5 Consideration of the evidence

The evaluation committee reviewed the data available on the benefits and costs of ataluren, having considered evidence on the nature of Duchenne muscular dystrophy (DMD) and the value placed on the benefits of ataluren by people with the condition, those who represent them, and clinical experts. It also took into account the value for money that ataluren represents and the effective use of resources for specialised commissioning.

Nature of the condition

5.1 The committee discussed the nature of nonsense mutation DMD and its impact on people with the condition. It understood that DMD is a serious, progressive condition that reduces life expectancy and causes debilitating symptoms associated with loss of muscle strength that severely affect the quality of life of people with the condition. The committee heard from the patient experts that one of the most important aspects of managing DMD is maintaining their child's ability to walk. It heard that this means their child can continue to lead a more rounded life, for example, going to school on the bus independently, participating more fully with their friends and siblings in social and sporting activities, and spending more time with family and friends. It also heard that a loss in walking is followed by a greater deterioration in functioning that usually means people need constant care to perform routine daily activities such as getting out of bed, eating and going to the toilet. The patient experts explained that the impact of the condition is even more crucial at the point when the disease progresses and the ability to walk is lost (that is, around adolescence). The clinical and patient experts noted that, in general, this is a difficult time for every child and that the impact of the condition at this time makes it even harder. The committee also heard from the patient experts that if the time to loss of walking could be delayed, patients would have the opportunity to have a normal adolescence and to enter adulthood with a better understanding of their condition. The committee concluded that DMD is a serious life-threatening condition that progressively affects quality of life, with the greatest impact after loss of walking.

5.2 The committee further discussed the nature of nonsense mutation DMD and its impact on the quality of life of people with the condition, and their parents and siblings. It considered the findings of the company's survey on the quality of life of a small number of caregivers, and noted that this showed that DMD had a serious impact on multiple aspects of caregivers' lives (see section 4.12). It noted that, in many cases, at least another family member in addition to both parents was involved in giving care (for example, siblings and grandparents). The committee heard from the clinical and patient experts about the severe impact that the condition has on the person with the condition, family and carers' quality of life. The committee understood that, while people are able to walk, they are able to do normal activities of daily living on their own with the support of 1 or more caregivers. It heard, however, that the need for support increases substantially after the person loses their ability to walk. Patient experts highlighted the importance to parents of seeing their children grow and develop in line with their peers for as long as possible. The committee heard from the clinical experts that other more common disorders could produce equally devastating disability. The committee concluded that, although not unique, DMD has a distinctive nature, particularly given the time in the patient's life at which the ability to walk is usually lost. It concluded that delaying loss of walking is important to patients and carers.

5.3 The committee considered the current treatment options for nonsense mutation DMD. It heard from the clinical experts that the mainstay of treatment is corticosteroid therapy, which can slow the decline in muscle strength and function. This, in turn, may help to prolong the ability to walk. It also heard, however, that corticosteroids can cause unwanted effects such as growth retardation, bone thinning, mood swings and weight gain. It further heard from the clinical experts that new treatments are desired that prolong the time a person is able to walk by addressing the underlying cause of disease and with a more favourable adverse-event profile. The committee concluded that there is a high unmet medical need and that further treatment options are needed to extend the time to loss of walking and thus maintain quality of life.

Impact of the new technology

5.4 The committee heard from the clinical experts that, because ataluren potentially addresses the nonsense mutation that causes DMD to develop, they considered it to be a step change in the management of DMD. The committee agreed that ataluren was an innovative treatment and would be likely to stimulate further research in this therapy area.

5.5 The committee discussed how treatment benefit was assessed in the clinical trials. It was aware that the primary end point in Study 007 and Study 020 was the 6‑minute walk distance (6MWD). It heard from the clinical experts that the 6MWD is a well-validated tool used in clinical trials to assess functioning in DMD. The committee considered the secondary outcomes in the trials and heard from the clinical experts that some of these measures, such as time to get up and stand or time to run 10 m, are used more often in clinical practice but are not as clinically informative as the 6MWD. The committee heard the company's suggestion that shorter tests can be less of a burden for patients with a 6MWD of less than 300 m. It appreciated that the North Star Ambulatory Assessment provided information relevant to clinicians, and that it was routinely used in clinical practice, but was unclear on what is thought to be a clinically meaningful difference with this outcome. The committee was unconvinced that it offered more valuable information than 6MWD in this population. The committee concluded that the 6MWD was an appropriate primary outcome to assess the benefits of treatment with ataluren in the clinical trials.

