Avatrombopag for treating primary chronic immune thrombocytopenia

Evidence-based recommendations on avatrombopag (Doptelet) for treating primary chronic immune thrombocytopenia in adults.

# Recommendations
Avatrombopag is recommended, within its marketing authorisation, as an option for treating primary chronic immune thrombocytopenia (ITP) refractory to other treatments (for example, corticosteroids, immunoglobulins) in adults. It is only recommended if the company provides it according to the commercial arrangement.
Why the committee made these recommendations
Current treatment for newly diagnosed primary chronic ITP usually includes corticosteroids and immunoglobulins. This is followed by thrombopoietin receptor agonists (TPORAs). Avatrombopag is another TPORA.
Clinical trial evidence shows that avatrombopag is more effective than placebo at increasing the number of platelets in the blood (cells that help the blood to clot) to a level that meaningfully reduces the risk of bleeding. Avatrombopag may be as effective as other TPORAs, but it has only been compared with them indirectly, which is uncertain.
There are also uncertainties with some assumptions in the economic modelling. Despite this, avatrombopag is likely to provide benefit for people who have primary chronic ITP. Also, the cost-effectiveness estimates are below what NICE normally considers an acceptable use of NHS resources. So, avatrombopag is recommended.# Information about avatrombopag

# Marketing authorisation indication
Avatrombopag (Doptelet, Swedish Orphan Biovitrum) is 'indicated for the treatment of primary chronic immune thrombocytopenia (ITP) in adult patients who are refractory to other treatments (e.g., corticosteroids or immunoglobulins)'.

# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics for avatrombopag.

# Price
The list price of a 10tablet pack of avatrombopag 20 mg is 640.00 (excluding VAT; BNF online, accessed June 2022).
The company has a commercial arrangement. This makes avatrombopag available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence submitted by Swedish Orphan Biovitrum, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.

# The condition

## Immune thrombocytopenia (ITP) is an autoimmune condition that is chronic in most affected adults
ITP is characterised by a platelet count less than 100109 per litre. This reduced platelet count is caused by abnormally high platelet destruction and reduced platelet production. ITP is a rare condition. About 3,000 to 4,000 adults in the UK are estimated to have ITP at any one time. To make a diagnosis, any other possible causes of thrombocytopenia, including impaired bone marrow, need to be excluded. Most diagnosed cases in adults progress to chronic ITP that may be difficult to control. Symptoms include fatigue, spontaneous bruising and regular bleeding episodes. The patient experts highlighted that the fatigue can be debilitating, reducing cognitive function and making it difficult to focus. The fatigue also often contributes towards increased bruising. This is because reduced coordination related to the fatigue may cause people to bump into things more often. Bleeding episodes can range from minor bleeds to severe, life-threatening haemorrhages. The patient experts emphasised the effect ITP has on mental as well as physical health. This is because many people with ITP worry about maintaining high enough platelet levels to prevent bleeding episodes. Treatment for ITP is usually introduced when the platelet count drops below 30109 per litre. Current treatments include corticosteroids, immunoglobulins, thrombopoietin receptor agonists (TPORAs) and immunosuppressants such as rituximab. The patient and clinical experts highlighted that the current treatments have disadvantages, including unpleasant and potentially harmful side effects, and the need for dietary changes. They emphasised a need for another treatment option that offered more normality for those affected by ITP. The committee concluded that ITP is a chronic condition that significantly affects the lives of those affected by it.

## People with chronic ITP would welcome new treatment options that maintain platelet counts at a level that prevents bleeds
ITP is a burden to people with the condition, as well as their families and carers. This burden is often linked to the unpredictable nature of the condition and the side effects of treatment. Also, some people with ITP need to inject some treatments themselves, so need to plan their life around injection dates, and ensure safe storage and administration of these treatments. The patient experts highlighted that this could affect everyday life. Self-injecting can also cause increased anxiety. One patient expert described how they still had stress about injecting 5 years into treatment. Also, soreness and bruising can occur at the injection site, particularly in people whose platelet counts are low. There is an oral TPORA, but this can cause side effects including chronic gastrointestinal issues and increased risk of blood clots. It can also be affected by diet, and people taking it may need to restrict what foods they eat, and when they eat them. Both the patient and clinical experts highlighted that this has a large effect on everyday life, adherence to treatment and effectiveness. Some treatments for ITP also cause immunosuppression, which increases the risk of infection. One patient expert explained that they had had 22 infections in an 18month period when taking an immunosuppressant for ITP. Infections can cause a drop in platelet count, which may need hospitalisation and rescue therapy if uncontrolled. Both the patient and clinical experts agreed that avatrombopag, an oral treatment with no dietary restrictions and no immunosuppression would be an advance in ITP treatment in the UK. They also agreed it could improve quality of life for people with ITP by increasing platelet count without being a difficult treatment to take. The committee agreed that a new treatment option for maintaining platelet counts would be welcomed by people with ITP.

