Price trends of reimbursed oncological drugs in Switzerland in 2005-2019: A descriptive analysis.

Increasing oncological treatment costs are a major global concern with the risk of entailing two-tiered health care. Among cost determining factors is the price of individual drugs. In recognition of the central role of this factor, we present a comprehensive overview of the development of monthly prices of oncological drugs introduced over the last 15 years in Switzerland. We identified all oncological drugs newly reimbursed by mandatory health insurance in 2005-2019, and searched public repositories for their package prices, indications with approval dates, and treatment regimens for the calculation of (indication-specific) monthly prices. We found 81 products covering 77 different substances (39.5% protein kinase inhibitors, 21.0% monoclonal antibodies). Most indications related to the topography "blood", followed by "lung and thorax" and "digestive tract". From 2005­2009 to 2015­2019, the median monthly product price over all distinct indications of all products decreased by 7.56% (CHF 5,699 [interquartile range 4,483­7,321] to CHF 5,268 [4,019­6,967]), whereas it increased by 73.7% for monoclonal antibodies. In December 2019, six products had monthly prices over CHF 10,000, all approved for hematological or dermatological cancers. Our analysis suggests that individual price developments of oncological drugs are presently not the major driver of rising cancer treatment costs. However, rising launch prices of some new, mostly hematological drugs are of concern and require continued monitoring.

Assessing the benefit of cancer drugs approved by the European Medicines Agency using the European Society for Medical Oncology Magnitude of Clinical Benefit Scale over time.

BACKGROUND: Increasingly, cancer drugs are being approved based on surrogate measurements of efficacy. Clinically meaningful data, such as overall survival (OS) and quality of life, are often only presented in subsequent publications. We examined if the clinical benefit of cancer drugs, as measured by the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS), improves post-European Medicines Agency (EMA) approval as more data emerges. METHODS: Cancer drug indications approved by the EMA from January 2006 to December 2016 were reviewed and trials cited for efficacy were identified. Primary and subsequent publications (up to December 2019) of scorable trials were included. Changes in benefit over time were measured using ESMO-MCBS thresholds for non-curative (≥4 for substantial, =3 for intermediate and ≤2 for low benefit) and curative intent (A or B for major benefit) scoring. RESULTS: Fifty-five non-curative and two curative intent trials were included. At approval, 29.1% of non-curative trials were substantial, 45.5% intermediate and 25.5% low benefit. For curative intent trials, one displayed major benefit and one displayed no major benefit. We identified 82 subsequent publications for reassessment. A change in ESMO-MCBS classification was seen in 34.5% of non-curative trials (11 raised and 8 lowered). At 3-year reassessment, 36.4% of non-curative trials were substantial, 34.5% intermediate and 29.1% low benefit. Both curative trials showed no major benefit at reassessment. CONCLUSION: As over a third of trials changed classification, in either direction, reassessing the ESMO-MCBS score of approved cancer drugs may help to inform patients and ensure ongoing relevance of regulatory and reimbursement decisions.

Considerations for the Management of Oncology Patients During the COVID-19 Pandemic.

Worldwide incidence and mortality due to the coronavirus disease 2019 (COVID-19) pandemic is greatest in the United States, with the initial epicenter in New York. In Nassau County, New York, where we practice, our institution has had more than 2500 cases and has discharged from the hospital more than 1000 patients. As many academic and private institutions have swiftly shifted their clinical and research priorities to address the pandemic, data are emerging regarding both the impact of malignancy on COVID-19 outcomes as well as the challenges faced in assuring that cancer care remains unimpeded. Of concern, recent studies of cancer patients primarily in China and Italy have suggested that advanced malignancy is associated with increased susceptibility to severe COVID-19 infection. At present, more than 500 clinical trials are underway investigating the pathogenesis and treatment of COVID-19, including expanded use of oncology drugs, such as small molecular inhibitors of cytokine pathways. Here, we begin by reviewing the latest understanding of COVID-19 pathophysiology and then focus our attention on the impact of this virus on hematologic and oncologic practice. Finally, we highlight ongoing investigational treatment approaches that are so relevant to the care of oncology patients during this extraordinary pandemic.