5.6 The committee considered the clinical effectiveness of ataluren in the intention-to-treat populations of Study 007 and Study 020. It noted that, in the intention-to-treat analysis in Study 007, there was no statistically significant difference in change in 6MWD at 48 weeks between the ataluren and best supportive care groups but that, in the corrected intention-to-treat analysis, there was a statistically significant difference favouring ataluren. The committee accepted that the company's post-hoc adjustment could be justified (see section 4.4) but considered that the results of Study 007 were uncertain. Likewise, it noted that there was no statistically significant difference in 6MWD at 48 weeks between ataluren and best supportive care in the intention-to-treat population in Study 020, even though the enrolment criteria for this confirmatory study had been intended to enrich the population in the decline phase of DMD (that is, when a treatment effect had been detected in a post-hoc analysis in a similar subgroup in Study 007; see section 4.5). The committee concluded that there was not a meaningful improvement in the rate of decline in 6MWD with ataluren compared with best supportive care in the intention-to-treat populations of Study 007 and Study 020. The committee noted the company's opinion that neither of the intention-to-treat populations in Study 007 and Study 020 was the optimal patient group for detecting a treatment effect within 48 weeks. It then discussed the results for the company's subgroup analyses separately.

5.7 The committee discussed which was the most appropriate patient population in the clinical trials to inform its decision-making. The committee heard from the clinical experts that the decline phase is a clinically observed effect in people with DMD, and that a treatment effect on slowing the rate of decline in muscle strength would be more likely to be detected during a period of rapid decline than of stability. The committee heard from the company that the patient populations in Study 007 and Study 020 have contributed to clinical knowledge about DMD and clinical trial design for treatments for the disease. It noted the company's assertion that, in 48‑week trials such as Study 007 and Study 020 that have change in 6MWD as a primary outcome, the optimum range in the 6MWD at baseline to detect a difference is 300–400 m. The company suggested that patients with a baseline 6MWD of more than 400 m appear to be too stable for a treatment effect to be detected within 48 weeks. It further suggested that patients with a baseline 6MWD of less than 300 m have such severe muscle loss it is not possible to detect a statistically significant treatment effect. The committee heard from the clinical experts that the company's rationale was plausible because a similar effect had been seen in patients who had treatment with corticosteroids. However, it still had concerns that a small and non-statistically significant difference had been found in the intention-to-treat population. The committee agreed to consider the 48‑week clinical trial data from a subgroup of patients with a baseline 6MWD of 300–400 m but expressed concerns about the uncertainty and generalisability of the results to the broader ambulant population.

5.8 The committee considered the company's results of a pre-specified subgroup analysis of patients in Study 020 with a baseline 6MWD of 300–400 m and a meta-analysis of the results from Study 007 and Study 020 for this subgroup. The committee noted that both sets of results for this subgroup showed statistically significant differences in the 6MWD at 48 weeks between ataluren and best supportive care (see section 4.10). The committee noted that the results from the timed function tests and the North Star Ambulatory Assessment were consistent with the 6MWD results but recalled its previous concerns about what difference could be regarded as clinically meaningful (see section 4.11). The committee noted that the company presented the results of the other subgroups (including the subgroups with a baseline 6MWD of more than 400 m and less than 300 m from Study 020) as commercial in confidence, so these could not be reported here. The committee concluded that the results of the clinical primary and secondary outcomes in Study 020 showed a benefit at 48 weeks of ataluren compared with best supportive care in patients with a baseline 6MWD of 300–400 m.

5.9 The committee asked the clinical experts when they would consider starting treatment with ataluren in clinical practice. It heard that they would ideally start treatment early, with the expectation of delaying loss of walking before the decline phase starts. The committee understood that a statistically significant benefit with ataluren compared with best supportive care had not been shown in the population in which it was intended to be used in clinical practice (that is, in line with its marketing authorisation for patients aged 5 years and older who can walk). Therefore, the committee concluded that, although ataluren seemed to provide a benefit compared with best supportive care in the 6MWD and other functional tests for some patients, the size of this benefit in the overall ambulant population (in which the drug is intended to be used in clinical practice) remains highly uncertain.

