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 an isolated 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 an isolated 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 an isolated 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 an isolated 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 an isolated deletion 5q cytogenetic abnormality when other therapeutic options are insufficient or inadequate. It noted that the evidence presented by the company was taken primarily from the MDS‑004 study. This 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', which was not an inclusion criteria for the study, and therefore those on the trial may have a better prognosis than the population specified by the marketing authorisation. In addition, the study included people with low‑ or intermediate‑1 risk MDS associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities, whilst the marketing authorisation specified an isolated deletion 5q cytogenetic abnormality. The Committee heard from the company during consultation that the additional cytogenetic abnormalities included in the trial population may mean the trial population had a poorer prognosis than that of the population covered by the marketing authorisation. The Committee agreed that, on balance, the study was generalisable to the marketing authorisation population, and how lenalidomide would be used in clinical practice. It concluded that it would be able to consider all of the evidence in the MDS‑004 study when making recommendations on lenalidomide for treating MDS associated with an isolated deletion 5q cytogenetic abnormality.

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 an isolated deletion 5q cytogenetic abnormality when other therapeutic options are insufficient or inadequate.

4.5 The Committee discussed overall survival from MDS‑004, noting 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 in the placebo arm could cross over to lenalidomide treatment after 16 weeks (see section 3.2), and therefore the overall survival benefit of lenalidomide compared with placebo may be under estimated. The Committee noted that the company had presented separate mortality curves for people who were transfusion dependent or independent at 8 weeks in 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 that the company's comments in response to consultation included an updated analysis of these data at 7 years, which continued to support a link between transfusion independence and overall survival. The Committee also considered the following:

  • ERG comments that it was reasonable to assume a two‑step relationship between lenalidomide response and transfusion independence, and then between transfusion independence and overall survival (see section 3.43).

  • 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 with those who did not receive treatment.

  • The ERG clinical expert had advised that there were uncertainties in the strength of the relationship between transfusion dependence and overall survival.

  • A clinical specialist stated that it was unclear if an increase in transfusion independence would improve overall survival in clinical practice, in the population specified by the marketing authorisation.

    Overall the Committee 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 company's systematic review that published data showed higher transfusion independence rates were associated with reduced risk of progression to AML (see section 3.41). The Committee noted that the company 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 3.43). The Committee was aware of the lenalidomide safety briefing sent from the company 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. 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 an isolated deletion 5q cytogenetic abnormality when other therapeutic options are insufficient or inadequate.

4.7 The Committee considered 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 company's original economic model, the company's revised economic model, the company's revised economic model with the patient access scheme, and the ERG's critique and exploratory analyses. It acknowledged that the company had amended the model in response to earlier concerns that were raised by the ERG and the Committee (sections 3.37 and 3.44). These amendments included the:

  • costs associated with iron chelation, AML and thrombocytopenia

  • incorporation of the patient access scheme

  • rate of AML progression which was assumed to be the same for lenalidomide and best supportive care

  • monitoring being conducted by a haematologist (rather than GP).

    The Committee concluded that the updated models were appropriate for decision‑making.

4.9 The Committee discussed further the overall survival estimates as presented in the company's models, and considered the following:

  • The company 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 company 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 (see section 4.5).

    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 the strength of the relationship was uncertain, 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.

4.10 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 company 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 company used values that were taken from a published study (Szende et al. 2009) that derived 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. This 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 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 company'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 £19,700 and £26,700 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 be used for decision‑making in this appraisal.

4.11 The Committee discussed the patient access scheme, noting that it was not a simple discount. The NHS pays for lenalidomide treatment for the first 26 cycles, after which it is provided free of charge, and therefore the whole population would not benefit from the reduction in price because only some people, those receiving it after 26 cycles, would be eligible. The Committee noted that the reduction in costs achieved through the patient access scheme would be based on the number of people remaining on treatment 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 numbers in the MDS‑004 trial (less than 38 people), and were therefore very uncertain. The Committee discussed whether the assumption in the model that 31.9% of people would remain on treatment 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 considered the company's evidence that supported the assumption of 31.9% of people reaching 26 cycles in practice (see section 3.47), 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 company 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, and therefore further validation of the proportion of people on treatment beyond 26 cycles was still required. The Committee recognised that the probabilistic sensitivity analysis presented by the company 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 (see sections 3.46 to 3.49) 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 uncertain but accepted that a commitment from the company to publish data on the proportion of people on treatment beyond 26 cycles would provide reassurance that the patient access scheme will provide value to the NHS.

