Fostamatinib for treating refractory chronic immune thrombocytopenia

3.1 Chronic immune thrombocytopenia (ITP) is an autoimmune condition characterised by platelet destruction, leading to a low number of platelets circulating in the blood. Platelets are a type of cell involved in blood clotting. Thrombocytopenia is usually defined as having a platelet count lower than 100x10⁹ per litre. Signs and symptoms include bruising easily, the appearance of red spots under the skin (petechiae), fatigue and bleeding. Frequency and severity of bleeding may differ in people with similar platelet counts. Some have no bleeding, some bleed from the skin, nose, or urinary tract, and others have more serious intracranial and gastrointestinal bleeding. Because of the risk of bleeding, people may become stressed or depressed. A particular concern is a sudden drop in platelets, which can lead to life‑threatening bleeds. Although treatments called thrombopoietin receptor agonists (TPO‑RAs) are available, they do not work for everyone and some people cannot take them. The patient and clinical experts explained that some of the treatment options suppress the immune system, and increase the risk of infection. The committee concluded that people with chronic ITP and clinicians would welcome an additional treatment option.

3.2 Initial treatment for ITP involves high-dose oral corticosteroids or intravenous immunoglobulin G (IVIgG). Later treatments include:

3.3 The clinical experts highlighted that they and people with ITP make treatment decisions based on platelet count and other risk factors for bleeding, such as age and use of anti‑platelet treatment. They explained that the objective of treatment is a platelet count higher than 30x10⁹ per litre to reduce the risk of bleeding. Platelet counts higher than 50x10⁹ per litre may be used as a target for maintenance treatment, to avoid fluctuating platelet levels and minimise the chance of counts dropping below 30x10⁹ per litre. The committee appreciated that treatment aims to achieve platelet counts lower than those used to define thrombocytopenia. It concluded that treatment decisions were based on more than platelet count.

3.4 Fostamatinib has a marketing authorisation for treating chronic ITP after previous treatments. The company proposed that fostamatinib is used after a TPO‑RA (for example, romiplostim or eltrombopag) or when TPO‑RAs are not suitable. This is narrower than the marketing authorisation. The clinical experts considered the company's proposed positioning to be reasonable. They noted that other treatments such as rituximab and mycophenolate may be used after TPO‑RAs at the point where the company proposed using fostamatinib. The clinical experts noted that rituximab is considered more effective for young women and people with other autoimmune conditions. However, some people may be concerned about rituximab's immunosuppressive effects so would prefer an alternative treatment. The clinical experts also highlighted that for people at risk of blood clots, TPO‑RAs may not be suitable so fostamatinib could be considered instead. They also noted that other treatments such as rituximab and mycophenolate may be used after TPO‑RAs, but before fostamatinib. The committee acknowledged that treatment is individualised. They also noted that people may be cautious about using immunosuppressive drugs during the COVID‑19 pandemic. It concluded that the company's positioning of fostamatinib in the treatment pathway was narrower than the marketing authorisation but broadly appropriate.

3.5 As relevant comparators, NICE's final scope included the TPO‑RAs romiplostim and eltrombopag, rituximab, splenectomy, cytotoxic agents, dapsone, danazol and 'watch and rescue'. However, the company excluded romiplostim and eltrombopag based on its positioning of fostamatinib after a TPO‑RA, or when TPO‑RAs are unsuitable. The company selected rituximab as the only comparator. For all other comparators, the company argued that there was little evidence to support comparisons with fostamatinib. The clinical experts agreed that many treatments used in practice do not have robust clinical trial data. They also noted that rituximab and mycophenolate are often used in clinical practice at the same point in the treatment pathway as the company proposed for fostamatinib (see section 3.4). The committee concluded that the relevant comparators for fostamatinib are rituximab and mycophenolate.

3.6 FIT1 and FIT2 are multinational, double-blind, randomised, phase 3 trials of the same design comparing fostamatinib with placebo. Both trials included adults with persistent or chronic ITP that had not responded to at least 1 treatment. Their average platelet count was less than 30x10⁹ per litre. The primary endpoint in both trials was stable platelet response. This was defined as a platelet count of 50x10⁹ per litre or more in at least 4 out of 6 assessments between week 14 and week 24. Secondary outcomes included:

3.7 Starting from week 12, the criteria used to define non-response in FIT1, FIT2 and the FIT3 extension study were:

3.8 The average age at baseline in FIT1 and FIT2 was between 53 and 54 years. The ERG was concerned that people enrolled in these trials were about 10 years younger than in clinical practice and had a lower risk of bleeding, which increases with age. The clinical experts highlighted that fostamatinib is likely to work equally well in clinical practice regardless of age. The committee concluded that the results of the FIT clinical trials are likely to be generalisable to NHS practice, but the absolute benefit may differ from the trials.

