The Department of Health has asked the National Institute for Health and Clinical Excellence (NICE or the Institute) to conduct a single technology appraisal (STA) of romiplostim for the treatment of chronic idiopathic (immune) thrombocytopenic purpura and provide guidance on its use to 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 formal consultees. It summarises the evidence and views that have been considered, and sets out the draft recommendations made by the Committee. NICE invites comments from the consultees and commentators for this appraisal (see appendix B) and the public. This document should be read along with the evidence base (the evaluation report), which is available from www.nice.org.uk

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

After consultation:

• The Appraisal Committee will meet again to consider the evidence, this appraisal consultation document and comments from the consultees.
• At that meeting, the Committee will also consider comments made by people who are not consultees.
• After considering these comments, the Committee will prepare the final appraisal determination (FAD).
• Subject to any appeal by consultees, the FAD may be used as the basis for NICE’s guidance on using romiplostim in the NHS in England and Wales.
• For further details, see the ‘Guide to the technology appraisal process’ (available at www.nice.org.uk).

The key dates for this appraisal are:

Closing date for comments: 26 November 2009

Second Appraisal Committee meeting: 7 January 2010

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 Romiplostim is not recommended for the treatment of people with chronic idiopathic (immune) thrombocytopenia purpura.

1.2 People currently receiving romiplostim for the treatment of chronic idiopathic (immune) thrombocytopenia should have the option to continue therapy until they and their clinicians consider it appropriate to stop.

2 The technology

2.1 Romiplostim (Nplate, Amgen) is a protein that mimics the action of thrombopoietin by acting as an agonist at thrombopoietin receptors. It stimulates the differentiation and proliferation of bone marrow cells responsible for producing platelets (megakaryocytes) and so increases platelet production. Idiopathic (immune) thrombocytopenic purpura (ITP) is an autoimmune bleeding disorder characterised by increased platelet destruction and, in some cases, inadequate platelet production. The disorder can result in low platelet counts with bleeding symptoms. ITP that lasts longer than 6 months is defined as chronic. The marketing authorisation for romiplostim states the following: ‘Nplate is indicated for adult chronic immune (idiopathic) thrombocytopenic purpura (ITP) splenectomised patients who are refractory to other treatments (e.g. corticosteroids, immunoglobulins). Nplate may be considered as second line treatment for adult non-splenectomised patients where surgery is contra-indicated.’

2.2 The summary of product characteristics (SPC) states that the recommended initial dose for romiplostim is 1 microgram/kg of actual body weight, administered once weekly as a subcutaneous injection. The dose may be adjusted by increments of 1 microgram/kg until a platelet count equal to or above 50 × 10⁹ platelets per litre of blood is achieved. A maximum dose of 10 micrograms/kg once weekly should not be exceeded. Platelet counts should be measured weekly until a stable count equal to or above 50 × 10⁹ platelets per litre for at least 4 weeks without dose adjustment has been achieved. Thereafter, platelet counts should be measured monthly. For full details of dose and administration, see the SPC.

2.3 The SPC lists a number of special warnings and precautions for the use of romiplostim, including: recurrence of thrombocytopenia and bleeding after cessation of treatment; increased bone marrow reticulin; thrombotic and/or thromboembolic complications (as a ‘theoretical risk’ from platelet counts above the reference range); and loss of response (which could be a result of immunogenicity or increased bone marrow reticulin). The SPC lists headache as a ‘very common’ undesirable effect. For full details of side effects and contraindications, see the SPC.

2.4 Romiplostim costs £1.928 per microgram; therefore a 250 microgram vial will cost £482 and a 500 microgram vial will cost £964. If romiplostim was given to a person weighing 80 kg at a set dose of 1 microgram/kg, the annual cost would be £8020; at a set dose of 5 micrograms/kg the annual cost would be £40,102, and at 10 micrograms/kg the annual cost would be £80,204. Treatment with romiplostim should be discontinued if the platelet count does not increase sufficiently to avoid clinically important bleeding after 4 weeks of romiplostim therapy at the highest weekly dose of 10 micrograms/kg. Romiplostim should also be discontinued if efficacy is lost and an abnormal peripheral blood smear indicative of increased bone marrow reticulin is observed. The cost of a course of treatment will vary depending on patient weight, dosing regimen and waste owing to unused drug from the single-use vials being discarded. Costs may vary in different settings because of negotiated procurement discounts.

