Eculizumab for treating atypical haemolytic uraemic syndrome

The Committee heard from the clinical experts that aHUS is a heterogeneous disease, with a wide variation in its natural history and in how it responds to treatment. It noted that aHUS is very rare; 20–30 new patients are diagnosed with the condition each year in England. The Committee considered the findings from the survey submitted by the patient experts and agreed that patients with aHUS have a greatly impaired quality of life, from both the severe symptoms they experience and the burden of treatment with dialysis and plasma therapy, and that the families and carers of patients with aHUS also experience substantial burden.

The Committee acknowledged that, until eculizumab became available and the NHS England clinical commissioning policy was developed, plasma therapy and dialysis were the main treatment options for aHUS, both of which had limited impact on disease morbidity and mortality but a substantial negative effect on a patient's quality of life. The Committee heard from the patient experts that the impact of eculizumab is influenced by the severity of the disease and the stage of life when a patient becomes affected. For patients with aHUS who have kidney failure, eculizumab offers them the potential for a kidney transplant and an opportunity to restore their health and have a life free from the restrictions of dialysis and the need for frequent plasma therapy. For patients with active disease, eculizumab offers them the possibility of avoiding end‑stage renal failure, dialysis and kidney transplantation, as well as other organ damage. It also offers patients the chance to have restored kidney function or retain their residual kidney function without the need for further dialysis treatment. The Committee heard from the clinical experts that they considered eculizumab to be a step change in the management of aHUS, and the Committee agreed with this.

The Committee considered the clinical‑effectiveness evidence for eculizumab presented by the company. It acknowledged that there were limitations in the evidence base, particularly the lack of randomised trial evidence. However, it noted that, in all of the studies, treatment with eculizumab led to substantial decreases in thrombotic microangiopathy activity, and an improvement in kidney function and quality of life in most patients. The Committee heard from the clinical experts that, since they began prescribing eculizumab, the benefits seen in their patients have been greater than they had originally anticipated. They remarked that many patients were able to stop dialysis after starting treatment with eculizumab, and that there were also non‑renal benefits such as improvements in gastrointestinal symptoms. The Committee noted the comments from the Evidence Review Group (ERG) and the patient experts that long‑term data on the optimal dose and duration of treatment with eculizumab are lacking. It acknowledged that, although there are ongoing studies that will capture longer‑term data, this information will not be available for some time. The Committee also heard from the clinical experts that an international aHUS registry has been established by the company as a commitment towards ensuring that long‑term data are collected for all patients with aHUS. The Committee also acknowledged that there are limited data available on the effectiveness of eculizumab in children and adolescents, but concluded that there was no reason to expect a different effect in this group compared with the adult population. Overall, the Committee concluded that eculizumab is a very effective treatment option for patients with aHUS.

