US Spending Associated With Transition From Daily to 3-Times-Weekly Glatiramer Acetate.

Importance: Market exclusivity for daily injections of glatiramer acetate, a disease-modifying therapy for multiple sclerosis, expired in 2015. In 2014, the manufacturer launched an alternate 3-times-weekly version that was widely adopted, sustaining market dominance of brand-name glatiramer until late 2017. Objective: To estimate excess US spending associated with the transition from daily to 3-times-weekly glatiramer. Design, Setting, and Participants: This economic evaluation estimated total US glatiramer spending from January 1, 2011, to June 30, 2019, using a national cohort from 3 data sources that collectively represent approximately 40% of the US glatiramer market: Medicare Part D, Medicaid, and a claims database of commercially insured and Medicare Advantage patients. Exposures: Calendar quarter. Main Outcomes and Measures: Outcomes were quarterly US glatiramer spending, estimated as price × use. Manufacturer list prices for generic products and estimates of net (postrebate) prices for brand-name products were used. Linear regression and interrupted time series models were used to compare spending trends in 3 periods: before generic competition (2011-2015), during generic competition for daily glatiramer (2015-2017), and during generic competition for daily and 3-times-weekly glatiramer (2017-2019). Results: From 2011 to 2015, US glatiramer spending increased to $962 million per quarter and did not decrease with generic competition of only daily glatiramer (2015-2017). After generic competition began for 3-times-weekly glatiramer in 2017, prices decreased by 47% to 64%, and spending decreased to $508 million per quarter in 2019 (P < .001 for slope). The delay in decreased spending from 2015 to 2017 was associated with excess spending of $4.3 billion to $6.5 billion. Conclusions and Relevance: These findings suggest that 2.5 years of delayed generic competition related to introduction of a new version of branded glatiramer acetate was associated with $4.3 billion to $6.5 billion in excess spending. Extended market exclusivity from introducing a new version of an existing brand-name drug can yield manufacturer returns out of proportion to the level of investment or risk involved; more limited incentives could encourage incremental innovations to existing drugs at a lower societal cost.

Differences Between Managed Care and Fee-for-Service Medicaid in the Use of Generics for High-Rebate Drugs: The Cases of Insulin Glargine and Glatiramer.

BACKGROUND: Statutory rebates and preferred drug lists (PDLs) may result in differential use of biosimilars and generics between Medicaid fee-for-service (FFS) and managed care organizations (MCOs), particularly for branded drugs with large price increases subject to large inflation rebates, which are not retained by MCOs. OBJECTIVE: To compare the use of 2 biosimilar/generics of branded drugs whose list price tripled in 2008-2018 across states with only FFS Medicaid, with MCOs not subject to statewide PDLs, with MCOs subject to statewide PDLs, and with MCOs where drug benefits have been carved out. METHODS: Using 2018 Medicaid drug utilization data, we extracted reimbursement records in Q1-Q3 2018 for insulin glargine 100 IU/mL and glatiramer. We calculated the market share of the biosimilar insulin glargine and generic glatiramer among the corresponding drugs. We compared the market share of these products across 4 state groups: states with only FFS Medicaid, states with MCOs not subject to statewide PDLs for each drug, states with MCOs subject to PDLs, and states with MCOs where drug benefits have been carved out into FFS. We evaluated the correlation between state-level penetration of MCOs and share of biosimilar/generic products. RESULTS: Nationally, the market share of these biosimilar/specialty generics was higher among MCOs than FFS (60.5% vs. 3.7% for biosimilar insulin glargine; 59.4% vs. 5.7% for generic glatiramer; all P < 0.001). The market share of these products was highest in states where MCOs were not subject to statewide PDLs for these drugs (59.1% for biosimilar insulin glargine, 52.8% for glatiramer) compared with states with MCOs subject to PDLs (2.4%, 18.0%); states with only FFS Medicaid (0.9%, 1.7%); or states where drug benefits have been carved out of MCOs (0.0%, 1.0%; all P < 0.001). There was a significant correlation between state-level MCO penetration and share of generic/biosimilar products (R = 0.50 for biosimilar insulin glargine and 0.57 for glatiramer; all P < 0.001). CONCLUSIONS: For 2 drug classes with large price increases, use of biosimilars/generics was greater in MCOs than FFS Medicaid, specifically in states without PDL requirements for MCOs. These findings may reflect financial incentives for MCOs to use drugs with lower list prices because they do not benefit from statutory Medicaid rebates. DISCLOSURES: No outside funding supported this study. Hernandez was funded by the National Heart, Lung and Blood Institute (grant number K01HL142847). The authors have nothing to disclose.

