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

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

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

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

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

After consultation:

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

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

The key dates for this appraisal are:

Closing date for comments: 22 January 2013

Second Appraisal Committee meeting: 20 February 2013

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

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

1  Appraisal Committee’s preliminary recommendations

1.1                  Eltrombopag is recommended within its marketing authorisation as an option for treating chronic immune (idiopathic) thrombocytopenia purpura:

• in adults who have had a splenectomy and whose condition is refractory to other treatments (for example, corticosteroids or immunoglobulins) or
• as second-line treatment, in adults who have not had a splenectomy because surgery is contraindicated.

and

• if the manufacturer provides eltrombopag with the discount agreed in the patient access scheme.

2  The technology

2.1                  Eltrombopag (Revolade, GlaxoSmithKline) increases platelet production by activating the thrombopoietin receptor, thereby stimulating platelet production and reducing bleeding. Eltrombopag has a UK marketing authorisation for the treatment of adult chronic immune (idiopathic) thrombocytopenia purpura (ITP) in patients who have had a splenectomy and whose condition is refractory to other treatments (for example, corticosteroids or intravenous immunoglobulins), and as a second-line treatment for patients who have not had a splenectomy because surgery is contraindicated.

2.2                  Eltrombopag is taken orally. The summary of product characteristics states that the recommended starting dose is 50 mg once daily (patients of East Asian ancestry should start eltrombopag at a reduced dose of 25 mg once daily). Patients should take eltrombopag at least 4 hours before or after any products such as antacids, dairy products (or other calcium-containing food products) or mineral supplements containing polyvalent cations (for example, iron, calcium, magnesium, aluminium, selenium and zinc). If, after initial therapy, platelet counts are below the clinically targeted level (50×10⁹ per litre), the dosage may be increased to a maximum of 75 mg once daily. Treatment should be stopped if the platelet count does not increase sufficiently to avoid clinically significant bleeding after 4 weeks of therapy at a dosage of 75 mg once daily. For full details of dosage and administration, see the summary of product characteristics.

2.3                  The summary of product characteristics lists the following adverse reactions for eltrombopag as common (1 or more patient in every 100 and fewer than 1 patient in every 10) or very common (1 or more patient in every 10): psychiatric disorders (insomnia), nervous system disorders (headache and paraesthesia), eye disorders (cataract and dry eye), gastrointestinal disorders (nausea, diarrhoea, constipation and upper abdominal pain), hepatobiliary disorders (increased alanine aminotransferase, increased aspartate aminotransferase, increased blood bilirubin and hyperbilirubinaemia and abnormal hepatic function), skin and subcutaneous tissue disorders (rash, pruritus and alopecia), musculoskeletal and connective tissue disorder (arthralgia, myalgia, muscle spasm and bone pain) and general disorders (fatigue and peripheral oedema). For full details of adverse reactions and contraindications, see the summary of product characteristics.

2.4                  The ‘British National Formulary’ (BNF; edition 64) states that the net price of a 28-tablet pack of 25 mg eltrombopag is £770 (a single 25 mg dose costs £27.50). The net price of a 28-tablet pack of 50 mg eltrombopag is £1540 (a single 50 mg dose costs £55). The cost per patient will vary with dose adjustment and treatment duration. The manufacturer indicated that the average daily cost of eltrombopag (based on the mean dose of eltrombopag in the EXTEND study of 51.3 mg per day) is £56.43. The manufacturer of eltrombopag (GlaxoSmithKline) agreed a patient access scheme with the Department of Health that makes eltrombopag available with a discount. The size of the discount is commercial in confidence. 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 (appendix A) considered evidence submitted by the manufacturer of eltrombopag and a review of this submission by the Evidence Review Group (ERG; appendix B).

3.1                  The manufacturer compared eltrombopag within a standard care pathway with the standard care pathway alone, and separately with romiplostim plus standard care. Splenectomy is curative in approximately two-thirds of patients, and so some patients for whom splenectomy is not contraindicated may prefer to undergo surgery over taking long-term oral medication. The manufacturer evaluated the clinical and cost effectiveness of eltrombopag for 2 groups: patients who had had a splenectomy and patients who had not had a splenectomy. The manufacturer defined standard care as a pathway of care without eltrombopag or romiplostim, that is, without thrombopoietin receptor agonists (non-TRO-RA pathway). Standard care consisted of a sequence of rituximab, azathioprine, mycophenolate mofetil, ciclosporin, dapsone, danazol, cyclophosphamide, vincristine and vinblastine.

Clinical effectiveness

3.2                  The manufacturer presented clinical evidence from 3 randomised placebo-controlled trials (RCTs): TRA 100773A, TRA 100773B and RAISE, and an extension study (EXTEND) that followed patients who had previously participated in the RCTs. The key clinical evidence was obtained from RAISE. The manufacturer also presented a meta-analysis of the results of the 3 eltrombopag RCTs (TRA 100773A, and TRA 100773B and RAISE), and 2 indirect comparisons, one between eltrombopag and romiplostim, and the other between eltrombopag and standard care.

3.3                  RAISE was a phase IIl multicentre RCT (including 9 UK centres) that evaluated the efficacy, safety and tolerability of eltrombopag plus standard care compared with placebo plus standard care in adults with a platelet count of less than 30×10⁹ per litre. RAISE was a 6-month study that followed patients for up to 4 weeks after treatment had been stopped then at 3 and 6 months. Investigators randomised 197 patients to eltrombopag (n=135) or placebo (n=62) and randomisation was stratified by baseline platelet counts (15×10⁹ per litre or less, and more than 15×10⁹ per litre), whether or not a participant had a splenectomy, and whether or not participants used medications for ITP at baseline. Approximately 30% of patients had ITP that was refractory to, or had relapsed after, splenectomy. Patients randomised to either arm of treatment received standard care (that is, treatment with corticosteroids, non-selective immunosuppressants and rescue medication) as needed, plus either 50 mg eltrombopag or placebo. The eltrombopag dose was increased to maintain a patient’s platelet count of 50–400×10⁹ per litre. Over the 6-month study period the mean dose of eltrombopag was 54.7 mg per person per day. At the end of the study, 69% of patients randomised to the placebo group and 55% of those in the eltrombopag group had received concomitant ITP medication.

3.4                  The primary outcome in the RAISE trial was the odds of achieving a platelet count of 50–400×10⁹ per litre at any point during the 6-month study period. Secondary outcomes included use of rescue treatment (defined as a composite of a newly prescribed ITP medication, an increased dose of a concomitant ITP medication, a platelet transfusion or a splenectomy), incidence and severity of bleeding, and health-related quality of life.

3.5                  In RAISE, the odds ratio (OR) reflecting a response during the 6-month study period (primary outcome) was 8.2 (99% confidence interval [CI] 3.59 to 18.73; p<0.001). At the end of the study, 52% of patients receiving eltrombopag and 17% of patients receiving placebo had platelet counts of 50–400×10⁹ per litre. Once treatment was stopped the proportions attaining target platelet counts in the eltrombopag and placebo groups converged, reaching 20% for eltrombopag and 14% for placebo 4 weeks after study medication was stopped. The manufacturer indicated that the response to eltrombopag did not depend on whether or not a patient had had a splenectomy (p-value for interaction was 0.562).

3.6                  The manufacturer carried out a post hoc analysis of platelet response in RAISE, that is, an analysis of how long during the study patients maintained platelet counts of 50–400×10⁹ per litre. The manufacturer categorised platelet response into ‘sustained’ platelet response, when a patient has a platelet count of 50–400×10⁹ per litre for at least 6 of the last 8 weeks of treatment; ‘transient’ platelet response, when a patient has a platelet response for 4 or more consecutive weeks during the treatment period; and ‘overall’ platelet response, when a patient has either a sustained or a transient response. The manufacturer performed the analysis on the intention-to-treat population and on the subset of patients treated with study medication for 6 months or more (that is, including patients who continued taking eltrombopag after study termination). A higher proportion of patients receiving eltrombopag had ‘sustained’ and ‘overall’ platelet responses compared with patients receiving placebo, in both subset of patients regardless of whether or not they had a splenectomy.

