Does Cost-Effectiveness Analysis Overvalue Potential Cures? Exploring Alternative Methods for Applying a "Shared Savings" Approach to Cost Offsets.

OBJECTIVES: To evaluate alternative methods to calculate and/or attribute economic surplus in the cost-effectiveness analysis of single or short-term therapies. METHODS: We performed a systematic literature review of articles describing alternative methods for cost-effectiveness analysis of potentially curative therapies whose assessment using traditional methods may suggest unaffordable valuations owing to the magnitude of estimated long-term quality-adjusted life-year (QALY) gains or cost offsets. Through internal deliberation and discussion with staff at the Health Technology Assessment bodies in England and Canada, we developed the following 3 alternative methods for further evaluation: (1) capping annual costs in the comparator arm at $150 000 per year; (2) "sharing" the economic surplus with the health sector by apportioning only 50% of cost offsets or 50% of cost offsets and QALY gains to the value of the therapy; and (3) crediting the therapy with only 12 years of the average annual cost offsets or cost offsets and QALY gains over the lifetime horizon. The impact of each alternative method was evaluated by applying it in an economic model of 3 hypothetical condition-treatment scenarios meant to reflect a diversity of chronicity and background healthcare costs. RESULTS: The alternative with greatest impact on threshold price for the fatal pediatric condition spinal muscular atrophy type 1 was the 12-year cutoff scenario. For a hypothetical one-time treatment for hemophilia A, capping cost offsets at $150 000 per year had the greatest impact. For chimeric antigen receptor T-cell treatment of non-Hodgkin's lymphoma, capping cost offsets or using 12-year threshold had little impact, whereas 50% sharing of surplus including QALY gains and cost offsets greatly reduced threshold pricing. CONCLUSIONS: Health Technology Assessment bodies and policy makers will wrestle with how to evaluate single or short-term potentially curative therapies and establish pricing and payment mechanisms to ensure sustainability. Scenario analyses using alternative methods for calculating and apportioning economic surplus can provide starkly different assessment results. These methods may stimulate important societal dialogue on fair pricing for these novel treatments.

The cost-effectiveness of bevacizumab, ranibizumab and aflibercept for the treatment of age-related macular degeneration-A cost-effectiveness analysis from a societal perspective.

BACKGROUND: The discussion on the use of bevacizumab is still ongoing and often doctors are deterred from using bevacizumab due to legal or political issues. Bevacizumab is an effective, safe and inexpensive treatment option for neovascular age-related macular degeneration (AMD), albeit unregistered for the disease. Therefore, in some countries ophthalmologists use the equally effective but expensive drugs ranibizumab and aflibercept. We describe the economic consequences of this dilemma surrounding AMD treatment from a societal perspective. METHODS: We modelled cost-effectiveness of treatment with ranibizumab (as-needed), aflibercept (bimonthly) and bevacizumab (as-needed). Effectiveness was estimated by systematic review and meta-analysis. The drug with the most favourable cost-effectiveness profile compared to bevacizumab was used for threshold analyses. First, we determined how much we overspend per injection. Second, we calculated the required effectiveness to justify the current price and the reasonable price for a drug leading to optimal vision. Finally, we estimated how much Europe overspends if bevacizumab is not first choice. RESULTS: Bevacizumab treatment costs €27,087 per year, about €4,000 less than aflibercept and €6,000 less than ranibizumab. With similar effectiveness for all drugs as shown by meta-analysis, bevacizumab was the most cost-effective. Aflibercept was chosen for threshold analyses. Aflibercept costs €943 per injection, but we determined that the maximum price to be cost-effective is €533. Alternatively, at its current price, aflibercept should yield about twice the visual gain. Even when optimal vision can be achieved, the maximum price for any treatment is €37,453 per year. Most importantly, Europe overspends €335 million yearly on AMD treatment when choosing aflibercept over bevacizumab. CONCLUSION: Bevacizumab is the most cost-effective treatment for AMD, yet is not the standard of care across Europe. The registered drugs ranibizumab and aflibercept lead to large overspending without additional health benefits. Health authorities should consider taking steps to implement bevacizumab into clinical practice as first choice.

