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BACKGROUND: It is increasingly common for two or more treatments for cancer to be combined as a single regimen. Determining value and appropriate payment for such regimens can be challenging. This study discusses these challenges, and possible solutions. METHODS: Stakeholders from around the world attended a 2-day workshop, supported by a background paper. This study captures key outcomes from the discussion, but is not a consensus statement. RESULTS: Workshop attendees agreed that combining on-patent treatments can result in affordability and value for money challenges that delay or deny patient access to clinically effective treatments in many health systems. Options for addressing these challenges include: (i) Increasing the value of combination therapies through improved clinical development; (ii) Willingness to pay more for combinations than for single drugs offering similar benefit, or; (iii) Aligning the cost of constituent therapies with their value within a regimen. Workshop attendees felt that (i) and (iii) merited further discussion, whereas (ii) was unlikely to be justifiable. Views differed on the feasibility of (i). Key to (iii) would be systems allowing different prices to apply to different uses of a drug. CONCLUSIONS: Common ground was identified on immediate actions to improve access to combination regimens. These include an exploration of the legal challenges associated with price negotiations, and ensuring that pricing systems can support implementation of negotiated prices for specific uses. Improvements to clinical development and trial design should be pursued in the medium and longer term.
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Oncología Médica , Neoplasias , Costos y Análisis de Costo , Humanos , Neoplasias/tratamiento farmacológicoRESUMEN
OBJECTIVES: Some countries make considerable effort to involve patients and patient groups in their health technology assessment (HTA) processes; others are only just considering or are yet to consider patient involvement in HTA. METHODS: This commentary offers four arguments why patient involvement should be prioritized by those HTA agencies that do not yet involve patients: (1) from a patients' rights perspective, (2) based on patient and community values, (3) centering on evidentiary contributions, and (4) from a methodological perspective. RESULTS: The first argument builds on the Alma-Ata Declaration, which holds that patients have a right and duty to have a say in the planning and delivery of their health care, individually and collectively. Where HTA is used to determine access to technologies and services, we argue that patients have a right to be heard. The second argues that decisions about treatments and services need to be aligned with the core values and morals of the patients whom the health system serves. The third argues that patients have unique knowledge and insights about living with a health condition and their needs for services and treatments regarding that condition, which can add to the knowledge base and value of the HTA process. The fourth argues that involvement of patients can facilitate methodological advancement of HTA, in areas such as early scientific advice and managed entry with evidence development. CONCLUSIONS: An HTA process that includes patient perspectives can, therefore, provide added value to patients, policy makers and healthcare professionals alike.
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Participación del Paciente , Evaluación de la Tecnología Biomédica , HumanosRESUMEN
OBJECTIVES: Treatment switching occurs when patients in a randomized clinical trial switch from the treatment initially assigned to them to another treatment, typically from the control to experimental treatment. This study discusses the issues this raises and possible approaches to addressing them in trials of cancer drugs. METHODS: Stakeholders from around the world were invited to a 1.5-day Workshop in Adelaide, Australia. This study attempts to capture the key points from the discussion and the perspectives of the various stakeholder groups, but is not a formal consensus statement. RESULTS: Treatment switching raises challenging ethical issues with arguments for and against allowing it. It is increasingly common in cancer drug trials and presents challenges for the interpretation of results by regulators, clinicians, patients, and payers. Proposals are offered for good practice in the design, management, and analysis of trials and wider development programs for cancer drugs in which treatment switching has occurred or is likely to. Recommendations are also offered for further action to improve understanding of the importance and challenges of treatment switching and to promote agreement between key stakeholders on guidelines and other steps to address these challenges. CONCLUSIONS: The handling of treatment switching in trials is of concern to all stakeholders. On the basis of the discussions at the Adelaide International Workshop, there would appear to be common ground on approaches to addressing treatment switching in cancer trials and scope for the development of formal guidelines to inform the work of regulators, payers, industry, trial designers and other stakeholders.