Drug-induced disseminated intravascular coagulation: a pharmacovigilance study on World Health Organization's database.

BACKGROUND: Disseminated intravascular coagulation (DIC) occurs in several clinical conditions, including drug therapy. We aim to investigate the association between the administration of several drug classes and the onset of DIC by using the reports of Adverse Drug Reactions (ADR) collected in Vigibase, the World Health Organization (WHO) database of ADR. METHODS: We collected reports of drug-related DIC from 1968 to September 2015, classified in Vigibase according to the MedDRA (Medical Dictionary for Regulatory Activities) term "Disseminated intravascular coagulation". A disproportionality analysis using Reporting Odds Ratio (ROR) with 95% Confidence Interval (CI95%) was performed. RESULTS: Overall, 4653 reports of drug-associated DIC were retrieved and the 75.9% of them was serious according to WHO seriousness criteria. DIC was significantly (ROR > 1, lower limit of CI95% > 1) associated with 88 drugs, mainly antineoplastic agents, antithrombotic agents and antibacterials for systemic use. Among of the most frequently reported individual drugs we found dabigatran (94 reports) ROR = 1.34 (CI95% 1.08-1.67), oxaliplatin and bevacizumab both with 75 reports and ROR = 1.77 (1.38-2.27) and 2.02 (1.57-2.61), respectively. CONCLUSION: A substantial number of drugs, widely used in the clinical practice, may be associated with the potential occurrence of DIC. For many of these drugs, the ADR is not acknowledged in the corresponding Summary of Product Characteristics. The high number of drugs involved underlines the importance of evaluate this condition such as an ADR that might occur during drug therapy.

Novel Small Molecule Inhibitors of Programmed Cell Death (PD)-1, and its Ligand, PD-L1 in Cancer Immunotherapy: A Review Update of Patent Literature.

BACKGROUND: In the last few decades, cancer immunotherapy has been extensively researched, and novel checkpoint signaling mechanisms involving Programmed Death (PD)-1 and PDLigand 1 (PD-L1) receptors have been targeted. The PD-1/PD-L1 binding and interaction play a critical role in the development of malignancies. OBJECTIVE: The present review focuses on recent patents on the pharmacological and biological cancerregulating properties of PD-1/PD-L1 inhibitors involved in immunotherapeutic cancer drug development. METHODS: Thorough patent literature search published during the last seven years, including the World Intellectual Property Organization (WIPO®), United States Patent Trademark Office (USPTO®), Espacenet®, and Google Patents, to identify PD-1/PD-L1-targeting small molecule immunomodulators. RESULTS: Several small molecule PD-1/PD-L1 inhibitors were patented for regulation of tumor progression by academic and industry-associated investigators. Most of the claimed patents have been validated and confined to in vitro and in vivo mouse models limiting their entry into clinical settings. Majority of the patents are claimed by the researchers at Aurigene Ltd. (India) on novel peptidomimetic compounds. It is worth to be noted that macrocyclic compounds such as the peptides QP20, HD20, WQ20, SQ20, and CQ-22 from Bristol-Myers Squibb (BMS) Company, biaryl, and heterocyclic derivatives including 1,3-dihydroxy-phenyl compounds were efficient in regulating the PD-1/PD-L1 protein-protein binding and interaction compared to those of the approved monoclonal antibodies. CONCLUSION: PD-1/PD-L1 inhibitors show significant anti-cancer responses as stand-alone agents and in combination with other cancer therapies. More efficient experimental studies and clinical trials are necessary to evaluate the host-tumor cells' interactions. Understanding the cancer microenvironment, and identifying specific biomarkers and X-ray crystalline structures of PD-1/PD-L1 complexes, including molecular and genomic signature studies are essential to determine the feasibility of PD-1/PD-L1 inhibitors for development into drug-like cancer immunotherapeutics.

Lack of correlation between the costs of anticancer drugs and clinical benefits in Japan.

