Managing high-priced biologic agents: challenges and potential solutions.

DISCLOSURES: No funding was received for the writing of this commentary. The authors report no conflicts of interest.

The effectiveness and value of targeted immune modulators for moderate to severe ulcerative colitis.

DISCLOSURES: Funding for this summary was contributed by Arnold Ventures, California Health Care Foundation, The Donaghue Foundation, Harvard Pilgrim Health Care, and Kaiser Foundation Health Plan to the Institute for Clinical and Economic Review (ICER), an independent organization that evaluates the evidence on the value of health care interventions. ICER's annual policy summit is supported by dues from AbbVie, Aetna, America's Health Insurance Plans, Anthem, Alnylam, AstraZeneca, Biogen, Blue Shield of CA, Boehringer-Ingelheim, Cambia Health Services, CVS, Editas, Evolve Pharmacy, Express Scripts, Genentech/Roche, GlaxoSmithKline, Harvard Pilgrim, Health Care Service Corporation, HealthFirst, Health Partners, Humana, Johnson & Johnson (Janssen), Kaiser Permanente, LEO Pharma, Mallinckrodt, Merck, Novartis, National Pharmaceutical Council, Pfizer, Premera, Prime Therapeutics, Regeneron, Sanofi, Spark Therapeutics, uniQure, and United Healthcare. Pandey, Fazioli, and Pearson are employed by ICER. Ollendorf reports grants from ICER related to this study and reports other support from the CEA Registry Sponsors and consulting and advisory board fees from EMD Serono, Amgen, Analysis Group, Aspen Institute/University of Southern California, GalbraithWight, Cytokinetics, Sunovion, University of Colorado, the Center for Global Development, and Neurocrine, unrelated to this work. Bloudek reports grants from ICER related to this work and reports fees from AbbVie, Astellas, Akcea, Dermira, GlaxoSmithKline, Sunovion, Seattle Genetics, TerSera Therapeutics, and Incyte, unrelated to this work. Carlson reports grants from ICER related to this work.

Cost-effectiveness of therapeutic drug monitoring in inflammatory bowel disease.

Inflammatory bowel disease (IBD) is increasingly common, and results in significant morbidity. Traditional therapies include corticosteroids, aminosalicylates, thiopurines and methotrexate but in more recent years biologics have transformed the management of IBD. However, these agents come with a significant financial cost, making them unavailable for many patients worldwide. Therapeutic drug monitoring (TDM) is an important means to optimise clinical outcomes from pharmacotherapy. Recent studies have also focussed on the cost-effectiveness as an outcome of TDM. TDM of traditional therapies is principally mediated through improved disease control. Cost-savings from TDM of biologic therapies arises mainly from reduced pharmaceutical use with equitable clinical outcomes. This review considers the cost-effectiveness of TDM for IBD therapies, with a focus on recent research into biologic TDM.

Systematic Review: Monoclonal Antibody-Induced Subacute Cutaneous Lupus Erythematosus.

BACKGROUND: Subacute cutaneous lupus erythematosus (SCLE) lacks consensus diagnostic criteria and the pathogenesis is poorly understood. There are increasing reports of SCLE induced by monoclonal antibodies (mAbs), but there are limited data on the aetiology, clinical characteristics and natural course of this disease. METHODS: We devised a set of diagnostic criteria for SCLE in collaboration with a multinational, multispecialty panel. This systematic review employed a two-layered search strategy of five databases for cases of mAb-induced SCLE (PROSPERO registered protocol CRD42019116521). To explore the relationship between relative mAb use and the number of SCLE cases reported, the estimated number of mAb users was modelled from 2013 to 2018 global commercial data and estimated annual therapy costs. RESULTS: From 40 papers, we identified 52 cases of mAb-induced SCLE, occurring in a cohort that was 73% female and with a median age of 61 years. Fifty percent of cases were induced by anti-tumour necrosis factor (TNF)-ɑ agents. A median of three drug doses preceded SCLE onset and the lesions lasted a median of 7 weeks after drug cessation. Oral and topical corticosteroids were most frequently used. Of the licensed mAbs, adalimumab, denosumab, rituximab, etanercept and infliximab were calculated to have the highest relative number of yearly users based on global sales data. Comparing the number of mAb-induced SCLE cases with estimated yearly users, the checkpoint inhibitors pembrolizumab and nivolumab showed strikingly high rates of SCLE relative to their global use, but ipilimumab did not. CONCLUSION: We present the first systematic review characterising mAb-induced SCLE with respect to triggers, clinical signs, laboratory findings, prognosis and treatment approaches. We identify elevated rates associated with the use of checkpoint inhibitors and anti-TNFɑ agents.

Effectiveness and Costs Among Rheumatoid Arthritis Patients Treated with Targeted Immunomodulators Using Real-World U.S. Data.