3.7                  The manufacturer reported results for secondary outcomes in the RAISE trial. Patients receiving eltrombopag needed fewer protocol-defined rescue treatments than patients receiving placebo (18% and 40% respectively). Among the safety population, the odds of experiencing bleeding (World Health Organisation [WHO] grades 1–4) during the study period were 76% lower among participants who took at least 1 dose of eltrombopag compared with at least 1 dose of placebo (OR 0.24; p<0.001; CI not given). At the end of the study, 57% of patients receiving placebo had experienced bleeding compared with 27% of patients receiving eltrombopag (OR 0.25; p>0.001; CI not given), of which 13% in the placebo group and 10% in the eltrombopag group had clinically significant bleeding (WHO grades 2–4). However, clinically significant bleeding was not statistically significantly different between treatment groups. The manufacturer performed a subgroup analysis of bleeding rates according to whether or not patients had had a splenectomy. It found that patients randomised to eltrombopag were statistically significantly less likely to have clinically significant bleeding at least once at any point during the study, regardless of splenectomy status.

3.8                  The manufacturer reported treatment-related adverse effects for 48 patients (36%) in the eltrombopag group and 18 patients (30%) in the placebo group (statistical comparisons were not presented). The most common adverse effects in the eltrombopag group were headache (30%), diarrhoea (13%), nausea (12%), nasopharyngitis (10%), upper respiratory tract infection (10%) and fatigue (10%). The manufacturer reported 2 thromboembolic events in the eltrombopag group and none in the placebo group. A post hoc analysis of patients treated with concomitant medications showed a statistically significant reduction of corticosteroid-related side effects, including dyspepsia, peripheral oedema and hyperglycaemia in the eltrombopag group.

3.9                  The RAISE trial assessed health-related quality of life at baseline, 6, 14 and 26 weeks using the SF-36 instrument, which consists of 8 subdomains and 2 component summary scores (representing physical and mental health). In addition, investigators used subscales of the Functional Assessment of Chronic Illness Therapy for Patients with Thrombocytopenia (FACIT-Th) and Functional Assessment of Chronic Illness Therapy (FACIT) instruments. The manufacturer reported that patients receiving eltrombopag improved more from baseline to week 26 across most domains for health and wellbeing of the SF-36 instrument than patients receiving placebo. There were statistically significant differences between treatment groups in the change from baseline in the component summaries for physical role, vitality, emotional role and mental health.

3.10               The manufacturer did a meta-analysis of TRA 100773A, TRA 100773B and RAISE to test whether treatment with eltrombopag relative to placebo improved platelet counts. The manufacturer reported the odds ratios for attaining a platelet count of 50×10⁹ per litre or more 6 weeks after the beginning of the study. Eltrombopag was associated with higher odds of responding to treatment compared with placebo, with an odds ratio from a fixed effects model of 8.23 (95% CI 4.68 to 14.48) and from a random effects model of 8.16 (95% CI 4.63 to 14.37); there was little evidence of statistical heterogeneity.

3.11               Because there were no head-to-head trials comparing eltrombopag with romiplostim, the manufacturer performed an indirect comparison between eltrombopag and romiplostim. A systematic review by the manufacturer had identified 2 RCTs comparing romiplostim with placebo (both reported in Kuter et al. [2008]), which the manufacturer used to compare eltrombopag with romiplostim for efficacy and rates of clinically significant bleeding. Both RCTs with romiplostim evaluated its safety and efficacy in patients with ITP; one recruited 63 patients who had had a splenectomy, and the other recruited 62 patients who had not. The 2 romiplostim studies enrolled patients with platelet counts of 30×10⁹ per litre or less whose condition had not responded to at least 1 previous treatment. Patients had been randomised to either romiplostim plus standard care, or standard care alone for 6 months. The primary outcome in both studies was the proportion of patients with a durable platelet response, that is, a platelet count of 50×10⁹ per litre or more in 6 or more weekly assessments in the last 8 weeks of treatment, and who did not need rescue medication. The manufacturer combined the results of the 2 studies using standard meta-analytic techniques and then treated them as a single trial for the indirect comparison.

3.12               The manufacturer used the Bucher method to compare indirectly eltrombopag (data from RAISE) with romiplostim (data from the 2 Kuter et al. [2008] trials), using placebo as a common comparator, and separately for patients who had or had not had a splenectomy. The manufacturer considered 2 main outcome measures: platelet response and clinically significant bleeding. The endpoints for platelet response differed between the eltrombopag and romiplostim trials. In Kuter et al., the primary outcome was the proportion of patients with platelet counts of 50×10⁹ per litre or more in 6 or more weekly assessments in the last 8 weeks of treatment without using rescue medication (durable platelet response), which the manufacturer equated to ‘sustained response’ as defined in the post hoc analyses of RAISE (section 3.6). The manufacturer further defined an ‘overall response’ as having either a durable response or a transient response. There were also differences in the definitions of bleeding between the eltrombopag and romiplostim trials. RAISE collected data using the WHO bleeding scale and the Common Terminology Criteria for Adverse Events (CTCAE) scale. Kuter et al. collected data on bleeding using an unnamed scale.

3.13               The manufacturer performed separate analyses for durable response and overall response. The results of the indirect comparison were framed so that the odds ratios of more than 1.00 favoured eltrombopag. When eltrombopag was compared with romiplostim, the odds ratio for attaining a durable response was 0.32 (95% CI 0.03 to 3.14) and for attaining an overall response was 0.22 (95% CI 0.05 to 1.02). These results were similar when the data were stratified by splenectomy status.

3.14               The indirect comparison of rates of bleeding showed that the point estimates favoured eltrombopag in some analyses and romiplostim in others, with no statistically significant differences between the 2 treatments. When eltrombopag was compared with romiplostim, the odds of a clinically significant bleed was 0.60 (95% CI 0.08 to 4.29), and that of a moderate or clinically significant bleed was 1.63 (95% CI 0.4.6 to 5.80).

3.15               The manufacturer highlighted that the indirect comparison showed no statistically significant differences between eltrombopag and romiplostim, and that the differences between individual studies should be acknowledged when interpreting the results. The manufacturer indicated that patients differed between RAISE and the 2 Kuter et al. (2008) trials in terms of duration of ITP, previous use ITP medications, use of concomitant medication, and whether or not patients had had a splenectomy. In addition, the manufacturer indicated that there were differences in the design of the trials in terms of timing of platelet count assessments, timeframes in which patients were allowed to reduce concomitant ITP medications, definitions of response and definitions of ‘period of rescue medication’. The manufacturer indicated that 2 published clinical guidelines, the ‘International consensus report on the investigation and management of primary immune thrombocytopenia’ (Provan et al. [2010]) and ‘The American Society of Haematology 2011 evidence-based practice guideline for immune thrombocytopenia’ (Neunert et al. [2011]), do not favour one treatment over the other. The manufacturer concluded that the indirect comparison between eltrombopag and romiplostim does not provide evidence of clinical superiority for one treatment relative to the other. The manufacturer did, however, conclude that eltrombopag and romiplostim have ‘equal efficacy’ and applied this assumption to the cost-effectiveness analysis.

