer dose interruptions (model 4). The updated base-case ICER was £25,310 per QALY gained for lenalidomide compared with best supportive care. Probabilistic sensitivity analyses estimated a mean ICER of £25,708 per QALY gained. The probability of being cost effective was 25.4% and 64.5% at £20,000 and £30,000 per QALY gained respectively. Increasing the length of interruptions reduced the ICER; accounting for 42 days of treatment interruptions reduced the ICER to £22,209 per QALY gained for lenalidomide compared with best supportive care.

3.48               At the request of the Committee, the manufacturer presented evidence to support the proportion of people who would be expected to be eligible for the patient access scheme (31.9%):

·      Published data (Fenaux et al. 2011) from an interim analysis showed that, of people in the 10 mg lenalidomide arm of MDS‑004, 38% were still on treatment after 26 cycles. The manufacturer applied a correction factor to this value to reduce survival on both arms to the levels seen in real-life practice, subsequently estimating that 31.9% would remain on treatment after 26 cycles in clinical practice.

·      Real-world UK data from the manufacturer’s in-house database suggested that 28% of people reached 26 cycles of treatment with lenalidomide.

·      Published registry data indicated that response duration ranged from 27.6 to 36 months.

The manufacturer presented a threshold analysis that showed if the proportion eligible for the patient access scheme was less than 27%, the ICER (model 4) would be greater than £30,000 per QALY gained.

3.49               The patient access scheme presented by the manufacturer would not take effect until after a minimum of 2 years and even more than that for patients with dose interruptions. At the request of the Committee, the manufacturer presented further cost-effectiveness analyses, including scenarios for various time horizons to understand how the cost effectiveness would change over time as the patient access scheme was implemented. Applying time horizons of 2, 3, 5 and 10 years in model 4 gave ICERs of £119,876, £63,780, £30,923 and £23,420 per QALY gained respectively for lenalidomide compared with best supportive care.

3.50               The ERG validated the changes to the manufacturer’s model, confirming that the patient access scheme was incorporatedappropriately. It agreed with the manufacturer that the real-world evidence suggestedthat about 30% of patients reach 26 cycles of treatment, and the ERG stated that this was a reasonable assumption. It commented that the manufacturer’s estimate of 16 days of treatment interruptions may be an underestimate and it could be closer to 19 days. The ERG showed thatthis had a negligible impact on the ICER with the manufacturer’s base case increasing from £25,310 per QALY gained to £25,445 per QALY gained once the ERG. It stated that the first 5 years of the model were more certain than the later years because they were based on available data. The ERG noted that most of the QALY gains in the model were in these first 5 years (64%), and that 90% of the QALY gains occur within 10 years.

3.51  Full details of all the evidence are in the manufacturer’s submission and the ERG report

4  Consideration of the evidence

The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of lenalidomide, having considered evidence on the nature of low- or intermediate-1 risk myelodysplastic syndromes (MDS) associated with a deletion 5q cytogenetic abnormality when other therapeutic options are insufficient or inadequate, and the value placed on the benefits of lenalidomide by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.

4.1  The Committee considered the treatment pathway in the UK for people with MDS associated with a deletion 5q cytogenetic abnormality, taking into account the marketing authorisation for lenalidomide (for treating transfusion-dependent anaemia caused by low- or intermediate-1 risk MDS associated with a deletion 5q cytogenetic abnormality when other therapeutic options are insufficient or inadequate). It heard from the clinical specialist that the main treatment option currently available for people with low- or intermediate-1-risk MDS associated with a deletion 5q cytogenetic abnormality is best supportive care, which involves regular red blood cell transfusions, and that low-dose standard chemotherapy or immunosuppressive therapies are used for some people. The clinical specialist also stated that some people would also receive an erythropoiesis stimulating agent (ESA) as part of best supportive care and that iron chelation therapy is used to avoid longer-term complications associated with transfusion. Therefore, the Committee agreed that, as defined in the scope, best supportive care was the appropriate comparator

4.2  The Committee heard from the clinical specialist that lenalidomide is an effective targeted therapy which reduces the need for blood transfusions. The patient experts agreed that this was a major benefit, with reduced fatigue significantly improving quality of life. They highlighted that having regular blood transfusions and blood tests at hospital is both inconvenient, because it needs regular time off work and usual activities, and demoralising because the person is constantly reminded of their condition. The patient experts suggested that lenalidomide, by contrast, is a convenient, effective oral drug that reduces the need for blood transfusions. The Committee recognised the need for treatments that would reduce blood transfusion dependence for people with MDS associated with a deletion 5q cytogenetic abnormality.