5.10 The committee considered whether all the possible treatment benefits associated with ataluren had been captured in Study 007 together with further evidence from Study 020. It noted that, in Study 007, there was no statistically significant difference in quality of life reported in the ataluren group compared with the best supportive care group (see section 4.6). Results of the Paediatric Outcomes Data Collection Instrument and Activities of Daily Living questionnaire from Study 020 were provided by the company as commercial in confidence and so cannot be presented here. The committee considered that the results of the Pediatric Quality of Life inventory in Study 007 did not reflect the statements received by the patient experts. The committee heard from the patient experts that they had seen meaningful stabilisation or improvements in their child's walking ability after having ataluren, which meant their child could continue daily activities unaided, such as getting out of bed, getting in the car and going to school. This was restated in the comments received from the patient organisations during consultation, which noted that the impact of ataluren on quality of life in people with DMD had not been appropriately captured. The committee further noted that the duration of Study 007 and Study 020 was 48 weeks, and considered that this was too short to determine any long-term benefits of treatment with ataluren (including loss of walking and mortality). This was important because the company had assumed in its submission that the decline in the ability to walk based on the 6MWD and so, loss of the ability to walk was correlated to mortality. Therefore, by slowing the rate of decline and delaying the loss of walking, ataluren has the potential to improve survival. The committee concluded that it was likely that the quality-of-life data collected during Study 007 and Study 020 had not fully captured the short-term benefits experienced by patients having ataluren, and that there was uncertainty about the longer-term benefits of ataluren treatment because of the limitations in the evidence base.

5.11 The committee considered the evidence on adverse events reported in Study 007 and Study 020. It noted that there was no significant difference in adverse events reported in Study 007. It heard from the clinical experts that, in their experience, ataluren is well tolerated and treatment has not been stopped because of adverse events. The committee understood that regulatory requirements around the risks associated with ataluren treatment are outlined in the summary of products characteristics and the European public assessment report for ataluren. The committee noted that the company stated that, in Study 020, there were similar adverse events in the ataluren and best supportive care groups. The committee concluded that there were no specific safety concerns associated with ataluren.

5.12 The committee considered the general structure of the proposed managed access agreement:

  • It was satisfied with the definition of patient eligibility for treatment with ataluren, and by the starting and stopping criteria.

  • It heard from the clinical experts that the rate of decline in physical functioning was largely uniform across different types of DMD and therefore found it reasonable to have a control group that did not have nonsense mutation DMD.

  • It noted the proposed exit strategy. The committee agreed that ongoing funding should not be provided by NHS England when the proposed managed access agreement ends if the clinical outcome data gathered while it is in force do not support continued treatment when the guidance is reviewed. The committee concluded that, when starting treatment, those involved in the proposed managed access agreement must ensure that any patient receiving ataluren whose treatment is funded by NHS England under such an agreement is made aware of these funding limitations and that the patient accepts the terms of such an agreement on signing the patient agreement. The committee was advised by NICE that this made it sufficiently clear to people starting treatment with ataluren in the context of the proposed managed access agreement that the treatment period could be finite.

5.13 The committee then focused on whether the data collection from patients in the proposed managed access agreement would generate meaningful data to inform a review of this guidance. The committee was largely satisfied with the proposed patient outcomes and noted that the clinical experts considered the North Star Ambulatory Assessment offered a comprehensive assessment of physical functioning. However, it was concerned that the 6MWD was not included because this was the primary outcome in Study 007 and Study 020 and it was this clinical evidence that underpinned the company's cost–consequence models. It heard from the clinical experts that, although 6MWD was often a primary outcome in clinical trials, it was not routinely used in clinical practice. Reasons for this included a lack of trained personnel, insufficient space and that it was unsuitable for children with behavioural problems. The committee further heard that the North Star Ambulatory Assessment offered a more comprehensive assessment and was routinely used in all centres. The committee had reservations about being able to combine data generated via a managed access agreement with existing data from Study 007 and Study 020 to inform the review of guidance. However, it heard from the company that North Star Ambulatory Assessment data were available for all patients in Study 020 and was eventually persuaded that omitting 6MWD was acceptable because the phase III Study 020 data could be combined with data collected during the proposed managed access agreement. The committee concluded that it accepted the list of patient outcomes that would be recorded as part of the proposed managed access agreement because they would meaningfully inform a review of this guidance.

5.14 The committee considered the quality-of-life data that would be captured as part of the proposed managed access agreement:

  • It noted the proposal to capture carer utility using EQ‑5D. The committee recalled that DMD had a serious impact on multiple aspects of caregivers' lives (see section 4.12) and that a significant caregiver disutility had been applied to multiple carers in the company's cost–consequence model to reflect this. It concluded that it is imperative that its future review of guidance includes carer utility data.

