5 Consideration of the evidence

The Evaluation Committee reviewed the data available on the benefits and costs of elosulfase alfa, having considered evidence on the nature of mucopolysaccharidosis type IVa (MPS IVa) and the value placed on the benefits of elosulfase alfa by people with the condition, those who represent them, and clinical experts. It also considered all comments received during consultation on the first and second evaluation consultation documents. It heard from the company, clinical experts and patient experts (including people with the condition, a parent of children with the condition, and the patient group) at the first, second and third meetings. It also took into account the value for money that elosulfase alfa represents and the effective use of resources for specialised commissioning.

Nature of the condition

5.1 The Committee discussed the nature of MPS IVa. It understood that MPS IVa is a serious condition that severely affects life expectancy and quality of life, leading to dramatic effects on the lives of people with the condition, and their families and carers. The Committee heard that the severity of the disease varies among people; some people have particularly severe disease with a short life expectancy, others have a form that progresses more slowly and they may live longer. The Committee understood that MPS IVa is a complex and highly heterogeneous disorder, and evidence on the natural history of the condition is still evolving. It heard that, at the outset of the clinical trials for elosulfase alfa, the clinical community believed that MPS IVa was purely a skeletal disorder, and this was also supported by the literature. The general belief at the time was that enzyme replacement therapy would not treat musculoskeletal symptoms. However, the clinical experience during the trials was unexpectedly positive, and remarkable improvement was seen in some patients, including those who had established skeletal disease for many years. It became apparent that the skeletal features, although important, were only part of a multi‑system disorder, and that non‑skeletal features, including cardiac and respiratory complications, contribute heavily to the burden of illness. The Committee heard from the clinical experts that emerging evidence suggests the disease has wide systemic involvement because glycosaminoglycan deposits have been found in various organs including the lungs, heart and connective tissues. The Committee concluded that, although the disease process is not yet fully understood, MPS IVa is a debilitating condition that affects the body across multiple organ systems.

5.2 The Committee discussed the long‑term clinical outcomes of MPS IVa. It noted that it is a multi‑system disorder leading to respiratory, cardiac and musculoskeletal symptoms, which can all cause variable long‑term clinical outcomes. The Committee understood that the respiratory and cardiac complications are the key drivers of mortality in patients with MPS IVa, accounting for 63% and 15% of all deaths respectively. It noted comments from experts that pain and fatigue are the main burdens of MPS IVa, with loss of endurance being the greatest single problem associated with the disease. The Committee heard from the clinical experts that, traditionally, cervical spinal cord damage was considered an important determinant of clinical outcomes in people with MPS IVa. However, most patients are now treated before damage occurs, with spinal surgery (cervical spine fusion and spinal decompression) currently being used prophylactically to reduce the risk of spinal cord damage. This, in turn, has significantly reduced the number of patients dying from this complication. The Committee understood that people with MPS IVa can be at risk of damage, and some will need spinal surgery at some point in their lives, particularly if they have disease with relatively rapid progression. Spinal cord damage can have an impact on mobility and quality of life, but the Committee agreed with the patient experts' view that its overall contribution to morbidity is generally small. The Committee concluded that the key determinants of mortality are the respiratory and cardiac complications, and that what matters the most to people with the condition is the ability to carry out normal everyday activities with sufficient endurance and without pain or fatigue.

Impact of the new technology

5.3 The Committee considered the clinical‑effectiveness evidence presented by the company. The Committee acknowledged the challenges in developing a clinical trial programme for such a rare condition, and heard from the company that the clinical trial programme included about 10% of the worldwide population of people with MPS IVa. The Committee was pleased to see that a detailed study of the natural history of MPS IVa involving many people was presented (MOR‑001). The Committee heard that the clinical trials included a wide range of people with different clinical manifestations of MPS IVa, including a large cohort from the UK and, in general, reflected the spectrum of people who would be expected to have treatment in England.

5.4 The Committee considered whether the endpoints assessed in the clinical trials had captured the important aspects of the condition and the benefits associated with elosulfase alfa. The Committee understood that important determinants of clinical outcomes for people with MPS IVa include cardiac and respiratory function, cervical spinal cord damage, bone health and the need for orthopaedic surgery.

  • Cardiac and respiratory function: the Committee heard that the clinical trials were not designed to explicitly study these, although they are the main causes of mortality (see section 5.2). In addition, long‑term follow up is needed to assess these outcomes, but the trials were relatively short. However, the Committee heard from the clinical expert that it is plausible that elosulfase alfa could affect these outcomes. It also noted comments suggesting treatment led to reduced chest infections and improved general lung function.