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Sustitución de Medicamentos , Neoplasias/tratamiento farmacológico , Proyectos de Investigación , Australia , Investigación Biomédica , Consenso , HumanosRESUMEN
Accelerated and conditional regulatory pathways for drug approvals are intended to enable earlier patient access to potentially life-saving treatments, or treatments that provide benefits in addressing a significant unmet need. However, there are questions about how well such pathways work, how appropriately they are applied, and how the work of regulators can be better coordinated with that of health technology assessment (HTA) and payer bodies, providers and health systems, and other stakeholders. In June 2023, a multi-stakeholder, international workshop was convened in Adelaide, Australia, to deliberate the challenges, goals, and opportunities to improve accelerated access pathways. Workshop attendees included representatives from patient organizations, regulators, HTA/payer bodies, universities (ethicists, health economists), and companies developing and marketing new medicines from Australia, Asia, Europe, and North America. We reviewed the contents of this workshop to identify areas of agreement and disagreement, report the key themes of the discussion, and delineate next steps for improving accelerated access pathways. We found that there was general agreement among workshop attendees that accelerated access could be improved significantly by strengthening processes for stakeholder coordination, and that coordinated efforts will be required to implement meaningful change moving forward.
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In this study, lead (Pb) bioaccessibility was assessed in peri-urban contaminated soils using a variety of established in vitro assays. Bioaccessibility data was then used to predict Pb relative bioavailability (RBA) using published in vivo-in vitro regression models in order to compare calculated estimates and measured values. Lead bioaccessibility varied depending on the in vitro methodology employed with the relative bioavailability leaching procedure (RBALP) and in vitro gastrointestinal (IVG) assays providing more conservative Pb bioaccessibility values compared to those determined using PBET, UBM and Rel-SBRC-I assays. When Pb RBA was calculated, predicted values using PBET-G and UBM-G data were similar to measured Pb RBA values. However, Pb RBA was over-estimated by 1.6-5.5- and 2.6-6.6-fold when data and regression models from RBALP and IVG-G assays were employed.
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Monitoreo del Ambiente/métodos , Plomo/análisis , Plomo/farmacocinética , Modelos Biológicos , Contaminantes del Suelo/análisis , Contaminantes del Suelo/farmacocinética , Animales , Disponibilidad Biológica , Monitoreo del Ambiente/estadística & datos numéricos , Predicción , Mucosa Gástrica/metabolismo , Humanos , Incineración , Mucosa Intestinal/metabolismo , Modelos Lineales , Eliminación de Residuos , Porcinos , Remodelación UrbanaRESUMEN
AIM: The aim of this scoping review was to determine the extent of off-patent prescription medicine use beyond registered indications in various Australian clinical settings. METHOD: The review followed the Joanna Briggs Institute approach and reported using PRISMA Extension for Scoping Reviews. Online databases were used to identify published literature about off-patent registered prescription medicines used for off-label indications in Australian public hospital, community and primary healthcare settings. In addition, empirical data from the Queensland and the South Australian state-wide medicine formularies were screened for the same medication/off-label indication dyads identified in the literature, and other locally approved uses. RESULTS: Overall, fourteen studies were included, conducted in public hospitals (n = 11), palliative care units (n = 2) and the community setting (n = 1). There were 213 reports extracted from the literature describing off-patent registered prescription medicines used for off-label indications, representing 128 unique medication/off-label indication dyads and 32 different medicines. Of these, just five medication/off-label indication dyads were approved for use on both the Queensland and South Australian state-wide medicine formularies, with 12 others only approved for use in Queensland and 16 others only approved for use in South Australia. Further examination of these state-wide formularies demonstrated that the use of off-patent registered prescription medicines beyond registered indications is more extensive than has been reported to date in the literature. There were 28 additional medication/off-label indication dyads approved on the Queensland state-wide medicine formulary and 14 such examples approved for use in South Australia. Of these, just two medication/off-label indication dyads were approved for use on both formularies. CONCLUSION: The extent to which off-patent registered prescription medicines have been repurposed in clinical settings for off-label indications in Australia is greater than previously reported in the literature. Usage and funded availability of certain medication/off-label indication dyads, varies across Australia. These results further expose the two tiered system of medicines regulation in Australia, and its impact on equity of access to medicines. Further research is required to support policy change to encourage submission of registration updates for off-patent prescription medicines.
