Cost-effectiveness of natalizumab versus fingolimod for the treatment of relapsing multiple sclerosis

Abstract

Background:

With the addition of new agents for the treatment of multiple sclerosis (MS) (e.g., fingolimod), there is a need to evaluate the relative value of newer therapies in terms of cost and effectiveness, given healthcare resource constraints in the United States.

Objective:

To assess the cost-effectiveness of natalizumab vs fingolimod in patients with relapsing MS.

Methods:

A decision analytic model was developed to estimate the incremental cost per relapse avoided of natalizumab and fingolimod from a US managed care payer perspective. Two-year costs of treating patients with MS included drug acquisition costs, administration and monitoring costs, and costs of treating MS relapses. Effectiveness was measured in terms of MS relapses avoided (data from AFFIRM and FREEDOMS trials). One-way and probabilistic sensitivity analyses were conducted to assess uncertainty.

Results:

Mean 2-year estimated treatment costs were $86,461 (natalizumab) and $98,748 (fingolimod). Patients receiving natalizumab had a mean of 0.74 relapses avoided per 2 years vs 0.59 for fingolimod. Natalizumab dominated fingolimod in the incremental cost-effectiveness analysis, as it was less costly and more effective in reducing relapses. One-way sensitivity analysis showed the results of the model were robust to changes in drug acquisition costs, administration costs, and costs of treating MS relapses. Probabilistic sensitivity analysis showed natalizumab was cost-effective 95.1% of the time, at a willingness-to-pay (WTP) threshold of $0 per relapse avoided, increasing to 96.3% of the time at a WTP threshold of $50,000 per relapse avoided.

Limitations:

Absence of data from direct head-to-head studies comparing natalizumab and fingolimod, use of relapse rate reduction rather than sustained disability progression as primary model outcome, assumption of 100% adherence to MS treatment, and not capturing adverse event costs in the model.

Conclusions:

Natalizumab dominates fingolimod in terms of incremental cost per relapse avoided, as it is less costly and more effective.     

Fingolimod versus natalizumab in patients with relapsing remitting multiple sclerosis: a cost-effectiveness and cost-utility study in Iran

Aims: Multiple sclerosis (MS) is a chronic, autoimmune, and inflammatory disease. If the first-line medicines are not effective enough, specialists will prescribe second-line medicines, such as natalizumab and fingolimod. This study aimed to compare the cost-effectiveness and cost-utility of fingolimod with those of natalizumab in patients with relapsing-remitting multiple sclerosis (RRMS) in Iran, Fars province in 2016.

Materials and methods: This study was a cost-effectiveness and cost-utility study in which a Markov model was used. The study used the census method to evaluate 81 patients with MS in Iran, Fars province who were being treated with fingolimod and natalizumab. In this study, costs were collected from the societal perspective, and the outcomes were the mean of relapse avoided rate and QALY. The cost data collection form, Kurtzke Expanded Disability Status Scale, and EQ-5D-3L questionnaire were used to collect the required data.

Results: The results showed that, compared to natalizumab, patients who used fingolimod had decreased costs (58,087 vs 201,707), increased QALYs (8.09 vs 7.37), and a better relapse avoided rate (6.27 vs 5.83) per patient over the lifetime. The results of the sensitivity analysis showed that the results of the study were robust. Also, the results of the scatter plots showed that fingolimod was more cost-effective based on the QALY and relapse avoided rate in 62% and 56%, respectively, of the simulations for the thresholds below $15,657 for the studied patients.

Conclusions: According to the results of this study, the cost-effectiveness and cost-utility of fingolimod were higher than those of natalizumab. Therefore, it is recommended that treatment with fingolimod be the first priority of second-line treatment for MS patients, and policy-makers and health managers are encouraged to make efforts in order to increase insurance coverage and reduce the out-of-pocket payments of these patients.     

Cost-minimization analysis of alemtuzumab compared to fingolimod and natalizumab for the treatment of active relapsing-remitting multiple sclerosis in the Netherlands

Aim: In active relapsing remitting multiple sclerosis (RRMS) patients requiring second-line treatment, the Dutch National Health Care Institute (ZiN) has not stated a preference for either alemtuzumab, fingolimod, or natalizumab. The aim was to give healthcare decision-makers insight into the differences in cost accumulation over time between alemtuzumab—with a unique, non-continuous treatment schedule—and fingolimod and natalizumab for second-line treatment of active RRMS patients in the Netherlands.

Methods: In line with ZiN’s assessment, a cost-minimization analysis was performed from a Dutch healthcare perspective over a 5-year time horizon. Resource use was derived from hospital protocols and summaries of product characteristics, and validated by two MS specialists. Unit costs were based on national tariffs and guidelines. Robustness of the base case results was verified with multiple sensitivity and scenario analyses.