  • Cervical spinal cord damage and bone health: the Committee noted that spinal cord damage from spinal stenosis had not been assessed in clinical trials because the perception had always been that enzyme replacement therapy would not affect bones. The clinical experts indicated, however, that growth had been seen beyond the usual time of growth failure in people receiving enzyme replacement therapy, suggesting a potential of growth in the vertebrae, which widens the spinal canal and reduces skeletal complications. The Committee heard from a clinical expert that attempts had been made in early clinical trials to measure bone health (such as bone length and bone mineral density) in people with MPS IVa, but there were difficulties in using these measures. The Committee noted comments from consultation stating that the true skeletal impact of elosulfase alfa will take years to be fully understood.

  • Orthopaedic surgery: the Committee understood that some people with MPS IVa may need orthopaedic surgery, including hip and knee surgery. It noted that MOR‑005 included an assessment of the time to orthopaedic surgery, but comparisons with the incidence of surgery in the natural history of MPS IVa (that is, from MOR‑001) were not available. The Committee noted that the European Public Assessment Report for elosulfase alfa states that it appears to reduce the incidence of orthopaedic surgery. The Committee did not consider there to be sufficient evidence from clinical trials on surgical outcomes.

    The Committee concluded that several benefits of elosulfase alfa treatment may have not been adequately captured in the clinical trials, so some of the true long term outcomes in people with MPS IVa remained uncertain.

5.5 The Committee discussed the endpoints assessed in the clinical trials. It understood that the primary outcome in the randomised clinical trials, the 6‑minute walk test (6MWT), is a surrogate outcome that provides a broad measure of overall functioning, including musculoskeletal health, cardiovascular and respiratory aspects, pain and fatigue. The Committee noted that the improvement in 6MWT with elosulfase alfa was statistically significant compared with placebo (see sections 4.6 to 4.8). It heard that the 6MWT has been used successfully in other MPS disorders, and is used in clinical practice to monitor progress in people with MPS IVa. Patient experts noted that improvements in 6MWT scores during clinical trials reflected improvements in other aspects of their condition and their quality of life, and emphasised that the ability to move around (for example, at school) is an important part of everyday life. The Committee noted the effect of treatment on wheelchair use was also assessed in the clinical trials (see section 4.8). However, it heard from the clinical and patient experts that the categories of wheelchair use in the clinical trials could have been subjective. They emphasised that patients use wheelchairs in different ways, to manage endurance and daily activities according to their individual needs, so the effect of treatment is not necessarily well represented by this measure. Furthermore, patients do not judge their quality of life by how much they are using the wheelchair. The Committee considered that this evidence was informative but was mindful of putting too much emphasis on it. The Committee agreed that, although the 6MWT was not a perfect measure, there were few alternatives. The Committee concluded that, as a proxy outcome that provides a broad measure of overall functioning, the 6MWT was broadly appropriate and useful in giving some indication of the real‑life benefits of treatment experienced by patients.

5.6 The Committee discussed the clinical benefits associated with elosulfase alfa as experienced by patients. It heard from the patient experts that, with treatment, patients can expect the disease to stabilise and also to get better. The clinical experts stated that most people treated with elosulfase alfa experienced clinical improvements beyond what could be attributed to a placebo effect, including improved endurance, pulmonary function, anthropometrics, wheelchair dependency and quality of life. The patient experts also described positive effects on sleep, pain, energy levels and fatigue, dexterity and ability to complete everyday activities. However, these benefits were not known at the onset of the clinical trials for elosulfase alfa, so the trials were not designed to capture them. In general, the patient experts considered that treatment offered substantial benefits to people with the condition, with some going from being non‑ambulant, unable to speak and having a short life expectancy to being in stable health, able to speak again and resume university studies. The Committee heard that young people who started treatment maintained their ability to walk and continued to grow. In addition, treatment improved pulmonary function, so reducing the frequency and severity of chest infections and allowing a normal recovery from common respiratory illnesses. The patient experts also highlighted the quicker recovery from physical exertion with elosulfase alfa, which saved energy for other day‑to‑day activities. Based on the patient testimonies, the Committee concluded that elosulfase alfa improved various abilities and aspects of health compromised by the disease, and that the patients' experience with treatment had been largely positive, with health and quality of life improving significantly in some patients. However, it was aware that anecdotal, patient‑reported outcomes are likely to vary between patients, so ought to be considered with some degree of caution.