BACKGROUND: Targeted immunomodulators (TIMs) are used for the treatment of moderate to severe rheumatoid arthritis (RA) and include biologic and nonbiologic medications with different mechanisms of action. Data describing disease activity levels in RA are not directly available in claims databases but can be determined using a claims-based effectiveness algorithm. Rheumatology has benefited from the recent introduction of new drugs, many with new mechanisms of action. We provide an analysis of this broader range of medications. OBJECTIVES: To (a) describe and summarize the effectiveness of available TIMs for the treatment of moderate to severe RA and (b) determine the RA-related health care costs per effectively treated patient, using recent data. METHODS: This was a retrospective analysis using data from the IBM MarketScan Commercial Claims and Encounters Database from July 1, 2012, through December 31, 2016. Index date was the new prescription claim for a TIM (abatacept, adalimumab, certolizumab pegol, etanercept, golimumab, infliximab, tocilizumab, or tofacitinib). A 6-month pre-index baseline period was used to determine demographic and clinical characteristics. Patients without a TIM claim during the baseline period were considered naive; patients with a TIM claim in the baseline period that was different than the index TIM were assessed as receiving second-line therapy. A claims-based algorithm was used to assess 12-month treatment effectiveness and total RA-related costs. Costs included RA-related pharmacy costs and medical costs. RESULTS: Data from 14,775 patients were analyzed, including patients prescribed abatacept (n = 1,250), adalimumab (n = 4,986), certolizumab pegol (n = 387), etanercept (n = 5,266), golimumab (n = 577), infliximab (n = 969), tocilizumab (n = 451), and tofacitinib (n = 889). Of these, 705 were receiving second-line therapy. TIM effectiveness by first-line and second-line therapy, respectively, were abatacept 27.1%, 18.1%; adalimumab 30.9%, 22.1%; certolizumab pegol 20.9%, 14.3%; etanercept 31.4%, 31.5%; golimumab 32.7%, 22.2%; infliximab 21.9%, 21.3%; tocilizumab 30.9%, 30.6%; and tofacitinib 26.0%, 21.6%. The main reason for failing effectiveness was not achieving an 80% medication possession ratio or being nonadherent. The 1-year total RA-related cost per effectively treated patient for first-line and second-line therapies, respectively, were abatacept $121,835, $174,090; adalimumab $112,708, $154,540; certolizumab pegol $149,946, $236,743; etanercept $102,058, $94,821; golimumab $108,802, $140,651; infliximab $155,123, $185,369; tocilizumab $93,333, $109,351; and tofacitinib $100,306, $130,501. CONCLUSIONS: The effectiveness of TIMs from this real-world experience showed that the range of patients who were effectively treated with first-line therapy was higher for certain tumor necrosis factor inhibitors and tocilizumab. The percentages of effectively treated patients were generally lower in second-line treatment compared with first-line except for etanercept, which had the same percentage between lines of therapy. Etanercept had the lowest RA-related cost per effectively treated patient among tumor necrosis factor inhibitors in first-line use and the lowest RA-related cost per effectively treated patient compared with all second-line treatments. DISCLOSURES: This study was sponsored by Amgen. Amgen employees contributed to study design, analysis of the data, and the decision to publish the results. Maksabedian Hernandez and Stolshek are employees and shareholders of Amgen; Gharaibeh was employed by Amgen at the time of this study. Bonafede was employed by IBM Watson Health, at the time of this study, and McMorrow is employed by IBM Watson Health, which received funding from Amgen to conduct this study. Data from this study were presented at AMCP Nexus, October 22-25, 2018, in Orlando, FL.

Physical wastage of immunobiological products in the state of Ceará, Brazil, 2014-2016. / Perdas físicas de imunobiológicos no estado do Ceará, 2014-2016.

OBJECTIVE: to describe discarded wasted immunobiological products provided by the National Im-munization Program (PNI) to the State of Ceará between 2014 and 2016, and the costs of discarded doses. METHODS: this was a descriptive study using data from suspect im-munobiological product evaluation forms and data from disposal approval forms. RESULTS: a total of 317 forms were included, 72.0% of which had a disposal approval form, and 160,767 discarded doses were identified, at a total cost of BRL 1,834,604.75; wastage accounted for 0.45%, 0.93% and 0.53% of the total cost of vaccines in 2014, 2015 and 2016, respectively; the main reason for the wastage identified was electric power shortage (54.9%). CONCLUSION: we identified a large number of discarded wasted doses, with high absolute cost; tighter control is necessary, as failures in conservation dynamics may interfere with the supply of immunobiologicals.