Both overall survival (OS) and progression-free survival (PFS) are primary endpoints of phase III studies of new anticancer drugs. Medical care expenditures, especially oncology drug prices, are rapidly increasing; however, the impact of oncology drug prices on OS and PFS is unclear. We analyzed the relationship between oncology drug prices and clinical outcomes in Japan. The costs of a full course or 1 year of treatment were estimated on the basis of the latest National Health Insurance Drug Price Standards, and the relationship between costs and improvements in OS or PFS obtained with each drug were analyzed. Cost-effectiveness was compared between new-class drugs and next-in-class drugs. We then developed a simple model for estimating the costs required to prolong OS and PFS by 1 day and used this model to compare cost-effectiveness. Drug costs were not significantly related to treatment outcomes in terms of PFS or OS. There was no significant difference in the median cost between novel drugs and the next-in-class drugs (P = 0.39). The oncology drug cost required to prolong PFS by 1 day was more expensive than the drug cost required for prolong OS by 1 day. Prices of oncology drugs should be decided on the basis of actual clinical benefits for cancer patients, and the drug price evaluation process should be disclosed in Japan.

Orphan Drugs and Their Impact on Pharmaceutical Development.

High levels of productivity, with an increasing number of approvals for new molecular entities (NMEs) by the FDA during the past decade, have coincided with the emergence of innovative drugs for treatments of rare diseases that have utilized the FDA orphan drug program. Since 2000, NMEs with orphan designation encompass a significant portion of approved drugs and constitute about 80% of the approved drugs that have established novel human genome-encoded products in recent years. Biological approvals are also expanding, with 40% of the approved biological agents having orphan designation. This trend illustrates a pivot within the pharmaceutical industry: from research programs that focus on canonical blockbuster indications and targets, towards the establishment of new treatments for rare and difficult to treat diseases.

Anticancer Drug Prescription Patterns in Japan: Future Directions in Cancer Therapy.

BACKGROUND: Despite their benefits, the rapid development of new cancer treatments has been a significant driver of increasing health care expenditures in the face of limited health care budgets. In this study, we analyzed the prescribing trends for anticancer drugs from 2010 through 2016 in Japan and sought to identify unique trends that could provide a basis for future medical economic research aiming to develop more efficacious and cost-effective cancer therapies. METHODS: We used publicly available marketing data for anticancer drugs in Japan for 2010-2016. The drugs selected for this research were categorized according to the Anatomical Therapeutic Chemical Classification System. We investigated the overall anticancer drug market size, the number of anticancer drugs, the top 30 selling anticancer categories, sales and prescription volumes, and changes in sales and prescription volumes between 2010 and 2016 in the country. RESULTS: The anticancer agent market expanded each year from 2010 to 2016, with sales exceeding 1 trillion yen in 2015. The proportion of molecular targeted drugs (antineoplastic mAbs and protein kinase inhibitors) among the top 30 selling anticancer categories has continued to increase, and both the sales and prescription volumes of these drugs exceeded those of drugs in other categories, suggesting that these treatments play a dominant role in cancer pharmacotherapy. CONCLUSION: The availability and increasing use of innovative but more expensive targeted therapies were major drivers of increases in pharmaceutical expenditures for cancer treatment in Japan. Therefore, the effective use of genetic testing can mitigate these rising costs.

Identifying cancer drug regimens in French health insurance database: An application in multiple myeloma patients.

PURPOSE: There is no consensus on how to handle complex drug combinations of cancer drugs through medico-administrative databases. Our objective was to develop an algorithm for identifying the nature and patterns of treatment lines in a cohort of newly treated multiple myeloma patients. METHODS: A cohort of multiple myeloma patients starting a first treatment line was built using both ambulatory and hospital data from regional data of the French national healthcare system database (SNIIRAM). Patients were identified from January 2011 to September 2013 using ICD-10 codes for multiple myeloma ('C90') within long-term conditions or diagnosis from hospital data. Drugs of interest for cycle identification included bortezomib, imids (thalidomide, lenalidomide), alkylating drugs (cyclophosphamide, melphalan, bendamustine, doxorubicin) and dexamethasone. An algorithm was applied to define combinations of treatment received in the first 6 months of treatment. RESULTS: Among the 236 patients included, 45% received bortezomib-melphalan-prednisone (VMP: n = 107), 22% bortezomib-thalidomide-dexamethasone (VTD/VTD-PACE: n = 52) and 21% melphalan-prednisone-thalidomide (MPT: n = 49). Other drug regimens consisted in melphalan-prednisone (MP: 7%, n = 17), lenalidomide-dexamethasone (RD) (4%, n = 9), bortezomib-cyclophosphamide-dexamethasone (VCD: n = 1) and bortezomib-bendamustine-dexamethasone (VBD: n = 1). Type of drug regimens and allocation by age class (±65 years) were in accordance with current recommendations. CONCLUSIONS: This study demonstrates the feasibility of identifying complex drug regimens in onco-haematology, using both outpatient and inpatient drug records in French health insurance databases.