5.7 The Committee discussed whether the evidence from clinical trials and the patient testimonies can be reconciled. It noted from the clinical experts that elosulfase alfa conferred substantial benefits that patients valued greatly and significantly improved several dimensions of quality of life. However, the Committee was aware that the clinical trials measured primarily proxy outcomes (for example, the 6MWT), and did not substantiate most of the direct health benefits described by patients. The Committee was aware that the patient experts' opinion, although useful, was subjective and may be at risk of bias because it may represent the experience of only a selected group of patients. The Committee acknowledged that real‑world data on the proportion of patients receiving and stopping treatment with elosulfase alfa, the doses used, adverse effects of treatment and clinically meaningful benefits of treatment realised by patients would be very useful to mitigate some of the existing uncertainties in the clinical evidence base. The Committee considered that the assessments described in the managed access agreement would generate evidence for MPS IVa that was directly relevant to patients in the UK through research and collection of 'real‑world' data. The Committee concluded that the data collected via the registry within the context of the managed access agreement would be likely to provide 'real‑world' data that would help to reconcile the differences between the patient testimonies and clinical trial data when this guidance is reviewed.

5.8 The Committee heard from a clinical expert that, although a high proportion of people treated with elosulfase alfa experienced adverse events during the trials, clinicians had substantial experience in managing infusion‑associated reactions and that established protocols were in place. Although some people had slowed infusions or pauses in treatment, no‑one stopped treatment because of adverse events. Patient experts reported experiencing some adverse reactions but emphasised that these were quickly controlled and were vastly outweighed by the benefits of treatment.

Cost to the NHS and Personal Social Services

5.9 The Committee considered the budget impact analyses submitted by the company. It noted that the company's analysis suggested that the net budget impact for elosulfase alfa at its list price would rise from £17.3 million in year 1 to £28.8 million in year 5 (the budget impact analyses incorporating the patient access scheme are commercial in confidence and so cannot be reported here).

5.10 The Committee explored the number of people who would receive elosulfase alfa if it were recommended. It heard from a patient expert that 77 people in England are thought to be eligible for treatment. The Committee heard that this excludes people with paraplegia or who are in the end stages of the disease and those who had expressed a clear preference not to have treatment. The clinical expert anticipated that most people with MPS IVa may be eligible for treatment based on clinical criteria, but the patient expert stated that, of the 77 known patients, some might not choose to have treatment. The Committee understood that about 3 new diagnoses of MPS IVa are made per year. However, the patient expert noted that, as well as new diagnoses, some people would die during the 5 years of the budget impact analysis, and so the total number of people being treated was unlikely to rise as much as the company had estimated. The Committee concluded that it is difficult to determine the specific groups of people who would not have elosulfase alfa treatment and, so, the precise number of people who would have treatment with elosulfase alfa in England if it were recommended is uncertain.

5.11 The Committee discussed the assumptions in the company's budget impact analysis. It noted that the company's model assumed that 50% of the total care time was provided by professional carers (with the remainder provided by family members). It heard from a patient expert that only 5 people with MPS IVa currently have professional care, and so considered that the company had over‑estimated the cost to the NHS of professional carers. The Committee noted that the company's original cost analyses included a reduction in the cost of elosulfase alfa when given at home, to reflect the fact that VAT is currently waived for treatments given via home care. The Committee noted that VAT had not been included in the cost of elosulfase alfa in the economic model or budget impact analysis, stating that reducing the cost of VAT in a model from which VAT was already excluded was inappropriate. The Committee therefore agreed that including the VAT waiver was not appropriate. In its addendum, the Evidence Review Group (ERG) presented a budget impact analysis incorporating the patient access scheme that excluded the VAT waiver for home care. The Committee concluded that the ERG's analysis excluding the VAT waiver should be used in its decision‑making.

5.12 The Committee noted that the company did not present an analysis of the costs associated with delivering elosulfase alfa at people's homes in its original submission. It highlighted that such costs would be borne by the NHS, and therefore asked the company for further explanation of these costs. It heard that, in practice, hospital trusts would be likely to fund home care services using tax savings associated with community prescribing. The company also noted that further savings could be made by reducing the hospital costs for infusion appointments. In response to consultation, the company provided an analysis of the budget impact of administering elosulfase alfa at people's homes. The differences between hospital costs and home costs were estimated at £3,069,111 in the first year, increasing over the years to £5,941,015 in the fifth year. The Committee was aware that treating people with MPS IVa costs the NHS around £10,000/patient/year exclusive of enzyme replacement therapy.

