Cost-effectiveness of ribociclib plus endocrine therapy versus placebo plus endocrine therapy in HR-positive, HER2-negative breast cancer.

BACKGROUND: The 2015 American Society of Clinical Oncology guidelines recommend first-line treatment of hormone receptor (HR)-positive breast cancer with endocrine therapy plus or minus palbociclib, a selective cyclin-dependent kinase (CDK)4/6 inhibitor. In 2018, the U.S. Food and Drug Administration approved ribociclib, a new orally available selective CDK4/6 inhibitor. While gains in progression-free survival (PFS) and overall survival (OS) from ribociclib are important for clinical and treatment outcomes, trade-offs in adverse events (AEs) and additional costs necessitate cost-effectiveness analysis (CEA) to assist consideration by third-party payer systems, physicians, and patients. OBJECTIVES: To (a) develop a Markov model and (b) determine the cost-effectiveness of ribociclib plus endocrine therapy versus endocrine therapy alone as treatment for premenopausal and perimenopausal patients with HR-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. METHODS: A lifetime 3-state Markov model ("stable," "progressed," and "dead" health states) was developed using a U.S. payer perspective. Transition probabilities were calculated based on OS and PFS outcomes from the randomized controlled phase 3 trial MONALEESA-7. These Kaplan-Meier curves were extended to lifetime by estimating best-fit distributions using loglogistic distribution for ribociclib curves and Weibull distribution for placebo curves. Costs were obtained from national data sources using 2019 U.S. dollars (USD) and discounted by 3%. Utilities were obtained via published breast cancer literature and were included for each health state and for time spent with each AE. Results were expressed as an incremental cost-effectiveness ratio (ICER) expressed as USD per quality-adjusted life-year (QALY) saved. Treatments were assumed to be cost-effective based on a willingness-to-pay (WTP) threshold of $150,000 per QALY gained. Base-case, 1-way sensitivity tornado diagrams and probabilistic sensitivity analyses demonstrated changes in the ICER and were driven by the cost of ribociclib and the utility of remaining in the stable health state. RESULTS: Ribociclib plus endocrine therapy was cost-effective at an ICER of $124,513 per QALY when compared with endocrine therapy alone at a WTP threshold of $150,000. The ribociclib plus endocrine therapy arm had an effectiveness of 5.28 QALYs and a total cost of $385,112, while placebo plus endocrine therapy provided only 2.46 QALYs at a lower total cost of $67.246. The model was sensitive to the cost of ribociclib and the utility of time spent in the stable health state. Probabilistic sensitivity analysis demonstrated that endocrine therapy alone was cost-effective until a WTP of $125,000 and was cost-effective 72% of the time at the WTP threshold. CONCLUSIONS: Ribociclib plus endocrine therapy is more cost-effective than endocrine therapy alone. Professionals in managed care settings should consider the pharmacoeconomic benefits of ribociclib for the treatment of HR-positive, HER2-negative breast cancer as they make value-based formulary decisions. Further CEAs should be considered as direct treatment comparison trials between CDK4/6 inhibitors are completed in the future. DISCLOSURES: No outside funding supported this study. The authors have nothing to disclose.

Conversion of Functional Assessment of Chronic Illness Therapy-Fatigue to Patient-Reported Outcomes Measurement Information System Fatigue Scores in Two Phase III Baricitinib Rheumatoid Arthritis Trials.

OBJECTIVE: The Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) is validated for measuring fatigue in rheumatoid arthritis (RA). However, 10 of 13 FACIT-F items are identified as relevant to patients with RA. The Patient-Reported Outcomes Measurement Information System (PROMIS) uses an item response theory-calibrated T score metric. The PROMIS Fatigue item bank includes the FACIT-F items, enabling score conversion. The performance of converted PROMIS Fatigue scores has not been evaluated in RA populations or clinical trials. Our objective was to assess the performance of converted PROMIS Fatigue scores in 2 RA clinical trials of baricitinib. METHODS: Crosswalk tables and pattern-scoring methods converted FACIT-F scores to PROMIS Fatigue for both the 13-item FACIT-F and the 10-item RA-optimized FACIT-F instrument, in 2 RA clinical trials evaluating baricitinib, RA-BEAM, and RA-BEACON. RA-BEAM patients had an inadequate response to methotrexate. RA-BEACON patients had an inadequate response or intolerance to ≥1 tumor necrosis factor inhibitor. Baricitinib was compared to all treatment arms via analysis of covariance on PROMIS Fatigue score conversions. RESULTS: Baseline FACIT-F-derived PROMIS Fatigue scores reflected severe fatigue across treatment groups and were similar using different scoring methods. At week 24 in both studies, baricitinib was associated with clinically meaningful improvements in PROMIS Fatigue scores. PROMIS Fatigue scores were consistent for conversion methods and for the 13-item or 10-item FACIT-F. CONCLUSION: All 4 conversion methods showed differentiation of active treatment compared with placebo from week 12, supporting the use of the PROMIS Fatigue and converting the 10-item FACIT-F to assess fatigue and demonstrate treatment benefit in RA clinical trials on a standardized metric.

