Glatiramer acetate and interferon beta-1a for intramuscular administration: a study of outcomes among multiple sclerosis intent-to-treat and persistent-use cohorts

Abstract

Objective:

To study outcomes of multiple sclerosis (MS) patients treated with either glatiramer acetate (Copaxone) or interferon beta-1a for once-weekly, intramuscular administration (Avonex).

Methods:

An ‘intent-to-treat’ (ITT) cohort (n?=?1282) was established, consisting of patients diagnosed with MS who began therapy on either glatiramer acetate (GA) or intramuscular interferon beta-1a (IFN beta-1a-IM) and had continuous insurance coverage from 6 months before to 24 months after the date when they began taking the medication. A ‘persistent use’ (PU) cohort (n?=?639) was also constructed, consisting of individuals who, in addition to the criteria listed above, had a claim for GA or IFN beta-1a-IM within 28 days of the end of the 2-year post-period. Data were obtained from the i3 InVision Data Mart Database from July 2001 to June 2006. Multivariate regressions were used to examine both the 2-year total direct medical costs and the likelihood of relapse associated with the use of each of these alternative MS medications. A relapse was defined as either being hospitalized with a principal diagnosis of MS or having an outpatient visit with a MS diagnosis followed within 7 days by a claim for a corticosteroid. All regressions controlled a wide range of factors that may potentially affect outcomes.

Results:

In the ITT cohort, patients who started therapy on GA had a significantly lower 2-year risk of relapse (10.01 vs. 5.18%; p?=?0.0034) as well as significantly lower 2-year total medical costs ($44,201 vs. $41,121; p?=?0.0294). In the PU cohort, patients who used GA also had a significantly lower 2-year risk of relapse (7.25 vs. 2.16%; p?=?0.0048) as well as significantly lower total medical costs ($67,744 vs. 63,714; p?=?0.0445).

Limitations:

The analyses relies on an administrative claims database of an insured population and hence, may not be generalizeable to other populations. In addition, such a database precludes measurement of lost work time, unemployment, caregiver burden or other costs associated with MS.

Conclusions:

Results from this study indicate that the use of GA is associated with significantly lower probability of relapse as well as significantly lower 2-year total direct medical costs than IFN beta-1a-IM.     

The fiscal consequences of public health investments in disease-modifying therapies for the treatment of multiple sclerosis in Sweden

Abstract

Background and aims: The economic consequences of multiple sclerosis (MS) are broader than those observed within the health system. The progressive nature suggests that people will not be able to live a normal productive life and will gradually require public benefits to maintain living standards. This study investigates the public economic impact of MS and how investments in disease-modifying therapies (DMTs) influence the lifetime costs to government attributed to changes in lifetime tax revenue and disability benefits based on improved health status linked to delayed disease progression.

Methods: Disease progression rates from previous MS Markov cohort models were applied to interferon beta-1a, peginterferon beta-1a, dimethyl fumarate, and natalizumab using a public economic framework. The established relationship between expanded disability status scale and work-force participation, annual earnings, and disability rates for each DMT were applied. Subsequently, we assessed the effect of DMTs on discounted governmental costs consisting of health service costs, social insurance and disability costs, and changes in lifetime tax revenues.

Results: Fiscal benefits attributed to informal care and community services savings for interferon beta-1a, peginterferon beta-1a, dimethyl fumarate, and natalizumab were SEK340,387, SEK486,837, SEK257,330, and SEK958,852 compared to placebo, respectively. Tax revenue gains linked to changes in lifetime productivity for interferon beta-1a, peginterferon beta-1a, dimethyl fumarate, and natalizumab were estimated to be SEK27,474, SEK39,659, SEK21,661, and SEK75,809, with combined fiscal benefits of cost savings and tax revenue increases of SEK410,039, SEK596,592, SEK326,939, and SEK1,208,023, respectively.

Conclusion: The analysis described here illustrates the broader public economic benefits for government attributed to changes in disease status. The lifetime social insurance transfer costs were highest in non-treated patients, and lower social insurance costs were demonstrated with DMTs. These findings suggest that focusing cost-effectiveness analysis only on health costs will likely underestimate the value of DMTs.     

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.     

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.     

Cost-effectiveness analysis of glatiramer acetate in the treatment of relapsing-remitting multiple sclerosis

SUMMARY

We have developed an economic model around the patient level data from the pivotal clinical trial for Copaxone® (glatiramer acetate), combined with published cost and natural history data, to demonstrate cost-effectiveness in relapsing-remitting multiple sclerosis (RRMS). Based upon analysis over 8 years, the cost per relapse avoided and cost per disability unit avoided was £11,000 and £8,862 respectively. To facilitate comparison with other therapies and across other disease areas we also calculated the cost per quality adjusted life year (QALY). Dependent upon the assumed utility loss associated with duration of relapse, the cost per QALY ranged between £22,586 and £64,636 over 8 years analysis. Given the nature of the disease and compared to accepted standards of cost-effectiveness in the UK, this analysis shows that glatiramer acetate is demonstrably cost-effective versus best supportive care alone.