The Committee heard that current use of eculizumab is being continually reviewed, with the aim of achieving optimal dosing and treatment duration for each patient. The Committee noted from the evidence submitted by clinical experts that very specific criteria are followed when starting treatment with eculizumab, and circumstances in which eculizumab treatment should be stopped have been defined. The Committee heard from the clinical experts that all patients have treatment with eculizumab for the first 8 weeks until results of their genetic tests are available. Treatment is then adjusted or stopped based on the test results. After consultation, the company stated that there is currently no robust evidence available to support dose adjustment or stopping treatment, and that considerable negative health outcomes may occur, such as recurrence of thrombotic microangiopathy, if treatment with eculizumab is stopped. The Committee acknowledged that the summary of product characteristics for eculizumab states that 'treatment is recommended to continue for the patient's lifetime, unless the discontinuation of eculizumab is clinically indicated'. However, the Committee noted comments from a professional organisation that there is no scientific or ethical imperative to continue lifelong treatment in all patients. The Committee heard from the clinical experts that there are clinical indications for which long‑term treatment with eculizumab may not be considered necessary, for example, in patients whose disease has responded to eculizumab and in whom renal function has returned to normal. The clinical experts also stated that restarting treatment with eculizumab has been successful in restoring renal function in patients whose disease has recurred. However, the company stated that rescue therapy could not be relied on. The Committee queried whether more up‑to‑date evidence on stopping treatment had become available since the marketing authorisation was granted. The company stated that, as part of its international aHUS registry, there is evidence that stopping and restarting treatment resulted in poor patient outcomes. The Committee heard from a clinical expert that the evidence is evolving and that, so far, the largest study investigating stopping treatment has been the study by 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. The company emphasised that the decision to stop treatment should lie with clinicians. The clinical experts reassured the Committee that, in clinical practice, this was explored on a case‑by‑case basis using clinical judgement. The Committee considered that this was not contrary to the specifications in the summary of products characteristics of eculizumab for aHUS, and was also supported by accumulation of experience in clinical practice. The clinical experts also emphasised that there was considerable enthusiasm in UK clinical practice to explore dose adjustment and the option of stopping eculizumab early. Comments received during consultation also supported this. The Committee considered that, with any treatment, the evidence base inevitably improves as clinical experience accumulates, and that this is particularly relevant in the context of highly specialised technologies for treating very rare lifelong conditions. The Committee concluded that there is a need to further investigate possible dose adjustment and the option of stopping treatment when clinicians consider it appropriate.

The Committee understood that patients welcome treatment with eculizumab because it gives them the opportunity to return to a life free from the disease (see section 5.2). However, the Committee noted that treatment with eculizumab involves repeated treatment infusions, which is burdensome for patients. It therefore considered that the opportunity to stop treatment, if clinically appropriate, would be far less burdensome for patients particularly because some types of monitoring, such as simple urine tests, can be self‑administered at home. The Committee noted comments from patient organisations pointing out that it is very important to reassure patients they will be able to restart treatment with eculizumab if clinically indicated. The Committee heard from a clinical expert that stopping eculizumab treatment involves strict monitoring for early signs of disease relapse so that eculizumab can be suitably reintroduced. The Committee also noted that, in response to consultation, patient organisations expressed their support for conducting research to improve the understanding of the underlying risks of aHUS, so that treatment can be managed with the increased chance of a safe outcome. The Committee confirmed that its recommendations did not imply that patients should be taken off treatment against clinical judgement. Instead, its recommendations encouraged exploring the possibility of stopping treatment with eculizumab in a structured manner when clinicians consider it appropriate, so that approaches in clinical practice could be coordinated and underpinned by research. The Committee restated the importance of investigating this under a research programme with robust methodology.

The Committee considered the adverse reactions associated with treatment with eculizumab. It noted from the clinical trials that eculizumab was generally well tolerated and, although most patients reported adverse reactions, only a few were considered to be specifically related to eculizumab use. The Committee also recognised that eculizumab is associated with an increased risk of meningococcal infection. The Committee understood that regulatory requirements around the risks associated with eculizumab are outlined in the summary of products characteristics and the European public assessment report for eculizumab.

The Committee noted advice from NICE to its advisory bodies that states that, in cases when treatment restores people who would otherwise die or have a very severely impaired life to full or near‑full health, and when this is sustained over a very long period (normally at least 30 years), a discount rate of 1.5% for costs and benefits may be considered. This advice can only be implemented if it is highly likely that, on the basis of the evidence presented, the long‑term health benefits are likely to be achieved. Having referred to this advice, the Committee considered that substantial restoration of health for a very long period is achieved with ongoing treatment with eculizumab. The Committee heard from the clinical experts that the underlying complement disorder is essentially reversed with eculizumab treatment and that there is emerging evidence that benefits are sustained over time. The Committee concluded that there was a case for applying a discount rate of 1.5%.

