4 RESULTS
4.5 Pharmacoeconomic Evaluation
4.5.3 Deterministic sensitivity analysis
a) Parameter Uncertainty
Sensitivity analysis around background costs
The background cost per EDSS states were derived from two Canadian studies and involved some extrapolation. To assess the uncertainty regarding the background costs, a sensitivity analysis was conducted by increasing and decreasing the cost by 100%. The results are presented in Table 29 and Table 45, showing that increasing the background costs results in lower ICURs.
Table 29: Results of the Univariate Sensitivity Analysis Regarding Background Cost
Scenario Result
Base case If λ < $118,242, glatiramer acetate is a cost-effective treatment.
If $118,242 < λ < $425,655, interferon beta-1b 250 mcg (Extavia) is a cost- effective treatment.
If $425,655 < λ < $872,972, dimethyl fumarate is a cost-effective treatment. If λ > $872,972, natalizumab is a cost-effective treatment.
Increase
background cost by 100%
If λ < $41,675, glatiramer acetate is a cost-effective treatment.
I If $41,675 < λ < $207,064, interferon beta-1b 250 mcg (Extavia) is a cost- effective treatment
If $207,064 < λ < $827,812, dimethyl fumarate is a cost-effective treatment. If λ > $827,812, natalizumab is a cost-effective treatment.
Decrease
background cost by 100%
If λ < $156,526, glatiramer acetate is a cost-effective treatment.
If $156,526 < λ < $227,517, interferon beta-1b 250 mcg (Extavia) is a cost- effective treatment.
If $227,517 < λ < $895,552, dimethyl fumarate is a cost-effective treatment. If λ > $895,552, natalizumab is a cost-effective treatment.
mcg = microgram.
In all scenarios, interferon beta-1a 30 mcg, interferon beta-1a 44 mcg, interferon beta-1a 22 mcg, interferon beta-1b 250 mcg (Betaseron), and fingolimod are dominated therapies.
Sensitivity analysis regarding natural history of disease progression
To explore the impact of using one data source for the natural history of disease, sensitivity analysis was conducted by varying the rate of disability progression. Results showed that if the rate of disability progression is slower than reported in the London Ontario study, then the ICURs would be higher than those in the base case. Results are presented in Table 30.
Table 30: Results of the Univariate Sensitivity Analysis Regarding the
Natural History of Disability Progression
Scenario Result
Base case If λ < $118,242, glatiramer acetate is a cost-effective treatment.
If $118,242 < λ < $425,655, interferon beta-1b 250 mcg (Extavia) is a cost- effective treatment.
If $425,655 < λ < $872,972, dimethyl fumarate is a cost-effective treatment. If λ > $872,972, natalizumab is a cost-effective treatment.
Increase natural history of disability progression by 50%
If λ < $67,609, glatiramer acetate is a cost-effective treatment;
I If $67,609 < λ < $375,641, interferon beta-1b 250 mcg (Extavia) is a cost- effective treatment.
If $376,641 <λ < $596,368, dimethyl fumarate is a cost-effective treatment. If λ > $827,812, natalizumab is a cost-effective treatment.
Decrease natural history of
disability progression by 50%
If λ < $396,532, glatiramer acetate is a cost-effective treatment.
If $396,532 < λ < $474,856, interferon beta-1b 250 mcg (Extavia) is a cost- effective treatment;
If $474,856 < λ < $1,410,447, dimethyl fumarate is a cost-effective treatment. If λ > $1,410,447 natalizumab is a cost-effective treatment.
mcg = microgram.
Sensitivity analysis around cost per relapse
To address the uncertainty regarding the cost of relapse univariate, a sensitivity analysis was conducted. The results show that this parameter does not have a significant impact on the results (Table 31).
