4 Evidence submissions

The evaluation committee (section 7) considered evidence submitted by Alexion, a review of this submission by the evidence review group (ERG) and evidence submitted by clinical experts, patient experts and NHS England.

Nature of the condition

4.1 Patient experts and patient groups described how hypophosphatasia can have a profound effect on health-related quality of life.

  • For people with perinatal- and 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 health-related quality of life.

  • Functional disability and pain were identified as the most burdensome aspects of juvenile-onset hypophosphatasia that affect health-related quality of life. They highlighted that many children with hypophosphatasia have difficulties with pain and mobility, and are therefore unable to take part in activities such as playing with friends or attending school. The emotional wellbeing of young people with hypophosphatasia may also be affected as they become more conscious of their condition (for example, experts noted that they may have anxiety or depression).

  • Adults with paediatric-onset hypophosphatasia are often unable to work because of mobility problems and the need to have numerous surgical procedures during their lives.

  • There is also a large burden on carers of people affected by hypophosphatasia, particularly carers of babies. There is a significant emotional effect on families because of the high risk of death associated with infantile-onset hypophosphatasia and the difficulty in parents accepting their child's condition. 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). The daily lives of carers 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. This sometimes leads to families relocating.

4.2 For people with perinatal- and infantile-onset hypophosphatasia, treatments that can help prolong survival are of considerable importance; improving health-related quality of life is viewed as a secondary consideration by parents and healthcare professionals. A patient group highlighted that the parents of 1 infant understood that, without asfotase alfa, their child was unlikely to survive to 9 months.

Clinical evidence

4.3 The company did a systematic literature review to identify studies evaluating the clinical effectiveness of asfotase alfa for treating paediatric-onset hypophosphatasia. It found 4 open-label phase II 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.

  • ENB‑003‑08, an extension study of ENB‑002‑08 that is evaluating 10 people for up to 5 years.

  • ENB‑010‑10, a non-randomised, dose-comparison study of asfotase alfa treatment for up to 48 months in 59 people of 5 years and under with infantile-onset hypophosphatasia.

  • ENB‑006‑09, a randomised 24‑week dose-comparison study in 13 people of 5–12 years with infantile- or juvenile-onset hypophosphatasia.

  • ENB‑008‑10, an extension study of ENB‑006‑09 that is evaluating 12 people for up to 5 years.

  • ENB‑009‑10, a randomised, 24‑week concurrent control study in 19 people of 13–66 years with paediatric-onset hypophosphatasia.

    Only ENB‑002‑08 and ENB‑006‑09 have finished. The company stated that patients included in the studies of asfotase alfa presented with clinical symptoms that were characteristic of their age at onset of hypophosphatasia and enrolment, and that a broad range of outcome measures were collected across studies to reflect the symptoms of the disease in each age group.

4.4 The company also identified 3 retrospective non-interventional studies:

  • ENB‑011‑10, a retrospective natural history study of babies with severe perinatal- and infantile-onset hypophosphatasia. Data on survival and the need for invasive ventilation were taken from medical records of children up to 5 years.

  • ALX‑HPP‑502, a retrospective natural history study of children with juvenile-onset hypophosphatasia (5–15 years). The study focused on functional assessments of physical abilities, changes in growth (height and weight) and skeletal improvement (severity of rickets).

  • ALX‑HPP‑502s, a single-centre substudy of ALX‑HPP‑502. Data for additional functional measures were taken from medical records and videos were obtained from a longitudinal natural history database to characterise gait.

4.5 The primary outcome of ENB‑002‑08 and ENB‑010‑10 was change in severity of rickets on skeletal radiographs from baseline to week 24, measured by the Radiographic Global Impression of Change (RGI‑C) scale. The RGI‑C is a 7‑point rating scale that ranges from −3 (indicates severe worsening of hypophosphatasia-associated rickets) to +3 (indicates complete or near complete healing of hypophosphatasia-associated rickets). An RGI‑C score of +2 or more is considered to be a response to treatment in people with hypophosphatasia. Secondary outcomes included height and weight Z‑scores and the number of people needing respiratory support. The Z‑score indicates how many standard deviations an infant's height or weight is from the mean of the general population.