# Treatment pathway and comparators

## The company's positioning of avatrombopag in the treatment pathway is appropriate
The company's positioning of avatrombopag was aligned with avatrombopag's marketing authorisation, that is, for treating primary chronic ITP in adults refractory to other treatments. When someone is diagnosed with ITP, they have an 'initial' treatment that includes corticosteroids, immunoglobulins or both. The clinical experts explained that TPORAs would not be used before corticosteroids and immunoglobulins but would be used if this initial treatment failed. The committee concluded that avatrombopag is likely to be used after initial treatment of newly diagnosed chronic ITP. It agreed that the company's positioning of avatrombopag in the treatment pathway was appropriate.

## The relevant comparators for avatrombopag are other TPO-RAs
In its submission, the company considered other TPORAs (eltrombopag and romiplostim) to be the only appropriate comparators for avatrombopag. The company's rationale for this was that:
TPORAs are considered to be well-established standard care for ITP
it would be inappropriate to consider rituximab or surgical splenectomy as the comparators given the availability of 2 other TPORAs.The ERG agreed that the company's positioning of avatrombopag was reasonable. But it highlighted uncertainty around the variations in rituximab use in clinical practice. The committee queried at what point in the treatment pathway TPORAs are prescribed in the NHS. The clinical experts explained that, while care is individualised to people with ITP, clinicians generally use TPORAs before rituximab. They also explained that, before the COVID19 pandemic, rituximab's use varied across the UK. But international guidance changes have caused a shift in practice to use TPORAs first after initial treatment has failed. This is because rituximab can suppress the immune system. They also confirmed that clinicians rarely offer splenectomy in the first year of diagnosis and do not consider it as an alternative to TPORAs. The committee concluded that eltrombopag and romiplostim were the appropriate comparators for avatrombopag.

# Clinical effectiveness

## The population of Study 302 may represent the likely NHS population, but there are uncertainties
The key clinical evidence for avatrombopag came from 1 clinical trial, Study 302, and its 72week open-label extension. Study 302 was a 26week, phase 3, multicentre, randomised, double-blind, parallel-group trial of avatrombopag compared with placebo. The company also submitted clinical evidence from 2 open-label clinical trials:
Study 305, a discontinued phase 3, multicentre, randomised, double-blind, parallel-group trial of avatrombopag compared with eltrombopag
CL003, a 28day, phase 2, double-blind, randomised, controlled trial of avatrombopag compared with placebo, and CL004, a 6month rollover study for people who completed CL003.The company only included Study 302 data in the economic model because it considered that it contained robust comparative data on key efficacy and safety outcomes. It stated that the results of the other studies largely supported the safety and efficacy profile of avatrombopag. But it did not think it was appropriate to include the data from these studies in the economic model. The ERG noted that, although Study 302 did not have a UK site, the baseline characteristics of its population would likely be applicable and relevant to an NHS population. But the committee noted that the trial's population may have been younger than the NHS population. The clinical experts explained that they would not expect the response to avatrombopag to be age specific. But more fatal bleeds and infection events may happen in older people, which the clinical experts thought may not have been fully captured in the trial. The committee also noted that 72% of the avatrombopag group were women compared with 47% in the placebo group. There were also people in the trial who had had a splenectomy, which would normally be done after treatment with avatrombopag. Neither the ERG nor the clinical experts thought that this would have had a meaningful effect on the trial results. The committee concluded that the population in Study 302 may represent the NHS population but that there were uncertainties in the study population's baseline characteristics. It took this into account in its decision making.

## The clinical trials of avatrombopag has recruitment and attrition issues, resulting in a limited evidence base
There were 49 people in Study 302, 32 in the avatrombopag group and 17 in the placebo group. Twenty two people on avatrombopag completed the trial, while 7 stopped because of inadequate treatment effects and 3 stopped for other reasons. One person on placebo completed the trial, while 15 stopped because of inadequate treatment effects and 1 stopped for other reasons. The clinical experts explained that it is difficult to have a true 'placebo' group for chronic ITP treatments. This is because people in a placebo group would not be expected to stay in a trial if they had extremely low platelets and bleeding episodes. This led to limitations when estimating the durable platelet response rate in the placebo group over the course of Study 302. The ERG was concerned with the robustness of the efficacy and safety data from Study 302 because of the imbalanced drop-out between the avatrombopag and placebo groups. During the first committee meeting, it highlighted that this also affected the results of the company's network meta-analysis (NMA) that indirectly compared avatrombopag with other TPORAs (see section 3.9) and used durable platelet response rate as the outcome. This was because the durable platelet response rate was a key outcome assessed in the NMA presented to the first committee meeting. The committee was aware that Study 305 was stopped early, and that the results of this study were not included in the economic model. It questioned why it was stopped early. The company explained that the trial protocol for Study 305 mandated unpleasant screening and monitoring procedures for people in the trial, and this contributed to recruitment challenges. It also commented that the trial started when eltrombopag was approved and became commercially available. It thought that people may have been reluctant to enrol and be randomised to avatrombopag, a non-approved treatment. So, the trial was stopped before durable platelet response rate could be measured. But the company thought that data from the study could have been used to provide information on other outcomes, including bleeding episodes. At the first committee meeting, the committee had concerns around the limitations of Study 302. In response, the company stated that there was a growing evidence base and clinical experience of using avatrombopag. It also stated that the efficacy of avatrombopag has been shown in randomised controlled trials and real-world settings. The committee understood that there was a limited evidence base for the clinical efficacy of avatrombopag because of recruitment and attrition issues in the clinical trials.