Clinical effectiveness

4.3 The Committee discussed the clinical effectiveness of lenalidomide in people with low- or intermediate-1 risk MDS associated with a deletion 5q cytogenetic abnormality when other therapeutic options are insufficient or inadequate. It noted that the evidence presented by the manufacturer was taken primarily from the MDS‑004 study, which recruited people with low- or intermediate-1 risk MDS associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities. It also noted that this study included a broader range of people than that specified in the marketing authorisation and NICE scope for lenalidomide because the marketing authorisation stated ‘when other therapeutic options are insufficient or inadequate’. The Committee heard from the manufacturer that around 59% of the study population had received previous treatment (see section 3.1), and therefore noted that the study population would have a better prognosis than those for whom the drug has a marketing authorisation, and that the generalisability of the study population was limited.

4.4   The Committee considered the results of the MDS‑004 study. It noted that the rates of transfusion independence (at 26 weeks, lenalidomide 10 mg: 56.1%, placebo: 5.9%; p<0.001, see section 3.5) and improvements in the Functional Assessment of Cancer Therapy-Anaemia (FACT‑An) questionnaire (mean change, lenalidomide 10 mg: 5.8, placebo: -2.5; p<0.05. See section 3.9) were significantly better in people treated with lenalidomide compared with placebo. The Committee concluded that lenalidomide is a clinically effective treatment for people with low- or intermediate-1-risk MDS associated with a deletion 5q cytogenetic abnormality when other therapeutic options are insufficient or inadequate.

4.5   The Committee discussed overall survival from MDS‑004. It noted the ERG comments that it was reasonable to assume a 2‑step relationship between lenalidomide response and transfusion independence, and then between transfusion independence and overall survival (see section 3.44). The Committee noted that overall survival with placebo and lenalidomide was greater than 35 months and that there was no statistically significant difference between lenalidomide and placebo (lenalidomide 10 mg: 36.9 months, placebo: 35.9 months). It was aware that people on the placebo arm could cross over to lenalidomide treatment after 16 weeks (see section 3.2). The Committee heard from the manufacturer that it did not consider it appropriate to use statistical approaches to adjust for this crossover because it occurred too early in the study for a reliable estimate of survival for the placebo arm. The Committee noted that the manufacturer had presented separate mortality curves for patients who were transfusion dependent or independent at 8 weeks on MDS-004 which suggested that survival was strongly related to transfusion status in people with low or intermediate-1 risk MDS associated with a deletion 5q cytogenetic abnormality. The Committee noted a consultation comment from a professional group that data suggested people with low risk MDS and anaemia whose condition responds to therapies that increase haemoglobin concentration have improved survival compared those who didn’t receive treatment. The Committee noted that the Evidence Review Group (ERG) had outlined the uncertainties in the strength of the relationship between transfusion dependence and overall survival, based on clinical expert opinion. The Committee also heard from a clinical specialist that it was unclear whether an increase in transfusion independence would improve overall survival in clinical practice, in the population specified by the marketing authorisation. The Committee noted that lenalidomide was associated with statistically significantly improved transfusion independence rates (compared with placebo), and agreed that it was reasonable to assume a relationship between transfusion independence and overall survival, although there remained uncertainty about the strength of this relationship. The Committee therefore concluded that it was plausible for lenalidomide to indirectly improve overall survival by improving transfusion independence.