Tumor Response Assessment in Diffuse Intrinsic Pontine Glioma: Comparison of Semiautomated Volumetric, Semiautomated Linear, and Manual Linear Tumor Measurement Strategies.

BACKGROUND AND PURPOSE: 2D measurements of diffuse intrinsic pontine gliomas are limited by variability, and volumetric response criteria are poorly defined. Semiautomated 2D measurements may improve consistency; however, the impact on tumor response assessments is unknown. The purpose of this study was to compare manual 2D, semiautomated 2D, and volumetric measurement strategies for diffuse intrinsic pontine gliomas. MATERIALS AND METHODS: This study evaluated patients with diffuse intrinsic pontine gliomas through a Phase I/II trial (NCT02607124). Clinical 2D cross-product values were derived from manual linear measurements (cross-product = long axis × short axis). By means of dedicated software (mint Lesion), tumor margins were traced and maximum cross-product and tumor volume were automatically derived. Correlation and bias between methods were assessed, and response assessment per measurement strategy was reported. RESULTS: Ten patients (median age, 7.6 years) underwent 58 MR imaging examinations. Correlation and mean bias (95% limits) of percentage change in tumor size from prior examinations were the following: clinical and semiautomated cross-product, r = 0.36, -1.5% (-59.9%, 56.8%); clinical cross-product and volume, r = 0.61, -2.1% (-52.0%, 47.8%); and semiautomated cross-product and volume, r = 0.79, 0.6% (-39.3%, 38.1%). Stable disease, progressive disease, and partial response rates per measurement strategy were the following: clinical cross-product, 82%, 18%, 0%; semiautomated cross-product, 54%, 42%, 4%; and volume, 50%, 46%, 4%, respectively. CONCLUSIONS: Manual 2D cross-product measurements may underestimate tumor size and disease progression compared with semiautomated 2D and volumetric measurements.

Quantification of Economic Impact of Drug Wastage in Oral Oncology Medications: Comparison of 3 Methods Using Palbociclib and Ribociclib in Advanced or Metastatic Breast Cancer.

BACKGROUND: Discarding unused drugs after dose changes or discontinuation can significantly affect pharmacy budgets. This is especially concerning for expensive oncology agents. However, few economic studies account for drug wastage, providing an inaccurate estimate of a drug's actual economic cost, cost-effectiveness, and value. OBJECTIVES: To (a) compare the economic impact of drug wastage between ribociclib and palbociclib-clinically similar oral medications for metastatic breast cancer-using 3 approaches (Markov model, pharmacy acquisition cost model, and a retrospective claims analysis) and (b) compare the modeling results with a published estimate of drug wastage for palbociclib from a claims analysis. METHODS: A Markov model and a pharmacy acquisitions cost model were developed to evaluate the economic impact of dose reductions for ribociclib and palbociclib over a 1-year time period. Data inputs were pharmacy costs (RED BOOK wholesale acquisition cost) and proportion of patients experiencing dose reductions from either ribociclib randomized clinical trials (MONALEESA-2, -3, or -7) or real-world observational data (Symphony Health retrospective claims analysis). The latter constituted the third approach for quantifying drug wastage. The economic impact of dose reductions for ribociclib and palbociclib in postmenopausal women with previously untreated HR-positive/HER2-negative advanced breast cancer was assessed. Drug wastage was defined as drug doses that could not be used by a patient following a dose reduction. The cost of drug wastage was defined as the cost associated with an unused drug resulting from a dose reduction. The predicted results from the 2 models were compared with a previously published claims analysis that estimated the effect of treatment costs and drug wastage for palbociclib based on the observed dosing patterns from the Symphony Health Solutions database. RESULTS: In the Markov model, relative to ribociclib, palbociclib users experienced drug wastage of $112,382 total, or $1,124 per treated patient, per year due to dose changes. In the pharmacy acquisition cost model, relative to ribociclib, palbociclib usage was associated with an increased cost of $7,196 per patient per year (based on a mid-cycle dose reduction) comprising dosing-based cost differences and drug wastage cost for palbociclib of $3,727. The previously published claims analysis found that palbociclib users experiencing a dose reduction had drug wastage costs of $5,471 per patient. CONCLUSIONS: In both models, dose reductions for ribociclib patients resulted in no wastage, since unused tablets could be administered in subsequent cycles, while dose reductions for palbociclib resulted in drug wastage and increased costs. The results from both models were consistent with previously published results from the claims analysis, demonstrating drug wastage costs for palbociclib. DISCLOSURES: This study received financial support from Novartis Pharmaceuticals, which has products approved for treatment of breast cancer. Tang was employed by Novartis during this study; Zacker and Dalal are employed by Novartis and own company stock. Biskupiak, Brixner, and Oderda received payment from Novartis for this study. Brixner serves as a consultant for Millcreek Outcomes Group and also declares consulting fees from Abbvie, AstraZeneca, Abbott, Becton Dickinson, and Xcenda, unrelated to this study.