## Avatrombopag may improve cumulative platelet response and durable platelet response rate, but the clinical evidence is highly uncertain
The primary outcome of Study 302 was the median cumulative number of weeks of platelet response, measured over 26 weeks. A platelet response was defined as 50109 per litre or more. Evidence suggested that the median cumulative number of weeks of platelet response was 12.4 weeks with avatrombopag and 0 weeks with placebo (p<0.0001). Other outcomes measured included:
secondary:
proportion of people with a platelet response without rescue therapy at day 8 (avatrombopag 65.6%, placebo 0%; p<0.0001)
proportion of people with a reduction in concomitant ITP medication (avatrombopag 33.3%, placebo 0%; p=0.13)
exploratory:
durable platelet response rate, that is, the proportion of people who had a platelet response for 6 or more of the last 8 weeks of treatment (avatrombopag 34.4%, placebo 0%; p=0.009)
incidence of any grade of bleeding (avatrombopag 43.8%, placebo 52.9%; p=0.54)
use of rescue therapy (avatrombopag 21.9%, placebo 11.8%; p=0.47). The ERG noted that the evidence suggested that, compared with placebo, avatrombopag improved the median cumulative number of weeks of platelet response over 26 weeks and the durable platelet response rate. But it highlighted that the interpretation of the evidence was difficult because of the high drop-out in the placebo group. The committee commented that a platelet response without any form of treatment is improbable. It noted the statistically significant difference in proportion of people with a platelet response without rescue therapy at day 8 between avatrombopag and placebo. It contrasted this with the relatively smaller difference between the 2 groups for the outcome of incidence of bleeds. It questioned what the most clinically meaningful outcomes for assessing clinical effectiveness would be. The clinical experts explained that time spent above a platelet count threshold is a clinically meaningful outcome, but this can be difficult to reach because ITP is variable. They thought that a platelet count of 30109 per litre or more could usually be taken as a response in practice. But they added that a platelet count of 50109 per litre or more indicates a clinically meaningful response. The company explained that sometimes a platelet count of 20109 per litre or more reduces bleeding risk and that there could be bleeding with a count of 50109 per litre or more. So, the company thought that the proportion of people with a platelet count of 50109 per litre or more without rescue therapy at day 8 could not be a reliable indicator for incidence of bleeds. It thought this was particularly so, given the imbalanced drop-out and follow-up times of the 2 groups in Study 302. The committee was aware that results on long-term durable platelet response rate were not recorded in another trial, Study 305. This was because the trial was stopped before they could be measured. The committee concluded that the evidence from Study 302 suggested that avatrombopag improved cumulative platelet response and the durable platelet response rate, but that this was highly uncertain.

## The frequency of adverse reactions is broadly similar between avatrombopag and placebo
In Study 302, the incidence of adverse reactions was compared between the avatrombopag and placebo groups at 26 weeks. Because of the imbalanced treatment durations between these groups (mean 22.8 weeks for avatrombopag compared with mean 8.9 weeks for placebo), the ERG adjusted the treatment duration times to allow a fair comparison. The adjusted analysis suggested that the frequencies of adverse reactions were broadly similar (avatrombopag 4.3%, placebo 6.6%; p value not reported). The ERG noted that higher adverse-reaction incidence rates were seen in Study 305 and CL003/004. But the incidence rates for the avatrombopag and comparator groups in these studies were largely similar. The committee highlighted that the small number of people in Study 302 meant that only adverse reactions occurring in more than 10% to 20% would have been identified. It concluded that, within the limitations of the data, the frequency of adverse reactions was broadly similar between avatrombopag and placebo.

