(ERT) for Infantile Pompe´s disease: Comparative perspective from

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).
Author names and affiliations: Hector E Castro J MD, Msc. Doctor in Medicine and
Surgery- Universidad del Rosario (Bogotá Colombia); Msc Occupational HealthUniversidad del Valle (Cali Colombia); Msc Health Policy, Planning and Financing- London
School of Hygiene and Tropical Medicine/London School of Economics and Political
Science, Doctor of Public Health & Policy (Candidate) London School of Hygiene and
Tropical Medicine. 43 Kinburn street. London SE16 6DW. United Kingdom. Telephone
4407538616626 [email protected]; [email protected]
ABSTRACT. The objective of this paper is to determine the cost- effectiveness from
payers perspective of ERT for Classic infantile form of Pompe´s disease (≤ 6 months of
age), usually related to complete deficiency of acid α- glucosidase in two different
settings, a High Income Country (HIC) and a Middle Income one (MIC). Classic infantile
and late onset forms of Pompe’s disease are very rare and have a combined incidence of
1:40.000 births with different distribution worldwide. It is unknown precisely how many
people suffer from this disorder. Methods: literature review of previous clinical studies and
historic databases were searched to obtain the natural course of disease in different
populations. Bibliographic databases were searched to identify existing cost reimbursed by
NHS in England and from third party payers in Colombia. Two Markov processes were
constructed to compare; patients moved between transition states, alive with symptoms
and dead. At least 75% survival rate was expected for patients aged ≤ than 6 months
under treatment. No long term assessment of health states have been made for
populations of patients alive under ERT so far. Most of the parameters were derived from
published literature. ERT was assumed to partially restore patient’s health up to a HRQoL of 0,700 using EQ-5D scale. Results: From the English perspective before running
the model the average cost per case per annum with ERT is £194 K and the ICER per
QALY gained was £234.307,7; from the Colombian side the average cost per case per
annum is £98 K and the ICER per QALY gained was £109.991. One way sensitivity
analysis showed that uncertainty about final HR-QoL with ERT, rate of progression of
disease and cost related to palliative and supportive inpatient care had the biggest impact
on ICER in both models, two way sensitivity analysis showed that if cost of ERT reduces
up to 10000 times per dose and a sustained HR-QoL between at least 0,750- 0,820 is
achieved 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
related to logistics and nationalization costs. Conclusions: ERT is more effective that no
ERT to treat the disorder, but high levels of uncertainty still remain about rates of survival,
progression and quality of life in the long run. ICER showed figures still very high if
compared with tacit or explicit international thresholds for decision making, 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.
Pompe´s disease treatment is categorized as an orphan drug; hence prices and
monopolistic power of manufacturer have a major impact on final CEA results. Further
research should be performed to dynamically inform changes in case long run survivals
with ERT are achieved in the future.
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. 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 1,92,1 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 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.
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.
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.
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.
The Markov Model
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. (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 (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)
Graph1a. English perspective ICER with various health states under ERT.
Graph1b. Colombian Perspective ICER with various health states under ERT.
Sensitivity analysis 2: Pompe´s disease is less aggressive/Better Supportive
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 αglucosidase), 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).
Graphs 2a and 2b. English and Colombian perspectives: ICER if disease were less aggressive
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)
Graphs 3a and 3b. ICER under different ranges cost of supportive care English and Colombian
Graphs 4a and 4b. ICER under different cost of ERT (20 mg/Kg dose) English and Colombian
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).
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.
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).
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).
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.
Our 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. We 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%. We 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.
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.
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