Why upfront use of CDK inhibitors for the treatment of advanced breast cancer may be wasteful, and how we can increase their value.

Three Cyclin Dependent Kinase 4/6 (CDK) inhibitors have been approved by the United Stated Food and Drug Administration for front line treatment of advanced hormone receptor positive breast cancer based on improvements in progression free survival against endocrine monotherapy. Two clinical trials have so far reported results on overall survival but both are negative. CDK inhibitors are usually tolerated well but they do add to inconvenience and cost - for example, grade III-IV neutropenia occur at a frequency of over 60% requiring frequent blood work at least during the initial months of treatment. These drugs cost over $ 13,500 for a 4-week cycle in the United States, and are responsible for billions of dollars annually in drug cost alone. Importantly, many women with metastatic breast cancer do well for a long time with endocrine therapy alone and CDK inhibitors do not have a predictive marker. Selective use of these agents in later lines may improve substantially the convenience and cost without compromise in overall outcome. However, with results demonstrating impressive improvements in PFS published in major medical journals coupled with patients' natural desire for "best available" options, the trend among oncologists is to prescribe these drugs as the default front-line treatment. In this commentary I caution readers against over interpretation of results from the CDK inhibitor trials, describe adverse consequences of routine front-line use, and explain why selective use in later line may yield a higher value.

Eficacia y seguridad del uso de nelarabina en pacientes pediátricos con leucemia linfoblástica aguda de células T con recaída o refractariedad a dos líneas de quimioterapia / Efficacy and safety of the use of nelarabine in pediatric patients with acute lymphoblastic leukemia of T-cells with relapse or refractory to two chemotherapy lines