4.6 The Committee discussed progression to acute myeloid leukaemia (AML). It understood from the manufacturer’s systematic review that published data showed higher transfusion independence rates were associated with reduced risk of progression to AML (see section 3.42). The Committee noted that the manufacturer had stated transfusion status was a statistically significant predictor for AML progression in MDS‑004, but that the ERG had presented contradictory evidence. (see section 3.44). The Committee was aware of the lenalidomide safety briefing sent from the manufacturer to healthcare professionals that outlined a 13.8% 2‑year risk of AML progression with lenalidomide treatment for MDS associated with a deletion 5q cytogenetic abnormality, and that lenalidomide’s summary of product characteristics stated lenalidomide was associated with an increase in AML progression and second primary malignancies in people with multiple myeloma. The Committee was aware from. However, it heard from the clinical specialist that longer-term data suggest that lenalidomide treatment does not increase the rate of AML progression in people who have low or intermediate-1 risk MDS with deletion 5q cytogenetic abnormality. The Committee concluded that there was considerable uncertainty over whether lenalidomide was associated with changes in the rates of AML progression for people with low or intermediate-1 risk MDS associated with a deletion 5q cytogenetic abnormality when other therapeutic options are insufficient or inadequate.

4.7   The Committee considered the further adverse reactions associated with lenalidomide treatment from the MDS‑004 study. It noted that the most frequently reported adverse reactions associated with lenalidomide treatment were neutropenia and thrombocytopenia. The Committee was also aware that lenalidomide may be associated with higher rates of venous thromboembolism than placebo. However, it heard from the clinical specialist that the risk of thromboembolic events was manageable for people with low- and intermediate-1 risk MDS. It heard from the clinical specialist and patient experts that adverse reactions associated with lenalidomide treatment are managed with dose interruptions and are generally well tolerated. The Committee concluded that, although lenalidomide is associated with some adverse reactions, these can be managed by dose interruptions.

Cost effectiveness

4.8  The Committee considered the 4 models presented by the manufacturer and the ERG’s critique and exploratory analyses. The Committee understood that the 4 models differed as follows:

• Model 1
• Base case
• Model 2
• Costs of iron chelation, AML, neutropenia and thrombocytopenia were amended from base case
• Errors in the model were corrected
• Number of visits was amended from base case
• Model 3
• Model 2 amendments included
• Patient access scheme was incorporated (results presented with and without the patient access scheme)
• Half cycle correction applied
• Rate of AML progression assumed the same for lenalidomide and best supportive care
• Routine monitoring was conducted by a haematologist (rather than a GP)
• Model 4
• Model 3 amendments included
• Treatment interruptions included (16 days)

The Committee acknowledged that the manufacturer had amended the model in response to concerns that were raised. The Committee considered models 3 and 4 the most appropriate for decision-making.

4.9   The Committee considered whether the population included in the manufacturer’s revised model was generalisable to UK clinical practice. It noted that, in clinical practice when other therapeutic options are insufficient or inadequate, the overall population with MDS associated with a deletion 5q cytogenetic abnormalitywas likely to have a poorer prognosis than the population included in the MDS‑004 trial, and therefore in the model, because it heard from the manufacturer that around 40% of people in the trial had not had previous treatments that had failed. The Committee agreed that the model represented a group of patients with less severe disease than that of the marketing authorisation and was therefore likely to overestimate survival and effectiveness of treatment on both treatment arms.  The Committee agreed, however, that the incremental difference in QALY gain could be generalisable to the marketing authorisation population.

4.10  The Committee discussed the overall survival estimates in the manufacturer’s models, and considered the following:

• The manufacturer did not extrapolate survival estimates for the lenalidomide and best supportive care arms from the MDS‑004 study because people could cross over after 16 weeks.
• The manufacturer had estimated survival based on transfusion dependency at 8 weeks in MDS‑004, stating that transfusion status was a predictor of overall survival in people with MDS.
• The population in the MDS‑004 study had a better prognosis than that specified in the marketing authorisation (see section 4.4), and therefore overall survival was likely to be overestimated.

The Committee agreed that increased transfusion independence could be associated with improved survival but recognised that its strength over the 20‑year time frame of the model was unclear (see section 4.6). The Committee concluded that, although it was reasonable for the model to include some benefit in overall survival for people whose condition responds to lenalidomide compared with best supportive care, the amount of survival benefit was highly uncertain, and could be overestimated in the model.

