Health Technology Reassessment: Addressing Uncertainty in Economic Evaluations of Oncology Drugs at Time of Reimbursement Using Long-Term Clinical Trial Data.

The evidence base to support reimbursement decision making for oncology drugs is often based on short-term follow-up trial data, and attempts to address this uncertainty are not typically undertaken once a reimbursement decision is made. To address this gap, we sought to conduct a reassessment of an oncology drug (pembrolizumab) for patients with advanced melanoma which was approved based on interim data with a median 7.9 months of follow-up and for which long-term data have since been published. We developed a three-health-state partitioned survival model based on the phase 3 KEYNOTE-006 clinical trial data using patient-level data reconstruction techniques based on an interim analysis. We used a standard survival analysis and parametric curve fitting techniques to extrapolate beyond the trial follow-up time, and the model structure and inputs were derived from the literature. Five-year long-term follow-up data from the trial were then used to re-evaluate the cost-effectiveness of pembrolizumab versus ipilimumab for treatment of advanced melanoma. The best fitting parametric curves and corresponding survival extrapolations for reconstructed interim data and long-term data reconstructed from KEYNOTE-006 were different. An analysis of the 5 year long-term follow-up data generated a base case incremental cost-effectiveness ratio (ICER) that was 28% higher than the ICER based on interim trial data. Our findings suggest that there may be a trade-off between certainty and the ICER. Conducting health technology re-assessments of certain oncology products on the basis of longer-term data availability, especially for those health technology adoption decisions made based on immature clinical data, may be of value to decision makers.

Appraisals by Health Technology Assessment Agencies of Economic Evaluations Submitted as Part of Reimbursement Dossiers for Oncology Treatments: Evidence from Canada, the UK, and Australia.

Publicly funded healthcare systems, including those in Canada, the United Kingdom (UK), and Australia, often use health technology assessment (HTA) to inform drug reimbursement decision-making, based on dossiers submitted by manufacturers, and HTA agencies issue publicly available reports to support funding recommendations. However, the level of information reported by HTA agencies in these reports may vary. To provide insights on this issue, we describe and assess the reporting of economic methods in recent oncology HTA recommendations from the Canadian Agency for Drugs and Technologies in Health (CADTH), National Institute for Health and Care Excellence (NICE), and Pharmaceutical Benefits Advisory Committee (PBAC). Publicly available HTA recommendations and reports for oncology drugs issued by CADTH over a 2-year period, 2019-2020, were identified and compared with the corresponding HTA documents from NICE and the PBAC. Reporting of key model characteristics and attributes, survival analysis methods, methodological criticisms, and re-assessment of the economic results were characterized using descriptive statistics. Dichotomous differences in the methodological criticisms observed between the three agencies were assessed using Cochran's Q tests and substantiated using pairwise McNemar tests. Chi-squared tests were used to assess the dichotomous differences in the reporting of methods and explore the potential relationships between categorical variables, where appropriate. HTAs published by CADTH, NICE, and the PBAC consistently reported a broad spectrum of descriptive information on the economic models submitted by manufacturers. While common economic evaluation attributes were well-reported across the three HTA agencies, significant differences in the reporting of survival analysis methods and methodological criticisms were observed. NICE consistently reported more comprehensive information, compared to either CADTH or PBAC. Despite these differences, broadly similar recommendation rates were observed between CADTH and NICE. The PBAC was found to be more restrictive. Based on our 2-year sample of oncology, the HTAs published by CADTH matched with the corresponding HTAs from NICE and PBAC; we observed important variations in the reporting of economic evidence, especially technical aspects, such as survival analysis, across the three agencies. In addition to guidelines for HTA submissions by manufacturers, the community of HTA agencies should also have common standards for reporting the results of their assessments, though the information and opinions reported may differ.

Health programmes and services addressing the prevention and management of infectious diseases in people who inject drugs in Canada: a systematic integrative review.

