Breast Cancer-Related Financial Toxicity in Sri Lanka: Insights From a Lower Middle-Income Country With Free Universal Public Healthcare.

Financial toxicity (FT) describes either objective or perceived excess financial strain due to a cancer diagnosis on the well-being of patients, families, and society. The consequences of FT have been shown to span countries of varied economic tiers and diverse healthcare models. This study attempts to describe FT and its effects in a lower- to middle-income country delivering predominantly public nonfee-levying healthcare. This was a cross-sectional study involving 210 patients with breast cancer of any stage (I to IV), interviewed between 6 and 18 months from the date of diagnosis. Financial toxicity was highly prevalent with 81% reporting 3 or more on a scale of 1 to 5. Costs incurred for travelling (94%), out-of-hospital investigations (87%), and consultation fees outside the public system (81%) were the most common contributors to FT. Daily compromises for food and education were made by 30% and 20%, respectively, with loss of work seen in over one-third. Greater FT was seen with advanced cancer stage and increasing distance to the nearest radiotherapy unit (P = .008 and .01, respectively). Family and relatives were the most common form of financial support (77.6%). In conclusion, FT is substantial in our group, with many having to make daily compromises for basic needs. Many opt to visit the fee-levying private sector for at least some part of their care, despite the availability of an established public nonfee-levying healthcare.

Health technology assessment for cancer medicines across the G7 countries and Oceania: an international, cross-sectional study.

BACKGROUND: Criticisms have emerged that cancer medicines offer modest benefits at increasingly high prices. Reimbursement decisions made by health technology assessment (HTA) agencies have become a complex endeavour for cancer medicines. Most high-income countries (HICs) use HTA criteria to identify high-value medicines for reimbursement under public drug coverage plans. We compared HTA criteria specific for cancer medicines in economically similar HICs, to understand how these criteria contribute to reimbursement decisions. METHODS: We did an international, cross-sectional analysis in collaboration with author investigators across eight HICs, from the Group of Seven (known as G7; Canada, England, France, Germany, Italy, and Japan) and Oceania (Australia and New Zealand). Publicly available data from HTA agency reports and official documentation were extracted and analysed between Aug 15, 2021, and July 31, 2022. We collected data pertaining to the decision-making criteria used by the national HTA agency; HTA reimbursement status for 34 medicine-indication pairs corresponding to 15 unique US top-selling cancer medicines; and HTA reimbursement status for 18 cancer medicine-indication pairs (13 unique medicines) with minimal clinical benefit (score of 1 on the European Society of Medical Oncology Magnitude of Clinical Benefit Scale). Descriptive statistics were used to compare HTA decision criteria and drug reimbursement recommendations (or for Germany and Japan, final reimbursement status) across the eight countries. FINDINGS: Therapeutic impact related to clinical outcomes of the new medicine was a uniform criterion across the eight countries, whereas quality of evidence (under the remit of therapeutic impact assessment) and equity were infrequently cited criteria. Only the German HTA agency mandated that surrogate endpoints be validated in therapeutic impact assessment. All countries except Germany included formal cost-effectiveness analyses within HTA reports. England and Japan were the only countries that specified a cost-effectiveness threshold. Of the 34 medicine-indication pairs corresponding to US top-selling cancer medicines, Germany reimbursed the maximum (34 [100%]), followed by Italy (32 [94%] recommended for reimbursement), Japan (28 [82%] reimbursed), Australia, Canada, England, and France (27 [79%] recommended for reimbursement), and New Zealand (12 [35%] recommended for reimbursement). Of the 18 cancer medicine-indication pairs with marginal clinical benefit, Germany reimbursed 15 (83%) and Japan reimbursed 12 (67%). France recommended nine (50%) for reimbursement, followed by Italy (seven [39%]), Canada (five [28%]), and Australia and England (three [17%] each). New Zealand did not recommend any medicine-indications with marginal clinical benefit for reimbursement. Considering the overall cumulative proportion across the eight countries, 58 (21%) of 272 indications for the US top-selling medicines and 90 (63%) of 144 marginally beneficial medicine-indications were not recommended for reimbursement or reimbursed. INTERPRETATION: Our findings indicate discordance in public reimbursement decisions across economically similar countries, despite overlapping HTA decision criteria. This suggests a need for improved transparency around the nuances of the criteria to ensure improved access to high-value cancer medicines, and deprioritisation of low-value cancer medicines. Health systems have opportunities to improve their HTA decision-making processes by learning from the systems in other countries. FUNDING: None.