Terapias modificadoras de la enfermedad en esclerosis múltiple: revisión sistemática de costo-efectividad / Disease modifying therapies in multiple sclerosis: cost-effectiveness systematic review

OBJETIVO: Identificar y describir los estudios de costo-efectividad que evalúan las terapias modificadoras de la enfermedad en esclerosis múltiple recurrente-remitente. MÉTODO: Revisión sistemática de la literatura en MEDLINE, Embase, Cochrane Library, LILACS, Tufts Medical Center cost-effectiveness analysis registry, National Health Service economic evaluation database y Open Grey; búsqueda limitada entre enero de 2010 y diciembre de 2017, se ejecutó en enero de 2018. Se incluyeron modelos de costo-efectividad con perspectiva de pagador para interferón beta-1a, interferón beta-1b, acetato de glatiramero, teriflunomida, fingolimod, dimetilfumarato, natalizumab, alemtuzumab y rituximab. La herramienta Quality of Health Economic Studies fue usada para determinar la calidad de los estudios, el sesgo se evaluó sin una herramienta estandarizada, dada su no existencia. Se analizaron costos directos, años de vida ajustados por calidad y la razón de costo-efectividad incremental. La extracción de los datos y la evaluación de la información se realizaron por cada autor de forma independiente Resultados: Se encontraron 401 referencias, se incluyeron nueve estudios; hubo variabilidad en múltiples aspectos metodológicos. Según la razón de costo-efectividad incremental (costo), dos trabajos mostraron que ninguna terapia de primera línea fue costo-efectiva, un tercer estudio reporta al interferón beta-1b como dominante sobre placebo (-315.109,45 dólar estadounidense [US$]) y un cuarto artículo expone a teriflunomida como dominante sobre interferones y acetato de glatiramero (-121.840,37 US$). Respecto a las terapias de segunda línea, dimetil fumarato fue costo-efectivo en un estudio comparado con acetato de glatiramero e interferón beta-1a y fue dominante en otro trabajo frente a acetato de glatiramero (-158.897,93 US$) y fingolimod (-92.988,97 US$). En la tercera línea de tratamiento, natalizumab fue costo-efectivo sobre fingolimod en un artículo, y alemtuzumab fue dominante contra fingolimod (-49.221 US$) en un segundo estudio. En un tercer ensayo el alemtuzumab fue dominante sobre natalizumab (-1.656.266,07 US$). Muchos estudios tuvieron sesgo de patrocinador. Ocho artículos obtuvieron alta puntuación de calidad con la herramienta Quality of Health Economic Studies. CONCLUSIONES: Este trabajo demuestra que existe una gran variabilidad metodológica entre los estudios de costo-efectividad, y algunos de ellos tienen resultados contradictorios. No es posible determinar qué terapia modificadora de la enfermedad en esclerosis múltiple recurrente-remitente es costo-efectiva

OBJECTIVE: To identify and describe cost-effectiveness studies that eva-luate disease modifying therapies in the context of relapsing-remitting mul-tiple sclerosis. METHOD: A systematic review of the literature was carried out by searching MEDLINE, Embase, the Cochrane Library, LILACS, the Tufts Medical Center Cost-Effectiveness Analysis Registry, the National Health Service Economic Evaluation Database and Open Grey. The search was performed in January 2018 and covered articles published between January 2010 and December 2017. The studies reviewed were payer-perspective cost-effectiveness analy-ses for interferon beta-1a, interferon beta-1b, glatiramer acetate, teriflunomide, fingolimod, dimethyl fumarate, natalizumab, alemtuzumab and rituximab. The Quality of Health Economic Studies instrument was used to determine the quality of the studies reviewed. Risk of bias was assessed without a standardized tool. An analysis was made of direct costs, quality-adjusted life-years and the incremental cost-effectiveness ratio. Data extraction and evaluation of information were conducted separately by each author. RESULTS: Four hundred one references were found; nine studies were included. A great degree of variability was identified for several methodological aspects. Two studies that applied the incremental cost-effectiveness ratio (cost) showed no first-line therapy to be cost-effective. A third study demonstrated dominance of interferon beta-1b over placebo (USD -315,109.45) and a fourth paper showed dominance of teriflu-nomide over interferons and glatiramer acetate (USD -121,840.37). As regards second-line therapies, dimethyl fumarate was cost-effective in a study that compared it to glatiramer acetate and interferon beta-1a and it was dominant in another study that compared it with glatiramer acetate (USD -158,897.93) and fingolimod (USD -92,988.97). In the third line of treatment, one study showed natalizumab to be cost-effective as compared with fingolimod, and another study showed alemtuzumab to be dominant over fingolimod (USD -49,221). A third trial demonstrated alemtuzumab to be dominant over natalizumab (USD -1,656,266.07). Many of the trials have sponsorship bias. Eight of the trials received a high QHES score. CONCLUSIONS: The present paper shows that cost-effectiveness studies have high levels of methodological variability, some of them reaching contradictory results. As a result, it is not possible to determine which disease-modifying therapy is really cost-effective in the context of relapsing-remitting multiple sclerosis

Disease-Modifying Therapy Adherence and Associated Factors in a National Sample of Medicare Patients With Multiple Sclerosis.