# NMA using durable platelet response rate as the outcome

## The ERG's continuity correction method proportional to sample size may be appropriate, but there are uncertainties
The company presented a series of NMAs to the first committee meeting because there was no direct comparison available. These NMAs compared avatrombopag's efficacy and safety with other TPORAs (eltrombopag and romiplostim), fostamatinib and placebo. The ERG highlighted that fostamatinib was included unnecessarily because it was not included in the final scope as a comparator and is not recommended by NICE. The ERG did not consider it in its own analysis. A frequentist approach using fixed effect models was considered appropriate by both the company and ERG after the technical engagement before the first committee meeting. The NMAs were done for 6 outcomes, including:
binary outcomes, reported as odds ratios (ORs):
proportion of people with a durable platelet response (durable platelet response rate)
proportion of people with reduced concomitant ITP medications
incidence rate ratio outcomes:
any bleeding episodes
bleeding episodes with World Health Organization bleeding assessment score grades 2 to 4
need for rescue therapy
any adverse events.The NMA for durable platelet response rate was done despite it not being the primary outcome of Study 302. The company stated that this was because it was the only platelet response outcome that could provide meaningful comparative effectiveness data between avatrombopag, and eltrombopag and romiplostim. During its first meeting, the committee's discussion focused on the durable platelet response rate NMA because it was the only outcome that informed the company's model. The committee understood that the company had chosen durable platelet response rate as the outcome for the feasibility of this NMA because all trials assessed it in a similar way. It noted that 2 other trials included in the NMA for this outcome had zero event or response in its placebo group because of early drop-out or no response. So, the company adjusted the zero events or response in placebo groups to calculate the ORs. Its first continuity correction attempt resulted in an OR of 102.80 (95% credible interval  3.87 to 2,796,448) for avatrombopag compared with placebo. The ERG pointed out that this estimate lacked face validity compared with the evidence from Study 302. It also noted that the company did not provide any detail on how it had corrected for zero events in placebo groups. The ERG preferred another continuity correction method. This involved adding 0.5 to both event and non-event cells in each treatment group to OR. It resulted in an OR of 18.72 (95% CrI 1.02 to 340) for avatrombopag compared with placebo using Study 302 as an example. During technical engagement, the company argued that this approach by the ERG was not appropriate. This was because people were randomised into placebo (n=17) and treatment groups (n=32) in a 1 to 2 proportion in Study 302. The company considered that the ERG's approach introduced directional bias and made the OR highly uncertain.
In response to the ERG's critique at technical engagement, the company revised its correction method. It did this by adding an adjustment value to each treatment group proportional to the sample size of the trial, but only to event cells. The company stated that this method was based on Sweeting et al. (2004). When there was a zero event or response cell in the placebo group, an adjustment value of 0.35 (17 of 49) was added to the placebo events cell but subtracted from placebo no-events cell. Also, an adjustment value of 0.65 (32 of 49) was added to any avatrombopag events cell but subtracted from an avatrombopag no-events cell. This was done to maintain the original number of people in each treatment group (17 in the placebo group and 32 in the avatrombopag group). This correction method resulted in an OR of 27.49 (95% confidence interval  0.88 to 855.90) for avatrombopag compared with placebo. The ERG acknowledged that Sweeting et al. suggested an option of correcting zero events or response by adding adjustment values proportional to the sample size to the cells. But it thought that the company had implemented the method incorrectly. This was because, according to Sweeting et al., any adjustments must be applied to both event and no-event cells. This then increases the total number of people in each group as well. So, the ERG did a study-specific sensitivity analysis that correctly implemented the adjustment method suggested by Sweeting et al. As a result, when there was a zero events or response cell in the placebo group, an adjustment value of 0.35 (17 of 49) was added to both events and no-events cells for the placebo group. Also, an adjustment value of 0.65 (32 of 49) was added to both events and no-events cells in the avatrombopag group. This resulted in an OR of 26.91 (95% CI 0.87 to 835.27). During the first committee meeting, the company stated that it agreed with the ERG's sensitivity analysis. The committee considered that any correction should have been done across both events and no events and would ideally have been weighted according to sample size. It concluded that the proportional to sample size approach used in the ERG's sensitivity analysis may have been appropriate for correcting zero events in placebo groups. But it considered that any correction methods would have been associated with a high level of uncertainty when assessing avatrombopag's clinical effectiveness relative to other TPORAs. The committee took this into account in its decision making.

# NMA using mean platelet count as a continuous outcome

## An alternative NMA with mean platelet count as a continuous outcome is needed
The committee noted the uncertainties associated with the clinical evidence from Study 302 during its first meeting because of the:
high attrition in the placebo group (see section 3.6)
uncertainties associated with the correction of zero events involved in the NMA analysis on the outcome of durable platelet response rate (see sections 3.9 and 3.10).The committee was aware that a durable platelet response would be unlikely with placebo. This would have made it challenging to compare treatments that had been compared with placebo for this outcome, regardless of the approach taken to adjust for the zero events. The committee was aware that the company's NMA results on the outcome of 'any bleeding events' suggested that avatrombopag may be associated with a lower risk of bleeding compared with placebo (OR 0.32, 95% CI 0.16 to 0.61), eltrombopag (OR 0.43, 95% CI 0.22 to 0.84) or romiplostim (OR 0.39, 95% CI 0.18 to 0.85). But durable platelet response rate was the only outcome that informed the model. The committee was aware that there is an alternative way of exploring avatrombopag's clinical effectiveness relative to other TPORAs, while avoiding the issue of zero events or response in placebo groups. This was to assess mean platelet count as a continuous outcome and transform the resulting estimates into response probabilities for the economic model using an appropriate distributional assumption. Given the uncertainties in the NMA for durable platelet response rate, the committee requested to see the results of an NMA with mean platelet count as a continuous outcome.

