The cost- effectiveness of enzyme replacement therapy (ERT) for Infantile Pompe´s disease: Comparative perspective from a High Income Country (England) and a Middle Income one (Colombia).

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ABSTRACT. Objective of this paper is to determine the cost- effectiveness of ERT for Classic form of Pompe´s disease, related to complete deficiency of acid α-glucosidase in two different settings, England and Colombia. Pompe’s disease is very rare (incidence of 1:40.000 births). Methods: bibliographic review and historic databases were searched for cost reimbursed by NHS in England and insurers in Colombia and expert´s opinion used and. Two Markov processes were constructed to compare; transition states were: alive with symptoms and dead. 75% survival rate was expected for patients aged ≤ than 6 months under ERT and assumed to partially restore patient’s health to a HR- QoL of 0,700 using EQ-5D scale. Results: For England ICER per QALY gained was £234.307,7; for Colombia ICER per QALY gained was £109.991. Uncertainty about final HR-QoL with ERT, disease progression and cost from palliative care had the biggest impact on ICER in both models, if cost of ERT reduces up to 10000 times per dose and HR-QoL is 0,750- 0,820 ICERs of £165 K and K£65 could be attainable for England and Colombia respectively. Transactional cost per case in Colombia accounted for an important overload. Conclusions: ERT is more effective that no ERT to treat the disorder, but high levels of uncertainty remain about survival rates, progression and QoL in the long run. ICER are still high compared to CE thresholds. Pompe´s treatment prices and monopolistic power of manufacturer have a major impact on final CEA results. Further research should be performed in the future.

RESUMEN. El Objetivo de este documento es determinar la costo- efectividad de la TRE como indicación para la forma clásica de la enfermedad de Pompe, relacionada con deficiencia completa de α-glucosidasa ácida desde dos perspectivas, Inglaterra y Colombia. La enfermedad de Pompe es muy rara (incidencia 1:40.000 nacimientos). Métodos: Revisiones bibliográficas y bases de datos para calcular costos del NHS en Inglaterra y aseguradores en Colombia y opinión de expertos. Dos procesos de Markov fueron construidos para comparar; los estados de transición fueron: vivo con síntomas y fallecido. Se estima 75% de sobrevida pacientes de ≤ 6 meses de edad con TRE, se asume esta restaura parcialmente el estado de salud asociado a calidad, HR-QoL 0.700 usando EQ-5D. Resultados: Inglaterra ICER por QALY ganado £234.307, 7; Colombia ICER por QALY ganado £109.991. Incertidumbre sobre HR-QoL con TRE, progresión de enfermedad y costo de cuidado paliativo tuvieron el mayor impacto en ICER para ambos casos, sí el costo de TRE fuera 10.000 menor y la HR-QoL 0.750 - 0.820 ICERs de £165.000 y £65.000 podrían ser alcanzables para Inglaterra y Colombia respectivamente. Costos transaccionales en Colombia fueron representativos. Conclusiones: Es más efectiva la TRE que no dar tratamiento, pero incertidumbre sobre tasas de sobrevida, progresión y HR-QoL permanecen a largo plazo. Los ICER siguen siendo altos

comparados a los umbrales establecidos de CE. Los precios del tratamiento de Pompe´s y el poder monopolístico del fabricante tienen un impacto importante en los resultados finales de CEA. Investigación adicional debe realizarse a futuro.

INTRODUCTION

Pompe´s disease is very rare autosomal recessive disorder, first described in 1932 by Dutch pathologist J.C. Pompe, it is also known as acid maltase deficiency or glycogen storage disease type II (1). Disease is characterised by a deficiency of acid α- glucosidase leading to progressive accumulation of glycogen on cardiac, skeletal and respiratory muscle tissue that could result in cardio- respiratory deficiency and death.

There are two clinical forms of disease, the classical infantile form usually lethal and related to complete deficiency of α- glucosidase and the milder usually later onset form that may present at any age (sub categorized in non classical infantile, childhood, juvenile and adult) usually related to a partial deficiency of enzyme (1–4).

All combined forms of Pompe’s disease have an incidence of 1:40.000 births with different distribution worldwide (5, 6). It is unknown precisely how many people suffer from it. But it is assumed that no more than 5000–10.000 people worldwide are affected. Although it occurs in people of all races, affects African Americans more often (1/14.000 births) than Caucasians (1/60.000 adults and 1/100.000 children)7. There is an estimated incidence of 0.137 per 10,000 people in the European Union. Consequently Pompe´s disease has been classified as an orphan disease, denomination used for rare conditions (less than de 200.000 people in North America and no more than 5 in 10.000 in Europe).

