3 Committee discussion

The evaluation committee considered evidence submitted by Alexion Pharma UK, a review of this submission by the external assessment group (EAG), and responses from stakeholders. See the committee papers for full details of the evidence.

The condition

Paediatric-onset hypophosphatasia

3.1 Hypophosphatasia is a genetic disorder caused by mutations in the tissue non-specific alkaline phosphatase (TNSALP) gene, which reduce its activity. This causes disruption of mineralisation, a process in which calcium and phosphorous are deposited in developing bones and teeth. Several clinical forms of hypophosphatasia are currently recognised:

perinatal onset (onset before or at birth)
infantile onset (onset at 0 to 6 months)
juvenile onset (also referred to as childhood onset; onset between 6 months and 17 years)
adult onset (onset at 18 years and over) and
odontohypophosphatasia (only dental symptoms).

Paediatric-onset hypophosphatasia includes everyone with hypophosphatasia of perinatal, infantile or juvenile onset. Adult-onset hypophosphatasia and odontohypophosphatasia are outside of the scope of this guidance. The signs and symptoms of hypophosphatasia vary widely and can appear any time from before birth to adulthood. They include rickets, softening and weakening of the bones (osteomalacia), bone deformity and a greater incidence of fractures. Hypophosphatasia can also lead to chronic debilitating pain, muscle weakness, generalised seizures because of vitamin B6 deficiency, and renal and respiratory complications. The most severe forms of the condition tend to occur before birth and in early infancy. Babies who present with hypophosphatasia in the first 6 months of life (that is, babies with perinatal- or infantile-onset disease) have a high mortality rate. About 50% to 100% of babies die within the first year of life, primarily because of respiratory failure. Juvenile-onset hypophosphatasia that develops later in childhood has a substantially lower mortality rate. But it is often debilitating and leads to bone deformities that may result in delayed walking, limb weaknesses, skeletal pain and non-traumatic fractures. The committee concluded that the morbidity and mortality associated with paediatric-onset hypophosphatasia varies depending on the age that symptoms start.

Effects on quality of life

3.2 Patient experts and patient groups described how hypophosphatasia is a debilitating condition in all age ranges and that it impacts people physically, socially and emotionally. For people with perinatal- or infantile-onset hypophosphatasia, respiratory compromise and seizures have the greatest effect on health-related quality of life. Babies who survive have significant ongoing morbidity and may still need invasive ventilation, further impairing their health-related quality of life. Hypophosphatasia in babies can also lead to difficulties with crawling, growth and feeding, which impacts the whole family. Poor mobility makes everyday activities and independent living difficult for adults and children, with walking aids or home adaptations needed. People who have hypophosphatasia find working very challenging because of physical limitations, mental challenges, sickness and time needed off work to attend appointments. Hypophosphatasia makes it difficult to have a normal and enjoyable social life and education can also be affected. There is also a large burden on carers of people who have hypophosphatasia, particularly carers of babies. Carers are likely to spend many days in hospital with their child, which reduces time with other family members and results in time away from work (or stopping work entirely). It is difficult to manage childcare and hospital appointments, which also often involve extra travel burden to get to them. Due to the rarity of hypophosphatasia there is little information or advice available. Families must adapt their hobbies and social lives around their child's hypophosphatasia, and parents can experience long-term mental health problems. The daily lives of carers of children with perinatal- or infantile-onset hypophosphatasia are affected because of the child's seizures and the need to regularly monitor oxygen levels. Patient experts highlighted that because of the limited numbers of centres treating hypophosphatasia in England, long journeys for appointments or inpatient stays may be needed regularly. The committee concluded that hypophosphatasia has a substantial impact on people with the condition and their families and carers.

Clinical management

Managed access agreement

3.3 Asfotase alfa has been available through a managed access agreement since the original NICE highly specialised technologies guidance for asfotase alfa (from here referred to as HST6) was published in 2017. The managed access agreement required collection of data on people having treatment and their families. Before this, the only treatment option was best supportive care. Best supportive care varies according to the type and severity of symptoms, but includes surgical, therapeutic and dental management techniques. The main goal of treatment in those most severely affected by hypophosphatasia, which is life threatening, is to keep them alive. Where people have less-severe disease, treatment goals include

improving bone mineralisation
minimising risk of seizures and respiratory complications in babies and children
attaining growth and developmental milestones in children
reducing the number and frequency of fractures
reducing pain
improving ambulation
improving oral health
improving quality of life for the person with hypophosphatasia and their caregiver.