Training General Practitioners in Oncology: A Needs Assessment Survey From Nepal.

PURPOSE: Nepal lacks enough cancer care providers to address the growing burden of cancer in the country. One way of addressing this issue is to train general practitioners (GPs) in oncology (GPOs) so that they can task-share and task-shift oncology care. However, limited information is available regarding the current level of oncology expertise of Nepali GPs and whether they perceive a need for, and have an interest in, such a GPO training program if available in Nepal. METHODS: A survey was distributed to GPs in Nepal to collect data on current oncology training and clinical practice and evaluate levels of interest and need for a GPO training program. The survey was distributed electronically from February to July 2021. RESULTS: The survey obtained 71 individual responses from GPs in Nepal. The majority of respondents were male (87%), and most worked as consultants or senior consultants (63%). Only 6% of respondents had a mandatory oncology rotation during their GP training, and only 15% indicated that their GP training had adequately prepared them to care for patients with cancer. Ninety-six percent of respondents perceived a need for a GPO training program in Nepal, with 94% indicating an interest in enrolling in such a program and 71% indicating that they were very interested. CONCLUSION: The findings indicate an urgent need for and an encouraging interest in establishing a GPO training program in Nepal. These findings will be used to guide the development and implementation of this type of program.

Prevalence of SARS-CoV-2 IgG antibodies in health care workers at a tertiary care academic medical center - An assessment of occupational infection risk.

BACKGROUND: The purpose of this study was to assess the occupational SARS-CoV-2 infection risk among health care workers (HCW) at University of Kentucky HealthCare (UKHC) by evaluating the prevalence of SARS-CoV-2 antibodies. METHODS: This is a prospective cohort study of HCW at UKHC. SARS-CoV-2 IgG antibody seropositivity was measured in a CLIA-certified laboratory utilizing the Abbott Architect SARS-CoV-2 IgG antibody assay. Demographics and work type were self-reported by study participants via an emailed survey. RESULTS: The overall antibody positivity rate of HCW was 1.55% (5/322; 95% confidence interval: 0.65%-3.71%) at cohort entry. There were no differences in antibody positivity between those that worked directly with SARS-CoV-2 infected patients and those that did not. The antibody rate of positivity of patients during the same time period was similar, 1.8% (9/499; 95% confidence interval 0.94%-3.45%). CONCLUSIONS: Antibody positivity was low and similar between HCW and patients tested during a similar time period. HCW positivity rates did not appear to be impacted by caring for known SARS-CoV-2 infected patients suggesting that appropriate use of personal protective equipment is effective in protecting individuals from transmission.

A cost/benefit analysis of clinical trial designs for COVID-19 vaccine candidates.

We compare and contrast the expected duration and number of infections and deaths averted among several designs for clinical trials of COVID-19 vaccine candidates, including traditional and adaptive randomized clinical trials and human challenge trials. Using epidemiological models calibrated to the current pandemic, we simulate the time course of each clinical trial design for 756 unique combinations of parameters, allowing us to determine which trial design is most effective for a given scenario. A human challenge trial provides maximal net benefits-averting an additional 1.1M infections and 8,000 deaths in the U.S. compared to the next best clinical trial design-if its set-up time is short or the pandemic spreads slowly. In most of the other cases, an adaptive trial provides greater net benefits.

