The Evaluation Committee (section 9 considered evidence submitted by the company who owns eculizumab, a review of the company's submission by the Evidence Review Group (ERG; section 10) and evidence submitted by clinical and patient experts and NHS England.
4.1 Evidence submitted by patient experts included a survey that was conducted in 2013 with the intention of better understanding the impact of atypical haemolytic uraemic syndrome (aHUS) on patients and their families. The survey was completed by 37 patients and highlighted that:
aHUS has a substantial impact on patients' productivity and may impact on patients' education.
aHUS may have a substantial impact on patients' day‑to‑day activities and participation in leisure activities.
Some patients (and their families) have to move house so that they can live closer to a specialist centre or are closer to a carer.
Patients may need up to 4 hours of travel time each week for hospital visits or medical appointments related to the management of their condition. When the patient is a child, a parent or carer usually must provide transportation and accompany them, adding to the burden.
Patients may need both formal and informal care. The average time a carer spends looking after a patient with aHUS is 44 hours per week.
aHUS can cause financial problems for patients and their families. Often parents of a patient with aHUS, or other family members, have to stop working to be able to provide care.
4.2 Evidence from patient and clinical experts highlighted that patients with aHUS have a greatly impaired quality of life, from both the frequent and severe symptoms they experience and the burden of treatment with dialysis and plasma therapy. Families and carers of patients with aHUS also experience substantial burden, and often have to reduce their work or daily activities to provide the necessary care.
4.3 The key clinical evidence came from 2 published (C08‑002A/B and C08‑003A/B) and 2 unpublished (interim data from C10‑003 and C10‑004) prospective studies, and 1 retrospective observational study (C09‑001r). No randomised controlled trials were identified. All prospective studies were phase 2, open‑label, non‑randomised, single‑arm studies that included patients with different clinical baseline characteristics. The prospective studies lasted 26 weeks; however, patients were allowed to continue treatment with eculizumab in a long‑term extension study.
4.4 Study C08‑002A/B included adolescent and adult patients (n=17) in the early phase of aHUS (median time from diagnosis to screening was 9.7 months) who were resistant to plasma therapy (that is, with evidence of progressive thrombotic microangiopathy after 4 or more sessions of plasma therapy in the week before starting the study treatment) and impaired kidney function. Before starting treatment with eculizumab, 94% (n=16) of patients had plasma therapy and 29% (n=5) were on dialysis. The primary endpoint of the study was reduction in thrombotic microangiopathy activity (measured by change in platelet count from baseline).
4.5 Study C08‑003A/B included adolescent and adult patients (n=20) with longer‑term aHUS (median time from diagnosis to screening was 48 months) who had chronic renal impairment without evidence of clinical thrombotic microangiopathy and who were having plasma therapy for a median of 10 months before study entry (that is, they were sensitive to plasma therapy). All patients had plasma therapy and 10% of patients (n=2) were on dialysis before they were given eculizumab. The primary endpoint of the study was reduction in thrombotic microangiopathy activity measured by thrombotic microangiopathy activity event‑free status (defined as no more than a 25% decrease in platelet count and no plasma therapy or new dialysis for at least 12 consecutive weeks).
4.6 Study C10‑003 included patients aged 1 month to 17 years (n=22) with aHUS who had thrombocytopenia, haemolysis and elevated serum creatinine. Patients who had had plasma therapy more than 5 weeks before enrolment or who were on chronic dialysis were excluded. Before having eculizumab, 45% (n=10) of patients had had plasma therapy and 50% (n=11) were on dialysis. The primary endpoint of the study was complete thrombotic microangiopathy activity response (determined by haematological normalisation and at least a 25% improvement in serum creatinine from baseline) confirmed by 2 consecutive measurements taken at least 4 weeks apart.
4.7 Study C10‑004 included adults (n=41) with aHUS who had thrombocytopenia, haemolysis and elevated serum creatinine. There was no requirement for plasma therapy or dialysis before starting eculizumab therapy. Patients on chronic dialysis were excluded from the study. Before having eculizumab, 85% (n=35) of patients had had plasma therapy and 59% (n=24) were on dialysis. The primary endpoint of the study was thrombotic microangiopathy activity response (determined by haematological normalisation and less than 25% worsening in serum creatinine from baseline) confirmed by 2 consecutive measurements taken at least 4 weeks apart.
4.8 Study C09‑001r was a retrospective chart review of 30 patients, including infants, children, adolescents and adults (median age 12 years [0.17–51.40 years]), who had been diagnosed with aHUS and had had at least 1 dose of eculizumab between 2007 and 2009, outside any company‑sponsored study. Before having eculizumab, 80% of patients (n=24) had had plasma therapy and 37% (n=11) were on dialysis.
4.9 Two ongoing observational studies were also identified: C11‑003, a follow‑up study designed to assess the long‑term efficacy of eculizumab in patients with aHUS who had previously been in an eculizumab study; and M11‑001, a global aHUS registry initiated in April 2012 to prospectively collect data every 6 months from patients with aHUS, regardless of treatment. Limited information from the ongoing studies was provided.