Copaxone is a registered trademark of Teva Pharmaceutical Industries, Israel     

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-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.     

Costs and effectiveness of fingolimod versus alemtuzumab in the treatment of highly active relapsing-remitting multiple sclerosis in the UK: re-treatment,discount, and disutility

Objective: Patients with relapsing-remitting multiple sclerosis (RRMS) treated with disease modifying therapies (DMTs) who continue to experience disease activity may be considered for escalation therapies such as fingolimod, or may be considered for alemtuzumab. Previous economic modeling used Markov models; applying one alternative technique, discrete event simulation (DES) modeling, allows re-treatment and long-term adverse events (AEs) to be included in the analysis.

Methods: A DES was adapted to model relapse-triggered re-treatment with alemtuzumab and the effect of including ongoing quality-adjusted life year (QALY) decrements for AEs that extend beyond previous 1-year Markov cycles. As the price to the NHS of fingolimod in the UK is unknown, due to a confidential patient access scheme (PAS), a variety of possible discounts were tested. The interaction of re-treatment assumptions for alemtuzumab with the possible discounts for fingolimod was tested to determine which DMT resulted in lower lifetime costs. The lifetime QALY results were derived from modeled treatment effect and short- and long-term AEs.

Results: Most permutations of fingolimod PAS discount and alemtuzumab re-treatment rate resulted in fingolimod being less costly than alemtuzumab. As the percentage of patients who are re-treated with alemtuzumab due to experiencing a relapse approaches 100% of those who relapse whilst on treatment, the discount required for fingolimod to be less costly drops below 5%. Consideration of treatment effect alone found alemtuzumab generated 0.2 more QALYs/patient; the inclusion of AEs up to a duration of 1 year reduced this advantage to only 0.14 QALYs/patient. Modeling AEs with a lifetime QALY decrement found that both DMTs generated very similar QALYs with the difference only 0.04 QALYs/patient.

Conclusions: When the model captured alemtuzumab re-treatment and long-term AE decrements, it was found that fingolimod is cost-effective compared to alemtuzumab, assuming application of only a modest level of confidential PAS discount.     

Cost-effectiveness analysis of utidelone plus capecitabine for metastatic breast cancer in China

Abstract

Objective: To estimate the cost-effectiveness of utidelone plus capecitabine therapy compared to capecitabine alone in patients with metastatic breast cancer (MBC) resistant to anthracyclines and taxanes treatment in the Chinese context and provide a reference for the marketing of utidelone in China.

Methods: A Markov model was developed based on the NCT02253459 clinical trial to simulate the clinical course of patients with metastatic breast cancer who had received taxanes and anthracycline therapy. The quality-adjusted life years (QALYs) and Incremental Cost Effectiveness Ratio (ICER) were then analyzed to evaluate the benefits. Two-parametric Weibull distribution was conducted to fit PFS and OS curves by using R. Sensitivity analyses were performed to evaluate the stability of the model designed.

Results: The addition of utidelone increased the cost and QALYs by $13,370.25 and 0.1961, respectively, resulting in an increased ICER of $68,180.78 per QALY. The most sensitive influential parameter on ICER was the price of utidelone. At the threshold of willingness-to-pay (WTP) of $24,380 (3 per capita GDP of China), the cost of utidelone per 30?mg of less than $18.5, $33.7, and greater than $48.8 resulted in a 100%, 50%, and 0% possibility of cost-effectiveness, respectively. The addition of utidelone was not cost-effective when it was $115.4 per 30?mg—the price of its analog paclitaxel. In consideration of varied economics levels across China, cost-effectiveness could be achieved with the price of utidelone ranging from $5.2 to $35.9.

Limitations: The survival curves extended beyond the follow-up time horizon, of which data were generated not from the real analyses but from our established two-parameter Weibull survival model.

Conclusion: It is recommended that the price of utidelone would be less than $18.5 per 30?mg in order to obtain cost-effectiveness for metastatic breast cancer patients resistant to anthracyclines and taxanes treatment in China.     

Long-term cost-effectiveness of home versus clinic-based management of chronic heart failure: the WHICH? study

Background: The cost-effectiveness of a heart failure management intervention can be further informed by incorporating the expected benefits and costs of future survival.

Methods: This study compared the long-term costs per quality-adjusted life year (QALY) gained from home-based (HBI) vs specialist clinic-based intervention (CBI) among elderly patients (mean age = 71 years) with heart failure discharged home (mean intervention duration = 12 months). Cost-utility analysis was conducted from a government-funded health system perspective. A Markov cohort model was used to simulate disease progression over 15 years based on initial data from a randomized clinical trial (the WHICH? study). Time-dependent hazard functions were modeled using the Weibull function, and this was compared against an alternative model where the hazard was assumed to be constant over time. Deterministic and probabilistic sensitivity analyses were conducted to identify the key drivers of cost-effectiveness and quantify uncertainty in the results.