The Committee considered the budget impact analysis submitted by the company, as well as the exploratory analyses by the ERG. All assumptions and results in these analyses are deemed commercial in confidence by the company. Despite multiple requests from NICE, the company refused to make this information publically available, including the likely proportion of patients with aHUS that will be children. To allow consultees and commentators to properly engage in the consultation process, the Institute prepared an illustration of the possible budget impact of eculizumab for aHUS, using information available in the public domain. This was based on a treatment cost of £340,200 per adult patient in the first year (based on the acquisition cost of the drug and the recommended dosing for an adult), and assumed a patient cohort of 170, as estimated by NHS England in its interim commissioning policy. If it is assumed that all of these adult patients with aHUS are treated with eculizumab, the budget impact for the first year would be £57.8 million. If an additional 20 new patients are treated the following year (based on a worldwide incidence of 0.4 million; see section 2.2), the budget impact would rise to £62.5 million in year 2, assuming all new patients are treated and all existing patients continue to be treated at the maintenance cost of £327,600 per year. Using the same assumptions, the budget impact would rise to £69 million in year 3 (190 existing and 20 new patients), £75 million in year 4 (210 existing and 20 new patients) and £82 million in year 5 (230 existing and 20 new patients). After consultation on the evaluation consultation document, the company stated that this budget analysis was flawed and overestimated the budget impact of eculizumab for treating aHUS. The Committee understood that an estimate based on publically available sources was necessary because of the large amount of data the company had marked as confidential. The Committee was clear that this analysis was not the sole basis for its decision‑making and was only used to illustrate the potential upper range of the budget impact.

The company's budget impact analysis, which at the moment is confidential and cannot be shared beyond those stakeholders who have signed a confidentiality agreement, was based on different assumptions for uptake and also included both paediatric and adult patients. The Committee heard from the clinical experts that, if eculizumab is recommended for use in line with its marketing authorisation, uptake is likely to be higher than the company's estimates. In addition, considering the substantial health gains associated with eculizumab treatment compared with standard care, the Committee considered that the company's analyses may have underestimated the true rate of uptake of eculizumab. The Committee also noted that, after consultation, a patient organisation provided alternative estimates of the possible budget impact of eculizumab for aHUS. It assumed a patient cohort of 111 in the base case, of which 74 patients were assumed to need a 1200 mg dose and 37 to need a 600 mg dose of eculizumab. The budget impact for the first year was estimated to be £36 million. If it was assumed that an additional 25 new patients would be treated in the following year, the budget impact was estimated to rise to £45 million in year 2 and up to £68 million in year 5. The Committee considered that uncertainty remained about the number of patients who would be considered for treatment with eculizumab for aHUS. However, it heard from a clinical expert that 56 people currently have eculizumab for aHUS as part of the NHS England interim commissioning policy, and understood that taking this number into account would lower the estimates provided by the patient organisation. After consultation on the second evaluation consultation document, the patient organisation stated that, taking into account the actual number of people having eculizumab, their estimation for year 5 would be £30 million lower. The clinical expert also advised the Committee that the incidence of new cases was possibly greater than previously thought. The Committee considered that there was uncertainty around the range of budget impact estimates it had been presented with, and acknowledged that the Institute's illustration represented the upper end of the impact on the budget for highly specialised services. The Committee concluded that, taking into account all the evidence, including the various budget impact analyses presented and the estimates of the size of the population, the budget impact of eculizumab for aHUS was very high and likely to increase with the onset of new cases.