4.12 The Committee noted that as the patient access scheme was based on the number of treatment cycles, any treatment interruptions would delay when the patient access scheme would take effect and therefore delay the time to the NHS receiving the rebate or discount. The Committee acknowledged that accounting for treatment interruptions reduced the ICER minimally (from £25,300 with 16 days of interruptions to £22,200 with 42 days; see section 3.46). The Committee was aware that accounting for treatment interruptions in the model reduced lenalidomide costs but did not affect treatment benefit. The Committee was aware 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. It heard from the company that they actively monitor the number of cycles that people receive and that this should provide reassurance that the scheme would be realised in practice. The Committee concluded that although treatment interruptions introduce uncertainty on the timing of when the patient access scheme could be claimed, this did not have a substantial impact on the ICER.

4.13 The Committee considered the ICERs resulting from the company's economic analyses, as well as the results of the ERG's exploratory analyses. The Committee noted that the revised company's base‑case ICER, which included the patient access scheme and accounted for treatment interruptions (model 4; see sections 3.46 to 3.49), for lenalidomide compared with best supportive care was approximately £25,300 per QALY gained. The Committee agreed that the patient access scheme increased all of the uncertainties, and there was a risk that savings from the patient access scheme would not be realised in clinical practice. The Committee acknowledged that the data collection committed to by the company will ensure that the uncertainties of the assumptions used to model the patient access scheme can be addressed when the guidance is reviewed. However, it would not be able to address the loss in health benefits for other patients in the NHS that may result in the interim from lenalidomide not being a cost effective use of NHS resources. It understood that the company is keen to work with the Department of Health should such a situation arise, to ensure that the NHS realises the full financial benefits of the patient access scheme. The Committee concluded that lenalidomide for treating MDS associated with an isolated deletion 5q cytogenetic abnormality was a cost‑effective use of NHS resources, when taking these assurances into account.

4.14 The Committee discussed how innovative lenalidomide is in its potential to make a significant and substantial impact on health‑related benefits. It heard about the notable benefits of lenalidomide from patient and professional groups during consultation. It agreed that the convenience of a new oral treatment and reduction in the need for blood transfusions meant that lenalidomide offered a substantial step change in treatment.

4.15 The Committee examined whether there were any potential issues affecting groups protected by equality legislation. The Committee 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 people, or about the effectiveness of lenalidomide in this population. Therefore the Committee agreed that it did not need to amend any of its recommendations for the group of people unable to receive blood transfusions.

Summary of Appraisal Committee's key conclusions

TA322

Appraisal title: Lenalidomide for treating myelodysplastic syndromes associated with an isolated deletion 5q cytogenetic abnormality

Section

Key conclusion

Lenalidomide is recommended as an option within its marketing authorisation, that is, for treating transfusion‑dependent anaemia caused by low or intermediate‑1‑risk myelodysplastic syndromes (MDS) associated with an isolated 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 an isolated 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. The Committee agreed that it was plausible for lenalidomide to indirectly improve overall survival by improving transfusion independence.

The Committee noted that the revised company's base‑case incremental cost‑effectiveness ratio (ICER) for lenalidomide compared with best supportive care with the patient access scheme was £25,300 per QALY gained. The Committee noted that the patient access scheme was not a simple discount and that would only benefit those on treatment after 26 cycles. The Committee agreed that because the proportion of people on treatment beyond 26 cycles was uncertain so were the potential cost savings from the patient access scheme, and 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 uncertain, because of the patient access scheme, but accepted that a commitment from the company to publish data on the proportion of people on treatment beyond 26 cycles would provide reassurance that lenalidomide for treating MDS associated with an isolated deletion 5q cytogenetic abnormality was recommended as a cost‑effective use of NHS resources.

1.1, 4.4, 4.5, 4.11, 4.13

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 an isolated 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 meant that lenalidomide offered a substantial step change in treatment

4.2, 4.14

What is the position of the treatment in the pathway of care for the condition?

Lenalidomide has a marketing authorisation 'for the treatment of 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 company presented data from a randomised controlled trial, MDS‑004, which didn't include many people but was still robust enough, and on balance was generalisable to the decision problem.