OBJECTIVES: People who inject drugs (PWID) experience a high burden of injection drug use-related infectious disease and challenges in accessing adequate care. This study sought to identify programmes and services in Canada addressing the prevention and management of infectious disease in PWID. DESIGN: This study employed a systematic integrative review methodology. Electronic databases (PubMed, CINAHL and Web of Science Core Collection) and relevant websites were searched for literature published between 2008 and 2019 (last search date was 6 June 2019). Eligible articles and documents were required to address injection or intravenous drug use and health programmes or services relating to the prevention or management of infectious diseases in Canada. RESULTS: This study identified 1607 unique articles and 97 were included in this study. The health programmes and services identified included testing and management of HIV and hepatitis C virus (n=27), supervised injection facilities (n=19), medication treatment for opioid use disorder (n=12), integrated infectious disease and addiction programmes (n=10), needle exchange programmes (n=9), harm reduction strategies broadly (n=6), mobile care initiatives (n=5), peer-delivered services (n=3), management of IDU-related bacterial infections (n=2) and others (n=4). Key implications for policy, practice and future research were identified based on the results of the included studies, which include addressing individual and systemic factors that impede care, furthering evaluation of programmes and the need to provide comprehensive care to PWID, involving medical care, social support and harm reduction. CONCLUSIONS: These results demonstrate the need for expanded services across a variety of settings and populations. Our study emphasises the importance of addressing social and structural factors that impede infectious disease care for PWID. Further research is needed to improve evaluation of health programmes and services and contextual factors surrounding accessing services or returning to care. PROSPERO REGISTRATION NUMBER: CRD42020142947.

The number needed to treat for net effect (NNTnet) as a metric for measuring combined benefits and harms.

Calculating the number needed to treat (NNT) has been widely used to help understand treatment effect results of randomized controlled trials (RCTs). Combined benefit and harm profiles from RCT results have to be taken into account to maximize benefits and minimize harms. Unfortunately, in the biomedical community, there is no easy and acceptable way to incorporate both benefit and harm information of treatments in a single summary statistic similar to an NNT. In this study, we propose a new metric, the "NNT for net effect" or NNTnet to present the combined benefit and harm effects of an intervention or therapy based on NNT-type information with the intention that it will advance decision-making for health professionals, researchers, and resource managers in real-world practice. Examples are provided to illustrate the calculation and application of the NNTnet in practice. An NNTnet is specifically applicable to the physicians and resource managers who interpret the data published in the literature to help with their decision-making and the researchers who present the trial data to the audiences in their studies and presentations, all of whom used to use NNT information to show and interpret beneficial and harmful effects separately.

Realigning the conventional routes of transmission: an improved model for occupational exposure assessment and infection prevention.

Current recommendations for standard and transmission-based precautions in place for patients who are suspected or known to be infected or colonized with infectious agents are best suited to prevent the transfer of micro-organisms to other patients - that is, to prevent the acquisition of a healthcare-associated infection, rather than to protect the healthcare worker from self-contamination resulting in a potential occupationally acquired infection. This article reviews current recommended infection prevention and control practices and offers a framework for better protection and controls from an occupational health point of view. We offer a model with two exposure routes - contact and aerosol - resulting from work activities and environments, shifting the focus away from particular pathogenic micro-organisms' typical methods for spreading to patients or to other non-workers in hospital and community settings.

Multiple uses of forest plots in presenting analysis results in health research: A Tutorial.

BACKGROUND AND OBJECTIVES: Forest plots are an important graphical method in meta-analyses used to show results from individual studies and pooled analyses. Forest plots are easy and straightforward to understand because they provide tabular and graphical information about estimates of comparisons or associations, corresponding precision, and statistical significance. This visual representation also makes it easier to see variations between individual study results. Forest plots are widely used in not only systematic reviews and meta-analyses but also observational studies and clinical trials. In this study, we aimed to show readers the various uses of forest plots in displaying analysis results. STUDY DESIGN AND SETTING: We used a tutorial type to show multiple uses of forest plots in meta-analyses, clinical trials, and observational studies according to the PICO (Population or Subgroup, Intervention or Exposure, Control, and Outcome) framework. RESULTS: We introduced forest plots' structure, application, current practice, and research advances in health research. We provided some examples from the literature to show the various uses of forest plot-type graphics in health research including meta-analyses, clinical trials, and observational studies. CONCLUSION: It is expected that our discussion of the current multiple uses of forest plots in meta-analyses, clinical trials, and observational studies provides a glimpse about their potential in displaying results in a way that makes comparisons between items easier.