Results: During the trial, mortality was the highest within 30 days of discharge and decreased thereafter in both groups, although the declining rate of mortality was slower in CBI than HBI. At 15 years (extrapolated), HBI was associated with slightly better health outcomes (mean of 0.59 QALYs gained) and mean additional costs of AU$13,876 per patient. The incremental cost-utility ratio and the incremental net monetary benefit (vs CBI) were AU$23,352 per QALY gained and AU$15,835, respectively. The uncertainty was driven by variability in the costs and probabilities of readmissions. Probabilistic sensitivity analysis showed HBI had a 68% probability of being cost-effective at a willingness-to-pay threshold of AU$50,000 per QALY.

Conclusion: Compared with CBI (outpatient specialized HF clinic-based intervention), HBI (home-based predominantly, but not exclusively) could potentially be cost-effective over the long-term in elderly patients with heart failure at a willingness-to-pay threshold of AU$50,000/QALY, albeit with large uncertainty.     

Estimating the rates of disability progression in people with active relapsing-remitting multiple sclerosis

SUMMARY

Estimated progression rates for people with active relapsing-remitting multiple sclerosis (RRMS) are essential for resource management but are poorly quantified according to disability severity. In this study data from the placebo arm of the AFFIRM study were used to estimate rates for a population of active RRMS patients and for a rapidly evolving severe (RES) subgroup of RRMS patients. A multistate Markov model was fitted to the data to derive a matrix of annual transition probabilities between disability states. The average progression over 2 years was estimated to be 0.27 Expanded Stability Status (EDSS) points (95% confidence interval (CI) 0.11-0.43) for active RRMS patients and 0.46 EDSS points (95% CI 0.16-0.79) for the RES subgroup. When similar baseline characteristics were used, progression in the RES subgroup was approximately 0.06-0.08 EDSS points faster per year than active RRMS patients. These results may be used for long-term forecasts of progression of these patient groups when used in conjunction with transition rates from RRMS to secondary progressive multiple sclerosis, and between secondary progressive multiple sclerosis EDSS states.     

聚乙二醇干扰素α-2a治疗慢性丙型肝炎的不良反应观察

目的观察聚乙二醇干扰素α-2a治疗慢性丙型肝炎的不良反应,探讨有效的处理措施。方法回顾性分析我院2011年1月～2012年1月收治的38例慢性丙型肝炎患者的临床资料,所有患者均给予聚乙二醇干扰素α-2a治疗,观察患者治疗期间的不良反应。结果本组38例患者治疗期间流感样症状发生率最高,为68.4%,患者主要表现为发热、鼻塞、关节肌肉痛,其次脱发的发生率为47.4%。肝功能损害、骨髓抑制反应、神经系统症状、皮疹的发生率分别为39.5%、28.9%、15.8%、7.9%。结论聚乙二醇干扰素α-2a治疗慢性丙型肝炎的不良反应较多,应引起临床医师的足够重视,一旦发生不良反应应迅速给予有效的对症处理,保证用药安全。     

Cost-effectiveness analysis of disease modifiying drugs (interferons and glatiramer acetate) as first line treatments in remitting-relapsing multiple sclerosis patients

Abstract

Objective:

The aim of this study was to assess cost-effectiveness of the different Disease Modifying Drugs (DMD) used as first-line treatments (interferons IM IFNβ-1a, SC IFNβ-1a, SC IFNβ-1b, and glatiramer acetate, GA) in Remitting-Relapsing Multiple Sclerosis (RRMS) in Spain.

Methods:

A Markov model was developed to simulate the progression of a cohort of patients with RRMS, during a period of 10 years. Seven health states, defined by the Expanded Disability Status Scale (EDSS), were considered in the model. Patients with an EDSS score less than 6.0 were assumed to be treated with one of the DMD. In addition, all patients were assumed to receive symptomatic treatment. The monthly transition probabilities of the model were obtained from the literature. The analysis was performed from the societal perspective, in which both direct and indirect (losses in productivity) healthcare costs (€, 2010) were included. A discount rate of 3% was applied to both costs and efficacy results.

Results:

GA was the less costly strategy (€322,510), followed by IM IFNβ-1a (€329,595), SC IFNβ-1b (€ 333,925), and SC IFNβ-1a (€348,208). IM IFNβ-1a has shown the best efficacy results, with 4.176 quality-adjusted life years (QALY), followed by SC IFNβ-1a (4.158 QALY), SC IFNβ-1b (4.157 QALY), and GA (4.117 QALY). Incremental costs per QALY gained with IM IFNβ-1a were €?1,005,194/QALY, €?223,397/QALY, and €117,914/QALY in comparison to SC IFNβ-1a, SC IFNβ-1b, and GA, respectively.

Conclusions:

First-line treatment with GA is the less costly strategy for the treatment of patients with RRMS. Treatment with IM IFNβ-1a is a dominant strategy (lower cost and higher QALY) compared with SC IFNβ-1a and SC IFNβ-1b. However, IM IFNβ-1a is not a cost-effective strategy vs GA, because incremental cost per QALY gained with IM IFNβ-1a exceeds the €30,000 per QALY threshold commonly used in Spain.

Limitations:

The highly-restrictive inclusion criteria of clinical trials limits generalization of the results on efficacy to all patients with multiple sclerosis. Availability of data for head-to-head comparisons is associated with the use of information from clinical trials.