Evaluation of Tucatinib in HER2-Positive Breast Cancer Patients With Brain Metastases: A United States-Based Cost-Effectiveness Analysis.

PURPOSE: To evaluate the cost-effectiveness of tucatinib in human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) patients with brain metastases (BMs) and the subgroup of active BMs from the United States (US) payer perspective. MATERIALS AND METHODS: A 3-state Markov model was developed to compare the cost-effectiveness of 2 regimens in HER2-positive BC patients with BMs: (1) tucatinib, trastuzumab, and capecitabine (TTC); (2) placebo, trastuzumab, and capecitabine (PTC). And subgroup analysis of active BMs was also performed. Lifetime costs, quality-adjusted life years (QALYs), incremental cost-effectiveness ratio (ICER) and incremental net-health benefit (INHB) were estimated. The willingness-to-pay (WTP) threshold was $200,000/QALY. The robustness of the model was tested by sensitivity analyses. Additional scenario analysis was also performed. RESULTS: Compared with PTC, the ICER yielded by TTC was $418,007.01/QALY and the INHB was -1.08 QALYs in patients with BMs. In the subgroup of active BMs, the ICER and the INHB were $324,465.03/QALY and -0.71 QALY, respectively. The results were most sensitive to the cost of tucatinib. Probabilistic sensitivity analyses suggested that the cost-effective probability of TTC was low at the current WTP threshold in the patients with BMs and the subgroup of active BMs. CONCLUSION: Tucatinib is unlikely to be cost-effective in HER2-positive BC patients with BMs from the US payer perspective but shows better economics in patients with active BMs. Selecting a favorable population, reducing the price of tucatinib or offering appropriate drug assistance policies might be considerable options to optimize the cost-effectiveness of tucatinib.

Cost-effectiveness of bedaquiline or delamanid plus background regimen for multidrug-resistant tuberculosis in a high-income intermediate burden city of China.

OBJECTIVE: Hong Kong is a high-income city of China with an intermediate tuberculosis (TB) burden, and 1% of TB cases are multidrug-resistant (MDR-TB). The aim of this study was to examine the potential cost-effectiveness of adding bedaquiline or delamanid to the background regimen (BR) for the treatment of MDR-TB in Hong Kong. METHODS: A decision-analytic model was designed to simulate outcomes over a 10-year time horizon for MDR-TB patients treated with bedaquiline plus BR (B-BR), delamanid plus BR (D-BR), or BR alone. Outcome measures included direct medical costs and quality-adjusted life-years (QALYs) gained. RESULTS: In the base-case analysis, BR was the least costly regimen (USD 47396) with the lowest QALYs gained (6.347). Compared to BR, B-BR gained an additional 0.731 QALYs with incremental cost of USD 9. The incremental cost-effectiveness ratio (ICER) of B-BR was USD 12/QALY. D-BR was more costly than BR by USD 20 164 and gained an additional 0.012 QALYs. The ICER of D-BR was USD 1 680333/QALY. In the probabilistic sensitivity analysis with 10000 Monte Carlo simulations, B-BR and D-BR were cost-effective 99.98% and 5.13% of the time, respectively, using 1× gross domestic product per capita (USD 46 182) as the willingness-to-pay threshold. CONCLUSIONS: Bedaquiline is more likely than delamanid to be cost-effective when added to BR for the treatment of MDR-TB in Hong Kong.

Incorporating social justice and stigma in cost-effectiveness analysis: drug-resistant tuberculosis treatment.