Effect of generic glatiramer acetate on spending and use of drugs for multiple sclerosis.

OBJECTIVE: To estimate changes in costs and utilization trends for disease-modifying therapies (DMTs) from 2011 to 2017 in the US Medicaid program. METHODS: Using quarterly Medicaid State Drug Utilization Data from 2011 to 2017, we summarize trends in spending, utilization, and costs per prescription for 15 multiple sclerosis (MS) DMTs including brand and generic versions of glatiramer acetate. We use interrupted time series regression to estimate the effect of market entry of generic glatiramer acetate on cost per prescription of other self-administered DMTs. RESULTS: Gross annual expenditures on MS DMTs increased from $453 million to $1.32 billion between 2011 and 2017 within the Medicaid program. Increased spending was primarily driven by increases in per prescription costs, which doubled during the study period. Although total utilization was stable, product specific utilization shifted from injectable to oral DMTs. However, throughout the study, the plurality of utilization was glatiramer acetate. The introduction of generic glatiramer acetate in Q2 of 2015 was associated with an immediate increase of $441 (95% confidence interval [CI] $184-$697; p < 0.001) in the cost per prescription of branded glatiramer acetate followed by a gradual $52 per prescription reduction (95% CI -$86 to -$18) over time. There were minimal changes in the costs for the other DMTs. CONCLUSIONS: Spending on MS DMTs in the Medicaid program have more than doubled over the last 7 years primarily as a function of higher costs per prescription. Introduction of a generic glatiramer acetate product in 2015 had nominal effects on overall price trajectories and utilization within the class.

Trends In Coverage For Disease-Modifying Therapies For Multiple Sclerosis In Medicare Part D.

The high cost of multiple sclerosis (MS) disease-modifying therapies can negatively affect access for patients through increased payer restrictions and higher out-of-pocket spending. Our objective was to describe changes in pharmacy benefit coverage and cost-sharing amounts for MS disease-modifying therapies in the Medicare Part D program, using enrollment-weighted Prescription Drug Plan Formulary files for the period 2007-16. Among therapies available throughout the study period, the rate of prior authorization use increased from 61-66 percent of plans to 84-90 percent. The share of plans with at least one therapy available without limitations declined from 39 percent to 17 percent. The projected cumulative out-of-pocket spending for 2019 was $6,894. The therapy with the highest out-of-pocket spending was generic glatiramer acetate. Policy makers need to consider both access restrictions and a growing cost-sharing burden as potential consequences of high and rising drug prices for people with MS.

Cost-Effectiveness of Alemtuzumab in the Treatment of Relapsing Forms of Multiple Sclerosis in the United States.

OBJECTIVE: To evaluate the cost-effectiveness of alemtuzumab compared with fingolimod, natalizumab, ocrelizumab, and generic glatiramer acetate 20 mg among patients with relapsing multiple sclerosis (RMS) in the United States. STUDY DESIGN: Markov model with annual periods from payer perspective. METHODS: The modeled population represented pooled patients from the CARE-MS I and II trials. Therapies' comparative efficacy at reducing relapses and slowing disability worsening was obtained from network meta-analyses. Safety information was extracted from package inserts. Withdrawal rates, treatment waning, resource use, cost, and utility inputs were derived from published studies and clinical expert opinion. To project the natural history of disease worsening, data from the British Columbia cohort was used. RESULTS: Alemtuzumab dominated comparators by accumulating higher total quality-adjusted life-years (QALYs) (8.977) and lower total costs ($421 996) compared with fingolimod (7.955; $1 085 814), natalizumab (8.456; $1 048 599), ocrelizumab (8.478; $908 365), and generic glatiramer acetate (7.845; $895 661) over a 20-year time horizon. Alemtuzumab's dominance was primarily driven by savings in treatment costs because alemtuzumab has long-term duration of response and is initially administered as 2 annual courses, with 36.1% of patients requiring retreatment over 5 years, whereas comparators are used chronically. In model scenarios where alemtuzumab's long-term duration of response was assumed not to hold and therapy had to be administered annually, probabilistic sensitivity analyses showed that alemtuzumab remained cost-effective versus ocrelizumab at a willingness-to-pay threshold of $100 000/QALY in 74% to 100% of model runs. CONCLUSIONS: Alemtuzumab was a cost-effective therapy. Model results should be used to optimize clinical and managed care decisions for effective RMS treatment.

Cost-Effectiveness of Peginterferon Beta-1a and Alemtuzumab in Relapsing-Remitting Multiple Sclerosis.