Value assessment of oncology drugs using a weighted criterion-based approach.

BACKGROUND: Globally, the rising cost of anticancer therapy has motivated efforts to quantify the overall value of new cancer treatments. Multicriteria decision analysis offers a novel approach to incorporate multiple criteria and perspectives into value assessment. METHODS: The authors recruited a diverse, multistakeholder group who identified and weighted key criteria to establish the drug assessment framework (DAF). Construct validity assessed the degree to which DAF scores were associated with past pan-Canadian Oncology Drug Review (pCODR) funding recommendations and European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS; version 1.1) scores. RESULTS: The final DAF included 10 criteria: overall survival, progression-free survival, response rate, quality of life, toxicity, unmet need, equity, feasibility, disease severity, and caregiver well-being. The first 5 clinical benefit criteria represent approximately 64% of the total weight. DAF scores ranged from 0 to 300, reflecting both the expected impact of the drug and the quality of supporting evidence. When the DAF was applied to the last 60 drugs (with reviewers blinded) reviewed by pCODR (2015-2018), those drugs with positive pCODR funding recommendations were found to have higher DAF scores compared with drugs not recommended (103 vs 63; Student t test P = .0007). DAF clinical benefit criteria mildly correlated with ESMO-MCBS scores (correlation coefficient, 0.33; 95% CI, 0.009-0.59). Sensitivity analyses that varied the criteria scores did not change the results. CONCLUSIONS: Using a structured and explicit approach, a criterion-based valuation framework was designed to provide a transparent and consistent method with which to value and prioritize cancer drugs to facilitate the delivery of affordable cancer care.

Adaptive crossover designs for assessment of symptomatic treatments targeting behaviour in neurodegenerative disease: a phase 2 clinical trial of intranasal oxytocin for frontotemporal dementia (FOXY).

BACKGROUND: There are currently no treatments for empathy deficits in neuropsychiatric disorders. Acute administration of the hormone oxytocin has been associated with symptomatic improvements across animal models and several neuropsychiatric disorders, but results of the majority of oxytocin randomised controlled trials (RCTs) of longer duration have been negative or inconclusive. This lack of efficacy of may be due to rapid habituation to oxytocin with chronic dosing. The objective of the present study is to describe the design of a phase 2 adaptive randomised controlled crossover trial of intranasal oxytocin in frontotemporal dementia (FOXY) as an efficient model for future investigations of symptomatic treatments in neuropsychiatric and neurodegenerative disorders. METHODS: Stage 1 will identify which of three dose schedules is most promising based on change in the primary outcome measure, the Neuropsychiatric Inventory apathy/indifference domain score, over 6 weeks of treatment. In stage 2, additional patients are enrolled at the most promising dose for preliminary efficacy analysis when combined with stage 1 to determine if a phase 3 trial is warranted. Objective measures include facial expression recognition, cerebrospinal fluid (CSF) oxytocin levels, and behavioural ratings of videotaped interactions. RESULTS: A total of 20 patients per arm will be entered into stage 1 for a total of 60 patients. In stage 2, an additional 40 patients will be enrolled in the most promising dose arm. CONCLUSIONS: The use of adaptive, crossover designs and inclusion of objective measures of change in CSF oxytocin levels and social behaviour will improve the efficiency and conclusiveness of RCTs of oxytocin and other symptomatic treatments in neuropsychiatric disorders. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03260920 . Registered on August 24, 2017.

RiseTx: testing the feasibility of a web application for reducing sedentary behavior among prostate cancer survivors receiving androgen deprivation therapy.