## The alternative NMA with mean platelet count as a continuous outcome does not resolve all the uncertainties
After the first committee meeting, the company provided an additional NMA comparing avatrombopag's efficacy with other TPORAs (eltrombopag and romiplostim). The outcome was change in mean platelet count from baseline at 25 to 26 weeks. This outcome, along with a distributional assumption, was used to derive the probability of avatrombopag, eltrombopag and romiplostim achieving a platelet count over 30109 per litre or 50109 per litre. The company used a Bayesian approach for this NMA, in both a fixed and random effects model. Results showed that avatrombopag was associated with a greater improvement in mean platelet count from baseline compared with placebo: 56.73 (95% CrI 30.62 to 83.13). But there was no difference between avatrombopag and eltrombopag: 1.30 (95% CrI, -27.57 to 30.24), or romiplostim: 10.46, (95% CrI -18.93 to 39.92). The additional analysis also showed that the probability for reaching a 30109 per litre or a 50109 per litre platelet count threshold was almost 100% for all treatments compared. Both the company and ERG highlighted the limitations associated with this additional NMA. The company noted the issue around mean change estimates having to be derived from median values for comparators. It also noted the high level of drop-out in the placebo group of Study 302, with only 1 person left at the end of 26week follow up. The ERG was particularly concerned with the last observation carried forward (LOCF) method the company had used to input missing data from the placebo group. It pointed out that LOCF was a less conservative approach to replace missing values compared with what had been done in the original NMA by zero correction methods. Also, the last recorded trial observation might have been made when the person was still on treatment and before the loss of efficacy or adverse events. So, it may have overestimated the efficacy of treatment compared with data at later timepoints. The ERG considered that the company should have explored the other more conservative missing data replacement methods. It continued that the company did not provide sufficient justifications for choosing the change in mean platelet count from baseline as the outcome for this additional NMA. This was because there were alternative outcomes that could have been explored. These included, for example, assessing the continuous outcome accounting for multiple timepoints, or adjusting for baseline imbalances. Other uncertainties associated with this additional NMA and noted by the ERG included:
The mean platelet count fluctuated over time, but the company chose the 26week follow-up timepoint for this analysis. This provided a limited view of the treatment response over time compared with the original NMA analysis using durable platelet response rate as the outcome.
The results of this additional NMA markedly differed from the NMA presented to the first committee meeting in terms of ranking efficacy of TPORAs.The company explained that it had chosen change in mean platelet count from baseline as the continuous outcome for this additional NMA and LOCF to input missing data because of time and resource reasons. Also, it chose the timepoint at 26week follow up because this was consistent with the timepoint at which the durable platelet response rate was measured in the trial. It continued that, although the ranking efficacy of TPORAs differed between the 2 analyses, both suggested that avatrombopag had the highest probabilities of being the best treatment. Given the high uncertainties, the ERG considered that this additional NMA did not resolve the uncertainties associated with avatrombopag's clinical effectiveness relative to other TPORAs. It noted that durable platelet response rate may be a more appropriate outcome for measuring treatment response to avatrombopag, as supported by its clinical expert. The committee noted that this additional NMA was requested in the hope to validate the NMA results with durable platelet rate as the outcome. This was because of the uncertainties associated with the zero correction methods in the company's original NMA (see section 3.10). The committee understood that this additional NMA was also subject to high uncertainties. This was because of the limitations in the evidence from Study 302, and the company's choice of change in mean platelet count from baseline as the continuous outcome. It is aware that durable platelet response rate is commonly used for assessing treatment response and has been used in previous appraisals for ITP. It agreed that the additional NMA did not resolve the uncertainties in the evidence, and it took this into account in its decision making.

# Avatrombopag's clinical effectiveness relative to other TPO-RAs

## Avatrombopag's treatment effect on durable platelet response rate may be similar to other TPO-RAs, but there are high uncertainties
The committee discussed the uncertainties associated with the 2 NMAs presented by the company. It recalled its discussions on whether durable platelet response would be likely with placebo (see section 3.6 and section 3.7). It was aware of the limitations in the evidence from both Study 302 and the 2 NMAs given the high attrition rate on the placebo arm. It noted that the outcome on durable platelet response rate may be more appropriate for assessing avatrombopag's treatment effect and informing the model. But the committee noted the considerable challenges when interpreting the results of the NMAs because there were exceptionally wide credible intervals and a high level of uncertainty in the results as a consequence. So, it was difficult for the committee to accept avatrombopag's superiority over other TPORAs. The committee was aware that avatrombopag is an oral treatment and associated with less dietary restrictions compared with the other oral treatment available for ITP (see section 3.2). Considering the challenges with the evidence generation, the committee concluded that, on balance, avatrombopag's treatment effect on durable platelet response rate may be broadly similar to other TPORAs. But it noted that there are high uncertainties. The committee took this into account in its decision making.