INTRODUCCIÓN: El presente dictamen expone la evaluación de tecnología de la eficacia y seguridad de nelarabina en el tratamiento de pacientes pediátricos con leucemia linfoblástica aguda de células T con recaída o refractariedad a dos líneas de quimioterapia. El tratamiento estándar en el manejo de pacientes pediátricos con leucemia linfoblástica aguda (LLA) con varias recaídas es el trasplante de progenitores hematopoyéticos (TPH), utilizado como terapia de consolidación una vez que el paciente se encuentra en remisión. En la actualidad, EsSalud cuenta con clofarabina como tratamiento que lleva a los pacientes a remisión de manera que puedan ser trasplantados. El uso por fuera del Petitorio Farmacológico de EsSalud de clofarabina para el tratamiento de pacientes con LLA (de linfocitos T [T-LLA] y de linfocitos B [B-LLA]) que han recaído luego de dos líneas de quimioterapia fue aprobado en el 2016 mediante el Dictamen Preliminar de Evaluación de Tecnología Sanitaria N° 001-SDEPFyOTS-DETS-IETSI-2016 y se encuentra vigente a la fecha. Sin embargo, los especialistas de la institución sostienen que, de acuerdo a su experiencia desde la aprobación de clofarabina hace más de dos años, si bien ésta muestra tasas de respuesta moderadas en pacientes con inmunofenotipo B (i.e., B-LLA), esto no se ha logrado en pacientes con inmunofenotipo T (i.e., T-LLA), y que por lo tanto se requiere de otra alternativa terapéutica en este subgrupo especifico de pacientes. Además, afirman que los pacientes no remitirán espontáneamente y que la sobrevida general es de alrededor de tres meses con tratamiento paliativo. TECNOLOGÍA SANITARIA DE INTERÉS: Nelarabina (2-amino-9ß-D-arabinosyl-6-methoxy-9H-guanina), de nombre comercial ARRANON®, es un análogo de purina de cuarta generación. Este es un profármaco del análogo de desoxiguanosina ara-G sintetizado (9-ß-D-arabinofuranosylguanina). Este profármaco es desmetilado rápidamente por la adenosina desaminasa (ADA) a ara-G y una vez dentro de la célula es fosforilado por la desoxiguanosina quinasa y la desoxicitidina quinasa a su metabolito 5´-monofosfato. Dicho metabolito monofosfato es convertido a la forma activa 5´-trifosfato ara-GTP. Ara-GTP se acumula en los blastos leucémicos lo que lleva a la incorporación preferente de ara-GTP en el ácido desoxirribonucleico (ADN), conduciendo a la inhibición de su síntesis. La inhibición de la síntesis de ADN lleva a la muerte de los blastos leucémicos. Es este el mecanismo a través del cual nelarabina podría tener un impacto sobre la proliferación de células cancerosas en pacientes con LLA. METODOLOGÍA: Se llevó a cabo una búsqueda de la literatura con respecto a la eficacia y seguridad de nelarabina en el tratamiento de pacientes pediátricos con LLA de células T con recaída o refractariedad a dos líneas de quimioterapia en las bases de datos de PubMed, Cochrane Library, el metabuscador TRIPdatabase y el sitio web ww.clinicaltrials.gov. Adicionalmente, se realizó una búsqueda de evaluaciones de tecnologías y guías de práctica clínica en las páginas web de grupos dedicados a la investigación y educación en salud en general como The National Institute for Health and Care Excellence (NICE), Canadian Agency for Drugs and Technologies in Health (CADTH), Scottish Medicines Consortium (SMC), Instituto de Evaluación de Efectividad Clínica y Sanitaria (IECS), Instituto de Evaluación de Tecnología en Salud (IETS); así como en organizaciones especializadas en oncología como European Society for Medical Oncology (ESMO), National Comprehensive Cancer Network (NCCN) y American Society of Clinical Oncology (ASCO). RESULTADOS: Se llevó a cabo una búsqueda de evidencia científica relacionada al uso de nelarabina en el tratamiento de pacientes pediátricos con LLA de células T recurrente o refractario a dos líneas de quimioterapia. En la presente sinopsis se describe la evidencia disponible según el tipo de publicación, siguiendo lo indicado en los criterios de elegibilidad (GPC, ETS, RS, MA y ECA fase III). A la fecha, la evidencia disponible relacionada al tratamiento con nelarabina de pacientes pediátricos con T-LLA es muy escasa, y no se ha publicado ningún estudio de la eficacia comparativa entre nelarabina y clofarabina. Con ello, la evidencia identificada en la presente búsqueda sistemática e incluida en el presente dictamen corresponde principalmente a un ensayo de fase IV no controlado del uso de nelarabina, una guía de práctica clínica (GPC) y una evaluación de tecnología sanitaria (ETS). Adicionalmente, en ausencia de estudios comparativos, y frente a la preocupación de los especialistas de una eficacia diferenciada de clofarabina entre inmunofenotipos, se llevó a cabo una búsqueda de la evidencia del uso de clofarabina en la población de pacientes con T-LLA específicamente, con la finalidad de evaluar si se trata de una alternativa factible para dicha subpoblación. De ella se obtuvo únicamente un ensayo de fase II de un solo brazo que explora la respuesta diferenciada al tratamiento con clofarabina/ciclofosfamida/etopósido entre pacientes pediátricos con B-LLA y T-LLA con dos o más recaídas. CONCLUSIONES: La evidencia identificada a la fecha no permite establecer la eficacia comparativa entre nelarabina y clofarabina. A pesar de que la evidencia que apoya el uso de nelarabina en pacientes con T-LLA es escasa y de baja calidad, y la comparación con clofarabina es descriptiva e indirecta, la baja tasa de respuesta y la tasa nula de supervivencia al año observada en la población con T-LLA tras el uso de clofarabina sugieren que este no sería una alternativa de tratamiento factible para dicho inmunofenotipo y, por lo tanto, nos encontraríamos en un escenario de vacío terapéutico. Además, considerando que, de acuerdo a los especialistas de la institución y la historia natural de la enfermedad, los pacientes no remitirán espontáneamente, se tiene entonces que nelarabina podría ofrecer una tasa de respuesta de alrededor de 40 %. el Instituto de Evaluación de Tecnologías en Salud e Investigación (IETSI), aprueba el uso fuera del petitorio de nelarabina en el tratamiento de pacientes pediátricos con diagnóstico de leucemia linfoblástica aguda de células T con recaída o refractariedad a dos líneas de quimioterapia. La vigencia del presente dictamen preliminar es de un año a partir de la fecha de publicación.

Cost-Effectiveness of Ribociclib plus Letrozole Versus Palbociclib plus Letrozole and Letrozole Monotherapy in the First-Line Treatment of Postmenopausal Women with HR+/HER2- Advanced or Metastatic Breast Cancer: A U.S. Payer Perspective.