Results: Alemtuzumab results in cost savings compared to fingolimod and natalizumab from, respectively, 3.3 and 2.8 years since treatment initiation onwards. At 5 years, total discounted costs per patient of alemtuzumab were €79,717, followed by fingolimod with €110,044 and natalizumab with €122,238, resulting in cost savings of €30,327 and €42,522 for alemtuzumab compared to fingolimod and natalizumab, respectively. Key drivers of the model are drug acquisition costs and the proportions of patients that do not require further alemtuzumab treatment after either two, three, or four courses.

Limitations: No treatment discontinuation and associated switching between treatments were incorporated. Consequences of JC virus seropositivity while continuing natalizumab treatment (e.g. additional monitoring) were omitted from the base case.

Conclusion: The current cost-minimization analysis demonstrates that, from the Dutch healthcare perspective, treating active RRMS patients with alemtuzumab results in cost savings compared to second-line alternatives fingolimod and natalizumab from ～3 years since treatment initiation onwards. After 5 years, alemtuzumab’s cost savings are estimated at €30k compared to fingolimod and €43k compared to natalizumab.     

The cost-effectiveness of disease-modifying therapies for the treatment of relapsing-remitting multiple sclerosis

Background: The safety and efficacy of disease-modifying therapies (DMTs) for relapsing-remitting multiple sclerosis (RRMS) has been established; however, it is not clear which provides optimal value, given benefit-risk profiles and costs.

Aims: To compare the cost-effectiveness of current DMTs for patients with RRMS in the US.

Materials and methods: A Markov model predicting RRMS course following initiation of a DMT was created comparing outcomes (e.g. relapses, disease progression) and costs of natalizumab (NTZ), dimethyl fumarate (DMF), and peginterferon beta-1a (PEG) with fingolimod (FIN), glatiramer acetate (GA, 20?mg daily), and subcutaneous interferon beta-1a (IFN, 44?mcg), respectively, over 10 years. RRMS and secondary-progressive MS (SPMS) EDSS state transitions were predicted in 3-month cycles in which patients were at risk of death, relapse, or discontinuation. Upon DMT discontinuation, natural history progression and relapse rates were applied. Incremental cost-effectiveness ratios (ICERs) were estimated for the cost per relapse avoided, relapse-free years gained, progression avoided, and progression-free years gained. The impact of model parameters on outcomes was evaluated via one-way sensitivity analyses.

Results: Costs ranged from $561,177 (NTZ) to $616,251 (GA). NTZ, DMF, and PEG were dominant (less costly and more effective) compared to FIN, GA, and IFN, respectively, for all ICERs. Variability in drug costs and parameters that affected drug cost accrual (e.g. discontinuation rates and the decision to drop out after SPMS conversion) had a considerable impact on ICERs.

Limitations: Several simplifying assumptions were made that may represent potential limitations of this analysis (e.g. a constant treatment effect over time was assumed).

Conclusions: The results from this analysis suggest that the NTZ, DMF, and PEG are cost-effective DMT choices compared to FIN, GA, and IFN, respectively. The actual impact on a particular plan will vary based on drug pricing and other factors affecting drug cost accrual.     

Fingolimod reduces direct medical costs compared to natalizumab in patients with relapsing–remitting multiple sclerosis in The Netherlands

Abstract

Objective:

To assess the costs of oral treatment with Gilenya® (fingolimod) compared to intravenous infusion of Tysabri® (natalizumab) in patients with relapsing–remitting multiple sclerosis (RRMS) in The Netherlands.

Methods:

A cost-minimization analysis was used to compare both treatments. The following cost categories were distinguished: drug acquisition costs, administration costs, and monitoring costs. Costs were discounted at 4%, and incremental model results were presented over a 1, 2, 5, and 10 year time horizon. The robustness of the results was determined by means of a number of deterministic univariate sensitivity analyses. Additionally, a break-even analysis was carried out to determine at which natalizumab infusion costs a cost-neutral outcome would be obtained.

Results:

Comparing fingolimod to natalizumab, the model predicted discounted incremental costs of ?€2966 (95% CI: ?€4209; ?€1801), ?€6240 (95% CI: ?€8800; ?€3879), ?€15,328 (95% CI: ?€21,539; ?€9692), and ?€28,287 (95% CI: ?€39,661; ?€17,955) over a 1, 2, 5, and 10-year time horizon, respectively. These predictions were most sensitive to changes in the costs of natalizumab infusion. Changing these costs of €255 within a range from €165–364 per infusion resulted in cost savings varying from €4031 to €8923 after 2 years. The additional break-even analysis showed that infusion costs—including aseptic preparation of the natalizumab solution—needed to be as low as the respective costs of €94 and €80 to obtain a cost neutral result after 2 and 10 years.