4.6 In ENB‑002‑08, treatment with asfotase alfa resulted in a mean change in RGI‑C scores from baseline to week 24 of +1.67 and median change of +2.00 (p=0.0039). Most people had an RGI‑C score between +2 and +3 (7 out of 11; 63.6%). No patients had an RGI‑C score of +3 by week 24 ('complete or near complete healing'). However, by week 240 of ENB‑003‑08, all 9 people who had been followed up had an RGI‑C score of +2 or more.

4.7 The company provided the results of an interim analysis of 28 people included in ENB‑010‑10. This analysis suggested that treatment with asfotase alfa resulted in a mean change in RGI‑C score from baseline to week 24 of +1.7 (p<0.0001). The company stated that the results of the primary outcome and the secondary outcomes for all 59 patients included in ENB‑010‑10, as presented in its evidence submission, were academic in confidence and cannot be reported here.

4.8 The company submitted a pre-specified analysis of overall survival for asfotase alfa from people in ENB‑002‑08, ENB‑003‑08 and ENB‑010‑10 compared with an untreated historical control group (ENB‑011‑10). In this analysis, 4 out of 37 people (10.8%) in the asfotase alfa group had died, compared with 35 out of 48 people (72.9%) in the untreated group during the time period evaluated (p<0.0001). The company presented median survival by diagnosis date. The median number of days from birth until death in the historical control group by year of diagnosis increased over time. The values are academic in confidence and cannot be reported here.

4.9 In response to clarification, the company provided survival analyses adjusted for the following potential biases:

  • differences in the year of diagnosis of the historical control group (see section 4.8)

  • survival estimated from birth in the historical control group compared with from the start of treatment in people having asfotase alfa.

    The company estimated an adjusted hazard ratio by excluding those diagnosed before 2000 and those who died before 38 weeks from the historical control group. The company stated that the adjusted hazard ratio was lower than the estimate for the unadjusted hazard ratio. The adjusted and unadjusted hazard ratios are academic in confidence and cannot be reported here. The company presented the results of a further analysis that was requested by the Committee for Medicinal Products for Human Use. This additional analysis retrospectively matched babies from its historical control data with babies having asfotase alfa from its clinical studies (n=37; 29 were considered exact matches). The results of the company's matched analysis are academic in confidence and cannot be reported here.

4.10 ENB‑006‑09 included 13 people randomised to asfotase alfa 2 mg/kg or 3 mg/kg 3 times a week for 24 weeks, and was the only study to include non-concurrent historical control patients selected from a natural history database (n=16). The primary outcome was change in the severity of rickets on skeletal radiographs from baseline to week 24, measured by RGI‑C, for asfotase alfa compared with the historical control. Treatment with asfotase alfa resulted in a median improvement in RGI‑C compared with the historical control (p=0.0007). Median RGI‑C scores for asfotase alfa and the historical control were +2.0 and 0.0 respectively. Nine out of 13 people having asfotase alfa had an RGI‑C score of +2 or more (69%) compared with 1 out of 16 people in the historical control group (6.3%; p=0.0010). Improvements in the severity of rickets for asfotase alfa compared with the historical control were maintained until the data cut-off at week 96 of the extension study (ENB‑008‑10). The company also presented results by age of hypophosphatasia onset but these are academic in confidence and cannot be reported here.

4.11 The height, weight and BMI Z‑scores, and 6‑minute walk test (6MWT) distance results from ENB‑006‑09 and ENB‑008‑10 are academic in confidence and cannot be reported here.

4.12 The company submitted a comparative analysis of people having asfotase alfa from ENB‑006‑09 and ENB‑009‑10 with historical control patients from 3 sources (ALX‑HPP‑502, ALX‑HPP‑502s and ENB‑006‑009/ENB‑008‑10) for rickets severity, growth and gait outcomes. The results of this comparative analysis are academic in confidence and cannot be reported here.

4.13 The results of a 6MWT at baseline and at 24 weeks were available for 13 people in the asfotase alfa group and 4 people in the historical control group of ENB‑009‑10. The 6MWT results from ENB‑009‑10 are academic in confidence and cannot be reported here.

4.14 The company noted that asfotase alfa is a lifetime therapy and stated that there is no evidence to guide the development of treatment continuation rules. Clinical experts suggested that, once a person's bone health has improved, individualised treatment regimens for maintaining bone health would need to be established (for example, exploring less frequent injections or lower doses).

