Impact of Out-of-Pocket Costs on Prescription Fills Among New Initiators of Biologic Therapies for Rheumatoid Arthritis.

BACKGROUND: Biologic disease-modifying antirheumatic drug (DMARD) therapies are a mainstay of treatment for rheumatoid arthritis (RA), yet high member out-of-pocket (OOP) costs for such therapies may limit patient access to these therapies. OBJECTIVE: To understand whether there is a relationship between OOP costs and the initial fill and subsequent refills of biologic DMARD treatments for RA members. METHODS: Members of a national Medicare Advantage and Prescription Drug (MAPD) plan with an adjudicated (paid or reversed) claim for a biologic DMARD indicated for RA were identified from July 1, 2007, to December 31, 2012, and followed retrospectively. The first adjudicated claim date was the index date. Members were required to have 180 days of continuous enrollment pre- and post-index and ≥ 1 diagnosis for RA (ICD-9-CM: 714.0 or 714.2) during pre-index or ≤ 30 days post-index. Low-income subsidy and Medicaid-Medicare dual-eligible patients were excluded. The analysis used multivariate regression models to examine associations between initial prescription (Rx) abandonment rates and OOP costs and factors influencing the refill of a biologic DMARD therapy based on pharmacy claims. RESULTS: The final sample size included 864 MAPD members with an adjudicated claim for a biologic DMARD. The majority were female (77.4%) and mean age was 63.5 years (SD = 10.9). Most (78%) had conventional nonbiologic DMARD utilization during pre-index. The overall initial abandonment rate was 18.2% for biologic DMARDs, ranging from 1.3% for the lowest OOP cost group ($0-$250) to 32.7% for the highest OOP cost group (> $550; P < 0.0001 for Cochran-Armitage trend test). ORs for abandonment rose from 18.4 to 32.7 to 41.2 for OOP costs of $250.01-$400.00, $400.01-$550.00, and > $550.00 respectively, relative to OOP costs of ≤ $250.00 (all P < 0.0001). Meeting the catastrophic coverage limit and utilization of a specialty pharmacy for the index claim were both associated with a decreased likelihood of abandoning therapy (OR = 0.29 and OR = 0.14, respectively; both P < 0.05). Among the subset of 533 members with a paid claim, 82.4% had at least 1 refill post-index. The negative association between OOP cost and likelihood of refilling an Rx was highly significant (P < 0.0001). CONCLUSIONS: This study suggests that the higher the member OOP cost, the less likely an MAPD member is to initiate or refill a biologic DMARD therapy for RA. Further research is needed to understand reasons for initial Rx abandonment and lack of refills, including benefit design and adverse events.

Development of biosimilars.

OBJECTIVE: To provide an overview of the underlying scientific principles and standards for developing a biosimilar product. METHODS: An Internet-based literature search through June 2015 was performed for information related to biosimilar manufacturing and development, including a review of regulatory guidelines and requirements. RESULTS: Biologics, both biosimilars and their corresponding reference products, are complex molecules produced by biotechnology in living systems. The development of biologics involves multiple levels of intricate, highly controlled manufacturing processes, combined with pre-clinical structural, functional, and biological assessments, as well as clinical efficacy and safety, including immunogenicity, analyses. In addition, to ensure a high degree of similarity, a biosimilar must undergo a comparability exercise at every step of its development, as outlined by regulatory agencies, to demonstrate that potential differences from the reference product are not clinically meaningful with regard to quality, safety, and efficacy [European Medicines Agency (EMA)] or safety, purity, and potency [US Food and Drug Administration (FDA)]. At the foundation of the biosimilar development process lays the establishment of a high degree of structural similarity with its reference product. State-of-the-art technologies must be employed to demonstrate a high degree of structural and functional similarity. Finally, clinical pharmacokinetic and pharmacodynamic as well as clinical efficacy and safety similarity must be confirmed between biosimilar and originator. Regulators, including the FDA and the EMA consider the totality of the evidence from this comprehensive step-wise comparative similarity exercise in its determination of biosimilarity for licensing. CONCLUSIONS: The rigorous and highly regulated processes required to develop a biosimilar have been designed as such to establish a high degree of biosimilarity with a reference product in terms of the structural, functional, biological, and clinical attributes.

Adherence to recommended dosing and monitoring for mitoxantrone in patients with multiple sclerosis: a healthcare claims database study supplemented with medical records--the RETRO study.

PURPOSE: Mitoxantrone was approved for treatment of multiple sclerosis (MS) in October 2000. Monitoring and dosing guidelines in the product labeling accompanying this indication include blood counts, liver function, and pregnancy tests at each administration. Due to potential cardiotoxicity, left ventricular ejection fraction (LVEF) testing prior to initial infusion and all infusions at a cumulative dose >or=100 mg/m(2) was recommended until April 2005 when LVEF testing before all infusions was recommended in the approved labeling. We sought to estimate provider adherence to dosing and monitoring guidelines and the effect of changes in LVEF monitoring guidelines. METHODS: MS patients who received mitoxantrone between October 2000 and June 2006 were selected from the claims of a large US health insurer. Claims for infusions and for specified tests prior to an infusion determined adherence to guidelines, with medical records providing additional information for a subset. RESULTS: There were 1827 mitoxantrone infusions to 548 eligible patients; medical records were obtained for 261 patients (1096 infusions). Most mitoxantrone recipients were 30-59 years of age and 73% were female. Adherence to recommended dosing was higher than for recommended monitoring. Blood counts were conducted for most infusions (78-83%), while liver function tests (LFT) were performed less often (47-54% of infusions). Pregnancy tests were performed for 10% or fewer of the infusions administered to reproductive age women. Adherence with LVEF testing guidelines improved following labeling changes. CONCLUSIONS: Adherence to recommended monitoring was incomplete, but amenable to change. Automated assessment through insurance claims supplemented with medical record data provides a balanced means for studying adherence to recommendations.

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.

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.