Direct comparative effectiveness and safety between non-vitamin K antagonist oral anticoagulants for stroke prevention in nonvalvular atrial fibrillation: a systematic review and meta-analysis of observational studies.

The non-vitamin K antagonist oral anticoagulants (NOACs) have been increasingly prescribed in clinical practice for stroke prevention in patients with nonvalvular atrial fibrillation (AF). Direct comparisons between NOACs in trials are lacking, leaving an important clinical decision-making gap. We aimed to perform a systematic review and meta-analysis to summarize the evidence of observational studies for direct comparative effectiveness and safety amongst NOACs in patients with AF. Conference proceedings and electronic databases including MEDLINE, CINAHL, EMBASE and PUBMED were systematically searched. We included observational studies directly comparing individual NOACs in patients with nonvalvular AF who were aged ≥ 18 years for stroke prevention. Primary outcome included effectiveness outcome (stroke or systemic embolism) and safety outcome (major bleeding). Data were extracted in duplicated by two reviewers independently. A random-effects meta-analysis was conducted to synthesize the data from included observational studies. We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) to rate the overall quality of evidence for each outcome. Fifteen studies were included for qualitative synthesis, twelve studies for meta-analyses. It was found that rivaroxaban and dabigatran were similar with regard to risk of stroke or systemic embolism (Hazard ratio [HR] = 1.00, 95% CI 0.91-1.10; evidence quality: low), but rivaroxaban was associated with higher risk of major bleeding (HR = 1.39, 95% CI 1.28-1.50; evidence quality: moderate). Compared with apixaban, a significantly higher risk of major bleeding was observed with rivaroxaban (HR = 1.71, 95% CI 1.51-1.94; evidence quality: low). Apixaban was associated with lower risk of major bleeding, in comparison with dabigatran (HR = 0.80, 95% CI 0.68-0.95; evidence quality: low). No differences in risk of stroke or systemic embolism was observed between rivaroxaban versus apixaban, and apixaban versus dabigatran. In this study, apixaban was found to have the most favorable safety profile amongst the three NOACs. No significant difference was observed in risk of stroke or systemic embolism between the NOACs. Such findings may provide some decision-making support for physicians regarding their choices amongst NOACs in patients with AF.Registration PROSPERO (identifier: CRD42016052908).

Minimally important difference and predictors of change in quality of life in type 2 diabetes: A community-based survey in China.

BACKGROUND: To identify the minimally important difference (MID) of the EQ-5D-3L and determinants of change in quality of life (QoL) as measured by the EQ-5D-3L over 1 year for Chinese type 2 diabetic patients (T2DPs). METHODS: Clinically diagnosed T2DPs were recruited from 66 community health centres in five Chinese cities using a multistage quota sampling method between December 2010 and October 2011. Demographics, diabetes-related information, and health-related behaviours were collected at baseline. The EQ-5D-3L was administered at baseline and at 12 months. Anchor-based and distribution-based approaches were employed to estimate MIDs. Using the MIDs as cut-points, we identified the change in EQ-5D-3L-measured QoL into "worsening," "no change," and "bettering." Logistic and ordered logistic regressions were conducted for those who reported best possible EQ-5D health state ("best possible HS") and impaired EQ-5D health states ("impaired HS") at baseline, respectively. Explanatory variables included demographics, diabetes-related information, and health-related behaviours. RESULTS: A total of 1958 patients (54.9% female, mean age 61.2 years, mean diabetes duration 7.9 years) were included in our analysis. MIDs of the EQ-5D-3L for deterioration and improvement were estimated as -0.066 to -0.003, and 0.049 to 0.077, respectively. For the impaired HS group, older age, lower education, and less exercise were significant predictors for worsening in QoL; whereas, those predictors were older age, female gender, and lower income for the best possible HS group. CONCLUSIONS: Minimally important differences for deterioration and improvement were estimated for the EQ-5D-3L. Age, gender, education, income, and exercise were significant determinants of QoL change for Chinese T2DPs.

Item reduction and validation of the Chinese version of diabetes quality-of-life measure (DQOL).