BACKGROUND: U.S. regulatory approvals of the cyclin-dependent kinase 4 and 6 (CDK 4/6) inhibitors ribociclib and palbociclib as add-ons to letrozole greatly enhance the prospects for treating postmenopausal women with hormone receptor-positive (HR+)/human epidermal receptor 2-negative (HER2-) advanced or metastatic breast cancer. Clinical trials have established that the combination of a CDK 4/6 inhibitor with letrozole can significantly improve progression-free survival (PFS) versus letrozole monotherapy and is safe and well tolerated. Cost-effectiveness studies are required to inform payers and clinical decision makers on the money value of combination treatment in clinical practice. OBJECTIVE: To evaluate the cost-effectiveness of ribociclib plus letrozole versus palbociclib plus letrozole and versus letrozole monotherapy in the first-line treatment of postmenopausal women with HR+/HER2- advanced or metastatic breast cancer from a U.S. private third-party payer perspective. METHODS: A partitioned survival model including 3 health states (progression free, with either overall response or stable disease; progressed disease; and death) simulated lifetime costs and outcomes over a 40-year lifetime horizon with a 1-month cycle length. Clinical efficacy data (PFS and overall survival [OS]) were derived from a phase III trial of ribociclib plus letrozole (MONALEESA-2; NCT01958021), a phase II trial of palbociclib plus letrozole (PALOMA-1; NCT00721409), and a Bayesian network meta-analysis. Health care costs included drug acquisition and monitoring, disease management, subsequent therapies, and serious drug-related adverse events. Effectiveness was measured in life-years, derived from survival projections, and in quality-adjusted life-years (QALYs), calculated from time spent in each state combined with health-state utility values. A one-way deterministic sensitivity analysis explored the impact of uncertainty in key model parameters on results, and probabilistic uncertainty was assessed through a Monte Carlo probabilistic sensitivity analysis. RESULTS: Ribociclib plus letrozole was dominant versus palbociclib plus letrozole, with a cost saving of $43,037 and a gain of 0.086 QALYs. Compared with letrozole monotherapy, ribociclib plus letrozole was associated with an incremental cost of $144,915 and an incremental QALY of 0.689, equating to an incremental cost-effectiveness ratio of $210,369 per QALY. Key model drivers included OS HRs for palbociclib plus letrozole versus letrozole and for ribociclib plus letrozole versus letrozole, the PFS HR for palbociclib plus letrozole versus letrozole, PD health-state costs, utility of response, and cost discount rate. The probabilities that ribociclib plus letrozole was cost-effective versus letrozole at thresholds of $50,000, $100,000 and $200,000 per QALY gained were 1.6%, 6.3%, and 50.5%, respectively. CONCLUSIONS: In the United States, ribociclib plus letrozole is a cost-effective alternative to palbociclib plus letrozole for the first-line treatment of postmenopausal women with HR+/HER2- advanced or metastatic breast cancer. Ribociclib plus letrozole is also cost-effective versus letrozole monotherapy at willingness-to-pay thresholds greater than $198,000 per QALY (for probabilistic analysis). DISCLOSURES: Funding for this study was provided by Novartis, which manufactures ribociclib and provided input on the study design and data collection, analysis, and interpretation. Mistry, May, Suri, and Young are employees of PAREXEL. Tang, Mishra, D. Bhattacharyya, and Dalal are employees of Novartis. S. Bhattacharyya was an employee of Novartis during the study period. Tang and Dalal hold stock in Novartis. Brixner, Oderda, and Biskupiak were paid by Millcreek Outcomes Group as consultants for work on this project. Brixner has also consulted for AstraZeneca, UCB, Regeneron, and Abbott.

Drivers of treatment patterns in patients with chronic lymphocytic leukemia stopping ibrutinib or idelalisib therapies.

Novel therapies including kinase inhibitors (KI) have led to high and durable response in patients with chronic lymphocytic leukemia (CLL), however, some patients stop therapy. This study evaluates reasons for treatment changes among CLL patients who stopped KI in real-world practice. Sixty-nine US oncologists/hematologists provided patient-level data abstracted from charts of CLL adult patients who initiated a KI and later (1) switched to another anti-neoplastic regimen (Switched cohort), (2) discontinued the KI and remained untreated (Discontinued cohort), or (3) restarted the same KI after an interruption of ≥60 days (Restarted cohort). Demographics, clinical/treatment characteristics, and reasons for stopping, restarting, and switching the KI therapy were described. In the Switched cohort, reasons for stopping included disease progression (72.5%), low/no disease activity (3.9%), adverse event [AE]/ intolerance/comorbidity (15.7%), and planned cellular therapies (7.9%). In the Discontinued cohort, approximately half (46.0%) of patients stopped KI therapy because they were terminally ill/died, or were moved to best supportive care - these patients were older, had more severe disease, and high comorbidity burden. The other half (54.0% of patients) stopped due to low/no disease activity (24.0%), AEs/toxicity (12.0%), or patient-requested drug holiday (18.0%). In the Restarted cohort, the most common reasons for stopping KIs were patient request (37.3%), AEs/intolerance (31.4%), and economic reasons (10%). Patients restarted when disease progressed (60.8%) or when they recovered from the AE (33%). Reasons for KI stop and subsequent treatment patterns were varied and multifactorial, suggesting heterogeneous disease management and a need for more evidence around supporting strategies and physician education.

Cost-utility analysis of idelalisib in combination with rituximab in relapsed or refractory chronic lymphocytic leukaemia.

