Estimating the true effectiveness of smoking cessation interventions under variable comparator conditions: A systematic review and meta-regression.

BACKGROUND AND AIMS: Behavioural smoking cessation trials have used comparators that vary considerably between trials. Although some previous meta-analyses made attempts to account for variability in comparators, these relied on subsets of trials and incomplete data on comparators. This study aimed to estimate the relative effectiveness of (individual) smoking cessation interventions while accounting for variability in comparators using comprehensive data on experimental and comparator interventions. METHODS: A systematic review and meta-regression was conducted including 172 randomised controlled trials with at least 6 months follow-up and biochemically verified smoking cessation. Authors were contacted to obtain unpublished information. This information was coded in terms of active content and attributes of the study population and methods. Meta-regression was used to create a model predicting smoking cessation outcomes. This model was used to re-estimate intervention effects, as if all interventions have been evaluated against the same comparators. Outcome measures included log odds of smoking cessation for the meta-regression models and smoking cessation differences and ratios to compare relative effectiveness. RESULTS: The meta-regression model predicted smoking cessation rates well (pseudo R2 = 0.44). Standardising the comparator had substantial impact on conclusions regarding the (relative) effectiveness of trials and types of intervention. Compared with a 'no support comparator', self-help was 1.33 times (95% CI = 1.16-1.49), brief physician advice 1.61 times (95% CI = 1.31-1.90), nurse individual counselling 1.76 times (95% CI = 1.62-1.90), psychologist individual counselling 2.04 times (95% CI = 1.95-2.15) and group psychologist interventions 2.06 times (95% CI = 1.92-2.20) more effective. Notably, more elaborate experimental interventions (e.g. psychologist counselling) were typically compared with more elaborate comparators, masking their effectiveness. CONCLUSIONS: Comparator variability and underreporting of comparators obscures the interpretation, comparison and generalisability of behavioural smoking cessation trials. Comparator variability should, therefore, be taken into account when interpreting and synthesising evidence from trials. Otherwise, policymakers, practitioners and researchers may draw incorrect conclusions about the (cost) effectiveness of smoking cessation interventions and their constituent components.

Shaping a research agenda to ensure a successful European health technology assessment: insights generated during the inaugural convention of the European access academy.

OBJECTIVES: Key challenges for a joint European Health Technology Assessment (HTA) include consolidated approaches towards the choice of adequate comparator(s), selection of endpoints that are relevant to patients with a given disease, dealing with remaining uncertainties as well as transparent and consistent management of related processes. We aimed to further crystallize related core domains within these four areas that warrant further research and scrutiny. METHODS: Building on the outcomes of a previously conducted questionnaire survey, four key areas, processes, uncertainty, comparator choice and endpoint selection, were identified. At the inaugural convention of the European Access Academy dedicated working groups were established defining and prioritizing core domains for each of the four areas. The working groups consisted of ~ 10 participants each, representing all relevant stakeholder groups (patients/ clinicians/ regulators/ HTA & payers/ academia/ industry). Story books identifying the work assignments were shared in advance. Two leads and one note taker per working group facilitated the process. All rankings were conducted on an ordinal Likert Response Scale scoring from 1 (low priority) to 7 (high priority). RESULTS: Identified key domains include for processes: i) address (resource-) challenge of multiple PICOs (Patient/ Intervention/ Comparator/ Outcomes), ii) time and capacity challenges, iii) integrating all involved stakeholders, iv) conflicts and aligning between different multi-national stakeholders, v) interaction with health technology developer; for uncertainty: i) early and inclusive collaboration, ii) agreement on feasibility of RCT and acceptance of uncertainty, iii) alignment on closing evidence gaps, iv) capacity gaps; for comparator choice: i) criteria for the choice of comparator in an increasingly fragmented treatment landscape, ii) reasonable number of comparators in PICOs, iii) shape Early Advice so that comparator fulfils both regulatory and HTA needs, iv) acceptability of Indirect Treatment Comparisons (ITC), v) ensure broad stakeholder involvement in comparator selection; for endpoint selection: i) approaching new endpoints; ii) patient preferences on endpoints; iii) position of HTA and other stakeholders; iv) long-term generation and secondary use of data; v) endpoint challenges in RCTs. CONCLUSIONS: The implementation of a joint European HTA assessment is a unique opportunity for a stronger European Health Union. We identified 19 domains related to the four key areas, processes, uncertainty, comparator choice and endpoint selection that urgently need to be addressed for this regulation to become a success.