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Uso Fuera de lo Indicado/estadística & datos numéricos , Patentes como Asunto/estadística & datos numéricos , Medicamentos bajo Prescripción/uso terapéutico , Australia , HumanosAsunto(s)
Seguro de Servicios Farmacéuticos , Programas Nacionales de Salud , Cuidados Paliativos/estadística & datos numéricos , Pautas de la Práctica en Medicina/estadística & datos numéricos , Medicamentos bajo Prescripción/uso terapéutico , Australia/epidemiología , Humanos , Cuidados Paliativos/economía , Pautas de la Práctica en Medicina/economía , Pautas de la Práctica en Medicina/organización & administración , Medicamentos bajo Prescripción/economíaRESUMEN
While arsenic is toxic to all multicellular organisms, some organisms become tolerant by an unknown mechanism. We have recently uncovered an inducible tolerance mechanism in insects, which is based on a sequestration of toxins and pathogens by lipid particles. To examine whether arsenic interacts with lipid particles from mammals we compared binding of arsenic to lipid particles from insect and pig plasma after separation of lipid particles by low-density gradient centrifugation. Arsenic was found in both organisms in an area of the gradient, which corresponds to lipid-rich lipid particles. Since iron is known to affect arsenic toxicity in some organisms, we asked whether iron may be present in lipid particles. When low density cell (LDC) gradient fractions were analysed for the presence of iron we detected a peak in very low-density fractions similar to those that carried arsenic. This could indicate that arsenic interacts with lipid particles that contain iron and, if arsenic is removed from the plasma by lipid particles, that would also reduce iron-containing lipid particles at the time of arsenic emergence in the plasma. To test this assumption we measured the iron content in plasma at various time periods after the toxin ingestion. This time course revealed that iron is depleted in plasma fractions when arsenic shows a peak. Our data suggest that arsenic interacts with invertebrate and vertebrate lipid particles that are associated with proteins that may lead to detoxification by cell-free or cellular sequestration mechanisms.
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Arsénico/farmacocinética , Contaminantes Ambientales/farmacocinética , Lípidos/química , Lipoproteínas/metabolismo , Animales , Arsénico/toxicidad , Centrifugación por Gradiente de Densidad , Contaminantes Ambientales/toxicidad , Hierro/metabolismo , Metabolismo de los Lípidos , Mariposas Nocturnas , Unión Proteica , Porcinos , Factores de TiempoRESUMEN
The assessment of arsenic (As) bioavailability from contaminated matrices is a crucial parameter for reducing the uncertainty when estimating exposure for human health risk assessment. In vivo assessment of As utilising swine is considered an appropriate model for human health risk assessment applications as swine are remarkably similar to humans in terms of physiology and As metabolism. While limited in vivo As bioavailability data is available in the literature, few details have been provided regarding technical considerations for performing in vivo assays. This paper describes, with examples, surgical, experimental design and analytical issues associated with performing chronic and acute in vivo swine assays to determine As bioavailability in contaminated soil and food.
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Arsénico/farmacocinética , Contaminación de Alimentos , Contaminantes del Suelo/farmacocinética , Animales , Disponibilidad Biológica , Exposición a Riesgos Ambientales/efectos adversos , Femenino , Humanos , Modelos Animales , Medición de Riesgo/métodos , Especificidad de la Especie , PorcinosRESUMEN
Arsenic (As) bioavailability in spiked soils aged for up to 12 months was assessed using in vitro and in vivo methodologies. Ageing (natural attenuation) of spiked soils resulted in a decline in in vivo As bioavailability (swine assay) of over 75% in soil A (Red Ferrosol) but had no significant effect on in vivo As bioavailability even after 12 months of ageing in soil B (Brown Chromosol). Sequential fractionation, however, indicated that there was repartitioning of As within the soil fractions extracted during the time course investigated. In soil A, the As fraction associated with the more weakly bound soil fractions decreased while the residual fraction increased from 12% to 35%. In contrast, little repartitioning of As was observed in soil B indicating that natural attenuation may be only applicable for As in soils containing specific mineralogical properties.
