Avatrombopag for treating primary chronic immune thrombocytopenia

3.1 ITP is characterised by a platelet count less than 100×10⁹ 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 30×10⁹ per litre. Current treatments include corticosteroids, immunoglobulins, thrombopoietin receptor agonists (TPO‑RAs) 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.

3.2 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 TPO‑RA, 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 18‑month 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.

3.3 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 TPO‑RAs 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.

3.4 In its submission, the company considered other TPO‑RAs (eltrombopag and romiplostim) to be the only appropriate comparators for avatrombopag. The company's rationale for this was that:

3.5 The key clinical evidence for avatrombopag came from 1 clinical trial, Study 302, and its 72‑week open-label extension. Study 302 was a 26‑week, 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:

3.6 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 TPO‑RAs (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.

3.7 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 50×10⁹ 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:

3.8 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 CL‑003/004. 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.

3.9 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 TPO‑RAs (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:

3.10 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 [CI] 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 TPO‑RAs. The committee took this into account in its decision making.

3.11 The committee noted the uncertainties associated with the clinical evidence from Study 302 during its first meeting because of the:

3.12 After the first committee meeting, the company provided an additional NMA comparing avatrombopag's efficacy with other TPO‑RAs (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 30×10⁹ per litre or 50×10⁹ 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 30×10⁹ per litre or a 50×10⁹ 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 26‑week 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:

3.13 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 TPO‑RAs. 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 TPO‑RAs. But it noted that there are high uncertainties. The committee took this into account in its decision making.

3.14 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 30×10⁹ 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 50×10⁹ 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 50×10⁹ 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 TPO‑RAs. 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 50×10⁹ 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.

3.15 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 24‑week timeframe to assess response to TPO‑RA treatments in the model based on Study 302. The ERG noted that, according to the summaries of product characteristics for TPO‑RAs, 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 TPO‑RA 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 24‑week 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 8‑week timeframe had a small effect on the cost-effectiveness results. The committee considered that the 24‑week timeframe to assess response did not reflect clinical practice. After the first committee meeting, the company updated its base case to reflect a 12‑week 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 12‑week 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 8‑week or 12‑week 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 50×10⁹ per litre for at least 6 of the last 8 weeks of treatment. But the ERG updated the model to use a 12‑week 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 12‑week timeframe was closer to clinical practice, but it noted the uncertainties associated with its use in the model. It concluded that the 12‑week timeframe for assessing non-response might be appropriate but there were uncertainties.

3.16 The company used a mixed treatment approach to model subsequent lines of treatment in the model. These included other TPO‑RAs and non-TPO‑RAs but did not consider treatment sequencing of TPO‑RAs. 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 TPO‑RAs had similar efficacy, safety, and long-term treatment durations. Also, avatrombopag would be considered for use in people who are suitable for other TPO‑RAs. 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 TPO‑RAs in the single-line model. But this assumed identical treatment durations among TPO‑RAs. 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 TPO‑RAs 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.

3.17 The company defined response for TPO‑RAs as durable platelet response rate (see section 3.7). But it defined the response for non-TPO‑RAs 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 TPO‑RAs and non-TPO‑RAs had mixed treatment response definitions. The ERG noted that the response rates used in subsequent lines of treatment for non-TPO‑RAs were high relative to the response rates used in the model for TPO‑RAs. 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-TPO‑RAs. But avatrombopag, eltrombopag and romiplostim all had a similar definition of durable platelet response rate (platelet response over 50×10⁹ 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 TPO‑RAs and non-TPO‑RAs 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-TPO‑RAs 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 TPO‑RAs and non-TPO‑RAs would have been preferrable. But it was also aware that this was not possible given the lack of evidence for non-TPO‑RAs. It concluded that having different definitions for responses for TPO‑RAs and non-TPO‑RAs led to uncertainties in the model. It took this into account in its decision making.

3.18 The company assumed long-term treatment duration to be 109 model cycles (436 weeks, or about 8.4 years) for all TPO‑RAs. It assumed the constant stopping rate to be 0.9% per 4‑week model cycle. The company took these estimates from Lee et al. (2013). This fitted a survival curve to:

3.19 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.

3.20 The committee noted that unresolved uncertainties remained in the company's evidence base and model assumptions, including:

3.21 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.

3.22 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.

3.23 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.