5.13 The Committee considered the cost of elosulfase alfa in the context of the costs incurred by the company for research, development and manufacturing, and asked the company for an explanation for the cost of the drug. The company stated that, because elosulfase alfa is a treatment that can only be used by a small number of patients, the high cost is largely driven by the need to recoup the investment in research and development, and manufacturing. The Committee heard that there are only about 3000 people with MPS IVa across the world, of whom an estimated 1000 to 2000 may be able to access the drug. Furthermore, it heard that developing drugs to treat rare conditions is expensive and that the manufacture of this drug is complex. The company estimated that the cost of the clinical trial programme for elosulfase alfa had been about $350 million over 10 years, with the company risking failure at each step because the level of scientific knowledge was low for MPS IVa. In addition, the company noted that it had invested more than $130 million in England through developing elosulfase alfa, and had built a new manufacturing facility. It cited 1 paper suggesting that the return on equity for manufacturers of treatments for rare diseases is only 28% of that of other pharmaceutical companies because the investment in research is higher, and argued that treatments for rare diseases need to have a high cost to be commercially viable. The Committee highlighted that the acquisition cost per kilogram body weight is substantially higher than that of galsulfase, one of the company's other enzyme replacement therapies used to treat MPS VI (£196/kg/week for galsulfase compared with £300/kg/week for elosulfase alfa). The Committee heard from the company that comparing the cost of elosulfase alfa and galsulfase using the acquisition cost per kilogram of body weight is inaccurate because it does not reflect the annual cost of treatment per patient. Although the vial acquisition costs for the 2 treatments differ, the actual annual treatment costs are similar because the average weights of patients differ; patients with MPS IVa weigh less than those with MPS VI in the UK. The Committee acknowledged the company's efforts to address its concerns about the cost of elosulfase alfa, but was not satisfied that its high cost was fully justified.

5.14 The Committee considered that further assurances were needed to ensure that the cost of elosulfase alfa to the NHS is appropriately contained before elosulfase alfa is routinely used for patients with MPS IVa. The Committee concluded that it was satisfied that the company and NHS England had included commercial arrangements in the managed access agreement to limit the total costs of elosulfase alfa during data collection.

Value for money

5.15 The Committee discussed the results of the company's cost–consequence model and the assumptions on which they were based. It noted that total costs associated with elosulfase alfa, and therefore the incremental costs, were deemed commercial in confidence by the company and so cannot be reported. The Committee noted that, in the original model, the company assumed that people whose disease responded to elosulfase alfa across both endurance and pulmonary outcomes ('multi‑domain responders'; see section 4.9) would not have any further progression of disease. This was based on a 10‑year study of people with MPS VI. The Committee saw that the ERG presented a scenario analysis in which elosulfase alfa slowed disease progression in 'multi‑domain responders' by 50% compared with established clinical management; this resulted in a much smaller gain in quality‑adjusted life years (QALYs) compared with established clinical management than in the company's original base case. The Committee agreed that elosulfase alfa was likely to slow disease progression, but would be unlikely to stop it entirely. The Committee noted that the company presented 2 additional analyses in response to consultation. In these, the company varied the rates of disease progression across health states for multi‑domain and single‑domain 'responders', with the rates used based on clinical advice to the company. The Committee understood that these analyses explored the possibility that the impact of elosulfase alfa on disease progression depended to some extent on how much irreversible damage was present when treatment started. The Committee heard from clinical experts that disease progression varies widely among people depending on factors such as age and disease pathology, and that it would be difficult to model this with reasonable accuracy. However, the clinical experts agreed that it would be more clinically plausible to assume a variable, rather than a constant, rate of disease progression depending on the burden of the disease at the point at which treatment is received. Therefore, they considered the company's additional analyses to be more realistic than the original base case. The Committee noted the patient perspective that people consider the disease to be stable when the benefit gained from treatment is maintained over time, and the patient is able to get on with their life without symptomatic progression. The Committee acknowledged that elosulfase alfa was likely to provide valuable clinical benefits to people with the condition. However, it considered that assuming that elosulfase alfa would completely stop disease progression in 'multi‑domain responders' is not plausible and would overestimate the benefit of treatment. The Committee concluded that varying the rate of disease progression across health states would better reflect the natural history of the disease instead of using constant rates.

5.16 The Committee noted that the company's utility estimates in their original submission included a substantial decline between people using a wheelchair some of the time and those who are dependent on a wheelchair. It heard from the company that this was consistent with a substantial jump in caregiving time between these states seen in the survey of the families of people with MPS IVa (see section 4.2), and with similar declines in utility seen in people with other conditions that are associated with increasing wheelchair use, such as multiple sclerosis. The Committee noted that the patient group submission highlighted that there are additional challenges in caring for people who are dependent on a wheelchair, compared with those who retain even a small amount of mobility, and that family life becomes more constrained as wheelchair use progresses. Patient expert submissions highlighted that a small improvement in mobility can make the difference between needing to adapt their whole house for a wheelchair and being able to walk around the home independently, or allow visits to shops or friends' houses that are not wheelchair accessible. The Committee concluded that the change in utility between the model's health states was acceptable.