4.15 Health-related quality-of-life data were measured at baseline and several time points using the Childhood Health Assessment Questionnaire (CHAQ; ENB‑006‑09 and ENB‑008‑10), Paediatric Outcome Data Collection Instrument (PODCI; ENB‑006‑09 and ENB‑008‑10) and the Lower Extremity Functional Scale (LEFS; ENB009‑10). These data are academic in confidence and cannot be reported here.

4.16 The company presented EuroQol‑5 dimensions survey (EQ‑5D) results from its European Patient Survey. The EQ‑5D instrument was completed by 10 parents on behalf of their child, and by 25 adults with hypophosphatasia. The mean EQ‑5D score for children having asfotase alfa was 0.76 (n=2) and 0.43 in children who did not have asfotase alfa (n=8). The company highlighted that the EQ‑5D scores were higher for children with normal walking ability (0.73, n=1) than for children with impaired walking ability (0.56, n=8) or who depended on walking aids (−0.24, n=1). All adults were untreated and had a mean EQ‑5D score of 0.39. The company noted that the EQ‑5D scores were only slightly higher for adults with normal walking ability (0.51, n=6) than for adults with impaired walking ability (0.48, n=14). The mean EQ‑5D score for adults who depended on walking aids was −0.01 (n=5).

4.17 The company presented adverse event data for people having asfotase alfa (no data were presented for people who did not have treatment or the historical controls). Median exposure to treatment with asfotase alfa was 1.90 patient years. In a pooled analysis of the interventional studies (excluding ENB‑001‑08), all people (n=102) had at least 1 adverse event. Most adverse events were considered unrelated to asfotase alfa treatment (2,542 out of 3,676) and were of mild intensity (2,758 out of 3,676). Over 25% of the adverse events were classified as injection-site reactions or injection-associated reactions. Treatment was stopped by 4 people, who withdrew from the studies. A total of 274 non-fatal serious adverse events were reported by 48 people (47.1%). Most of these events were in people with infantile-onset hypophosphatasia (262 out of 274 events). Overall, 8 deaths were reported (1 of which was before treatment started).

Managed access arrangement

4.18 The company proposed a managed access arrangement, which was developed with clinical experts and patient groups and revised after advice from NICE and discussion with NHS England. The arrangement was proposed to last 5 years, and includes defined criteria for starting and stopping asfotase alfa treatment, and monitoring and data collection requirements:

  • A national committee made up of experts in hypophosphatasia, pain management and commissioning will discuss all decisions to start or stop asfotase alfa treatment within the managed access arrangement.

  • To be considered for asfotase alfa treatment, patients must agree to the terms of the arrangement (including attending regular follow-up clinics and inclusion in the data collection).

  • Starting criteria: All people with perinatal- and infantile-onset hypophosphatasia, regardless of current age, can start treatment with asfotase alfa. Asfotase alfa can be considered for children (aged 1–4 years and 5–18 years) with juvenile-onset disease if they do not reach motor milestones, have pain with significant disability or have restricted mobility. The drug can also be considered for adults (18 years and over) with juvenile-onset disease if they have 2 of the following: current fractures or a history of fractures characteristic of hypophosphatasia; persistent or recurrent pain with disability; and restriction of mobility.

  • Stopping criteria: Babies under 1 year with respiratory problems can continue treatment for the duration of the managed access arrangement unless they develop serious adverse events, other life-limiting conditions or remain ventilator dependent after 2 years. Children with juvenile-onset disease will stop treatment if 2 of the 3 stopping criteria are met: loss of height or growth impairment; no improvement in physical function or fall in mobility score; and no reduction in pain. Adults with juvenile-onset disease will stop treatment if 1 of the following criteria are met: no improvement in physical function or fall in mobility score; continued fractures over a 3‑year period; and no reduction in pain.

  • Monitoring and data collection: Data will be collected from everyone who has asfotase alfa within the managed access arrangement, and will be recorded in a dedicated database. The company stated that NHS England will have access to this database for audit and analysis of individual-level data, and will also be provided with relevant data extracts from the global hypophosphatasia registry database to assist in assessing asfotase alfa.