Novel therapies for multidrug-resistant tuberculosis (MDR-TB) are likely to be expensive. The cost of novel drugs (e.g., bedaquiline, delamanid) may be so prohibitively high that a traditional cost-effectiveness analysis (CEA) would rate regimens containing these drugs as not cost-effective. Traditional CEA may not appropriately account for considerations of social justice, and may put the most disadvantaged populations at greater risk. Using the example of novel drug regimens for MDR-TB, we propose a novel methodology, 'justice-enhanced CEA', and demonstrate how such an approach can simultaneously assess social justice impacts alongside traditional cost-effectiveness ratios. Justice-enhanced CEA, as we envision it, is performed in three steps: 1) systematic data collection about patients' lived experiences, 2) use of empirical findings to inform social justice assessments, and 3) incorporation of data-informed social justice assessments into a decision analytic framework that includes traditional CEA. These components are organized around a core framework of social justice developed by Bailey et al. to compare impacts on disadvantage not otherwise captured by CEA. Formal social justice assessments can produce three composite levels: 'expected not to worsen…', 'may worsen…', and 'expected to worsen clustering of disadvantage'. Levels of social justice impact would be assessed for each major type of outcome under each policy scenario compared. Social justice assessments are then overlaid side-by-side with cost-effectiveness assessments corresponding to each branch pathway on the decision tree. In conclusion, we present a 'justice-enhanced' framework that enables the incorporation of social justice concerns into traditional CEA for the evaluation of new regimens for MDR-TB.

Cost-effectiveness of adding novel or group 5 interventions to a background regimen for the treatment of multidrug-resistant tuberculosis in Germany.

BACKGROUND: Treatment of multidrug-resistant tuberculosis (MDR-TB) is complex, lengthy, and involves a minimum of four drugs termed a background regimen (BR), that have not previously been prescribed or that have proven susceptible to patient sputum culture isolates. In recent years, promising new treatment options have emerged as add-on therapies to a BR. The aim of this study was to evaluate the long-term costs and effectiveness of adding the novel or group 5 interventions bedaquiline, delamanid, and linezolid to a background regimen (BR) of drugs for the treatment of adult patients with pulmonary multidrug-resistant tuberculosis (MDR-TB), within their marketing authorisations, from a German healthcare cost-effectiveness perspective. METHODS: A cohort-based Markov model was developed to simulate the incremental cost-effectiveness ratio of bedaquiline plus BR, delamanid plus BR, or linezolid plus BR versus BR alone in the treatment of MDR-TB, over a 10-year time horizon. Effectiveness of treatment was evaluated in Quality-Adjusted Life-Years (QALYs) and Life-Years Gained (LYG), using inputs from clinical trials for bedaquiline and delamanid and from a German observational study for linezolid. Cost data were obtained from German Drug Directory costs (€/2015), published literature, and expert opinion. A 3% yearly discount rate was applied. Probabilistic and deterministic sensitivity analyses were conducted. RESULTS: The total discounted costs per-patient were €85,575 for bedaquiline plus BR, €81,079 for delamanid plus BR, and €80,460 for linezolid plus BR, compared with a cost of €60,962 for BR alone. The total discounted QALYs per-patient were 5.95 for bedaquiline plus BR, 5.36 for delamanid plus BR, and 3.91 for linezolid plus BR, compared with 3.68 for BR alone. All interventions were therefore associated with higher QALYs and higher costs than BR alone, with incremental costs per QALY gained of €22,238 for bedaquiline, €38,703 for delamanid, and €87,484 for linezolid, versus BR alone. In a fully incremental analysis, bedaquiline plus BR was the most cost-effective treatment option at thresholds greater than €22,000 per QALY gained. In probabilistic analyses, the probability that bedaquiline plus BR was the most cost-effective treatment strategy at a willingness-to-pay threshold of €30,000 was 54.5%, compared with 22.9% for BR alone, 18.2% for delamanid plus BR, and 4.4% for linezolid. CONCLUSIONS: In Germany, the addition of bedaquiline, delamanid, or linezolid to a BR would result in QALY gains over BR alone. Based on this analysis, bedaquiline is likely to be the most cost-effective intervention for the treatment of MDR-TB, when added to a BR regimen at thresholds greater than €22,000 per QALY.

Estimated generic prices for novel treatments for drug-resistant tuberculosis.