OBJECTIVES: Disease-modifying therapies (DMTs) reduce relapse rates and disability progression for relapsing multiple sclerosis (MS). Although 25% to 30% of all US patients with MS are Medicare beneficiaries, limited information exists on this population. This is the first study using national Medicare data to (1) describe characteristics of patients with MS using DMTs, (2) estimate adherence to DMTs over a 1-year and 3-year follow-up, and (3) examine factors associated with DMT adherence. METHODS: This retrospective claims analysis used 2011-2014 100% Medicare files. Monthly adherence to MS DMTs was defined as the proportion of days covered ≥0.80 with any DMT in each month for 1-year (n = 36 593) and 3-year (n = 17 599) follow-up samples of MS DMT users. Generalized estimating equation logistic regressions were used to estimate factors associated with adherence to DMTs. RESULTS: Over 90% of patients were eligible for Medicare owing to disability, and about three-quarters qualified for low-income subsidies. A downward trend in DMT adherence was observed over time in both samples. Monthly adherence dropped significantly between December of the prior year to January of the following year (from 76% to 65% in the 1-year follow-up sample and similar drops seen across all years in the 3-year follow-up sample). Multivariable regressions indicated characteristics such as being low-income, having a disability, and having high patient out-of-pocket DMT costs associated with poor adherence to DMTs. CONCLUSION: Our study provides important insights into the characteristics and DMT adherence of Medicare patients with MS and highlights the need for interventions and policies mitigating barriers to adherence in this population.

Dose Escalation Assessment Among Targeted Immunomodulators in the Management of Inflammatory Bowel Disease.

BACKGROUND: The need for individualized treatment regimens is becoming more important in the management of patients with inflammatory bowel disease (IBD). Gastroenterologists may dose adjust either by increasing the dose or shortening the dosing interval from the initial recommended maintenance dose to achieve an appropriate clinical response. Understanding the role of dose escalation in the treatment of IBD in clinical practice provides payers in the United States insight into the real-world cost-effectiveness of targeted immunomodulators (TIMs) in the management of IBD. OBJECTIVE: To assess the prevalence and magnitude of dose escalation for approved IBD therapies. METHODS: Using the Source Healthcare Analytics database, patients with IBD who initiated treatment with a drug of interest from July 2015 to June 2017 were identified. Patient utilization of the TIMs was tracked for 12 months following initiation. All included patients had at least 2 diagnoses for ulcerative colitis or Crohn disease before TIM initiation and at least 5 claims for a drug of interest within the 12 months following initiation. Dose escalation was defined as an increase of at least 30% in the average daily dose (ADD) relative to the patient's expected maintenance dose on 2 consecutive prescriptions. The proportion of patients with dose escalation in the first 12 months after treatment initiation was determined. The magnitude of dose escalation was determined by calculating the patient's ADD across all noninduction dose claims and comparing it with the expected daily dose. Dose escalation prevalence and magnitude were used to quantify the equivalent patient treatment rate representing the number of patients per 100 that could have been treated with standard dosing, given the prevalence of dose escalation in the treated population. RESULTS: 7,028 patients (2,406 infliximab, 1,966 adalimumab, 1,745 vedolizumab, 472 ustekinumab, 285 certolizumab pegol, and 154 golimumab) met eligibility criteria and were included in the study. Among IBD therapies, dose escalation occurred most frequently with infliximab (39%), followed by adalimumab (28%), vedolizumab (23%), ustekinumab (22%), certolizumab pegol (20%), and golimumab (14%). The magnitude of dose escalation was greatest for ustekinumab (131%), followed by infliximab (70%), vedolizumab (62%), adalimumab (59%), certolizumab pegol (50%), and golimumab (45%). The calculated patient equivalence was highest for infliximab (128) and ustekinumab (128) compared with adalimumab (116), vedolizumab (114), certolizumab pegol (110), and golimumab (106). CONCLUSIONS: Among patients with IBD, dose escalation occurred with all TIMs examined with varying degrees of prevalence and magnitude. Real-world utilization patterns of TIMs indicate that dose escalation is an important part of the clinical management of IBD and needs to be considered when evaluating the cost-effectiveness of IBD treatments. DISCLOSURES: Financial support for this study was provided by AbbVie, which participated in study design, research, data collection, analysis and interpretation of data, writing, reviewing, and approving the publication. All authors contributed to the development of the publication and maintained control over the final content. Ehrenberg and McDonald are employees of IQVIA, which received funding from AbbVie to participate in this research. Griffith and Theigs are employed by AbbVie and may own stock or stock options in AbbVie.