Perioperative Management of Antiplatelet Therapy: A Systematic Review and Meta-analysis.

Objective: To summarize the available evidence about the perioperative management of patients who are receiving long-term antiplatelet therapy and require elective surgery/procedures. Methods: This systematic review supports the development of the American College of Chest Physicians guideline on the perioperative management of antiplatelet therapy. A literature search of MEDLINE, EMBASE, Scopus and Cochrane databases was conducted from each database's inception to July 16, 2020. Meta-analyses were conducted when possible. Results: In patients receiving long-term antiplatelet therapy and undergoing elective noncardiac surgery, the available evidence did not show a significant difference in major bleeding between a shorter vs longer antiplatelet interruption, with low certainty of evidence (COE). Compared with patients who received placebo perioperatively, aspirin continuation was associated with increased risk of major bleeding (relative risk [RR], 1.31; 95% CI, 1.15-1.50; high COE) and lower risk of major thromboembolism (RR, 0.74; 95% CI, 0.58-0.94; moderate COE). During antiplatelet interruption, bridging with low-molecular-weight heparin was associated with increased risk of major bleeding compared with no bridging (RR, 1.86; 95% CI, 1.24-2.79; very low COE). Continuation of antiplatelets during minor dental and ophthalmologic procedures was not associated with a statistically significant difference in the risk of major bleeding (very low COE). Conclusion: This systematic review summarizes the current evidence about the perioperative management of antiplatelet therapy and highlights the urgent need for further research, particularly with the increasing prevalence of patients taking 1 or more antiplatelet agents.

How can a joint European health technology assessment provide an 'additional benefit' over the current standard of national assessments? : Insights generated from a multi-stakeholder survey in hematology/oncology.

OBJECTIVES: We conducted a multi-stakeholder survey to determine key areas where a joint European health technology assessment (HTA) could provide 'additional benefit' compared to the status quo of many parallel independent national and subnational assessments. METHODS: Leveraging three iterative Delphi cycles, a semiquantitative questionnaire was developed covering evidence challenges and heterogeneity of value drivers within HTAs across Europe with a focus on hematology/oncology. The questionnaire consisted of five sections: i) background information; ii) value drivers in HTA assessments today; iii) evolving evidence challenges; iv) heterogeneity of value drivers across Europe; v) impact of Europe's Beating Cancer Plan (EBCP). The questionnaire was circulated across n = 189 stakeholder institutions comprising HTA and regulatory bodies, clinical oncology associations, patient representatives, and industry associations. RESULTS: N = 30 responses were received (HTA bodies: 9; regulators: 10; patients' and physicians' associations: 3 each; industry: 5). Overall, 17 countries and EU level institutions were represented in the responses. Consistency across countries and stakeholder groups was high. Most relevant value drivers in HTAs today (scale 1, low to 5, high) were clinical trial design (mean 4.45), right endpoints (mean 4.40), and size of comparative effect (mean 4.33). Small patient numbers (mean 4.28) and innovative study designs (mean 4.1) were considered the most relevant evolving evidence challenges. Heterogeneity between regulatory and HTA evidence requirements and heterogeneity of the various national treatment standards and national HTA evidence requirements was high. All clinical and patient participants stated to have been with EBCP initiatives. CONCLUSIONS: For a European HTA to provide an 'additional benefit' over the multitude of existing national assessments key methodological and process challenges need to be addressed. These include approaches to address uncertainty in clinical development; comparator choice; consistency in approaching patient-relevant endpoints; and a transparent and consistent management of both HTA and regulatory procedures as well as their interface, including all involved stakeholder groups.

Validation of a Surgical Objective Structured Clinical Examination (S-OSCE) Using Convergent, Divergent, And Trainee-Based Assessments of Fidelity.