BACKGROUND: Given the high levels of sedentary time and treatment-related side effects in prostate cancer survivors (PCS), interventions targeting sedentary behavior (SED) may be more sustainable compared to physical activity (PA). PURPOSE: To examine the feasibility of a web-based intervention (RiseTx) for reducing SED and increasing moderate-to-vigorous physical activity (MVPA) among PCS undergoing ADT. Secondary outcomes include changes in SED, MVPA, light intensity PA, and quality of life. METHODS: Forty-six PCS were recruited from two cancer centres in Toronto, Ontario, Canada between July 2015-October 2016. PCS were given an activity tracker (Jawbone), access to the RiseTx website program, and provided with a goal of increasing walking by 3000 daily steps above baseline levels over a 12-week period. A range of support tools were progressively released to reduce SED time (e.g., self-monitoring of steps) during the five-phase program. Objective measures of SED, MVPA, and daily steps were compared across the 12-week intervention using linear mixed models. RESULTS: Of the 46 PCS enrolled in the study, 42 completed the SED intervention, representing a 9% attrition rate. Measurement completion rates were 97 and 65% at immediately post-intervention and 12-week follow-up for all measures, respectively. Overall adherence was 64% for total number of logins (i.e., > 3 visits each week). Sample mean age was 73.2 ± 7.3 years, mean BMI was 28.0 ± 3.0 kg/m2, mean number of months since diagnosis was 93.6 ± 71.2, and 72% had ADT administered continuously. Significant reductions of 455.4 weekly minutes of SED time were observed at post-intervention (p = .005). Significant increases of + 44.1 for weekly minutes of MVPA was observed at immediately post-intervention (p = .010). There were significant increases in step counts of + 1535 steps from baseline to post-intervention (p < .001). CONCLUSIONS: RiseTx was successful in reducing SED and increasing MVPA in PCS. PCS were satisfied with the intervention and its components. Additional strategies may be needed though for maintenance of behavior change. The next step for RiseTx is to replicate these findings in a larger, randomized controlled trial that will have the potential for reducing sedentary time among PCS. TRIAL REGISTRATION: NCT03321149 (ClinicalTrials.gov Identifier).

Diffusion-weighted imaging or computerized tomography perfusion assessment with clinical mismatch in the triage of wake up and late presenting strokes undergoing neurointervention with Trevo (DAWN) trial methods.

Rationale Efficacy of mechanical thrombectomy for acute stroke due to large vessel occlusion initiated beyond 6 h of time last seen well has not been demonstrated in randomized trials. Aim To establish whether subjects considered to have substantial areas of salvageable brain based on age-adjusted clinical core mismatch who can undergo endovascular treatment within 6-24 h from time last seen well (TLSW) have better outcomes at three months compared to subjects treated with standard medical therapy alone. Age-adjusted clinical core mismatch is defined by age (≤80 or >80 years), baseline National Institutes of Health Stroke Scale (NIHSS) (10-20 or ≥21), and core size (0-20 cm3 in subjects older than 80 and, in subjects younger than 80, 0-30 cm3 with NIHSS 10-20 and 31-50 cm3 with NIHSS ≥21). Design Prospective, randomized, multicenter, Bayesian adaptive-enrichment, open label trial with blinded endpoint assessment. For the purpose of enrolment, ischemic core size will be evaluated by CT perfusion or magnetic resonance imaging-diffusion-weighted imaging measured by automated software (RAPID). Procedures Subjects with acute ischemic stroke due to computed tomography angiography- or magnetic resonance angiogram-proven arterial occlusion of the intracranial internal carotid and/or proximal middle cerebral artery (M1) with age-adjusted clinical core mismatch in whom treatment can be initiated between 6 and 24 h from TSLW are randomized in a 1:1 ratio to receive mechanical embolectomy with the Trevo device or medical management alone. Sequential interim analyses allowing adaptation of enrolment criteria or stopping new enrolment for futility or predicted success will occur in every 50 randomized patients starting at 150 to a maximum of 500 patients. Study outcomes The primary endpoint is the modified Rankin Scale score at 90 days. The primary safety outcome is stroke-related mortality at 90 days. Analysis The primary endpoint, expressed as a utility-weighted modified Rankin Scale score is analyzed using a Bayesian posterior probability with adjustment for ischemic core size. For regulatory reasons, a nested co-primary endpoint analysis was added consisting of the proportion of subjects with modified Rankin Scale 0-2 between the active and control groups also analyzed using a Bayesian model.