BACKGROUND: The Diabetes Quality-of-Life (DQOL) Measure is a 46-item diabetes-specific quality of life instrument. The original English version of the DQOL has been translated into Chinese after cultural adaption, and the Chinese DQOL has been validated in the Chinese diabetic patient population and used in diabetes-related studies. There are two recognized problems with the Chinese DQOL: 1) the instrument is too long, and 2) the non-response rate of certain items is relatively high. This study aimed to develop and validate a short version for the Chinese DQOL. METHODS: Item reduction was conducted based on the classical test theory (CTT) and item response theory (IRT), each combined with exploratory factor analysis (EFA). The confirmatory factor analysis (CFA) and Spearman correlation coefficient were employed in validating the short versions. RESULTS: Both the study sample (n = 2,886) and the validation sample (n = 2,286) were from a longitudinal observation study of Chinese type 2 diabetic patients. The CTT kept 32 items, and the IRT kept 24 items from the original 46-item version. The two short versions were comparable in psychometric properties. CONCLUSION: The 24-item IRT-based short version of the Chinese DQOL was selected as the preferred short version because it imposes a lower burden on patients without compromising the psychometric properties of the instrument.

A systematic review of comparisons between protocols or registrations and full reports in primary biomedical research.

BACKGROUND: Prospective study protocols and registrations can play a significant role in reducing incomplete or selective reporting of primary biomedical research, because they are pre-specified blueprints which are available for the evaluation of, and comparison with, full reports. However, inconsistencies between protocols or registrations and full reports have been frequently documented. In this systematic review, which forms part of our series on the state of reporting of primary biomedical, we aimed to survey the existing evidence of inconsistencies between protocols or registrations (i.e., what was planned to be done and/or what was actually done) and full reports (i.e., what was reported in the literature); this was based on findings from systematic reviews and surveys in the literature. METHODS: Electronic databases, including CINAHL, MEDLINE, Web of Science, and EMBASE, were searched to identify eligible surveys and systematic reviews. Our primary outcome was the level of inconsistency (expressed as a percentage, with higher percentages indicating greater inconsistency) between protocols or registration and full reports. We summarized the findings from the included systematic reviews and surveys qualitatively. RESULTS: There were 37 studies (33 surveys and 4 systematic reviews) included in our analyses. Most studies (n = 36) compared protocols or registrations with full reports in clinical trials, while a single survey focused on primary studies of clinical trials and observational research. High inconsistency levels were found in outcome reporting (ranging from 14% to 100%), subgroup reporting (from 12% to 100%), statistical analyses (from 9% to 47%), and other measure comparisons. Some factors, such as outcomes with significant results, sponsorship, type of outcome and disease speciality were reported to be significantly related to inconsistent reporting. CONCLUSIONS: We found that inconsistent reporting between protocols or registrations and full reports of primary biomedical research is frequent, prevalent and suboptimal. We also identified methodological issues such as the need for consensus on measuring inconsistency across sources for trial reports, and more studies evaluating transparency and reproducibility in reporting all aspects of study design and analysis. A joint effort involving authors, journals, sponsors, regulators and research ethics committees is required to solve this problem.

A scoping review of comparisons between abstracts and full reports in primary biomedical research.

BACKGROUND: Evidence shows that research abstracts are commonly inconsistent with their corresponding full reports, and may mislead readers. In this scoping review, which is part of our series on the state of reporting of primary biomedical research, we summarized the evidence from systematic reviews and surveys, to investigate the current state of inconsistent abstract reporting, and to evaluate factors associated with improved reporting by comparing abstracts and their full reports. METHODS: We searched EMBASE, Web of Science, MEDLINE, and CINAHL from January 1st 1996 to September 30th 2016 to retrieve eligible systematic reviews and surveys. Our primary outcome was the level of inconsistency between abstracts and corresponding full reports, which was expressed as a percentage (with a lower percentage indicating better reporting) or categorized rating (such as major/minor difference, high/medium/low inconsistency), as reported by the authors. We used medians and interquartile ranges to describe the level of inconsistency across studies. No quantitative syntheses were conducted. Data from the included systematic reviews or surveys was summarized qualitatively. RESULTS: Seventeen studies that addressed this topic were included. The level of inconsistency was reported to have a median of 39% (interquartile range: 14% - 54%), and to range from 4% to 78%. In some studies that separated major from minor inconsistency, the level of major inconsistency ranged from 5% to 45% (median: 19%, interquartile range: 7% - 31%), which included discrepancies in specifying the study design or sample size, designating a primary outcome measure, presenting main results, and drawing a conclusion. A longer time interval between conference abstracts and the publication of full reports was found to be the only factor which was marginally or significantly associated with increased likelihood of reporting inconsistencies. CONCLUSIONS: This scoping review revealed that abstracts are frequently inconsistent with full reports, and efforts are needed to improve the consistency of abstract reporting in the primary biomedical community.