OBJECTIVE: Describe the validation of a surgical objective structured clinical examination (S-OSCE) for the purpose of competency assessment based on the Royal College of Canada's Can-MEDS framework. DESIGN: A surgical OSCE was developed to evaluate the management of common orthopedic surgical problems. The scores derived from this S-OSCE were compared to Ottawa Surgical Competency Operating Room Evaluation (O-SCORE), a validated entrustability assessment, to establish convergent validity. The S-OSCE scores were compared to Orthopedic In-Training Examination (OITE) scores to evaluate divergent validity. Resident evaluations of the clinical encounter with a standardized patient and the operative procedure were scored on a 10-point Likert scale for fidelity. SETTING: A tertiary level academic teaching hospital. PARTICIPANTS: 21 postgraduate year 2 to 5 trainees of a 5-year Canadian orthopedic residency program creating 160 operative case performances for review. RESULTS: There were 5 S-OSCE days, over a 4-year period (2016-2019) encompassing a variety of surgical procedures. Performance on the S-OSCE correlated strongly with the O-SCORE (Pearson correlation coefficient 0.88), and a linear regression analysis correlated moderately with year of training (R²â€¯= 0.5345). The Pearson correlation coefficient between the S-OSCE and OITE scores was 0.57. There was a significant increase in the average OITE score after the introduction of the surgical OSCE. Resident fidelity ratings were available from 16 residents encompassing 8 different surgical cases. The average score for the overall simulation (8.0±1.6) was significantly higher than the cadaveric surgical simulation (6.5 ± 0.8) (p < 0.001) CONCLUSIONS: The S-OSCE scores correlate strongly with an established form of assessment demonstrating convergent validity. The correlation between the S-OSCE and OITE scores was less, demonstrating divergent validity. Although residents rank the overall simulation highly, the fidelity of the cadaveric simulation may need improvement. Administration of a surgical OSCE can be used to evaluate preoperative and intraoperative decision making and complement other forms of assessment.

Use of External Comparators for Health Technology Assessment Submissions Based on Single-Arm Trials.

BACKGROUND: Single-arm trial (SAT) data is increasingly reviewed for drug approvals by regulators and Health Technology Assessment (HTA) bodies. Supplementary data in the form of external comparators (ECs) can be used to provide clinical context to support these drug evaluations. In this study we characterized HTAs for SAT-based submissions, the use of supplementary EC data and outcomes from HTA review. METHODS: HTA Accelerator database was used to describe SAT-based HTA submissions with decisions (2011-2019). RESULTS: A total of 433 SAT-based HTA submissions were identified between 2011 and 2019 with a 13-fold increase during this period. Around 65%(283/433) were in oncology or hem-oncology. Around 52%(226/433) of submissions contained some type of EC data, including prior clinical trials (24%, 104) and real-world data (RWD) (20%, 87), but 40%(175) contained no EC data. The overall acceptance rate for SAT-based submissions was 48% and with RWD EC data acceptance was 59%. In the latest 5-year period (2015-2019), use of RWD ECs increased 22% as a proportion of submissions per year, whereas, prior trial ECs decreased (-14%) and use of no EC remained stable (-2%). Between 2015 to 2017 and 2018 to 2019, acceptance rate for RWD ECs increased by 20% (41% in 2015-2017 to 61% in 2018-2019) whereas prior trial EC use decreased by 10% and no EC submissions decreased 16%. Of 226 submissions using ECs, only 29%(66) used an adjusted indirect treatment comparison method. CONCLUSIONS: SAT-based submissions to HTA bodies are rapidly evolving in terms of composition and acceptance. Types of EC and methodological approach used are important determinants of positive outcomes.

The Use of Active Comparators in Self-Controlled Designs.