3.16               The manufacturer presented an indirect comparison of eltrombopag with standard care alone (excluding eltrombopag and romiplostim). The manufacturer restricted the treatments used in standard care to those included in the international consensus report: intravenous immunoglobulin G, anti-D, rituximab, corticosteroids, vinca alkaloids, mycophenolate mofetil, ciclosporin, cyclophosphamide, danazol and dapsone. The manufacturer’s systematic review identified 113 studies (including 20 RCTs). However, the manufacturer altered its inclusion criteria after performing the search which resulted in it excluding most of the identified studies. The manufacturer combined results from 37 studies including 6 RCTs to calculate weighted averages of response rate, time to response and duration of response for each drug used within the standard care pathway. The manufacturer pooled data regardless of the definition of response, and calculated the efficacy of each intervention using a simple average. The manufacturer highlighted that the results of the weighted averages for each of the included treatments were obtained mainly from non-randomised, highly heterogeneous, older trials; however, the manufacturer acknowledged that the results largely reflected the response rates outlined in the international consensus report (Provan et al. 2010) and in Romiplostim for the treatment of chronic immune or idiopathic thrombocytopenic purpura (NICE technology appraisal guidance 221).

Cost effectiveness

3.17               The manufacturer developed a de novo economic model to assess the cost effectiveness of eltrombopag in 2 populations of chronic ITP:

• adults who have not had a splenectomy
• adults who have had a splenectomy, but are refractory to previous treatments.

The group of patients who have not had a splenectomy was assumed to reflect patients for whom a splenectomy is contraindicated.

3.18               The cost-effectiveness model developed by the manufacturer is a state-transition Markov cohort model that adopts a 4-week cycle length. The model simulates patients with chronic ITP who receive eltrombopag plus standard care, romiplostim plus standard care, or standard care alone, and estimates their costs and outcomes. The manufacturer assumed that all patients entering the model are refractory to first-line treatment with corticosteroids or immunoglobulins. In a cohort of patients starting a treatment, the model permits the platelet count to reach a level of 50×10⁹ per litre or more (equal to a response) in the first, second, third or fourth cycle, when each cycle represents a specific treatment. When the platelet count reaches a level of 50×10⁹ per litre, patients have a treatment-specific probability of losing the response in each cycle, and of receiving rescue therapy when bleeding occurs or a patient is at high risk of bleeding. If the platelet count does not reach a level of 50×10⁹ per litre, patients stop treatment, but may receive rescue therapy (intravenous immunoglobulin, anti-D and corticosteroids), which would result in a temporary platelet response lasting for 1 cycle. During each cycle, a proportion of patients whose platelet count did not respond exit the ‘non-responder’ state and move on to other treatments further down the treatment sequence. Rates of rescue treatment, rates of non-severe bleeds treated in the outpatient setting, and rates of severe bleeds treated in the inpatient setting differed by response status, with patients whose condition responds experiencing lower rates than those whose condition does not. The model assumes that patients who are less likely to bleed are less likely to die.

3.19               The economic evaluation compared 3 treatment sequences: a pathway reflecting standard care without a thrombopoietin agonist (sequence ‘a’: azathioprine, mycophenolate mofetil, ciclosporin, danazol, dapsone, cyclophosphamide, vinblastine and vincristine), eltrombopag with standard care (eltrombopag followed by sequence ‘a’), and a pathway of romiplostim with standard care (romiplostim followed by sequence ‘a’). The sequence of treatments for standard care reflects that used by the manufacturer of romiplostim for NICE technology appraisal guidance 221, except that the current submission removes rituximab from the sequence for the base-case analysis. This is because, as the manufacturer explained, UK local guidance to clinical practice suggests that clinicians are likely to offer rituximab to patients before eltrombopag or romiplostim. The manufacturer discounted costs and benefits at an annual 3.5% rate.

3.20               The manufacturer submitted 3 separate economic evaluations: a base case, an ‘alternative’ evaluation and a scenario analysis. In the base case, the manufacturer applied a set of assumptions it deemed most relevant to the decision problem, using NICE technology appraisal guidance 221 as its main source of data and assumptions. The only base-case model parameters that were sourced from the RAISE and EXTEND data are the TPO-RA response rates and the TPO-RA time on treatment. The alternative evaluation applied data from RAISE and EXTEND along with clinical evidence retrieved from the manufacturer’s systematic review updated for this appraisal. In the scenario analysis, the manufacturer applied all available assumptions and model inputs used in the economic evaluation for romiplostim in NICE technology appraisal guidance 221(including those that were not used for the base case) to try to replicate the analysis in this technology appraisal as closely as possible.

3.21               In the base case and alternative evaluation, the manufacturer assumed that the response rate (attaining a platelet count of 50–400×10⁹ per litre, at any time during the 6-month study period) for eltrombopag was the same as that observed in RAISE. The manufacturer assumed in the model that, if a patient attained a platelet response at any time during the 6-month period, the patient maintained the platelet response while on treatment and had a probability of bleeding and death as if the platelet concentration had remained elevated. Both the base case and alternative evaluation assumed complete clinical equivalence between eltrombopag and romiplostim, and so, a patient in the model taking eltrombopag had the same rate of platelet response as a patient taking romiplostim. The manufacturer assumed that the effectiveness of the 2 treatments was the same because its indirect comparison had not shown that the treatments were different (section 3.15). However, the manufacturer included sensitivity analyses to test the possibility that romiplostim was more effective than eltrombopag by applying the odds ratio for overall response for eltrombopag compared with romiplostim (0.22) from its indirect comparison.

3.22               For treatments considered to be standard care, the manufacturer took response rates from NICE technology appraisal guidance 221 for the base case, in which the response rates were calculated from a systematic review done by the manufacturer of romiplostim. In the alternative evaluation, the manufacturer estimated response rate for each treatment from its indirect comparison between eltrombopag and treatments comprising standard care (section 3.16).

3.23               In the base case and alternative evaluation, the time to platelet response for eltrombopag was taken by the manufacturer from RAISE and assumed to be 15 days (standard error 3.75 days). For romiplostim, the time to response was assumed to be 28 days (standard error 7 days) as observed in the Kuter et al. (2008) trials. For treatments comprising standard care for the base case, time to response was taken from NICE technology appraisal guidance 221, and for the alternative evaluation, from the manufacturer’s indirect comparison between eltrombopag and standard care (section 3.16).

3.24               Because the manufacturer assumed that eltrombopag and romiplostim were equally effective, it also assumed that time on treatment was the same for eltrombopag and romiplostim. To extrapolate the time on treatment beyond the period observed in the trials and over a lifetime horizon, the manufacturer modelled time on treatment as a survival variable based on patient-level treatment discontinuation data from RAISE and EXTEND, and carried out a parametric analysis. The analysis showed that, among patients who achieved a response to treatment, those who had a splenectomy spend less time on eltrombopag or romiplostim than those who did not have a splenectomy.

3.25               For the time on treatment for therapies included in standard care, the manufacturer took values from NICE technology appraisal guidance 221 to apply to its base case. In its alternative evaluation, the manufacturer took the value from the indirect comparison between eltrombopag and standard care (section 3.16). The manufacturer assumed that, in the absence of robust data, time on treatment for standard therapy followed an exponential distribution.

3.26               The manufacturer assumed that the risk of bleeding in the model is a function of platelet response irrespective of treatment and so, patients with platelet counts of 50×10⁹ per litre or more were at risk of bleeds that were non-severe (treated as an outpatient), and patients with platelet counts of less than 50×10⁹ per litre had a risk of bleeds that were either severe (needing inpatient care) or non-severe. For its base case, the manufacturer applied the rates of bleeding previously used in NICE technology appraisal guidance 221 of romiplostim. For patients not attaining a platelet response, the rate of severe bleeds applied for the base-case modelling was 4.3% per month. For its alternative evaluation, the manufacturer used the rate of severe bleeds from RAISE and EXTEND (0.8% per month). The manufacturer assumed that patients who are refractory to all previous treatments are twice as likely to bleed as patients whose condition does not respond to treatment but who are between treatments. The manufacturer took this assumption from NICE technology appraisal guidance 221.

3.27               The manufacturer modelled mortality from chronic ITP as a function of severe bleeds in the base case and alternative evaluation, and explored the possibility that mortality was a function of the platelet count in a sensitivity analysis. For each bleed for which a patient needed to be hospitalised, the manufacturer applied a mortality rate from Danese et al. (2009), and assumed that this rate is twice the normal rate for patients who are refractory to all previous treatments. The manufacturer considered that the categories of bleeds that, if experienced by patients, required them to be hospitalised included gastrointestinal haemorrhage, intracranial haemorrhage and haemorrhage resulting from a ‘coagulation disorder’.