3 The manufacturer’s submission

The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of romiplostim and a review of this submission by the Evidence Review Group (ERG; appendix B).

3.1 The manufacturer’s submission compared romiplostim in addition to standard care with standard care alone for patients with ITP who had undergone splenectomy and, separately, patients with ITP who had not undergone splenectomy. Evidence was derived from two placebo-controlled randomised controlled trials (RCTs) of romiplostim. One trial enrolled only patients with ITP who had undergone splenectomy; the other recruited only patients with ITP who had not undergone splenectomy. The latter RCT appeared to be not restricted to patients with a contraindication to splenectomy. Outcomes included platelet count, response rate, durable response, need for rescue treatments, use of concurrent treatments, reduction in symptoms, adverse effects of treatment, mortality and health-related quality of life.

3.2 The manufacturer reported the results of a literature review that included two phase III double-blind placebo-controlled RCTs: one enrolled patients who had undergone splenectomy (42 patients assigned to romiplostim, 21 to placebo), and the other enrolled patients who had not undergone splenectomy (41 patients assigned to romiplostim, 21 to placebo). In both studies, patients with ITP (defined as the mean of three platelet counts being below or equal to 30 × 10⁹ per litre, with none of the three counts being above 35 × 10⁹ per litre) who were refractory to at least one previous treatment were randomised to romiplostim plus standard care or standard care alone for 24 weeks. Romiplostim was given weekly. Platelet counts were monitored and dose of romiplostim adjusted to achieve and maintain a platelet count of between 50 × 10⁹ and 200 × 10⁹ per litre. Initially, the dose could be increased by 2 micrograms/kg each week (for platelet counts of 10 × 10⁹ per litre or below) or every 2 weeks (after 2 consecutive weeks of platelet counts between 10 × 10⁹ and 50 × 10⁹ per litre). The dose remained stable for platelet counts above 50 × 10⁹ per litre. If a patient’s platelet count reached 50 × 10⁹ per litre or more and subsequently fell, the maintenance dose could be increased by 1 microgram/kg each week (if the platelet count fell to 10 × 10⁹ per litre or below) or every 2 weeks (after 2 consecutive weeks if the platelet count fell to between 10 × 10⁹ and 50 × 10⁹ per litre). The dose remained stable for platelet counts of greater than 50 × 10⁹ per litre up to 200 × 10⁹ per litre. The maximum dose was 15 micrograms/kg (which is higher than the maximum dose of 10 micrograms/kg recommended in the SPC).

3.3 No studies compared romiplostim with pre-specified sequential treatment pathways. Concurrent or rescue ITP medications were used at the investigators’ discretion. One open-label extension study of the phase III RCTs and six non-RCTs of romiplostim were reported in the manufacturer’s submission.

3.4 The primary endpoint of the two RCTs was the incidence of a durable response (a platelet count of at least 50 × 10⁹ per litre in at least six weekly assessments in the last 8 weeks of treatment without the use of rescue medication). Rescue medication included corticosteroids (oral or intravenous), intravenous immunoglobulin and intravenous anti-D immunoglobulin. Other outcomes were: overall response (durable or transient platelet response, where a transient response was a platelet count of at least 50 × 10⁹ per litre in at least four weekly assessments during weeks 2 to 25 of treatment, with no weekly response eligible within 8 weeks of the use of rescue medication and in the absence of a durable response); time to platelet response (Kaplan-Meier estimated time to first platelet response); duration of platelet response; use of rescue treatments; mortality; adverse effects of treatment; and health-related quality of life.