Limitations:

Neither treatment discontinuation and subsequent re-initiation nor patient compliance were taken into account. As a consequence of the applied cost-minimization technique, only direct medical costs were included.

Conclusion:

The present analysis showed that treatment with fingolimod resulted in considerable cost savings compared to natalizumab: starting at €2966 in the first year, increasing to a total of €28,287 after 10 years per RRMS patient in the Netherlands.     

Cost-effectiveness of fingolimod versus interferon beta-1a for relapsing remitting multiple sclerosis in the United States

Abstract

Objective:

Fingolimod has been shown to be more efficacious than interferon (IFN) beta-1a, but at a higher drug acquisition cost. The aim of this study was to assess the cost-effectiveness of fingolimod compared to IFN beta-1a in patients diagnosed with relapsing-remitting multiple sclerosis (RRMS) in the US.

Methods:

A Markov model comparing fingolimod to intramuscular IFN beta-1a using a US societal perspective and a 10-year time horizon was developed. A cohort of 37-year-old patients with RRMS and a Kurtzke Expanded Disability Status Scale score of 0–2.5 were assumed. Data sources included the Trial Assessing Injectable Interferon vs FTY720 Oral in Relapsing–Remitting Multiple Sclerosis (TRANSFORMS) and other published studies of MS. Outcomes included costs in 2011 US dollars, quality-adjusted life years (QALYs), number of relapses avoided, and incremental cost-effectiveness ratios (ICERs).

Results:

Compared to IFN beta-1a, fingolimod was associated with fewer relapses (0.41 vs 0.73 per patient per year) and more QALYs gained (6.7663 vs 5.9503), but at a higher cost ($565,598 vs $505,234). This resulted in an ICER of $73,975 per QALY. Results were most sensitive to changes in drug costs and the disutility of receiving IFN beta-1a. Monte Carlo simulation demonstrated fingolimod was cost-effective in 35% and 70% of 10,000 iterations, assuming willingness-to-pay thresholds of $50,000 and $100,000 per QALY, respectively.

Limitations:

Event rates were primarily derived from a single randomized clinical trial with 1-year duration of follow-up and extrapolated to a 10-year time horizon. Comparison was made to only one disease-modifying drug—intramuscular IFN beta-1a.

Conclusion:

Fingolimod use is not likely to be cost-effective compared to IFN beta-1a unless fingolimod cost falls below $3476 per month or a higher than normal willingness-to-pay threshold is accepted by decision-makers.     

Cost-effectiveness of alemtuzumab and natalizumab for relapsing-remitting multiple sclerosis treatment in Iran: decision analysis based on an indirect comparison

Background: Alemtuzumab and natalizumab are approved as second-line therapies for relapsing-remitting multiple sclerosis (RRMS) patients in Iran who have shown an inadequate response to other disease-modifying therapy (DMT). In the absence of head-to-head trials, evaluations based on decision analytic modeling may be a suitable alternative to compare alemtuzumab and natalizumab in RRMS.

Purpose: To evaluate the cost-effectiveness of alemtuzumab compared with natalizumab in RRMS in Iran, based on an indirect comparison of clinical trial data.

Methods: A cost-utility analysis was conducted using a cohort-based Markov model to analyze cost-utility in a cohort of 1,000 RRMS patients treated with alemtuzumab or natalizumab who had failed at least one previous DMT. Costs were measured in 2018?US Dollars, and were estimated from both the societal and National Healthcare Service (NHS) perspective over a 20-year time horizon in Iran. One-way deterministic sensitivity analyses were carried out to investigate the impact of individual variables on model results.

Results: Alemtuzumab dominated natalizumab in both NHS and societal perspective analyses. From the NHS perspective, the total discounted costs per patient were estimated at $147,417 and $150,579 for alemtuzumab and natalizumab, respectively, over 20 years. The discounted quality-adjusted life years were estimated to be 7.07 and 6.05, respectively. Results were similar for the societal perspective analysis. Results were most sensitive to acquisition costs and the time horizon, while no sensitivity was observed for Expanded Disability Status Scale (EDSS) health-states utility, relapse relative risk, adverse event or EDSS-related costs, and laboratory/monitoring costs.

Conclusion: Alemtuzumab was dominant in the treatment of RRMS compared with natalizumab due to lower total cost, greater efficacy and slowing of disease progression, and lower rate of relapses over a 20-year time horizon in Iran. Comparative head-to-head trials and long-term follow-up are needed to confirm these results.     