[Region-wide professional practice evaluation with regards to antiemetic prescription into chemotherapy-induced nausea and vomiting]. / Évaluation régionale des pratiques professionnelles sur l'utilisation des antiémétiques chez les patients atteints de cancer.

The anticancer drug technical commission (COTECH) of the Auvergne OMEDIT has set up a region-wide professional practice evaluation (PPE) with regards to antiemetic prescription practices in chemotherapy-induced nausea and vomiting (CINV), in order to evaluate their compliance with OMEDIT's guidelines. Are not included pediatric and hematologic protocols. A prospective survey was carried from November 2013 to January 2014 out in 14 medical centers in Auvergne. This clinical audit was based on the HAS (national healthcare authority) framework and used as a reference regional standards based on the MASCC Antiemetic Guidelines. Altogether, 346 antiemetic prescriptions were compared to guidelines. We observed respectively 81 % and 42 % conformity rates in acute and delayed emesis for high emesis risk chemotherapy (HE); 86 % and 35 % conformity rates in acute and delayed emesis for moderate emesis risk chemotherapy (ME); 66 % and 85 % conformity rates in acute and delayed emesis for low emesis risk chemotherapy (LE). These results highlight deficiencies in compliance with guidelines, especially in the management of delayed CINV in HE and ME chemotherapy. The COTECH identified three priority improvement areas: under-prescribe NK1 antagonists in HE cure; under-prescribe corticosteroid; over-prescribe 5HT3 antagonists for delayed emesis. The COTECH is publicizing these results all over the Auvergne region, together with a reminder of recommendations.

[Prescription of high-cost medicines in French Hospitals: Regulation and procedures of reimbursement]. / Modalités de prescription hospitalières des molécules onéreuses : cadre réglementaire global et spécificités de la prescription hors GHS.

The high cost of several drugs or medical devices involves specific reimbursement procedures in French hospitals. Specific prescription rules have been developed and a regular survey by regional health authorities is performed. These particular funding procedures allow patients to access to innovative drugs. Some questions have recently been raised in France about the list of cancer drugs that could be concerned by an additional funding by health insurance. In this setting, this article proposes to summarize the current modalities of reimbursement of high-cost medicines in French Hospitals to enlighten the current debate.

Patterns of use of oral anticancer treatments in France: a Retrospective Analysis of Cancer Treatments given ORally from 2004 to 2012 (Re-ACTOR study).

BACKGROUNDS AND OBJECTIVES: Increasing use of oral anticancer treatments (OATs) in oncology is modifying the treatment paradigm for cancer. Nonetheless, available data on the pattern of use of OATs and its evolution over time are limited. The objective of this study was to describe the patterns of use of OATs in France from 2004 to 2012. METHODS: A retrospective analysis was performed using Oncology Analyzer, a physician survey database. All patients actively treated by an oral or an intravenous anticancer treatment between October 2004 and September 2012 were enrolled in the database. Descriptive analyses were performed by treatment category with a focus on the last year of collection and the evolution across the study period. RESULTS: From October 2011 to September 2012, a sample of 7426 patients treated by oral or intravenous active anticancer treatments was analyzed: 74% of patients receiving an OAT were diagnosed with a solid tumor, 52% of whom had a stage IV cancer. The use of OATs increased with age and was the highest in patients over 80 years. From 2004 to 2012, the proportion of cancer patients receiving OATs increased by four percentage points (from 28.4% to 32.5%). Additionally, for treatments available in both forms, a marked preference for oral formulations was observed. LIMITATIONS: The patterns and trend of use prior to 2004 were not addressed due to lack of information in the database. The use of a market research database is relevant for highly prevalent cancers but for rare cancers the sample size is limited, underlining the utility of using other data sources such as cancer registries. CONCLUSIONS: The Re-ACTOR study provides an overview of OAT use in France, which was prescribed to 32% of cancer patients in France in 2012, principally to older patients and to those with solid tumors and with metastatic disease.