OBJECTIVE: To evaluate the incremental cost-utility ratio (ICUR) of idelalisib in combination with rituximab (IR) versus rituximab monotherapy (R) in the treatment of patients with relapsed or refractory (R/R) chronic lymphocytic leukaemia (CLL), from the Spanish National Health System (NHS) perspective. METHODS: A partitioned survival Markov model for a lifetime horizon (30 years) was developed to estimate costs (€, 2016) and quality-adjusted life years (QALY) with IR and R. Initial cohort included patients with CLL receiving a second or subsequent line (2L) of treatment with IR or R. Survival data were based on CLL clinical trial. Drug, administration, monitoring, adverse events and clinical management of CLL costs were included in the model. Costs and outcomes were discounted using a 3% annually. Deterministic and probabilistic sensitivity analyses (PSA) were performed. RESULTS: Compared to R, 2L IR treatment resulted in QALY gain of 3.147 (4.965 versus 1.818). Total costs were €118 254 for IR versus €23 874 for R. ICUR was €29 990/QALY gained with IR versus R. In the PSA, IR was cost-effective in 78% of iterations using a threshold of €45 000/QALY. CONCLUSION: IR can be considered a cost-effective treatment compared to R, in the treatment of R/R CLL patients for the Spanish NHS.

Impact of ibrutinib and idelalisib on the pharmaceutical cost of treating chronic lymphocytic leukemia at the individual and societal levels.

PURPOSE: To evaluate the impact of approval of ibrutinib and idelalisib on pharmaceutical costs in the treatment of chronic lymphocytic leukemia (CLL) at the societal level and assess individual out-of-pocket costs under Medicare Part D. METHODS: Average wholesale price of commonly used CLL treatment regimens was ascertained from national registries. Using the population of Olmsted County, Minnesota, we identified the proportion of patients with newly diagnosed CLL who experience progression to the point of requiring treatment. Using these data, total pharmaceutical cost over a 10-year period after diagnosis was estimated for a hypothetic cohort of 100 newly diagnosed patients under three scenarios: before approval of ibrutinib and idelalisib (historical scenario), after approval of ibrutinib and idelalisib as salvage therapy (current scenarios A and B), and assuming use of ibrutinib as first-line treatment (potential future scenario). RESULTS: Estimated 10-year pharmaceutical costs for 100 newly diagnosed patients were as follows: $4,565,929 (approximately $45,659 per newly diagnosed patient and $157,446 per treated patient) for the historical scenario, $7,794,843 (approximately $77,948 per newly diagnosed patient and $268,788 per treated patient) for current scenario A, $6,309,162 (approximately $63,092 per newly diagnosed patient and $217,557 per treated patient) for current scenario B, and $16,414,055 (approximately $164,141 per newly diagnosed patient and $566,002 per treated patient) for the potential future scenario. Total out-of-pocket cost for 100 patients with newly diagnosed CLL under Medicare Part D increased from $9,426 under the historical scenario (approximately $325 per treated patient) to $363,830 and $255,051 under current scenarios A and B (approximately $8,800 to $12,500 per treated patient) and to $1,031,367 (approximately $35,564 per treated patient) under the future scenario. CONCLUSION: Although ibrutinib and idelalisib are profound treatment advances, they will dramatically increase individual out-of-pocket and societal costs of caring for patients with CLL. These cost considerations may undermine the potential promise of these agents by limiting access and reducing adherence.

Ulcerative colitis: epidemiology, diagnosis, and management.

Ulcerative colitis is a chronic idiopathic inflammatory bowel disease characterized by continuous mucosal inflammation that starts in the rectum and extends proximally. Typical presenting symptoms include bloody diarrhea, abdominal pain, urgency, and tenesmus. In some cases, extraintestinal manifestations may be present as well. In the right clinical setting, the diagnosis of ulcerative colitis is based primarily on endoscopy, which typically reveals evidence of continuous colonic inflammation, with confirmatory biopsy specimens having signs of chronic colitis. The goals of therapy are to induce and maintain remission, decrease the risk of complications, and improve quality of life. Treatment is determined on the basis of the severity of symptoms and is classically a step-up approach. 5-Aminosalycilates are the mainstay of treatment for mild to moderate disease. Patients with failed 5-aminosalycilate therapy or who present with more moderate to severe disease are typically treated with corticosteroids followed by transition to a steroid-sparing agent with a thiopurine, anti-tumor necrosis factor agent, or adhesion molecule inhibitor. Despite medical therapies, approximately 15% of patients still require proctocolectomy. In addition, given the potential risks of complications from the disease itself and the medications used to treat the disease, primary care physicians play a key role in optimizing the preventive care to reduce the risk of complications.

Management of ED under the "severe distress" criteria in the NHS: a real-life study.

