Treating relapsing multiple sclerosis with subcutaneous versus intramuscular interferon-beta-1a: modelling the clinical and economic implications.

The EVIDENCE trial concluded that administering high-dose/high-frequency subcutaneous (SC) interferon-beta-1a (IFNb1a) was more effective in preventing relapses among patients with relapsing multiple sclerosis (MS) than low-dose weekly intramuscular (IM) IFNb1a after 64 weeks. This analysis utilized discrete-event simulation (DES) to model the potential longer-term clinical and economic implications of this trial. A DES predicting the course of relapsing MS and incorporating the effect of IFNb1a therapy was developed. The model began by randomly reading in actual patient data from the trial to create 1000 patients. Each simulated patient was replicated - one was assigned to receive SC IFNb1a three times a week and the other to receive IM IFNb1a once a week. During the simulation, patients may (i) experience relapses, with associated short- and long-term impacts on costs and disability; (ii) develop new T2 lesions detected by a magnetic resonance imaging scan; (iii) discontinue treatment because of adverse events or lack of response; (iv) advance to secondary progressive MS; or (v) die. Model inputs were mainly obtained from the EVIDENCE trial, but were taken from published literature if they could not be obtained from the trial. Direct medical costs ($US, year 2006 values) to the US payers were primarily obtained by updating a published cost analysis. Costs and benefits were discounted at 3% per annum. Extensive sensitivity analyses were conducted to test the robustness of the model results. Based on 100 replications of 1000 patient pairs over 4 years, SC IFNb1a was predicted to enable more patients to avoid relapse (216 vs 147). Total mean costs per patient (discounted) were $US79 890 with SC IFNb1a versus $US74 485 with IM administration, a net increase of $US5405 per patient. However, SC IFNb1a was estimated to prevent 0.50 relapses and save 23 relapse-free days per patient, yielding incremental cost-effectiveness ratios of $US10 755 per relapse prevented and $US232 per relapse-free day gained. Sensitivity analyses revealed that the result was most sensitive to the treatment efficacy, model time horizon and cost of IFNb1a treatment. Based on the results observed in the EVIDENCE trial, the model predicted that SC IFNb1a would yield greater health benefits over 4 years than IM IFNb1a, at a cost that would seem to be a reasonable trade-off.

Comparing the cost-effectiveness of disease-modifying drugs for the first-line treatment of relapsing-remitting multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) is an inflammatory autoimmune disorder of the central nervous system that primarily afflicts young adults. Approximately 400,000 people in the United States are affected by MS. Although several forms of MS exist, the most common course is known as relapsing-remitting MS (RRMS), which affects about 85% of MS patients. This form of MS is characterized by relapses of neurologic symptoms followed by periods of recovery. Progression of disease can lead to increasingly severe disability. Since the introduction of immunomodulatory biologic agents, such as interferon betas and glatiramer acetate, treatment has helped to change the course of the disease. Under budgetary constraints, health services payers are challenged to differentiate the economic value of these agents for formulary selection and/or placement. OBJECTIVE: The primary objective of this analysis was to evaluate the 2-year cost-effectiveness of 4 disease modifying drugs (DMDs) used as first-line treatment of RRMS: glatiramer acetate, interferon (IFN) Beta-1a IM injection, IFN Beta-1a SC injection, and IFN Beta-1b SC injection. METHODS: An Excel-based model was developed to compare the relative effectiveness and cost components of relapses, disability progression, and DMDs in the treatment of RRMS over a 2-year time horizon. The relative risk reduction (RRR) method was used to compare reduction in relapse rates and disease progression data from pivotal randomized double-blind placebo-controlled clinical trials of the DMDs. RRRs for relapses and disability progression, respectively, were calculated as the relative difference (treatment vs. placebo) in relapse rates and disease progression rates from placebo-controlled clinical trials. These RRRs were applied to the weighted average rates of relapse and number of disability progression steps seen in the placebo arms of the pivotal studies. The evaluation was conducted from the perspective of a U.S. health care payer (only direct medical costs considered). Medical savings were calculated as costs saved due to relapses avoided and prevention in disability progression steps. In the base case analysis, we assumed 89.4% persistence, a cost per relapse of $4,682, and a cost per disability progression step of $1,788. Monthly cost of therapy was defined as wholesale acquisition cost ($0 contractual discounts and $25 patient copayment assumed in the base case analysis) plus routine monitoring costs as assessed by an expert panel. The primary economic endpoint was cost per relapse avoided. Costs and outcomes occurring in the second year were discounted 3% to bring to 2008 present values. Oneway and multiway probabilistic (Monte Carlo) sensitivity analyses were conducted on key input variables to assess their impact on cost per relapse avoided. RESULTS: Without DMD treatment, patients were predicted to experience 2.55 relapses and 0.44 disability progression steps over a 2-year period (discounted values). The 2-year reductions in clinical relapses for treatment with glatiramer acetate, IFN Beta-1a IM injection, IFN Beta-1a SC injection, and IFN Beta-1b were 0.66, 0.42, 0.74, and 0.70, respectively. The 2-year reductions in disability progression steps for treatment with glatiramer acetate, IFN Beta-1a IM injection, IFN Beta-1a SC injection, and IFN Beta-1b were 0.05, 0.15, 0.12, and 0.11, respectively. In the base case analysis, IFN Beta-1a SC injection, IFN Beta-1b SC injection, and glatiramer acetate had the most favorable costs per relapse avoided ($80,589; $87,061; and $88,310; respectively) and IFN Beta-1a IM injection had the least favorable cost-effectiveness ratio ($141,721 per relapse avoided). Sensitivity analyses showed that these results were robust to changes in key input parameters, such as the number of relapses and disease progression steps in untreated patients, the RRR in clinical relapse and progression rates, the rate of persistence, the average cost of relapse, and the average cost of a disease progression step. CONCLUSION: This evaluation suggests that IFN Beta-1a SC injection, IFN Beta-1b SC injection, and glatiramer acetate represent the most cost-effective DMDs for the treatment of RRMS, where cost-effectiveness is defined as cost per relapse avoided, assuming that (a) the RRR in relapses and disease progression steps calculated from multiple DMD placebo-controlled clinical trials reflect real differences among DMDs over 2 years; and (b) resource unit costs derived from published sources reflect economic consequences of relapses and disease progression.