BACKGROUND: Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system, affecting 2.5 million people globally and 400,000 people in the United States. While no cure exists for MS, the goal is to manage the disease using disease-modifying therapies (DMTs), which have been shown to slow disease progression and prevent relapses. Relapsing-remitting MS (RRMS) is the most common form of MS at the time of diagnosis. Peginterferon beta-1a (PEG) and alemtuzumab (ALT) were recently approved and have demonstrated good clinical outcomes, including reduced relapse rates in clinical trials. High costs associated with these DMTs necessitates cost-effectiveness analyses to understand their overall value in RRMS management. OBJECTIVES: To assess the cost-effectiveness of (a) Model 1: PEG relative to intramuscular interferon beta-1a (IM IFN), subcutaneous interferon beta-1b (SC IFN), glatiramer acetate 20 mg per mL (GA), fingolimod (FIN), natalizumab (NAT), and dimethyl fumarate (DMF), and (b) Model 2: ALT relative to subcutaneous interferon beta-1a 44 µg (IFN beta-1a 44 µg). Both analyses were conducted from a U.S. third-party payer perspective. METHODS: Two static decision models were used to compare the cost-effectiveness of PEG and ALT over a 1-year and a 2-year time horizon, respectively. Model inputs were drug acquisition costs (wholesale acquisition cost from RED BOOK); drug administration and monitoring costs (package inserts and Centers for Medicare & Medicaid Services 2015 Physician Fee Schedule); relapse rates and relapse rate reduction (clinical trials); and cost of managing relapses (published literature). All costs were adjusted to 2015 U.S. dollars using the medical care component of the Consumer Price Index. Outcomes measured were total cost of therapy per patient, cost per relapse avoided, and incremental cost-effectiveness ratios (ICERs) calculated as cost per relapse avoided. Sensitivity analysis was conducted to test model robustness given the uncertainty of model inputs and study assumptions. RESULTS: Model 1 results showed that PEG dominated IM IFN and GA, compared with SC IFN; PEG had an ICER of $1,978,000 per relapse avoided. Compared with FIN, NAT, and DMF, PEG was less expensive and less effective. Model 2 showed that ALT had an ICER of $25,276 per relapse avoided relative to IFN beta-1a 44 µg. CONCLUSIONS: In patients with RRMS, PEG is a viable alternative when compared with the DMTs in our model. Deciding whether to choose PEG over other DMTs would depend on multiple factors. On the other hand, ALT had an ICER of $25,276 cost per relapse avoided relative to IFN beta-1a 44 µg. The study results will assist payers in evaluating different medication choices for effective therapy. DISCLOSURES: No outside funding supported this study. Kamal has received research funding from Novartis Pharmaceuticals and the College of Psychiatric and Neurologic Pharmacists and also serves as a consultant for the Lynx Group. Dashputre and Pawar report no conflicts of interest. Study concept and design were primarily contributed by Dashputre, along with Kamal and Pawar. Dashputre took the lead in data collection, along with Kamal, and data analysis was performed by Dashputre, Kamal, and Pawar. The manuscript was written and revised primarily by Dashputre, along with Kamal and Pawar.

Two decades of glatiramer acetate: From initial discovery to the current development of generics.

Multiple sclerosis (MS) is a chronic, incurable, inflammatory disease of the central nervous system (CNS). In the United States, several US Food and Drug Administration (FDA)-approved disease-modifying treatments (DMTs) are available, including glatiramer acetate (GA; Copaxone®), one of the most longstanding treatments. GA was discovered serendipitously in the late 1960s/early 1970s while attempting to produce a synthetic antigen capable of inducing experimental autoimmune encephalomyelitis (EAE), an animal model of autoimmune inflammatory CNS disorders, including MS. Instead, GA was found to be protective in EAE models. Subsequent clinical evaluations resulted in GA's FDA approval for relapsing-remitting MS in 1996, followed by a change to the current indication of relapsing forms of MS along with approval of a higher dose and less frequently administered version in 2014. The cost of DMTs including GA remains high, highlighting the potential value of generic therapies for MS. A rigorous scientific approach may be undertaken to demonstrate equivalence between the generic and innovator drug. The introduction of generic versions of GA into the MS treatment landscape has the potential to reduce treatment costs, improving access to these much-needed treatments.

Difference-in-Differences Method in Comparative Effectiveness Research: Utility with Unbalanced Groups.