3.28               For the base case, the modelling assumed that only patients with platelet counts of less than 50×10⁹ per litre receive rescue medication, the types and rates of which were used in NICE technology appraisal guidance 221. The rate of rescue therapy for patients who had a splenectomy was 68%, and for patients who did not have splenectomy was 33%. The rescue medications included intravenous immunoglobulin, anti-D and corticosteroids, and were modelled in the proportions in which they would be used based on a physician survey of 169 UK haematologists conducted by the manufacturer of romiplostim for NICE technology appraisal guidance 221. In the alternative evaluation, the manufacturer used data from countries with healthcare resources comparable to the UK in RAISE and EXTEND to estimate the rate of rescue for patients with platelet counts above and below 50×10⁹ per litre.

3.29               Adverse events in the model were considered as either severe or ‘other’. In the base case and alternative evaluation, the manufacturer assumed that adverse event rates for eltrombopag and romiplostim were equivalent and used the rate from NICE technology appraisal guidance 221. The manufacturer estimated adverse event rates for treatments included in standard care from the same technology appraisal.

3.30               Although RAISE and EXTEND included health-related quality-of-life data, the manufacturer chose to use utility data for the base case and alternative evaluation from a study it had identified (Szende et al. 2010). This study developed 6 ITP-related health states that investigators had evaluated using time trade-off in 359 members of the UK general public.

3.31               The manufacturer undertook a systematic review of relevant resource data for the UK, but did not identify any relevant studies. Therefore, it used unpublished data to estimate costs including the costs of acquisition and administration of the intervention and comparators, and the costs of the rescue medications, as well as the costs of monitoring. The manufacturer took the list prices of the different drugs from BNF edition 63 and applied the patient access schemes for eltrombopag and romiplostim. The manufacturer calculated the average doses of eltrombopag from RAISE, and after the 6-month study period, it estimated a stable dose from the EXTEND study. For romiplostim, the manufacturer calculated the average doses from Kuter et al. (2008) and assumed that the dose on which a patient is likely to remain (the stable dose) equals the last dose from the trials. Dosages of drugs other than romiplostim and eltrombopag were taken from Provan et al. (2010), the international consensus report, or NICE technology appraisal guidance 221. Eltrombopag and other oral treatments did not have administration costs. Because romiplostim is subcutaneous, it can be administered at home or at hospital; the manufacturer assumed that costs were incurred only when the drug was administered in hospital. The cost of bleeds covered cost of drugs, hospitalisation and follow-up. The manufacturer assumed that all patients, regardless of treatment, needed monitoring by a haematologist and 2 laboratory tests every 4 weeks.

3.32               In the manufacturer’s base-case cost-effectiveness analyses, eltrombopag dominated romiplostim (was more effective and less costly) for patients who had or did not have a splenectomy. When eltrombopag was compared with standard care, eltrombopag dominated standard care in the analysis for patients who had a splenectomy, and the incremental cost-effectiveness ratio (ICER) was £15,105 per quality-adjusted life year (QALY) gained in the analysis of patients who did not have a splenectomy.

3.33               The manufacturer carried out a wide range of sensitivity analyses on the base case varying 1 parameter at a time. For patients who had a splenectomy, eltrombopag dominated the standard care pathway in all analyses explored. Eltrombopag dominated romiplostim in all analyses except when the model included the odds ratio from the indirect comparison (0.22, section 3.13) to estimate the relative efficacy of eltrombopag compared with romiplostim for overall response. In this scenario, romiplostim offered 0.56 additional QALYs compared with eltrombopag, but at an additional cost of £95,649 for romiplostim. This gave an ICER for eltrombopag compared with romiplostim of £171,156 saved per QALY lost (that is, eltrombopag is less effective but also less expensive than romiplostim). For patients who did not have a splenectomy, the ICER for eltrombopag compared with standard care remained below £33,000 per QALY gained in all scenarios except when a 6-month time horizon was used, in which case the ICER for eltrombopag compared with standard care was £74,250 per QALY gained, and for the comparison of eltrombopag with romiplostim, eltrombopag consistently dominated romiplostim, except when the odds ratio from the indirect comparison was used to estimate the relative efficacy of eltrombopag and romiplostim for overall response (OR 0.22, section 3.13). In this scenario, romiplostim offered 0.46 additional QALYs compared with eltrombopag, but at an additional cost of £51,416. This gave an ICER for eltrombopag compared with romiplostim of £110,983 saved per QALY lost. The manufacturer did not perform one-way sensitivity analyses on the results of the alternative evaluation or the scenario analysis.

3.34               The manufacturer also carried out probabilistic sensitivity which showed that there was a 65% probability that the base-case ICER was lower than £20,000 per QALY gained, and a 70% probability that it was lower than £30,000 per QALY gained for patients who had a splenectomy. For patients who did not have a splenectomy, the probability that the base-case ICER was lower than £20,000 and £30,000 per QALY gained was 54% and 63% respectively.

3.35               In the manufacturer’s alternative evaluation, eltrombopag dominated romiplostim in the analyses for patients who had or did not have a splenectomy. When eltrombopag was compared with standard care, the ICER for eltrombopag was £61,337 per QALY gained in the analysis for patients who had a splenectomy, and £95,536 per QALY gained in the analysis for patients who did not have a splenectomy.

3.36               The manufacturer presented a scenario analysis to replicate the analysis for NICE technology appraisal guidance 221. For example, the manufacturer:

• assumed that eltrombopag and romiplostim are administered before rituximab in the treatment pathway
• assumed that time on treatment followed an exponential distribution (instead of a log-normal distribution for the base case)
• remodelled the response rates for eltrombopag and romiplostim to exclude patients whose condition responded to unlicensed doses
• calibrated rescue rates to produce rates when the treatment pathway is set to exclude maintenance treatments.
• based utility values on pooled EQ-5D and vignette utility data as per NICE technology appraisal guidance 221
• estimated the number of vials of romiplostim needed from NICE technology appraisal guidance 221
• set administration costs to £262 per cycle for all treatments and assumed that romiplostim did not incur further costs of administration.

3.37               In the scenario analysis, eltrombopag dominated both romiplostim and standard care in all patients.

Evidence Review Group critique and exploratory analyses

3.38               The ERG reviewed the clinical evidence submitted by the manufacturer and stated that the manufacturer identified all relevant studies comparing eltrombopag with placebo and presented a suitable meta-analysis. The ERG considered that the literature review carried out by the manufacturer to estimate efficacy for standard care was reasonable.

3.39               For the indirect comparison of eltrombopag with romiplostim, the manufacturer used a Mantel-Haenszel fixed-effect approach to combine the results of the 2 Kuter et al. (2008) trials and then used the Bucher method. The ERG expressed the following concerns about this methodology:

• Heterogeneity exists between the 2 Kuter et al. trials, and pooling their results may have introduced bias.
• Although differences exist between RAISE and the 2 Kuter et al. trials (section 3.15), the ERG felt that it was reasonable for the manufacturer to proceed with the indirect comparison, but advised caution with respect to the results.
• Because the manufacturer had presented the indirect comparison stratified by splenectomy status, the analyses do not preserve randomisation in RAISE, and the ERG considered them to be observational analyses.

3.40               The ERG performed an exploratory indirect comparison between eltrombopag and romiplostim for durable and overall response outcomes, and for clinically significant and moderate bleeds using a Bayesian network meta-analysis to account for the heterogeneity between studies. For durable response and bleeding, the ERG found similar results to that of the manufacturer. For overall response, the manufacturer had found no statistically significant difference between treatments (OR 0.22; 95% CI 0.05 to 1.02), but the ERG found a statistically significant benefit for romiplostim (OR 0.15; 95% credible interval 0.02 to 0.84).