In all scenarios, interferon beta-1a 30 mcg and interferon beta-1a 22 mcg are dominated by glatiramer acetate and interferon beta-1b 250 mcg (Extavia). Interferon beta-1b 250 mcg (Betaseron) is dominated by interferon beta-1b 250 mcg (Extavia). Interferon beta-1a 44 mcg is dominated by glatiramer acetate, interferon beta-1b 250 mcg (Extavia) and dimethyl fumarate. Fingolimod is dominated by dimethyl fumarate.
Table 31: Results of the Univariate Sensitivity Analysis Regarding Cost of Relapse
Scenario Result
Base case62
Cost per mild or moderate relapse =$6,402 Cost per severe relapse = $15,364
If λ < $118,242, glatiramer acetate is a cost-effective treatment.
If $118,242 < λ < $425,655, interferon beta-1b 250 mcg (Extavia) is a cost-effective treatment.
If $425,655 < λ < $872,972, dimethyl fumarate is a cost-effective treatment.
If λ > $872,972, natalizumab is a cost-effective treatment.
Grima et al.74
Cost per relapse = $1,405
If λ < $109,519, glatiramer acetate is a cost-effective treatment.
If $109,519 < λ < $503,474, interferon beta-1b 250 mcg (Extavia) is a cost-effective treatment.
If $503,474 < λ < $913,177, dimethyl fumarate is a cost-effective treatment.
If λ > $913,177, natalizumab is a cost-effective treatment.
Karampampa et al.75
Cost per relapse = $6,402
If λ < $115,694 glatiramer acetate is a cost-effective treatment.
If $115,694 < λ < $448,383, interferon beta-1b 250 mcg (Extavia) is a cost-effective treatment.
If $448,383 < λ < $884,714, dimethyl fumarate is a cost-effective treatment.
If λ>$884,714, natalizumab is cost-effective treatment.
Increase cost of relapse for 100%
Cost per mild or moderate relapse = $12,804 Cost per severe relapse = $30,728
If λ < $128,702, glatiramer acetate is a cost-effective treatment.
If $128,702 < λ < $332,343, interferon beta-1b 250 mcg (Extavia) is a cost-effective treatment;
If $332,343 < λ < $824,762, dimethyl fumarate is a cost-effective treatment. If λ > $824,762, natalizumab is a cost-effective treatment. mcg = microgram. Utilities
There were several studies reporting utilities associated with RRMS. Although the utilities from Prosser et al.62 were used, the impact of using other sources was assessed.
When considering the different data sources for utility values, while there were numerical changes to the QALYs gained, these were no significant changes to the cost-effectiveness results (Table 32).
Table 32: Univariate Sensitivity Analysis — Health Utilities Source for Utilities Result Prosser et al.62 (Base case)
If λ < $118,242, glatiramer acetate is cost-effective treatment.
If $118,242 < λ < $425,655, interferon beta-1b 250 mcg (Extavia) is a cost-effective treatment.
If $425,655 < λ < $872,972, dimethyl fumarate is a cost-effective treatment. If λ > $872,972, natalizumab is a cost-effective treatment.
Kobelt et al.77 If λ < $139,729, glatiramer acetate is cost-effective treatment.
If $139,729 < λ < $436,994, interferon beta-1b 250 mcg (Extavia) is a cost-effective treatment.
If $436,994 < λ < $942,812, dimethyl fumarate is a cost-effective treatment. If λ > $942,812, natalizumab is a cost-effective treatment.
ScHARR78 If λ < $105,735, glatiramer acetate is cost-effective treatment.
If $105,735 < λ < $416,432, interferon beta-1b 250 mcg (Extavia) is a cost-effective treatment.
If $416,432 < λ < $802,304, dimethyl fumarate is a cost-effective treatment. If λ > $802,304, natalizumab is a cost-effective treatment.
Earnshaw et al.79
If λ < $131,124, glatiramer acetate is a cost-effective treatment.
If $131,124 < λ < $432,653, interferon beta-1b 250 mcg (Extavia) is a cost-effective treatment.