Patient groups said that asfotase alfa has been life saving for babies and life changing for all people, with a clear impact on overall health for people with hypophosphatasia and their families and carers. Benefits include
the need for fewer medical appointments
improved mobility
children being able to breathe independently
better control of symptoms
improved performance in school
improved work and social life
improved quality of life.

These benefits were said to outweigh difficulties with administration of asfotase alfa in babies and young children. Clinical experts described how asfotase alfa has had a big impact on both morbidity and mortality whilst reducing the reliance on carers.

Clinical effectiveness

Data sources

3.4 Evidence on asfotase alfa for this review came from 6 sources. This included 4 clinical trials that were considered by the committee in the original appraisal and new data from 2 real-world studies. The clinical trials were phase 2 open-label studies of asfotase alfa (2 of which had associated extension studies):

ENB‑002‑08, a non-randomised 24‑week single-arm study in 11 people of 36 months and under with infantile-onset hypophosphatasia. With an extension study (ENB‑003‑08) that followed 10 people for up to 7 years.
ENB‑010‑10, a non-randomised, dose-comparison study of asfotase alfa treatment in 69 people of 5 years and under with perinatal- or infantile-onset hypophosphatasia followed for up to 6 years.
ENB‑006‑09, a randomised 24‑week dose-comparison study in 13 people of 5 years to 12 years with paediatric-onset hypophosphatasia. With an extension study ENB‑008‑10 that followed 12 people for up to 7 years.
ENB‑009‑10, a randomised, 24‑week concurrent control study in 19 people of 13 years to 66 years with hypophosphatasia (18 of 19 people had paediatric-onset hypophosphatasia) followed for up to 5 years.

Real-world data was collected under the managed access agreement (UK MAA data) in people with paediatric-onset hypophosphatasia, regardless of current age, who had asfotase alfa. Follow up was up to 4 years. Further real-world data is available from the ongoing Global Hypophosphatasia Registry and includes people who have had asfotase alfa and people who have not. The outcomes included in the trials and real-world studies were similar and included:
mortality
pain
radiographic response
severity of rickets
respiratory function
craniosynostosis and intracranial pressure
growth
tooth loss
cognitive development and motor skills
adverse effects of treatment
fractures
health-related quality of life.

The company's comparative analysis focused on overall survival and ventilator-free survival (see section 3.7). The committee considered all sources of evidence within its decision making.

Categorisation of population

3.5 In 2 of the studies presented by the company (UK MAA data and ENB-009-10), results were presented by age at study entry: under 18 years or 18 years and over. The EAG noted that these categories did not align with the accepted categories of paediatric-onset hypophosphatasia: perinatal, infantile and juvenile onset. This made it difficult to assess the data against the decision problem and between asfotase alfa trials. The company highlighted that the managed access agreement did not require data to be collected by age at onset of symptoms. It also reported that ENB-006-08/ENB-008-10 included subgroup analysis for juvenile-onset hypophosphatasia where the results were similar to the main analysis. The EAG said that all relevant evidence should have been included and categorised as per the subgroups in the scope for the whole paediatric-onset population. The experts described how there is a lot of overlap in people with perinatal- or infantile-onset hypophosphatasia, but that people with juvenile-onset hypophosphatasia have a different prognosis. Bone issues are common across all forms of paediatric-onset hypophosphatasia. But mortality is much higher in people with perinatal- or infantile-onset hypophosphatasia, especially in the first year of life. People with perinatal- or infantile-onset hypophosphatasia who survive are likely to experience greater challenges throughout childhood and have different complications than people with juvenile-onset hypophosphatasia due to the severity of illness they experienced as babies. The committee concluded that evidence should be presented for perinatal- or infantile-onset hypophosphatasia and juvenile-onset hypophosphatasia separately because prognosis varies between these 2 groups.