The Committee was made aware of the annual costs of a range of other treatments that are available through nationally commissioned specialised and highly specialised services. However; it was not provided with information that explains the difference between the costs of developing and manufacturing eculizumab for aHUS and those costs for other treatments. The Committee noted that the company had no plans for further clinical studies into the use of eculizumab for the treatment of aHUS. The Committee heard from the company that the cost per patient of treatments for very rare diseases are high because there are only a small number of patients from whom to recover the research, development and manufacturing costs. However, the Committee noted that eculizumab is also licensed for the treatment of paroxysmal nocturnal haemoglobinuria. The size of the combined population is an important consideration in helping to understand the price being asked for a drug for its second and subsequent indications. The Committee concluded that it had not been presented with sufficient justification for the high cost per patient of eculizumab in light of the manufacturing, research and development costs of a medicinal product for the treatment of a very rare condition. It asked the company to provide additional information on the following matters:

• whether there were any clinical or safety requirements during clinical development that might justify the development cost of eculizumab being materially greater than for other treatments for small populations

• the post‑marketing research plans, and their costs, for eculizumab for the treatment of aHUS and for other indications

• an explanation of the relationship between the development costs of eculizumab and the price being proposed for the NHS

• any additional information that the company considers will help the Committee reach a conclusion on whether the incremental therapeutic improvement over standard therapy justifies the proposed cost of eculizumab.

The Committee noted the response from the company stating that research and development costs only explain a small proportion of the cost variance between highly specialised technologies and technologies for treating conditions that affect larger populations. The company stated that, because of a very small number of patients, there is a higher level of financial risk involved in entering the market for very rare diseases, and that there is a need to set up several sites to recruit patients into clinical trials, invest in clinical and patient education, and reinvest resources for new indications. The company also stated that there is a higher risk of failure associated with discovering new treatments for very rare diseases. However, the Committee noted that the company's justification of costs were not exclusive to eculizumab and would apply to all highly specialised technologies for very rare diseases. The Committee also took into account the annual number of patients (adults and children) treated with each of the highly specialised technologies and noted that the number of people treated with eculizumab for aHUS did not represent the smallest patient population compared with other highly specialised technologies. Therefore, the Committee concluded that it had not been presented with a justification of why the overall cost of eculizumab was materially higher than the overall cost of other highly specialised technologies. The company emphasised that the Committee should consider the differential value and benefit from the technology combined with the limited size of the treated population. The Committee stated that the value of eculizumab had been recognised (see sections 5.2 and 5.3), but that this would need to be discussed in the context of the substantial impact eculizumab was expected to have on the budget for highly specialised services.

The Committee noted that the company also included information on the annual treatment cost per patient of different specialised technologies. The Committee noted that, in this analysis, the annual cost per patient was estimated based on an average weight of 75 kg for adults across conditions. The company highlighted that, based on this analysis, eculizumab was not the most expensive highly specialised technology. However, the Committee heard from a clinical expert and the NHS England representative that the assumption of an average weight of 75 kg for adults in calculating per patient cost for the different drugs was unrealistic because the average weight of adults with most of these conditions was considerably less. Moreover, the average weight varies across conditions. The Committee noted comments from the company stating that there is no evidence on the age‑related weight of patients with very rare diseases. The company also stated that the cost difference seen in the analysis for 2 other highly specialised technologies, idursulfase and galsulfase, was twice that of eculizumab in adults. The company stated that eculizumab would only be more expensive than these 2 technologies if adults having these drugs weighed less than half of patients with aHUS, which in the opinion of the company's clinical experts was unlikely. However, based on clinical advice, the Committee considered that it was likely that adults with conditions such as Hunter syndrome, associated with a distinctly smaller stature, would weigh significantly less than adults with aHUS. The Committee heard from the clinical experts that, if the annual treatment cost per patient for adults was adjusted by the average weight of patients for the different indications, eculizumab would be the most expensive treatment. The Committee concluded that the annual cost of eculizumab per patient was considerably higher than the annual cost per patient of other highly specialised technologies for very rare diseases.

The Committee discussed the results of the company's cost–consequence model and the assumptions on which they were based. It heard from the company that they aspired to develop a simple, transparent model informed by the available clinical evidence, and that they considered that their model underestimated the value of eculizumab because they were unable to include the effects of eculizumab on non‑renal health states because of the lack of data. The Committee noted that the company assumed a higher health utility in patients having eculizumab to compensate for this and agreed that, even with this, its model was likely to be conservative.