4.10 Efficacy and safety data for eculizumab are limited for patients under 18 years. Results from the prospective studies showed that, compared with baseline, treatment with eculizumab improved systemic thrombotic microangiopathy activity and led to clinically significant improvements in kidney function and gains in quality of life by 26 weeks. Further results from extension studies (median 114 weeks in C08‑002A/B and C08‑003A/B) showed that the benefits of eculizumab were sustained.
4.11 In C08‑002A/B, dialysis was stopped in 80% (n=4) of patients who had needed dialysis at the time of starting eculizumab, and these patients remained free from dialysis throughout eculizumab treatment. Similar results were seen in C10‑003 and C10‑004, with 82% (n=9/11) and 83% (n=20/24) of patients respectively who were on dialysis at baseline no longer needing dialysis during eculizumab treatment.
4.12 In the retrospective C09‑001r study, improvements were seen in all measured endpoints by 26 weeks. A subgroup analysis of 19 paediatric patients (under 2 years [n=5]; 2–11 years [n=10]; 12–17 years [n=4]) in the study showed that treatment with eculizumab reduced thrombotic microangiopathy activity (as demonstrated by platelet count normalisation) in 89% (n=17) of paediatric patients. In 47% (n=9) of paediatric patients, kidney function improved, and 50% (n=4) of paediatric patients who previously needed dialysis were able to stop dialysis during treatment with eculizumab. Thrombotic microangiopathy activity event‑free status (defined as no plasma therapy, no new dialysis and no more than a 25% decrease in platelet count from baseline for 12 weeks or more) was seen in 68% (n=13) of paediatric patients. Efficacy outcomes were similar in another subgroup analysis of 15 paediatric patients aged under12 years: kidney function improved in 53% (n=8) of patients and thrombotic microangiopathy activity event‑free status was seen in 73% (n=11) of patients.
4.13 Most patients reported at least 1 adverse reaction in studies C08‑002A/B (n=17) and C08‑003A/B (n=20), but only 43% (16/37) of these patients had an adverse reaction that was considered by study investigators to be related to the use of eculizumab. Leukopenia, nausea, vomiting and accelerated hypertension were the most common treatment‑related adverse reactions in study C08‑002A/B, whereas headache, leukopenia and lymphoma were the most commonly reported reactions in study C08‑003A/B. No deaths were reported in the 26‑week study period in either study. Additional data from the extension study period (a 2‑year data update) provided a similar adverse events profile. One death, which was not considered by the study investigators to be related to eculizumab use, was reported in the extension period.
4.14 Limited safety information from the unpublished prospective studies (C10‑003 and C10‑004) is available; however, no deaths were reported in either study. In the retrospective C09‑001r study, 73% (n=22) of patients reported at least 1 adverse reaction. Two (7%) deaths (due to a cerebrovascular accident and a fatal carotid artery dissection), which were considered to be unrelated to eculizumab, were reported.
4.15 Five patients stopped eculizumab therapy in the C08‑002A/B (n=4) and C08‑003A/B (n=1) studies (1 because of an exclusion criterion, 1 because of an adverse event unrelated to eculizumab treatment and 3 because they chose not to continue treatment with eculizumab after completing the 26‑week treatment period). Thirteen patients stopped treatment in the retrospective C09‑001r study. After stopping eculizumab, there were 7 severe thrombotic microangiopathy activity complications reported, including graft failure needing haemodialysis, renal insufficiency, end‑stage renal failure and respiratory distress needing intubation. No patients in the prospective studies developed neutralising antibodies to eculizumab. There were no reported meningococcal infections in the C08‑002A/B and C08‑003A/B studies. One meningococcal infection was reported in C09‑001r after the data cut‑off point, and it was noted that the patient fully recovered without sequelae and remained on eculizumab.
4.16 Five registry sources for patients with aHUS having standard care (plasma therapy or transplantation) were identified. Two of the registries (Fremeaux‑Bacchi 2013 and Norris 2010) included patients with a confirmed clinical diagnosis of aHUS. Results from these 2 registries showed that 45% of patients had end‑stage renal failure at 3 years, and the average length of survival was estimated to be between 3 (Norris) and 5 (Fremeaux‑Bacchi) years. Comparison between the registries at individual time points was not possible because the times selected for analysis differed between the registries.
4.17 At the Committee meeting, a clinical expert highlighted an Italian study (Ardissino et al. 2014), which included a cohort of 10 patients with aHUS. In this study, disease relapsed in 3 patients after stopping eculizumab; all had identifiable genetic mutations that would preclude stopping eculizumab under current national practice. Patients were closely monitored using home urine tests so that recurrence could be identified early and eculizumab reintroduced immediately if needed, allowing renal function to return to the level it was before treatment was stopped.