Cost-Effectiveness Analysis of Different Sequences of the Use of Epidermal Growth Factor Receptor Inhibitors for Wild-Type KRAS Unresectable Metastatic Colorectal Cancer.

PURPOSE: Patients with unresectable wild-type KRAS metastatic colorectal cancer benefit from fluoropyrimidines (FP), oxaliplatin (O), irinotecan (I), bevacizumab (Bev), and epithelial growth factor receptor inhibitors (EGFRI). The most cost-effective regimen remains unclear. METHODS: A Markov model was constructed to examine the costs and outcomes of three treatment strategies: strategy A (reference strategy): EGFRI monotherapy in third line ([3L]; ie, first-line [1L]: Bev + FOLFIRI [FP + I] or FOLFOX [FP + O]; second line [2L]: FOLFIRI/FOLFOX; 3L: EGFRI); strategy B: EGFRI and I in 3L (ie, 1L: Bev + FOLFIRI/FOLFOX; 2L: FOLFIRI/FOLFOX; 3L: EGFRI + I); and strategy C: EGFRI in 1L (ie, 1L: EGFRI + FOLFIRI/FOLFOX; 2L: Bev + FOLFIRI/FOLFOX; 3L: best supportive care). Efficacy data of the treatments were obtained from the literature. Health system resource use information was derived from chart review and the literature. Using Euro-QOL 5 Dimensions, utilities were obtained by surveying medical oncologists and costs from the Ontario Ministry of Health and the literature. The perspective of the Canadian public health care system was used over a 5-year time horizon with a 5% discount in 2012 Canadian dollars. RESULTS: All three strategies had similar efficacy, but strategy C was most expensive. The incremental cost-effectiveness ratios (ICERs) for strategies B and C compared with A were 119,623 and 3,176,591, respectively. The model was primarily driven by the acquisition cost of the drugs. Strategy B was most cost effective when the willingness-to-pay threshold was > $130,000 per quality-adjusted life-year. Sensitivity analysis showed that strategy C would be cost-effective only when the progression-free survival of EGFRI is better than Bev in 1L with hazard ratio < 0.23 at willingness-to-pay of $150,000 per quality-adjusted life-year. CONCLUSION: First-line use of EGFRI in metastatic colorectal cancer is not cost effective at its current pricing relative to Bev.

Using Exclusion-Based Sample Preparation (ESP) to Reduce Viral Load Assay Cost.

Viral load (VL) measurements are critical to the proper management of HIV in developing countries. However, access to VL assays is limited by the high cost and complexity of existing assays. While there is a need for low cost VL assays, performance must not be compromised. Thus, new assays must be validated on metrics of limit of detection (LOD), accuracy, and dynamic range. Patient plasma samples from the Joint Clinical Research Centre in Uganda were de-identified and measured using both an existing VL assay (Abbott RealTime HIV-1) and our assay, which combines low cost reagents with a simplified method of RNA isolation termed Exclusion-Based Sample Preparation (ESP).71 patient samples with VLs ranging from <40 to >3,000,000 copies/mL were used to compare the two methods. We demonstrated equivalent LOD (~50 copies/mL) and high accuracy (average difference between methods of 0.08 log, R2 = 0.97). Using expenditures from this trial, we estimate that the cost of the reagents and consumables for this assay to be approximately $5 USD. As cost is a significant barrier to implementation of VL testing, we anticipate that our assay will enhance access to this critical monitoring test in developing countries.

The use of EGFR inhibitors in colorectal cancer: is it clinically efficacious and cost-effective?