3.5 In the RCT that recruited only splenectomised patients, no patients in the placebo group (n =21) and 16 patients (38.1%) in the romiplostim group experienced the primary endpoint of a durable platelet response. No patients in the placebo group and 33 patients (78.6%) in the romiplostim group achieved an overall platelet response. The median time to the first platelet response was 3.0 weeks. The mean period with a platelet response was 0.2 weeks for the placebo group and 12.3 weeks for the romiplostim group (difference 12.1 weeks; 95% confidence interval [CI] 8.7 to 15.6 weeks; p < 0.0001). Twelve patients (57.1%) in the placebo group and 11 patients (26.2%) in the romiplostim group received rescue medication during the treatment period (odds ratio 0.278; 95% CI 0.094 to 0.822; p = 0.0175). Three patients in the placebo group died; the causes of death were pneumonia (after the end of the study), pulmonary embolism and cerebral haemorrhage. There were no deaths in the romiplostim group.

3.6 The manufacturer’s submission stated that in the RCT that recruited non-splenectomised patients, one patient (4.8%) in the placebo group and 25 patients (61.0%) in the romiplostim group experienced the primary endpoint of a durable platelet response (odds ratio 24.45; 95% CI 3.34 to 179.18; p < 0.0001). Three patients (14.3%) in the placebo group and 36 patients (87.8%) in the romiplostim group achieved an overall platelet response (odds ratio 34.74; 95% CI 7.77 to 155.38; p < 0.0001). The median time to the first platelet response was 2.0 weeks. The mean period with a platelet response was 1.3 weeks for the placebo group and 15.2 weeks for the romiplostim group (difference 13.9 weeks; 95% CI 10.5 to 17.4 weeks; p < 0.0001). Twenty one patients (61.9%) in the placebo group in the romiplostim group received rescue medication during the treatment period. The corresponding figure for the romiplostim group was submitted as in confidence information by the manufacturer. A publication of the RCT reported this to be 17.1%.No patients in the placebo group and one patient in the romiplostim group died. The cause of death was intracranial haemorrhage 2 weeks after discontinuation of romiplostim.

3.7 The manufacturer’s submission reported results for bleeding events, adverse events and health-related quality-of-life outcomes pooled from both RCTs. These showed that 54% (45 of 84) of patients in the combined romiplostim groups (a revised figure of 57% [48 of 84] was given in the ERG report using data provided by the manufacturer following a request for clarification) and 61% (25 of 41) of patients in the combined placebo groups experienced at least one bleeding event of any severity. A serious bleeding event, as defined by the regulatory protocol, was reported for 6% (5 of 84) of patients in the combined romiplostim groups and 10% (4 of 41) of patients in the combined placebo groups. Bleeding of grade 3 severity or greater occurred in 7% (6 of 84) of patients in the combined romiplostim group and 12% (5 of 41) of patients in the combined placebo group. Bleeding events of grade 2 (moderate) severity or greater were reported to have occurred in 15% (13 of 84) of patients in the romiplostim group and 34% (14 of 41) of patients in the placebo group.

3.8 Safety data were derived from combined results from the two RCTs and seven case series, which included dose-finding studies, an open-label extension study (which included patients from other romiplostim studies), a study of patients with severe refractory ITP and a bone marrow morphology sub-study. Safety data were submitted as in confidence information by the manufacturer.

3.9 Health related quality of life data in the form of linear regression analysis of EQ–5D data from the two RCTs was presented in a revised submission from the manufacturer. The analysis showed statistically significant differences (favouring romiplostim over placebo) in the mean change in EQ‑5D score between the romiplostim and placebo groups. Statistically significant differences were not, however, identified by the regression method used in the manufacturer’s original submission. Combined data from the two RCTs for the change from baseline in the ITP-Patient Assessment Questionnaire (a disease-specific instrument for recording health-related quality of life that comprises 10 scales) indicated that, for splenectomised patients, those in the romiplostim group had a statistically significantly greater (p < 0.05) improvement in the ‘Symptoms’, ‘Bother’, ‘Social Activity’ and ‘Women’s Reproductive Health’ scales compared with those in placebo group. In non-splenectomised patients, those in the romiplostim group had a statistically significant greater improvement in the ‘Activity’ scale than those in the placebo group.

3.10 No studies were identified that compared romiplostim with specific comparator treatments used in standard care. The manufacturer assessed clinical guidelines, systematic reviews and comparative as well as observational studies for evidence on standard care. Efficacy data from different studies, but examining the same treatment, were combined by a method described in the manufacturer’s submission as ‘taking a weighted average, weighting by sample size’. The number of studies that were combined varied for different interventions.