Population in the decision problem and clinical efficacy evidence provided

3.6 The company's analyses comparing asfotase alfa with best supportive care were in people with perinatal- or infantile-onset hypophosphatasia. The comparative analyses done by the company (see section 3.7) did not include people with juvenile-onset hypophosphatasia. The EAG highlighted that this meant there was a lack of evidence about the relative efficacy of asfotase alfa in relation to best supportive care in this subgroup. The company stated that there is comparative data that includes people with juvenile-onset hypophosphatasia from ENB-006-09/ENB-008-10 and that a pooled analysis for this group was inappropriate for several reasons. These included that:

current clinical status is more important than age at onset
the majority of the clinical trials were based around age at enrolment rather than onset
there is substantial variation in study inclusion criteria, making pooling difficult, and that survival analysis are not relevant in this group because hypophosphatasia is not typically life threatening.

The EAG acknowledged that there are limitations with all sources of comparative data. But, the EAG did not consider that the comparative efficacy of asfotase alfa and best supportive care were suitably addressed for all populations and outcomes in the scope. The experts explained that the prognosis of people with perinatal- or infantile-onset hypophosphatasia is different to people with juvenile-onset hypophosphatasia (see section 3.5). The committee concluded that analyses comparing asfotase alfa with best supportive care should be done in the subgroup of people with juvenile-onset hypophosphatasia.

Comparative analysis based on survival outcomes

3.7 The company did a comparative analysis of overall survival and ventilator-free survival in people with perinatal- or infantile-onset hypophosphatasia only. Data on people who had received asfotase alfa was taken from ENB-002-08/ENB-003-08 (n=11) and ENB-010-10 (n=69). Data on best supportive care was taken from untreated historical controls from ENB-011-10, a global non-interventional, retrospective, epidemiologic chart review study including 48 people. The comparative analysis showed that asfotase alfa significantly improved overall survival at 7 years (87% survival; 95% confidence interval [CI] 0.77 to 0.93) compared with best supportive care (27% survival; 95% CI 0.15 to 0.40). Ventilator-free survival at 7 years was also significantly improved (81% [95% CI: 0.68 to 0.89] compared with 25% [95% CI: 0.14 to 0.38]). The EAG considered that this comparative analysis is a form of indirect treatment comparison, but that the methods were flawed (see sections 3.8, 3.9 and 3.10). It also stated that comparative analyses should be conducted for all relevant outcomes using all relevant data for people having asfotase alfa and for those having best supportive care. Despite limited data, this should not stop a comparison being made. The clinical experts explained that since asfotase alfa has been available, there have been improvements in mortality and morbidity. They added that people with perinatal- or infantile-onset hypophosphatasia who would not have survived previously now do. This makes quantifying the benefit on morbidity difficult. The committee concluded that survival outcomes in people with perinatal- or infantile-onset hypophosphatasia are improved with asfotase alfa but recognised the uncertainty in the analyses described in sections 3.8, 3.9 and 3.10. It further recognised that some benefit is expected in other outcomes.

Changes in best supportive care

3.8 The company used historical control data in its comparative analysis (see section 3.7) to inform the effectiveness of best support care. The EAG was concerned that the data used was mostly from people who were diagnosed with hypophosphatasia and started treatment before the year 2000. At that time, people receiving best supportive care did not live for as long as they do today. The EAG said that this may bias the results of the comparative analysis in favour of asfotase alfa. The experts said that there may have been improvements in respiratory care in the last 20 years that could have influenced survival. However, best supportive care has not changed otherwise. The EAG suggested that the company should have used all available data on best supportive care to inform the comparison, including data from the Global Hypophosphatasia Registry. The company stated that the Global Hypophosphatasia Registry has only existed since asfotase alfa has been available. Therefore, the people in the registry with perinatal- or infantile-onset hypophosphatasia who are having best supportive care, have less-severe disease than those having asfotase alfa. The clinical experts agreed that people having asfotase alfa as part of the managed access agreement are unlikely to be comparable to people having best supportive care in the Global Hypophosphatasia Registry. The company also said that the number of people with perinatal- or infantile-onset hypophosphatasia in the Global Hypophosphatasia Registry is small, with only 1 person having died. The committee concluded that the use of the historical data may bias the results of the comparative analysis in favour of asfotase alfa. But, if the Global Hypophosphatasia Registry data had been sufficient for use, this may have biased the results in favour of best supportive care.