Use of an early disease-modifying drug adherence measure to predict future adherence in patients with multiple sclerosis.

BACKGROUND: Patients with multiple sclerosis (MS) who are adherent to their treatment regimens are less likely to experience relapses and the cost associated with relapse. Pharmacists whose practice involves these specialty pharmaceuticals used to treat MS are striving for ways to improve outcomes by achieving treatment adherence in their patients. Specialty pharmacies have reported higher adherence rates than traditional pharmacies, which may translate to improved outcomes. Identifying patients who warrant increased adherence intervention is critical. Models using administrative health care claims to predict adherence have typically included demographic characteristics, comorbidities, and/or previous consumption of health care resources. Addition of a measure of early adherence may improve the ability to predict future adherence outcomes.  OBJECTIVE: To evaluate early adherence with disease-modifying drugs (DMDs) as a predictor of future adherence in patients with MS.  METHODS: The first DMD claim (i.e., index event) for adult MS patients (aged ≥18 years and aged ≤ 65 years) who received self-injected DMDs between January 1, 2006, and May 31, 2010, was identified in a national U.S. managed care database. Patients were required to have continuous eligibility for 12 months pre- and 24 months post-index. Multiple regression models were used to predict future adherence as measured by the proportion of days covered (PDC). The base model included age, gender, a medication intensity measure, presence of a non-MS-related hospitalization pre-index, and markers for physical difficulty, forgetfulness, or depression/stress. Models adding early DMD adherence as a covariate were analyzed using incrementing 30-day periods predicting the subsequent 360 days.  RESULTS: There were 4,606 patients included with an average age of 46.0 (SD 9.4) years, and 78.7% were female. Average PDC in the first 360 days post-index was 80.0% (SD 26.0). Using the first 60 days of early adherence as the only predictor in the model showed an R2 of 20.6%. The base model (i.e., no early adherence measure but other covariates included) yielded an adjusted R2 of only 2.3%. As the time period of early adherence is increased (from 60 to 360 days), the explained variance as measured by adjusted R2 values increased from 20.6% to 53.5% (early adherence-only models). Addition of the covariates, other than early adherence, increased the R2 by 1% to 2%.  CONCLUSIONS: Statistical predictive models that include early adherence with DMDs were able to explain the variance in future adherence outcomes to a greater extent than models based solely on baseline characteristics. The efficiency of an adherence intervention in reaching its intended target can be improved by using models such as these with enhanced specificity and selectivity.

Treatment adherence and other patient-reported outcomes as cost determinants in multiple sclerosis: a review of the literature.