[Economic evaluation of Thrombopoietin Receptor Agonists in the treatment of chronic primary immune thrombocytopenia]. / Evaluación económica del tratamiento de la trombocitopenia inmune primaria crónica refractaria con agonistas del receptor de la trombopoyetina.

PURPOSE: To develop a tool to assist the decision-making for selection of Thrombopoyetin Receptor Agonists of adult patients with chronic immune primary thrombocytopenia (PTI). METHODS: Stochastic cost-effectiveness analysis with a 6-Health- States Markov model: stable, bleeding type 2, 3 or 4, post-type 4 bleeding and death. Each simulation analyzes a randomly generated scenario that describes patients characteristics, results measured in quality adjusted life years (QALYs) and costs (in ?2011). Distributions were obtained from the Spanish data of the European health survey of 2009, the INE estimate of population for 2011 and the 6-months clinical studies for Eltrombopag and Romiplostim. Utility values were obtained from the literature and the costs from Spanish official rates lists. A set of 10.000 random scenarios were generated and the patients evolution of each scenario was simulated during a time horizon of five years (in 2-weeks cycles). National Health System Perspective was used and the annual discount rate was set at 3%. RESULTS: Eltrombopag showed more effectiveness in 9.983 scenarios and there was no difference in 17. In 7.048 scenarios the alternative Eltombopag was dominant. It was cost-effective in another 19 (threshold 30,000 ??/AVAC). CONCLUSIONS: Eltrombopag was the most cost-effective alternative in 70,67% of the simulated scenarios and its use could produce lower costs to the NHS.

Objetivo: Desarrollar una herramienta de apoyo a la decisión en la selección de agonistas del receptor de trombopoyetina en el tratamiento de pacientes adultos con trombocitopenia inmune primaria crónica (PTI) refractaria. Métodos: Análisis coste-efectividad estocástico con un modelo de Markov de seis estados: estable, sangrado tipo 2, 3 ó 4, post-sangrado 4 y muerte. Cada simulación analiza un escenario aleatoriamente generado que describe las características del paciente, los resultados medidos en años de vida ajustados a calidad (AVACs) y los costes (en ?2011). Se obtuvieron distribuciones a partir de los datos para España de la Encuesta Europea de Salud de 2009, de la estimación de población para 2011 del INE, de los estudios a 6 meses de Eltrombopag y Romiplostim, de las utilidades obtenidas de la bibliografía y de las tarifas oficiales en España para procesos y actividad. Se generaron 10.000 escenarios aleatorios y se simuló la evolución de los pacientes de cada escenario durante un horizonte temporal de cinco años (ciclos de dos semanas). Perspectiva del Sistema Nacional de Salud (SNS). Tasa de descuento anual del 3% para costes y efectos. Resultados: En 9.983 escenarios Eltrombopag mostró mayor efectividad y en 17 no hubo diferencias. Eltombopag fue la alternativa dominante en 7.048 escenarios y la más coste efectiva en otros 19 (umbral 30.000 ?/AVAC). Conclusiones: Eltrombopag es la alternativa más coste-efectiva en el 70,67% de los escenarios simulados, por lo que su uso podría producir menores costes al SNS.

Cost effectiveness of biologic therapies for plaque psoriasis.