3.11 The manufacturer submitted a cohort-type economic model using a lifetime horizon, assessing the impact of romiplostim for patients with ITP who had undergone splenectomy and those who had not. It was assumed that all modelled patients started with a platelet count below 50 × 10⁹ per litre. The cost effectiveness of romiplostim was compared with standard care in a structure whereby modelled patients initially enter ‘watch and rescue’ standard care (treated as necessary with intravenous immunoglobulin, anti-D [non-splenectomised patients] or intravenous corticosteroids) or are treated initially with romiplostim followed by ‘watch and rescue’ care. In the model, patients move through a care pathway consisting of active therapies and ‘watch and rescue’ care. When a patient becomes refractory to an active treatment they move back to ‘watch and rescue’ care. The active treatments modelled in the remainder of the care pathway were rituximab, immunosuppressive agents (azathioprine, mycophenolate mofetil, ciclosporin), danazol, dapsone and cytotoxic agents (such as cyclophosphamide and vinca alkaloids).

3.12 Seven health states were used in the model. The utility values for five of these were derived from the time trade-off method in research conducted on a general population sample, which was commissioned by Amgen. These data were submitted as in confidence information by the manufacturer. For the remaining two health states included in the model – low platelet count with gastrointestinal bleed and low platelet count with other bleeding events requiring hospitalisation – utilities were extracted from the literature; these were estimated at a value of 0.54 for both health states.

3.13 Resource use and costs were divided into cost of treatment per 4-week cycle for both splenectomised and non-splenectomised patients and cost of management of bleeds. Costs of treatment included those of the romiplostim vials, testing (four tests), physician appointments (two sessions), and other drugs. Costs of management of bleeds included those for minor bleeds treated in an outpatient setting, gastrointestinal bleeds and other bleeds requiring hospitalisation, and intracranial haemorrhage.

3.14 Other costs for drugs used in treatment and in managing bleeds were taken from the British National Formulary (edition 55) and NHS reference costs.

3.15 The manufacturer’s base-case analysis gave incremental cost-effectiveness ratios (ICERs) of £14,633 per quality-adjusted life year (QALY) gained for non-splenectomised patients, and £15,595 per QALY gained for splenectomised patients, when using romiplostim as a first-option treatment compared with ‘watch and rescue’ standard care and a target platelet count of 50 × 10⁹ per litre. These ICERs reflect new inputs added to the model at request of the ERG during the clarification step.

3.16 Sensitivity analyses included: changes in drug costs to account for vial wastage in practice; the use of EQ‑5D data available from the RCTs for serious adverse effects; the cost of a bone marrow assessment required when the response to the romiplostim is lost; and costs of blood film tests (which are required before treatment with romiplostim can begin). Analysis assuming a target platelet count of 30 × 10⁹ per litre was also carried out.

3.17 The one-way sensitivity analysis that had most effect on the ICER was an adjustment of drug costs to account for vial wastage that would occur in practice, based on the smallest available vial size of 250 micrograms. By changing the number of vials from 0.93 to 1 for non-splenectomised patients, the ICER increased from £14,633 to £21,214 per QALY gained. For splenectomised patients, the change in the number of vials from 1.38 to 2.0 increased the ICER from £15,595 to £91,406 per QALY gained. The additional costs incurred by providing blood film tests before the treatment increased the ICER from £14,633 to £19,230 per QALY gained for non-splenectomised patients and from £15,595 to £22,068 per QALY gained for splenectomised patients. These analyses used a target platelet count of 50 × 10⁹ per litre.

3.18 Sensitivity analysis in which a target platelet count of 30 × 10⁹ per litre (instead of 50 × 10⁹per litre) was assumed resulted in ICERs of £14,840 per QALY gained for non-splenectomised patients and £14,655 per QALY gained for splenectomised patients using romiplostim as a first-option treatment compared with ‘watch and rescue’ standard care.