Biopharmaceutics classification system-based biowaivers for generic oncology drug products: case studies.

Establishing bioequivalence (BE) of drugs indicated to treat cancer poses special challenges. For ethical reasons, often, the studies need to be conducted in cancer patients rather than in healthy volunteers, especially when the drug is cytotoxic. The Biopharmaceutics Classification System (BCS) introduced by Amidon (1) and adopted by the FDA, presents opportunities to avoid conducting the bioequivalence studies in humans. This paper analyzes the application of the BCS approach by the generic pharmaceutical industry and the FDA to oncology drug products. To date, the FDA has granted BCS-based biowaivers for several drug products involving at least four different drug substances, used to treat cancer. Compared to in vivo BE studies, development of data to justify BCS waivers is considered somewhat easier, faster, and more cost effective. However, the FDA experience shows that the approval times for applications containing in vitro studies to support the BCS-based biowaivers are often as long as the applications containing in vivo BE studies, primarily because of inadequate information in the submissions. This paper deliberates some common causes for the delays in the approval of applications requesting BCS-based biowaivers for oncology drug products. Scientific considerations of conducting a non-BCS-based in vivo BE study for generic oncology drug products are also discussed. It is hoped that the information provided in our study would help the applicants to improve the quality of ANDA submissions in the future.

Prioritising anticancer drugs for environmental monitoring and risk assessment purposes.

Anticancer drugs routinely used in chemotherapy enter wastewater through the excretion of the non-metabolised drug following administration to patients. This study considers the consumption and subsequent behaviour and occurrence of these chemicals in aquatic systems, with the aim of prioritising a selection of these drugs which are likely to persist in the environment and hence be considered for environmental screening programmes. Accurate consumption data were compiled from a hospital survey in NW England and combined with urinary excretion rates derived from clinical studies. Physical-chemical property data were compiled along with likely chemical fate and persistence during and after wastewater treatment. A shortlist of 15 chemicals (from 65) was prioritised based on their consumption, persistency and likelihood of occurrence in surface waters and supported by observational studies where possible. The ecological impact of these 'prioritised' chemicals is uncertain as the measured concentrations in surface waters generally fall below standard toxicity thresholds. Nonetheless, this prioritised sub-list should prove useful for developing environmental screening programmes.

[Efficiency of oncologic treatments for solid tumours in Spain]. / Eficiencia de tratamientos oncológicos para tumores sólidos en España.

OBJECTIVE: To provide estimates of the efficiency for chemotherapy strategies used in Spain. METHODS: Published reports of the phase-III clinical trials for chemotherapies used for the most prevalent solid tumours in Spain were retrieved. The incremental cost-effectiveness ratio (ICER) was calculated for each strategy compared to the control group in the clinical trial, with the National Health System perspective. The total cost (?, 2012) including only drug cost (exfactory price) was estimated based on the total units of each drug required for administration (no vial wastage), with the dosification and number of cycles specified in the publication for each treatment arm. Effectiveness was measured as month of overall survival (OS) and/or month of progression free survival (PFS). RESULTS: A total of 40 chemotherapies for 13 different advanced or metastatic tumours were assessed. OS ranged from 5.3 to 33.3 months for the 34 therapies that included the information with hazard ratios (HR) values from 0.49 to 1.15 when compared with its control group. PFS ranged, from 39 therapies with these data, between 1.5 to 12.4 months, with HR from 0.33 to 1.52. ICERs were between ?2,142.57 and ?60,996.37 per each OS month gained, and from ?2,102.54 to ?661,845.27 per PFS month gained. CONCLUSION: The variety and heterogenicity of survival and ICERs results, suggest disparity of criteria in the price and reimbursement process of drugs in Spain. The continuous advances in oncology seem to require economic revaluations of drugs.