3.9 The committee recalled that there was no evidence directly comparing fostamatinib with rituximab or mycophenolate. The company's base case discussed at the first committee meeting included rituximab as the only relevant comparator. Clinical efficacy data for rituximab was based on clinical expert opinion, rather than published literature. After consultation, the company did a network meta-analysis comparing fostamatinib with rituximab, with an outcome of overall platelet response. The definition of overall platelet response varied across studies included within the meta-analysis, so the company did 3 separate analyses:

3.10 The company excluded mycophenolate from its network meta-analysis because it did not identify any randomised trials of mycophenolate being used after TPO-RAs. It noted that mycophenolate does not have a marketing authorisation for ITP. The company presented data from the UK ITP registry and a panel of clinical experts, who revealed that a substantial proportion of people do have mycophenolate after TPO-RAs. (The exact proportion is confidential and cannot be reported here.) The committee noted that this further supports its use in NHS clinical practice. The ERG confirmed the lack of evidence for mycophenolate. The committee noted that relevant comparators are selected based on their routine use in NHS clinical practice, regardless of whether they have a marketing authorisation for that indication. It also noted that rituximab does not have a marketing authorisation for ITP, but the company included it as a relevant comparator. The committee maintained that both rituximab and mycophenolate are relevant comparators for fostamatinib (see section 3.5). But it acknowledged that there is no published evidence showing how well mycophenolate works for people with ITP.

3.11 The company used a Markov cohort state transition model to estimate the cost effectiveness of fostamatinib compared with rituximab. The model cohort was split into 2 groups based on whether a person had intracranial bleeding. The company's original model included 3 health states in each group:

3.12 For the rapid review, the company submitted an updated model which corrected an error in the calculation of the cost of rescue treatment. The error resulted in the total acquisition cost of rescue treatment being underestimated. This error had a significant impact on the cost‑effectiveness results. The ERG reviewed the amended model and was satisfied with the company's approach for correcting this error. The committee concluded that the company's corrected method for calculating the cost of rescue treatments was appropriate and it would use the amended model for its decision making in the rapid review.

3.13 The committee recalled that the criteria for non-response and stopping treatment in the FIT trials were not in line with clinical practice (see section 3.7). The company's original model followed the stopping rule from the FIT trials. However, after consultation, for the second committee meeting, the company changed the stopping rule in its economic model to a platelet count lower than 30 x 10⁹ per litre, in line with clinical practice. The ERG explained that the model applied this stopping rule at 12 weeks, with a half-cycle correction. Applying a half-cycle correction effectively means that treatment would be stopped 2 weeks earlier, at 10 weeks, if a platelet count of 30x10⁹ per litre or more was not reached. The company noted this was a conservative assumption because a clinical expert panel advised that treatment could be stopped earlier, by 8 weeks, if platelet response was not reached. The committee noted that fostamatinib's marketing authorisation includes a 12‑week stopping rule if platelet count is 'not sufficient'. The ERG explained that removing the half-cycle correction applied to the stopping rule increased the cost-effectiveness estimates. This was because treatment costs for people whose disease does not respond to treatment are incurred for longer. The committee concluded that the revised criteria for non-response and stopping were in line with clinical practice but should be applied at 12 weeks, without a half-cycle correction.

3.14 In the company's original submission, people who had fostamatinib moved to watch and rescue treatment if their platelet count fell below 30x10⁹ per litre (non-response). However, people who had rituximab did not move to watch and rescue treatment. Instead, they remained in the lower than 30x10⁹ per litre health state and could never have a platelet count higher than 30x10⁹ per litre after cycle 4 in the model. This led to a worse modelled outcome than was seen with placebo in the fostamatinib clinical trials. The company explained that its clinical experts had advised that in clinical practice, people do not have other treatments at the same time as rituximab. The clinical experts at the first committee meeting agreed but noted that rituximab is used only for a short time. After that, treatment is offered to raise platelet counts to a level higher than 30x10⁹ per litre. The committee also noted that some people who do not have a response to fostamatinib may get rituximab, instead of watch and rescue treatment. At its first meeting, the committee concluded that subsequent treatments should be modelled consistently between arms and include all relevant sequences. After consultation, at the second committee meeting, the company updated its base case to allow watch and rescue treatment after rituximab, when platelet count is lower than 30x10⁹ per litre. The ERG confirmed that the company applied the change correctly. The committee noted that the company's revised approach did not include all relevant treatment sequences. For example, it did not include an option of having rituximab after fostamatinib. The ERG explained that modelling a full treatment sequence across the pathway was difficult because of evidence limitations. This was a key model limitation and contributed to the overall uncertainty. The committee concluded that the company's revised approach to modelling subsequent treatments had limitations but was acceptable for decision making.