4.11  The Committee considered the utility values associated with transfusion status. The Committee noted that EQ-5D utility values were collected at the start of the MDS‑004 study but not at subsequent follow-up, and that the manufacturer stated it was not possible to reliably estimate utility values by mapping from the FACT‑An scores to the EQ-5D because of differences between the EQ-5D utility values collected in the MDS‑004 study and those predicted by mapping. The Committee noted that the manufacturer used values that were taken from a published study (Szende et al. 2009) that estimated utility values according to transfusion dependence and independence directly from people with MDS. It considered the ERG’s comments that using a utility value of 0.65 for people in the transfusion-dependent state may favour lenalidomide because people in the best supportive care group spent a much longer time in this health state which would increase the QALY difference between the treatment arms. It was aware that the utility values from Szende et al. were not in line with the NICE reference case for measuring and valuing health effects, which states that the value of changes in patients’ health-related quality of life should be based on public preferences rather than people who have the condition. However, the Committee heard from the patient experts that the utility values used in the manufacturer’s base-case analyses were a reasonable reflection of the negative impact that transfusion dependence has on health-related quality of life. It noted that sensitivity analyses which varied the utility values in model 4, including the patient access scheme, gave a range of ICERs between £22,600 and £28,600 per QALY gained (base case: £25,300 per QALY gained) for lenalidomide compared with best supportive care. The Committee concluded that the utility values were a reasonable reflection of the impact of transfusion status on health-related quality of life in people with low or intermediate-1 risk MDS associated with deletion 5q cytogenetic abnormality, and could therefore use these values for decision-making in this appraisal.

4.12    The Committee discussed the patient access scheme, noting that it was a standard scheme, that is, it was not a simple discount. The NHS pays for lenalidomide treatment for all patients for up to 26 cycles, and therefore the whole population will not benefit from the reduction in price because only some patients would be eligible. The Committee heard from the manufacturer that there were a number a ways for the NHS to implement the patient access scheme which involved receiving vouchers or free stock of the medicine once 26 cycles had been reached for individual patients. The Committee noted the importance of considering how the patient access scheme will be implemented in the NHS as part of the cost-effectiveness analysis, to take into account any further uncertainties the scheme may bring. It noted that the reduction in costs achieved through the patient access scheme would be based on the number of people surviving after 26 cycles, and how long they survived and continued treatment. The Committee was aware that the data supporting survival after 26 cycles were from small patient numbers in the MDS‑004 trial (less than 38 patients), and were therefore very uncertain. The Committee discussed whether the assumption in the model that 31.9% of people would survive for more than 26 cycles was realistic, and whether the cost savings associated with the patient access scheme were likely to be realised in clinical practice. The Committee noted that the overall survival estimates, and the survival benefit achieved with lenalidomide, were very uncertain. Furthermore, it recognised that these data were derived from MDS‑004, which included people with MDS who had a better prognosis than the population included in the marketing authorisation (see section 4.4). The Committee considered the manufacturer’s evidence that supported the assumption of 31.9% of people reaching 26 cycles in practice (see section 3.48), and noted that this was supported by a clinical specialist. It was concerned, however, about discrepancies between this estimate and those implied by the published paper, but heard from the manufacturer that this was because the published paper included data from an earlier time point. The Committee agreed that, because the proportion of people surviving beyond 26 cycles in clinical practice was uncertain (see above and section 4.5), so were the potential cost savings from the patient access scheme. The Committee recognised that the probabilistic sensitivity analysis presented by the manufacturer was unlikely to have captured the uncertainty of the patient access scheme in terms of the proportion who would survive beyond 26 cycles. It noted that the base case of model 4 was associated with a 25% chance of lenalidomide being cost effective at £20,000 per quality-adjusted life year (QALY) gained (and 65% at £30,000 per QALY gained). It also noted that, if the proportion of people who reached 26 cycles was less than 27%, the ICER would be greater than £30,000 per QALY gained. The Committee agreed that the ICER was therefore very uncertain. The Committee noted that without the patient access scheme and without treatment interruptions the ICER (from model 3) was £68,000 per QALY gained for lenalidomide compared with best supportive care. Therefore the Committee concluded that if there were concerns in establishing when the patient access scheme would come into effect, the ICER could be considerably higher than £25,300 per QALY gained as presented by the manufacturer, because of the uncertainty associated with patient access scheme.