For self-controlled studies of medication-related effects, time-varying confounding by indication can occur if the indication varies over time. We describe how active comparators might mitigate such bias, using an empirical example. Approaches to using active comparators are described for case-crossover design, case-time-control design, self-controlled case-series, and sequence symmetry analyses. In the empirical example, we used Danish data from 1996-2018 to study the association between penicillin and venous thromboembolism (VTE), using roxithromycin, a macrolide antibiotic, as comparator. Upper respiratory infection is a transient risk factor for VTE, thus representing time-dependent confounding by indication. Odds ratios for case-crossover analysis were 3.35 (95% confidence interval: 3.23, 3.49) for penicillin and 3.56 (95% confidence interval: 3.30, 3.83) for roxithromycin. We used a Wald-based method or an interaction term to estimate the odds ratio for penicillin with roxithromycin as comparator. These 2 estimates were 0.94 (95% confidence interval: 0.87, 1.03) and 1.03 (95% confidence interval: 0.95, 1.13). Results were similar for the case-time-control analysis, but both the self-controlled case-series and sequence symmetry analysis suggested a weak protective effect of penicillin, seemingly explained by VTE affecting future exposure exclusively for penicillin. The strong association of antibiotics with VTE suggests presence of confounding by indication. Such confounding can be mitigated by using an active comparator.

Using electronic health record data to identify comparator populations for comparative effectiveness research.

Electronic health records (EHRs) can define real world patient populations with high levels of clinical specificity, potentially addressing some of the shortcomings of other types of real world data (RWD) when informing decisions about the comparative effectiveness of medical technologies. An important but under-recognized concern for EHR-derived RWD, however, is that the rich clinical data permits creation of very homogenous subpopulations from the larger group of eligible patients, thereby reducing the representativeness of the cohort relative to clinical practice. In this article, we discuss the tradeoffs between choosing clinical specificity versus representativeness in population sampling for comparative effectiveness research. Using EHR-derived RWD, we provide an example in non-small cell lung cancer to illustrate the concepts, showing wide variation in outcomes among potential comparator cohorts. We close with several recommendations for selecting comparator populations from EHRs that address the balance between matching clinical guidelines and capturing practice variability in comparative effectiveness research.

Exploring the relative value of end of life QALYs: Are the comparators important?

In the UK, life extending, end-of-life (EoL) treatments are an exception to standard cost-per-quality-adjusted life year (QALY) thresholds. This implies that greater value is placed on gaining these QALYs, than QALYs gained by the majority of other patient groups treated for anything else in the health system, even for other EoL contexts (such as quality of life (QoL) improvements alone). This paper reports a Person Trade-Off (PTO) study to test whether studies that find societal support for prioritising EoL life extensions can be explained by the severity, in terms of prospective QALYs loss, of the non-terminal comparator scenarios. Eight health scenarios were designed depicting i) QoL improvements for non-EoL temporary (T-QoL) and chronic (C-QoL) health problems and ii) QoL improvements and life extensions (LEs) for EoL health problems. Preferences were elicited from a quota sample of 901 Scottish respondents in 2016 using PTO techniques via Computer Assisted Personal Interview (CAPI). Our results indicate that there is little evidence to suggest that the severity of non-EoL comparator scenarios influence preferences for EoL treatments. Respondents do not appear to have a preference for EoL over non-EoL health gains; instead there is some indication that non-EoL health gains are preferred, particularly when compared to EoL-LE health gains. Comparing between QoL and life extending EoL scenarios, our results suggest QoL improvements are preferred to life extensions. Overall, results challenge current UK EoL policy which gives additional weight to EoL health gains, particularly EoL life extensions in the case of the National Institute for Health and Care Excellence (NICE).

Exploring bacterial resistome and resistance dessemination: an approach of whole genome sequencing.

For several decades antibiotics are used to combat against pathogenic bacteria, but their misuse and overuse have caused the emergence of resistant bacteria. The scarcities of effective antibiotics along with unavailability of alternative solutions have exacerbated bacterial infections and mortality rate. This review provides the concept of bacterial resistome and mechanisms of resistance. It has also described the utility of whole genome sequencing in identifying resistance and its dissemination in association with available bioinformatics tools and databases. Moreover, the whole genome sequencing methodology described in this review will help to select effective antibiotics, maintain unparalleled surveillance of resistance and provide early diagnosis during resistance outbreaks. The provided information could be used to control infection caused by resistant microorganisms.

Make up a missed lesson-New policy to ensure the interchangeability of generic drugs in China.