3.41               For the indirect comparison of eltrombopag with standard care, the ERG expressed concerns about the methodological rigor of the manufacturer’s approach. Because the manufacturer excluded studies from the systematic review after the review had been performed, and had pooled response estimates using a simple weighted average regardless of the definition of response, the ERG considered that bias may exist. The ERG recommended caution when considering the result of the indirect comparison.

3.42               The ERG noticed that a major weakness of the manufacturer’s base case related to the manufacturer having chosen not to use data from eltrombopag’s RCTs directly or from its systematic review, and instead having opted to populate the base-case model with parameter estimates from NICE technology appraisal guidance 221 for romiplostim. Because of this, the ERG considered the alternative evaluation to be more appropriate.

3.43               The ERG had concerns about the assumption made by the manufacturer that eltrombopag and romiplostim are equally effective, given the uncertainty around the results of the indirect comparison of eltrombopag and romiplostim (section 3.15).

3.44               The ERG noted that the manufacturer did not address the optimal positioning of eltrombopag and romiplostim within the treatment sequence in the model. The manufacturer assumed that, in the treatment pathway, eltrombopag and romiplostim followed after rituximab, but before other drugs used in standard care. In addition, the ERG indicated that there is uncertainty about the optimal place of eltrombopag and romiplostim if one assumes they are not clinically equivalent. The ERG stated that the manufacturer should have explored additional treatment sequences.

3.45               The ERG had concerns about the manufacturer’s assumption that ‘response’ and ‘platelet response’ are the same. The ERG noted that, in RAISE, only 60–80% of patients who achieved a response to eltrombopag had an ongoing platelet response of more than 50×10⁹ per litre. Because, in the model, platelet counts drive bleeding rates and mortality, the manufacturer’s assumption would improve the ICERs for eltrombopag and romiplostim.

3.46               The manufacturer averaged eltrombopag and romiplostim doses from the relevant trials across patients whose condition had responded and patients whose condition had not. The ERG noted that, in the Kuter et al. (2008) trials, the average romiplostim dose in patients whose condition had responded was 40–60% lower than that across the trial as a whole. If a similar argument holds for eltrombopag, the ERG indicated that the cost effectiveness of eltrombopag compared with standard care may improve, but the cost effectiveness of eltrombopag compared with romiplostim may worsen given the low dose for patients attaining a durable response with romiplostim. The ERG stated that eltrombopag and romiplostim doses should be response-specific.

3.47               To model utility, the ERG considered that the manufacturer should have used the SF-6D health-related quality-of-life data collected from the trials (RAISE and EXTEND) in the base case because these are directly collected patient-level data derived from a validated generic instrument.

3.48               The ERG questioned the manufacturer’s assumption that the severe bleed rate doubles for patients whose ITP is refractory to all previous treatments, noting that these rates were high.

3.49               The ERG undertook exploratory sensitivity analyses to the base case and alternative evaluation to check the impact on the ICERs, which included the following:

• The ERG applied the overall response rates from the manufacturer’s indirect comparison (OR 0.22) to the base case and alternative evaluation. In both the base-case analysis and alternative evaluation, the ERG found that eltrombopag was associated with both fewer QALYs and lower costs compared with romiplostim for all patients when the overall response rates were applied. For the base analysis, the ICERs for eltrombopag compared with romiplostim suggested savings of £174,503 per QALY lost for people who had a splenectomy. The ERG reported modelled costs and QALYs for the base case for people who did not have a splenectomy, and also for both subpopulations using the alternative evaluation. For the base-case analysis, when eltrombopag was compared with other drugs used in standard care, eltrombopag was dominant for people who had a splenectomy and gave an ICER of £15,843 per QALY gained for people who did not have a splenectomy. For the alternative evaluation, the ICERs for eltrombopag (compared with drugs used in standard care) were £73,335 and £108,336 per QALY gained for people who had or did not have a splenectomy respectively.
• The ERG applied the SF-6D utility data collected from RAISE and EXTEND to the base case and alternative evaluation. The ERG found that eltrombopag dominated romiplostim for both the base case and alternative evaluation regardless of whether or not the patient has had a splenectomy. For the base-case analysis, when eltrombopag was compared with other drugs used in standard care, eltrombopag was dominant for people who had a splenectomy and gave an ICER of £18,489 per QALY gained for people who did not have a splenectomy. When the ERG applied the utility values to the alternative evaluation, eltrombopag (compared with drugs used in standard care) was associated with ICERs of £90,753 and £133,508 per QALY gained for people who had or did not have a splenectomy respectively.
• The ERG reduced modelled doses of romiplostim by 40% for patients who had a splenectomy and 60% for patients who did not have a splenectomy in the base case and alternative evaluation. The ERG found that, despite the reduced cost of romiplostim, eltrombopag dominated romiplostim in both the base case and alternative evaluation regardless of whether patients had a splenectomy or not.

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

4  Consideration of the evidence

4.1                  The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of eltrombopag, having considered evidence on the nature of chronic ITP and the value placed on the benefits of eltrombopag by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.

4.2                  The Committee discussed the nature of the condition with patient experts and clinical specialists, and heard that chronic ITP impacts on quality of life by affecting both the physical and emotional wellbeing of people with the condition. The Committee heard that the symptoms associated with chronic ITP vary; some people may not have any signs or symptoms, while others have fatigue and bruise easily. The Committee heard from patient experts and clinical specialists that chronic ITP may cause a patient to worry about the risk of bleeding because significant bleeding would normally cause a person to seek medical care, receive rescue treatment and possibly be hospitalised. The Committee recognised that the anxiety related to bleeding may affect work or leisure activities, and, in extreme cases, cause people to become housebound. The Committee heard that family members may also worry on behalf of their relatives about the complications that may result from low platelet counts. The Committee recognised that adequate treatment could psychologically benefit people with chronic ITP and their families by reducing anxiety and enabling them to lead more normal lives. The Committee agreed that these benefits may not be fully captured in the QALY within the modelling.

4.3                  The Committee discussed the clinical management of chronic ITP. The clinical specialists explained to the Committee that the management of ITP varies depending on individual circumstances, and the specialists could define no single treatment pathway as routine practice. The Committee understood that treatment would not normally be determined solely on the platelet count, but that clinicians tended to offer active treatment to patients with low platelet counts or before surgery. The Committee heard that splenectomy would be considered as first-line, second-line or subsequent-line treatment, and that approximately two-thirds of patients can expect splenectomy to succeed. The Committee was aware that splenectomy might be contraindicated in patients at greater risk of bleeding, but that laparoscopic procedures for splenectomy have lowered the risk of bleeding.

4.4                  The Committee heard from patient experts about the perceived benefits of eltrombopag for patients with chronic ITP. It understood that a daily oral treatment would represent significant value for some patients with chronic ITP, while other patients preferred romiplostim administered weekly by subcutaneous injections. The Committee heard from patient experts that some patients take a tablet of eltrombopag only once every 3 days rather than daily. The Committee noted that the summary of product characteristics states potential interactions of eltrombopag with dairy or calcium-containing products. The patient experts felt that, given the severity of ITP and the alternative treatment options available, few patients would have difficulties adhering to eltrombopag’s dosage regimen because most patients would take the medication before bedtime to minimise the impact of dairy or calcium-containing foods on absorption. The Committee recognised that an oral treatment would add value for patients who have an aversion to needles.

4.5                  The Committee considered the place of eltrombopag in the treatment pathway for people with chronic ITP and discussed the appropriate comparators, noting the licensed indications for eltrombopag. The Committee heard from the clinical specialists that there are few treatment options licensed for people with chronic ITP and that eltrombopag, along with romiplostim, represents an effective approach. The Committee heard from clinical specialists that they are likely to offer eltrombopag to people whose condition is refractory to rituximab, or who are intolerant of rituximab although rituximab is not licensed for the treatment of chronic ITP.