Potential for immortal time bias in the overall survival comparison

3.9 The company used historical control data in its comparative analysis (see section 3.7) to inform the effectiveness of best support care. The EAG was concerned about the potential for immortal time bias to occur within the comparison, which would bias the results in favour of asfotase alfa. The Kaplan-Meier curves based on 'survival from birth' can erroneously indicate that people having asfotase alfa had it from birth, whereas they were given treatment only after the study enrolment. Immortal time bias can occur, in observational studies, where there is a delay to the start of treatment. This wait period is considered immortal because individuals who enter the treatment group have survived until treatment is started. The death of more severely affected people can occur between birth and treatment initiation. In ENB-002-08/ENB-003-08 people with hypophosphatasia aged 3 or below were enrolled meaning that people who had survived infancy were included and had asfotase alfa. In the natural history study (ENB-011-10) used for the comparison this bias could not occur because people were likely followed from a younger age. The company excluded people who received best supportive care and died on the first day after baseline, because these people would be unlikely to start on asfotase alfa treatment to help reduce the potential for bias. The committee concluded that there is the potential for immortal time bias to occur in the comparative analysis and that it would ideally prefer the survival analysis to censor matched people receiving best supportive care until they would otherwise have had the opportunity receive treatment with asfotase alfa. The committee recognised that limitations with the availability of data may have prevented this type of analysis being done.

Comparative analysis methods to minimise bias

3.10 The comparative analysis done by the company did not attempt to match people given treatment with asfotase alfa and untreated controls using key demographic and clinical characteristics. It also did not adjust for potential confounders, meaning there remained uncertainty about whether the treatment and control groups were clinically similar. The company considered the demographic, baseline and hypophosphatasia medical histories of people in the 2 groups to be clinically similar. But the EAG noted there was not enough information provided to make this judgement. It also recommended that comparative analyses should be done by adjusting for potential confounders according to the methods described in the NICE technical support document (TSD) 17. During technical engagement, the company explored whether matching between people in the clinical trials and Global Hypophosphatasia Registry data could take place using the 6-minute walk test (6MWT) outcome. It found that the number of people having best supportive care with multiple 6MWT measures was very small. The company found limited patient numbers when considering the use of the Global Hypophosphatasia Registry for mortality (see section 3.8). The company focused its consideration on mortality and 6MWT. This was because these outcomes were important for the economic model (see section 3.11) and were generally better reported in the registry than other outcomes like health-related quality of life. The committee would have liked to see individual patient data used to carry out matched analyses using the methods described in NICE TSD 17 for all relevant outcomes. However, it recognised that the available data may have been too limited for this analysis to be meaningful. It therefore concluded that the comparative analyses presented for people with perinatal- or infantile-onset hypophosphatasia could be used to inform the economic model.

Economic model

Company's modelling approach

3.11 In HST6, the company developed a Markov model that compared asfotase alfa with best supportive care. It had 6 states: 4 according to the level of severity defined by 6MWT distance, a state for people who needed invasive ventilation and death (including hypophosphatasia-related and age-related death). For the current review, the company updated the model so that it was structured differently for people aged under 5 compared with those aged 5 or over. Those aged under 5 could be in 3 health states: alive with no invasive ventilation, alive with invasive ventilation or death (including hypophosphatasia-related and age-related death). For those aged 5 or over, 4 health states represented increasing levels of disease severity (1 to 4) defined by 6MWT distance or death (age-related death only). The company updated the model to capture the increased risks of ventilation and hypophosphatasia-related mortality in younger people. The EAG was broadly happy with the model structure but flagged that the company's assumption that all people surviving to the age of 5 enter the model in the most severe health state. They noted that not all these people would require invasive ventilation so may not be in the most severe health state. The EAG was also unclear why the company did not use the UK MAA data to inform the baseline cohort characteristics, given the UK MAA data is the source for most of the new data on people who had asfotase alfa included in submission. The model generated results for 2 populations: people with perinatal- or infantile-onset hypophosphatasia and people with juvenile-onset hypophosphatasia. The committee was concerned that the population entering the model when results for a juvenile-onset hypophosphatasia were generated was not based on disease severity in that subgroup. Instead, it was based on paediatric-onset hypophosphatasia more generally. This meant that the juvenile-onset hypophosphatasia may model more severely affected people than expected. This may cause a high proportion of the modelled population to enter the most severe health states over the course of the model. The committee concluded that the model structure was generally appropriate for decision making. But the juvenile-onset hypophosphatasia results should be based on a starting cohort distributed between health states according to data specific to a juvenile-onset population.