5.17 The Committee also noted that the company had applied a utility increment to the elosulfase alfa group to reflect the benefits beyond the slowing of disease progression and improving endurance. The ERG considered that this double counted the treatment benefits. This utility increment was estimated using 6MWT results from the clinical trials. The Committee noted that the effect of the condition on quality of life had been assessed using the EuroQol (EQ‑5D‑5L) questionnaire in the natural history study (MOR‑001), but that the clinical trials for elosulfase alfa collected only limited evidence on quality of life, and did not collect EQ‑5D data. The Committee considered the additional analyses presented by the company in response to consultation, in which the company modelled the utility benefit associated with elosulfase alfa based on utility estimates obtained from the literature. It noted that this had a modest impact on incremental QALYs. The Committee understood that measures of quality of life had not been extensively used in clinical trials for this condition. It heard from the company that the MPS Childhood Health Assessment Questionnaire was initially thought to be the best available measure of quality of life in children, but it later became apparent that it did not adequately capture all the dimensions of health that matter to patients. The Committee heard from the patient experts that it can be very difficult to fill in quality‑of‑life questionnaires, particularly for children who usually do not recollect their quality of life before treatment to compare it with how they feel after treatment. One patient expert felt that the questionnaires did not ask the right questions because they elicited information on the patient's ability to do day‑to‑day activities, whereas the ability might be similar before and after treatment but the critical difference is in how the patient feels after doing the activity; that is, in their recovery. The Committee noted that, as the determinants of quality of life have become better understood, alternative measures are being studied and new creative ways to capture quality of life are being considered (for example, using smartphones). Having considered the evidence from clinical trials and the testimonies of the patient experts, the Committee acknowledged that elosulfase alfa improves several dimensions of quality of life, including endurance and fatigue, pain, education, work and social life (see section 5.6). The Committee therefore agreed that it was reasonable to include a utility increment associated with elosulfase alfa in the economic model. However, it appreciated that the evidence on quality of life was limited, and that what evidence there was had been synthesised using methods that had not been fully developed or validated. The Committee concluded that the existing evidence did not allow the utility benefit associated with elosulfase alfa to be robustly modelled.

5.18 The Committee considered whether the benefits in mortality associated with elosulfase alfa may have been double counted, by including a mortality benefit both through delaying disease progression and through the relative risk of death. It heard from the ERG that the 10‑year death rate in the company's original model was about 6 times higher in the elosulfase alfa group than in the established management group, but would be expected to be about 3 times higher given the hazard ratio between these groups. The Committee heard that this discrepancy provided evidence for the double counting. The Committee noted that the hazard ratio was based on limited evidence from MPS VI, and recalled that extrapolation between MPS VI and MPS IVa was difficult. It was uncertain whether the company's modelling of survival accurately reflected the mortality risks associated with MPS IVa, such as the risks of cervical complications, trauma and heart failure. In response to consultation, the company modelled 2 alternative scenarios excluding the mortality benefit of elosulfase alfa (see section 4.39). The Committee concluded that these scenarios were more clinically plausible.

5.19 The Committee considered the overall value for money provided by elosulfase alfa. It noted comments from NHS England that there is a single budget for specialised services of £13 billion and no separate budget for highly specialised technologies. NHS England stated that only a small portion of the overall budget for specialised services is available for commissioning technologies such as this, and that about 80 technologies were being considered for commissioning at the time of the evaluation. The Committee noted that, although it understood the evidence of clinical benefits from clinical trials and the patient testimonies, the magnitude of overall benefit offered by elosulfase alfa was uncertain. On the basis of the available evidence on overall benefit, the Committee considered that the cost of elosulfase alfa incorporating the patient access scheme was too high for it to be recommended outside the context of a managed access agreement. It noted that, in addition to the patient access scheme, the managed access agreement included other commercial arrangements that reduced the total costs to the NHS. The Committee concluded that including these other commercial arrangements in the managed access agreement as well as the patient access scheme would offer a more acceptable value for money in the context of the uncertainty of the clinical benefits.

5.20 The Committee supported the company's commitment to continue to strengthen the evidence base for this condition, through patient registries and research, as part of a managed access agreement with NHS England. The Committee was aware that elosulfase alfa will be made available through the managed access agreement and that people would consent when starting treatment that ongoing funding cannot be guaranteed to be provided by NHS England after 5 years if the clinical outcome data do not support continued treatment. The Committee was advised by NICE that this made it sufficiently clear to people starting treatment with elosulfase alfa in the context of the managed access agreement that the treatment period could be finite.