  • The committee noted that the proposed managed access agreement included collection of Child Health Utility 9D quality-of-life data for boys aged 7 years and older. It considered it essential that quality-of-life data are captured for all boys receiving ataluren, including proxy data for younger children (that is, those aged less than 7 years).

5.15 The committee discussed the proposed monitoring in the proposed managed access agreement. It had some concerns about the governance of the data generated during the proposed managed access agreement and encouraged independent oversight. It had significant reservations about the potential that the extrapolation of the declines in the ataluren and matched control group would be recalibrated at 2 years and required that a formal analysis plan be agreed at the outset.

Cost to the NHS and Personal Social Services

5.16 The committee considered the results of the company's budget impact model. It noted that, at list price, the total cost per person per year of treatment with ataluren is £246,448 (assuming a weight of 26 kg). It further noted that the company had estimated that, in year 1, the total cost of treating nonsense mutation DMD with ataluren (at list price) is £8.6 million, rising to £16 million in year 5 (see section 4.22). The committee noted that the patient numbers in the budget impact model that accompanied the proposed managed access agreement were slightly different to the original version, and that these had been deemed confidential. It acknowledged that the costs would be lower than those using the list price when using the price incorporating the patient access scheme and confidential financial components that formed part of the proposed managed access agreement, but considered that, even when including this discount, the budget impact of ataluren was still high.

5.17 The committee considered the cost of ataluren in the context of the costs incurred by the company for research, development and manufacturing. It heard from the company that the cost of ataluren is driven by the need to recoup the high costs of research and development (and to fund future investment in other therapy areas), as well as manufacturing and marketing a treatment that can only be used by a small number of patients. It noted that, in response to the committee's request, the company provided figures associated with the investment on the discovery, development and commercialisation of ataluren in England and worldwide. The committee also heard from the company that it will incur further costs in continuing to gather data on the natural history of the disease and the clinical effectiveness of ataluren in DMD through a registry. The committee acknowledged that developing orphan and ultra-orphan treatments was associated with challenges that were different from treatments with bigger patient populations. But, it noted that there were no exceptional features in the development or production of ataluren that would justify the cost of ataluren being materially greater than for other treatments for small populations. The committee compared the cost of ataluren per patient with other highly specialised technologies available to NHS patients (using the list price of each technology). After taking other cost implications such as patient access schemes and managed access agreements into consideration where possible, the committee considered that it had been presented with sufficient evidence to show that the cost of ataluren was not materially greater than that for other treatments for small populations in relation to the benefits it offered. Furthermore, after considering the size of the investment by the company on ataluren and the number of patients likely to have ataluren in England and worldwide, the committee concluded that, when including the patient access scheme and confidential financial components in the proposed managed access agreement, the cost of ataluren per patient could be considered reasonable in the context of recouping manufacturing, research and development costs from sales to a small population in comparison with other highly specialised treatments for small populations.

Value for money

5.18 The committee considered the company's third cost–consequence model, which used clinical data from Study 007 and Study 020 for the subgroup of patients with a baseline 6MWD of 300–400 m and incorporated the patient access scheme and the other financial components included in the proposed managed access agreement. It noted that the company had addressed some of the concerns about the original model that had been expressed by the committee in the evaluation consultation document and by the evidence review group (ERG) in its critique of the second model (see sections 4.28 and 4.29). The committee also noted that, by including costs associated with ventilation assistance and increasing the disutility faced by caregivers, the company's third model partially addressed consultation comments from patient organisations. These stated that the company's original model did not appropriately reflect the impact of the condition and ataluren on the patient and caregivers' quality of life, or fully capture the costs associated with each health state. The committee concluded that several of the company's changes were appropriate, such as including the cost of ataluren for 6 months after loss of walking, extending the time horizon to be lifetime and using a discount rate of 3.5% for costs and benefits. The committee determined that ataluren did not meet the criteria in NICE's guide to methods of technology appraisal for considering a non-reference case discount rate of 1.5% for costs and benefits because ataluren did not restore people to full health and it was unclear if its benefits were sustained over a very long period (normally 30 years). The committee was concerned about the values the company used for the disutility associated with scoliosis and the disutility faced by caregivers, and was unconvinced that scoliosis never occurred after puberty or that different utility values for ataluren and best supportive care should be applied after loss of walking. The committee acknowledged the arguments put forward by the company and ERG about the methods used to extrapolate the clinical trial results to the lifetime horizon, and considered that both had merits and flaws. The committee concluded that it would use the company's and the ERG's analyses in its decision-making.