Value for money

4.19 The company submitted a Markov state transition model that compared asfotase alfa with best supportive care. The company's economic model 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). People who needed invasive ventilation moved to severity IV (that is, the most severe state). The company acknowledged that the 6MWT does not capture all the symptoms of hypophosphatasia (for example, craniosynostosis, severe pain, renal complications). However, the company stated that 6MWT distance was identified by its UK clinical experts as the outcome measure from its trials that most closely reflected the latent severity of disease. The company base-case analysis used a threshold of 17.8% to define a minimal clinically important difference between each severity level (that is, twice the minimal clinically important difference for the 6MWT distance in people with Duchenne muscular dystrophy, which the company stated provided the closest proxy available for people with paediatric-onset hypophosphatasia). The company used a 12‑week cycle length, and applied a half-cycle correction to the first and last cycles. The company did the economic analysis from an NHS perspective and chose a lifetime time horizon. Costs and health effects were discounted at an annual rate of 1.5% in the base case; a discounting rate of 3.5% per year was presented in scenario analyses.

4.20 Observations of the 6MWT were available from the trials for 28 people with either infantile- or juvenile-onset hypophosphatasia who had asfotase alfa and best supportive care (ENB‑006‑09, ENB‑008‑10 and ENB‑009‑10). The 28 people had at least 2 assessments of 6MWT distance, and their baseline age of hypophosphatasia onset ranged from 0 to 4.0 years (mean 1.3 years). For these 28 people, there were 250 observed transitions for people having asfotase alfa and 34 observed transitions for people having best supportive care. The company stated that between each 12‑week visit, the average distance walked:

  • improved by 11.6 m and 1.35 percentage points in per cent predicted in people having asfotase alfa and

  • decreased by 13.6 m and 3.91 percentage points in per cent predicted in people having best supportive care.

    Their baseline age at the first trial visit ranged from 5.9 years to 59.3 years (mean 26 years). To estimate the transition probabilities between each of the 6MWT severity levels in the economic model, the company used an ordered probit regression model that controlled for age and the days elapsed between healthcare visits. The distributions for the baseline level of severity were based on clinical trial data.

4.21 Hypophosphatasia-related deaths and invasive ventilation occurred in the company's model at the same time at which they were seen in the trials (ENB‑002‑08, ENB‑003‑08, ENB‑010‑10 and ENB‑011‑10). The company's base-case analysis used a mean starting age of 5.8 years (average age across the trials). Therefore, in the company's base case, there was no risk of hypophosphatasia-related deaths or invasive ventilation because none of these events were seen in the trials in people 5 years and over. The company explored different starting ages and levels of severity in scenario analyses.

4.22 Drug costs for asfotase alfa were based on its list price and the confidential commercial terms, using the recommended dosage in the summary of product characteristics. The company initially assumed that the list price for asfotase alfa reduced by 30% after 10 years because of a loss of data exclusivity (this assumption was removed in later analyses). The company took unit cost data for monitoring and managing hypophosphatasia from NHS reference costs 2013–14, the Personal Social Services Research Unit and the Royal Manchester Children's Hospital. Healthcare resource use estimates for managing each severity level were based on clinical expert opinion. Mean utility values included in the company's economic model were estimated by 9 clinical experts who completed the EQ‑5D‑5L for vignettes for each severity level state. Annual costs and utility values for each 6MWT state are presented in table 1. The company excluded costs and disutility values associated with adverse reactions because it considered that asfotase alfa was well tolerated and most adverse reactions were mild to moderate in severity.

Table 1 Summary of the company's costs and utility values for each health state

Health state

Annual cost

Utility value

Base case

Severity level I

£1,399

0.86

Severity level II

£3,976

0.67

Severity level III

£5,846

0.54

Severity level IV

£14,358

0.23

Scenario analysis (when starting age is below 5 years) 1

Invasive ventilation

£399,467

−0.33

1 No patients aged 5 years and over needed invasive ventilation in the asfotase alfa studies.

4.23 The company presented the results of its cost–consequence analysis for asfotase alfa compared with best supportive care. Total costs and incremental costs for asfotase alfa compared with best supportive care for all analyses are commercial in confidence so cannot be reported here. In the company's base case (discounting rate of 1.5%), asfotase alfa was estimated to produce an additional 25.04 quality-adjusted life years (QALYs) compared with best supportive care (37.53 total QALYs with asfotase alfa, 12.48 total QALYs with best supportive care). With a discounting rate of 3.5%, asfotase alfa was estimated to produce an additional 14.25 QALYs compared with best supportive care.