If $432,653 < λ < $911,411, dimethyl fumarate is a cost-effective treatment. If λ > $911,411, natalizumab is a cost-effective treatment.
Karampampa et al.75
If λ < $101,765, glatiramer acetate is a cost-effective treatment.
If $101,765 < λ < $413,253, interferon beta-1b 250 mcg (Extavia) is a cost-effective treatment.
If $413,253 < λ < $784,639, dimethyl fumarate is a cost-effective treatment. If λ > $784,639, natalizumab is a cost-effective treatment.
In all scenarios, interferon beta-1a 30 mcg and interferon beta-1a 22 mcg are dominated by glatiramer acetate and interferon beta-1b 250 mcg (Extavia). Interferon beta-1b 250 mcg (Betaseron) is dominated by interferon beta-1b 250 mcg (Extavia). Interferon beta-1a 44 mcg is dominated by glatiramer acetate, interferon beta-1b 250 mcg (Extavia), and dimethyl fumarate. Fingolimod is dominated by dimethyl fumarate.
Disutility of relapse
Several studies reported disutilities associated with relapse; however, only Prosser et al.62 made a distinction between mild or moderate and severe relapse. It was assumed that the reported disutility in the alternative sources was for mild or moderate relapse. Therefore, to estimate the utility decrement associated with severe relapse by using the alternative data sources, the ratio between disutility associated with mild or moderate relapse and severe relapse used in the Prosser et al. study62 was applied to the disutility reported by the alternative sources to estimate the disutility associated with severe relapse.
Table 33: Disutilities Associated With Relapse Based on Alternative Data Sources
Disutility Values Prosser et al.62
(base case)
Parkin et al97 ScHARR78 Earnshaw79
Mild or moderate relapse –0.091 –0.0136 –0.078 –0.094 Severe relapse –0.302 –0.451a –0.259a –0.312a a Estimated value
Results were not sensitive to the disutility associated with relapse (Table 34).
Table 34: Results of the Univariate Sensitivity Regarding Disutility of Relapse Source for
Utilities
Result Prosser et al.62
(Base case)
If λ < $118,242, glatiramer acetate is a cost-effective treatment.
If $118,242 < λ < $425,655, interferon beta-1b 250 mcg (Extavia) is a cost- effective treatment.
If $425,655 < λ < $872,972, dimethyl fumarate is a cost-effective treatment. If λ > $872,972, natalizumab is a cost-effective treatment.
Parkin et al.97 If λ < $118,855, glatiramer acetate is a cost-effective treatment.
If $118,855 < λ < $411,514, interferon beta-1b 250 mcg (Extavia) is a cost- effective treatment.
If $411,514 < λ < $858,226, dimethyl fumarate is a cost-effective treatment. If λ > $858,226, natalizumab is a cost-effective treatment.
ScHARR78 If λ < $116,245, glatiramer acetate is a cost-effective treatment.
If $116,245 < λ < $480,638, interferon beta-1b 250 mcg (Extavia) is a cost- effective treatment.
If $480,630 < λ < $925,974, dimethyl fumarate is a cost-effective treatment. If λ > $925,974, natalizumab is a cost-effective treatment.
Earnshaw et al.79 If λ < $118,715, glatiramer acetate is a cost-effective treatment.
If $118,715 < λ < $414,652, interferon beta-1b 250 mcg (Extavia) is a cost- effective treatment.
If $414,652 < λ < $861,530, dimethyl fumarate is a cost-effective treatment. If λ > $861,530, natalizumab is a cost-effective treatment.
mcg = microgram.
In all scenarios, interferon beta-1a 30 mcg and interferon beta-1a 22 mcg are dominated by glatiramer acetate and interferon beta-1b 250 mcg (Extavia). Interferon beta-1b 250 mcg (Betaseron) is dominated by interferon beta-1b 250 mcg (Extavia). Interferon beta-1a 44 mcg is dominated by glatiramer acetate, interferon beta-1b 250 mcg (Extavia) and dimethyl fumarate. Fingolimod is dominated by dimethyl fumarate.