5.21 The Committee discussed whether applying criteria for starting and stopping treatment could improve the value for money of elosulfase alfa. It heard from the clinical experts that the National Advisory Group for Lysosomal Storage Disorders has developed such criteria for enzyme replacement therapy, which the company also cited in its response to consultation. The clinical experts indicated that these criteria were developed 2 years ago and may need to be adjusted over time, but that they can be used for the time being to target treatment to people who would benefit most. The Committee heard that the criteria for starting and stopping treatment are not based on evidence and need to be individualised for each patient, but that some general principles can guide treatment decisions in clinical practice. For example, treatment is likely to be offered to people with early stage disease because these people are thought more likely to benefit from treatment, whereas those with severe forms of the disease may not. Once started, treatment would not normally continue in people whose disease does not respond at all, or in those who are unable to comply fully with the treatment schedule. Importantly, the clinical experts emphasised the importance of having a discussion with patients before treatment starts to manage the patient's expectations and talk through the clinical scenarios in which treatment may be stopped. The patient experts recognised the limited resources available and supported using criteria for starting and stopping treatment, particularly the upfront discussion with clinicians to ensure that the patient had realistic expectations from treatment. The Committee heard from the company that starting and stopping criteria are estimated to reduce costs by 20% and QALYs gained by 10%. The clinical experts pointed out that treatment can appear to offer benefit after being stopped, sometimes for up to 2 years, during which time no costs would be incurred. The Committee would have liked the economic impact of starting and stopping criteria to have been explored in more detail, but it acknowledged there are significant uncertainties that would be included in the modelling (including the most appropriate starting and stopping criteria), which might result in estimates that are not appropriate for decision‑making. The Committee was aware that MPS IVa is a heterogeneous condition, with a response to treatment that varies greatly among patients. Although the economic impact of using criteria for starting and stopping treatment had not been established because of the absence of robust evidence, the Committee concurred with comments from the clinical experts. It considered the criteria in the managed access agreement for starting and stopping elosulfase alfa, including the response criteria for continuing treatment. The Committee concluded that the criteria in the managed access agreement would encourage a discussion before treatment starts to manage patients' expectations of treatment, and to get agreement on the clinical scenarios for potentially stopping treatment.

5.22 The Evaluation 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 elosulfase alfa. The Committee noted NICE's position statement in this regard, 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 with regard to the relevance of the PPRS to this evaluation of elosulfase alfa. It therefore concluded that the PPRS Payment Mechanism was irrelevant for the consideration of the value for money offered by elosulfase alfa.

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

5.23 The Committee understood that elosulfase alfa may provide important benefits to patients and their families in addition to the direct health benefits of treatment. It heard from patient experts that improving endurance and reducing fatigue allows people with MPS IVa to continue working, and understood that this had important financial implications. As well as the direct benefits on physical aspects of the condition, elosulfase alfa may provide important indirect mental health benefits. Patient experts emphasised that treatment with elosulfase alfa can provide additional predictability in the condition and therefore introduce normality and control in people's lives. The Committee heard that people can maintain independence, participate in social activities, develop longer‑term plans and have fewer unplanned hospital visits. The Committee heard that, for children with MPS IVa, improved management of the condition has important benefits for education, particularly if elosulfase alfa can be given at school to minimise disruption. The Committee noted in particular that MPS IVa does not affect cognitive function, and was aware that this makes it distinct from other lysosomal storage disorders. The Committee concluded that elosulfase alfa is likely to have a significant impact on people's lives beyond its direct health benefits.

5.24 The Committee noted that treatment with elosulfase alfa needs weekly infusions, and heard from the patient experts that travelling to a specialist centre can be a significant burden. The Committee also understood that elosulfase alfa may be given in people's homes, and that this would dramatically reduce this burden. The Committee noted comments from patient experts that some people had already begun to have treatment at home or in school (through programmes offered by the company and some hospitals) with great success. The patient experts noted that this has had positive effects both on people with the condition and their families, who may be able to return to work and avoid the financial costs of travelling to hospital. The Committee understood that people with MPS IVa have complex needs in emergency situations, but was reassured that robust safeguards were in place.

5.25 The Committee understood that it was not anticipated that substantial changes to the delivery of specialised services would be needed to use elosulfase alfa. It noted that, in this respect, elosulfase alfa was not significantly different to other enzyme replacement therapies. The Committee concluded that the impact of elosulfase alfa on the delivery of specialised services was likely to be relatively negligible.