4.13     The Committee considered the logistics of the patient access scheme, noting that the NHS has experience with this patient access scheme because it is available for multiple myeloma. The Committee questioned whether all the savings would be realised in practice for every patient because of the administration process involved. The Committee concluded that this added to the uncertainty of the cost reductions associated with the patient access scheme.

4.14    The Committee noted that the patient access scheme was based on the number of treatment cycles, and therefore any treatment interruptions would delay when the patient access scheme would take effect and therefore the time to the NHS receiving the rebate or discount for those patients with dose interruptions. The Committee acknowledged that accounting for treatment interruptions reduced the ICER minimally (from £25,300 with 16 days of interruptions to £25,700 with 42 days; see section 3.47). The Committee was aware that accounting for treatment interruptions reduced lenalidomide costs but did not affect treatment benefit. The Committee concluded that the nature of the patient access scheme meant that accounting for treatment interruptions introduces uncertainty about when people would reach 26 cycles of treatment, and therefore when the savings from the patient access scheme could be claimed by the NHS.

4.15   The Committee considered the ICERs resulting from the manufacturer’s economic analyses, as well as the results of the ERG’s exploratory analyses. The Committee noted that the revised manufacturer’s base-case ICER (model 3) without the patient access scheme for lenalidomide compared with best supportive care was approximately £68,100 per QALY gained (see section 3.46), and that applying the patient access scheme (and accounting for treatment interruptions) reduced the ICER to £25,300 per QALY gained (model 4). It considered the manufacturer’s threshold analyses, which showed that if less than 27% of people were still benefiting from lenalidomide after 26 cycles the ICER would increase above £30,000 per QALY gained. The Committee agreed that the patient access scheme increased all of the uncertainties, and added further uncertainty in terms of costs. The Committee also agreed there was a risk that savings from the patient access scheme would not be realised in clinical practice, both because of the uncertainty about survival estimates, and also the logistics of the scheme itself. The Committee therefore concluded that lenalidomide for treating MDS associated with a deletion 5q cytogenetic abnormality was not recommended as a cost-effective use of NHS resources.

4.16  The Committee discussed how innovative lenalidomide is in its potential to make a significant and substantial impact on health-related benefits. It agreed that the convenience of a new oral treatment and reduction in the need for blood transfusions offered a step change in treatment. The Committee considered that there were no additional gains in health-related quality of life over those already included in the QALY calculations. Therefore, the Committee concluded that the innovative aspects of lenalidomide were already incorporated in the economic analyses.

4.17 The Committee examined whether there were any potential issues affecting groups protected by equality legislation. The Committee noted comments from some consultees that MDS associated with a cytogenetic abnormality predominately affects older people and women. The Committee considered that this cannot be addressed within this technology appraisal because guidance could not address this issue. The Committee also noted the comments from consultees about the Jehovah’s Witness group who are unable to receive blood transfusion for religious reasons. However, the Committee noted that no representations had been made or evidence received about the pathway of care for this particular group of patients, or about the effectiveness of lenalidomide in this patient population. Therefore the Committee agreed that it did not need to amend any of its recommendations for the group of patients unable to receive blood transfusions.