Discontinuation rate
There is evidence to suggest that there are no significant differences in adherence between the disease-modifying agents.65 There is some difference in opinion regarding the rates of treatment discontinuation, ranging from annual rates of 10% (based on expert opinion, and other health economic evaluations) to 25% reported by Wong et al.65 In the base case, a constant annual rate of 15% was assumed across all treatments for the first two years, based on the
discontinuation rate in the clinical trials included in the systematic review. After two years, the discontinuation rate was assumed to be zero, assuming that all patients who discontinue treatment would have done so by the end of the second year. Sensitivity analysis was also conducted, varying the constant discontinuation rate.Results show that ICURs are not very
sensitive to the discontinuation rate. In addition, exploratory analysis was conducted assuming a lower discontinuation rate with the oral treatments — fingolimod and dimethyl acetate — (10%) versus injectable treatments (25%), which resulted with an increased ICUR for natalizumab but did not change which treatments would comprise the cost-effectiveness frontier (Table 35, Table 49).
Table 35: Results of the Univariate Sensitivity Analysis Regarding
Annual Discontinuation Rate
Scenario Result
15% for the first 2 years (base case)
If λ < $118,242, glatiramer acetate is a cost-effective treatment. If $118,242 < λ < $425,655, interferon beta-1b 250 mcg (Extavia) is a cost-effective treatment.
If $425,655 < λ < $872,972, dimethyl fumarate is a cost-effective treatment.
If λ > $872,972, natalizumab is a cost-effective treatment.
0% annual
discontinuation rate
If λ < $122,032, glatiramer acetate is a cost-effective treatment. If $122,032 < λ < $426,213, interferon beta-1b 250 mcg (Extavia) is a cost-effective treatment.
If $426,213 < λ < $880,388, dimethyl fumarate is a cost-effective treatment.
If λ > $880,388, natalizumab is a cost-effective treatment.
25% annual
discontinuation rate for the first 2 years
If λ < $15,584, glatiramer acetate is a cost-effective treatment. If $115,584 < λ < $425,339, interferon beta-1b 250 mcg (Extavia) is a cost-effective treatment.
If $425,339 < λ < $867,743, dimethyl fumarate is a cost-effective treatment.
If λ > $867,743, natalizumab is a cost-effective treatment.
10% annual
discontinuation rate of oral treatments, 25% of injectable treatments for the first 2 years
If λ < $115,584, glatiramer acetate is a cost-effective treatment. If $115,584 < λ < $416,037, interferon beta-1b 250 mcg (Extavia) is a cost-effective treatment.
If $416,037 < λ < $1,449,326, dimethyl fumarate is a cost-effective treatment.
If λ > $1,449,326, natalizumab is a cost-effective treatment.
mcg = microgram.
In all scenarios, interferon beta-1a 30 mcg and interferon beta-1a 22 mcg are dominated by glatiramer acetate and interferon beta-1b 250 mcg (Extavia). Interferon beta-1b 250 mcg (Betaseron) is dominated by interferon beta-1b 250 mcg (Extavia). Interferon beta-1a 44 mcg is dominated by glatiramer acetate, interferon beta-1b 250 mcg (Extavia), and dimethyl fumarate. Fingolimod is dominated by dimethyl fumarate.
Percent of PML associated with natalizumab
Table 36: Results of Threshold Analysis Regarding PML Associated With Natalizumab
PML rate Mortality rate Total Cost Total QALYs Versus Glatiramer
Acetate ICUR 0.00% 18.5% $482,692 11.585 $514,201 0.15% (base case) 18.5% $482,436 11.580 $522,472 0.20% 18.5% $482,348 11.578 $525,377 1.00% 18.5% $480,983 11.549 $575,626 0.15% 0% $482,692 11.585 $514,201 0.15% 10% $482,550 11.582 $518,755 0.15% 18.50% (base case) $482,436 11.580 $522,472 0.15% 30% $482,293 11.577 $527,229
ICUR = incremental cost-utility ratio; PML = progressive multifocal leukoencephalopathy; QALY = quality-adjusted life-year.
