Comparison of Sales Income and Research and Development Costs for FDA-Approved Cancer Drugs Sold by Originator Drug Companies.

Importance: High costs and risks of research and development (R&D) have been used to justify the high prices of cancer drugs. However, what the return on R&D investment is, and by extension what a justifiable price might be, is unclear. Objective: To compare incomes from the sales of cancer drugs with the estimated R&D costs. Design, Setting, and Participants: This observational study used global pharmaceutical industry sales data to quantify the cumulative incomes generated from the sales of cancer drugs for companies that have held patents or marketing rights (originator companies). All cancer drugs approved by the US Food and Drug Administration from 1989 to 2017 were identified from the United States Food and Drug Administration's website and literature. Itemized product sales data were extracted from the originator companies' consolidated financial reports. For drugs with data missing in specific years, additional data was sought from other public sources, or where necessary, estimated values from known reported values. Drugs were excluded if there were missing data for half or more of the years since approval. Data analysis was conducted from May 2018 to October 2018. Main Outcomes and Measures: Sales data were expressed in 2017 US dollars with adjustments for inflation. Cumulative incomes from the sales of these drugs were compared against the R&D costs estimated in the literature, which had been adjusted for the costs of capital and trial failure (risk adjusted). Results: Of the 156 US Food and Drug Administration-approved cancer drugs identified, 99 drugs (63.5%) had data for more than half of the years since approval and were included in the analysis. There was a median of 10 years (range, 1-28 years) of sales data with 1040 data points, 79 (7.6%) of which were estimated. Compared with the total risk-adjusted R&D cost of $794 million (range, $2827-$219 million) per medicine estimated in the literature, by the end of 2017, the median cumulative sales income was $14.50 (range, $3.30-$55.10) per dollar invested for R&D. Median time to fully recover the maximum possible risk-adjusted cost of R&D ($2827 million) was 5 years (range, 2-10 years; n = 56). Cancer drugs continued to generate billion-dollar returns for the originator companies after the end-of-market exclusivity, particularly for biologics. Conclusions and Relevance: Cancer drugs, through high prices, have generated returns for the originator companies far in excess of possible R&D costs. Lowering prices of cancer drugs and facilitating greater competition are essential for improving patient access, health system's financial sustainability, and future innovation.

Cost-effectiveness thresholds: pros and cons.

Cost-effectiveness analysis is used to compare the costs and outcomes of alternative policy options. Each resulting cost-effectiveness ratio represents the magnitude of additional health gained per additional unit of resources spent. Cost-effectiveness thresholds allow cost-effectiveness ratios that represent good or very good value for money to be identified. In 2001, the World Health Organization's Commission on Macroeconomics in Health suggested cost-effectiveness thresholds based on multiples of a country's per-capita gross domestic product (GDP). In some contexts, in choosing which health interventions to fund and which not to fund, these thresholds have been used as decision rules. However, experience with the use of such GDP-based thresholds in decision-making processes at country level shows them to lack country specificity and this - in addition to uncertainty in the modelled cost-effectiveness ratios - can lead to the wrong decision on how to spend health-care resources. Cost-effectiveness information should be used alongside other considerations - e.g. budget impact and feasibility considerations - in a transparent decision-making process, rather than in isolation based on a single threshold value. Although cost-effectiveness ratios are undoubtedly informative in assessing value for money, countries should be encouraged to develop a context-specific process for decision-making that is supported by legislation, has stakeholder buy-in, for example the involvement of civil society organizations and patient groups, and is transparent, consistent and fair.