Summary of Appraisal Committee’s key conclusions

TAXXX	Appraisal title: Lenalidomide for treating myelodysplastic syndromes associated with a deletion 5q cytogenetic abnormality		Section
Key conclusion
Lenalidomide is not recommended within its marketing authorisation, that is, for treating transfusion-dependent anaemia caused by low or intermediate-1-risk myelodysplastic syndromes (MDS) associated with a deletion 5q cytogenetic abnormality when other therapeutic options are insufficient or inadequate. The Committee concluded that lenalidomide is a clinically effective treatment for people with low- or intermediate-1-risk MDS associated with a deletion 5q cytogenetic abnormality when other therapeutic options are insufficient or inadequate, because it was associated with a statistically significant improvement in transfusion independence and health related quality of life compared with placebo. There remained uncertainty about the overall survival benefit of lenalidomide, but the Committee agreed a survival benefit was plausible.			1.1 4.4, 4.5 4.12
The Committee discussed the patient access scheme, noting that it was not a simple discount and that that the whole population would not benefit from the reduction in price for lenalidomide in MDS, because only some people would be eligible after 26 cycles.  It noted that the reduction in costs achieved through the patient access scheme would be based on the number of people surviving after 26 cycles, and how long they survived and continued treatment. The Committee also noted that the data from MDS‑004 that estimated survival, and therefore the savings from the patient access scheme, were from small patient numbers (less than 38 patients) and were therefore very uncertain.
The Committee noted that the revised manufacturer’s base-case incremental cost-effectiveness ratio (ICER) without the patient access scheme for lenalidomide compared with best supportive care was approximately £68,100 per quality-adjusted life year (QALY) gained, and that applying the patient access scheme reduced the ICER to £25,300 per QALY gained. The Committee agreed that the patient access scheme increased all of the uncertainties, and added further uncertainty in terms of costs.			4.15
Current practice
Clinical need of patients, including the availability of alternative treatments		The main treatment option currently available for people with low- or intermediate-1-risk MDS associated with a deletion 5q cytogenetic abnormality when other therapeutic options are insufficient or inadequate is best supportive care, which involves regular red blood cell transfusions.	4.1
The technology
Proposed benefits of the technology How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?		The Committee heard that lenalidomide is an effective targeted therapy which reduces the need for blood transfusions, subsequently reducing fatigue significantly and improving quality of life. The patient experts suggested that lenalidomide is a convenient, effective oral drug. The Committee agreed that the convenience of a new oral treatment and reduction in the need for blood transfusions offered a step change in treatment, but that this was already captured in the QALY calculation and therefore, the Committee concluded that the innovative aspects of lenalidomide were already incorporated in the economic analyses.	4.2, 4.18
What is the position of the treatment in the pathway of care for the condition?		Lenalidomide has a marketing authorisation ‘for the treatment of patients with transfusion-dependent anaemia due to low- or intermediate-1-risk myelodysplastic syndromes associated with an isolated deletion 5q cytogenetic abnormality when other therapeutic options are insufficient or inadequate’.	2.1
Adverse reactions		The Committee concluded that, although lenalidomide is associated with some adverse reactions, these can be managed by dose interruptions.	4.7
Evidence for clinical effectiveness
Availability, nature and quality of evidence		The Committee concluded that, on the basis of the evidence on transfusion independence and health-related quality of life, lenalidomide is a clinically effective treatment for people with low- or intermediate-1-risk MDS associated with a deletion 5q cytogenetic abnormality when other therapeutic options are insufficient or inadequate,. The Committee concluded that it was reasonable to assume a relationship between lenalidomide response rates and transfusion independence, and transfusion independence and overall survival, although there remained uncertainty about the strength of the relationship. The Committee therefore concluded that it was plausible for lenalidomide to indirectly improve overall survival by improving transfusion independence	4.4, 4.5
Relevance to general clinical practice in the NHS		The Committee noted that the MDS‑004 study included a broader range of patients than that specified in the marketing authorisation because the marketing authorisation specified ‘when other therapeutic options are insufficient or inadequate’. The Committee heard from the manufacturer that around 59% of the study population had received previous treatment (see section 3.1), and therefore the study population would have a better prognosis than those for whom the drug has a marketing authorisation and the generalisability of the study population was limited.	4.3