3.15 The company explained that its base case did not include tapering dosages or stopping treatment in people with a sustained platelet response. It assumed that those people remain on the full treatment dose until loss of response or death. However, the company stated that tapering was common with other ITP treatments and was likely with fostamatinib. The company did a scenario analysis in which it assumed that 40% of people with a sustained platelet response to fostamatinib (platelet counts above 30x10⁹ per litre after 1 year) stop active treatment, but maintain the full clinical benefit. This scenario improved fostamatinib's cost-effectiveness estimates, as did an ERG scenario in which only people with a sustained platelet count higher than 50x10⁹ per litre taper treatment. But, the company recognised that it did not have data to support tapering or stopping fostamatinib without losing benefit. The committee recognised that maintaining treatment benefit after tapering or stopping treatment was speculative. It also noted that fostamatinib's marketing authorisation does not include treatment tapering or stopping in people with a sustained platelet response. The committee concluded that it is not appropriate to assume that people with sustained platelet response can taper or stop treatment without losing clinical benefit.

3.16 As outlined in section 3.6, the pooled results from FIT1 and FIT2 showed that the benefits of fostamatinib may decrease over time. The company's model captured loss of response for the first 24 weeks by the probabilities of transitioning to the 'no response' health states which were informed by the FIT1 and FIT2 data. The level of sustained response beyond 24 weeks was informed by the extension study (FIT3). The ERG considered the company's approach to inform the loss of fostamatinib response over time was conservative, but noted that it was a source of uncertainty. The committee noted that the model included a stopping rule to reflect the marketing authorisation of fostamatinib. If the condition stopped responding to fostamatinib, that is platelet count was lower than 30x10⁹ per litre, treatment would stop. The committee acknowledged that the model reflects available clinical evidence for fostamatinib over the long term and that people would stop treatment if they were no longer benefiting. But they concluded that any loss of benefit and the timing of any loss of benefit is a source of uncertainty in the cost-effectiveness results.

3.17 In its original base case, the company used FIT trials data to inform the frequency and type of rescue treatments. After consultation, it used the UK ITP registry data instead. The use of rescue treatments in the UK ITP registry depended on platelet count and included IVIgG, intravenous methylprednisolone, platelet transfusion, oral prednisolone, and oral dexamethasone. The company justified using the UK ITP registry because:

3.18 The committee recalled that the trials included 2 doses of rituximab (see section 3.9). In the 2014 NICE evidence summary for rituximab in ITP, most studies included the higher dose of 375 mg/m² per week. Some used a fixed dose of 100 mg per week. International guidelines for ITP recognised that 100 mg per week is an alternative dosing schedule. Statements from several NHS clinical commissioning groups recommended only the lower dose. One clinical expert explained that they offer a dose of 100 mg per week. They noted that ITP registry data suggested that the effects of this dose are equivalent to the 375 mg/m² per week dose. The other clinical expert noted that they use the higher dose in practice. After consultation, the company analysed the use of rituximab in the UK ITP registry in people who had prior treatment with TPO‑RAs. It found that both doses were used (exact usage is confidential and cannot be reported here). The company updated its base case to include a mean dose of rituximab calculated from the UK ITP registry. It also did a scenario analysis using the 100 mg rituximab dose. The ERG was concerned that the company may have underestimated the mean rituximab dose in the UK ITP registry. The ERG corrected this, which led to a small increase in the mean dose. However, it explained that it preferred to use the lower, fixed 100 mg dose which was increasingly recommended for use in NHS clinical practice. The committee considered the clinical advice and UK ITP registry data and agreed that both rituximab doses are used in NHS clinical practice. Therefore, it concluded that both doses are relevant and should be included in the model.