Les analyses de rentabilité permettent de comparer les coûts et les résultats de différentes options politiques. Chaque ratio coût-efficacité qui en découle indique l'importance des avantages supplémentaires pour la santé par unité supplémentaire de ressources dépensée. Les seuils de rentabilité permettent de déterminer les ratios coût-efficacité qui représentent une bonne ou une très bonne rentabilité. En 2001, la Commission macroéconomie et santé de l'Organisation mondiale de la Santé a suggéré des seuils de rentabilité définis d'après des multiples du produit intérieur brut (PIB) par habitant d'un pays. Dans certains pays, ces seuils ont servi de règles pour décider quelles interventions financer ou non. Cependant, l'expérience d'utilisation de ces seuils fondés sur le PIB dans les processus décisionnels des pays montre qu'ils ne tiennent pas compte des spécificités des pays; cela, ajouté à une certaine incertitude concernant la modélisation des ratios coût-efficacité, peut entraîner la prise de mauvaises décisions quant à l'utilisation des ressources sanitaires. Les informations sur la rentabilité des interventions devraient être prises en compte parallèlement à d'autres considérations, comme l'impact budgétaire et la faisabilité, dans le cadre d'un processus décisionnel transparent et non de façon isolée sur la base d'une seule valeur seuil. Bien que le caractère informatif des ratios coût-efficacité soit indéniable lorsqu'il s'agit d'évaluer la rentabilité des interventions, les pays devraient être encouragés à développer un processus de prise de décision spécifique au contexte, qui soit encadré par la législation et qui ait l'adhésion des parties intéressées, avec par exemple l'implication d'organisations de la société civile et de groupes de patients, et qui soit transparent, cohérent et équitable.

El análisis de rentabilidad se utiliza para comparar los costes y resultados de opciones políticas alternativas. Cada relación de rentabilidad resultante representa la magnitud de sanidad adicional obtenida por unidad adicional de recursos utilizados. Los umbrales de rentabilidad permiten la identificación de las relaciones de rentabilidad que representan un valor bueno o muy bueno del capital. En 2001, los umbrales de rentabilidad propuestos por la Comisión sobre Macroeconomía y Salud de la Organización Mundial de la Salud se basaron en múltiplos del producto interior bruto (PIB) per cápita de un país. En algunos contextos, se han utilizado estos umbrales para decidir qué intervenciones sanitarias financiar y cuáles no. No obstante, la experiencia con el uso de dichos umbrales basados en el PIB en los procesos de toma de decisiones a nivel nacional muestra la ausencia de especificidad según el país. Esto, además de la incertidumbre de las relaciones de rentabilidad modelo, puede dar lugar a una toma de decisiones equivocada sobre cómo emplear los recursos sanitarios. La información relativa a la rentabilidad debería utilizarse teniendo en cuenta otros factores (por ejemplo, el impacto presupuestario y aspectos de viabilidad) en un proceso transparente de toma de decisiones, en lugar de únicamente teniendo como referencia un solo valor del umbral. A pesar de que las relaciones de rentabilidad son indudablemente esclarecedoras a la hora de evaluar el valor del capital, es necesario fomentar que los países desarrollen un proceso específico del contexto apoyado por la legislación para tomar decisiones, como, por ejemplo, si las partes interesadas han aceptado la implicación de las organizaciones de la sociedad civil y grupos de pacientes y si es transparente, coherente y justa.

Incorporating considerations of cost-effectiveness, affordability, and resource implications in guideline development: article 6 in Integrating and coordinating efforts in COPD guideline development. An official ATS/ERS workshop report.

INTRODUCTION: Professional societies, like many other organizations around the world, have recognized the need to use rigorous processes to ensure that health care recommendations are based on the best available research evidence. This is the sixth of a series of 14 articles prepared to advise guideline developers for respiratory and other diseases on how to achieve this goal. In this article, we focused on integrating cost and resource information in guideline development and formulating recommendations focusing on four key questions. METHODS: We addressed the following specific questions. (1) When is it important to incorporate costs, and/or resource implications, and/or cost-effectiveness, and/or affordability considerations in guidelines? (2) Which costs and which resource use should be considered in guidelines? (3)What sources of evidence should be used to estimate costs, resource use, and cost-effectiveness? (4) How can cost-effectiveness, resource implications, and affordability be taken into account explicitly? Our work was based on a prior review on this topic and our conclusions are based on available evidence, consideration of what guideline developers are doing, and workshop discussions. RESULTS AND DISCUSSION: Many authorities suggest that there is a need to include explicit consideration of costs, resource use, and affordability during guideline development. Where drug use is at issue, "explicit consideration" may need to involve only noting whether the price (easily determined and usually the main component of "acquisition cost") of a drug is high or low. Complex interventions such as rehabilitation services are to a greater degree setting- and system-dependent. Resources used, and the costs of those resources, will vary among systems, and formal identification by a guideline group of the resource requirements of a complex intervention is essential. A clinical guideline usually contains multiple recommendations, and in some cases there are hundreds. Defining costs and resource use for all of them-especially for multiple settings-is unlikely to be feasible. At present, disaggregated resource utilization accompanied by some cost information seems to be the most promising approach. The method for assigning values to costs, including external or indirect cost (such as time off work), can have a significant impact on the outcome of any economic evaluation. The perspective that the guideline assumes should be made explicit. Standards for evidence for clinical data are usually good-quality trials reporting a relevant endpoint that should be summarized in a systematic review. Like others, we are therefore proposing that the ideal sources of evidence for cost and resource utilization data for guideline development are systematic reviews of randomized controlled trials that report resource utilization, with direct comparisons between the interventions of interest.