BACKGROUND: During the last decade, the implementation of biologic agents has changed the therapeutic management of severe psoriasis. Biologic agents have clinically proven efficacy, but their use is associated with a much higher cost compared with traditional treatment options. Therefore, when assessing the use of these drugs for the treatment of psoriasis, it is important to consider their cost effectiveness. OBJECTIVE: The objective of this study was to determine and compare the cost effectiveness of biologic agents with regard to the cost per patient achieving a minimally important difference (MID) in the Dermatology Life Quality Index (DLQI) and the cost per patient achieving a 75% improvement in the Psoriasis Area Severity Index (PASI-75). METHODS: A PubMed literature search was conducted to identify studies describing the efficacy of all currently US FDA-approved biologic therapies. The cost effectiveness of each agent over a 12-week period was determined and a sensitivity analysis was performed. Based on clinical efficacy at 12 weeks, treatment paradigms were extrapolated to estimate cost-effectiveness ratios after 1 year of treatment. Pooled data on each biologic agent at different doses were compared in a one-way sensitivity analysis and in an extreme case scenario analysis. RESULTS: Twenty-seven studies were included in the analysis. Intravenous (IV) infliximab 3 mg/kg was the most cost-effective biologic agent with respect to both the cost per patient achieving PASI-75 and the cost per patient achieving a DLQI MID. The next most cost-effective agents in terms of cost per patient achieving PASI-75 were subcutaneous (SQ) adalimumab 40 mg administered every other week (eow) after an 80-mg loading dose, SQ adalimumab 40 mg eow, and IV infliximab 5 mg/kg. In terms of cost per patient achieving DLQI MID, IV infliximab 5 mg/kg, SQ etanercept 25 mg once weekly, SQ etanercept 50 mg once weekly, and SQ adalimumab 50 mg eow after an 80-mg loading dose were the next most cost-effective agents behind IV infliximab 3 mg/kg. For both costs per patient achieving DLQI MID and PASI-75, alefacept was the least cost-effective agent up to a 10% level of variation at all doses except 0.025 mg/kg once weekly. LIMITATIONS: This study was limited by the use of efficacy data from 12-week clinical trials that did not compare treatments head to head to determine relative efficacy and may not be generalizable to longer treatment periods. Additionally, the estimated cost of treatment did not take into account indirect costs or variations in costs due to insurance company price contracting. CONCLUSIONS: Biologic treatments that were most cost effective were so in respect to both the cost per patient achieving DLQI MID and per patient achieving PASI-75. This suggests that the same agents that are effectively clearing the disease are also effective in improving the patients' subjective assessment of dermatology-related quality of life.

A plant-derived recombinant human glucocerebrosidase enzyme--a preclinical and phase I investigation.

UNLABELLED: Gaucher disease is a progressive lysosomal storage disorder caused by the deficiency of glucocerebrosidase leading to the dysfunction in multiple organ systems. Intravenous enzyme replacement is the accepted standard of treatment. In the current report, we evaluate the safety and pharmacokinetics of a novel human recombinant glucocerebrosidase enzyme expressed in transformed plant cells (prGCD), administered to primates and human subjects. Short term (28 days) and long term (9 months) repeated injections with a standard dose of 60 Units/kg and a high dose of 300 Units/kg were administered to monkeys (n = 4/sex/dose). Neither clinical drug-related adverse effects nor neutralizing antibodies were detected in the animals. In a phase I clinical trial, six healthy volunteers were treated by intravenous infusions with escalating single doses of prGCD. Doses of up to 60 Units/kg were administered at weekly intervals. prGCD infusions were very well tolerated. Anti-prGCD antibodies were not detected. The pharmacokinetic profile of the prGCD revealed a prolonged half-life compared to imiglucerase, the commercial enzyme that is manufactured in a costly mammalian cell system. These studies demonstrate the safety and lack of immunogenicity of prGCD. Following these encouraging results, a pivotal phase III clinical trial for prGCD was FDA approved and is currently ongoing. TRIAL REGISTRATION: ClinicalTrials.gov NCT00258778.

The cost-effectiveness of basiliximab induction in "old-to-old" kidney transplant programs: Bayesian estimation, simulation, and uncertainty analysis.