Background: The estimated worldwide annual incidence of MDR-TB is 480 000, representing 5% of TB incidence, but 20% of mortality. Multiple drugs have recently been developed or repurposed for the treatment of MDR-TB. Currently, treatment for MDR-TB costs thousands of dollars per course. Objectives: To estimate generic prices for novel TB drugs that would be achievable given large-scale competitive manufacture. Methods: Prices for linezolid, moxifloxacin and clofazimine were estimated based on per-kilogram prices of the active pharmaceutical ingredient (API). Other costs were added, including formulation, packaging and a profit margin. The projected costs for sutezolid were estimated to be equivalent to those for linezolid, based on chemical similarity. Generic prices for bedaquiline, delamanid and pretomanid were estimated by assessing routes of synthesis, costs/kg of chemical reagents, routes of synthesis and per-step yields. Costing algorithms reflected variable regulatory requirements and efficiency of scale based on demand, and were validated by testing predictive ability against widely available TB medicines. Results: Estimated generic prices were US$8-$17/month for bedaquiline, $5-$16/month for delamanid, $11-$34/month for pretomanid, $4-$9/month for linezolid, $4-$9/month for sutezolid, $4-$11/month for clofazimine and $4-$8/month for moxifloxacin. The estimated generic prices were 87%-94% lower than the current lowest available prices for bedaquiline, 95%-98% for delamanid and 94%-97% for linezolid. Estimated generic prices were $168-$395 per course for the STREAM trial modified Bangladesh regimens (current costs $734-$1799), $53-$276 for pretomanid-based three-drug regimens and $238-$507 for a delamanid-based four-drug regimen. Conclusions: Competitive large-scale generic manufacture could allow supplies of treatment for 5-10 times more MDR-TB cases within current procurement budgets.

New Gram Positive Agents to Treat Acute Bacterial Skin and Skin Structure Infections.

The FDA guidance published in 2013 provided requirements for conducting ABSSSI trials. In 2014, dalbavancin, oritavancin, and tedizolid were introduced into the market after phase III noninferiority clinical trials against vancomycin (for the lipoglycopeptides) and linezolid (for tedizolid), demonstrating clinical efficacy for the treatment of ABSSSI. Great interest exists for these agents because of the postulated financial impact. Due to favorable pharmacokinetics which allow for less frequent medication administration and shorter treatment durations, these agents may prove to reduce hospital admissions and length of stay.

Cost effectiveness of treating multi-drug resistant tuberculosis by adding Deltyba™ to background regimens in Germany.

OBJECTIVE: To assess the cost-effectiveness of adding delamanid (Deltyba™) to a background regimen (BR) for treating multidrug-resistant tuberculosis (MDR-TB) in Germany. METHODS: The incremental cost-effectiveness of treating a cohort of MDR-TB patients, 38-years old on average, with Deltyba™ plus BR versus a five drug- BR regimen alone was compared in a Markov model over a period of 10 years. Cost per quality-adjusted life year (QALY) and disability-adjusted life years (DALY) were determined from a societal perspective. Recent data from a German cost calculation on MDR-TB were applied to the 24-month outcome results of patients participating in the placebo-controlled, phase II Otsuka's Trial 204. Costs and effectiveness were discounted at a rate of 3% and subjected to deterministic as well as probabilistic sensitivity analysis in a Monte Carlo simulation. RESULTS: Based on the current market prices the total discounted cost per patient on BR plus Deltyba™ was €142,732 compared to €150,909 for BR alone. The total discounted QALYs per patient were 8.47 for Deltyba™ versus 6.13 for BR alone. Accordingly, the addition of Deltyba™ proved to be dominant over the BR alone-strategy by simultaneously saving €8177 and gaining 2.34 QALYs. Deltyba™ was cost saving in 73% of probabilistic sensitivity analyses compared to BR alone and 100% cost effective at a willingness-to-pay (WTP) threshold of €10,000. CONCLUSIONS: Under conditions prevalent in Germany, Deltyba™ added to a five drug BR regimen is likely to be cost-saving compared to BR alone under a wide range of assumptions. Adding delamanid remained cost-effective when costs due to loss of productivity were excluded as the QALYs gained by lower lethality and a higher proportion of successfully treated patients outweighed the delamanid drug costs. These results strongly support the application of Deltyba™ in treating MDR-TB patients.