Transition probabilities for invasive ventilation in under 5 model cohort

3.12 Transition probabilities for invasive ventilation in both arms came from a study published by Whyte et al. (2014). A 12-weekly probability of receiving invasive ventilation of 0.0220 for asfotase alfa and 0.0618 for best supportive care were used in the model. These values were applied as a constant risk between the ages of 0 and 5 years and are age independent. The company stated that this was to capture the potential need for repeated invasive ventilation support. The EAG said that a time-to-event analysis would be more informative provided that repeated ventilation was not needed by many people. The company noted that a time-to-event analysis would not allow people to come off ventilation. The committee considered that people require ventilation for different reasons. Some people will not survive without ventilation and for these people a time-to-event analysis would be reasonable. Other people will go on and off ventilation as needed and for these people a time-to-event analysis would not be reasonable. The committee concluded that whilst there is uncertainty in the transition probabilities, the approach taken by the company is broadly reasonable. However, it noted that in the juvenile-onset hypophosphatasia model, transition probabilities should be based on data specific to this subgroup.

Utility values

Source of utility values

3.13 The company used health state utility values that were based on a vignette study rated by UK clinical experts. The same values were used as in the original appraisal, except for people aged under 5 years on ventilation. For this group, utility was changed from -0.09 in the original model to 0.00 in the current model. The EAG said that patient-reported data collected in the UK MAA data or Global Hypophosphatasia Registry should be used to inform the utility values, rather than them being based on expert opinion from the vignette study. The company considered the UK MAA data and noted that there was a lack of utility estimates available in the data for people in the worst severity health states. There were 2 people (4 records) in severity level 2 and 3 people (7 records) in severity level 1. It also said that the utility values for severity level 3 and level 4 were similar to those in the vignette. The committee concluded that in the absence of sufficient data to produce reliable utility values by health state, the use of the vignette results was reasonable.

Carer disutility

3.14 The impact on carer health-related quality of life was included by the company in 2 ways:

All health states, except the lowest severity level in people aged 5 years and over, included a disutility to account for the impact on carers. Because no data was available for hypophosphatasia, the company used data for Duchenne's muscular dystrophy. This was because it was considered to have a similar burden on caregivers. They used a value of 0.17 for the most severe health state with lower values in the other health states. The EAG updated the disutility in the most severe state to 0.11 because this was the value used in NICE's highly specialised technologies guidance on ataluren for treating Duchenne muscular dystrophy. The committee was concerned that the use of the values from Duchenne's muscular dystrophy did not fully capture the impact on carers of people with hypophosphatasia. It recognised that events such as seizures, which have a profound impact on carers, are more common in hypophosphatasia. The company restricted the duration of the disutility so that it only applied for a similar length of time in the 2 groups. This was to avoid the counterintuitive outcome whereby increased survival with asfotase alfa reduced the quality-adjusted life year (QALY) gain because carers experienced this disutility for longer. The EAG also changed the model so that this disutility was applied for as long as care is provided based on survival in each arm, rather than for the same time-period in both arms. The committee agreed with this correction. They considered that the use of the EAG's approach in the model was technically correct but produced the counterintuitive outcome mentioned above and preferred to consider this aspect qualitatively.
The impact of infant death on the health-related quality of life of carers was also included by the company in its base case. A reduction in utility of 0.04 in 2 carers was applied for the remainder of their lives, based on scenario presented by a company, and rejected by the committee, in NICE's highly specialised technologies guidance on strimvelis for treating adenosine deaminase deficiency–severe combined immunodeficiency. The EAG noted that the inclusion of disutility to account for bereavement is rare and preferred to include this analysis as a scenario rather than including the impact in the base case. The committee agreed that it would consider the disutility associated with bereavement qualitatively.