Conclusion

5.26 The Committee discussed the appropriate recommendations for elosulfase alfa for MPS IVa. It acknowledged that MPS IVa is a serious condition that has severe effects on the lives of people with the condition, as well as their families and carers. The Committee accepted that elosulfase alfa can provide valuable clinical benefits for some aspects of the condition, including quality of life. It also considered that elosulfase alfa could provide distinctive benefits beyond those directly related to health. The Committee noted that some patients who received elosulfase alfa reported significant health and quality‑of‑life benefits, but that the clinical trials measured primarily proxy outcomes and the evidence from them could not be reconciled with the patient testimonies (see section 5.7). In addition, the Committee noted the high acquisition cost of elosulfase alfa and did not consider that this had been fully justified. Taken together, the Committee had concerns about the true value for money provided by elosulfase alfa, and could not ascertain whether the benefits of treatment measured in short‑term clinical trials would, on average, be associated with gains in longevity and persisting benefits in those outcomes that are important to patients. On the basis of the available evidence on overall benefit, the Committee considered that the cost of elosulfase alfa, incorporating the patient access scheme, was too high for it to be recommended outside the context of a managed access agreement. However, it was satisfied that there was sufficient evidence that some patients did well on elosulfase alfa to justify further exploration of its costs and benefits in routine clinical practice, within the context of a managed access agreement, to inform a future review of this guidance. The Committee concluded that including other commercial arrangements in the managed access agreement in addition to the patient access scheme would offer more acceptable value for money in the context of the uncertainty of the clinical benefits. Because of this, the Committee concluded that elosulfase alfa could be recommended for treating MPS IVa if it is given according to the conditions in the managed access agreement.

Summary of Evaluation Committee's key conclusions

HST2

Evaluation title: Elosulfase alfa for treating mucopolysaccharidosis type IVa

Section

Key conclusion

Elosulfase alfa, within its marketing authorisation, is recommended for funding for treating mucopolysaccharidosis type IVa (MPS IVa) according to the conditions in the managed access agreement for elosulfase alfa.

1.1

On the basis of the available evidence on overall benefit, the Committee considered that the cost of elosulfase alfa incorporating the patient access scheme was too high for it to be recommended outside the context of a managed access agreement. However, it was satisfied that there was sufficient evidence that some patients did well on elosulfase alfa to justify further exploration of its costs and benefits in routine clinical practice, within the context of a managed access agreement, to inform a future review of this guidance.

5.26

Current practice

Nature of the condition, including availability of other treatment options

The Committee understood that MPS IVa is a serious condition that severely affects life expectancy and quality of life and leads to dramatic effects on the lives of people with the condition and their families and carers. The Committee heard that initially, MPS IVa was believed to be purely a skeletal disorder, but it later became apparent that the skeletal features were only part of a multi‑system disorder, and that non‑skeletal features contribute heavily to the burden of illness. The Committee concluded that the disease process is not yet fully understood but that MPS IVa is a debilitating and highly heterogeneous condition that affects the body across multiple organ systems.

5.1

The Committee concluded that the key determinants of mortality are the respiratory and cardiac complications, and that what matters the most to people with the condition is the ability to carry out normal everyday activities with sufficient endurance and without pain or fatigue. The Committee agreed that, although spinal cord damage can have an impact on mobility and quality of life, its overall contribution to morbidity is generally small.

5.2

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 clinical experts stated that most people treated with elosulfase alfa experienced improvements in endurance, pulmonary function, anthropometrics, wheelchair dependency and quality of life. The patient experts also described positive effects on sleep, pain, energy levels and fatigue, dexterity and ability to complete everyday activities. The Committee concluded that elosulfase alfa improved various abilities and aspects of health compromised by the disease, and that the health and quality of life of some patients improved significantly on treatment.

5.6

Before elosulfase alfa became available, there were no treatments that address the underlying disease.

2.3

Adverse reactions

Patient experts reported experiencing some adverse reactions but emphasised that these were quickly controlled and were vastly outweighed by the benefits of treatment.

5.8

Clinical evidence

Availability, nature and quality of evidence

The Committee was pleased to see that a detailed study of the natural history of MPS IVa involving many people was presented.

The Committee was satisfied that the clinical trials generally reflected the spectrum of people who would be expected to have treatment in England.

5.3

The Committee noted that various benefits experienced by patients who received elosulfase alfa were not known at the onset of the clinical trials, and so the trials were not designed to capture them.

5.4

The Committee noted that the primary outcome in the randomised clinical trials, the 6‑minute walk test (6MWT), is a surrogate outcome that provides a broad measure of overall functioning, which it concluded was broadly appropriate and useful in giving some indication on the real‑life benefits of treatment experienced by patients.

5.5

The Committee noted that much of the evidence represented anecdotal, patient‑reported outcomes.

5.6

Uncertainties generated by the evidence

The Committee concluded that some of the true long‑term outcomes in people with MPS IVa, such as cardiac and respiratory function and the need for orthopaedic surgery, remained uncertain.

5.4

The Committee was aware that the patient experts' opinion was subjective and was at risk of bias because it may represent the experience of only a selected group of patients.

The Committee was aware that the clinical trials measured primarily proxy outcomes, and did not substantiate most of the direct health benefits described by patients. The Committee concluded that data collected within the context of the managed access agreement would help to reconcile the differences between the patient testimonies and clinical trial data when this guidance is reviewed.