BACKGROUND: Comparative effectiveness research (CER) often includes observational studies utilizing administrative data. Multiple conditioning methods can be used for CER to adjust for group differences, including difference-in-differences (DiD) estimation. OBJECTIVE: This study presents DiD and demonstrates how to apply this conditioning method to estimate treatment outcomes in the CER setting by utilizing the MarketScan® Databases for multiple sclerosis (MS) patients receiving different therapies. METHODS: The sample included 6762 patients, with 363 in the Test Cohort [glatiramer acetate (GA) switched to fingolimod (FTY)] and 6399 in the Control Cohort (GA only, no switch) from a US administrative claims database. A trend analysis was conducted to rule out concerns regarding regression to the mean and to compare relapse rates among treatment cohorts. DiD analysis was used to enable comparisons among the Test and Control Cohorts. Logistic regression was used to estimate the probability of relapse after switching from GA to FTY, and to compare group differences in the pre- and post-index periods. RESULTS: Crude DiD analysis showed that in the pre-index period more patients in the Test Cohort experienced an MS relapse and had a higher mean number of relapses than in the Control Cohort. During the pre-index period, numeric and relative data for MS relapses in patients in the Test Cohort were significantly higher than in the Control Cohort, while no significant between-group differences emerged during the post-index period. Generalized linear modeling with DiD regression estimation showed that the mean number of MS relapses decreased significantly in the post-index period among patients in the Test Cohort compared with patients in the Control Cohort. CONCLUSION: In this study, an MS population was utilized to demonstrate how DiD can be applied to estimate treatment effects in a heterogeneous population, where the Test and Control Cohorts varied greatly. The results show that DiD offers a robust method for comparing diverse cohorts when other risk-adjustment methods may not be adequate.

Impact on the Incremental Cost-Effectiveness Ratio of Using Alternatives to EQ-5D in a Markov Model for Multiple Sclerosis.

OBJECTIVES: This study responds to a request in the National Institute for Health and Care Excellence (NICE) guidance to assess the impact of using alternative sources of utility values, applied to multiple sclerosis (MS). METHODS: Incremental cost-effectiveness ratios (ICERs) were calculated using utility values based on UK and Dutch values of EQ-5D, two UK mappings and one Dutch mapping of EQ-5D and two condition-specific instruments: the UK eight-dimensional Multiple Sclerosis Impact Scale (MSIS-8D) and the Dutch Multiple Sclerosis Impact Scale Preference-Based Measure (MSIS-PBM). Deterministic and Monte-Carlo simulation-based ICERs were estimated for glatiramer acetate versus symptom management using a lifetime Markov model. RESULTS: For both UK and Dutch perspectives, mapped and condition-specific utility values expressed significantly higher quality of life for the worst health state of the model than did EQ-5D. The ICER of glatiramer acetate with EQ-5D was US$182,291 for The Netherlands and US$153,476 for the UK. Ratios for mapped and condition-specific utilities were between 20 and 60 % higher. CONCLUSION: The overestimation of quality of life of patients with MS by mapped EQ-5D or condition-specific utility values, relative to observed EQ-5D, increases the ICER substantially in a lifetime Markov model.

The cost-effectiveness of delayed-release dimethyl fumarate for the treatment of relapsing-remitting multiple sclerosis in Canada.

BACKGROUND: Multiple sclerosis (MS) causes significant disability and diminished quality-of-life. Delayed-release dimethyl fumarate (DMF; also known as gastro-resistant DMF) is a new oral treatment for relapsing-remitting MS (RRMS) approved in the US, Australia, Canada, and Europe. OBJECTIVES: A cost-effectiveness model was developed to compare the health economic impact of DMF against other disease-modifying therapies (DMTs) as first-line RRMS treatment from a Canadian Ministry of Health perspective. METHODS: A Markov cohort model was developed to simulate patients' progression through health states based on the Kurtzke Expanded Disability Status Scale (EDSS) over a life-time horizon. Patients entered the model based on a distribution of baseline EDSS scores, from which they could progress to higher or regress to lower EDSS state, or remain in the same state. Relapses could occur at any EDSS score. Results from a mixed-treatment comparison were used to inform model inputs for disease progression and relapse rates per treatment. Costs included direct medical costs stratified by EDSS score. Utilities were accrued based on time spent in each EDSS state. RESULTS: Compared with glatiramer acetate, DMF yielded 0.528 incremental quality-adjusted life-years (QALYs) at an incremental cost of $23 338 Canadian dollars (CAD), resulting in an incremental cost-effectiveness ratio (ICER) of CAD $44 118/QALY. The ICER for DMF compared with Rebif 44 mcg was CAD $10 672. Results were consistent across a wide range of one-way and probabilistic sensitivity analyses. CONCLUSIONS: Based on traditional cost-effectiveness thresholds in Canada (CAD $50 000-60 000), DMF can be considered a cost-effective option compared to other first-line DMTs.