When does economic model type become a decisive factor in health technology appraisals? Learning from the expanding treatment options for relapsing–remitting multiple sclerosis

Objectives: Specific economic model types often become de facto standard for health technology appraisal over time. Markov and discrete event simulation (DES) models were compared to investigate the impact of innovative modeling on the cost-effectiveness of disease-modifying therapies (DMTs) in relapsing–remitting multiple sclerosis (RRMS). Fingolimod was compared to dimethyl fumarate (DMF; in highly active [HA] RRMS), alemtuzumab (in HA RRMS) and natalizumab (in rapidly evolving severe RRMS). Comparator DMTs were chosen to reflect different dosing regimens.

Materials and methods: Markov and DES models used have been published previously. Inputs were aligned in all relevant respects, with differences in the modeling of event-triggered attributes, such as relapse-related retreatment, which is inherently difficult with a memoryless Markov approach. Outcomes were compared, with and without different attributes.

Results: All results used list prices. For fingolimod and DMF, incremental cost-effectiveness ratios (ICERs) were comparable (Markov: £4206/quality-adjusted life year [QALY] gained versus DES: £3910/QALY gained). Deviations were observed when long-term adverse events (AEs) were incorporated in the DES (Markov: £25,412 saved/QALY lost, versus DES: £34,209 saved/QALY lost, fingolimod versus natalizumab; higher ICERs indicate greater cost-effectiveness). For fingolimod versus alemtuzumab, when relapse-triggered retreatment was included in the DES, large cost differences were observed (difference between incremental cost is £35,410 and QALY is 0.10).

Limitations: UK payer perspective, therefore societal approach was not considered. Resource utilization and utilities for both models were not derived from the subpopulations; as the focus is on model type, input limitations that apply to both models are less relevant.

Conclusions: Whilst no model can fully represent a disease, a DES allows an opportunity to include features excluded in a Markov structure. A DES may be more suitable for modeling in RRMS for health technology assessment purposes given the complexity of some DMTs. This analysis highlights the capabilities of different model structures to model event-triggered attributes.     

Implications of Real-world Adherence on Cost-effectiveness Analysis in Multiple Sclerosis

Abstract

Objectives:

Adherence to medication is essential for optimal outcomes, especially for chronic diseases such as multiple sclerosis (MS). Studies in MS indicate that lower adherence is associated with an increased risk of relapse, hospitalization or emergency room (ER) visits, and higher medical costs. A previous investigation assessed the cost per relapse avoided for patients with MS receiving first-line disease modifying therapies (DMTs); however, the model assumed 100% adherence.

Methods:

Because real-world utilization patterns influence the actual effectiveness of medications, this analysis assessed the impact of real-world adherence from a US commercial payer perspective, using updated costs.

Results:

As was seen in the original study, in this revised model, fingolimod was associated with the lowest cost per relapse avoided ($90,566), followed by SC IFN β-1b (Extavia: $127,024), SC IFN β-1b (Betaseron: $137,492), SC IFN β-1a ($144,016), glatiramer acetate ($160,314), and IM IFN β-1a ($312,629). The model inputs that had the greatest impact on the results were adherence-adjusted relative relapse rate reduction (RRR) of fingolimod, the wholesale acquisition costs of fingolimod, and the average number of relapses in untreated patients with MS.

Limitations:

The estimates of DMT adherence are from a single claims database study of a large national pharmacy benefit manager that only measured adherence, not actual relapses, and the model does not incorporate manufacturer discounts and rebates, which are not publicly available.

Conclusion:

These results suggest that economic analyses of MS therapies should incorporate real-world adherence rates where available, rather than relying exclusively on trial-based efficacy estimates when considering the economic value of treatment alternatives, and that highly efficacious therapies with low adherence may yield real-world efficacy that is substantially lower than that observed in closely monitored clinical trials.     

Cost-effectiveness analysis of ocrelizumab versus subcutaneous interferon beta-1a for the treatment of relapsing multiple sclerosis

Aim: To conduct a cost-effectiveness analysis to compare ocrelizumab vs subcutaneous (SC) interferon beta-1a for the treatment of relapsing multiple sclerosis (RMS).

Methods: A Markov cohort model with a 20-year horizon was developed to compare ocrelizumab with SC interferon beta-1a from a US payer perspective. A cohort of patients with relapsing-remitting MS (RRMS) and Expanded Disability Status Scale (EDSS) scores of 0–6, who initiated treatment with ocrelizumab or SC interferon beta-1a, were entered into the model. The model considered 21 health states: EDSS 0–9 in RRMS, EDSS 0–9 in secondary-progressive multiple sclerosis (SPMS), and death. Patients with RRMS could transition across EDSS scores, progress to SPMS, experience relapses, or die. Transition probabilities within RRMS while patients received ocrelizumab or SC interferon beta-1a were based on data from the two SC interferon beta-1a-controlled Phase III OPERA I and OPERA II trials of ocrelizumab in RMS. Transitions within RRMS when off-treatment, RRMS-to-SPMS transitions, transitions within SPMS, and transitions to death were based on the literature. Utilities of health states, disutilities of relapses, costs of therapies, and medical costs associated with health states, relapse, and adverse events were from the literature and publicly available data sources. The model estimated per-patient total costs, incremental cost per life year (LY) gained, and incremental cost per quality-adjusted LY (QALY) gained. Deterministic sensitivity analyses (DSA) and probabilistic sensitivity analysis (PSA) were conducted to evaluate the robustness of the model results.