Uncertainties generated by the evidence		The Committee agreed that it was reasonable to assume a relationship between transfusion independence and overall survival, although there remained uncertainty about the strength of this relationship.	4.5
		The Committee concluded that there was uncertainty about whether lenalidomide was associated with changes in the rates of AML progression for people with low- or intermediate-1-risk MDS associated with a deletion 5q cytogenetic abnormality when other therapeutic options are insufficient or inadequate,.	4.6
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?		None were identified.
Estimate of the size of the clinical effectiveness including strength of supporting evidence		The Committee concluded that, on the basis of the evidence on transfusion independence and health-related quality of life, lenalidomide is a clinically effective treatment for people with low- or intermediate-1-risk MDS associated with a deletion 5q cytogenetic abnormality when other therapeutic options are insufficient or inadequate,.	4.4
Evidence for cost effectiveness
Availability and nature of evidence		The manufacturer developed a de novo Markov model that compared lenalidomide 10 mg with best supportive care for low- to intermediate-1 risk MDS with deletion 5q.	3.11
Uncertainties around and plausibility of assumptions and inputs in the economic model		The Committee concluded that, although it was reasonable for the model to include some benefit in overall survival for people whose condition responds to lenalidomide compared with best supportive care, the amount of survival benefit was highly uncertain, and could be overestimated in the model The Committee was aware that the data supporting survival after 26 cycles were from very small patient numbers in the MDS‑004 trial (less than 38 patients), and were therefore very uncertain. The Committee questioned whether all the savings would be realised in practice for every patient because of the administration process involved. The Committee concluded that this added to the uncertainty of the cost reductions associated with the patient access scheme	4.11 4.12 4.13
Incorporation of health-related quality-of-life benefits and utility values Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?		The Committee concluded that the utility values were a reasonable reflection of the impact of transfusion status on health-related quality of life in people with low or intermediate-1 risk MDS associated with deletion 5q cytogenetic abnormality, and could therefore use these values for decision-making in this appraisal.	4.11
Are there specific groups of people for whom the technology is particularly cost effective?		Not applicable.
What are the key drivers of cost effectiveness?		The Committee noted that overall survival and the patient access scheme were key drivers of the ICER estimates in the manufacturer’s model.	4.12
Most likely cost-effectiveness estimate (given as an ICER)		The Committee noted that without the patient access scheme and without treatment interruptions the ICER (from model 3) was £68,000 per QALY gained for lenalidomide compared with best supportive care. Therefore the Committee concluded that if there were concerns in establishing when the patient access scheme would come into effect, the ICER could be considerably higher than £25,300 per QALY gained as presented by the manufacturer, because of the uncertainty associated with patient access scheme.	4.12
Additional factors taken into account
Patient access schemes (PPRS)		The Committee discussed the patient access scheme, noting that it was a standard scheme. The NHS pays for lenalidomide treatment for all patients for up to 26 cycles, and The patient access scheme presented would not benefit the whole patient population because only some people would only be eligible. It noted that the reduction in costs achieved through the patient access scheme would be based on the number of people surviving after 26 cycles, and how long they survived and continued treatment. The Committee was aware that the data supporting survival after 26 cycles were from very small patient numbers in the MDS‑004 trial (less than 38 patients), and were therefore very uncertain.	4.12
End-of-life considerations		Not applicable.
Equalities considerations and social value judgements		The Committee noted comments from some consultees that MDS associated with a cytogenetic abnormality predominately affects older people and women. The Committee considered that this cannot be addressed within this technology appraisal because guidance could not address this issue. The Committee also noted the comments from consultees about the Jehovah’s Witness group who are unable to receive blood transfusion for religious reasons. However, the Committee noted that no representations had been made or evidence received about the pathway of care for this particular group of patients, or about the effectiveness of lenalidomide in this patient population. Therefore the Committee agreed that it did not need to amend any of its recommendations for the group of patients unable to receive blood transfusions	4.17