4.24 The company explored parameter and structural uncertainties in its economic model in a 1‑way sensitivity analysis, scenario analyses and a probabilistic sensitivity analysis. The 1‑way sensitivity analysis suggested that the results were most sensitive to the discounting rate used for costs and health effects, and changes to the utility values. In the probabilistic sensitivity analysis (based on 500 simulations), asfotase alfa treatment produced an additional 18.4 QALYs compared with best supportive care (compared with 25.04 QALYs in the corresponding deterministic analysis). Incremental costs are commercial in confidence and cannot be presented here.

4.25 The company presented results for subgroups based on the age at which treatment began, and for additional scenario analyses in which the population baseline characteristics (age and disease severity) were adjusted to match those of people for whom asfotase alfa would be considered under the proposed managed access arrangement. Incremental costs are commercial in confidence and cannot be presented here; incremental QALYs are shown in table 2. Adjusting the baseline characteristics to match the managed access arrangement population increased the expected QALY gain (compared with the base case). This reflected the expectation that the arrangement would identify the people with more severe hypophosphatasia who would therefore benefit more from treatment with asfotase alfa. The company stated that, in adults with juvenile-onset hypophosphatasia, the QALY gain with asfotase alfa decreased as the age at which treatment started increased.

Table 2 Results of the company's cost–consequence analysis with baseline characteristics adjusted to match the managed access arrangement population

Perinatal and infantile onset

Juvenile onset

0–4 years

5–11 years

12–17 years

18 years and over

Incremental QALYs

18.21

16.66

15.64

15.19

13.47

This analysis is based on a discounting rate of 3.5%. The company also presented results with a discounting rate of 1.5%; these results are not reproduced here.

Abbreviation: QALYs, quality-adjusted life years.

Cost to the NHS and personal social services

4.26 The company explained that limited information was available for estimating the prevalence and incidence of hypophosphatasia in England. With no national statistics available, the company used the incidence rates for paediatric-onset hypophosphatasia from a German study by Beck et al. (2003) and applied them to the population in England in its base-case budget impact model. Beck et al. estimated that the incidence of hypophosphatasia was 0.8 per 1,000,000 in children younger than 1 year and 2.8 per 1,000,000 in children younger than 18 years. To estimate the prevalent population in England in people 18 years and over, the company assumed a life expectancy of 81 years and applied the incidence for children younger than 18 years from Beck et al. Therefore, the company estimated that the numbers of people with paediatric-onset hypophosphatasia in England were 1.9, 149.4 and 553.5 in people aged 0‑1 year, 1–17 years, and 18 years and over respectively. The company considered that the rates of diagnosis of paediatric-onset hypophosphatasia would increase if asfotase alfa was used in the NHS, and that uptake of treatment would be higher in younger populations.

4.27 The company presented the results of a budget impact analysis over 5 years. It calculated the drug costs for asfotase alfa based on a weighted average for the weights and ages of patients taking part in the clinical trials. The company initially assumed an 80% rate of adherence, with a 100% rate of adherence explored in a scenario and subsequent analyses. The company estimated the number of people for whom treatment would be considered within the managed access arrangement, taking into account published data from the US (Whyte et al. 2015) and surveys of expert centres in the UK. The company subsequently submitted a revised budget impact model, using the latest available evidence on population size, taking into account additional patients identified during the consultation period and including the commercial terms agreed with NHS England. The results were presented for the whole population and broken down by age of disease onset. The estimated budget impact of asfotase alfa is commercial in confidence and cannot be reported here.

Evidence review group review

Clinical evidence

4.28 The ERG did not believe any relevant studies were missed by the company's searches.

4.29 The ERG stated that conclusions about the treatment effect may be confounded because some of the studies did not include a control group (limiting the robustness of the efficacy data). For the asfotase alfa prospective studies without a concurrent control group, and the ERG considered it reasonable to compare the asfotase alfa data with natural history data to provide a historical control group. However, the ERG considered that each of the comparative analyses was at high risk of bias in favour of asfotase alfa.