Costs

Asfotase alfa cost

3.15 Asfotase alfa has a weight-based dosing regimen. Therefore, the company's model needed the mean weight of the people having asfotase alfa to be estimated to calculate the treatment cost. The company used data from the clinical trials and the UK MAA study to determine mean weight value curves. The curves were them smoothed using a third degree polynomial model. This resulted in weight estimates that were lower than that of the general population. The company said that this is reasonable because the weight of people under 18 with hypophosphatasia is similar to the 25th percentile of the UK population. In adults the estimated weight was below the UK average. However, the company stated that both the estimated weight and UK average require the same dose of asfotase alfa. So there is no impact on the drug cost. The EAG considered that only the weight modelled by the company in people aged under 9 was lower than the 25th percentile of the UK population. So the EAG did a scenario analysis where UK general population median weight values were used at all ages. The clinical experts looked at the values used by the company and said that the company's estimates of weight in children seemed plausible. The committee concluded that the approach taken by the company to model weight was reasonable.

Drug wastage

3.16 The company stated that in clinical practice drug wastage is minimised by rounding down the dose per administration. This is provided the reduction is not more than 3 mg to 4 mg per administration. Based on this, the company's base case accounted for rounding down if the administered dose was 12 mg less than the required weekly dose. The EAG took a more conservative approach where the number of vials required for a dose was rounded up and any wastage not used. The committee considered that the EAG's approach aligns with the recommended dosage in the summary of product characteristics. They concluded that drug wastage using rounding up should be included in the model.

Assumed reduction in price from loss of market exclusivity

3.17 The company originally assumed a reduction in the price of asfotase alfa after 7 years because of patent expiration. The EAG understood the company's justification for this approach but considered that there was no robust basis for making this assumption. The EAG also considered the size of the reduction to be arbitrary. This was discussed at technical engagement and the company agreed to remove this price reduction. The committee stated that it had not previously considered price reductions resulting from the potential introduction of generics or biosimilars. This is because it is speculative and the impact of their introduction is unknown. It highlighted that the cost of several other resources included in the company's economic model could change over time. The committee noted that NICE's health technology evaluations: the manual (2022) states that analyses should be based on price reductions when it is known that some form of price reduction is available across the NHS. The committee concluded the price reduction after 7 years was inappropriate and should not be included in the analysis.

QALY weighting

3.18 The committee understood that NICE's health technology evaluations: the manual (2022) specifies that a most plausible incremental cost-effectiveness ratio (ICER) of below £100,000 per QALY gained for a highly specialised technology is usually considered an effective use of NHS resources. For a most plausible ICER above £100,000 per QALY gained, judgements about the acceptability of the highly specialised technology as an effective use of NHS resources must take account of the size of the incremental therapeutic improvement. This is shown by the number of additional QALYs gained and by applying a 'QALY weight'. The committee understood that a weight between 1 and 3 can be applied when the QALY gain is between 10 and 30 QALYs. It discussed the number of undiscounted QALYs in the analysis. The estimated QALY gains are commercial in confidence so cannot be reported here but are substantially above 30 QALYs. Therefore, the committee noted that the undiscounted QALY gains for the scenarios incorporating its preferred assumptions met the criteria for applying a QALY weight. It acknowledged there was uncertainty in the estimates but agreed the extra health and quality-of-life benefits of asfotase alfa are likely to be substantial.

Cost-effectiveness estimates

Cost-effectiveness estimates in perinatal- or infantile-onset hypophosphatasia

3.19 The company's base case resulted in a probabilistic ICER of £39,069 per QALY gained in perinatal- or infantile-onset hypophosphatasia with the QALY weighting applied. This includes both the confidential discount for asfotase alfa (see section 2.3) and the assumed reduction in price from loss of market exclusivity (see section 3.17). The EAG's base-case results after technical engagement resulted in a probabilistic ICER of £99,756 per QALY gained in perinatal- or infantile-onset hypophosphatasia with the QALY weighting applied. This includes the confidential discount for asfotase alfa, but not the assumed price reduction from loss of market exclusivity. The committee considered that the assumptions underpinning the EAG's ICER are more closely aligned with its preferred assumptions in people with perinatal- or infantile-onset hypophosphatasia. After qualitative consideration of the carer burden and with the QALY weighting applied, this was within the threshold normally considered an effective use of NHS resources in a highly specialised technology.