Using internet snapshot surveys to enhance our understanding of the availability of the novel psychoactive substance 4-methylaminorex and 4,4'-dimethylaminorex.

4,4'-Dimethylaminorex is a stimulant novel psychoactive substance (NPS) first detected in Europe in November 2012. It is a derivative of 4-methylaminorex, a substance controlled under Schedule 1 of the 1971 United Nations Convention on Psychotropic Substances. There is currently no information on the availability or cost of these substances from Internet suppliers. An Internet snapshot study was undertaken in English using established European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) methodology to determine the availability of 4-methylaminorex and 4,4'-dimethylaminorex in April 2014. Twenty Internet sites selling 4-methylaminorex were identified, 18 selling in US dollars and two in GB Pound Sterling. Fourteen (70 %) Internet sites had a minimum purchase amount of ≥10 g (compared to user doses of 10-25 mg). For the 18 suppliers selling in US$, 9 quoted a fixed price per gram irrespective of the amount ordered and 11 had a reducing price per gram with increasing purchase quantity (US$30.8 ± 34.2/g for 1 g purchase to US$15.2 ± 20.3/g for 1 kg purchase). Only one Internet site selling 4,4'-dimethylaminorex was identified, selling in Euros. The minimum purchase quantity was 500 mg. The price per gram reduced from 36.08/g for a 500 mg purchase to 2.20/g for a 100 g purchase. This Internet snapshot demonstrated that there was a greater availability from Internet suppliers of products advertised as 4-methylaminorex than 4,4'-dimethylaminorex, despite the 4-methylaminorex being an internationally controlled substance. Whilst this may reflect misunderstanding by suppliers, it has the potential to put those purchasing at risk of contravening border control and/or local law enforcement legislation. The use of methodology such as Internet snapshot surveys is of increasing interest to clinical/medical toxicologists in their understanding of the supply, availability and cost of novel psychoactive substances.

Principles for designing future regimens for multidrug-resistant tuberculosis.

Fewer than 20% of patients with multidrug-resistant (MDR) tuberculosis are receiving treatment and there is an urgent need to scale up treatment programmes. One of the biggest barriers to scale-up is the treatment regimen, which is lengthy, complex, ineffective, poorly tolerated and expensive. For the first time in over 50 years, new drugs have been developed specifically to treat tuberculosis, with bedaquiline and potentially delamanid expected to be available soon for treatment of MDR cases. However, if the new drugs are merely added to the current treatment regimen, the new regimen will be at least as lengthy, cumbersome and toxic as the existing one. There is an urgent need for strategy and evidence on how to maximize the potential of the new drugs to improve outcomes and shorten treatment. We devised eight key principles for designing future treatment regimens to ensure that, once they are proven safe in clinical trials, they will be clinically effective and programmatically practicable. Regimens should contain at least one new class of drug; be broadly applicable for use against MDR and extensively drug-resistant Mycobacterium tuberculosis complex strains; contain three to five effective drugs, each from a different drug class; be delivered orally; have a simple dosing schedule; have a good side-effect profile that allows limited monitoring; last a maximum of 6 months; and have minimal interaction with antiretrovirals. Following these principles will maximize the potential of new compounds and help to overcome the clinical and programmatic disadvantages and scale-up constraints that plague the current regimen.