3.19 The manufacturer estimated the probability that romiplostim is cost effective using a target platelet count of 50 × 10⁹ per litre at different acceptability threshold levels of £10,000, £20,000 and £30,000 per QALY gained to be 10%, 60% and 81% respectively for non-splenectomised patients (mean ICER £14,633 per QALY gained) and 25%, 55% and 77% respectively for splenectomised patients (mean ICER £15,595 per QALY gained).

3.20 The ERG noted that limited evidence was available on the treatment of patients with chronic ITP, including with romiplostim and potential comparators, and particularly for long-term outcomes. The ERG also considered that, for comparators, evidence for non-splenectomised and splenectomised patients was commonly not distinguished. A key concern was the methods used for estimating efficacy data for romiplostim and comparators. The ERG acknowledged that pooling using formal methods may also have been inappropriate, and no additional evidence that would significantly alter the results presented in the manufacturer’s submission was identified.

3.21 Explorative sensitivity analyses were performed by the ERG using the manufacturer’s model and a target platelet count of 50 × 10⁹ per litre. These included multivariate analysis that combined sensitivity analyses conducted by the ERG with those provided by the manufacturer. When patients entered the model on an active therapy (rituximab) in the comparator arm (rather than ‘watch and rescue’) the ERG reported ICERs which increased from £14,633 to £21,674 per QALY gained for non-splenectomised patients and increased from £15,595 to £29,771 per QALY gained for splenectomised patients. When patients entered the model on active treatment (with rituximab) and whole numbers of vials of romiplostim were used, the ICER increased from £16,633 to £28,556 per QALY gained for non-splenectomised patients (one 250 microgram vial used) and from £15,595 to £109,802 per QALY gained for splenectomised patients (two 250 microgram vials used). In multivariate analysis that incorporated the use of EQ-5D data from the RCTs, the changes in the number of vials, a reduction of serious adverse events by half, the cost of bone marrow tests and the cost of blood film assessment, the ICERs increased from £14,633 to £37,290 and from £15,595 to £131,017 per QALY gained for non-splenectomised and splenectomised patients respectively.

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

4 Consideration of the evidence

4.1 The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of romiplostim for the treatment of chronic ITP, having considered evidence on the nature of the condition and the value placed on the benefits of romiplostim 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 noted evidence submitted and presented by the patient experts and clinical specialists on the clinical signs and symptoms associated with chronic ITP, and in particular that the morbidity associated with low platelet counts is variable. It noted that bleeding and bruising can have considerable impact on the daily activities of people with chronic ITP, may attract a social stigma associated with the appearance of bruises and can limit lifestyle choices. The Committee heard that many people with ITP experience fatigue, but that there is no clear relationship between this symptom and platelet count or haemoglobin concentration. It also understood that anxiety about the risk of bleeding can additionally affect quality of life and a person’s ability to travel and/or undertake leisure activities.

4.3 The Committee discussed the clinical management of chronic ITP and the pathway of care for people with the condition. It heard from clinical specialists that the pathway of care for ITP would vary depending on individual person’s circumstances, and that no single standard treatment pathway could be defined as routine practice with confidence. It understood that treatment protocols would not normally be determined solely on the basis of platelet count, but that there is a greater propensity to offer active treatment when platelet count is low. However, the Committee heard from the clinical specialists that active treatment is more likely to be considered when a person is thought to be at greater risk of bleeding, for example when undergoing surgical procedures or participating in sports. Active treatment is therefore more likely to be considered for those people with severe symptoms or at high risk of bleeding, and in particular when current standard treatments are failing to produce satisfactory platelet counts or relief of symptoms. For those people without severe symptoms or not perceived to be at high risk of bleeding, the preferred approach would be a strategy of ‘watch and rescue’ (with intervention dictated by the frequency of bleeding episodes) rather than active treatment.

4.4 The Committee then discussed the place of romiplostim in the pathway of care for people with chronic ITP, and in doing so considered the appropriate comparators for romiplostim – primarily on the basis of an active treatment approach. It noted that the licensed indication for romiplostim for people who have undergone splenectomy is restricted to those who are refractory to other treatments such as corticosteroids and immunoglobulin, and that in people with a contraindication to splenectomy the technology may be considered as a second-line treatment. The Committee understood that for most people with ITP the first-line treatment would be corticosteroids. The Committee concluded that active treatment was the most appropriate comparator for romiplostim, although it understood that people undergoing active treatments would additionally require monitoring and need to be offered rescue treatment from time to time as required.