The results of the analysis show that, because of the low rate of PML associated with
natalizumab, the scenario assuming no PML associated with natalizumab has similar results to the base case.
Threshold analysis regarding the price of emerging treatments
Because there is uncertainty regarding the price of emerging treatments, threshold analysis was conducted exploring what the treatment costs need to be in order for treatments to be
considered cost-effective under different willingness-to-pay thresholds. The results are presented in Table 37.
Table 37: Sensitivity Analysis Regarding Cost of Emerging Treatments
Treatment Estimated
Annual cost
λ = $50,000
(ICUR versus glatiramer acetate)
λ = $100,000
(ICUR versus glatiramer acetate)
Alemtuzumab 12 mg $40,281a $21,900 $25,000
Alemtuzumab 24 mg $40,281a $23,550 $26,950
Teriflunomide 14 mg $24,184b $16,420 $16,650
ICUR = incremental cost-utility ratio; mg = milligram.
a Assumption, based on the price of natalizumab. b
Assumption, based on the US price.
b) Structural uncertainty
Stopping rule
For the base case scenario, it was assumed that, once patients progress to EDSS = 7.0 or SPMS, they will discontinue treatment. Due to the differences in stopping rules across the Canadian provincial plans, a sensitivity analysis was conducted varying the EDSS score that would lead to treatment discontinuation, as well as treatment discontinuation with the
progression to SPMS. Results are presented in Figure 8 and in Table 53.
The analysis showed that a stopping rule at EDSS = 6 or progression to SPMS would lead to lower ICURs. The ICURs were very close to those when considering a stopping rule at EDSS = 7. However, earlier treatment discontinuation at EDSS = 5, as well as late
discontinuation at EDSS > 7, increased the ICURs. Because the model assumes no treatment benefit for patients who have progressed to SPMS, a stopping rule without considering SPMS progression would result in much higher ICURs.
Figure 8: Sensitivity Analysis Regarding Stopping Rule
EDSS = Expanded Disability Status Scale; QALY = quality-adjusted life-year; SPMS = secondary-progressive multiple sclerosis. Note: The dominated treatments are not included.
Time horizon of 10 years, 30 years, and 40 years
The base case scenario was based on a time horizon of 25 years. Sensitivity analysis was conducted by varying the time horizon within the range of 10 years to 40 years (lifetime).
Figure 9 shows the impact of the time horizon of the economic model on the sequential ICURs. (Figure 9).
Figure 9: Sensitivity Analysis Regarding Time Horizon
Improvements in EDSS scores
The base case model includes improvements on the EDSS scale, based on findings from the study by Tremlett et al.,63 which concluded that disability improvements in MS over one or two years are not unusual. A scenario analysis was conducted to measure the impact of not
allowing improvements in EDSS in the economic model. The analyses resulted in slightly lower, but not significantly lower, ICURs. Results are presented in Table 38, and in more detail in Table 51.
Table 38: Results of the Univariate Sensitivity Analysis Regarding Improvements on EDSS
Scale
Source for Utilities Result
Improvements on EDSS scale (base case)
If λ < $118,242, glatiramer acetate is a cost-effective treatment.
If $118,242 < λ < $425,655, interferon beta-1b 250 mcg (Extavia) is a cost- effective treatment.
If $425,655 < λ < $872,972, dimethyl fumarate is a cost-effective treatment. If λ > $872,972, natalizumab is a cost-effective treatment.
No improvements on EDSS scale
If λ < $104,221, glatiramer acetate is a cost-effective treatment.