5    Implementation

5.1  NICE has developed tools [link to /proxy/?sourceUrl=http%3a%2f%2fguidance.nice.org.uk%2fTAXXX] to help organisations put this guidance into practice (listed below). [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.

6    Related NICE guidance

Details are correct at the time of publication. Further information is available on the NICE website.

Azacitidine for the treatment of myelodysplastic syndrome, chronic myelomonocytic leukaemia and acute myeloid leukaemia. NICE technology appraisal guidance 218 (2011)

Improving outcomes in haemato-oncology cancer. NICE clinical guideline CSGHO (2003)

7  Proposed date for review of guidance

7.1  NICE proposes that the guidance on this technology is considered for review by the Guidance Executive in May 2017. 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.

Andrew Stevens
Chair, Appraisal Committee
April 2014

8   Appraisal Committee members and NICE project team

8.1   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 4 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 Andrew Stevens

Chair of Appraisal Committee C, Professor of Public Health, University of Birmingham

 

Professor Eugene Milne

Vice Chair of Appraisal Committee C, Deputy Regional Director of Public Health, North East Strategic Health Authority, Newcastle upon Tyne

Professor Kathryn Abel

Director of Centre for Women’s Mental Health, University of Manchester

 

Dr David Black

Medical Director, NHS South Yorkshire and Bassetlaw

 

David Chandler

Lay Member

Gail Coster

Advanced Practice Sonographer, Mid Yorkshire Hospitals NHS Trust

 

Professor Peter Crome

Honorary Professor, Dept of Primary Care and Population Health, University College London

Professor Rachel A Elliott

Lord Trent Professor of Medicines and Health, University of Nottingham

 

Dr Greg Fell

Consultant in Public Health, Bradford Metropolitan Borough Council

 

Dr Wasim Hanif

Consultant Physician and Honorary Senior Lecturer, University Hospital Birmingham

 

Dr Alan Haycox

Reader in Health Economics, University of Liverpool Management School

 

Dr Janice Kohler

Senior Lecturer and Consultant in Paediatric Oncology, Southampton University Hospital Trust

 

Emily Lam

Lay Member

Dr Nigel Langford

Consultant in Clinical Pharmacology and Therapeutics and Acute Physician Leicester Royal Infirmary

 

Dr Allyson Lipp

Principal Lecturer, University of South Wales

 

Dr Claire McKenna

Research Fellow in Health Economics, University of York

 

Professor Gary McVeigh

Professor of Cardiovascular Medicine, Queens University Belfast and Consultant Physician, Belfast City Hospital

 

Dr Grant Maclaine

(Formerly) Director, Health Economics and Outcomes Research, BD, Oxford

 

Dr Andrea Manca

Health Economist and Senior Research Fellow, University of York

 

Dr Paul Miller

Director, Payer Evidence, Astrazeneca UK Ltd

Dr Suzanne Martin

Reader in Health Sciences

Professor Stephen O’Brien

Professor of Haematology, Newcastle University

 

Dr Anna O’Neill

Deputy Head of Nursing and Healthcare School/Senior Clinical University Teacher, University of Glasgow

 

Alan Rigby

Academic Reader, University of Hull

 

Professor Peter Selby

Consultant Physician, Central Manchester University Hospitals NHS Foundation Trust

 

Professor Matt Stevenson

Technical Director, School of Health and Related Research, University of Sheffield

 

Dr Paul Tappenden

Reader in Health Economic Modelling, School of Health and Related Research, University of Sheffield

Professor Robert Walton

Clinical Professor of Primary Medical Care, Barts and The London School of Medicine & Dentistry

 

Dr Judith Wardle

Lay Member

 

8.2   NICE project team

Each technology appraisal is assigned to a team consisting of 1 or more health technology analysts (who act as technical leads for the appraisal), a technical adviser and a project manager.

Christian Griffiths/Carl Prescott
Technical Leads

Melinda Goodall
Technical Adviser

Nicole Fisher
Project Manager

9    Sources of evidence considered by the Committee

A. The Evidence Review Group (ERG) report for this appraisal was prepared by Kleijnen Systematic Reviews Ltd:

• Riemsma R, Al M, Blommestein H, Deshpande S, Ryder S, Worthy G, Noake C, Armstrong N, Severens JL, Kleijnen J. Lenalidomide for the treatment of myelodysplastic syndromes associated with deletion 5q cytogenetic abnormality: a Single Technology Appraisal. York: Kleijnen Systematic Reviews Ltd, 2013

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 UK

II. Professional/specialist and patient/carer groups:

• Royal College of Nursing
• Royal College of Physicians
• Royal College of Pathologists
• The British Society for Haematology
• MDS UK Support Group
• Rarer Cancer Foundation
• Leukaemia Care

III. Other consultees:

None

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

• National Collaborating Centre for Cancer

C. The following individuals were selected from clinical specialist and patient expert nominations from the non-manufacturer/sponsor consultees and commentators. They gave their expert personal view on lenalidomide for treating myelodysplastic syndromes associated with a deletion 5q cytogenetic abnormality by attending the initial Committee discussion and providing written evidence to the Committee. They were also invited to comment on the ACD.

• None

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