INTRODUCTION: The United Kingdom is unusual in that a significant proportion of patients with erectile dysfunction (ED) have their treatment fully reimbursed by the National Health Service (NHS). This may have consequences for the choice of treatment and for compliance with treatment. AIMS: The aim of this study was to evaluate the use and cost implications of phosphodiesterase type 5 inhibitor in an NHS setting. METHODS: Basic demographics and data on ED management for patients treated from January 2000 to April 2011 were obtained from a prospectively accrued database. We reviewed drug usage and costs as well as switching between drugs. Patients were given the choice of all available therapies and were followed up annually. MAIN OUTCOME MEASURES: Switching, compliance, and costs of treating ED under the "severe distress" criteria in the NHS were reviewed for this study. RESULTS: Two thousand one hundred fifty-nine patients qualified for reimbursed therapy. Two hundred twenty-six patients were excluded from further analysis owing to missing data. Patients were followed up on an annual basis. The mean patient age was 60.2 years (min 23, max 90), and the mean follow-up was 50.8 months (min 1, max 127). Six hundred ninety-six were started on sildenafil, 990 on tadalafil, 163 on vardenafil, and 84 on intracavernosal alprostadil. Eighteen percent of patients initially started on the scheme and stopped medication unilaterally. Of the patients, 12.3% changed their medication during follow-up. The cost of drugs increased year by year from £257,100 in 2007 to £352,519 in 2011. CONCLUSIONS: Our real-life observational study shows that in our institution, dropout of therapy is unusual. We hypothesize that this reflects, in part, the reimbursement issue. We also found that switching between drugs was unusual, although there are several possible explanations for that. Although this is a successful system for the patients, the hospital, which bears the costs of medication, is finding this an increasing economic drain.

Sildenafil and analogous phosphodiesterase type 5 (PDE-5) inhibitors in herbal food supplements sampled on the Dutch market.

Herbal food supplements, claiming to enhance sexual potency, may contain deliberately added active pharmacological ingredients (APIs) that can be used for the treatment of erectile dysfunction (ED). The aim of this study was to determine whether herbal food supplements on the Dutch market indeed contain APIs that inhibit phosphodiesterase type 5 (PDE-5) inhibitors, such as sildenafil and analogous PDE-5 inhibitors. Herbal food supplements intended to enhance sexual potency (n = 71), and two soft drinks, were sampled from 2003 up to and including 2012. In 23 herbal supplements, nine different PDE-5 inhibitors were identified; in a few cases (n = 3), more than one inhibitor was indentified. The presence of these APIs was however not stated on the label. The concentrations of PDE-5 inhibitors per dose unit were analysed. Furthermore, the potential pharmacologically active properties of the detected PDE-5 inhibitors were estimated by using data from the scientific and patent literature regarding (1) in vitro PDE-5 activity, (2) reported effective doses of registered drugs with PDE-5 inhibitor activity and (3) similarity to other structural analogues. It was concluded that 18 of the 23 herbal food supplements, when used as recommended, would have significant pharmacological effects due to added APIs. Adequate use of existing regulation and control measures seems necessary to protect consumers against the adverse effects of these products.

The efficacy and safety of on-demand Elonza; a generic product of sildenafil in Thai men with erectile dysfunction.

OBJECTIVE: To evaluate the efficacy and safety of Elonza (generic product of sildenafil) 100 mg, a phosphodiesterase type 5 (PDE5) inhibitor, in Thai men with erectile dysfunction (ED). MATERIAL AND METHOD: This prospective, Cohort study was conducted for eight weeks. Two hundred ten male patients, older than 20 years of age with ED were enrolled to receive generic product of sildenafil 100 mg taken as needed. Efficacy is evaluated through the International Index of Erectile Function (IIEF) scores for the five separate response domains, erectile function, orgasmic function, sexual desire, intercourse satisfaction, and overall satisfaction domain. RESULTS: After sildenafil administration, erectile function domain scores were significantly increased from baseline, 5.02 (p < 0.001) and 7.19 (p < 0.001) in one month and two months, respectively. Intercourse satisfaction domain scores and overall satisfaction domain scores were significantly increased from baseline, 3.17 (p < 0.001) and 1.74 (p < 0.001) in two months, respectively. Most treatment emergent adverse events were mild or moderate. The most frequent treatment-emergent adverse events were flushing (13.2%), nasal congestion (9.8%), abnormal vision (4.9%), headache (4.4%), dizziness (2.9%), and dyspepsia (0.5%). CONCLUSION: Elonza, a generic product of sildenafil, was an effective and well-tolerated treatment for ED in Thai men.

Diabetic nephropathy: new approaches for improving glycemic control and reducing risk.