The Committee discussed whether the assessment of the change in health‑related quality of life had been adequately captured. It heard from the clinical and patient experts that people who had eculizumab could lead an active and fulfilling life and were able to contribute much more to society. The Committee accepted that eculizumab is a step change in the management of aHUS and could be considered a significant innovation for a disease with a high unmet clinical need. The Committee acknowledged that the company had attempted to capture the benefits of treatment on extra‑renal manifestations in the higher utility value assigned to the health states for those having eculizumab compared with standard care. Even with this, the Committee felt that it was likely that other benefits of a substantial nature had not been adequately captured in the model, and therefore may have led to the underestimation of the overall effectiveness of eculizumab.

The Committee noted the concerns of the ERG about uncertainties in the company's model and considered the exploratory analyses conducted by the ERG. The Committee was aware that the company considered the ERG's modifications to their model to be unreliable. The Committee noted that, although the incremental quality‑adjusted life years (QALYs) estimated in the ERG's analysis were markedly lower than those calculated by the company (10.14 QALYs compared with 25.22 QALYs), both analyses produced substantial QALY gains of a magnitude rarely seen for a new drug treatment. The Committee noted that the company's estimate of the incremental cost of eculizumab compared with standard care was considerable, and that incremental costs estimated by the ERG were even higher (results are designated confidential by the company). The Committee also noted that in the analysis presented by the company in response to the evaluation consultation document, comparing eculizumab with other highly specialised technologies, the company highlighted that eculizumab was associated with the highest QALY gain. The Committee noted that, while there is no specific budget for the provision of highly specialised services in the NHS in England, the resources available for commissioning such services are not unlimited and therefore it remained uncertain on whether the results of the cost–consequence analysis demonstrated good value for money. The Committee therefore sought further information from NHS England on what considerations relating to the management of its specialised commissioning budget it considers should be taken into account when determining a reasonable overall treatment cost for eculizumab. The Committee acknowledged ongoing work initiated by NICE to develop a set of cost reference points for highly specialised treatments compared with other treatments commissioned through specialised services. However, it noted that this work will only be used to inform the future development of methods for evaluating highly specialised technologies. It was not taken into consideration for this evaluation.

The Committee noted the response to consultation from NHS England stating that, if all patients with aHUS were treated with eculizumab, the cost associated with commissioning eculizumab would add considerable pressure to the budget available for specialised commissioning. The Committee queried the reasoning behind NHS England's decision to commission eculizumab through an interim commissioning policy. It heard that there were potential irreversible implications for patients with aHUS if they did not have eculizumab treatment while waiting for the outcome of the NICE evaluation of eculizumab for aHUS. The budget needed to support the interim commissioning of eculizumab had already been identified. Acknowledging the substantial impact eculizumab would have on the budget, the Committee discussed how the budget available for highly specialised commissioning is distributed. It understood that the budget covers the commissioning of both services and medicines and is not ring fenced, but noted the comment from NHS England that the budget allocated for highly specialised services in 2013–14 was £544 million, of which the spend on high‑cost drugs was £156 million. The Committee heard that, if eculizumab was to be recommended, it would need to be included in the budget planning for the next few years in the context of flat‑term funding, and therefore other services may be affected. The Committee also considered that, if recommended, the use of eculizumab for aHUS would be expected to increase. The Committee heard that so far commissioning had not been stopped for any highly specialised services, but the approach was to incorporate very clear start and stop criteria developed in collaboration with a small group of clinicians. For example, eculizumab for paroxysmal nocturnal haemoglobinuria is funded for only 100 of the 300 symptomatic patients with the most severe form of disease. The Committee considered that this was important for its considerations, particularly in light of its considerations on dose adjustment and stopping treatment discussed in sections 5.4 and 5.5.