Results: Ocrelizumab was associated with a cost savings of $63,822 and longer LYs (Δ?=?0.046) and QALYs (Δ?=?0.556) over a 20-year time horizon. The results of the model were robust in the DSA and PSA.

Limitations: The model did not consider subsequent treatments and their impact on disease progression.

Conclusions: The results suggest that ocrelizumab is more cost-effective than SC interferon beta-1a for the treatment of RMS.     

Cost-utility analysis of alemtuzumab in comparison with interferon beta,fingolimod, and natalizumab treatment for relapsing-remitting multiple sclerosis in Austria

Background: Multiple sclerosis (MS), a chronic progressive, demyelinating, inflammatory disease, affects 2.5 million people worldwide. Approximately 63% of cases are classified as relapsing–remitting MS (RRMS) at the time of diagnosis. The aim of this cost-utility analysis is to evaluate alemtuzumab vs interferon beta (intramuscular [IM] interferon beta-1a, subcutaneous [SC] interferon beta-1a, SC interferon beta-1b, and SC pegylated interferon beta-1a) in previously treated, and vs SC interferon beta-1a, fingolimod, and natalizumab in untreated RRMS patients to determine the incremental cost-effectiveness ratio among the treatment alternatives as prices, the route, and the frequency of administration of considered products vary significantly.

Methods: The primary outcome was the modeled incremental cost-effectiveness ratio (ICER; €/quality-adjusted life-year [QALY] gained). Markov modeling with a 10-year time horizon was carried out. During each 3-month cycle, patients maintained the Expanded Disability Status Scale (EDSS) score or experienced progression, developed secondary progressive MS (SPMS), or showed EDSS progression in SPMS; experienced relapses; suffered from an adverse event (AE); changed treatment; or died. A published network meta-analysis (NMA) was used for indirect comparison. The possibility of a therapy switch was considered. Clinical input data and resource utilization data were derived from the literature. Costs were extracted from price lists published in Austria and were calculated from the payer’s perspective.

Results: In treatment naïve patients, alemtuzumab is associated with costs of €132,663 and 5.25 QALYs in a 10-year time horizon. Costs for SC interferon beta amount to €164,159 and generate 4.85 QALYs. Also, in the pre-treated patients, alemtuzumab dominated comparators by accumulating higher total QALYs (4.88) and lower total costs (€137.409) compared to interferon beta-1a (€200.133), fingolimod (€240.903), and natalizumab (€247.758).

Conclusion: The analysis shows that alemtuzumab is a cost-saving alternative to treat RRMS in pre-treated and therapy naïve patients. From the patient perspective, alemtuzumab improves quality-of-life.     

A discrete event simulation to model the cost-utility of fingolimod and natalizumab in rapidly evolving severe relapsing-remitting multiple sclerosis in the UK

Objective: Two disease-modifying therapies are licensed in the EU for use in rapidly-evolving severe (RES) relapsing-remitting multiple sclerosis (RRMS), fingolimod and natalizumab. Here a discrete event simulation (DES) model to analyze the cost-effectiveness of natalizumab and fingolimod in the RES population, from the perspective of the National Health Service (NHS) in the UK, is reported.

Methods: A DES model was developed to track individual RES patients, based on Expanded Disability Status Scale scores. Individual patient characteristics were taken from the RES sub-groups of the pivotal trials for fingolimod. Utility data were in line with previous models. Published costs were inflated to NHS cost year 2015. Owing to the confidential patient access scheme (PAS) discount applied to fingolimod in the UK, a range of discount levels were applied to the fingolimod list price, to capture the likelihood of natalizumab being cost-effective in a real-world setting.

Results: At the lower National Institute of Health and Care Excellence (NICE) threshold of £20,000/quality-adjusted life year (QALY), fingolimod only required a discount greater than 0.8% of list price to be cost-effective. At the upper threshold of £30,000/QALY employed by the NICE, fingolimod was cost-effective if the confidential discount is greater than 2.5%. Sensitivity analyses conducted using fingolimod list-price showed the model to be most sensitive to changes in the cost of each drug, particularly fingolimod.

Conclusions: The DES model shows that only a modest discount to the UK fingolimod list-price is required to make fingolimod a more cost-effective option than natalizumab in RES RRMS.     