Nephropathy is a common consequence of diabetes, with a high prevalence in patients with type 1 (15%-25%) and type 2 diabetes mellitus (T2DM; 30%-40%). Nephropathy is associated with a poor prognosis and high economic burden. The risk of developing nephropathy increases with the duration of diabetes, and early diagnosis and treatment of risk factors for nephropathy (e.g., tight control of glycemia and hypertension) can reduce the development and progression of diabetic nephropathy. Advances in our understanding of the mechanisms of renal complications associated with diabetes and the etiology of nephropathy have identified additional risk factors for nephropathy, and novel therapeutic options are being explored. This review discusses the pathophysiology of diabetic nephropathy and common risk factors. Furthermore, we discuss emerging treatments for T2DM that could potentially slow or prevent the progression of diabetic nephropathy. The use of incretin-based therapies, such as the dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) analogs, is growing in patients with T2DM, due to their efficacy and tolerability profiles. As renal safety is a key factor when choosing treatment options to manage patients with T2DM, drugs that are suitable for use in patients with varying degrees of renal impairment without a requirement for dose adjustment, such as the DPP-4 inhibitor linagliptin, are of particular use. The ongoing advances in T2DM therapy may allow optimization of glycemic control in a wide range of patients, thereby helping to reduce the increasing morbidity and mortality associated with diabetic nephropathy.

Prescription opioids for back pain and use of medications for erectile dysfunction.

STUDY DESIGN: Cross-sectional analysis of electronic medical and pharmacy records. OBJECTIVE: To examine associations between use of medication for erectile dysfunction or testosterone replacement and use of opioid therapy, patient age, depression, and smoking status. SUMMARY OF BACKGROUND DATA: Males with chronic pain may experience erectile dysfunction related to depression, smoking, age, or opioid-related hypogonadism. The prevalence of this problem in back pain populations and the relative importance of several risk factors are unknown. METHODS: We examined electronic pharmacy and medical records for males with back pain in a large group model health maintenance organization during 2004. Relevant prescriptions were considered for 6 months before and after the index visit. RESULTS: There were 11,327 males with a diagnosis of back pain. Males who received medications for erectile dysfunction or testosterone replacement (n = 909) were significantly older than those who did not and had greater comorbidity, depression, smoking, and use of sedative-hypnotics. In logistic regressions, the long-term use of opioids was associated with greater use of medications for erectile dysfunction or testosterone replacement compared with no opioid use (odds ratio, 1.45; 95% confidence interval, 1.12-1.87, P < 0.01). Age, comorbidity, depression, and use of sedative-hypnotics were also independently associated with the use of medications for erectile dysfunction or testosterone replacement. Patients prescribed daily opioid doses of 120 mg of morphine-equivalents or more had greater use of medication for erectile dysfunction or testosterone replacement than patients without opioid use (odds ratio, 1.58; 95% confidence interval, 1.03-2.43), even with adjustment for the duration of opioid therapy. CONCLUSION: Dose and duration of opioid use, as well as age, comorbidity, depression, and use of sedative-hypnotics, were associated with evidence of erectile dysfunction. These findings may be important in the process of decision making for the long-term use of opioids. LEVEL OF EVIDENCE: 4.

A systematic review assessing the economic impact of sildenafil citrate (Viagra) in the treatment of erectile dysfunction.

INTRODUCTION: Sildenafil was the first oral phosphodiesterase type 5 (PDE5) inhibitor introduced as primary therapy for erectile dysfunction (ED). In the 7 years following its market launch, sildenafil was prescribed by more than 750,000 physicians to more than 23 million men worldwide. To date, few studies have evaluated the economic impact of sildenafil in treating ED. AIM: To evaluate the cost-effectiveness and impact of sildenafil on health care costs for patients with ED in multiple countries. MAIN OUTCOMES MEASURES: Economic outcomes including cost, cost-effectiveness, cost of illness, cost consequence, resource use, productivity, work loss, and willingness to pay (WTP) were investigated. METHODS: Using keywords related to economic outcomes and sildenafil, we systematically searched literature published between July 2001 and July 2011 using MEDLINE and EMBASE. Included articles pertained to costs, WTP, and economic evaluations. RESULTS: In the last 10 years, 12 studies assessed economic outcomes associated with sildenafil for ED. Most studies were conducted in the United States and the United Kingdom, with one study identified in Canada and one from Mexico. Six studies evaluated cost of illness, cost consequence, or cost of care, and four studies evaluated WTP or drug pricing by country in the United States and the United Kingdom. In the United States and the United Kingdom, costs to health care systems have increased with demand for treatment. Cost analyses suggested that sildenafil would lower direct costs compared with other PDE5 inhibitors. U.S. and U.K. studies found that patients exhibited WTP for sildenafil. The two cost-effectiveness models we identified examined ED sub-groups, those with spinal cord injury and those with diabetes or hypertension. These models indicated favorable cost-effectiveness profiles for sildenafil compared with other active-treatment options in both Mexico and Canada. CONCLUSIONS: The relative value of sildenafil vs. surgically implanted prosthetic devices and other PDE5 inhibitors, is underscored by patients' WTP, and cost-effectiveness in ED patients with comorbidities.