5.19 The committee discussed whether it was reasonable to assume that scoliosis will never occur after puberty. It heard from the clinical experts that, although the risk of developing scoliosis is substantially reduced after puberty and close to zero, it is not possible to conclude it would be completely eliminated. The committee agreed with the clinical experts' view, and concluded that it was not appropriate to assume that the risk of developing scoliosis will be completely eliminated after puberty.

5.20 The committee discussed whether it was appropriate to apply different utility values to the ataluren and best supportive care groups after loss of walking. The committee noted the company's assumption that the quality of life of patients when they lose their ability to walk would be greater with ataluren because loss of walking would occur later. The committee heard from the company and the clinical experts that this would be plausible if patients who have ataluren have greater upper limb muscle strength when they lose their ability to walk. The committee understood that there was no available evidence showing superior muscle strength after loss of walking with ataluren compared with best supportive care. The committee concluded that it was unreasonable to assume different utility values for each treatment group once the ability to walk is lost because there was no evidence available to support this assumption.

5.21 The committee noted that the company used 2 methods to extrapolate the clinical trial results to the lifetime horizon: a linear extrapolation and a stepped decline method. The committee noted the ERG's concerns about the linear extrapolation method because the company applied the data from the subgroup of people with a baseline 6MWD of 300–400 m to the overall population in the model (see section 4.29). The committee considered that it was unclear whether the results for this subgroup could be considered applicable to the overall ambulant population, given the small and non-statistically significant benefit of ataluren in the intention-to-treat population (see section 5.6). The committee also noted the ERG's critique on the stepped decline extrapolation method, which stated that the company had not directly used the data from the trials for the subgroups of people with a baseline 6MWD of less than 300 m and of more than 400 m, but had replaced these with other values that favoured ataluren. The committee considered that both extrapolation methods favoured ataluren in the long term. The committee noted the ERG's exploratory analyses using both the linear and stepped decline extrapolation methods, which applied assumptions less likely to favour ataluren than those in the updated company's model (see section 4.29). The committee concluded that, given the lack of long-term evidence on the benefit of ataluren, it was uncertain which extrapolation method would lead to more clinically plausible results. It therefore considered both approaches in its decision-making based on the company and ERG's analyses.

5.22 The committee discussed the results of the company's third cost–consequence model. It considered that the company's analyses, in which patients switched from ataluren to best supportive care after 5 years (that is, when the proposed managed access agreement ended), were not relevant to its decision-making and set them aside. This was because it had heard from the clinical experts that, if recommended, ataluren would be used in clinical practice until loss of walking. It noted that the results of analyses using the company's model showed that ataluren was associated with between 2.389 and 8.562 additional quality-adjusted life years (QALYs) compared with best supportive care, depending on the method used to extrapolate the treatment effect and whether the company's or ERG's preferred assumptions were used. The incremental costs for ataluren compared with best supportive care that incorporated the patient access scheme and financial components in the proposed managed access agreement were considered commercial in confidence and cannot be reported. The committee noted that the cost–consequence results showed a greater increase in the incremental QALYs gained when adopting the company's preferred assumptions rather than the ERG's, and recalled that it did not find all of these to be reasonable (see section 5.18). The committee concluded that, based on the uncertainty around the evidence available, the incremental QALY gain for ataluren compared with best supportive care was associated with a high degree of uncertainty and was therefore likely to fall between the ERG's exploratory estimates and the company's estimates.