4.30 For the company's comparative analysis of overall survival in people with infantile-onset hypophosphatasia, the ERG noted that the results were biased in favour of asfotase alfa for 2 reasons:

  • Year of diagnosis: Despite no disease-modifying treatment, the company showed that the probability of survival for people with infantile-onset hypophosphatasia had improved over the years. Of the historical control group, 13 people were diagnosed before 1990, 14 between 1990 and 1999, and 21 after 2000. All 11 people having asfotase alfa were diagnosed after 2005.

  • Age at enrolment: The historical control group probably included more people younger than 1 month and younger than 1 week (people with hypophosphatasia younger than 1 month are at higher risk of death than older people) than the asfotase alfa group.

4.31 The ERG considered that the lower mean age and lower age of hypophosphatasia onset in the historical control group may bias the results of ENB‑006‑09 in favour of asfotase alfa. However, it considered that the patient populations were more comparable in this analysis than the populations included in the other 2 comparative analyses provided by the company.

4.32 The ERG agreed that people having asfotase alfa in the company's comparative analysis of people with juvenile-onset hypophosphatasia showed clear improvements in skeletal structure, growth and gait compared with the historical control and the pre-treatment group. The ERG commented that, without data for several important baseline characteristics, it was unclear whether the groups were comparable. Therefore, the precise benefit of asfotase alfa treatment was not clear.

4.33 The ERG stated that, although there is considerable follow-up in some of the asfotase alfa studies, it was only a fraction of the expected lifetime treatment as proposed by the company. The ERG explained that it cannot be expected that a treatment works equally well or even at all in all people, and stated that the effectiveness of treatment may diminish over time. The ERG concluded that the long-term efficacy and safety of asfotase alfa was uncertain, and that stopping rules for asfotase alfa should be considered given the many differences among people with paediatric-onset hypophosphatasia.

Value for money

4.34 The ERG emphasised that the 6MWT does not capture all of the symptoms of hypophosphatasia, nor does it capture all of the important domains of health-related quality of life as measured by the EQ‑5D, such as mental health and pain. The ERG considered that the company should have submitted separate models for people under 5 years and for people 5 years and over because the symptoms of hypophosphatasia and the effect of asfotase alfa are different in these populations.

4.35 The ERG noted that the company used an annual discounting rate of 1.5% in its base-case analyses, rather than the 3.5% rate specified in the reference case, and explored whether there were circumstances that might justify using this rate in this case. It described the evidence around whether asfotase alfa restored people who would have died or who would have had a very severely impaired life to full or near full health, and the long-term effects of treatment. The ERG acknowledged that the company's economic model indicated that more people would be in the least severe health states, but questioned the extent to which this could be considered 'full health' and whether the treatment effect would be maintained for their lifetime.

4.36 The ERG stated that the transition probabilities estimated by the company's probit model for best supportive care were associated with considerable uncertainty because of the very limited number of 6MWT observations for people having best supportive care. It noted that the company's chosen covariates in the probit model (age, time since previous visit) may not fully reflect the disease severity progression. Therefore, the ERG considered it would have been more appropriate for the company to estimate the transition probabilities with a single probit model controlled for treatment effect rather than with separate probit models for the asfotase alfa and best supportive care groups. The ERG was further concerned that the company's chosen transition probabilities were from a population of people 5 years and over, and that the transition probabilities for younger patients relied on backwards extrapolation, which was not validated (particularly because credible reference 6MWT distances are not available for people younger than 3 years).

4.37 The ERG noted that it was not clear how the baseline age and severity levels in the base case were derived or whether they reflected a UK paediatric-onset hypophosphatasia population.

4.38 The ERG noted that the company's unadjusted approach for estimating survival and the need for invasive ventilation in the economic model may have been biased:

  • The historical controls included people from the time of diagnosis, whereas clinical studies can only include people who survive to study enrolment.

  • There were differences in the year of diagnosis.

  • The survival curves were estimated from birth rather than from the start of treatment.

    The ERG highlighted that the survival analyses provided by the company in response to a request for clarification showed that the company's method of estimating survival in the economic model was potentially biased. The ERG concluded that the company should have attempted to match the populations between asfotase alfa and best supportive care and taken into account the age at enrolment and year of disease when estimating survival in its economic model.