Cetuximab (Erbitux) and panitumumab (Vectibix) are monoclonal antibodies to the EGFR. They are used as monotherapy or in combination with cytotoxic chemotherapy and increase both progression-free survival and overall survival in patients with wild-type RAS metastatic colorectal cancer. The most common side effects of therapy are dermatological, including skin (acneiform) rash, pruritus and hair changes. Despite their clinical activity, cost-effectiveness of the two drugs should be addressed in a discussion of their usage in everyday care. This study provides an up-to-date review of the clinical efficacy and cost-effectiveness of anti-EGFR inhibitors.

A Combined Fabrication and Instrumentation Platform for Sample Preparation.

While potentially powerful, access to molecular diagnostics is substantially limited in the developing world. Here we present an approach to reduced cost molecular diagnostic instrumentation that has the potential to empower developing world communities by reducing costs through streamlining the sample preparation process. In addition, this instrument is capable of producing its own consumable devices on demand, reducing reliance on assay suppliers. Furthermore, this instrument is designed with an "open" architecture, allowing users to visually observe the assay process and make modifications as necessary (as opposed to traditional "black box" systems). This open environment enables integration of microfluidic fabrication and viral RNA purification onto an easy-to-use modular system via the use of interchangeable trays. Here we employ this system to develop a protocol to fabricate microfluidic devices and then use these devices to isolate viral RNA from serum for the measurement of human immunodeficiency virus (HIV) viral load. Results obtained from this method show significantly reduced error compared with similar nonautomated sample preparation processes.

Exclusion-Based Capture and Enumeration of CD4+ T Cells from Whole Blood for Low-Resource Settings.

In developing countries, demand exists for a cost-effective method to evaluate human immunodeficiency virus patients' CD4(+) T-helper cell count. The TH (CD4) cell count is the current marker used to identify when an HIV patient has progressed to acquired immunodeficiency syndrome, which results when the immune system can no longer prevent certain opportunistic infections. A system to perform TH count that obviates the use of costly flow cytometry will enable physicians to more closely follow patients' disease progression and response to therapy in areas where such advanced equipment is unavailable. Our system of two serially-operated immiscible phase exclusion-based cell isolations coupled with a rapid fluorescent readout enables exclusion-based isolation and accurate counting of T-helper cells at lower cost and from a smaller volume of blood than previous methods. TH cell isolation via immiscible filtration assisted by surface tension (IFAST) compares well against the established Dynal T4 Quant Kit and is sensitive at CD4 counts representative of immunocompromised patients (less than 200 TH cells per microliter of blood). Our technique retains use of open, simple-to-operate devices that enable IFAST as a high-throughput, automatable sample preparation method, improving throughput over previous low-resource methods.

Estimating the Long-Term Clinical and Economic Outcomes of Daclatasvir Plus Asunaprevir in Difficult-to-Treat Japanese Patients Chronically Infected with Hepatitis C Genotype 1b.

OBJECTIVES: Japan has one of the highest endemic rates of hepatitis C virus (HCV) infection. Treatments in Japan are currently limited to interferon-alfa-based regimens, which are associated with tolerability and efficacy issues. A novel regimen combining two oral HCV therapies, daclatasvir and asunaprevir (DCV + ASV), has shown favorable results in Japanese patients with chronic genotype 1b HCV infection. Comparisons of clinical and economic outcomes associated with DCV + ASV treatment and current standards of care were investigated. METHODS: The MOdelling the NAtural histoRy and Cost-effectiveness of Hepatitis cost-effectiveness model projected outcomes in 1000 patients aged 70 years with either chronic hepatitis C or compensated cirrhosis over a lifetime simulation. Japanese-specific disease transition rates were used, and discounting was applied annually at a rate of 2%. Efficacy data for DCV + ASV and telaprevir triple therapy (telaprevir + pegylated interferon-alfa + ribavirin [TVR + pegIFN-α/RBV]) were obtained from a Japanese subgroup analysis found within a global meta-analysis: sustained virological response rates of 74%, 85%, and 87% were reported for null responders (NRs), partial responders (PRs), and interferon-alfa-ineligible/intolerant patients, respectively, treated with DCV + ASV, and rates of 42% and 59% were reported for NRs and PRs, respectively, treated with TVR + pegIFN-α/RBV. RESULTS: Initiating DCV + ASV treatment in patients in the chronic hepatitis C disease stage resulted in quality-adjusted life-year gains of 0.96 and 0.77 over TVR + pegIFN-α/RBV for NRs and PRs, respectively, and a gain of 2.61 in interferon-alfa-ineligible/intolerant patients over no treatment. Similarly, quality-adjusted life-year gains of 1.11, 0.90, and 3.05 were observed when initiating treatment in patients in the compensated cirrhosis stage. Cumulative lifetime events of decompensated cirrhosis, hepatocellular carcinoma, and liver-related mortality were reduced by up to 66, 115, and 128, respectively, with DCV + ASV treatment. CONCLUSIONS: There is a lack of successful therapies for patients with HCV who have previously failed to achieve sustained virological response or are ineligible for interferon-alfa-based therapies. Results demonstrate that the provision of an alternative, interferon-alfa-free regimen, such as DCV + ASV, offers significant value in terms of avoiding life-threatening liver complications and increasing patients' quality of life.