Generic drugs should be interchangeable with originators in terms of quality and efficacy. With relative lower prices, generic drugs are playing an important role in controlling health expenditures and ensuring access. However, the widespread understanding of "cheap price equals low quality" has a negative impact on the acceptance of generic drugs. In China, medical doctors doubt the efficacy and quality of generic drugs manufactured domestically. To address these concerns, the Chinese State Council released a policy in 2016 to ensure the interchangeability by re-evaluating the quality and efficacy of generic drugs. It intends to make up a missed lesson in the regulation to be in line with internationally accepted practices. Generic drugs firms, depends on the availability of appropriate comparators, should conduct either comparative bioequivalence studies or full scale clinical trials. The re-evaluation will be implemented in a stepwise approach with the essential medicines covered in the first step. The policy could achieve several benefits by increasing confidence on the Chinese produced generic drugs, upgrading regulatory standards, streamlining the Chinese generic drug industry and creating a healthy competition market. Nevertheless, enormous challenges remain in enlarging the capacity to review applications, selecting appropriate comparators, ensuring the capacity of domestic clinical research sites, and achieving the acceptance of re-evaluated generic drugs.

Prevalence and comorbidities of chronic hepatitis C: a nationwide population-based register study in Sweden.

PURPOSE: The aim of this study was to estimate the prevalence of physician-diagnosed and registered chronic hepatitis C (CHC), and to estimate the reported frequencies of Charlson comorbidities compared with matched comparators from the general population. MATERIALS AND METHODS: Patients were identified according to ICD codes for CHC in the Swedish National Patient Register (1997-2013). Prevalence was estimated according to different patient identification algorithms and for different subgroups. Charlson comorbidities were ascertained from the same register and compared with age/sex/county of residence matched general population comparators. RESULTS: A total of 34,633 individuals with physician-diagnosed CHC were alive in Sweden in 2013 (mean age, 49 years; 64% men), corresponding to a physician-diagnosed prevalence of 0.36%. The prevalence varied by case definition (0.22%-0.36%). The estimate dropped to 0.14% for monitored CHC disease (defined as ≥1 CHC-related visit in 2013). Overall, 41.3% of the CHC patients had ≥1 physician-registered Charlson comorbidity; the most common was liver diseases (22.1%). Compared with matched comparators from the general population (n = 171,338), patients with CHC had more physician-diagnosed and registered diseases such as chronic pulmonary disease (10.2% vs. 4.0%), diabetes (10.6% vs. 5.5%) and liver-related cancer (1.3% vs. 0.2%; all p < .01). No information on behavioural factors, such as smoking, alcohol consumption or on-going illicit drug use, was available. CONCLUSION: The physician-diagnosed prevalence of CHC was slightly lower than previously reported estimates, and varied by case definition. The additional comorbidities observed in the CHC group should be taken into consideration, as these comorbidities add to the disease burden.

Improving pulse detection in multibin photon-counting detectors.

Energy-discriminating, photon-counting (EDPC) detectors are attractive for their potential for improved detective quantum efficiency and for their spectral imaging capabilities. However, at high count rates, counts are lost, the detected spectrum is distorted, and the advantages of EDPC detectors disappear. Existing EDPC detectors identify counts by analyzing the signal with a bank of comparators. We explored alternative methods for pulse detection for multibin EDPC detectors that could improve performance at high count rates. The detector signal was simulated in a Monte Carlo fashion assuming a bipolar shape and analyzed using several methods, including the conventional bank of comparators. For example, one method recorded the peak energy of the pulse along with the width (temporal extent) of the pulse. The Cramer-Rao lower bound of the variance of basis material estimates was numerically found for each method. At high count rates, the variance in water material (bone canceled) measurements could be reduced by as much as an order of magnitude. Improvements in virtual monoenergetic images were modest. We conclude that stochastic noise in spectral imaging tasks could be reduced if alternative methods for pulse detection were utilized.

Natural genetic variability reduces recalcitrance in poplar.