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Arsénico/metabolismo , Arsénico/farmacocinética , Suelo/análisis , Animales , Disponibilidad Biológica , Porcinos , Factores de TiempoRESUMEN
Considerable information is available in the literature regarding the uptake of arsenic (As) from contaminated soil and irrigation water by vegetables. However, few studies have investigated As speciation in these crops while a dearth of information is available on As bioavailability following their consumption. In this study, the concentration and speciation of As in chard, radish, lettuce and mung beans was determined following hydroponic growth of the vegetables using As-contaminated water. In addition, As bioavailability was assessed using an in vivo swine feeding assay. While As concentrations ranged from 3.0 to 84.2mg As kg(-1) (dry weight), only inorganic As (arsenite and arsenate) was detected in the edible portions of the vegetables. When As bioavailability was assessed through monitoring blood plasma As concentrations following swine consumption of As-contaminated vegetables, between 50% and 100% of the administered As dose was absorbed and entered systemic circulation. Arsenic bioavailability decreased in the order mung beans>radish>lettuce=chard.
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Alimentación Animal/análisis , Arsénico/farmacocinética , Contaminantes del Suelo/farmacocinética , Porcinos , Verduras/metabolismo , Animales , Arsénico/sangre , Arsénico/metabolismo , Disponibilidad Biológica , Modelos Animales , Contaminantes del Suelo/sangre , Contaminantes del Suelo/metabolismoRESUMEN
OBJECTIVES: Pricing polices used in many countries are often viewed in the United States as a mechanism of price constraint. Support for this contention has arisen from pricing studies which demonstrate that the United States pays higher prices for many pharmaceutical products. No study to date, however, has examined the prices paid for pharmaceuticals that provide significant health gain, which might be expected to be lower where price constraints were operating. This study aimed to examine prices paid by federal government programs and agencies in Australia and the United States for pharmaceutical products that provide significant health gain. METHODS: Products identified by the US Food and Drug Administration and the Canadian Patented Medicines Prices Review Board as likely to confer significant health gains between 1999 and 2004 were identified. Australian and USfederal government prices ($US) and US average manufacturer prices (AMP), which do not include discounts or rebates, during the second quarter of 2006 were compared. RESULTS: Of 22 products for which comparisons were possible, Australian prices were higher than the US Federal Supply Schedule (FSS) prices for 14 (64%) products. When compared with AMP, Australian prices were higher for eight of the 22 products. Overall, Australian prices were higher on average by 4.2% when compared with the FSS and lower by 14.4% when compared with the AMP. CONCLUSION: These results suggest that Australian prices for medicines representing significant advances in therapy are similar to those paid under key US programs despite fundamental differences in policy contexts.
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Costos de los Medicamentos , Internacionalidad , Programas Nacionales de Salud/economía , Método de Control de Pagos , Australia , Humanos , Mecanismo de Reembolso , Estados UnidosRESUMEN
An in vivo swine assay was utilised for the determination of arsenic (As) bioavailability in contaminated soils. Arsenic bioavailability was assessed using pharmacokinetic analysis encompassing area under the blood plasma-As concentration time curve following zero correction and dose normalisation. In contaminated soil studies, As uptake into systemic circulation was compared to an arsenate oral dose and expressed as relative As bioavailability. Arsenic bioavailability ranged from 6.9+/-5.0% to 74.7+/-11.2% in 12 contaminated soils collected from former railway corridors, dip sites, mine sites and naturally elevated gossan soils. Arsenic bioavailability was generally low in the gossan soils and highest in the railway soils, ranging from 12.1+/-8.5% to 16.4+/-9.1% and 11.2+/-4.7% to 74.7+/-11.2%, respectively. Comparison of in vivo and in vitro (Simplified Bioaccessibility Extraction Test [SBET]) data from the 12 contaminated soils and bioavailability data collected from an As spiked soil study demonstrated that As bioavailability and As bioaccessibility were linearly correlated (in vivo As bioavailability (mgkg(-1))=14.19+0.93.SBET As bioaccessibility (mgkg(-1)); r(2)=0.92). The correlation between the two methods indicates that As bioavailability (in vivo) may be estimated using the less expensive, rapid in vitro chemical extraction method (SBET) to predict As exposure in human health risk assessment.