# Economic model

## The company's economic model structure is appropriate for decision making
The economic model was a Markov cohort model consisting of 4 mutually exclusive health states: 'active treatment' (up to 24 weeks waiting for a response), 'responder', 'no treatment no response' (watch and wait) and 'death'. People began in the 'active treatment' state with a platelet count of less than 30109 per litre and remained there until their response status was determined. People moved to the 'responder' state if their platelet count increased to more than 50109 per litre. There, they continued active treatment. People stopped active treatment and moved to the 'no treatment no response' state if their platelet count did not increase above 50109 per litre while on active treatment. 'Responders' could also stop treatment and move to the 'no treatment no response' state if relapse occurred. People in the 'no treatment no response' state restarted active treatment if a bleeding episode occurred, or if there was a need for rescue therapy. At this point, they had an alternative active treatment from their first-line treatment option. People could move into the 'death' state from any of the other model states. Each model cycle lasted 4 weeks, with a time horizon of 56 years representing a lifetime horizon. The ERG considered the model structure to be broadly representative of ITP, and appropriate for modelling the effect of TPORAs. The clinical experts noted that people with a low platelet count would typically have active treatment. But they explained that this is not the only factor considered when determining treatment. But the platelet response threshold of 50109 per litre is widely used to define treatment response and has been used in previous NICE technology appraisals for ITP. The committee concluded that the economic model structure was appropriate for decision making.

## The 12-week timeframe for assessing non-response might be appropriate but there are uncertainties
The company used durable platelet response rate to measure the clinical effectiveness of avatrombopag. During the first committee meeting, the company took a pragmatic approach and assumed a 24week timeframe to assess response to TPORA treatments in the model based on Study 302. The ERG noted that, according to the summaries of product characteristics for TPORAs, treatment should be stopped if there is no response within 4 weeks of prescribing the maximum dose. The clinical experts explained that they would expect to assess response over a period of 8 to 12 weeks rather than 24 weeks. They anticipated that the time taken to titrate an oral treatment would be 4 to 8 weeks, followed by 4 weeks at maximum dose to determine response. They also noted that choice of TPORA could affect this. For example, romiplostim has 10 dosing levels so it can take longer to titrate and to determine response to its maximum dose. The committee queried the effect on the cost-effectiveness analysis of changing this timeframe. The ERG explained that the 24week was a relatively short timeframe because the model considered a lifetime horizon. It thought that this may have been the reason why its scenario analysis with an 8week timeframe had a small effect on the cost-effectiveness results. The committee considered that the 24week timeframe to assess response did not reflect clinical practice. After the first committee meeting, the company updated its base case to reflect a 12week timeframe for assessing response to treatment in the model. The company stated that it had updated this to be in line with the ERG's base case after the technical engagement and before the first committee meeting. The ERG clarified that its base case presented at the first committee meeting did not use a 12week timeframe. It noted that it was considered unlikely that people would remain on avatrombopag for 24 weeks if there was no response. But it explained that either an 8week or 12week time frame would not align with the definition of durable platelet rate used in the model. This was defined as a platelet response equal or larger than 50109 per litre for at least 6 of the last 8 weeks of treatment. But the ERG updated the model to use a 12week timeframe for assessing response after the first committee meeting. It noted that this had a minor effect on the cost-effective estimates. The committee agreed with this and understood that the 12week timeframe was closer to clinical practice, but it noted the uncertainties associated with its use in the model. It concluded that the 12week timeframe for assessing non-response might be appropriate but there were uncertainties.

## The company's approach to modelling subsequent treatments is acceptable
The company used a mixed treatment approach to model subsequent lines of treatment in the model. These included other TPORAs and non-TPORAs but did not consider treatment sequencing of TPORAs. As a result, response rates for subsequent lines may have been higher than for first-line treatment in the company's model (see section 3.17). The company did not consider that assessing treatment sequencing in the model was plausible from a clinical perspective. This was because it considered that avatrombopag and other TPORAs had similar efficacy, safety, and long-term treatment durations. Also, avatrombopag would be considered for use in people who are suitable for other TPORAs. The ERG disagreed with the company. It stated that a comprehensive assessment of fixed treatment sequences, weighted according to treatment pathways in UK clinical practice, would have more appropriately reflected treatment variability. The ERG did a scenario analysis simulating sequences of treatment options. It noted that, when compared with sequences without avatrombopag, sequences including avatrombopag appeared to provide similar value for money as avatrombopag compared with other TPORAs in the single-line model. But this assumed identical treatment durations among TPORAs. The clinical experts explained that treatment for ITP is highly individualised in practice because the condition is variable. Also, there is no fixed treatment sequence that is followed in clinical practice. People with ITP are also able to switch between TPORAs if their condition stops responding or they become intolerant to a specific one. The committee acknowledged that it was difficult to determine fixed treatment sequences for ITP. It concluded that the company's approach to modelling subsequent treatments was acceptable.