An adaptive, phase II, dose-finding clinical trial design to evaluate L-carnitine in the treatment of septic shock based on efficacy and predictive probability of subsequent phase III success.

OBJECTIVES: Sepsis is the tenth leading cause of death in the United States. Despite extensive research, mortality rates for sepsis have not substantially improved in the last several decades. We describe an innovative phase II clinical trial design for evaluating the addition of L-carnitine to the treatment of vasopressor-dependent septic shock. DESIGN: The design incorporates a variety of features to increase efficiency, including a normal dynamic linear dose-response model, adaptive randomization, and early stopping for futility or success based on the probability that a future phase III trial using a 28-day mortality outcome would be successful. SETTING: Trial design and computer simulation of a trial to be conducted in the emergency department and ICU. INTERVENTIONS: Proposed to study intravenous L-carnitine. MEASUREMENTS: The proposed trial uses an early endpoint, the 48-hour change in Sequential Organ Failure Assessment score, to drive adaptive randomization and dose selection. MAIN RESULTS: We use existing data to model the expected relationship between the Sequential Organ Failure Assessment change and the 28-day mortality to determine the trial's operating characteristics using Monte Carlo simulation. CONCLUSIONS: The resulting trial efficiently identifies the best dose of L-carnitine and provides clear guidance regarding whether to continue development into phase III.

In a survey, marked inconsistency in how oncologists judged value of high-cost cancer drugs in relation to gains in survival.

Amid calls for physicians to become better stewards of the nation's health care resources, it is important to gain insight into how physicians think about the cost-effectiveness of new treatments. Expensive new cancer treatments that can extend life raise questions about whether physicians are prepared to make "value for money" trade-offs when treating patients. We asked oncologists in the United States and Canada how much benefit, in additional months of life expectancy, a new drug would need to provide to justify its cost and warrant its use in an individual patient. The majority of oncologists agreed that a new cancer treatment that might add a year to a patient's life would be worthwhile if the cost was less than $100,000. But when given a hypothetical case of an individual patient to review, the oncologists also endorsed a hypothetical drug whose cost might be as high as $250,000 per life-year gained. The results show that oncologists are not consistent in deciding how many months an expensive new therapy should extend a person's life before the cost of therapy is justified. Moreover, the benefit that oncologists demand from new treatments in terms of length of survival does not necessarily increase according to the price of the treatment. The findings suggest that policy makers should find ways to improve how physicians are educated on the use of cost-effectiveness information and to influence physician decision making through clinical guidelines that incorporate cost-effectiveness information.

Addressing the incremental benefit of histamine dihydrochloride when added to interleukin-2 in treating acute myeloid leukemia: a Bayesian meta-analysis.