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Arsénico/farmacocinética , Contaminantes del Suelo/farmacocinética , Suelo/análisis , Animales , Área Bajo la Curva , Arsénico/sangre , Disponibilidad Biológica , Femenino , Valor Predictivo de las Pruebas , Contaminantes del Suelo/sangre , PorcinosRESUMEN
Arsenic (As) bioaccessibility in contaminated soils (n=50) was assessed using the simplified bioaccessibility extraction test (SBET). Soils used in the study were collected from sites where As was used as an herbicide (railway corridor) or pesticide (cattle dip sites), from former gold mines and from highly mineralised locations containing geogenic As sources (gossans). In all but three soils, As bioaccessibility was less than 50% indicating that a significant proportion of the total As concentration may not be available for absorption in the gastrointestinal tract following incidental soil ingestion. When regression models were developed based on soil properties, the descriptive variables best able to describe As bioaccessibility in railway corridor, dip site and mine site soils were total As and total or dithionite-citrate extractable (free) iron (Fe). While As bioaccessibility could be predicted (r(2)=0.955, n=50) in these contaminated soils, As bioaccessibility for gossan soils was a poor fit using linear or multivariate regression analysis.
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Arsénico/análisis , Jugo Gástrico/química , Contaminantes del Suelo/análisis , Fenómenos Geológicos , Geología , Oro , Herbicidas/análisis , Concentración de Iones de Hidrógeno , Residuos Industriales , Insecticidas/análisis , Hierro/análisis , MineríaRESUMEN
BACKGROUND: Millions of people worldwide consume arsenic-contaminated rice; however, little is known about the uptake and bioavailability of arsenic species after arsenic-contaminated rice ingestion. OBJECTIVES: In this study, we assessed arsenic speciation in greenhouse-grown and supermarket-bought rice, and determined arsenic bioavailability in cooked rice using an in vivo swine model. RESULTS: In supermarket-bought rice, arsenic was present entirely in the inorganic form compared to greenhouse-grown rice (using irrigation water contaminated with sodium arsenate), where most (approximately 86%) arsenic was present as dimethylarsinic acid (organic arsenic). Because of the low absolute bioavailability of dimethylarsinic acid and the high proportion of dimethylarsinic acid in greenhouse-grown rice, only 33 +/- 3% (mean +/- SD) of the total rice-bound arsenic was bioavailable. Conversely, in supermarket-bought rice cooked in water contaminated with sodium arsenate, arsenic was present entirely in the inorganic form, and bioavailability was high (89 +/- 9%). CONCLUSIONS: These results indicate that arsenic bioavailability in rice is highly dependent on arsenic speciation, which in turn can vary depending on rice cultivar, arsenic in irrigation water, and the presence and nature of arsenic speciation in cooking water. Arsenic speciation and bioavailability are therefore critical parameters for reducing uncertainties when estimating exposure from the consumption of rice grown and cooked using arsenic-contaminated water.
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Arsénico/farmacocinética , Contaminación de Alimentos/análisis , Oryza/química , Animales , Arsénico/administración & dosificación , Arsénico/sangre , Disponibilidad Biológica , Ácido Cacodílico/administración & dosificación , Ácido Cacodílico/sangre , Ácido Cacodílico/farmacocinética , Humanos , Medición de Riesgo , PorcinosRESUMEN
UNLABELLED: An animal model of gastric emptying may have use in the study of gastric physiology and pharmacoscintigraphy. The pig has anatomy and physiology similar to that of humans. Our aim was to develop a model of gastric emptying in the pig. It was not possible to perform this study in conscious pigs; therefore, an anesthetic model was developed. METHODS: Fifteen studies were performed on 4 pigs (age, 2-6 mo; weight, 20-100 kg). After acclimatization and training, pigs were fasted overnight before the study. Pigs were anesthetized using inhaled isoflurane without the use of injected premedication agents. An orogastric tube was inserted for the administration of a liquid meal, which consisted of (99m)Tc-diethylenetriaminepentaacetic acid either in water (nonnutrient) or with dextrose (nutrient meal). The pig was laterally positioned to enable right lateral dynamic acquisition to be performed. Anesthesia was maintained at 2% +/- 0.5% isoflurane in 4 studies and 0.8% +/- 0.5% in 11 studies (4 nutrient, 7 nonnutrient). RESULTS: With 2% +/- 0.5% isoflurane, there was delayed gastric emptying with a mean 50% emptying time (+/-SEM) of 141 +/- 14 min. With 0.8% +/- 0.5% isoflurane, the liquid meal emptied in an exponential manner similar to that of humans, with mean 50% emptying times (+/-SEM) of 30 +/- 7 min (nutrient) and 31 +/- 4 min (nonnutrient). CONCLUSION: The results indicate that high-dose anesthesia inhibits gastric emptying, but with low-dose anesthesia a useful pig model of liquid gastric emptying can be developed.