5.7

Impact of the technology

Based on the patient testimonies, the Committee concluded that elosulfase alfa improved various abilities and aspects of health compromised by the disease, and that the patients' experience with treatment had been largely positive, with health and quality of life improving significantly in some patients. However, it was aware that patient testimonies ought to be considered with some degree of caution.

5.6

Cost evidence

Availability and nature of evidence

The company presented a cost–consequence analysis comparing elosulfase alfa 2 mg/kg/week with established clinical management. The analysis was based on a Markov model with a lifetime time horizon and a 1‑year cycle length. The analysis was conducted from the perspective of the NHS and Personal Social Services (PSS), and costs and benefits were discounted at a rate of 1.5% per year.

4.11

The company presented a budget impact analysis to predict the costs of elosulfase alfa in the NHS and PSS.

4.18

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

The cost‑consequence analysis

The Committee heard that disease progression varies widely among people, and that it would be difficult to model this with reasonable accuracy. The Committee concluded that varying the rate of disease progression across health states would better reflect the natural history of the disease instead of using constant rates.

5.15

It was uncertain whether the company's original modelling of survival accurately reflected the mortality risks associated with MPS IVa, such as the risks of cervical complications, trauma and heart failure. In response to consultation, the company modelled 2 alternative scenarios excluding the mortality benefit of elosulfase alfa, which the Committee concluded were more clinically plausible.

5.18

The budget impact analysis

The Committee concluded that the precise number of people who would have treatment with elosulfase alfa in England if it were recommended is uncertain.

5.10

The company's model assumed that 50% of the total care time was provided by professional carers. The Committee heard from a patient expert that only 5 people with MPS IVa currently have professional care, and so considered that the company had overestimated the cost to the NHS of professional carers. The Committee concluded that the budget impact analyses used in its decision‑making should exclude the VAT waiver.

5.11

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 the company's utility estimates in their original submission included a substantial decline between people using a wheelchair some of the time and those who are dependent on a wheelchair. It heard from the company that this was consistent with a substantial jump in caregiving time between these states. The Committee noted that there are additional challenges in caring for people who are dependent on a wheelchair.

5.16

The Committee agreed that it was reasonable to include a utility increment associated with elosulfase alfa in the economic model. However, it appreciated that the evidence on quality of life was limited, and that what evidence there was had been synthesised using methods that had not been fully developed or validated. The Committee concluded that the existing evidence did not allow the utility benefit associated with elosulfase alfa to be robustly modelled.

5.17

Cost to the NHS and PSS

The Committee noted that the company's budget impact analysis at the list price suggested that the net budget impact for elosulfase alfa would rise from £17.3 million in year 1 to £28.8 million in year 5. The analyses incorporating the patient access scheme are confidential and cannot be reported here. The managed access agreement includes further commercial arrangements between the company and NHS England for the duration of the agreement.

5.9

The Committee was not satisfied that the high cost of elosulfase alfa was fully justified and considered that further assurances were needed to ensure that the cost of elosulfase alfa to the NHS is appropriately contained before elosulfase alfa is used routinely for patients with MPS IVa. The Committee concluded that it was satisfied that the company and NHS England had included commercial arrangements in the managed access agreement to limit the total costs of elosulfase alfa during data collection.

5.14

Value for money

The Committee noted that some patients who received elosulfase alfa reported significant benefits, but that the clinical trials primarily measured proxy outcomes and the evidence from them could not be reconciled with the patient testimonies. In addition, the Committee noted that the high cost of elosulfase alfa had not been fully justified. Taken together, the Committee had concerns about the true value for money provided by elosulfase alfa, and could not ascertain whether the benefits of treatment could be generalised to the average patient. Based on the available evidence on overall benefit, the Committee considered that the cost of elosulfase alfa (incorporating the patient access scheme) was too high for it to be recommended outside the context of a managed access agreement. The Committee concluded that including other commercial arrangements in the managed access agreement in addition to the patient access scheme would offer more acceptable value for money in the context of the uncertainty of the clinical benefits.

5.26

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

The Committee understood that elosulfase alfa may provide important benefits to patients and their families in addition to the direct health benefits of treatment.

5.23

The Committee noted that treatment with elosulfase alfa needs weekly infusions, but understood that elosulfase alfa may be given in people's homes.

5.24

The Committee concluded that the impact of elosulfase alfa on the delivery of specialised services was likely to be relatively negligible.

5.25

Additional factors taken into account

Patient access schemes (PPRS)

The company has proposed a patient access agreement, in which elosulfase alfa would be provided at a discounted cost; the discount is commercial in confidence and so cannot be reported here. The managed access agreement includes further commercial arrangements between the company and NHS England for the 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 elosulfase alfa.

5.22

Equalities considerations and social value judgements

There were no potential issues relating to equality considerations that needed to be discussed by the Committee.