BACKGROUND: Treatment adherence is one of the key factors for achieving optimal clinical outcomes. In order to assess costs related to adherence to, and persistence and compliance with, disease-modifying therapies (DMTs) in patients with multiple sclerosis (MS), a narrative review of the literature was performed. Satisfaction with and preference for DMTs and their delivery devices were also assessed, as both can have an influence on patients' adherence and persistence. METHODS: Electronic databases (MEDLINE, PubMed, Google Scholar, congress proceedings) were searched to identify publications analyzing MS costs related to adherence, persistence, satisfaction, and preferences for MS treatments. Bibliographic references were hand searched. English or Spanish studies published between January 2007 and January 2013 were selected. RESULTS: A total of 398 titles were identified, of which 12 met the inclusion criteria. Six studies evaluated the impact of adherence, persistence, and compliance on treatment costs; four publications analyzed satisfaction with DMTs; and two assessed treatment preferences based on attributes of the delivery device. Increased adherence and persistence were associated with better clinical outcomes, leading to lower relapse risk (odds ratio [OR]: 0.71; 95% confidence interval [CI]: 0.59-0.85) and a decrease in health care resource use, such as MS-related hospitalizations (OR: 0.63; 95% CI: 0.47-0.83) and emergency department visits (OR: 0.80; 95% CI: 0.60-1.07). This reduction in resource use led to a patient/year total cost reduction (excluding DMT costs) of up to 22%. CONCLUSION: This review highlights the importance of ensuring adequate adherence in MS patients through treatments and devices better tailored to patients' needs that could enhance clinical outcomes and reduce MS costs. Understanding the factors underlying satisfaction and compliance with treatment and patients' preference for certain therapies could help in the development of strategies that can improve adherence.

Medication possession ratio: implications of using fixed and variable observation periods in assessing adherence with disease-modifying drugs in patients with multiple sclerosis.

BACKGROUND: The purpose of this study was to compare two methods of adherence calculation using administrative data for patients with multiple sclerosis (MS) who are prescribed disease-modifying drugs. METHODS: Pharmacy-billed disease-modifying drug prescription claims were selected from the 2007-2008 LifeLink™ Health Plan Claims Database. The index date was the first disease-modifying drug prescription claim. Two cohorts were created: all patients with a disease-modifying drug claim in 2007 and a subset with continuous eligibility for 12 months post-index. Adherence was calculated across all disease-modifying drugs for 12 months post-index. Medication possession ratios (MPRs) with variable (start to end of therapy) and fixed (365 days) duration denominators were calculated. Variable MPR was calculated by summing days supply from the first to the last prescription (inclusive) divided by time between the last prescription date plus days supply and the first prescription date. Variable MPR was evaluated for all patients and the continuously eligible cohort. Fixed MPR used the same numerator but divided by 365 days of follow-up and evaluated only for the continuously eligible cohort. RESULTS: There were 3405 patients with MS and a disease-modifying drug claim in 2007 and 2145 in the continuously eligible cohort. Means for variable MPR ranged from 87.5% ± 16.6% for the continuously eligible cohort to 90.5% ± 16.0% for the 2007 cohort. The comparable value for fixed MPR was 78.0% ± 28.2% for the continuously eligible cohort. Fixed MPR gave a consistently lower rate of adherence than variable MPR at an 80% adherence threshold. CONCLUSION: Different adherence measures can yield different outcomes, especially when using different eligibility criteria. These results demonstrate the importance of full disclosure of methods used for calculations and specification of the study population.

One-year clinical and economic consequences of oral atypical antipsychotics in the treatment of schizophrenia.

OBJECTIVE: To assess the clinical and economic consequences of oral atypical antipsychotic treatment (aripiprazole, olanzapine, paliperidone ER, quetiapine, risperidone, and ziprasidone) in schizophrenia over one-year from a US healthcare system perspective. METHODS: The decision model captured rates of discontinuation, symptom response, frequency and duration of relapse, adverse events (extrapyramidal symptoms and weight gain), resource utilization, and unit costs. Published randomized, double-blind, placebo-controlled clinical trial data were used to obtain response rates for comparators. Published clinical trial data from long-term effectiveness trials reflective of typical clinical settings were used for time on therapy, rates of discontinuation, likelihood of switching, relapse rates, and adverse event rates. Drug costs were based on Wholesale Acquisition Cost weighted by Wolters Kluwer Retail and First Databank Pricing drug utilization data. PharMetrics Patient-Centric database was utilized for length of stay, frequency of relapse, and unit cost of healthcare resource data. A clinical expert panel provided resource-use information not available in published literature or healthcare databases. To test the robustness of the findings, sensitivity analyses were performed using plausible ranges of key model input parameters. RESULTS: The model estimated that, over 1 year, clinical outcomes of patients administered oral atypical antipsychotics would not vary considerably. This is partly due to differences 'washing out' because of frequent switching and discontinuation of medication. Economic outcomes did vary among pharmacotherapies: paliperidone ER was associated with cost savings in direct medical costs per patient per year compared to risperidone (cost savings using paliperidone ER vs. risperidone: $793), quetiapine ($1191), olanzapine ($1259), ziprasidone ($2159), and aripiprazole ($2204)). Limitations of this analysis include the absence of direct head-to-head long-term comparative data for antipsychotics. However, the results of the decision analysis held true when tested through a multitude of sensitivity analyses. CONCLUSION: This modeling study showed that paliperidone ER had the most favorable clinical and economic outcomes compared to other oral atypical antipsychotics for patients with schizophrenia. The analysis supports the notion that frequent discontinuation of medication is a problem with all oral antipsychotic treatments for schizophrenia.