Cost-effectiveness analysis of peginterferon beta-1a compared with interferon beta-1a and glatiramer acetate in the treatment of relapsing-remitting multiple sclerosis in the United States.

Objective Peginterferon beta-1a 125 mcg, administered subcutaneously (SC) every 2 weeks, a new disease-modifying therapy (DMT) for relapsing-remitting multiple sclerosis (RRMS), was approved by the US Food and Drug Administration in 2014. This study assesses the cost-effectiveness of peginterferon beta-1a vs interferon beta-1a (44 mcg SC 3 times per week) and glatiramer acetate (20 mg SC once-daily) in the treatment of RRMS from the perspective of a US payer over 10 years. Methods A Markov cohort economic model was developed for this analysis. The model predicts disability progression, occurrence of relapses and other adverse events and translates them into quality-adjusted life years (QALYs) and costs. Natural history data were obtained from the placebo arm of the ADVANCE trial of peginterferon beta-1a, the London Ontario (Canada) database and a large population-based MS survey. Comparative efficacy of each DMT vs placebo was obtained from a network meta-analysis. Costs (in 2014 US dollars) were sourced from public databases and literature. Clinical and economic outcomes were discounted at 3% per year. Results Over 10 years, peginterferon beta-1a was dominant (i.e., more effective and less costly), with cost-savings of $22,070 and additional 0.06 QALYs when compared with interferon beta-1a 44 mcg and with cost-savings of $19,163 and 0.07 QALYs gained when compared with glatiramer acetate 20 mg. Results were most sensitive to variations in the treatment effect of each DMT, treatment acquisition costs of each DMT and the time horizon. Probabilistic sensitivity analyses indicated that peginterferon beta-1a remains dominant in >90% of 5,000 replications compared with either DMTs. Conclusion This analysis suggests that long-term treatment with peginterferon beta-1a improves clinical outcomes at reduced costs compared with interferon beta-1a 44 mcg and glatiramer acetate 20 mg and should be a valuable addition to managed care formularies for treating patients with RRMS.

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.

New FDA-Approved Disease-Modifying Therapies for Multiple Sclerosis.

PURPOSE: Interferon injectables and glatiramer acetate have served as the primary disease-modifying treatments for multiple sclerosis (MS) since their introduction in the 1990s and are first-line treatments for relapsing-remitting forms of MS (RRMS). Many new drug therapies were launched since early 2010, expanding the drug treatment options considerably in a disease state that once had a limited treatment portfolio. The purpose of this review is to critically evaluate the safety profile and efficacy data of disease-modifying agents for MS approved by the US Food and Drug Administration (FDA) from 2010 to the present and provide cost and available pharmacoeconomic data about each new treatment. METHODS: Peer-reviewed clinical trials, pharmacoeconomic studies, and relevant pharmacokinetic/pharmacologic studies were identified from MEDLINE (January 2000-December 2014) by using the search terms multiple sclerosis, fingolimod, teriflunomide, alemtuzumab, dimethyl fumarate, pegylated interferon, peginterferon beta-1a, glatiramer 3 times weekly, and pharmacoeconomics. Citations from available articles were also reviewed for additional references. The databases publically available at www.clinicaltrials.gov and www.fda.gov were searched for unpublished studies or studies currently in progress. FINDINGS: A total of 5 new agents and 1 new dosage formulation were approved by the FDA for the treatment of RRMS since 2010. Peginterferon beta-1a and high-dose glatiramer acetate represent 2 new effective injectable options for MS that reduce burden of administration seen with traditional interferon and low-dose glatiramer acetate. Fingolimod, teriflunomide, and dimethyl fumarate represent new oral agents available for MS, and their efficacy in reducing annualized relapse rates is 48% to 55%, 22% to 36.3%, and 44% to 53%, respectively, compared with placebo. Alemtuzumab is a biologic given over a 2-year span that reduced annualized relapse rates by 55% in treatment-naive patients and by 49% in patients relapsing on prior disease-modifying agents. Treatment emergent adverse effects were common with all new drug treatments. The cost of treating MS remains high, because MS therapies accounted for the highest spending growth of any specialty drug class in 2013. Most therapies cost, on average, US $6000/mo based on wholesale acquisition cost, and few cost-benefit studies are available for new treatments. IMPLICATIONS: With expansion of new treatments, patients and providers now have multiple options and improved flexibility in managing MS. The relative place in therapy of new treatments is unknown, and treatment decisions are largely based on patient preference, efficacy, and risk potential. The cost of treating MS continues to be high, even with more treatment options available.