The Committee acknowledged the potential wider societal benefits of eculizumab treatment proposed by the company and patient experts, including the ability to contribute to society or continue education, and cost savings from personal expenses for patients and carers for transportation and housing. It acknowledged the concerns from the ERG that the company's analysis of these non‑health benefits did not consider the expected cost savings due to the displacement of other technologies and services to fund eculizumab. However, on balance, the Committee was persuaded that the non‑health effects were likely to be substantial but proportionate to the health effects. The Committee also considered the impact of eculizumab on the delivery of the highly specialised service, and acknowledged statements from clinical experts that showed that, because eculizumab is already available through an interim national aHUS service, all of the components necessary to deliver eculizumab within a national specialised service are already in place and functioning. The Committee was therefore satisfied that no significant additional staffing and infrastructure requirements will be needed in centres where patients with aHUS are currently treated.

After considering all available evidence and the opinions of the clinical and patient experts, the Committee agreed that eculizumab represents an important treatment option and effectively decreases thrombotic microangiopathy activity and improves kidney function in most patients with aHUS. The Committee noted that the use of eculizumab would be of significant value to patients with aHUS, but it was aware of its need to consider the extent to which the cost to the NHS of doing so was reasonable. The Committee still considered that it had not been presented with enough justification for the high cost per patient of eculizumab, or for the overall cost of eculizumab with reference to what could be expected to be reasonable in the context of a highly specialised service.

The Committee considered that the budget impact of recommending eculizumab for aHUS in relation to the substantial benefits it offered to patients, families and carers would be lower if the potential for dose adjustment and stopping treatment was taken into account. However, the Committee was aware of the limited evidence about stopping treatment, despite the significant clinical interest in investigating this possibility. It recalled its considerations on the appropriateness of further investigating possible dose adjustments and the option of stopping treatment when clinicians consider it appropriate, the accumulation of experience in clinical practice and the importance of coordinating clinical practice on the basis of robust research (see sections 5.4 and 5.5). The Committee also took into account NHS England's current approach to commissioning technologies for very rare diseases on the basis of clear stop and start criteria. Based on these considerations, the Committee concluded that eculizumab, within its marketing authorisation, could be recommended for funding for treating aHUS, only if all the following arrangements are in place:

• coordination of eculizumab use through an expert centre

• monitoring systems to record the number of people with a diagnosis of aHUS and the number who have eculizumab, and the dose and duration of treatment

• a national protocol for starting and stopping eculizumab for clinical reasons

• a research programme with robust methods to evaluate when stopping treatment or dose adjustment might occur.
  
  The long‑term budget impact of eculizumab for treating aHUS is uncertain but will be considerable. NHS England and the company (Alexion Pharma UK) should consider what opportunities might exist to reduce the cost of eculizumab to the NHS.

The Committee noted the company's concerns that the Committee was stepping beyond its remit in asking for a justification for whether eculizumab represents a reasonable cost to the NHS. However, the Committee was clear that it is within its remit it to take into account the total budget for specialised services and how it is allocated, as well as the scale of the investment in comparable areas of medicine. The Committee will also take into account what could be considered a reasonable cost for the medicine in the context of recouping manufacturing, research and development costs from sales to a limited number of patients.

The Committee noted the potential equality issue raised by a patient organisation stating that, although the recommendations do not exclude anyone from having rescue therapy with eculizumab if needed, there is a concern for people who risk disease recurrence through pregnancy. The Committee heard from the patient expert that more research should be conducted on the use of eculizumab before or during pregnancy. The Committee heard from a clinical expert that people who became pregnant are intensively monitored and continue to be offered treatment with eculizumab. The clinical expert also noted that more research is being conducted on the underlying risk of pregnancy and aHUS, and on the use of eculizumab during pregnancy, and the Committee supported this. The Committee concluded that, because its recommendations do not restrict access to eculizumab during pregnancy, there was no need to alter them.