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Anestésicos por Inhalación , Vaciamiento Gástrico/efectos de los fármacos , Isoflurano , Anestésicos por Inhalación/análisis , Animales , Femenino , Isoflurano/análisis , Radiofármacos , Porcinos , Pentetato de Tecnecio Tc 99mRESUMEN
OBJECTIVE: To determine the proportion of South Australians accessing online health care information, predictive characteristics of online health seekers, nature of the information sought and consumer behaviour. METHODS: A probability-based survey of 3,027 South Australians, aged 15 years and older, as part of the Spring 2000 South Australian Health Omnibus. RESULTS: Internet access decreases with age, while the prevalence of online health seekers is constant (26% to 28%) among people aged between 15 and 54 years. Predictive characteristics of online health seekers include gender, age, education and income. Most commonly sought information is the cause or description of disease (60%). Consumers use online health information as a second opinion (19%), discuss it with their doctor or pharmacist (16%), or change their health care management (11%). CONCLUSIONS: The Australian prevalence of online health seekers is likely to be slightly higher than 21%. IMPLICATIONS: The Intemet can deliver preventative and clinical health information to a critical mass of Australians, but poorer and older Australians may be unable to access it.
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Servicios de Información/estadística & datos numéricos , Internet/estadística & datos numéricos , Aceptación de la Atención de Salud/estadística & datos numéricos , Adolescente , Adulto , Anciano , Demografía , Femenino , Accesibilidad a los Servicios de Salud , Humanos , Masculino , Persona de Mediana Edad , Probabilidad , Factores Socioeconómicos , Australia del SurRESUMEN
The increasing costs of health care, including new technologies and pharmaceuticals, pose challenges for all countries both in the developed and the developing world. It is essential that the increased expenditure on pharmaceuticals represents value for money and is seen as an investment in health care rather than simply the purchase of the latest released agent. The system in Australia uses a cost-effectiveness approach to guide the decisions as to whether a new drug can be recommended for subsidy. The need for a greater understanding and transparency of the processes is essential in order for a well-informed public debate to occur about the challenges to the system and its sustainability. The relevant issues are discussed in this article to assist that debate.
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Comités Consultivos/organización & administración , Aprobación de Drogas/organización & administración , Industria Farmacéutica/legislación & jurisprudencia , Financiación Gubernamental/legislación & jurisprudencia , Formularios Farmacéuticos como Asunto , Seguro de Servicios Farmacéuticos/legislación & jurisprudencia , Comités Consultivos/legislación & jurisprudencia , Australia , Ensayos Clínicos como Asunto , Análisis Costo-Beneficio , Toma de Decisiones en la Organización , Países Desarrollados/economía , Aprobación de Drogas/legislación & jurisprudencia , Costos de los Medicamentos , Industria Farmacéutica/economía , Industria Farmacéutica/tendencias , Prescripciones de Medicamentos/economía , Accesibilidad a los Servicios de Salud/economía , Humanos , InternacionalidadRESUMEN
Pharmaceutical companies have a good understanding of the needs and requirements of regulatory bodies, but the evidence expectations of health technology assessment (HTA) and coverage/payer bodies are less well understood and addressed. This paper seeks to improve this understanding by providing an overview of the expectations of HTA and coverage/payer bodies, explaining how and why these differ from those of regulators, and describing the extent and limitations of work on harmonization. The article goes on to describe ways in which HTA and coverage/payer bodies' expectations can be addressed, and to encourage industry to interact with HTA and coverage/payer bodies to increase mutual understanding and hence promote more efficient development of and access to innovative medicines.