Cost-effectiveness estimates in juvenile-onset hypophosphatasia

3.20 The company's base case resulted in a probabilistic ICER £46,519 per QALY gained in juvenile-onset hypophosphatasia with the QALY weighting applied. This includes both the confidential discount for asfotase alfa (see section 2.3) and the assumed reduction in price from loss of market exclusivity (see section 3.17). The EAG's base-case results after technical engagement resulted in probabilistic ICER of £122,629 per QALY gained in juvenile-onset hypophosphatasia with the QALY weighting applied. This includes the confidential discount for asfotase alfa, but not the assumed price reduction from loss of market exclusivity. ICERs under £100,000 per QALY gained are normally considered to be a cost-effective use of NHS resources in a highly specialised technology. The committee recalled that neither the company nor EAG's analyses accounted for its preferred assumptions. It would need the company to do the following to allow it to make a decision about the cost effectiveness of asfotase alfa in people with juvenile-onset hypophosphatasia:

Present subgroup analyses of data specific to people with juvenile-onset hypophosphatasia based on data collected during the managed access agreement, the asfotase alfa clinical trial programme and from the global registry for all relevant outcomes (see section 3.5).
Present comparative efficacy analysis of asfotase alfa and best supportive care in people with juvenile-onset hypophosphatasia for all relevant outcomes (see section 3.6).
Update the severity of disease of the starting cohort in the model so that it is based on data from people with juvenile-onset hypophosphatasia. That is, the distribution across health states should be specific to people with juvenile-onset hypophosphatasia (see section 3.11).
Update the effectiveness data in the model using data specific to people with juvenile-onset hypophosphatasia in both the asfotase alfa and best supportive care arms of the model (see section 3.12).

Other factors

Equality issues

3.21 The company noted that the current UK managed access agreement excludes some adults with paediatric-onset hypophosphatasia from accessing asfotase alfa. It was also noted that if recommendations differ by age then there could be potential equality considerations. The committee discussed this in light of its recommendations, which do differ by age at onset. However, the committee was clear that this is because the burdens of hypophosphatasia and the evidence it was presented with differ between perinatal- or infantile-onset and juvenile-onset hypophosphatasia. No other potential equality issues were identified by the committee.

Uncaptured benefits

3.22 The patient experts said that asfotase alfa allowed people to regain control of their symptoms, resulting in improved performance in school, and improved work and social life. The company presented a scenario that included the cost of productivity losses associated with hypophosphatasia. The committee did not consider cost savings and benefits incurred outside the NHS to be qualitatively greater than those provided by other similar highly specialised technologies.

Conclusion

Recommendations

3.23 The committee recognised that paediatric-onset hypophosphatasia is rare and can substantially affect the lives of people with the condition, their families and carers. It understood that the only alternative to asfotase alfa is best supportive care, which varies according to the type and severity of symptoms. The committee understood that symptoms vary between people and that the prognosis of hypophosphatasia is more severe in those with perinatal- or infantile-onset hypophosphatasia than those with juvenile-onset hypophosphatasia. The committee considered all evidence presented, and the opinions of the clinical and patient experts. The committee took into account its preferred assumptions, indirect treatment benefits and other factors. It considered that in people with perinatal- or infantile-onset hypophosphatasia the most plausible ICERs were likely to be below the threshold considered to provide value for money in the context of a highly specialised service when the company's confidential discount was applied. So, asfotase alfa is recommended in people with perinatal- or infantile-onset hypophosphatasia. It further considered that the lack of subgroup analyses on the comparative efficacy of asfotase alfa in people with juvenile-onset hypophosphatasia and uncertainties in the modelling meant that the cost-effectiveness estimates in this subgroup would be highly uncertain. They would also likely be above the threshold considered to provide value for money in the context of a highly specialised service even when considering other factors such as the impact on carers' quality of life. So, the committee was minded not to recommend asfotase alfa with the current evidence base in people with juvenile-onset hypophosphatasia.

How are you taking part in this consultation?

Asfotase alfa for treating paediatric-onset hypophosphatasia (review of HST6)