## Defining response differently between TPO-RAs and non-TPO-RAs leads to uncertainties in the model
The company defined response for TPORAs as durable platelet response rate (see section 3.7). But it defined the response for non-TPORAs based on NICE's technology appraisal guidance on romiplostim for treating chronic ITP. This definition combined data on efficacy from different studies and took a weighted average. The subsequent lines of treatments that included a mix of TPORAs and non-TPORAs had mixed treatment response definitions. The ERG noted that the response rates used in subsequent lines of treatment for non-TPORAs were high relative to the response rates used in the model for TPORAs. The company explained that, because subsequent lines of treatment included treatments unlicensed for ITP, there was a lack of published evidence for durable platelet response rate for non-TPORAs. But avatrombopag, eltrombopag and romiplostim all had a similar definition of durable platelet response rate (platelet response over 50109 per litre for at least 6 of the last 8 weeks of treatment). The company also explained that its approach of using different definitions for TPORAs and non-TPORAs could have underestimated the response associated with avatrombopag. But it pointed out that a similar approach had been taken in previous NICE technology appraisals. The ERG highlighted that, in fact, the previous appraisals only included non-TPORAs at subsequent lines, which was different to the company's model. The ERG also noted that it was unclear whether this approach was conservative for avatrombopag. The committee considered that similar definitions for response for TPORAs and non-TPORAs would have been preferrable. But it was also aware that this was not possible given the lack of evidence for non-TPORAs. It concluded that having different definitions for responses for TPORAs and non-TPORAs led to uncertainties in the model. It took this into account in its decision making.

## The same treatment duration of 109 cycles for all TPO-RAs in the long term may be appropriate but there are uncertainties
The company assumed long-term treatment duration to be 109 model cycles (436 weeks, or about 8.4 years) for all TPORAs. It assumed the constant stopping rate to be 0.9% per 4week model cycle. The company took these estimates from Lee et al. (2013). This fitted a survival curve to:
romiplostim data based on a phase 3, placebo-controlled, 24week trial and a follow-on, open-label extension of up to 6.0 years
eltrombopag data based on results from the open-label EXTEND trial of up to 5.5 years.The company estimated a mean treatment duration of 393 cycles for romiplostim and 109 cycles for eltrombopag, based on data from Lee et al. The ERG highlighted that the difference in mean times on treatment between eltrombopag and romiplostim suggested that there was a difference in treatment durations and stopping rates between TPORAs. During technical engagement, the company provided the results from a survey that it did among 9 clinicians in the UK. It explained that the results supported similar long-term treatment duration between TPORAs. The clinical experts noted that 109 cycles is already a long time for people to be on treatments, so 393 cycles would be unrealistic. They noted that TPORAs may have similar treatment durations and stopping rates, but that some people might stay longer on oral treatment options with less dietary restrictions. The committee noted that about 31% (10 of 32) of people stopped avatrombopag in Study 302. This would equate to about 1.7% per month stopping avatrombopag during its 72week extension period. The clinical experts explained that sometimes people stop treatments because their condition becomes stable. The committee was aware the company's approach of using stopping rates from Lee et al. represented a departure from the approach taken by NICE's technology appraisal guidance on romiplostim and eltrombopag. These appraisals modelled time on treatment using patient-level data from the pivotal trials. The company explained that the estimates from Lee et al. were based on longer trial periods (up to 6.0 years for romiplostim and 5.5 years for eltrombopag) than Study 302 (26 weeks plus a 72week extension). During its first meeting, the committee considered that treatment duration might be similar between TPORAs. But it requested more scenario analyses to enable it to compare what the company assumed in the model, including:
estimated treatment duration based on modelling stopping rates from Study 302
a scenario using the empirical data from the extension of Study 302.The company provided these scenario analyses after the first committee meeting. It fitted a log-normal distribution to the KaplanMeier data from the trial and its extension. This resulted in an average treatment duration of 57 cycles (229 weeks or 4.4 years) based on Study 302 alone, and 633 cycles (2,531 weeks or 48 years) with the extension. The company stated that the treatment duration of 109 cycles used in the model was based on long-term trials for the comparators. So, it would be more appropriate to include the extension of Study 302 when determining treatment duration. The ERG explained that the company's approach of analysing data from Study 302 was reasonable because it was similar to that used in Lee et al. But the ERG highlighted that only a few people were at risk in the extension (less than 10 people at risk in 1 year). These small numbers at risk were extrapolated into the longer term, resulting in an average treatment duration of about 48 years for avatrombopag. This was clinically unlikely giving the starting age of 45 years in the model. The company explained that this new extrapolation was presented to confirm that avatrombopag's treatment duration could be as long as other TPORAs. It explained that its original treatment duration of 109 cycles remained unchanged in its base case. The committee noted the uncertainties. On balance, it considered that it was likely that TPORAs would have similar treatment durations in the long term. It concluded that a long-term treatment duration of 109 model cycles for all TPORAs was appropriate for decision making.