5.23 The committee considered the overall value for money provided by ataluren. It was aware that NHS England has a single budget for specialised services of £13 billion, which includes a budget of £156 million for high-cost drugs. The committee noted that the company had estimated the total budget impact (list price) for 35 patients in year 1 to be £8.6 million rising to £16.0 million in year 5, and that the total cost per year of treatment with ataluren (list price) assuming an average weight of 26 kg is £246,448 per patient. The committee acknowledged that the cost per patient per year and total budget impact would be lower when using the price incorporating the patient access scheme and incorporating the confidential financial components in the proposed managed access agreement. The committee considered the overall value of ataluren, taking into account both its health benefits measured in QALYs gained and associated incremental costs in the context of other highly specialised technologies that it had evaluated (described in the evaluation consultation document) and others. It recalled that NICE guidance on eculizumab for treating atypical haemolytic uraemic syndrome stated that incremental QALYs for eculizumab compared with standard care were estimated to be 25.22 by the company and 10.14 by the ERG. Similarly, incremental QALYs for elosulfase alfa for treating mucopolysaccharidosis type IVa were estimated to be 18.18 by the company and 10.03 by the ERG. The committee noted that, compared with these other highly specialised technologies, ataluren was associated with substantially lower incremental QALYs (see section 4.36). However, the committee considered that the nature of DMD meant that it might be appropriate to view the QALYs gained differently because of the time in a child's life when the QALYs are predominantly gained compared with best supportive care (that is, delaying loss of walking in childhood and adolescence). The committee was aware that total costs to the NHS of some of the other technologies that it had previously evaluated would be lower than the list price and acknowledged that the total costs of ataluren would also be lower than the list price when the patient access scheme and confidential financial components in the proposed managed access agreement were applied. In reaching its conclusion on value for money, the committee considered the evidence of improved outcomes from clinical trials and the patient testimonies, as well as the results of the company's cost–consequence models and ERG's exploratory analyses. The committee considered that the condition was distinct, there was unmet need and some of the potential quality-of-life benefits of ataluren still might not have been not fully captured in the model. Although it remained concerned that the overall health benefits of ataluren had not been shown in the population for which it would be used in clinical practice, the committee considered that, based on current evidence, the potential benefits associated with ataluren treatment were great enough to justify its cost to the NHS when the patient access scheme and confidential financial components in the proposed managed access agreement were applied. The committee therefore concluded that, because of the uncertainty about the clinical benefits in the relevant population in clinical practice, ataluren would represent acceptable value for money to the NHS only when it was given in the context of a proposed managed access agreement at a price that incorporated the patient access scheme and included other financial components that reduced the total costs to the NHS.

5.24 The committee considered whether it should take into account the consequences of the Pharmaceutical Price Regulation Scheme (PPRS) 2014, and in particular the PPRS payment mechanism, when evaluating ataluren. The committee noted NICE's position statement about this, and accepted the conclusion 'that the 2014 PPRS payment mechanism should not, as a matter of course, be regarded as a relevant consideration in its assessment of the cost effectiveness of branded medicines'. The committee heard nothing to suggest that there is any basis for taking a different view about the relevance of the PPRS to this evaluation of ataluren. It therefore concluded that the PPRS payment mechanism was irrelevant in considering the value for money offered by ataluren.

Impact of the technology beyond direct health benefits and on the delivery of the specialised service

5.25 The committee acknowledged the potential wider societal benefits of ataluren treatment proposed by the company and patient experts, including the ability to contribute to society, continue education and spend more time with friends and family. It heard from the patient experts that, because ataluren is expected to delay the loss of walking, it will enable people with DMD to maintain their independence for longer and this will lead to cost savings. The committee heard that potential cost savings include parents and carers staying in work for longer, a reduction in out-of-pocket expenses for travel to appointments and delaying moving house or making home modifications. The committee acknowledged the expected cost savings but considered that, because ataluren was not a curative treatment, some costs may only be delayed until the disease progressed. However, on balance, the committee was persuaded that the non-health effects of ataluren were likely to be of value in the short term.

5.26 The committee considered the impact of ataluren on the delivery of the highly specialised service, and acknowledged statements from NHS England showing that treatment with ataluren is unlikely to involve additional services or monitoring costs. It heard from the clinical experts that services are already in place to monitor and treat people with DMD and, if ataluren were to be recommended for use, additional funding would not be needed. However, it noted that, in response to the evaluation consultation document, a professional group highlighted that additional diagnostic laboratory tests may be needed and that currently only 1 laboratory in the UK offers this analysis for DMD. The committee considered that, apart from these possible additional diagnostic needs, no significant additional staffing and infrastructure would be needed in centres where patients with nonsense mutation DMD currently have treatment.