Moins de 20% des patients atteints de tuberculose multirésistante (MDR) reçoivent actuellement un traitement et il est urgent de renforcer les programmes de traitement. Un des plus grands obstacles à ce renforcement est le schéma thérapeutique qui est long, complexe, inefficace, mal toléré et coûteux. Pour la première fois en plus de 50 ans, de nouveaux médicaments ont été développés spécifiquement pour traiter la tuberculose, dont la bedaquiline et potentiellement la delamanid qui devraient être bientôt disponibles pour traiter les cas de MDR. Cependant, si les nouveaux médicaments sont juste ajoutés au schéma thérapeutique actuel, le nouveau schéma thérapeutique sera au moins aussi long, lourd et toxique que celui qui existe déjà. Il est urgent d'élaborer une stratégie et d'obtenir des preuves concernant la façon de maximiser le potentiel des nouveaux médicaments pour améliorer les résultats et raccourcir la durée du traitement. Nous avons mis au point huit principes clés pour la conception des futurs schémas thérapeutiques afin de s'assurer que, une fois qu'ils aient été éprouvés comme sûrs dans des essais cliniques, ils soient cliniquement efficaces et utilisables dans le cadre d'un programme. Les schémas thérapeutiques doivent comprendre au moins une nouvelle classe de médicament; être généralement applicables pour une utilisation contre les MDR et plus largement contre les souches complexes de Mycobacterium tuberculosis multirésistantes; comprendre trois des cinq médicaments efficaces, chacun provenant d'une classe de médicament différent; être administré par voie orale; avoir un schéma posologique simple; avoir un bon profil d'effets secondaires permettant un suivi limité; durer au moins 6 mois et avoir le moins d'interaction possible avec les antirétroviraux. Suivre ces principes maximisera le potentiel des nouveaux composés et permettra de surmonter les inconvénients cliniques et programmatiques, ainsi que les contraintes qui plombent le schéma thérapeutique actuel.

Menos del 20 % de los pacientes con tuberculosis multirresistente (MDR) recibe tratamiento, al tiempo que existe una necesidad apremiante de ampliar los programas de tratamiento. Uno de los mayores obstáculos para la ampliación es el propio programa de tratamiento, el cual resulta largo, complejo, ineficaz, caro y no se tolera bien. Por primera vez en más de 50 años se han desarrollado fármacos nuevos específicos para tratar la tuberculosis y se espera que la bedaquilina y, potencialmente, la delamanida estén disponibles pronto para tratar los casos de tuberculosis multirresistente. Sin embargo, si se limitan a introducir los fármacos nuevos al programa de tratamiento actual, el programa nuevo será, como mínimo, tan largo, complicado y tóxico como el presente. Es, por tanto, muy urgente diseñar una estrategia y reunir pruebas sobre cómo maximizar el potencial de los fármacos nuevos para mejorar los resultados y acortar el tratamiento. Hemos establecido ocho principios esenciales para el diseño de los programas de tratamiento futuros a fin de garantizar que, una vez que se hayan probado en ensayos clínicos, sean eficaces desde el punto de vista clínico y viables mediante programación. Los programas deben contener, al menos, un tipo nuevo de fármaco, poder aplicarse de forma amplia para su uso contra la tuberculosis multirresistente y las cepas complejas de Mycobacterium tuberculosis ultrarresistentes, contener de tres a cinco medicamentos eficaces, cada uno de una clase de fármaco diferente; suministrarse por vía oral, tener un horario de dosificación simple y un perfil adecuado de efectos secundarios que permita una supervisión restringida, durar un máximo de 6 meses y tener una interacción mínima con antirretrovirales. Si se siguen estos principios, se maximizará el potencial de los compuestos nuevos y será más fácil superar los inconvenientes clínicos y programáticos, así como las barreras a la ampliación que abundan en el programa actual.

[Zolmitriptan]. / Le zolmitriptan.

One of the outstanding therapeutic revolutions of this last decade has been the introduction of selective serotonin agonists in the acute treatment of migraine. After sumatriptan, introduced in Belgium in 1992, other "triptans" are emerging. The efficacy and the pharmacoeconomic profile of zolmitriptan, the second "triptan" now available in Belgium, are reviewed and the arrival of a third triptan, naratriptan is announced.