4.6                  The Committee noted that the manufacturer’s decision problem compared a pathway of eltrombopag plus standard care with a pathway of standard care alone, and separately with a pathway of romiplostim plus standard care. In all 3 pathways, the manufacturer defined standard care as sequential use of rituximab, azathioprine, mycophenolate mofetil, ciclosporin, dapsone, danazol, cyclophosphamide, vincristine and vinblastine. The Committee was aware that, since the publication of NICE technology appraisal guidance 221, standard care within the NHS in England and Wales includes romiplostim. The Committee therefore considered it appropriate for the manufacturer primarily to examine the clinical and cost effectiveness of eltrombopag compared with the pathway incorporating romiplostim.

 Clinical effectiveness

4.7                  The Committee considered the evidence on the clinical effectiveness of eltrombopag, noting that the evidence was derived mainly from the RAISE trial. It concluded that the available evidence showed that eltrombopag was clinically effective when compared with placebo in attaining the target platelet count and reducing the need of rescue medication.

4.8                  The Committee discussed the safety and tolerability of eltrombopag and noted that the adverse effects other than bleeding were similar between the eltrombopag and placebo groups in RAISE. The Committee heard from the clinical specialists that the adverse effects of standard treatments for chronic ITP (such as those associated with corticosteroid use) limit both the use and duration of treatment, and that eltrombopag had a different mode of action. The Committee recognised the lack of long-term safety data for both eltrombopag and romiplostim; however, it acknowledged that both treatments had good safety profiles when compared with other available treatments for chronic ITP.

4.9                  The Committee discussed the appropriateness of the manufacturer’s indirect comparison between eltrombopag and romiplostim. The Committee was aware that both the manufacturer and the ERG had highlighted differences in baseline patient characteristics between RAISE and the 2 Kuter et al. (2008) trials. It noted that the differences were modest but suggested that, because more patients in the romiplostim trials had been on multiple previous therapies, they were more reflective of patients whose disease had not responded, and whose disease was less likely to respond than patients in the eltrombopag trials. For the outcomes of bleeding, the Committee considered the different scales that had been used in the trials. It heard from the clinical specialists that no scales are used routinely, and that existing scales categorise the bleeds in a broadly similar way. The Committee concluded that it would be appropriate to perform an indirect comparison between both treatments.

4.10               The Committee considered the results of the manufacturer’s indirect comparison and the ERG’s exploratory analysis between eltrombopag and romiplostim, noting the difference in the statistical approaches used to arrive at the estimates. The Committee noted that the manufacturer’s indirect comparison gave point estimates that suggested that romiplostim is more effective than eltrombopag, but for overall response the upper limit of the 95% confidence interval was 1.02. The Committee understood that the statistical approach used by the manufacturer did not account for heterogeneity between the 2 Kuter et al. (2008) trials. The Committee considered the exploratory indirect comparison performed by the ERG, which treated the Kuter et al. trials separately and used a Bayesian approach. It noted that, for durable response and bleeding, the ERG found similar results to those of the manufacturer. However, for overall response, the ERG found that romiplostim was superior to eltrombopag (OR 0.15; 95% credible interval 0.02 to 0.84). The Committee noted that the ERG’s results depended on the degree of heterogeneity assumed. The Committee agreed that the point estimates in both the manufacturer’s and the ERG’s analyses were associated with uncertainty.

4.11               The Committee considered the relative effectiveness of eltrombopag and romiplostim in light of the manufacturer’s indirect comparison and the ERG’s exploratory analysis. It noted that the manufacturer interpreted the effectiveness of the 2 drugs as the same (that is, not different). The Committee heard from the clinical specialists that it is difficult to know if one treatment is superior to the other, but that the use of eltrombopag and romiplostim in clinical practice is broadly interchangeable. The clinical specialists indicated that the manufacturer’s indirect comparison may have underestimated the clinical effectiveness of romiplostim given that romiplostim preceded eltrombopag, and so trials for romiplostim enrolled patients whose condition was relatively more severe. The Committee agreed that the available evidence suggested that romiplostim was likely to be more effective than eltrombopag rather than equally effective and therefore it did not agree with the manufacturer’s interpretation of the evidence. The Committee concluded that, given the uncertainty around the point estimates obtained from the indirect comparison, when eltrombopag is compared with romiplostim, the most plausible odds ratio for overall response is likely to be less than 1.00, but more than 0.22.

4.12               The Committee understood that there was no direct evidence comparing eltrombopag with standard care, and discussed the manufacturer’s indirect comparison. The Committee noted that the evidence was derived mainly from non-randomised, highly heterogeneous trials, and that the manufacturer had altered its inclusion criteria after performing the review. As the Committee had decided that the appropriate comparison should be with romiplostim, it did not consider further the clinical effectiveness of eltrombopag compared with standard care that did not involve romiplostim.

Cost effectiveness

4.13               The Committee considered the manufacturer’s estimates of cost effectiveness that compared eltrombopag with romiplostim, and the ERG’s comments on the analyses. The Committee was aware that all 3 analyses applied the manufacturer’s assumption that eltrombopag and romiplostim were equally effective. The Committee agreed with the ERG’s view that, of the 3 economic evaluations (the base-case analysis, the alternative evaluation and the scenario analysis), the alternative evaluation represented the most valid analysis because the modelling applied data derived directly from pivotal trials of eltrombopag and the manufacturer’s own systematic review. The Committee discussed the ERG’s concerns about the source of health-related quality of life data used by the manufacturer in the model. The Committee noted that the manufacturer did not use the SF-6D utility data collected from RAISE and EXTEND to model health- related quality of life, incorporating them into a sensitivity analysis for the base case, but not into the alternative evaluation favoured by the Committee. Therefore, the Committee instead considered the analysis carried out by the ERG in which it incorporated the SF-6D utility data within the alternative evaluation. In this, the Committee noted that eltrombopag dominated romiplostim for all patients.

4.14               The Committee discussed the ERG’s concern about romiplostim dosing in the analyses (section 3.46). It noted that the doses of romiplostim used in the manufacturer’s model were not response-specific (that is, did not depend on whether or not the patient’s condition had responded), and that in the Kuter et al. (2008) trials, the average romiplostim dose in patients whose condition had responded was 40–60% lower than that across the trial as a whole. The Committee considered the exploratory analysis carried out by the ERG in which it incorporated a reduced dose of romiplostim within the alternative evaluation as a one-way sensitivity analysis. In this, the Committee noted that despite the dose reduction and the subsequent cost reduction of romiplostim, eltrombopag dominated romiplostim in the alternative evaluation (and the base case) regardless of the splenectomy status.

4.15               The Committee discussed what would be the most plausible ICERs for eltrombopag compared with romiplostim. The Committee preferred the manufacturer’s alternative evaluation, but because the Committee did not accept the assumption of clinical equivalence between eltrombopag and romiplostim (section 4.11), it instead considered the manufacturer’s one-way sensitivity analysis of the base case, which had applied the overall response estimate from the indirect comparison (OR 0.22) suggesting superiority of romiplostim. In this instance, eltrombopag was associated with both fewer QALYs and lower costs compared with romiplostim for all patients; the corresponding pairwise ICERs suggested savings of £171,156 and £110,983 per QALY lost for patients who had or who did not have a splenectomy respectively. The Committee noted that the ICER for people who had a splenectomy from the equivalent ERG’s sensitivity analysis was similar with £174,503 per QALY lost. The Committee noted that the ERG did not explicitly report ICERs for eltrombopag compared with romiplostim from its exploratory sensitivity analyses from the alternative evaluation, but from the costs and QALYs presented in the ERG report, the Committee estimated that using the point estimates from the indirect comparison (wherein romiplostim is more effective than eltrombopag) would lead to ICERs (savings) of more than £400,000 per QALY lost for both subpopulations. The Committee considered that even if romiplostim relative to eltrombopag were somewhat less effective, the ICERs would remain high. The Committee considered that in situations where an ICER is derived from decreased effectiveness and decreased costs, the commonly assumed decision rule of accepting ICERs below a given threshold is reversed, and so the higher the ICER, the more cost effective a treatment becomes. The Committee therefore concluded that the ICERs in this case indicate that eltrombopag can be considered cost effective compared with romiplostim.