INTRODUCTION: Markov models are employed in economic analyses to evaluate all possible expectations in a dilemna. The introduction of a new clinical protocol (Basiliximab induction with calcineurin-sparing protocols) for a group of kidney transplant recipients receiving organs from marginal donors was validated with a Markov simulation model, demonstrating the usefulness of combining simulation with Bayesian estimation methods for analysis of cost-effectiveness data collected alongside a clinical trial. We sought to determine whether calcineurin-sparing protocols using anti-interleukin-2/antibody induction (Simulect) would show a beneficial effect on initial kidney function and reduce transplantation costs upon admission, clinical incidences, graft function, and complications during the first month after transplant. PATIENTS AND METHODS: A Markov Chain Monte Carlo (MCMC) was used to estimate a system of generalized linear models relating costs and outcomes to a kidney transplant process affected by treatment under alternative therapies. The Markov simulation model was established following three chains: a calcineurin-free regimen with Basiliximab induction (chain A); a calcineurin-sparing protocol with Basiliximab induction (chain B); and a conventional immunosuppressive regimen (chain C). The MCMC draws were used as parameters in simulations that yielded inferences about the relative cost-effectiveness of the novel therapy under a variety of scenarios. After designing the Markov chain and cohorts, 31 patients from the "old-to-old" program were assigned; eight to chain A; eight to chain B; and 15 to chain C. A year after transplantation a cost-benefit study was performed guided by the three branches of the Markov model. RESULTS: The Markov model showed a benefit of induction therapies in elderly patients. A cost-benefit model showed that after a year, there was a clear benefit from calcineurin-free plus Basiliximab induction therapies, with a slight benefit from calcineurin-sparing protocols. CONCLUSIONS: Markov models are extremely useful when introducing new clinical therapies. The approach allows flexibility in assessing treatment using various premises and quantifies the global effect of parametric uncertainty on a decision maker's confidence to adopt one therapy over another. In our transplant program, a cost-effective analysis of outcomes in old patients using the Markov model showed a clear benefit of calcineurin-sparing protocols with Basixilimab induction.

Advancements in the treatment of psoriasis: role of biologic agents.

OBJECTIVE: To evaluate the role of biologic agents as antipsoriatic therapy. SUMMARY: Mild psoriasis can generally be managed with topical therapy. Moderate-to-severe psoriasis has traditionally been treated with systemic therapies such as cyclosporine, methotrexate, retinoids, and phototherapy (ultraviolet B, psoralen plus ultraviolet A). The treatments for moderate-to-severe psoriasis often do not meet patient and physician expectations because of significant side effects (e.g., organ toxicity, skin cancer), lack of durable efficacy, and inconvenient administration schedules (e.g., daily dosing, multiple weekly exposures). The recognition of psoriasis as a T-cell.mediated disease has led to the development of biologic agents that more specifically target key steps in the pathologic process. A review of the literature was conducted to identify randomized controlled trials that have been published on the efficacy, safety, and quality-of-life effects of both approved and investigational biologics for the treatment of psoriasis. The first 2 biologic agents for the treatment of moderate-to-severe chronic plaque psoriasis were approved by the U.S. Food and Drug Administration (FDA) in 2003, alefacept in January and efalizumab in October. Both agents have demonstrated favorable safety profiles in clinical trials and significant benefits on patient quality of life. Head-to-head trials are lacking, but in placebo controlled trials, similar percentages of patients appear to respond to each of these 2 drugs. An advantage of alefacept is that it has been shown in clinical trials to provide durable off-treatment efficacy (approximately 7 months). Efalizumab has a relatively quick onset of antipsoriatic effect, but it needs to be administered once weekly continuously to maintain symptom control. Etanercept (approved by the FDA for treating moderate-to-severe plaque psoriasis in May 2004) and infliximab (not FDA-approved for psoriasis treatment) have also shown promise in randomized controlled trials, although less data are available on these agents. Case reports and pilot studies suggest that other biologics under investigation may also prove useful for the treatment of psoriasis. Patient populations that may particularly benefit from biologic therapy are discussed. CONCLUSION: Biologic agents appear to offer a safe and effective alternative to conventional systemic therapies and phototherapy for the treatment of moderate-to-severe chronic plaque psoriasis. The biologics appear to be safer than traditional therapies, although long-term safety data still need to be established.

Induction immunosuppression in kidney transplant recipients older than 60 years of age : safety and efficacy of ATGAM, OKT3 and Simulect.