4.18 The company developed a de novo cost–consequence model that used a Markov structure to estimate the costs and consequences for a population of 28‑year‑olds over a lifetime horizon, discounted at a rate of 1.5%. The model simulated the experience of patients with aHUS having eculizumab or standard care in terms of progression of kidney damage (defined as severity of chronic kidney disease) and its impact in terms of costs, health‑related quality of life and survival. Five mutually exclusive health states were included in the model: 3 health states reflected the patient's level of kidney function (based on the National Kidney Foundation Outcomes Quality Initiative, determined by estimated glomerular filtration rate and the level of kidney damage); 1 was a temporary health state for patients who had had a kidney transplant; and 1 was for death. The transition probabilities between the 3 chronic kidney disease health states were taken from the C08‑002A/B and C08‑003A/B prospective studies for the eculizumab group, and from a retrospective analysis of available pre‑treatment data for the standard care group. Results from the other available studies were not used to inform the model parameters. Additional transition probabilities for the transplant health state and for mortality risks were taken from the wider literature. For the eculizumab group, transitions to better or worse health states were possible in any model cycle. In the standard care group, only transitions to worse health states were possible, except when transplantation was assumed to be successful. Transitions to the transplant health state were assumed to apply only to the standard care group. Costs of treatment, including administration costs, were estimated from standard sources.
4.19 Health utility values were estimated from EQ‑5D data collected within the C08‑002A/B and C08‑003A/B studies from 37 patients. The weighted improvement in mean utility score from baseline to week 64 across both studies was 0.208. This value was applied as a disutility to all chronic kidney disease health states in the standard care group (to characterise the difference between health‑related quality of life for patients having standard care and for those having eculizumab).
4.20 At a discount rate of 1.5%, eculizumab was estimated to produce 24.08 additional years of life and 25.22 additional quality‑adjusted life years (QALYs) per patient compared with standard care. The discounted incremental cost of eculizumab compared with standard care presented in their evidence submission has been designated confidential by the company because they consider this information relates to their commercial interests. The company also conducted a probabilistic sensitivity analysis that showed that eculizumab is consistently expected to produce large incremental QALY gains and higher incremental costs compared with standard care. Other sensitivity analyses from the company showed that the estimates of incremental health benefit and incremental cost are particularly sensitive to assumptions about a patient's age at the start of eculizumab treatment and the use of discounting in the model.
4.21 The company also developed a budget impact model to estimate the total costs to the NHS of the assumed uptake of eculizumab in England from 2013 to 2017. The company designated all results from their analysis as confidential because they consider these relate to their commercial interests. The company's model predicted a steady increase in the number of patients in England who would be treated with eculizumab for the treatment of aHUS over the 5‑year period (specific patient numbers by year are confidential). The company considered that its budget impact of eculizumab was likely to be overestimated because the budget impact of health utility improvements was excluded from the analysis. In addition, indirect costs (which the company considered would be reduced by eculizumab) were also not included.
4.22 To estimate the impact of eculizumab beyond direct health benefits the company used: lost productivity and government benefits and tax revenues for patients and carers; and cost savings associated with personal expenses for patients and carers, such as transportation and housing, and other carer costs.
4.23 The ERG reviewed the company's submission. It considered that the company had included all relevant studies in its evidence submission. The ERG expressed some concern about several limitations and uncertainties in the evidence base and, in particular, considered that the optimal dose and duration of treatment with eculizumab was unclear. While the summary of product characteristics recommends lifelong treatment with eculizumab unless stopping treatment is clinically indicated, evidence‑submissions from patient organisations noted the need for well‑controlled prospective studies to define the optimal length of treatment for eculizumab and to determine whether all patients need to continue long‑term therapy.
4.24 To explore the suitability and robustness of the company's model, the ERG made amendments and conducted exploratory analyses to assess the impact of different assumptions. Most assumptions made by the company were retained within the ERG's exploratory analysis; however, the prognosis of standard care was estimated using published aHUS registry data, rather than pre‑treatment data from the C08‑002A/B and C08‑003A/B studies. The changes made by the ERG resulted in a better prognosis for patients having standard care compared with the predictions of the company's model.
4.25 Results from the ERG's exploratory analyses suggested that, at a discount rate of 3.5%, eculizumab is expected to produce 10.14 additional QALYs compared with standard care. Incremental costs from the analysis were higher than those estimated in the company's analysis, and are designated confidential by the company. The ERG highlighted that the estimates of overall survival for the standard care group were considerably higher in the ERG's exploratory analysis (ERG's exploratory analysis, 35.47 undiscounted life years; company's model, 9.97 undiscounted life years). These differences in survival, together with different transition probabilities assumed for the chronic kidney disease states and lower transplant rates assumed for the standard care patients, led to lower estimates of incremental QALYs gained between the treatment groups within the ERG's exploratory analysis.
4.26 The ERG considered that the estimates for uptake of eculizumab in the company's budget impact analysis were low. It presented results from a range of uptakes up to 100%. Results from the analysis are designated confidential by the company.
4.27 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.