Cost-minimization analysis of fingolimod compared with natalizumab for the treatment of relapsing–remitting multiple sclerosis in Sweden

Abstract

Background:

Fingolimod and natalizumab have the same European Union licence for the treatment of relapsing multiple sclerosis, and are considered by the Committee for Medicinal Products for Human Use (CHMP) to have broadly similar efficacy.

Objective:

A cost-minimization analysis was performed to compare differences in treatment costs between fingolimod and natalizumab from a societal perspective in Sweden.

Methods:

This analysis included costs associated with initiating and following treatment (physician visits and monitoring), continuing therapy (drugs and administration), and lost patient productivity and leisure time. Unit costs (in Swedish krona [SEK]) were based on regional data (median prices for physician visits and monitoring sessions). Natalizumab infusion costs were obtained from the national cost-per-patient database. Drug costs for both therapies were 15,651 SEK/28 days.

Results:

After 3 years, fingolimod use was associated with savings of 124,823?SEK/patient compared with natalizumab (total cost/patient: 566,718 SEK vs 691,542 SEK). Cost savings with fingolimod were 40,402 SEK/patient after 1 year and 301,730 SEK/patient after 10 years. Treatment with natalizumab was 18% more expensive than fingolimod therapy after 1 year and 23% more expensive after 10 years.

Limitations:

Based on the CHMP assessment, it was assumed that fingolimod and natalizumab have similar efficacy. The analysis was conducted for Sweden, and caution is needed in extrapolating the results to other countries.

Conclusion:

Fingolimod is cost-saving compared with natalizumab for the treatment of relapsing–remitting multiple sclerosis in Sweden.     

The cost effectiveness and budget impact of natalizumab for formulary inclusion

Abstract

Background: Crohn's disease (CD) and multiple sclerosis (MS) are debilitating autoimmune diseases, which represent a substantial cost burden in the context of managed care. As a corollary, there is an unmet pharmacotherapeutic need in patient populations with relapsing forms of MS, in addition to populations with moderately to severely active CD with evidence of inflammation who have experienced an inadequate response to other mainstream therapies. The purpose of this study was to analyze the clinical and economic data associated with natalizumab (Tysabri) and to determine the potential impact of its formulary inclusion in a hypothetical health plan.

Findings: Regarding MS, the implemented cost-effectiveness and budget-impact models demonstrated an anticipated reduction in relapse rate of 67% over 2 years, and a total therapy cost of $72,120 over 2 years, equating to a cost per relapse avoided of $56,594. With respect to the model assumptions, the market share of natalizumab would experience an increase to 8.5%, resulting in a total per-member, per-month healthcare cost increase of $0.003 ($0.002 for pharmacy costs and $0.001 for medical costs).

Regarding CD, over a 2-year period outlined by the model, natalizumab produced the highest average time in remission, steroid-free remission, and remission or response in comparison to the other agents. The mean total costs associated with the initiation of natalizumab, infliximab, and adalimumab were $68,372, $62,090, and $61,796, respectively. Although natalizumab's costs were higher, the mean time spent in remission while on this medication was 4.5 months, as opposed to 2.4 months for infliximab and 2.9 months with adalimumab. This shift in market share was used to estimate the change in total costs (medical + pharmacy), and the per-member per-month change for the model's base case was calculated to be $0.035.

Limitations: The aforementioned cost-effectiveness results for natalizumab in the treatment for CD and MS were limited by the model's predetermined assumptions. These assumptions include anticipated reduction in relapse rate after 2 years of therapy and acquisition costs in the MS model, as well as assuming a certain percentage of patients were primary and secondary failures of TNFα inhibitor therapy in the CD model.

Conclusion: The evidence presented here demonstrates that natalizumab provides clinical practitioners with another tool in their fight against both MS and CD, albeit by way of a different mechanism of action. After a thorough review of the evidence, the authors find that natalizumab has been shown to be relatively cost effective in the treatment of both conditions from a payer perspective; the therapy adds a new option for those patients for whom conventional treatment was unsuccessful.     

Using observational analysis of multiple sclerosis relapse to design outcomes-based contracts for disease-modifying drugs: a feasibility assessment

Abstract

Objective:

To assess predictors and costs of multiple sclerosis (MS) relapse, a potential outcome measure in payer-manufacturer risk-sharing agreements for disease-modifying drugs (DMDs).

Methods:

A retrospective cohort analysis of medical/pharmacy claims was used. Study patients had ≥1 DMD (interferon beta, glatiramer, natalizumab) claim, without DMD claims in a 6-month pre-period before DMD initiation; were aged 18–64 years and continuously enrolled from the pre-period through a 24-month post-period; and had ≥2 MS medical claims during the 30-month study period. Post-period relapse cohorts included: (1) severe (hospitalization with MS diagnosis); (2) moderate (outpatient services including intravenous methylprednisolone); and (3) none. Poisson regression modeled severe relapse frequency, logistic regression modeled ≥1 severe relapse, and generalized linear modeling predicted healthcare costs. Tested predictors included demographics, insurance type, index DMD, pre-period health status, and DMD medication possession ratio (MPR).

