Health Technology Assessment 2006; Vol 10: number 24
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M Connock,1 A Burls,1 E Frew,1 A Fry-Smith,1 A Juarez-Garcia,1 C McCabe,2 A Wailoo,2 K Abrams,3 N Cooper,3 A Sutton,3 A OHagan2 and D Moore1*
1 West Midlands Health Technology Assessment Collaboration (WMHTAC), University of Birmingham, UK
2 School of Health and Related Research (ScHARR), University of Sheffield, UK
3 Department of Health Sciences, University of Leicester, UK
* Corresponding author
Enzyme replacement therapy (ERT; intravenous imiglucerase) is used in the treatment of people with symptomatic type I and type III Gauchers disease in order to reduce symptoms of the disease and prevent long-term damage. The aim of this review is to determine the clinical effectiveness and cost-effectiveness of ERT in the treatment of symptomatic Gauchers disease.
Gauchers disease is an inherited disorder caused by deficient activity of the enzyme glucocerebrosidase, found mainly in lysosomes. This results in an accumulation of glucocerebroside in the lysosomes of macrophages, predominantly in the reticuloendothelial system. Consequences of this abnormal storage include:
The severity of symptoms and rate of progression vary considerably from patient to patient and range from asymptomatic to severe with early death. The variability is partly related to genotype (over 200 different mutations have been identified). Although, at a population level, different genotypes tend to be associated with certain phenotypes, making it difficult to generalise findings from one country to another, the relationship between genotype and phenotype is not rigid, as background genetics and environment also play a role. Prediction of the clinical course of an individual patient based on genotype alone is uncertain.
Gauchers disease is classified into three subtypes by clinical features. Type I can present at any age and has predominantly visceral symptoms without neurological effects. Type II causes severe progressive brain disease and death occurs in infancy. Type III presents in childhood and has neurological and visceral symptoms.
Imiglucerase (Cerezyme®) is a recombinant enzyme modified to enhance its uptake into lysosomes. It is given intravenously to replace the defective enzyme and is licensed for use in symptomatic type I disease and to treat the visceral symptoms of type III disease. Intravenous Cerezyme® cannot cross the bloodbrain barrier and is not effective for neurological manifestations.
Over 90% of affected individuals have type I Gauchers disease. It is rare, affecting between 1 in 40,000 and 1 in 60,000 individuals. There are thought to be around 250 people affected in England and Wales. Type III is even rarer, affecting less than 1 in 100,000 individuals. The focus of this report is mainly type I Gauchers disease.
This technology is already widely used in the NHS as patients with significant clinical symptoms have had access to the therapy following the recommendations of the National Specialist Commissioning Advisory Group. Current provision of ERT is said to cost the NHS in England and Wales around £20 million per annum. Although this currently represents a steady state, if ERT reduces disease-specific mortality, the figure will grow as the population being treated ages. Extending use to patients who are mildly symptomatic or asymptomatic individuals as a prophylactic measure would also increase the burden on the NHS.
Given the paucity of evidence from randomised controlled trials (RCTs) and controlled studies that compare ERT with alternative treatments, it was decided a priori to seek information from all study designs, including uncontrolled or poorly controlled studies, and from patient registries. The aim was to review and synthesise this information to estimate the likely clinical effectiveness and cost-effectiveness of ERT.
Scoping searches were performed to identify existing reviews and health technology assessments and to inform the development of the review protocol. Broad search strategies were used so that publications on effectiveness, natural history of the disease, and prevalence and incidence would be captured. References from searches of MEDLINE, Cochrane Library, EMBASE and CINAHL from their inception to August 2003 were obtained from an existing Reference Manager database that was compiled for a previous rapid review. The searches were then updated from January 2003 to July/August 2004.
Terms for β-glucocerebrosidase were added to the updated searches to identify references that may have been missed previously. Searches were also made for ongoing and completed but unpublished studies on major research registers.
Data on type of disease, method and period of ascertainment, population and prevalence rates were extracted from included studies. A data extraction form was developed based on the range of symptoms of type I Gauchers disease described in literature reviews and highlighted in discussions with clinical experts and Genzyme, the manufacturers of Cerezyme. Data on study characteristics, quality and results reported were extracted into tables by one reviewer and checked by another. The quality of the studies of ERT effectiveness was assessed according to study design. Disagreements were resolved by consensus. For those studies that were RCTs or probably cohort or casecontrol designs, the quality assessment was performed using quality recommended criteria. For other studies the following broad criteria were used, based on factors that influence the generalisability of findings reported in case-series. Where the number of patients assigned was the same as the number analysed it was assumed that withdrawals did not occur and thus were accounted for, even in the absence of an explicit statement by the authors. Where units were not equal, which can be the result of missing data or withdrawal, and the textual context did not resolve this, it was concluded that withdrawals were unaccounted for.
As most effectiveness studies were not controlled, to estimate the extent to which the outcomes observed were the results of ERT, it was important to consider what would have happened to the patients in the absence of ERT. Thus, the relevance of prevalence and natural history studies were assessed for their relevance to the UK context and the review question.
The bibliographic databases were also searched to identify existing cost studies, economic evaluations and models. To be included in the review, studies had to analyse the treatment of Gauchers disease in terms of both the costs and effectiveness. There were no language exclusions.
Primary studies of any design, reporting at least ten patients, were included. Sixty-three studies were included. Only one RCT compared ERT with usual treatment. This was a well-designed study, but underpowered (29 patients randomised to three arms) because of poor recruitment. One other RCT compared recombinant imiglucerase with the placenta-derived predecessor alglucerase and thus only provided before and after data on the effectiveness of ERT. The rest of the studies were of moderate quality at best and none had reliable comparator data.
All studies are suggestive of benefit with ERT.