4.3, 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 people than that specified in the marketing authorisation and the NICE scope because the marketing authorisation specified 'when other therapeutic options are insufficient or inadequate', which was not an inclusion criteria of the study. In addition, the study included people with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities. The company explained that the additional cytogenetic abnormalities included in the trial population may mean the trial population had a poorer prognosis than that of the marketing authorisation. Despite these differences the Committee agreed that on balance the study was generalisable to the marketing authorisation population, and how lenalidomide would be used in clinical practice.

4.3

Uncertainties generated by the evidence

The main uncertainty in the clinical evidence was the relationship between lenalidomide response, transfusion independence and overall survival. Overall survival could not be estimated from the clinical trial as people on the placebo arm could receive lenalidomide after 16 weeks. Instead overall survival was estimated based upon transfusion independence. During consultation the company presented longer term data (from 7 years follow up rather than 5) that continued to support a relationship between transfusion independence and overall survival. The Committee agreed that it was plausible for lenalidomide to indirectly improve overall survival by improving transfusion independence, but that this was uncertain.

4.5

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 an isolated deletion 5q cytogenetic abnormality when other therapeutic options are insufficient or inadequate.

4.4

Evidence for cost effectiveness

Availability and nature of evidence

The company 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.

The Committee considered revised models from the company in response to a NICE request for additional analyses relating to the modelling of the patient access scheme. It acknowledged that the company had amended the model in response to concerns that were raised. The Committee considered the revised models appropriate for its decision‑making.

3.11

4.9

Uncertainties around and plausibility of assumptions and inputs in the economic model

The realisation of the patient access scheme in clinical practice was uncertain. The patient access scheme was not a simple discount, instead, after 26 cycles, lenalidomide would be provided free of charge to the NHS. The survival estimates in the model were uncertain and therefore so was the proportion of people who would remain on treatment after 26 cycles to become eligible for the patient access scheme, and therefore the cost savings to the NHS under this scheme were uncertain. The Committee agreed that the ICER was uncertain but accepted that a commitment from the company to publish data on the proportion of people on treatment beyond 26 cycles would provide reassurance that the patient access scheme will provide value to the NHS.

4.11

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.

The Committee agreed that the convenience of a new oral treatment and reduction in the need for blood transfusions meant that lenalidomide offered a substantial step change in treatment.

4.10

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 company's model.

4.11

Most likely cost‑effectiveness estimate (given as an ICER)

The Committee noted that the revised company's base‑case ICER, which included the patient access scheme and accounted for treatment interruptions (model 4), for lenalidomide compared with best supportive care was approximately £25,300 per QALY gained.

The Committee agreed that the patient access scheme increased all of the uncertainties, and there was a risk that savings from the patient access scheme would not be realised in clinical practice, because of the uncertainty about survival estimates.

The Committee acknowledged that the data collection committed to by the company will ensure that the uncertainties of the assumptions used to model the patient access scheme can be addressed when the guidance is reviewed. However, it would not be able to address the loss in health benefits for other patients in the NHS that may result in the interim from lenalidomide not being a cost effective use of NHS resources. It understood that the company is keen to work with the Department of Health should such a situation arise, to ensure that the NHS realises the full financial benefits of the patient access scheme. The Committee concluded that lenalidomide for treating MDS associated with an isolated deletion 5q cytogenetic abnormality was a cost‑effective use of NHS resources, when taking these assurances into account

4.13

Additional factors taken into account

Patient access schemes (PPRS)

The Committee discussed the patient access scheme, noting that it was not a simple discount, The NHS pays for lenalidomide treatment for up to 26 cycles. The patient access scheme presented would not benefit the whole patient population because only some people would become eligible, those who continued to receive lenalidomide 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, and that this was uncertain. The Committee highlighted that if the patient access scheme could be underwritten, for example, by the company offering a rebate in the event that the number of people remaining on treatment after 26 cycles was less than 31.9%, this could provide some reassurance and reduce some of the uncertainty associated with the scheme.

4.12

End‑of‑life considerations

Not applicable.

Equalities considerations and social value judgements

The Committee 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 people, 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 people unable to receive blood transfusions.

4.15

  • National Institute for Health and Care Excellence (NICE)