Ocrelizumab for Treating Patients with Primary Progressive Multiple Sclerosis: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

Ocrelizumab is indicated for relapsing remitting and primary progressive multiple sclerosis (RRMS and PPMS, respectively). In an appraisal undertaken by the National Institute for Health and Care Excellence (NICE), the company Roche presented the evidence for ocrelizumab used in patients with PPMS, which came from one single randomised controlled trial (RCT) comparing ocrelizumab versus placebo. Based on results from this trial, the licensed indication was restricted to patients with early PPMS in terms of disease duration and level of disability, and with imaging features characteristic of inflammatory activity. Overall, the Evidence Review Group (ERG) found that the RCT had a low risk of bias. In the post-hoc defined magnetic resonance imaging (MRI) active subgroup, matching the label indication, the risk of confirmed disability progression sustained for 12 weeks (CDP-12) was significantly delayed in the ocrelizumab group compared to placebo. However, considering the same risk with progression sustained for 24 weeks (CDP-24), which was deemed the most clinically relevant, the benefit from ocrelizumab did not reach statistical significance. In the same MRI active subgroup, benefits from ocrelizumab on functional outcomes and on health-related quality of life were not clearly demonstrated. A de novo Markov model was used to estimate the cost-effectiveness of ocrelizumab versus best supportive care (BSC) for treating patients with PPMS. Health states were defined by the Expanded Disability Status Scale (EDSS), ranging from 0 to 9. Disability progression was based on the MSBase natural history cohort that exhibited disease progression in the absence of disease-modifying therapy. Treatment with ocrelizumab delayed disability progression, with evidence of its clinical effectiveness obtained from the RCT. The economic analysis was undertaken from the National Health Service and Personal Social Services perspective, and the outcomes were reported in terms of life years gained and quality-adjusted life years (QALYs), with the overall results reported in terms of an incremental cost-effectiveness ratio (ICER), expressed as cost per QALY gained over a 50-year time horizon. Both costs and effects were discounted at 3.5% per annum. The company undertook deterministic one-way sensitivity analyses and scenario analyses, including probabilistic sensitivity analysis (PSA). The ERG raised several concerns, which were discussed at the appraisal committee meetings, resulting in the committee's preferences being applied and a revised economic analysis from the company. Under an approved patient access scheme with appraisal committee preferences applied, analyses yielded an ICER of approximately £78,300 per QALY. Sensitivity analysis results indicated that the treatment effect on CDP-12 had the greatest impact. Results for the PSA showed that at a willingness-to-pay threshold of £30,000 per QALY gained, ocrelizumab versus BSC had a zero probability of being cost-effective. Following new analyses submitted by the company, with a revised confidential patient access scheme, NICE recommended ocrelizumab in the treatment of early PPMS in adults with imaging features characteristic of inflammatory activity.

Cost-Effectiveness of Natalizumab Compared With Fingolimod for Relapsing-Remitting Multiple Sclerosis Treatment in Colombia.

OBJECTIVES: Multiple sclerosis (MS) is a degenerative neurological disorder. Treatment aims to avoid relapses and disability progression. The purpose of this study was to evaluate the cost-effectiveness of natalizumab compared with fingolimod for treating highly active relapsing-remitting MS (RRMS) patients from the Colombian third-party payer perspective. METHODS: We used a Markov economic model from the perspective of the Colombian healthcare system to estimate the cost-effectiveness of natalizumab compared with fingolimod for RRMS with high disease activity or failure of interferons as first-line therapy. This model was centered on disability progression and relapses. We considered a 5-year time horizon with a 5% discount rate. We included only direct medical costs. Local experts were consulted to obtain resource utilization estimates, and local standardized costing methodologies and sources were used. Outcome was considered in terms of quality-adjusted life-years (QALYs). Utilities were extracted or calculated from the literature. Transition probabilities were calculated from available efficacy and safety information (1 USD = 3050.98 COP). RESULTS: Natalizumab showed lower total costs (USD 80 024 vs USD 98 137) and higher QALY yield (3.01 vs 2.94) than fingolimod, dominating it (incremental cost-effectiveness ratio = -$1861). Univariate sensitivity analysis showcased the relevance of the measures of effect on disability progression for natalizumab on model results. Probabilistic sensitivity analysis replicated base-case results in most simulations. CONCLUSIONS: This study showed that natalizumab dominated fingolimod with lower costs and higher QALYs in patients with high-activity RRMS. These results are consistent with previous published international literature.

The Cost-effectiveness of Initial Immunomodulators or Infliximab Using Modern Optimization Strategies for Crohn's Disease in the Biosimilar Era.