4.5 The Committee considered the evidence presented by the manufacturer on the clinical effects of romiplostim compared with placebo and standard care. It was mindful that evidence was derived from two small placebo-controlled RCTs. The Committee noted that romiplostim improved platelet count (the response measure used in the trials) and reduced the frequency of bleeding events – particularly the occurrence of moderate and severe bleeding episodes. The Committee was, however, mindful that these two RCTs did not provide clear evidence about the relative effectiveness of romiplostim compared with the active comparator treatments listed in the scope for this appraisal. It noted the manufacturer’s view that such evidence had been difficult to obtain because of heterogeneity among studies of the comparators. It heard from clinical specialists that romiplostim may confer benefits over other active treatments by producing a sustained platelet response while treatment is continued, and because treatment can be continued for a longer time and in a wider population than with some other active treatments (such as corticosteroids) for which the duration of treatment is limited by adverse effects. The Committee concluded that although there is evidence that romiplostim is more clinically effective than placebo, and that in the opinion of clinical specialists the technology has advantages over other active treatments, there is no clinical trial evidence to demonstrate its relative effectiveness compared with other active treatments.

4.6 The Committee next considered the economic model submitted by the manufacturer. It broadly accepted the model structure and health states, but was not convinced that the care pathway starting with ‘watch and rescue’ in the manufacturer’s base case was the correct comparator. The Committee was also particularly concerned that the additional costs of treatment with romiplostim instead of its comparators were likely to have been underestimated. The Committee additionally had concerns about other key assumptions in the manufacturer’s base case, which it discussed by considering the sensitivity analyses performed by the manufacturer and the explorative analyses produced by the ERG using the manufacturer’s model.

4.7 The Committee did not consider the manufacturer’s base-case comparison with a care pathway starting with ‘watch and rescue’ to be an appropriate comparator for romiplostim because the population for whom romiplostim holds a marketing authorisation would be those for whom active treatment would be offered in current UK practice. The Committee considered an alternative scenario in which the comparator pathway was initiated with rituximab treatment. This pathway was described by the ERG after undertaking explorative analyses using functions available within the manufacturer’s submitted model using a target platelet count of 50 × 10⁹ per litre. The Committee noted that sensitivity analyses using initial active treatment with rituximab resulted in increased ICERs compared with the base case (which compared romiplostim with ‘watch and rescue’). The ICER increased both for people who had undergone splenectomy (from a base case of £15,600 to £29,800 per QALY gained) and for those who had not (from a base case of £14,600 to £21,700 per QALY gained). The Committee also noted that other plausible treatment pathways including less costly comparators, such as those starting with dapsone and ciclosporin, were also likely to result in increases in the ICERs. The Committee concluded that appropriate comparator pathways for romiplostim are those that start with active treatments and use ‘watch and rescue’ alongside these rather than the comparator pathway in the manufacturer’s base case, which commenced with ‘watch and rescue’ alone.

4.8 The Committee discussed the cost of romiplostim and noted that the ICER was very sensitive to the assumption of average drug cost. It noted that the possible dose for an individual person could range from 1 microgram/kg to 10 micrograms/kg, corresponding to a range in annual drug cost of approximately £8000 to theoretically £80,000 per person. It noted that the median dose used in the small RCTs was 3 micrograms/kg for splenectomised patients and 2 micrograms/kg for non-splenectomised patients, but was mindful that the average dose that would be used in clinical practice is unknown.