Feeding problems, failure to gain weight, muscular weakness, motor development retardation, cardiac problems, respiratory difficulty, and airway infections were frequently reported as main symptoms during the first months of life (mean 1,9- 2,1 months) and most infants die within the first year (92-95%) usually after a short period of inpatient care (median 2,8- 4,0 Months) from cardio respiratory Insufficiency (7,8) . Late-onset Pompe’s disease presents predominantly as a slowly progressive proximal myopathy that affects young and middle aged individuals; symptoms are mostly related to mobility problems and limb girdle weakness, disability varies among patients. Delayed diagnosis of more than 5 years after first symptoms in up to 28% of patients and respiratory problems are a major cause of death for this type of disease. Before ERT was introduced, treatment was only palliative and supportive; but since 2006 a recombinant α-glucosidase under the trade name Myozyme® was approved as the first and only drug to be used in Pompe´s disease replacement

therapy. Evidence supports that Alglucosidase alpha significantly prolonged total and ventilator free survival in patients with classic infantile onset of disease. Patients with severe deficiency and early onset of ERT (before 6 months of age) seem to show the most marked benefit (9).

Under a ERT scheme of 20mg/kg every two weeks it is expected to increase survival rates for 52 weeks from 73% (95% CI 45, 92) to 89% (95% CI: 68,100) according to some clinical studies 10. Cox proportional hazards regression demonstrated that Alglucosidase alfa reduced the risk of death by 99% (hazard ratio: 0.01; 95% CI: 0.00, 0.10; p<0.0001) on patients aged ≤ 6 months and 71% (hazard ratio: 0.29; 95% CI: 0.11, 0.81; p<0.018) for patients aged > 6 months to ≤ 36 months. In addition, Alglucosidase alpha treated patients experienced improvements in cardio-myopathy, growth, weight gain, motor development and functional status. According to the manufacturer at least 76% survival rate is expected for patients aged < than 6 months under treatment. No long term assessment of HR-QoL has been made for populations of patients alive with ERT.

Although potentially all patients treated with Myozyme® (Alglucosidase alpha) could develop adverse events ranging from temporary mild to severe ones. The most common adverse reactions requiring intervention were infusion related (up to 51% of cases during the 2 hours following infusion), most of them mild to moderate; clinical trials and post marketing safety experience with Myozyme® have showed approximately 1% of patients developed anaphylactic shock and/or cardiac arrest during Myozyme® infusion that required life-support measures and approximately another 14% have developed other major allergic reactions.

METHODS AND MATERIALS

Eight different studies were reviewed to establish the natural course of disease (early classic form and the late onset form). Since the focus of this paper is in the early onset classic form, one of the main comparative reviews of historic cohorts came from a Dutch study from 2003 8, were a mortality rate of 92% was observed (109/ n=119) during the first year of life after birth for children with Pompe´s disease and no ERT. Some assumptions have been made in constructing the decision model: Since usually death overcomes after a period of 78 days of inpatient palliative and supportive care, this average length of stay was introduced and multiplied by average cost per diem to calculate the average cost of supportive and palliative care, we assumed that all patients will be treated at some point at ICU before death. Two other studies were referenced to determine the effectiveness rate of ERT that was assumed for the model in a 75% survival rate for each year (9, 10).

Costs were calculated for inpatient palliative and supportive care at Paediatric Intensive care Unit (PICU) cost, ERT with Myozyme® was set every two weeks in doses of 20mg/Kg (26 per cycle), also non drug costs of ERT infusion and cost of treating complications from ERT application were included. A total probability of

51% for complications from ERT was included, since they require any kind of extra treatment, being severe allergies (including anaphylactic shock and respiratory failure) the most severe ones (11), therefore an assumption that any complication form ERT application would account for at least a 10% extra cost of inpatient care. All costs related to the diagnostic phase were not included under the assumption that children will enter the model after being diagnosed and since when disease progresses it is mostly likely treated as inpatient, average ambulatory specialist´s consultations were assumed to be similar for both groups, hence cost related to ambulatory care other than ERT infusion were neglected. Inpatient care costs, ERT cost and costs from treating complications from ERT application for the English perspective were obtained from NHS sources, HRGs, parliament reports and British National Formulary from different years. Non drug costs of ERT application obtained from a Dutch study from 2003 (12). All costs were calculated to present value (according to inflation rates reported by the Office for National Statistics U.K) (13,14). For the Colombian perspective, average costs faced by third party payers from the Social Health Insurance Scheme (SHI) were calculated; COOMEVA EPS one of the biggest insurers shared historic data of average inpatient care, ERT, non drug and treating ERT application complications costs. Then they were brought to present value according to inflation figures of DANE in Colombia and exchanged from Colombian peso to British Pounds to ease comparison (15,16). An extra cost of £4104 per cycle was added to the Colombian model derived from costs of importation and logistics faced by third party payers (£342 per month) All summary costs can be seen in table 1.