Mapping the availability, price, and affordability of antiepileptic drugs in 46 countries.

PURPOSE: In low- and middle-income countries (LMICs), a large proportion of people with epilepsy do not receive treatment. An analysis of the availability, price, and affordability of antiepileptic drugs (AEDs) was conducted to evaluate whether these factors contribute to the treatment gap. METHODS: Data for five AEDs (phenytoin, carbamazepine, valproic acid, phenobarbital, and diazepam) were obtained from facility-based surveys conducted in 46 countries using the World Health Organization/Health Action International (WHO/HAI) methodology. Outcome measures were percentage availability, ratios of local prices to international reference prices, and number of days' wages needed by the lowest-paid unskilled government worker to purchase treatment. Prices were adjusted for inflation/deflation and purchasing power parity. KEY FINDINGS: The average availability of generic AEDs in the public sector was <50% for all medicines except diazepam injection. Private sector availability of generic oral AEDs ranged from 42.2% for phenytoin to 69.6% for phenobarbital. Public sector patient prices for generic carbamazepine and phenytoin were 4.95 and 17.50 times higher than international reference prices, respectively, whereas private sector patient prices were 11.27 and 24.77 times higher, respectively. For both medicines, originator brand prices were about 30 times higher. The highest prices were observed in the lowest income countries. The lowest-paid government worker would need wages from 1-2.6 days' to purchase a month's supply of phenytoin, whereas carbamazepine would cost 2.7-16.2 days' wages. Despite its widespread use in LMICs, WHO/HAI survey data for phenobarbital was only available from a small number of countries. SIGNIFICANCE: In LMICs, availability and affordability of AEDs are poor and may be acting as a barrier to accessing treatment for epilepsy. Ensuring a consistent supply of AEDs at an affordable price should be a priority.

Cost-effectiveness analysis for clinicians.

In a climate of economic uncertainty, cost effectiveness analysis is a potentially important tool for making choices about health care interventions. Methods for such analyses are well established, but the results need to be interpreted carefully and are subject to bias. Making decisions based on results of cost-effectiveness analyses can involve setting thresholds, but for individual patients, there needs to be disaggregation of benefits and harms included in a quality adjusted life year to ensure appropriate consideration of benefits and harms as well as personal preferences and circumstances.

Characteristics and quality of reporting of cluster randomized trials in children: reporting needs improvement.

OBJECTIVE: To describe the characteristics and quality of reporting of cluster randomized trials (CRTs) in children published from 2004 to 2010. STUDY DESIGN AND SETTING: Four databases were searched for reports of CRTs in children (0-18 years). Characteristics of the studies were summarized and the quality of reporting assessed using consolidated standards of reporting trial-CRT (CONSORT-CRT). RESULTS: Of 1,949 identified references, 106 were included. The number of published CRTs in children increased since 2004. The greatest proportion of CRTs was undertaken in Europe (29%), whereas 40% was conducted in low- and middle-income countries. Most studies were of complex rather than simple interventions (83%); were preventive rather than treatment interventions (76%); and most frequently addressed infectious disease (21%), diet/physical activity interventions (19%), health-risk behaviors (15%), and undernutrition (13%). The majority used schools as units of randomization (72%) and enrolled 1,000-10,000 children per study (51%). Reporting was generally poor, with 34% of CRTs inadequately reporting on more than half of the CONSORT-CRT criteria. Although 85% of CRTs reported that they had ethics approval for the study, consent or assent was not obtained from children in most studies. CONCLUSION: Children-specific elements of reporting are needed to improve the quality of reporting of CRTs and consequently their planning and implementation.