BACKGROUND: Treatment cost, efficacy, and safety are integral considerations when optimizing management of Crohn's disease (CD). This study assessed the cost-effectiveness of initial immunomodulator and anti-tumor necrosis factor (anti-TNF) agents for the treatment of CD from a US third-party perspective, incorporating current treatment algorithms, optimization strategies, and reduced costs availed by biosimilars. METHOD: A 1-year Markov model was developed to simulate the cost and quality-adjusted life-years (QALYs) of initial azathioprine, infliximab, and combination therapy for moderate to severe CD. Treatment was changed based on tolerability and clinical disease activity at 3-monthly intervals. Efficacy data were based on published literature. RESULTS: Initial azathioprine had the lowest cost and utility ($35,337 and 0.63 QALYs), whereas combination therapy was the costliest yet conferred the highest health benefits ($57,638 and 0.67 QALYs). The incremental cost-effectiveness of infliximab and combination therapy compared with azathioprine were both in excess of $500,000 per QALY gained. Initial azathioprine remained the most cost-effective treatment on sensitivity analysis compared with infliximab and combination therapy, with 90% reductions in anti-TNF therapy costs and a 5-year time horizon, although combination therapy had an acceptable cost-effectiveness when costs were reduced in the extended model. Initial infliximab, ustekinumab, and vedolizumab were dominated by combination therapy. CONCLUSIONS: In the biosimilar era, initial azathioprine with escalation to infliximab appeared more cost-effective in the short term compared with infliximab or combination therapy, although initial combination therapy yields acceptable ICERs in the long term with continued reductions in anti-TNF therapy costs and will likely be the preferred treatment strategy in the future.

Differentiating societal costs of disability worsening in multiple sclerosis.

BACKGROUND: In multiple sclerosis (MS), confirmed disability progression (CDP) can be either the result of progression independent of relapse activity (PIRA) or relapse-associated worsening (RAW). However, the economic effect of PIRA and RAW on societal economic costs in patients with MS is not well understood. OBJECTIVE: To determine societal economic costs of patients achieving disease activity free status (DAF) and compare them with those having PIRA and RAW events. METHODS: We used a roving EDSS score analysis to detect PIRA and RAW events with confirmation after at least 6 months. We estimated the age-, gender-, EDSS-adjusted effects of PIRA and RAW on total, direct medical, direct non-medical and indirect societal economic costs. Patients achieving DAF were assigned to as reference. RESULTS: Overall, 1959 patients were analyzed. Total mean quarterly societal economic costs including disease-modifying therapies (DMTs) were 6929€ (SD: 2886€) per patient averaged over a period of 2 years. Excluding DMTs, patients achieving DAF had total mean quarterly costs of 1703€ (SD: 2489€). PIRA caused 29% (IRR: 1.29; CI 1.06-1.50, p < 0.05) higher total costs compared to DAF. On the contrary, RAW increased total costs by factor 1.56 (CI 1.30-1.87, p < 0.001). The effect of PIRA and RAW was striking for direct medical costs which increased by factor 1.48 (95% CI 1.13-1.95, p < 0.01) and 2.25 (95% CI 1.72-2.94, p < 0.001), respectively. CONCLUSION: Disease progression increases societal economic costs significantly. Thus, delaying or even preventing disease progression in MS may reduce the societal economic burden of MS.

The impact of diagnostic criteria and treatments on the 20-year costs for treating relapsing-remitting multiple sclerosis.

OBJECTIVE: To assess whether the introduction of the new diagnostic criteria and disease modifying therapies (DMTs) is associated with higher cost for treating multiple sclerosis (MS). METHODS: This is a regression-based quasi-experimental study employing interrupted time series analysis, including data from 2229 patients (age 42.1 ±â€¯11.2 years; female 63.34%), with incident diagnosis of relapsing remitting MS (RRMS) and followed up from 1997 to 2017, extracted from the database of the MS Clinical Care and Research Centre of the Federico II University Hospital of Naples (Italy). Annual healthcare costs for DMT (e.g., prescription, staff involved in DMT administration) and management (e.g., neurological consultations, other consultations related to DMT safety, MRI, laboratory exams), were calculated and inflated to the most recent value. RESULTS: Annual costs per patient for DMT prescription and management were not affected by the introduction of 2001 and 2005 criteria, but decreased by 0.4% after the introduction of 2011 criteria (PD= -0.4%; 95% C.I. -0.7%/-0.0%; p = 0.023). Annual costs per patient increased by 11.2% after the introduction of Natalizumab in 2007 (PD= 11.2%; 95% C.I.= 9.4%/13.0%; p <0.001), by 10.9% after the introduction of tablets in 2011 (Fingolimod, Teriflunomide and Dimethyl Fumarate) (PD= 10.9%; 95% C.I. 9.2%/12.7%; p<0.001), and by 10.7% after the introduction of Alemtuzumab in 2015 (PD= 10.7%; 95% C.I. 9.0%/12.4%; p< 0.001). DISCUSSION: DMTs remain the main responsible for increased medical direct costs in MS, whilst improved diagnostic skills and subsequent patient profiling can at least in part mitigate costs for MS treatment and management.