Conclusion

5.27 The committee discussed the appropriate recommendations for ataluren for nonsense mutation DMD. It appreciated that DMD is a serious condition that has severe effects on the lives of people with the condition, as well as their families and carers and that it is associated with a high unmet need. The committee noted that ataluren is considered an important treatment by patients with nonsense mutation DMD and their caregivers, and recognised the distinctiveness of the condition, particularly because of the time in the patient's life in which the potential benefits of ataluren could be shown. After considering all available evidence, and the opinions of the clinical and patient experts, the committee agreed that ataluren represents an important development in the treatment of nonsense mutation DMD. Based on the results from Study 007 and Study 020, it accepted that ataluren was associated with a meaningful improvement in the rate of decline in 6MWD compared with best supportive care in the subgroup of patients with a baseline 6MWD of 300–400 m over a 48‑week period. The committee was disappointed that results from the intention-to-treat population of Study 020 had not provided the expected evidence of a treatment benefit in a broader group of patients in the decline phase, and considered that there was still considerable uncertainty about long-term benefits. It considered the size and duration of ataluren's treatment benefit to be highly uncertain, and was unsure if the positive results from the subgroup of patients with a baseline 6MWD of 300–400 m could be generalised to the broader population of ambulatory people with nonsense mutation DMD. The committee was satisfied that the proposed managed access agreement offered an opportunity to address some of this uncertainty when this guidance is reviewed. It accepted the definition of patient eligibility for treatment with ataluren, and the starting and stopping criteria. It considered that the patient outcomes in the proposed managed access agreement would meaningfully inform a review of this guidance. The committee noted that the proposed managed access agreement would capture caregiver quality-of-life data and considered it imperative that its future review of guidance includes these data, given the large associated effect in the company's cost–consequence model. It also considered it essential that Child Health Utility 9D quality-of-life data are captured for all boys receiving ataluren, not just those aged 7 years and older, and that proxy data for younger children should also be collected. The committee was aware of its need to consider the extent to which the cost to the NHS of providing ataluren was reasonable. The committee concluded that, because of the uncertainty of the clinical benefits in the relevant population in clinical practice, ataluren would represent acceptable value for money to the NHS only when it was given in the context of a managed access agreement at a price that incorporated the patient access scheme and included other financial components that reduced the total costs to the NHS. The committee considered that the proposed managed access agreement offered an opportunity to allow patients access to ataluren in the NHS while collecting both longer-term data and data from the full population with nonsense mutation DMD covered in the marketing authorisation, and to limit the financial risk associated with introducing ataluren in the NHS given the uncertainty around its benefits. Therefore, the committee recommended ataluren for treating nonsense mutation DMD.

Summary of evaluation committee's key conclusions

HST3

Evaluation title: Ataluren for treating Duchenne muscular dystrophy with a nonsense mutation in the dystrophin gene

Section

Key conclusion

Ataluren, within its marketing authorisation, is recommended for treating Duchenne muscular dystrophy resulting from a nonsense mutation in the dystrophin gene in people aged 5 years and older who can walk, only when:

  • the company provides ataluren with the discount agreed in the patient access scheme

  • the conditions under which ataluren is made available are set out in the managed access agreement between the company and NHS England, which should include the considerations set out in sections 5.12–5.15 and 5.23 of this guidance.

The committee concluded that, because of the uncertainty about the clinical benefits in the relevant population in clinical practice, ataluren would represent acceptable value for money to the NHS only when it was given in the context of a managed access agreement at a price that incorporated the patient access scheme and included other financial components that reduced the total costs to the NHS.

1.1, 5.23

Current practice

Nature of the condition, including availability of other treatment options

The committee heard from the patient experts that DMD is a serious, progressive condition that reduces life expectancy and causes debilitating symptoms associated with loss of muscle strength that severely affect the quality of life of people with the condition, and their parents and siblings.

The committee heard from the clinical experts that the mainstay of treatment is corticosteroid therapy, which can slow the decline in muscle strength and function. This, in turn, may help to prolong walking. It also heard, however, that corticosteroids can cause unwanted effects such as growth retardation, bone thinning, mood swings and weight gain.

5.1, 5.2, 5.3

The technology

Proposed benefits of the technology

How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?

The committee heard from the clinical experts that, because ataluren potentially addresses the nonsense mutation that causes DMD to develop, they considered it to be a step change in the management of DMD.

5.4

Adverse reactions

The committee concluded that there were no specific safety concerns associated with ataluren.

5.11

Clinical evidence

Availability, nature and quality of evidence

The committee concluded that the 6‑minute walk distance (6MWD) was an appropriate primary outcome to assess the benefits of treatment with ataluren in the clinical trials.

The committee concluded that there was not a meaningful improvement in the rate of decline in 6MWD with ataluren compared with best supportive care in the intention-to-treat populations of Study 007 and Study 020.

5.5, 5.6

Uncertainties generated by the evidence

The committee noted that, in Study 007 and Study 020, there was no statistically significant difference in change in 6MWD between the ataluren and best supportive care groups in the intention-to-treat analyses.

The committee noted the company's assertion that, in 48‑week trials such as Study 007 and Study 020 that have change in 6MWD as a primary outcome, the optimum range in the 6MWD at baseline to detect a difference is 300–400 m. It agreed to consider the 48‑week clinical trial data from a subgroup of patients with a baseline 6MWD of 300–400 m in Study 020. However, the committee expressed concerns about the uncertainty and generalisability of the results to the broader ambulant population.