Results:

Severe relapse was experienced by 14.5% and moderate relapse by 13.8% of 2291 patients. In logistic regression, severe relapse was predicted by plan type; age (odds ratio [OR]?=?1.018, 95% confidence interval [CI]?=?1.005–1.031); pre-period Charlson Comorbidity Index (OR?=?1.307, 95% CI?=?1.166–1.464); pre-period proxy measure indicating impaired activities of daily living (OR?=?1.470, 95% CI?=?1.134–1.905); pre-period MS hospitalization (OR?=?2.174, 95% CI?=?1.537–3.074); and DMD non-adherence (MPR OR?=?0.101, 95% CI?=?0.068–0.151). Poisson regression results were similar. Predicted mean [standard deviation] all-cause healthcare expenditures were tripled for patients with severe compared with moderate relapse ($48,173 [$8665] and $13,334 [$1929], respectively).

Limitations:

Commercially insured patients from a single payer; use may have been inconsistent with approved indications; proxy relapse measure may have misclassified patients.

Conclusions:

Severe MS relapses requiring hospitalization, although affecting less than 15% of patients initiating DMD treatment, are associated with high medical costs. The only actionable predictor of severe relapse identified in observational analysis was MPR, raising questions about the feasibility of using observational data to guide outcomes-based contracting.     

Cost-effectiveness of delayed-release dimethyl fumarate for the treatment of relapsing forms of multiple sclerosis in the United States

Objective:

To assess the cost-effectiveness of delayed-release dimethyl fumarate (DMF, also known as gastro-resistant DMF), an effective therapy for relapsing forms of multiple sclerosis (MS), compared with glatiramer acetate and fingolimod, commonly used treatments in the US.

Methods:

A Markov model was developed comparing delayed-release DMF to glatiramer acetate and fingolimod using a US payer perspective and 20-year time horizon. A cohort of patients, mean age 38 years, with relapsing-remitting MS and Kurtzke Expanded Disability Status Scale (EDSS) scores between 0–6 entered the model. Efficacy and safety were estimated by mixed-treatment comparison of data from the DEFINE and CONFIRM trials and clinical trials of other disease-modifying therapies. Data from published studies were used to derive resource use, cost, and utility inputs. Key outcomes included costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios. Alternative scenarios tested in a sensitivity analysis included drug efficacy, EDSS-related or relapse-related costs, alternative perspectives, drug acquisition costs, and utility.

Results:

Base-case results with a 20-year time horizon indicated that delayed-release DMF increased QALYs +0.450 or +0.359 compared with glatiramer acetate or fingolimod, respectively. Reductions in 20-year costs with delayed-release DMF were ?$70,644 compared with once-daily glatiramer acetate and ?$32,958 compared with fingolimod. In an analysis comparing delayed-release DMF to three-times-weekly glatiramer acetate and assuming similar efficacy and safety to the once-daily formulation, 20-year costs with delayed-release DMF were increased by $15,806 and cost per QALY gained was $35,142. The differences in costs were most sensitive to acquisition cost and inclusion of informal care costs and productivity losses. The differences in QALYs were most sensitive to the impact of delayed-release DMF on disease progression and the EDSS utility weights.

Conclusion:

Delayed-release DMF is likely to increase QALYs for patients with relapsing forms of MS and be cost-effective compared with fingolimod and glatiramer acetate.     

Cost-effectiveness of cladribine tablets,alemtuzumab, and natalizumab in the treatment of relapsing-remitting multiple sclerosis with high disease activity in England

Aims: Cladribine tablets were the first oral short-course treatment approved for highly active relapsing multiple sclerosis (MS). The Association of British Neurologists guidelines currently recommend two infusion therapies, alemtuzumab and natalizumab, to treat high disease activity relapsing remitting MS (HDA-RRMS). This analysis assessed the cost-effectiveness of cladribine tablets in HDA-RRMS compared with alemtuzumab and natalizumab, from the perspective of the National Health Service (NHS) in England.

Materials and methods: A cohort-based Markov model with 11 health states (10 Expanded Disability Status Scale [EDSS] plus death) was developed. Transition matrices from the British Columbia registry were used to model the natural history of EDSS. The treatment effect on EDSS was modelled using hazard ratios for 6-month confirmed disability progression from an indirect treatment comparison (ITC). Relapses and drug-related adverse events were modeled via annualized relapse rates and event probabilities, with associated costs and quality-adjusted life year (QALY) losses. Utilities were derived from trials and the literature, and costs from NHS and literature sources. Uncertainty was assessed via probabilistic and deterministic sensitivity analyses.