BACKGROUND: The choice of induction immunosuppression for kidney transplantation in elderly recipients is dictated by the consideration of the risk of infection as well as efficacy in the prevention of acute rejection, thus allowing a reduction in subsequent maintenance immunosuppression and its attendant long-term adverse effects. OBJECTIVE: To compare the efficacy and safety of the antibody induction immunosuppression strategies in elderly recipients of kidney transplants. PATIENTS AND METHODS: We present retrospective data analysis on 183 kidney transplant recipients > or = 60 years of age at Hahnemann University Hospital (Philadelphia, PA, USA) over a 12-year period. We compared four consecutive cohorts of kidney transplant recipients receiving lymphocyte immune globulin, equine antithymocyte globulin (ATGAM) [n = 29]; muromonab CD3 (OKT3) [n = 45]; basiliximab (Simulect) with corticosteroid maintenance [n = 40]; and Simulect without corticosteroid maintenance (n = 69). RESULTS: Delayed graft function (DGF) was observed in 48% of patients receiving ATGAM, 35.6% in the OKT3 group and 35% in the Simulect group with corticosteroid maintenance and 36.2% in the Simulect group without corticosteroid maintenance. The rejection rate within the first 3 months was 31% in the ATGAM and OKT3 groups, 17.5% in the Simulect group with corticosteroid maintenance and 14.5% in the Simulect group without corticosteroid maintenance. These differences for DGF and acute rejection were statistically significant between patients receiving ATGAM and OKT3, ATGAM or OKT3 and both groups of Simulect (all p < 0.05). Patients receiving Simulect were free of adverse effects typically encountered by patients receiving polyclonal and monoclonal antibodies for induction. Patients receiving Simulect had much shorter hospital stays and benefited from significant reduction of costs compared with other groups. CONCLUSION: Our data indicate that kidney transplant recipients > or = 60 years of age benefit from induction therapy with Simulect followed by corticosteroid-free maintenance immunosuppression.

Considerations for assessing the cost of biologic agents in the treatment of psoriasis.

OBJECTIVE: This paper will establish the rationale for developing a long-term cost model to assess the utilization and associated economics of biologic agents in the treatment of moderate-to-severe psoriasis. This information should assist with defining the total cost of drug treatment when using biologic therapy to treat psoriasis. SUMMARY: The development of biologic therapies has effected the treatment of many chronic diseases, including psoriasis. Managed care organizations are debating the appropriate use of these injectable drugs because of the associated acquisition costs and administration requirements. Important considerations for evaluating these agents include the ability to produce off-treatment remissions, the ability to improve patients. quality of life, and safety and tolerability profiles. A remittive therapy may be a good early treatment for these patients because it offers the chance to avoid lifelong therapy. In addition, the safety and tolerability profiles of all biologic agents are substantially improved compared with conventional systemic psoriasis treatments. However, therapy must be individualized because risks vary with each agent. Thus, these differences in the biologic agents should be considered in the assessment of the economic impact and drug utilization of biologics for patients with psoriasis. CONCLUSION: The biologic agents currently used in the treatment of psoriasis offer patients new hope for safe and effective therapy. Comparison of these agents by managed care decision makers requires consideration of characteristics that differentiate the agents, including efficacy, duration of off-treatment response, and safety and tolerability.

Alefacept: potential new therapy for patients with moderate-to-severe psoriasis.

Alefacept is a new biotechnology product designed for the treatment of patients with chronic plaque-type psoriasis who have disease severe enough to make them eligible for phototherapy or systemic therapy. In two randomized controlled phase III trials of patients with moderate-to-severe disease, alefacept showed a modest but statistically significant increase in the number of responders compared to placebo. Alefacept's dose-dependent CD4+ T lymphocyte-depleting effect requires monitoring; however, no association has been found between this adverse effect and serious adverse events, particularly infection. Due to lack of direct comparative data, it is difficult to predict exactly how alefacept will fit into the current rotational psoriasis therapy paradigm.