4.16               The Committee discussed the implications of considering a treatment that may be less effective and is less costly than romiplostim. The Committee noted that the statistical evidence was not robust enough to confirm clinically important differences in eltrombopag compared with romiplostim. The Committee was aware that some patients would prefer eltrombopag to romiplostim. The Committee was aware that no sensitivity analysis was available that included the point estimates from the indirect comparison, the SF-6D utility data collected from RAISE and EXTEND and the reduced dose of romiplostim but estimated that including all of these factors would not lower the ICERs to a degree where the Committee would change its decision. The Committee concluded that eltrombopag should be recommended as an option for treating chronic ITP in people who had a splenectomy and whose condition is refractory to standard active treatments and rescue therapies or who did not have a splenectomy because of contraindications to surgery for splenectomy, and if the manufacturer provides eltrombopag with the discount agreed in the patient access scheme.

4.17               The Committee was aware that the UK ITP Registry collects data on the long-term outcomes of patients treated with romiplostim and eltrombopag. The Committee concluded that these data would be useful for future appraisals of treatments for chronic ITP.

Summary of Appraisal Committee’s key conclusions

TAXXX	Appraisal title: Eltrombopag for treating chronic immune (idiopathic) thrombocytopenic purpura (review of technology appraisal 205)		Section
Key conclusion
Eltrombopag is recommended within its marketing authorisation as an option for treating chronic immune (idiopathic) thrombocytopenia purpura: in adults who have had a splenectomy and whose condition is refractory to other treatments (for example, corticosteroids or immunoglobulins) or as second-line treatment, in adults who have not had a splenectomy because surgery is contraindicated. and if the manufacturer provides eltrombopag with the discount agreed in the patient access scheme. The Committee considered that the principal comparator for eltrombopag is romiplostim. However, the Committee agreed that the available evidence did not support the manufacturer’s assumption that eltrombopag is equally effective as romiplostim, and that the indirect comparison suggested that eltrombopag was less effective than romiplostim. In the analyses applying the odds ratio for overall response from the indirect comparison, eltrombopag was associated with both fewer QALYs and lower costs than romiplostim, which gave very high ICERs. In situations where an ICER is derived from decreased effectiveness and decreased costs, the commonly assumed decision rule of accepting ICERs below a given threshold is reversed, and so the higher the ICER, the more cost effective a treatment becomes. The ICERs in this case indicate that eltrombopag can be considered cost effective compared with romiplostim.			1.1, 4.6, 4.11, 4.15
Current practice
Clinical need of patients, including the availability of alternative treatments		The Committee heard that chronic ITP impacts on quality of life by affecting both the physical and emotional wellbeing of people with the condition. The patient experts indicated that the symptoms associated with chronic ITP vary; some people may not have any symptoms, while others have fatigue and bruise easily. The Committee heard from patient experts and clinical specialists that chronic ITP may be associated with varying levels of anxiety caused by the worry about the risk of bleeding, and the need to urgently seek medical care, which may affect the ability of patients with chronic ITP to lead a normal life. The Committee heard that family members may also worry on behalf of their relatives. The Committee recognised that adequate treatment could psychologically benefit people with chronic ITP and their families by reducing anxiety and enabling them to lead more normal lives. The Committee heard from the clinical specialists that there are few treatment options licensed for people with chronic ITP and that eltrombopag, along with romiplostim, represents an effective approach.	4.2, 4.5
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 understood that a daily oral treatment would represent significant value for some patients with chronic ITP.	4.4
What is the position of the treatment in the pathway of care for the condition?		The Committee heard from clinical specialists that they are likely to offer eltrombopag to people whose condition is refractory to rituximab, or who are intolerant of rituximab.	4.5
Adverse reactions		The adverse effects other than bleeding were similar between the eltrombopag and placebo groups in RAISE. The Committee heard from the clinical specialists that the adverse effects of standard treatments for chronic ITP (such as those associated with corticosteroid use) limit both the use and duration of treatment, and that eltrombopag had a different mode of action. The Committee recognised the lack of long-term safety data for both eltrombopag and romiplostim; however, it acknowledged that both treatments had good safety profiles when compared with other available treatments for chronic ITP.	4.8
Evidence for clinical effectiveness
Availability, nature and quality of evidence		The evidence on the clinical effectiveness of eltrombopag was derived mainly from the RAISE trial. It showed that eltrombopag was clinically effective when compared with placebo. In the manufacturer’s indirect comparison between eltrombopag and romiplostim, both the manufacturer and the ERG had highlighted sources of heterogeneity in RAISE and the 2 Kuter et al. (2008) trials. The Committee concluded that it would be appropriate to perform an indirect comparison between both treatments, acknowledging the uncertainty around the point estimates in both the manufacturer’s and the ERG’s indirect comparisons.	4.7, 4.9, 4.10
Relevance to general clinical practice in the NHS		No specific Committee considerations on the relevance to general clinical practice in the NHS.
Uncertainties generated by the evidence		The Committee discussed the sources of heterogeneity in RAISE and the 2 Kuter et al. (2008) trials. It noted that the differences in baseline patient characteristics were modest but suggesting that patients in the romiplostim trials were representative of those whose disease was less likely to respond than were patients in the eltrombopag trials. For the outcomes of bleeding, different scales had been used in the trials, and the Committee heard from the clinical specialists that no scales are used routinely, and that existing scales categorise the bleeds in a broadly similar way. The Committee considered the results of the manufacturer’s indirect comparison and the ERG’s exploratory analysis between eltrombopag and romiplostim, noting the difference in the statistical approaches used to arrive at the estimates. The Committee understood that the statistical approach used by the manufacturer did not account for the heterogeneity between the 2 Kuter et al. (2008) trials, and noted that the ERG’s results depended on the degree of heterogeneity assumed. The Committee agreed that the point estimates in both the manufacturer’s and the ERG’s analyses were associated with uncertainty.	4.9, 4.10
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?		Not applicable.
Estimate of the size of the clinical effectiveness including strength of supporting evidence		The available evidence showed that eltrombopag was clinically effective when compared with placebo. Given the uncertainty around the point estimates obtained from the indirect comparison, when eltrombopag is compared with romiplostim, the most plausible odds ratio for overall response is likely to be less than 1.00, but more than 0.22.	4.7, 4.11
Evidence for cost effectiveness
Availability and nature of evidence		The manufacturer provided estimates of cost effectiveness for eltrombopag within a standard pathway of care compared with a standard pathway of care alone, and with romiplostim within a standard pathway of care. The manufacturer presented 3 economic analyses: a base-case analysis, an alternative evaluation and a scenario analysis.	4.13
Uncertainties around and plausibility of assumptions and inputs in the economic model		The Committee’s view was that, of the 3 analyses presented by the manufacturer, the alternative evaluation was the most valid because the modelling applied data derived directly from pivotal trials of eltrombopag and the manufacturer’s own systematic review. All economic analyses (base case, alternative evaluation and scenario analysis) incorporated the manufacturer’s assumption that eltrombopag and romiplostim were equally effective. As the Committee did not accept this assumption, it instead considered the manufacturer’s and the ERG’s sensitivity analyses, which had applied the effect estimate for overall response from the manufacturer’s indirect comparison (OR 0.22).	4.13, 4.15
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 manufacturer did not use the SF-6D utility data collected from RAISE and EXTEND to model health- related quality of life, incorporating them into a sensitivity analysis for the base case, but not into the alternative evaluation favoured by the Committee. Therefore, the Committee instead considered the analysis carried out by the ERG in which it incorporated the SF-6D utility data within the alternative evaluation. In this, eltrombopag dominated romiplostim for all patients. The Committee recognised that adequate treatment could psychologically benefit people with chronic ITP and their families by reducing anxiety and enabling them to lead more normal lives. The Committee agreed that these benefits may not be fully captured in the QALY within the modelling.	4.13, 4.2
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 key driver of cost effectiveness is the relative effect size of eltrombopag and romiplostim. The Committee did not favour the assumption of clinical equivalence between eltrombopag and romiplostim, and so considered the sensitivity analyses applying the overall response estimate from the manufacturer’s indirect comparison. In this, eltrombopag became less costly and less effective than romiplostim.	4.15
Most likely cost-effectiveness estimate (given as an ICER)		The ERG did not explicitly report ICERs for eltrombopag compared with romiplostim from its exploratory sensitivity analyses from the alternative evaluation, but from the costs and QALYs presented in the ERG report, the Committee estimated that using the point estimates from the indirect comparison (wherein romiplostim is more effective than eltrombopag) would lead to ICERs (savings) of more than £400,000 per QALY lost for both subpopulations. The Committee was aware that no sensitivity analysis was available that included the point estimates from the indirect comparison, the SF-6D utility data collected from RAISE and EXTEND and the reduced dose of romiplostim but estimated that including all of these factors would not lower the ICERs to a degree where the Committee would change its decision.	4.15, 4.16
Additional factors taken into account
Patient access schemes (PPRS)		The manufacturer of eltrombopag agreed a patient access scheme with the Department of Health, in which a confidential discount on the list price of eltrombopag is offered.	2..4
End-of-life considerations		Not applicable.
Equalities considerations and social value judgements		No equality issues were identified during scoping or in the submissions, expert statements or ERG report, or in the Committee meeting.