Objetivo: Proporcionar estimadores de la eficiencia de esquemas oncológicos empleados en España. Métodos: Se seleccionaron las publicaciones de ensayos clínicos en fase III usados para indicación de las terapias oncológicas de alto impacto empleadas para tratamiento de tumores sólidos en estadíos III-IV. Para cada esquema se calculó la relación costeeficacia incremental (RCEI) respecto al comparador del ensayo, con la perspectiva del Sistema Nacional de Salud. El coste (?, 2012) farmacológico, en PVL, de cada esquema y comparador se estimó con las unidades de medicamento requeridas en cada administración (aprovechamiento máximo de viales) considerando la posología y el número de ciclos especificado en el ensayo para cada una de las ramas. La efectividad se expresó en meses de supervivencia global (SG) y/o supervivencia libre de progresión (SLP). Resultados: Se analizaron 40 esquemas oncológicos para trece tumores metastásicos. La SG osciló entre 5,3 y 33,3 meses para las 34 terapias que incluían esa información, con valores de Hazard ratio (HR) respecto a sus comparadores de 0,49 a 1,15. La SLP osciló entre 1,5 y 12,4 meses para las 39 terapias con este dato, con HR de 0,33 a 1,52. Los valores de RCEI oscilaron entre 2.142,57 ?-60.996,37 ?/mes de SG adicional y entre 2.102,54 ?-661.845,27 ?/mes de SLP adicional. Conclusión: La dispersión y heterogeneidad de la supervivencia y RCEI estimadas, sugieren disparidad de criterios en la decisión de precio y financiación de las terapias, en España. Los continuos avances en terapias oncológicas parecen requerir reevaluaciones económicas de los medicamentos.

CORAL: classification model for predictions of anti-sarcoma activity.

A modified version of the CORAL software (http://www.insilico.eu/coral) allows building up the classification model for the case of the Yes/No data on the anti-sarcoma activity of organic compounds. Three random splits into the sub-training, calibration, and test sets of the data for 3017 compounds were examined. The performance of the proposed approach is satisfactory. The average values of the statistical characteristics for external test set on three random splits are as follows: n=1173-1234, sensitivity = 0.8903±0.0390, specificity = 0.9869±0.0013, and accuracy = 0.9759±0.0043. Mechanistic interpretation of the suggested model is discussed.

Oncogenic targets, magnitude of benefit, and market pricing of antineoplastic drugs.

PURPOSE: The relationship between market pricing of new anticancer drugs and the magnitude of clinical benefit caused by them has not been reported. PATIENTS AND METHODS: Randomized clinical trials (RCTs) that evaluated approved new agents for solid tumors by the U.S. Food and Drug administration since the year 2000 were assessed. Hazard ratios (HRs) and 95% CIs were extracted for time-to-event end points described for each RCT. HRs were pooled for three groups: agents directed against a specific molecular target, for which the target population is selected by a biomarker (group A); less specific biologic targeted agents (group B); and chemotherapeutic agents (group C). Monthly market prices of these different drugs were compared. RESULTS: For overall survival (OS), the pooled HR was 0.69 (95% CI, 0.59 to 0.81) for group A (six drugs, six trials); it was 0.78 (95% CI, 0.74 to 0.83) for group B (seven drugs, 14 trials); and it was 0.84 (95% CI, 0.79 to 0.90) for group C (eight drugs, 12 trials). For progression-free survival (PFS), the pooled HR was 0.42 (95% CI, 0.36 to 0.49) for group A (six drugs, seven trials); it was 0.57 (95% CI, 0.51 to 0.64) for group B (seven drugs, 14 trials); and it was 0.75 (95% CI, 0.66 to 0.85) for group C (six drugs, 10 trials). Tests for heterogeneity between subgroups were highly significant for PFS (P < .001) and OS (P = .02). The median monthly prices for standard doses of drugs were $5375 for group A, $5644 for group B, and $6584 for group C (P = .87). CONCLUSION: New agents with specific molecular targets are clinically the most beneficial, but their monthly market prices are not significantly different from those of other anticancer agents.