Oral Oncology Parity Laws, Medication Use, and Out-of-Pocket Spending for Patients With Blood Cancers.

BACKGROUND: In this study, we sought to estimate the association between oral oncology parity law adoption and anticancer medication use for patients with chronic myeloid leukemia or multiple myeloma. METHODS: This was an observational study of administrative claims from 2008 to 2017. Among individuals initiating tyrosine kinase inhibitors (TKIs) for chronic myeloid leukemia or immunomodulatory drugs for multiple myeloma, we compared out-of-pocket spending, adherence, and discontinuation before and after parity among individuals in fully insured plans (subject to parity) vs self-funded plans (exempt from parity) using propensity-score weighted difference-in-differences regression models. RESULTS: Among patients initiating TKIs (N = 2082) or immunomodulatory drugs (N = 3326) there were no statistically significant differences in adherence or discontinuation associated with parity. The proportion of patients with initial out-of-pocket payments of $0 increased in fully insured plans after parity from 5.7% to 46.1% for TKIs and from 10.9% to 48.8% for immunomodulatory drugs. Relative to changes in self-funded plans, those in fully insured plans were 4.27 (95% CI = 2.20 to 8.27) times as likely to pay nothing for TKIs and 1.96 (95% CI = 1.40 to 2.73) times as likely to pay nothing for immunomodulatory drugs after parity. Similarly, the proportion paying more than $100 decreased from 30.3% to 24.7% for TKIs and 30.6% to 27.5% for immunomodulatory drugs in fully insured plans after parity. Relative to changes in self-funded plans, those in fully insured plans were 0.74 (95% CI = 0.54 to 1.01) times as likely to pay more than $100 for TKIs and 0.85 (95% CI = 0.68 to 1.06) times as likely to pay more than $100 for immunomodulatory drugs after parity. CONCLUSIONS: Among patients initiating TKIs or immunomodulatory drugs, parity was not associated with better adherence or less discontinuation of therapy but yielded decreased patient out-of-pocket payments for some patients.

Healthcare resource utilization and costs for multiple sclerosis management in the Campania region of Italy: Comparison between centre-based and local service healthcare delivery.

BACKGROUND: Multiple sclerosis (MS) requires multidisciplinary management. We evaluated differences in healthcare resource utilization and costs between Federico II and Vanvitelli MS Centres of Naples (Italy), representative of centralised (i.e., MS Care Unit) and local service-based models of multidisciplinary care, respectively. METHODS: We included MS patients continuously seen at the same local healthcare services and MS Centre (Federico II = 187; Vanvitelli = 90) from 2015 to 2017. Healthcare resources for MS treatment and management were collected and costs were calculated. Adherence was estimated as the rate of medication possession ratio (MPR) during 3-years of follow-up. Mixed-effect linear regression models were used to estimate differences in all outcomes between Federico II and Vanvitelli. RESULTS: Patients at Federico II had more consultations within the MS centre (p<0.001), blood tests (p<0.001), and psychological/cognitive evaluations (p = 0.040). Patients at Vanvitelli had more consultations at local services (p<0.001). Adherence was not-significantly lower at Vanvitelli (p = 0.060), compared with Federico II. Costs for MS treatment and management were 10.6% lower at Vanvitelli (12417.08±8448.32EUR) (95%CI = -19.0/-2.7%;p = 0.007), compared with Federico II (15318.57±10919.59EUR). DISCUSSION: Healthcare services were more complete (and expensive) at the Federico II centralised MS Care Unit, compared with the Vanvitelli local service-based organizational model. Future research should evaluate whether better integration between MS Centres and local services can lead to improved MS management and lower costs.

Economic burden of multiple sclerosis in France estimated from a regional medical registry and national sick fund claims.

BACKGROUND: Estimating direct healthcare costs of patients with multiple sclerosis (MS) and identifying risk factors of high costs including relapse are important drivers of public health decision making in France. METHODS: This is a longitudinal retrospective study based on patient charts (qualified registry of MS in Lorraine (ReLSEP)) and claims data (from the main compulsory health insurance and national hospital database estimated monthly. All patients with MS not deceased or lost to follow-up reported in the registry in 2013-2014 were included. Outpatient costs were those paid to the healthcare provider and inpatient costs were those related to national cost estimates. Mean total costs per patient by disease severity were estimated monthly, accounting for MS evolution over the study period. Costs of MS relapse were estimated using a general linear model. RESULTS: A total of 4373 patients were identified in the ReLSEP registry, and 2166 of these patients were included in the study. Among those, outpatient claims were available for 1366 and 627 were hospitalized at least once. The average annual direct costs for patients with MS were estimated to be €12,296 in 2014. Furthermore, ambulatory costs represented 87.8% out of those costs and were mainly driven by medications (60.6%) and paramedic visits (11.2%). Monthly direct costs were higher in patients with severe disease (€1249 for EDSS 7-9) compared to those with mild or moderate disease (€992 for EDSS 0-3; €953 for EDSS 4-6) (p < 0,006). Interestingly, drug costs were higher in patients with mild disease, whereas costs related to paramedical care, medical devices, and transportation were higher in those with severe MS. The unit cost of relapse was estimated between €1681 and €2193. CONCLUSIONS: Costs were mainly driven by medications and highly related to disease severity. Relapse cost was the main contributor to total cost.