Relationship between hyperbaric oxygen therapy and quality of life in participants with chronic diabetic foot ulcers: data from a randomized controlled trial.

AIMS: To investigate the effect of hyperbaric oxygen therapy on health-related quality of life (HRQoL) in participants with diabetes and chronic foot ulcers. METHODS: Using data from a randomized controlled trial, we included 103 participants (49 in hyperbaric oxygen therapy group and 54 in sham group) for analyses. The primary outcome was HRQoL as measured by the EQ-5D-3L instrument, while secondary outcomes included quality of life evaluated by the Short Form 36 (SF-36) and Diabetic Foot Ulcers Scale-Short Form (DFS-SF). We used the analysis of covariance to assess whether the EQ-5D index values in hyperbaric oxygen therapy group differed from the sham group. Logistic regression was used to assess the relationship between hyperbaric oxygen therapy and the responses of 'problems' for the EQ-5D health states. RESULTS: No significant differences in EQ-5D index values were found between the hyperbaric oxygen therapy and sham groups: 0.01 (95% CI -0.25, 0.28; p = 0.93) at week 12; 0.07 (95% CI -0.21, 0.34; p = 0.64) at week 6. Hyperbaric oxygen therapy was found to be associated with fewer participants reporting 'problems' in mobility (OR 0.24, 95% CI 0.07, 0.85 at week 12) and pain or discomfort (OR 0.20, 95% CI 0.07, 0.61 at week 6; OR 0.32, 95% CI 0.11, 0.97 at week 12), compared with the sham group. No significant differences in SF-36 or DFS-SF were observed. CONCLUSIONS: No significant effect of hyperbaric oxygen therapy on HRQoL measured by EQ-5D index value was found in this study. Due to the potential insufficient power to assess statistical difference, more large-scale research is needed to further evaluate the effect of hyperbaric oxygen therapy on HRQoL in participants with chronic diabetic foot ulcers.

State of reporting of primary biomedical research: a scoping review protocol.

INTRODUCTION: Incomplete or inconsistent reporting remains a major concern in the biomedical literature. Incomplete or inconsistent reporting may yield the published findings unreliable, irreproducible or sometimes misleading. In this study based on evidence from systematic reviews and surveys that have evaluated the reporting issues in primary biomedical studies, we aim to conduct a scoping review with focuses on (1) the state-of-the-art extent of adherence to the emerging reporting guidelines in primary biomedical research, (2) the inconsistency between protocols or registrations and full reports and (3) the disagreement between abstracts and full-text articles. METHODS AND ANALYSES: We will use a comprehensive search strategy to retrieve all available and eligible systematic reviews and surveys in the literature. We will search the following electronic databases: Web of Science, Excerpta Medica Database (EMBASE), MEDLINE and Cumulative Index to Nursing and Allied Health Literature (CINAHL). Our outcomes are levels of adherence to reporting guidelines, levels of consistency between protocols or registrations and full reports and the agreement between abstracts and full reports, all of which will be expressed as percentages, quality scores or categorised rating (such as high, medium and low). No pooled analyses will be performed quantitatively given the heterogeneity of the included systematic reviews and surveys. Likewise, factors associated with improved completeness and consistency of reporting will be summarised qualitatively. The quality of the included systematic reviews will be evaluated using AMSTAR (a measurement tool to assess systematic reviews). ETHICS AND DISSEMINATION: All findings will be published in peer-reviewed journals and relevant conferences. These results may advance our understanding of the extent of incomplete and inconsistent reporting, factors related to improved completeness and consistency of reporting and potential recommendations for various stakeholders in the biomedical community.