If $104,221 < λ < $438,617, interferon beta-1b 250 mcg (Extavia) is a cost- effective treatment.
If $438,617 < λ < $829,108, dimethyl fumarate is a cost-effective treatment. If λ > $829,108, natalizumab is a cost-effective treatment.
EDSS = Expanded Disability Status Scale; mcg = microgram.
In all scenarios, interferon beta-1a 30 mcg and interferon beta-1a 22 mcg are dominated by glatiramer acetate and interferon beta-1b 250 mcg (Extavia). Interferon beta-1b 250 mcg (Betaseron) is dominated by interferon beta-1b 250 mcg (Extavia). Interferon beta-1a 44 mcg is dominated by glatiramer acetate, interferon beta-1b 250 mcg (Extavia), and dimethyl fumarate. Fingolimod is dominated by dimethyl fumarate.
Relapse rate being modelled as a constant rather than time-dependent variable
There is available evidence suggesting that the frequency of relapse is affected by a patient’s age and disease duration;68 i.e., is a time-dependent variable.5 To assess the impact, a sensitivity analysis was conducted by applying a constant relapse rate, as per alternative sources.62,64,69 Table 39 summarizes the reported relapse rates for untreated patients in the identified studies. Table 40 presents the results of the sensitivity analysis showing that increasing the relapse rates decreases the ICURs.
Table 39: Relapse Rate Based on Natural History of Disease
Source Relapse Rate
EDSS 0-2 EDSS 3-5
ScHARR64 0.835 1.423
Prosser et al.(2004)62 1.395 1.395
Patzold and Pocklington (1982) (constant, time since onset 5 years)69
1.110 1.110
Table 40: Results of the Univariate Sensitivity Analysis Regarding Relapse Rates Source for utilities Result
Time-dependent variable
(base case)
If λ < $118,242, glatiramer acetate is cost-effective treatment.
If $118,242 < λ < $425,655, interferon beta-1b 250 mcg (Extavia) is a cost- effective treatment.
If $425,655 < λ < $872,972, dimethyl fumarate is a cost-effective treatment. If λ > $872,972, natalizumab is cost-effective treatment.
ScHARR64
Relapse rate = 0.835 (EDSS = 0-2) Relapse rate = 1.423 (EDSS = 3-5)
If λ < $124,172, glatiramer acetate is cost-effective treatment.
If $124,172 < λ < $354,333, interferon beta-1b 250 mcg (Extavia) is a cost- effective treatment.
If $354,333 < λ < $803,519, dimethyl fumarate is a cost-effective treatmen. If λ > $803,519, natalizumab is a cost-effective treatment.
Prosser et al. (2004)62
Relapse rate = 1.395
If λ < $140,432 glatiramer acetate is cost-effective treatment.
If $140,432 < λ < $241,362 interferon beta-1b 250 mcg (Extavia) is a cost- effective treatment.
If $241,362 < λ < $665,950, dimethyl fumarate is a cost-effective treatment. If λ > $665,950, natalizumab is a cost-effective treatment.
Patzold and Pocklington (1982)69
Relapse rate = 1.1
If λ < $132,012, glatiramer acetate is cost-effective treatment.
If $132,012 < λ < $297,194, interferon beta-1b 250 mcg (Extavia) is a cost- effective treatment.
If $297,194 < λ < $737,176, dimethyl fumarate is a cost-effective treatment. If λ > $737,176, natalizumab is a cost-effective treatment.
EDSS = Expanded Disability Status Scale; mcg = microgram.
In all scenarios, interferon beta-1a 30 mcg and interferon beta-1a 22 mcg are dominated by glatiramer acetate and interferon beta-1b 250 mcg (Extavia). Interferon beta-1b 250 mcg (Betaseron) is dominated by interferon beta-1b 250 mcg (Extavia). Interferon beta-1a 44 mcg is dominated by glatiramer acetate, interferon beta-1b 250 mcg (Extavia) and dimethyl fumarate.