Identifying barriers to the availability and use of Magnesium Sulphate Injection in resource poor countries: a case study in Zambia.

BACKGROUND: Pre-eclampsia and eclampsia are serious complications of pregnancy and major causes of maternal mortality and morbidity worldwide. According to systematic reviews and WHO guidelines magnesium sulphate injection (MgSO4) should be the first -line treatment for severe pre-eclampsia and eclampsia. Studies have shown that this safe and effective medicine is unavailable and underutilized in many resource poor countries. The objective of this study was to identify barriers to the availability and use of MgSO4 in the Zambian Public Health System. METHODS: A 'fishbone' (Ishikawa) diagram listing probable facilitators to the availability and use of MgSO4 identified from the literature was used to develop an assessment tool. Barriers to availability and use of MgSO4 were assessed at the regulatory/government, supply, procurement, distribution, health facility and health professional levels. The assessment was completed during August 2008 using archival data, and observations at a pragmatic sample of health facilities providing obstetric services in Lusaka District, Zambia. RESULTS: The major barrier to the availability of MgSO4 within the public health system in Zambia was lack of procurement by the Ministry of Health. Other barriers identified included a lack of demand by health professionals at the health centre level and a lack of in-service training in the use of MgSO4. Where there was demand by obstetricians, magnesium sulphate injection was being procured from the private sector by the hospital pharmacy despite not being registered and licensed for use for the treatment of severe pre-eclampsia and eclampsia by the national Pharmaceutical Regulatory Authority. CONCLUSIONS: The case study in Zambia highlights the complexities that underlie making essential medicines available and used appropriately. The fishbone diagram is a useful theoretical framework for illustrating the complexity of translating research findings into clinical practice. A better understanding of the supply system and of the pattern of demand for MgSO4 in Zambia should enable policy makers and stakeholders to develop and implement appropriate interventions to improve the availability and use of MgSO4.

Antiepileptic drugs in children in developing countries: research and treatment guideline needs.

Epilepsy is the most common neurologic disorder in childhood. Effective interventions are available for treatment; however, the treatment gap in children is more than 80% in many developing countries. An important reason for this huge treatment gap is limited access to antiepileptic drugs (AEDs). This article discusses the reasons for such a treatment gap, and possible ways forward in improving care of children with epilepsy worldwide.

A comparison of two methods for measuring anti-hypertensive drug use: concordance of use with South African standard treatment guidelines.

OBJECTIVE: To assess prescriber adherence to standard anti-hypertensive treatment guidelines in South Africa, determine if supply data are useful indicators of drug use, and assess the cost implications of not complying with the guidelines. METHODS: We undertook two studies: an analysis of records of the anti-hypertensive drugs supplied to all 54 public-sector hospitals with a hypertension clinic in KwaZulu-Natal, and a direct-observation survey of anti-hypertensive drug prescriptions presented to pharmacies in a subset of 16 of the 54 hospitals. We calculated the relative use of each anti-hypertensive drug group as a proportion of all anti-hypertensive drugs supplied or prescribed. We ranked drug groups in order of use for comparison with recommended South African standard treatment guidelines, and we compared the proportions derived from supply data with those derived from the prescription survey. FINDINGS: Supply data showed that, in line with treatment guidelines, diuretics and angiotensin-converting enzyme inhibitors were the most frequently supplied medicines (42% and 27%, respectively). However, methyldopa - not included in the treatment guidelines - represented 10% of all anti-hypertensives supplied, but the proportion varied widely between hospitals (0-37%). Reserpine, second choice in the treatment guidelines, was used in high amounts by only two hospitals. Calcium channel blockers and beta blockers represented a small proportion of the anti-hypertensive drugs supplied: 6% each. Results from the prescription survey were in concordance with supply data for the most frequently prescribed drugs but gave slightly different estimates of the use of others. CONCLUSION: Supply data, the most available source of information about drug use in developing countries, are (with some provisos) a reliable data source for the evaluation of adherence to treatment guidelines. Our results showed substantial non-adherence to standard treatment guidelines.