4.9 The Committee noted that the manufacturer’s economic model assumed there to be no wastage of vial contents. It also noted that the SPC states that vials are for ‘single use’. The Committee agreed that, in practice, it is likely that there will be wastage from each vial and that vial sharing would not occur. The Committee noted that the smallest vial size available is 250 micrograms. The Committee was persuaded that the availability of a smaller vial size would increase the flexibility of dosing, reduce wastage and consequently improve the overall cost effectiveness of romiplostim. The Committee then considered the sensitivity analysis undertaken by the ERG (incorporating the alternative comparator pathway with initial use of rituximab, as in section 4.7) in which it was assumed that whole 250-microgram vials would be used to treat people with chronic ITP. For people who had undergone splenectomy, the use of two 250-microgram vials was assumed, whereas the use of a single 250-microgram vial was assumed for non-splenectomised people. These sensitivity analyses resulted in an increase in the ICER for splenectomised people from £29,800 to £110,000 per QALY gained and an increase in that for non-splenectomised people from £21,700 to £28,600 per QALY gained. The Committee concluded that the drug costs of romiplostim had been underestimated in the manufacturer’s base case and that using more plausible assumptions about vial wastage resulted in substantially higher ICERs.

4.10 The Committee noted that the submitted model assumed a mortality benefit associated with romiplostim, with 2.92 and 2.03 estimated life years gained for the non-splenectomised and splenectomised group respectively. Specifically, the Committee noted that the economic modelling attributed a survival advantage to the romiplostim group as a result of avoiding severe bleeding episodes and the associated mortality. The Committee heard from the clinical specialists that this assumption was plausible, but there was substantial uncertainty about the magnitude of the effect and the validity of modelling data from short-term clinical trials to a lifetime horizon. Furthermore, the manufacturer did not identify this uncertainty appropriately or provide relevant sensitivity analyses related to survival. The Committee concluded that this increased the degree of uncertainty around the ICERs presented in the manufacturer’s submission and those estimated by the ERG using the manufacturer’s model.

4.11 The Committee considered other univariate sensitivity analyses undertaken by the ERG and noted that inclusion of revised costs such as those for a blood film assessment (which is required before treatment with romiplostim), bone marrow testing and the use of EQ-5D utility values from the romiplostim RCTs increased the ICERs for romiplostim compared with the base case. The Committee thought that each of these assumptions was more plausible than those in the manufacturer’s base case, and concluded that in UK clinical practice the true ICER of romiplostim compared with appropriate active comparators would be substantially higher than presented in the manufacturer’s base case. The Committee noted that an exploratory scenario analysis undertaken by the ERG using the manufacturer’s model that combining all of the ERG assumptions (above) with accounting for vial wastage, using an active comparator and assuming a reduced frequency of physician visits resulted in ICERs for romiplostim of £37,300 per QALY gained in the non-splenectomised group and £131,000 per QALY gained in the splenectomised group.

4.12 The Committee discussed the assumptions regarding ‘watch and rescue’ in the manufacturer’s model in the context of being used alongside care with active treatments. The Committee noted that the use of intravenous immunoglobulin was a major cost within the comparator ‘watch and rescue’ care proposed by the manufacturer. It noted that clinical trials had been used to model the resource use and cost of ‘watch and rescue’ care by assuming that a proportion of patients required rescue medication per monthly cycle of the economic model. It heard from the ERG that the proportion of patients assumed in the model was approximately 70%, of whom approximately 60% required intravenous immunoglobulin, but that it was unclear what impact changes in these assumptions would have on the estimated cost per QALY gained when ‘watch and rescue’ was not the first-line comparator. The Committee discussed whether these assumptions were plausible and heard descriptions of current practice from clinical specialists. It concluded that both the frequency and cost of rescue treatment had been overestimated in the manufacturer’s submission compared with current UK practice. The Committee then considered the monitoring assessments that the manufacturer assumed during ‘watch and rescue’. It heard from clinical specialists that monitoring and provision of treatment is largely symptom dependent and may only be required infrequently. The Committee therefore concluded that the cost of ‘watch and rescue’ care was overestimated in the model and that the true ICER of romiplostim compared with a comparator pathway starting with active treatment rather than ‘watch and rescue’ would be higher than the ICERs in section 4.11.