Insert Table 1

Two Markov processes were constructed based on patients moving between transition states alive with symptoms and dead; since the disorder is always progressive and symptomatic after being diagnosed, no alive asymptomatic transition state was considered. ERT was assumed to partially restore patient’s QoL due to the limited long term evidence of clinical course with ERT. Motor development impairment and respiratory insufficiency progression are expected to occur in our model in the long run.

Three scenarios were assumed to classify symptomatic patients alive with Pompe´s disease. Using EQ-5D from physician´s perspective, the worse off state scenario would be health state 22322 with a utility value of 0,189, a middle state would be 22221 with a utility value of 0,587 and the better off state would be 21211 with a value of 0,814 17. Since there is a 50% chance due to uncertainty to move from the better off or middle state to the worse off state, either with or without ERT; we combined these states into two main health states (0,189*0,5) +(0,587*0,5) = 0,388 and (0,587*0,5)+(0,814*0,5) = 0,700 (17), and under the assumption that ERT favours a higher HR-QoL we assigned the higher combined value to being alive with ERT and the lower combined one to being alive without ERT. Most of the parameters were derived from the published literature. Each cycle was considered yearly based and the model was run for 20 cycles since

some expert´s opinion state that age as an option for life expectancy (9). Assuming a marked deviation from normal weight gain curves for boys and girls with Pompe´s disease due to chronic illness, 5% Percentile for weight was used as reference framework for calculating total dose of ERT per case (18). Discounting rates were 5% for both costs and effects in each cycle. Effectiveness was calculated in QALYs gained and cost in GBP year 2010. Markov processes were run using TreeAge® pro 2009.

Insert Markov Model

RESULTS

England´s perspective after running the model showed decision branch No ERT resulted in a cost of £149.178 per 0,16 QALYs gained and branch ERT showed £1.337.118 per 5,23 QALYs gained, the incremental cost- effectiveness ratio ICER per QALY was £234.307,7.

Insert table 2a

From the Colombian perspective branch No ERT resulted in a cost of £49.676 per 0,16 QALYs gained and branch ERT showed £607.329 per 5,23 QALYs gained, the incremental cost- effectiveness ratio ICER per QALY was £109.991

Insert table 2b

A number of one-way and two way sensitivity analyses are presented to reflect alternative structural assumptions.

Sensitivity analysis 1: ERT has different impact on Health State: It is likely that ERT does not resolve all disease symptoms and patients remain at least in a mild disease state. In the present model all patients are assumed to live a QoL valued in 0,700 under ERT treatment, some limited literature shows that cardiac hypertrophy may resolve after ERT but other complications like inability to achieve normal motor development, feeding problems and mild respiratory symptoms might persist or even progress with an expected impact on the HR-QoL value. If glycogen deposits continue to exist even with ERT HR-QoL could be much lower than expected. Sensitivity analysis 1 included utility values ranging from 0,100 to 0,900. Under these circumstances the ICER under ERT substantially decreases the more optimistic the assumption is about HR-QoL. From the English perspective at 0,900 the ICER is near to £180 K and slopes up near to £2015 K when value is 0,100. From the Colombian perspective at 0,900 the ICER is near to £85 K and slopes up to near to £946 K when value is 0,100 (See graphs 1a and 1b)

Insert Graphs 1a and 1b

Sensitivity analysis 2: Pompe´s disease is less aggressive/Better Supportive care: Natural course of disease from different sources accounts for mortality rates per year ranging from 92%- 99% in the classic infantile form without ERT and are estimated to be around 25% under ERT. Although the focus of this study is on infantile form (usually related to total deficiency or very low activity of Acid α- glucosidase), what if mild or late onset forms of disease can be seen with lower rates of mortality and progression also PICU potential technological innovation could in the future increase survival rates for patients with severe Pompe´s disease under supportive treatment.

This uncertainty in estimates of mortality rates have been incorporated in probabilistic sensitivity analysis lowering hypothetical probability of death in a rage from 0 -10% to reflect this alternative assumption.

In the English scenario if probability to die from Pompe´s disease is 5% with or without ERT the ICER is 0, but if probability to die raises to 6% ICER for ERT goes up to near £143 K; from the Colombian perspective if probability to die is 4% with or without ERT the ICER is 0, but if probability to die raises to 5% ICER goes up to near £915 K sloping down to near £207K when probability to die is 10%. (See graphs 2a and 2b).