IL-2 has been investigated as maintenance therapy for patients with AML in five randomized trials. None has shown a statistically significant benefit. A randomized trial of HDC + IL-2 showed a statistically significant benefit for leukemia-free survival (LFS) in comparison with standard of care. Because HDC + IL-2 has not been randomized against IL-2 alone, the question remains as to whether and to what extent HDC + IL-2 is an improvement compared to IL-2 alone. This is a literature-based meta-analysis. We employ two versions of a Bayesian hierarchical model to compare HDC + IL-2 versus IL-2 alone on the basis of LFS in patients in remission from AML.

Continental Divide? The attitudes of US and Canadian oncologists on the costs, cost-effectiveness, and health policies associated with new cancer drugs.

PURPOSE: Oncologists in the United States and Canada work in different health care systems, but physicians in both countries face challenges posed by the rising costs of cancer drugs. We compared their attitudes regarding the costs and cost-effectiveness of medications and related health policy. METHODS: Survey responses of a random sample of 1,355 United States and 238 Canadian medical oncologists (all outside of Québec) were compared. RESULTS: Response rate was 59%. More US oncologists (67% v 52%; P < .001) favor access to effective treatments regardless of cost, while more Canadians favor access to effective treatments only if they are cost-effective (75% v 58%; P < .001). Most (84% US, 80% Canadian) oncologists state that patient out-of-pocket costs influence their treatment recommendations, but less than half the respondents always or frequently discuss the costs of treatments with their patients. The majority of oncologists favor more use of cost-effectiveness data in coverage decisions (80% US, 69% Canadian; P = .004), but fewer than half the oncologists in both countries feel well equipped to use cost-effectiveness information. Majorities of oncologists favor government price controls (57% US, 68% Canadian; P = .01), but less than half favor more cost-sharing by patients (29% US, 41% Canadian; P = .004). Oncologists in both countries prefer to have physicians and nonprofit agencies determine whether drugs provide good value. CONCLUSION: Oncologists in the United States and Canada generally have similar attitudes regarding cancer drug costs, cost-effectiveness, and associated policies, despite practicing in different health care systems. The results support providing education to help oncologists in both countries use cost-effectiveness information and discuss drug costs with their patients.

Bayesian meta-analyses for comparative effectiveness and informing coverage decisions.

BACKGROUND: Evidence-based medicine is increasingly expected in health care decision-making. The Centers for Medicare and Medicaid have initiated efforts to understand the applicability of Bayesian techniques for synthesizing evidence. As a case study, a Bayesian analysis of clinical trials of implantable cardioverter defibrillators was undertaken using patient-level data not typically available for analysis. PURPOSE: Conduct Bayesian meta-analyses of the defibrillator trials using published results to demonstrate a Bayesian approach useful to policy makers. DATA SOURCES, STUDY SELECTION, DATA EXTRACTION: We reconsidered trials in a 2007 systematic review by Ezekowitz et al (Ann Intern Med. 2007;147:251-262) and extracted information from the original published articles. Employing a Bayesian hierarchical approach, we developed a base model and 2 variants, and modeled hazard ratios separately within each year of follow-up. We considered sequential meta-analyses over time and found the predictive distribution of the results of the next trial, given its sample size. DATA SYNTHESIS: For the most robust of 3 models, the probability that the mean defibrillator effect (in the population of trials) is beneficial is greater than 0.999. In that model, about 5% of trials in the population of trials would have a detrimental effect. Despite the moderate amount of heterogeneity across the trials, there was stability of conclusions after the first 3 of the 12 total trials had been conducted. This stability enabled reasonable predictions for the results of future trials. LIMITATIONS: Inability to assess treatment effects within subsets of patients. CONCLUSIONS: Bayesian meta-analyses based on literature surveys can effectively inform coverage decisions. Bayesian modeling for endpoints such as mortality can elucidate treatment effects over time. The Bayesian approach used in a sequential manner over time can predict results and help assess the utility of future clinical trials.