The one relevant RCT showed a potentially beneficial effect in two haematological surrogates (haemoglobin and platelet levels) and, to a lesser extent, on hepatomegaly. The other studies consistently demonstrated improvements in haematological parameters and in hepatomegaly and splenomegaly. Most measures of disease involvement on average tended to return towards normal in the majority of patients after about 1 or more years of treatment. For organomegaly and haemoglobin the rates and extent of response appeared greater the more abnormal the pre-ERT condition. Platelet levels appeared to improve more slowly and to a lesser degree the more severe the initial thrombocytopenia. Liver size in most cases approached 1.2 times that expected for body weight. Spleen enlargement appeared to reduce to between five and ten times normal in most patients.
The effect of ERT on skeletal involvement also appeared to be positive in terms of pain, bone crises and fracture rate, but the quantitative evidence for these benefits was extremely weak. There was some evidence that ERT may exacerbate the depletion in bone density; thus, caution is needed in interpretation of results and careful monitoring is required.
The way in which all of these effects translate into patient well-being and survival or the need for services and resources has not been reliably estimated.
Quality of life improvements with ERT have been reported. Nonetheless, studies based on the Short Form 36 (SF-36) indicate that patients treated with ERT continue to have reduced health-related quality of life (HRQoL) compared with the general population. No study attached utility values to quality of life measures for ERT-treated patients.
Benefit from treatment probably exceeds the health gain demonstrated by before and after studies, because Gauchers disease is a progressive condition and future deterioration may be prevented. Therefore, to be able to determine the full extent of health gain from treatment it was necessary to review the natural history of untreated Gauchers disease to estimate the health loss prevented.
Thirty-one studies relevant to the natural history of the disease were found. Sixteen looked at multiple clinical characteristics of a cohort of patients with type I Gauchers disease. There was considerable within-study and between-study heterogeneity, but all showed that Gauchers disease was a progressive condition. Some suggested that the disease may become more indolent in adulthood; however, studies were discrepant on this point. Most disease is diagnosed in adulthood, although about one-quarter presented in childhood, these patients having the most severe symptoms and greatest rate of progression.
Modelling of natural history was undertaken using the five papers that reported the Severity Score Index (SSI) for each patient, along with patient-level data on age, age at diagnosis, splenectomy status and genotype, to address the question of whether disease stabilises in adulthood and the degree of correlation between phenotype and genotype. Analysis of the available data suggested that disease progression is likely to slow markedly in adulthood and that genotype is a useful predictor of clinical expression of the disease.
Five studies looked at quality of life. Data on this topic were also obtained from the registries. The evidence suggests that the vast majority of the clinical characteristics of type I Gauchers disease have little impact on subjective HRQoL and that therefore for the majority of people with type I Gauchers Disease this may not be a severe condition. Bone and skeletal symptoms contribute most to the morbidity of the disease and can lead to severe pain and immobility.
The mean cost per patient treated was approximately £86,000 per annum in England and Wales. The cost per patient varied considerably by dose.
Four existing economic evaluations were found, all of which calculated a very high cost per quality-adjusted life-year (QALY). The most recently published report was from 1996, therefore, a de novo economic model was developed. A Markov decision model was constructed based on patients moving between states defined by the modified SSI. Most of the parameters were derived from the published literature. ERT was assumed to restore patients to full health in the base case. The estimated incremental cost per QALY [incremental cost-effectiveness ratio (ICER)] in the base case ranged from £380,000 to £476,000 per QALY, depending on genotype.
Univariate sensitivity analyses examined ERT not restoring full health, more severe disease progression in the untreated cohort, and only treating the most severely affected patients. These produced ICERs of approximately £1.4 million, £296,000 and £275,000 per QALY, respectively. The base-case unit cost of the drug is £2.975. The unit cost would have had to be reduced ten-fold, to £0.30, to obtain an ICER of £30,000 per QALY. At a unit cost of £1 the ICER would be £120,000 per QALY.
The evidence for effectiveness is generally based on studies that are not of a robust design. Such designs tend to exaggerate apparent treatment effects and are therefore unlikely to have contributed to the high estimate of the ICER.
Because of the weak evidence base, several substantial assumptions were required to produce an estimate of the cost-effectiveness (wherever possible assumptions that favour ERT were chosen). These assumptions are:
Although ERT for treating the average Gauchers disease patient exceeds the normal upper threshold for cost-effectiveness seen in NHS policy decisions by over ten-fold, some argue that since orphan drug legislation encouraged the manufacture of Cerezyme, and Gauchers disease can be defined as an orphan disease, the NHS has little option but to provide it, despite its great expense.
More information is required before the generalisability of the findings can be determined. Although data from the UK have been used wherever possible, these were very thin indeed. Nonetheless, even large errors in estimates of the distribution of genotype, genotypephenotype associations, effectiveness and numbers of patients will not reduce the ICER to anywhere near the upper level of treatments usually considered cost-effective.
Further research could help to clarify the many uncertainties that exist. However, although doing so will be of clinical interest, it is questionable whether, within the current pricing environment, such research would have any substantive impact on policy decisions. It is highly improbable that, whatever the findings of such research, the ICER could be brought down by the orders of magnitude required to make ERT an efficient use of health service resources. (The possible exception to this would be investigating the most efficient alternative treatment strategies for using ERT in a paediatric population only.) Moreover, if under equity considerations for orphan diseases the NHS feels it is important to provide this drug, regardless of its cost-effectiveness, then refining the precision of the ICER estimate also becomes superfluous.
Connock M, Burls A, Frew E, Fry-Smith A, Juarez-Garcia A, McCabe C, et al. The clinical effectiveness and cost-effectiveness of enzyme replacement therapy for Gauchers disease: a systematic review. Health Technol Assess 2006;10(24).
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