Overview of rabies post-exposure prophylaxis access, procurement and distribution in selected countries in Asia and Africa, 2017-2018.

BACKGROUND: Rabies is a neglected zoonotic disease with a global burden of approximately 59,000 human deaths a year. Once clinical symptoms appear, rabies is almost invariably fatal; however, with timely and appropriate post-exposure prophylaxis (PEP) consisting of wound washing, vaccine, and in some cases rabies immunoglobulin (RIG), the disease is almost entirely preventable. Access to PEP is limited in many countries, and when available, is often very expensive. METHODS: We distributed a standardized assessment tool electronically to a convenience sample of 25 low- and middle-income countries in Asia and Africa to collect information on rabies PEP procurement, forecasting, distribution, monitoring and reporting. Information was collected from national rabies focal points, focal points at the World Health Organization (WHO) country offices, and others involved in procurement, logistics and distribution of PEP. Because RIG was limited in availability or unavailable in many countries, the assessment focused on vaccine. Data were collected between January 2017 and May 2018. RESULTS: We received responses from key informants in 23 countries: 11 countries in Asia and 12 countries in Africa. In 9 of 23 (39%) countries, rabies vaccine was provided for free in the public sector and was consistently available. In 10 (43%) countries, all or some patients were required to pay for the vaccine in the public sector, with the cost of a single dose ranging from US$ 6.60 to US$ 20/dose. The primary reason for the high cost of the vaccine for patients was a lack of funding at the central level to subsidize vaccine costs. In the remaining 4 (17%) countries, vaccine was provided for free but was often unavailable so patients were required to purchase it instead. The majority of countries used the intramuscular route for vaccine administration and only 5 countries exclusively used the dose-sparing intradermal (ID) route. Half (11/22; 50%) of all countries assessed had a standardized distribution system for PEP, separate from the systems used for routine childhood vaccines, and almost half used separate storage facilities at both central and health facility levels. Approximately half (9/22; 41%) of all countries assessed reported having regular weekly, monthly or quarterly reporting on rabies vaccination. CONCLUSIONS: While all countries in our assessment had rabies vaccines available in the public sector to some extent, barriers to access include the high cost of the vaccine to the government as well as to patients. Countries should be encouraged to use ID administration as this would provide access to rabies vaccine for many more people with the same number of vaccine vials. In addition, standardized monitoring and reporting of vaccine utilization should be encouraged, in order to improve data on PEP needs.

Patients' preferences and willingness-to-pay for disease-modifying therapies.

BACKGROUND: While disease-modifying therapies (DMTs) for multiple sclerosis (MS) treatments are costly, patient valuation of DMTs has not been examined. The objective of this study was to examine patients' preferences and willingness-to-pay (WTP) for DMTs. METHODS: Six attributes (i.e., number of relapses, percentage of disability progression, percentage of severe adverse events, route of administration, frequency of administration, and out-of-pocket cost) and their levels were used to develop a discrete choice experiment questionnaire. Each questionnaire comprised seven choice sets and each choice set contained two hypothetical DMTs and an opt-out alternative. A total of 1,200 U.S. patients with MS were asked to choose a DMT option or opt-out in each choice set. Multinomial logit model was used to determine relative preferences of each attribute. WTPs for all attributes and DMTs were calculated. RESULTS: A total of 508 patients were analyzed. Patients preferred DMTs with lower relapse rate, lower disability progression, lower severe adverse event, lower frequency of administration, and lower cost. In addition, they preferred oral DMTs. They were willing to pay $2,768, $289, $292, and $76 a month in exchange for every 1-time decrease in the number of relapses in two years, every 1% decrease in disability progression in two years, every 1% decrease in severe adverse events, and every 1-time decrease in the frequency of administration per month, respectively. The patients were willing to pay, in relation to market prices, between $7,020 and $134,934 per year for all DMTs, but interferon beta-1a SC. CONCLUSIONS: Patients with MS considered relapse rate, disability progression, severe adverse events, route of administration, frequency of administration, and out-of-pocket cost, when they chose DMTs. Their WTPs for DMTs varied widely.