3.19 People who have a platelet count below 30x10⁹ per litre may need prophylactic treatment to increase platelet count before surgery. In its original submission, the company assumed that prophylactic treatments were the same as rescue treatments. These include IVIgG, intravenous methylprednisolone and platelet transfusions, but not oral prednisolone. At the first committee meeting, the ERG explained that only 1 course of treatment is used, and this is based on the type of surgery (minor or major). It suggested that IVIgG was used for major surgery, which the ERG's clinical expert estimated accounts for 44% of people having surgery. Oral prednisolone was used for minor surgery in the remaining 56% of people. This affected the cost-effectiveness estimates because prednisolone costs much less than IVIgG. The clinical experts explained that oral prednisolone is used in clinical practice, contrary to the company's assumption. Also, they emphasised that the use of prophylaxis before surgery depends on the timing of the surgery. For example, IVIgG works more quickly than oral prednisolone. After consultation, the company asked a panel of 8 clinical experts about which treatments are used as prophylaxis before surgery in NHS clinical practice. Oral prednisolone was the most frequently used treatment for both minor (average use 54% [range 0% to 100%]) and major surgery (62% [0% to 100%]). This was followed by IVIgG for both minor (45% [10% to 75%]) and major (49% [10% to 85%]) surgery. The company assumed the same proportions of minor (56%) and major (44%) surgery as the ERG. The ERG agreed with the company's approach to estimating the use of prophylaxis before surgery and noted it was consistent with its expert opinion. The committee was satisfied that the revised company base case was in line with NHS clinical practice.

3.20 The company's base case discussed at the first committee meeting used pooled data from FIT1 and FIT2 for people 65 years and over to estimate the rate of adverse events for fostamatinib. This age group was considered more relevant because it is in line with the starting age in the model. This group had a higher rate of adverse events than the younger people in the trial. The company assumed that the rate of adverse events with rituximab was the same as with fostamatinib. At its first meeting, the committee concluded that adverse events with fostamatinib and rituximab were different and should be modelled separately. After consultation, the company agreed that rituximab was associated with fewer adverse events than fostamatinib and watch and rescue treatments. In its revised base case, adverse events with rituximab were based on a randomised controlled trial comparing 375 mg/m² rituximab with placebo (Ghanima et al.). The ERG was satisfied with the company's revised approach but noted some limitations. Rituximab can cause very rare fatal progressive multifocal leukoencephalopathy, which the company excluded from its analysis. The median age in the Ghanima et al. trial was 46 years, compared with the starting age in the model of 65 years. Adverse events in older people are likely to be more frequent, as seen with fostamatinib in the FIT trials. The committee noted that these assumptions likely favoured rituximab. The ERG explained that the rate of adverse events with the 100 mg weekly dose was likely to be lower than with the higher dose. The committee recalled that at its first meeting, a clinical expert explained that the 100 mg per week dose is well tolerated. The committee noted that assuming equal rates of adverse events with both doses favours fostamatinib. The ERG also explained that the company applied adverse events for rituximab for as long as response was maintained, even though it is only taken for 4 weeks (see section 3.9). However, the ERG advised that this likely has a small impact on the cost-effectiveness estimates, because cycle-specific costs and disutilities of adverse events with watch and rescue are similar to rituximab. In terms of modelling adverse events with fostamatinib, the company applied the same rate of adverse events for the full duration of treatment when in the response health state. The ERG noted that the company could instead have used the longest available data from the FIT3 extension study to model long-term adverse events with fostamatinib. However, the company explained that this data was not yet available. But it noted that new long-term safety issues were unlikely to emerge because fostamatinib's long-term safety profile in rheumatoid arthritis was consistent with the earlier data for that disease. The committee acknowledged the limitations of the company's approach to modelling adverse events with fostamatinib and rituximab. It noted that overall, it was not clear if this approach favoured rituximab or fostamatinib. However, it concluded that the company's approach was acceptable for decision making.

3.21 In the company's original base case, it estimated the risk of dying in the non-response health state from the General Practice Research Database (Schoonen et al. 2009). The risk of dying was 1.6 times higher than that of the age and sex-matched general population, with 13% of deaths from bleeding and 19% from infection. The risk of death was reported for everyone diagnosed with ITP, that is, it was not reported separately by platelet count. The company assumed all excess deaths happened in the lowest platelet count health state (non-response). All other health states had a risk of death that matched the general population. The ERG noted that assuming all deaths in Schoonen et al. happened in the non-response health state was an important limitation of the company's approach. After consultation, the company identified 2 new studies reporting the risk of dying from ITP and used them in its revised base case. In the 3‑health state model, the hazard ratio for mortality was 4.2 in the non-response state (Portielje et al. 2001), 2.5 in the partial response state (Adelborg et al. 2019) and 1.0 in the complete response health state. The 2-health state model used a hazard ratio for mortality of 4.2 in the non-response health state and 1.0 in the merged response health state. The ERG had concerns with the new sources:

3.22 The company used utility values for the model health states from published literature because of the low number of responses to the quality-of-life questionnaire used in the FIT clinical trials (SF‑36). The committee noted that the company used utility values for the health states of the group without intracranial bleeding from NICE's technology appraisal guidance on romiplostim. The company's original base case applied a lower utility value for people in the partial and no response health states than in the response health state. This was because the romiplostim appraisal used different utility values for people with platelet counts of 50x10⁹ per litre or more (response) and those with platelet counts below 50x10⁹ per litre (non-response). In its revised base case after consultation, the company applied different utility values to the response (platelets 30x10⁹ per litre or more) and the non-response health states (platelets below 30x10⁹ per litre). The committee acknowledged that people with platelet counts below 30x10⁹ per litre would be unlikely to feel worse than people with platelet counts of 30x10⁹ per litre or above. But if a person knows that they are at higher risk of bleeding, this could cause anxiety and affect their daily life if they avoid their usual activities. For the group who had severe intracranial bleeding and for their carers, the company used published utility values. The ERG noted that because intracranial bleeding is rare, including carer quality of life affected the cost-effectiveness estimates minimally. The company also applied a transient disutility for people with other bleeds, adverse events or when needing rescue treatment. The committee concluded that the utility values in the model, including those for carers of people who had severe intracranial bleeding, were appropriate.

3.23 The ERG did an analysis for mycophenolate as a comparator, assuming equal efficacy and safety to rituximab. It assumed that mycophenolate is taken twice a day as a 500 mg tablet and stopped at 12 weeks if platelet response is not reached, or later if this response is lost. The analysis predicted that median treatment duration is 12 to 16 weeks, which is longer than the median duration of mycophenolate treatment in the UK ITP registry (exact figures are confidential and cannot be reported here). The model predicted that mycophenolate had higher total treatment costs than 100 mg rituximab at its list price, but lower than 375 mg/m² rituximab at its list price. The ERG highlighted that this analysis is exploratory, because assuming equal efficacy of rituximab and mycophenolate is uncertain. It noted that there were lower complete and partial responses to mycophenolate in Taylor et al. (2015) compared with responses to rituximab in Ghanima et al. The ERG emphasised that this comparison was highly uncertain because it reflects a naive comparison between 2 different studies, and Taylor et al. was a small, non-randomised, retrospective study. Clinical experts confirmed that assuming equal efficacy of mycophenolate and rituximab is uncertain. They explained that there are no head-to-head comparisons between these 2 treatments, but they expect their efficacy and safety to differ. The 2 drugs are used for different groups of people. Mycophenolate is generally well tolerated and taken as a tablet, so it does not cause infusion-related reactions. The committee agreed that mycophenolate was unlikely to have the same efficacy and safety as rituximab and this was a limitation of the exploratory analysis. It concluded that it would focus on the comparison of fostamatinib with rituximab in its decision making.

3.24 The company revised its base case after consultation. The committee noted that it attempted to address its preferences from the first meeting. For the rapid review, the company's revised base case included the committee's preferred assumptions from the time of the original guidance, namely:

3.25 The patient and clinical experts value individualised treatment. The committee noted fostamatinib's novel mechanism of action and the lack of immunosuppression associated with it. This is important because the clinical experts highlighted that the rates of death from infection and from bleeding are similar in people with ITP. This is particularly relevant during the COVID‑19 pandemic because clinicians are being careful about using anti‑CD20 antibody treatments like rituximab which may make people more susceptible to infection. Additionally, treatment options are limited for people who cannot have TPO‑RAs. The committee concluded that while the benefits of treatment are captured in the model (see section 3.18), having alternative treatment options that do not suppress the immune system and could be used when TPO‑RAs are not suitable would be highly beneficial.

3.26 The committee recognised that people with refractory chronic ITP have benefited from fostamatinib and that the treatment has advantages over other available treatments. It acknowledged that fostamatinib improves outcomes compared with rituximab, but that there are uncertainties over the size of the benefit and its duration. The committee noted that fostamatinib was not compared with mycophenolate, a relevant comparator. But they acknowledged the evidence limitations which underpinned this decision. The committee considered the remaining sources of uncertainty in the model, and also the benefits of fostamatinib which may not be captured in the cost-effectiveness results. The committee concluded that the most plausible ICERs using its preferred modelling assumptions were within the range that NICE normally considers to be a cost-effective use of NHS resources. So, it recommended fostamatinib for treating refractory chronic ITP after TPO‑RAs or when they are not suitable.