Insert graph 2a and 2b

Sensitivity Analysis 3: Treating progression of disease is less expensive: In our model progression of disease accounted for at least 78 days of PICU before death, and total costs of supportive care were calculated multiplying average length of stay by average cost per diem (PICU). But if effectiveness of ERT reduces either the frequency, average inpatient length of stay or the level of health care required; then it would mean a reduction in total cost of supportive and palliative care, then ICER could be ostensibly different. The effect of altering total cost of supportive treatment resulted in an ICER per QALY of £45 K when cost of supportive treatment was 0, an ICER of £92 K when cost was £37 K and so on, up to an ICER of £234K when cost of supportive treatment was £148 K in the English model. An ICER per QALY of £47K when cost of supportive treatment was 0, an ICER of £62,7 when cost was 12K and so on, up to ICER £110 K when cost of supportive treatment was £39 K in the Colombian model (See graphs 3a and 3b)

Insert graphs 3a, 3b

Analysis 4: Changes in drug cost: ERT is a relatively costly treatment. The base-case analysis estimates an annual patient cost per Kg of £3833 for England and

£4166.5 for Colombia. In sensitivity analysis 4, the extent to which the unit cost of ERT drives the cost-effectiveness model is identified. The cost per Kg is varied between £0 and the final estimates included in each country and the resulting ICERs are plotted in graphs 4a and 4b. Results showed a mild impact over ICER ranging from £ 200 K at cost per Kg of £0 up to £ 234 K at actual cost in England and from £ 73 K at cost per Kg of £0 up to £ 110 K at actual cost in Colombia.

Insert Graph 4a and 4b

Analysis 5: Additional transaction cost: For the Colombian model it was simulated a scenario were no transaction cost of importation and transportation were included. Ranging from £0 to up to £41040, 10 times its actual cost of importation (£4104) since this cost is associated to every patient under treatment, then hypothetically simulating and increase in the incidence or a concentration of chronically ill individuals in a single insurer. Resulted that at no cost of importation ICER goes down from its actual £110 K to £104 K and if importation cost goes up 10 times ICER increases up to £164K (See graph 5).

Insert graph 5

Analysis 6: Cost of treatment vs effectiveness: Using two way sensitivity analysis if costs of ERT were 10000 times lower, near £0,38 and £0,41 respectively in each model, lower ICER might be seen (£165K for England and £ 65K for Colombia) but only if utility (HR- QoL) obtained from treatment is at least 0,820 from English perspective and 0,750 from the Colombian one (See graph 6a and 6b).

Insert graph 6a and 6b

DISCUSSION

There is clinical evidence that supports the effectiveness of ERT with Alglucosidase alpha (Myozyme®) in the short run for patients with early onset classic form of Pompe´s disease. Survival rates in the first year could improve from 8% without treatment to 40% and even close to 100% under ERT, a decrease in cardiac hypertrophy, achievement of major milestones of motor development and

later progression of respiratory insufficiency could increase the life expectative at birth of this population up to at least 20 years according to expert´s opinion (1,2,3,8,9).

Although all this optimistic findings there is still very limited evidence and lack of long term data to prove that the HR-QoL achieved is close to life in full health (utility value of 1) and if this population of patients under ERT can live a productive less dependent life. Rate disease progression with ERT has not been reported sufficiently yet, and under the assumption that the more severe the disease, the bigger the chances to demand costly inpatient and intensive care has a negative impact on the model´s results. If Pompe´s disease under ERT stabilized or regressed a new transitional state of alive asymptomatic under ERT could be introduced in future models. Two models were run to compare different perspectives, one form a high income country: England, with a health system based on taxation, a single payer such NHS, a strong culture and processes for Health Technology Assessment (HTA) and Colombia a Middle Income Country, with a Social Health Insurance scheme, multiple purchasers and a very recent history of HTA. One remarkable finding is the fact that in average cost of ERT per case in Colombia might be 9% more costly, probably due to a segmented purchasing power from different insurers compared with a stronger single purchaser power; also extra transaction cost of £4104 was observed in Colombia (importation and nationalization cost) and none in the English model. ICER per QALY are in both cases still very high £234K in England and £90 K in Colombia if compared with “established” CE thresholds per QALY or YL gained (tacitly or explicitly) .e.g. £ 30.000 in UK, USD$50.000 in USA, NZ$20.000 New Zealand, US$69000 Sweden, AU$ 42.000 Australia and so on (19,20), in some other countries especially LIC and MIC there are not thresholds named or discussed by their societies yet (19), despite it is clear decisions in health are not on the appeal of arbitrary numbers, CE thresholds are still objective national benchmarks related to the affordability criterion of each society. The results of our model from England´s perspective were coincident to those of the Scottish NHS 2007 (Scottish Medicines Consortium) where the cost per QALY gained for children ≤ 6 months was £244,450 ours was £234,308 per QALY gained; in 2007 the final advice by the SMC was not to recommend the use of Alglucosidase alpha (Myozyme®) within NHS Scotland for the treatment of Pompe´s disease (9).