4.13 In summary, the Committee considered that, in current UK practice, treatment with romiplostim would be prescribed only for people with chronic ITP who have symptoms or a risk of bleeding severe enough to warrant intervention, and therefore the appropriate comparator pathways are those starting with active treatment rather than ‘watch and rescue’. It considered that although there are reasons to suggest that romiplostim may confer clinical benefits over other active treatments, evidence for its relative effectiveness compared with other active treatments is lacking. The Committee also noted that significant wastage of vial contents would occur in practice and therefore the drug cost of romiplostim would be substantially higher than that proposed in the manufacturer's submission. The Committee also concluded that several assumptions in the manufacturer’s base case resulted in underestimation of the cost per QALY gained. These included: the cost of comparator treatments; cost of blood film assessment; and the use of EQ-5D utility values other than from the RCTs to model health-related quality of life. The Committee therefore concluded that it could not recommend romiplostim for the treatment of people with chronic ITP as a cost-effective use of NHS resources.

5 Implementation

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

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

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

6 Related NICE guidance

Under development

NICE is developing the following guidance (details available from www.nice.org.uk):

• Eltrombopag for the treatment of chronic idiopathic (immune) thrombocytopenic purpura. NICE technology appraisal guidance (Earliest anticipated date of publication June 2010).

7 Proposed date for review of guidance

7.1 NICE proposes that the guidance on this technology is considered for review by the Guidance Executive in September 2012. NICE welcomes comment on this proposed date. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.

David Barnett
Chair, Appraisal Committee
October 2009

Appendix A: Appraisal Committee members and NICE project team

A Appraisal Committee members

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

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

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

Professor Keith Abrams
Professor of Medical Statistics, University of Leicester

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

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

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

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

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

Dr Martin Duerden
Medical Director, Conwy Local Health Board

Mrs Eleanor Grey
Lay member

Mr Terence Lewis
Lay member

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

Dr Ruairidh Milne
Senior Lecturer in Public Health, National Coordinating Centre for Health Technology Assessment

Dr Neil Milner
General Practitioner, Tramways Medical Centre, Sheffield

Dr John Pounsford
Consultant Physician, Frenchay Hospital, Bristol

Dr Stephen Saltissi
Consultant Cardiologist, Royal Liverpool University Hospital

Dr Lindsay Smith
General Practitioner, East Somerset Research Consortium

Mr Roderick Smith
Finance Director, West Kent Primary Care Trust

Mr Cliff Snelling
Lay member

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

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

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

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

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

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

B NICE project team

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

Dr Ruaraidh Hill and Panagiota Vrouchou
Technical Leads

Helen Chung
Technical Adviser

Jeremy Powell
Project Manager

Appendix B: Sources of evidence considered by the Committee

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

• Mowatt G, Boachie C, Crowther M et al., Romiplostim for the treatment of chronic immune or idiopathic thrombocytopenic purpura (ITP): a single technology appraisal, December 2008

B The following organisations accepted the invitation to participate in this appraisal. They were invited to comment on the draft scope, the ERG report and the appraisal consultation document (ACD). Organisations listed in I were also invited to make written submissions. Organisations listed in II and III had the opportunity to give their expert views. Organisations listed in I, II and III also have the opportunity to appeal against the final appraisal determination.

I Manufacturer/sponsor

• Amgen

II Professional/specialist and patient/carer groups

• British Committee for Standards in Haematology
• 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
• Eastern and Coastal Kent Teaching Primary Care Trust
• Welsh Assembly Government

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

• Actavis UK
• Baxter BioScience
• Bio Products Laboratory
• CSL Behring
• Department of Health, Social Services and Public Safety for Northern Ireland
• Focus Pharmaceuticals
• GlaxoSmithKline UK
• NHS Quality Improvement Scotland
• Pharmacia

C The following individuals were selected from clinical specialist and patient advocate nominations from the non-manufacturer/sponsor consultees and commentators. They gave their expert personal view on romiplostim for the treatment of chronic idiopathic (immune) thrombocytopenic purpura by attending the initial Committee discussion and providing written evidence to the Committee. They are invited to comment on the ACD.

• Dr Paula Bolton-Maggs, Consultant Haematologist, Manchester Royal Infirmary, nominated by the Royal College of Pathologists and the British Committee for Standards in Haematology – clinical specialist
• Dr John Grainger, Consultant Paediatric Haematologist, Royal Manchester Children’s 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
• Mrs Shirley Watson, Chief Executive, ITP Support Association, nominated by the ITP Support Association – patient expert
• Mr Derek Elston, nominated by the ITP Support Association – patient expert