Comparing non-safety with safety device sharps injury incidence data from two different occupational surveillance systems.

The United States Occupational Safety and Health Administration (OSHA) Bloodborne Pathogens Standard as amended by the Needlestick Safety and Prevention Act requiring the use of safety-engineered medical devices to prevent needlesticks and sharps injuries has been in place since 2001. Injury changes over time include differences between those from non-safety compared with safety-engineered medical devices. This research compares two US occupational incident surveillance systems to determine whether these data can be generalized to other facilities and other countries either with legislation in place or considering developing national policies for the prevention of sharps injuries among healthcare personnel.

A Practical Methodology for Disaggregating the Drivers of Drug Costs Using Administrative Data.

BACKGROUND: Prescription drug expenditures represent a significant component of health care costs in Canada, with estimates of $28.8 billion spent in 2014. Identifying the major cost drivers and the effect they have on prescription drug expenditures allows policy makers and researchers to interpret current cost pressures and anticipate future expenditure levels. OBJECTIVES: To identify the major drivers of prescription drug costs and to develop a methodology to disaggregate the impact of each of the individual drivers. METHODS: The methodology proposed in this study uses the Laspeyres approach for cost decomposition. This approach isolates the effect of the change in a specific factor (e.g., price) by holding the other factor(s) (e.g., quantity) constant at the base-period value. The Laspeyres approach is expanded to a multi-factorial framework to isolate and quantify several factors that drive prescription drug cost. Three broad categories of effects are considered: volume, price and drug-mix effects. For each category, important sub-effects are quantified. RESULTS: This study presents a new and comprehensive methodology for decomposing the change in prescription drug costs over time including step-by-step demonstrations of how the formulas were derived. CONCLUSIONS: This methodology has practical applications for health policy decision makers and can aid researchers in conducting cost driver analyses. The methodology can be adjusted depending on the purpose and analytical depth of the research and data availability.

Modifying the Phenotypic Frailty Model in Predicting Risk of Major Osteoporotic Fracture in the Elderly.

INTRODUCTION: The phenotypic frailty (PF) model (including slow walking, low physical activity, exhaustion, weakness, and unintentional weight loss) has been widely used to quantify the degree of frailty and predict risks of adverse health outcomes for the elderly. However, evidence has shown that not all the components included in the PF model contribute equally, and low predictive accuracy of the PF model has been reported in predicting risks of outcomes. We aimed to improve predictive accuracy of the PF model in risk of major osteoporotic fracture (MOF) in the elderly by modifying its weighting of individual components. METHODS: Data from the Global Longitudinal Study of Osteoporosis in Women (GLOW) 3-year Hamilton cohort were used for this study. We used the multivariable Cox regression model to identify the updated weighting for components in the original PF model. The goodness of fit and discrimination were assessed for model performances. RESULTS: There were 3985 women included for analyses (mean age: 69.4 years). In the modified PF model, the updated weighting was 3 points for slowness and weakness, 2 points for weight loss, 1 point for poor endurance and exhaustion, and 1 point for low physical activity, respectively. The modified PF model could capture and categorize the future risk of MOF more accurately than the original model. Significant relationship between risks of MOF, falls, and death and the modified PF model was found. Compared with the original model, the modified PF model was a better fit to the data and with improved predictive accuracy. CONCLUSION: Based on a simple and practical rescoring and recategorizing algorithm, the modified PF model could predict risks of adverse outcomes more accurately than the original model, reflecting a cost-effective way. More evidence is needed to validate the modified PF model and support its application in geriatric practice.

An overview of osteoporosis and frailty in the elderly.

Osteoporosis and osteoporotic fractures remain significant public health challenges worldwide. Recently the concept of frailty in relation to osteoporosis in the elderly has been increasingly accepted, with emerging studies measuring frailty as a predictor of osteoporotic fractures. In this overview, we reviewed the relationship between frailty and osteoporosis, described the approaches to measuring the grades of frailty, and presented current studies and future research directions investigating osteoporosis and frailty in the elderly. It is concluded that measuring the grades of frailty in the elderly could assist in the assessment, management and decision-making for osteoporosis and osteoporotic fractures at a clinical research level and at a health care policy level.