5.6, 5.7

Impact of the technology

The committee concluded that the results of the clinical primary and secondary outcomes in Study 020 showed a benefit at 48 weeks of ataluren compared with best supportive care in patients with a baseline 6MWD of 300–400 m. However, it also concluded that the size of this benefit in the overall ambulant population (in which the drug is intended to be used in clinical practice) remains highly uncertain.

5.8, 5.9

Cost evidence

Availability and nature of evidence

The committee considered the company's updated cost–consequence model, which incorporated results from Study 020, and addressed some of the concerns about the company's original model that had been expressed by the committee in the evaluation consultation document and further amendments considered appropriate by the company.

The company presented a budget impact analysis to predict the costs of ataluren in the NHS and Personal Social Services.

5.16, 5.18

Uncertainties around and plausibility of assumptions and inputs in the economic model and budget impact analysis

Cost–consequence analysis

The committee considered the company's third cost–consequence model, which used clinical data from Study 007 and Study 020 for the subgroup of patients with a baseline 6MWD of 300–400 m and incorporated the patient access scheme and the other financial components included in the proposed managed access agreement. The committee was concerned about the values the company used for the disutility associated with scoliosis and the disutility faced by caregivers, and was unconvinced that scoliosis never occurred after puberty, or that different utility values for ataluren and best supportive care should be applied after loss of walking. The committee acknowledged the arguments put forward by the company and evidence review group (ERG) about the methods used to extrapolate the clinical trial results to the lifetime horizon, and considered that both had merits and flaws. The committee concluded that it would use the company's and the ERG's analyses in its decision-making.

5.18, 5.21

Incorporation of health-related quality-of-life benefits and utility values

Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?

The committee noted that, by increasing the disutility faced by caregivers, the company's third model partially addressed consultation comments from patient organisations, which had stated that the company's original model did not appropriately reflect the impact of the condition and ataluren on the patient and caregivers' quality of life, or fully capture the costs associated with each health state.

The committee considered that the nature of DMD meant that it might be appropriate to view the quality-adjusted life years (QALYs) gained differently because of the time in a child's life when the QALYs are predominantly gained compared with best supportive care (that is delaying loss of walking in childhood and adolescence).

5.18, 5.23

Cost to the NHS and Personal Social Services

The committee noted that the company had estimated that, in year 1, the total cost of treating nonsense mutation DMD with ataluren (at list price) is £8.6 million, rising to £16 million in year 5. It acknowledged that the costs would be lower than using the list price when using the price incorporating the patient access scheme and confidential financial components that formed part of the proposed managed access agreement but considered that, even when including this discount, the budget impact of ataluren was still high.

5.16

Value for money

In reaching its conclusion on value for money, the committee considered the evidence of improved outcomes from clinical trials and the patient testimonies, as well as the results of the company's cost–consequence models and the ERG's exploratory analyses. The committee considered that the condition was distinct, there was unmet need and some of the potential quality-of-life benefits of ataluren still might not be not fully captured in the model. Although it remained concerned that the overall health benefits of ataluren had not been shown in the population for which it would be used in clinical practice, the committee considered that, based on current evidence, the potential benefits associated with ataluren treatment were great enough to justify its high cost when the patient access scheme and confidential financial components in the proposed managed access agreement were applied.

5.23

Impact beyond direct health benefits and on the delivery of the specialised service

The committee acknowledged the potential wider societal benefits of ataluren treatment proposed by the company and patient experts, including the ability to contribute to society, continue education and spend more time with friends and family. It heard that potential cost savings include parents and carers staying in work for longer, a reduction in out-of-pocket expenses for travel to appointments and delaying moving house or making home modifications.

The committee noted that additional diagnostic laboratory tests may be needed and that currently only 1 laboratory in the UK offers this analysis for DMD. The committee considered that, apart from these possible additional diagnostic needs, no significant additional staffing and infrastructure would be needed in centres where patients with nonsense mutation DMD currently have treatment.

5.25, 5.26

Additional factors taken into account

Patient access schemes (PPRS)

The company has proposed a patient access scheme in which ataluren would be provided at a discounted cost; the discount is commercial in confidence and so cannot be reported here. The proposed managed access agreement includes further financial components to reduce the cost to the NHS for the proposed duration of the agreement.

3.3

The Committee concluded that the PPRS Payment Mechanism was irrelevant for the consideration of the value for money offered by ataluren.

5.24

Equalities considerations and social value judgements

No equality issues that needed to be taken into consideration by the committee were identified.