4.39 The ERG highlighted the company's assumption of a reduced price for asfotase alfa after 10 years because of a loss of data exclusivity (in the company's initial analysis), and presented exploratory analyses in which this price reduction was removed. The ERG also queried whether the size of the reduction was not reasonably justified by the company. This assumption was removed in the company's later analyses. The ERG noted that the company did not include costs associated with personal social services.

4.40 The ERG felt that it was a limitation that utility values were from clinical experts rather than from the clinical studies. It noted that the face validity of the utility values obtained by the experts for each of the health states seemed quite reasonable. However, the company's vignettes assumed strong correlation among all dimensions of health, which may lead to underestimation of the true variation in health-related quality of life within each health state.

4.41 The ERG presented the results of an exploratory analysis that:

  • estimated the transition probabilities using a single probit model for both asfotase alfa and best supportive care, and controlled for treatment effect (see section 4.35)

  • estimated the survival and need for invasive ventilation in a matched population using a parametric model (the ERG explored 6 distributions and selected the Gompertz distribution as the best fit based on tests of internal and external validity)

  • only used historical control survival data from people who were diagnosed after 2000

  • excluded the price reduction for asfotase alfa after 10 years

  • discounted the costs and health effects at an annual rate of 3.5%.

    This analysis did not include adjustment of the baseline characteristics to match the managed access arrangement population. Total costs and incremental costs for all analyses are commercial in confidence so cannot be reported here. The ERG estimated that asfotase alfa would produce an additional 14.13 QALYs compared with best supportive care (21.59 total QALYs with asfotase alfa, 7.46 total QALYs with best supportive care). The ERG also presented the results of this analysis in subgroups based on the age at which treatment began (table 3).

Table 3 Results of the ERG's exploratory cost–consequence analysis grouped by the age at which treatment began

Company base case (3.5% discounting rate; see section 4.23 )

ERG exploratory analysis

Overall population

Perinatal and infantile onset

Juvenile onset

0–4 years

5–11 years

12–17 years

≥18 years

Incremental QALYs

14.25

14.13

15.6

14.7

14.2

14.1

9.8

Note: This analysis is based on the original population baseline characteristics – that is, the baseline characteristics have not been adjusted to match the managed access arrangement population.

Abbreviation: ERG, evidence review group; QALYs, quality-adjusted life years.

4.42 The ERG did an additional exploratory analysis for younger people with paediatric-onset hypophosphatasia (starting age of 0). For this analysis, the ERG developed a new model structure with 2 health states: alive and dead. Patients who were alive could also have invasive ventilation. The ERG considered that an alternative model structure was appropriate given the differences in the symptoms of hypophosphatasia and the effect of asfotase alfa for this population compared with the company's base-case population (mean age of 5.8 years). The ERG stated this was supported by the differences between rates for mortality and the need for invasive ventilation. This ERG exploratory model included people from birth and used a time horizon of about 5 years. Total costs and incremental costs for asfotase alfa compared with best supportive care for all analyses are commercial in confidence so cannot be reported here. At a discounting rate of 3.5%, the ERG estimated that asfotase alfa was estimated to produce an additional 0.91 QALYs compared with best supportive care for younger people over the 5‑year time horizon (2.46 total QALYs with asfotase alfa, 1.55 total QALYs with best supportive care). When combining this with the ERG's estimate of cost and consequences beyond 5 years (obtained by applying the ERG's preferred model assumptions to the company model), the ERG estimated a lifetime QALY gain of 13.92 when treating hypophosphatasia in people from birth. The ERG emphasised that its exploratory model for younger people was simple and based on the little evidence available. Therefore, the ERG stated that the results should be interpreted with caution.

Cost to NHS and personal social services

4.43 The ERG noted that several of the parameters used in the company's budget impact analysis were the same as those in the cost–consequence model, and that the same limitations would apply to both. However, it noted that the assumptions such as the discounting rate and drop in asfotase alfa price after 10 years were not relevant in the context of the 5‑year budget impact analysis. The ERG considered the assumptions made by the company in the initial budget impact analysis to be reasonable.

4.44 Full details of all the evidence are in the submissions received for this evaluation, and in the ERG report, which are all available in the committee papers.

  • National Institute for Health and Care Excellence (NICE)