 

5  Implementation

5.1                  The Secretary of State and the Welsh Assembly Minister for Health and Social Services have issued directions to the NHS in England and Wales on implementing NICE technology appraisal guidance. When a NICE technology appraisal recommends use of a drug or treatment, or other technology, the NHS must usually provide funding and resources for it within 3 months of the guidance being published. If the Department of Health issues a variation to the 3-month funding direction, details will be available on the NICE website. When there is no NICE technology appraisal guidance on a drug, treatment or other technology, decisions on funding should be made locally.

5.2                  The technology in this appraisal may not be the only treatment for chronic ITP recommended in NICE guidance, or otherwise available in the NHS. Therefore, if a NICE technology appraisal recommends use of a technology, it is as an option for treating a disease or condition. This means that the technology should be available for a patient who meets the clinical criteria set out in the guidance, subject to the clinical judgement of the treating clinician. The NHS must provide funding and resources (in line with section 5.1) when the clinician concludes and the patient agrees that the recommended technology is the most appropriate to use, based on a discussion of all available treatments.

5.3                  The Department of Health and the manufacturer have agreed that eltrombopag will be available to the NHS with a patient access scheme that makes eltrombopag available with a discount. The size of the discount is commercial in confidence. It is the responsibility of the manufacturer to communicate details of the discount to the relevant NHS organisations. Any enquiries from NHS organisations about the patient access scheme should be directed to the manufacturer.

5.4                  NICE has developed tools to help organisations put this guidance into practice (listed below). These are available on our website (www.nice.org.uk/guidance/TAXXX). [NICE to amend list as needed at time of publication]Slides highlighting key messages for local discussion.

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

6  Proposed recommendations for further research

6.1                  The Committee recommends that research should be performed to directly compare eltrombopag with non-TPO-RA treatments routinely used in UK clinical practice.

7  Related NICE guidance

Published

• Romiplostim for the treatment of chronic immune or idiopathic thrombocytopenic purpura. NICE technology appraisal guidance 221 (2011).
• Eltrombopag for the treatment of chronic immune or idiopathic thrombocytopenic purpura. NICE technology appraisal guidance 205 (2010).

8  Proposed date for review of guidance

8.1                  NICE proposes that the guidance on this technology is considered for review by the Guidance Executive together with NICE technology appraisal guidance 221 ‘Romiplostim for the treatment of chronic immune or idiopathic thrombocytopenic purpura’ in March 2014. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.

Amanda Adler
Chair, Appraisal Committee
December 2012

Appendix A: Appraisal Committee members and NICE project team

A  Appraisal Committee members

The Appraisal Committees are standing advisory committees of NICE. Members are appointed for a 3-year term. A list of the Committee members who took part in the discussions for this appraisal appears below. There are four Appraisal Committees, each with a chair and vice chair. Each Appraisal Committee meets once a month, except in December when there are no meetings. Each Committee considers its own list of technologies, and ongoing topics are not moved between Committees.

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

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

Dr Amanda Adler (Chair)

Consultant Physician, Addenbrooke's Hospital

Professor Ken Stein (Vice Chair)

Professor of Public Health, Peninsula Technology Assessment Group (PenTAG), University of Exeter

Dr Ray Armstrong

Consultant Rheumatologist, Southampton General Hospital

Dr Jeff Aronson

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

Dr Peter Barry

Consultant in Paediatric Intensive Care, Leicester Royal Infirmary

Professor John Cairns

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

Mark Chapman

Health Economics and Market Access Manager, Medtronic UK

Professor Fergus Gleeson

Consultant Radiologist, Churchill Hospital, Oxford

Professor Daniel Hochhauser

Consultant in Medical Oncology

Dr Neil Iosson

General Practitioner

Anne Joshua

Associate Director of Pharmacy, NHS Direct

Terence Lewis

Lay Member

Dr Rubin Minhas

General Practitioner and Clinical Director, BMJ Evidence Centre

Dr Elizabeth Murray

Reader in Primary Care, University College London

Dr Peter Norrie

Principal Lecturer in Nursing, DeMontfort University

Dr Sanjeev Patel

Consultant Physician & Senior Lecturer in Rheumatology, St Helier University Hospital

Dr John Pounsford

Consultant Physician, Frenchay Hospital, Bristol

Dr Danielle Preedy

Lay member

Alun Roebuck

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

Roderick Smith

Finance Director, West Kent Primary Care Trust

Cliff Snelling

Lay Member

Professor Andrew Stevens

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

Dr Nerys Woolacott

Senior Research Fellow, Centre for Health Economics, University of York

B  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.

Ahmed Elsada

Technical Lead

Nicola Hay

Technical Adviser

Jeremy Powell

Project Manager

  Appendix B: Sources of evidence considered by the Committee

A          The Evidence Review Group (ERG) report for this appraisal was prepared by Aberdeen HTA Group:

• Cummins E, Fielding S, Scott N, et al., Eltrombopag for the treatment of chronic immune thrombocytopenic purpura (ITP):A Single Technology Appraisal (October 2012)

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 and II also have the opportunity to appeal against the final appraisal determination.

I            Manufacturer/sponsor:

• GlaxoSmithKline

II           Professional/specialist and patient/carer groups:

• British Blood Transfusion Society
• British Society for Haematology
• ITP Support Association
• Royal College of Nursing
• Royal College of Pathologists
• Royal College of Physicians

III          Other consultees:

• Department of Health
• NHS North Yorkshire and York
• Welsh Government

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

• Amgen
• Commissioning Support Appraisals Service
• Department of Health, Social Services and Public Safety for Northern Ireland
• Healthcare Improvement Scotland
• Roche

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 eltrombopag by attending the initial Committee discussion and providing written evidence to the Committee. They are invited to comment on the ACD.

• Dr Nichola Cooper, Consultant haematologist, Hammersmith Hospital, nominated by the ITP Support Association – clinical specialist
• Dr Jennie Wimperis, Consultant haematologist, Norfolk and Norwich University Hospital, nominated by the ITP Support Association – clinical specialist
• Chris Allen nominated by the ITP Support Association – patient expert
• Shirley Watson, nominated by the ITP Support Association – patient expert

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

• GlaxoSmithKline