Results: Cladribine tablets were dominant (i.e., less costly and more effective) vs alemtuzumab and natalizumab in pairwise comparisons, and the dominant strategy in fully incremental analyses. Incremental cost was driven largely by drug acquisition and administration costs, and incremental QALY gain largely by differences in delayed EDSS progression. Cladribine tablets had a 93% probability of being cost-effective at a threshold of GBP 30,000 per QALY gained, and remained dominant across the scenario analyses tested. The greatest influence on results was the treatment effect on disability progression derived from the ITC.

Limitations: Uncertainty over the efficacy of DMT beyond trial durations. In line with other comparative effectiveness analyses, the network meta-analysis informing this cost-effectiveness analysis was associated with a degree of uncertainty. No treatment switching analyses were undertaken.

Conclusions: Cladribine tablets are a cost-effective alternative to alemtuzumab and natalizumab in the treatment of HDA-RRMS from the perspective of the NHS in England.     

Incremental net monetary benefit of ocrelizumab relative to subcutaneous interferon β-1a

Aim: Disease-modifying therapies (DMTs) impact the natural history of relapsing forms of multiple sclerosis (RRMS) by reducing annual relapse rates and slowing disability progression. The effect of DMTs on indirect costs has not been consistently explored in cost-effectiveness studies thus far. The value to patients of an emerging DMT, ocrelizumab, was quantified in comparison to subcutaneous interferon beta-1a (IFNβSC) for the prevalent RRMS population with mild-to-moderate disability in the US, based on two Phase 3 trials, OPERA I and OPERA II, of ocrelizumab vs IFNβSC in RRMS.

Materials and methods: A Markov model was developed to compare disability progression as measured by Expanded Disability Status Scale (EDSS) and relapse outcomes over a 30-year horizon for ocrelizumab vs IFNβSC. Direct, indirect, and informal costs (2016?US dollars) and utilities for EDSS health states were obtained from the literature. Hazard ratios for disability progression and relapse rates were estimated from clinical trials. Value was assessed by calculating the net monetary benefit (NMB), defined as the monetary value of discounted quality-adjusted life years (QALYs) minus total costs, where the value of a QALY was $150,000. One-way sensitivity analyses were conducted.

Results: Ocrelizumab was associated with an incremental gain of 0.84 QALYs and cost savings of $287,713 relative to IFNβSC, resulting in an incremental NMB (INMB) of $413,611 per person over 30 years. The INMB increased by $151,763 for those initiating ocrelizumab at EDSS level 1 vs level 4. Influential parameters were QALY value, treatment costs, and disability progression; however, all sensitivity analyses indicated that the INMB for ocrelizumab relative to IFNβSC was ≥$300,000 per person.

Conclusions: Ocrelizumab provides greater value to RRMS patients compared with IFNβSC. Initiating ocrelizumab at lower EDSS levels leads to a greater cumulative value due to slower disability progression, which extends years with higher quality-of-life.     

Cost-effectiveness analysis of roflumilast/tiotropium therapy versus tiotropium monotherapy for treating severe-to-very severe COPD

Abstract

Objective:

To conduct a cost-effectiveness analysis comparing roflumilast/tiotropium therapy vs tiotropium monotherapy in patients with severe-to-very severe COPD.

Methods:

The economic evaluation applied a disease-based Markov cohort model with five health states: (1) severe COPD, (2) severe COPD with a history of severe exacerbation, (3) very severe COPD, (4) very severe COPD with a history of severe exacerbation, and (5) death. Within a given health state, a patient may have a mild/moderate or severe exacerbation or die. Data from roflumilast clinical trials and published literature were used to populate model parameters. The model calculated health outcomes and costs for roflumilast/tiotropium therapy vs tiotropium monotherapy over a 5-year horizon. Incremental cost and benefits were then calculated as cost-effectiveness ratios, including cost per exacerbation avoided and cost per quality adjusted life year ($/QALY).

Results:

Over a 5-year horizon, the estimated incremental costs per exacerbation and per severe exacerbation avoided were $589 and $5869, respectively, and the incremental cost per QALY was $15,815. One-way sensitivity analyses varying key parameters produced an incremental cost per QALY ranging from $1963–$32,773.

Limitations:

A number of key parameters used in the model were obtained from studies in the literature that were conducted under different contexts. Specifically, the relative risk estimate for severe COPD patients originates from a small trial not designed to demonstrate the impact of roflumilast on frequency of exacerbations. In addition, the model extrapolates the relative risk estimates over periods of 5–30 years, even though the estimates were only observed in trials that spanned less than a year.

Conclusions:

The addition of roflumilast to tiotropium is cost-effective for the treatment of severe to very severe COPD patients.