The model had several limitations basically because of limited sources of data. Real world wide prevalence is not clear, utility values for different levels of disease (mild, moderate or severe) or with or without ERT have not been elicitated. EQ- 5D despite of cultural and geographical differences was applied in both models to assign values, uncertainty about possible future clinical attainment or deterioration

are present. It also assumed that because of a chronic disease impact on weight gain will be persistent, so we used 5% percentile throughout it, but uncertainty remains if after chronic ERT treatment weight gain curves would become closer to normal distribution. Also probability of death after anaphylactic shock from ERT application was assumed at 50% chance of an overall risk of 1%. It was assumed as well that since Pompe´s disorder is progressive and once diagnosed it is always symptomatic, no alive asymptomatic transition state was included. Costs from diagnostic phase and ambulatory care were considered irrelevant as seen in previous economic studies concerning Lysosomal Storage Disorders (LSD) (21). Additional limitations are related to inflation rates and trends in both countries and also from currency exchange rates since the latest world economy crisis on its possible impact over costs and prices in international and pharmaceutical markets.

In conclusion, the aim of this analysis was to run two comparative models to assess the cost- effectiveness of ERT with Alglucosidase alpha for Classic infantile Pompe´s disease. The results showed that ERT is more effective that no ERT to treat the disorder, but high levels of uncertainty still remain about life expectancy, survival rates, progression, quality of life under long term treatment and so on. ICER showed figures between about £234 K for England and £110 K for Colombia, still very high if compared with tacit or explicit international thresholds for decision making. Costs related to inpatient and palliative care have the biggest impact on overall cost due to the aggressive natural course of disease. Pompe´s disease treatment is categorized as an orphan drug and treatment options are still limited and costs of research and development for new medicines very high, hence prices and monopolistic power of manufacturers still have a big impact on final CEA results; paradoxically MIC might be facing higher fees than HIC when reimbursing Alglucosidase alpha; issues related to purchasing power and local regulation should be bear in mind when assessing this evidence in detail. Comparing different countries´ perspectives is not about what is right and wrong, but about informing what could be learned from one to the other.

CE thresholds as said before are benchmarks to consider whenever budgetary constraints strake and can support decision making when used along side with other social and technical tools. Since there are not clinical comparators for ERT other than supportive and palliative care for Pompe´s disease, further economic evaluation should include considerations on the real costs of inpatient and ambulatory care for both patients with and without ERT, but ethical considerations would allow only comparisons with historic NO ERT cohorts and patients under ERT, also an international sample big enough of patients under Alglucoidase alpha might be hard to get. Patients around the world are receiving treatment regardless

of sustainability, lack of enough evidence about long term QoL or rate of disease progression under ERT so additional research, specially from different approaches than from purchaser perspective is advisable to inform about carer´s time cost, potential productivity and so on, to produce further information about social welfare losses or gains under ERT in the long run.

Acknowledgments

The author would like to thank Faisal Latif and Ayotunde Uko for helping as a team in gathering data. Cora Peterson and Dr Alec Miners for their initial comments and advice on the general approach of the analysis and Dr Virgilio Barco and his team from COOMEVA EPS in Colombia for kindly sharing information to feed the Colombian Markov model.

References

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Table 1.

The Markov Model

(Table 2a.)

(Table 2b.)

Graph1a. English perspective ICER with various health states under ERT.

Graph1b. Colombian Perspective ICER with various health states under ERT.

.

Graphs 2a and 2b. English and Colombian perspectives: ICER if disease were less aggressive

Graphs 3a and 3b. ICER under different ranges cost of supportive care English and Colombian perspective

Graphs 4a and 4b. ICER under different cost of ERT (20 mg/Kg dose) English and Colombian perspective

Graph 5. ICER under different cost of impotation and nationalization, Colombian Perspective

Graphs 6a and 6b. Two way sensitivity analysis Cost of ERT per Kg and Utility of alive with ERT (WTP £165K England and £65K Colombia).