# Resource use and costing in the economic model

## It is appropriate to cost bleeding episodes based on NHS reference costs using the weighted average
In its original submission, the company stratified rescue therapy events into bleed related and non-bleed related. But it nested bleed-related rescue therapies within bleeding episodes. The company also commissioned independent market research to inform the resource use associated with non-minor bleeding episodes. Resources used included hospital stays, diagnostic imaging, blood test and therapeutic interventions. The ERG preferred to cost rescue therapies and bleed-specific unit costs independently. It noted that the company's bleed-specific unit costs informed by its market research data were much higher than those based on NHS reference costs, and those applied in NICE's technology appraisal guidance on romiplostim and eltrombopag. The ERG also noted that there was no clear reporting of which bleed-specific costs were excluded from NHS reference costs and how using the market research captured these alleged omissions. It explained that, because bleed-related rescue therapies were nested within bleeding episodes, the bleed-specific costs were also difficult to interpret. The company aligned its approach to costing to that of the ERG's by modelling bleeding episodes and rescue therapies independently after the technical engagement, except for bleed-specific unit costs. The company took the midpoint between the NHS reference costs and its market research data to represent bleed-specific unit costs and presented it to the first committee meeting. The ERG remained concerned because the company's market research data for bleed-specific unit costs may still have included the costs of rescue therapies. It highlighted that taking this midpoint suggested that bleed-specific costs may not be independent from the costs of rescue therapy, and that this midpoint was still difficult to interpret. The committee noted that there was a lack of detail on the methods of the company's market research. The committee considered that the ERG's approach of using the NHS reference costs would have been appropriate. But the committee recognised that there might be additional resources not covered by the NHS reference costs. So, it requested to see the detailed methods of the company's market research, and how the company derived the bleed-specific unit costs from its qualitative survey questions. After the first committee meeting, the company provided further details on the methods of it market research. It did not use costs from this market research but updated its analyses using NHS reference costs for bleed-specific unit costs in the model. This was in line with the ERG's approach. But the company's bleed-specific unit costs were based on the highest unit cost for the different types of bleeds, rather the weighted average as done by the ERG. The company justified this because duration of different bleeds in people with ITP tend to be longer than the general population. It also explained that this was because additional time is usually needed to increase the person's platelet count and to stabilise the bleed, and bleeds in these people tend to be more severe. The committee questioned where this information had come from. The company explained that it had sought further advice from UK clinicians. But it acknowledged that it was reliant on clinical opinion and there was no published evidence to support these claims. The ERG explained that the company's approach may be reasonable. But it noted that the company's selection of highest unit costs for each type of bleed deviated from methods used in previous appraisals for ITP. Given the uncertainties in the evidence and the model, the committee concluded that the ERG's approach of using the weighted average costs for bleed-specific unit costs was preferrable.

# Cost-effectiveness estimates

## Uncertainties remain in the clinical evidence and in the company's modelling assumptions
The committee noted that unresolved uncertainties remained in the company's evidence base and model assumptions, including:
the recruitment and attrition issues with avatrombopag studies (see section 3.6 and section 3.7)
the results from the NMA on durable platelet response rate (see sections 3.9 and 3.10)
the different definitions of response between TPORAs and non-TPORAs (see section 3.17)
the long-term treatment duration (see section 3.18)
the company's approach to costing bleeding episodes in the model (see section 3.19)
probabilistic sensitivity analyses were only conducted for pairwise comparisons because of how the company's model was designed.

## Avatrombopag is likely to be cost effective for primary chronic ITP in adults
NICE's guide to the methods of technology appraisal notes that judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the incremental cost-effectiveness ratio (ICER). The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. At the first committee meeting, the committee concluded that the true ICER was not known because of the uncertainties in the clinical evidence provided and in the modelling. The company attempted to reduce these uncertainties by providing updated analyses. In addition, the company provided a comparison of the net cost to the NHS that showed avatrombopag had a cost similar to or lower than its comparators. When the company updated its base case after the first committee meeting, the ICER was below what NICE normally considers an acceptable use of NHS resources. Because of confidential commercial arrangements for avatrombopag and comparator treatments, the cost-effectiveness results cannot be reported here. Scenario analyses exploring other areas of uncertainty did not increase the ICER above an acceptable use of NHS resources. There was further assurance provided with the comparison of costs. So, the committee considered that avatrombopag is cost effective for primary chronic ITP in adults.

## It is unclear whether there are additional benefits of avatrombopag not captured in the model
There were no equality issues identified for avatrombopag. The company considers avatrombopag to be innovative because it will offer an additional effective treatment choice to those with chronic ITP. More treatment options are needed because people with ITP can experience loss of response or adverse events with current treatment options. The company also highlighted that there may be uncaptured benefits with avatrombopag because it is an oral treatment and can be taken without the need for dietary restrictions. This might improve treatment adherence. The patient experts emphasised the importance of having the choice of a treatment such as avatrombopag because anxiety around injecting is common, and maintaining dietary restrictions is burdensome. The company also noted that, unlike eltrombopag, avatrombopag does not cause hepatoxicity. This means that less monitoring is needed, and that it can be used for people with ITP who also have liver disease. The committee concluded there might be additional benefits with avatrombopag. But, given the uncertainties in the evidence and in the model (see section 3.20), it was unclear whether there were any not captured in the cost-effectiveness analysis.

# Conclusion

## Avatrombopag is recommended as an option for treating primary chronic ITP in adults
Avatrombopag is recommended for use in the NHS as an option for treating primary chronic ITP in adults. The cost-effectiveness estimates for people with ITP were uncertain because of uncertainties within the clinical evidence and in the modelling. But they were highly likely to be below what is considered an acceptable use of NHS resources.