BACKGROUND: Lignin content and structure are known to affect recalcitrance of lignocellulosic biomass to chemical/biochemical conversion. Previously, we identified rare Populus trichocarpa natural variants with significantly reduced lignin content. Because reduced lignin content may lower recalcitrance, 18 rare variants along with 4 comparators, and BESC standard Populus was analyzed for composition of structural carbohydrates and lignin. Sugar yields from these plants were measured at 5 process conditions: one for just enzymatic hydrolysis without pretreatment and four via our combined high-throughput hot water pretreatment and co-hydrolysis (HTPH) technique. RESULTS: Mean of glucan + xylan yields and the best glucan + xylan yield from rare natural poplar variants were 34 and 50 relative percent higher than the high lignin comparator (BESC-316) at the highest severity HTPH condition, respectively. The ability of HTPH to solubilize a large portion of xylan from solids led to small differences in xylan yields among poplar variants. However, HTPH showed large differences in glucan yields, and hence glucan + xylan yields, among the poplar variants. The high lignin comparator did not display lowest glucan + xylan yields with HTPH at moderate pretreatment severity compared to rare variants, but on the other hand, the low lignin comparator was a consistent top performer at all 5 process conditions. Furthermore, the low lignin comparator (GW-11012) showed a 15 absolute percent increase in glucan + xylan yield compared to the high lignin comparator at the most severe HTPH condition. Overall, relative variant rankings varied greatly with pretreatment severity, but poplar deconstruction was significantly enhanced when the pretreatment temperature was increased from 140 and 160 to 180 °C at the same pretreatment severity factor. CONCLUSIONS: Glucan yields from high severity HTPH of rare natural poplar variants with reduced lignin content were significantly higher than from the high lignin comparator. Because of the significant effect of processing conditions on the performance rankings, selection of the best performing biofuel feedstocks should be based on sugar yields tested at conditions that represent industrial practice. From a feedstock perspective, the most consistent variants, SKWE-24-2 and GW-11012, provide key insights into the genetic improvement of versatile lignocellulosic biofuels feedstock varieties.

Important issues in the justification of a control treatment in paediatric drug trials.

OBJECTIVE: The value of comparative effectiveness trials in informing clinical and policy decisions depends heavily on the choice of control arm (comparator). Our objective is to identify challenges in comparator reasoning and to determine justification criteria for selecting a control arm in paediatric clinical trials. DESIGN: A literature search was completed to identify existing sources of guidance on comparator selection. Subsequently, we reviewed a randomly selected sample of comparators selected for paediatric investigation plans (PIPs) adopted by the Paediatric Committee of the European Medicines Agency in 2013. We gathered descriptive information and evaluated their review process to identify challenges and compromises between regulators and sponsors with regard to the selection of the comparator. A tool to help investigators justify the selection of active controls and placebo arms was developed using the existing literature and empirical data. RESULTS: Justifying comparator selection was a challenge in 28% of PIPs. The following challenging paediatric issues in the decision-making process were identified: use of off-label medications as comparators, ethical and safe use of placebo, duration of placebo use, an undefined optimal dosing strategy, lack of age-appropriate safety and efficacy data, and drug dosing not supported by extrapolation of safety/efficacy evidence from other populations. CONCLUSIONS: In order to generate trials that will inform clinical decision-making and support marketing authorisations, researchers must systemically and transparently justify their selection of the comparator arm for their study. This report highlights key areas for justification in the choice of comparator in paediatric clinical trials.

An Adaptive Reconfigurable Active Voltage Doubler/Rectifier for Extended-Range Inductive Power Transmission.

We present an adaptive reconfigurable active voltage doubler (VD)/rectifier (REC) (VD/REC) in standard CMOS, which can adaptively change its topology to either a VD or a REC by sensing the output voltage, leading to more robust inductive power transmission over an extended range. Both active VD and REC modes provide much lower dropout voltage and far better power conversion efficiency (PCE) compared to their passive counterparts by adopting offset-controlled high-speed comparators that drive the rectifying switches at proper times in the high-frequency band. We have fabricated the active VD/REC in a 0.5-µm 3-metal 2-poly CMOS process, occupying 0.585 mm2 of chip area. In an exemplar setup, VD/REC extended the power transmission range by 33% (from 6 to 8 cm) in relative coil distance and 41.5% (from 53° to 75°) in relative coil orientation compared to using the REC alone. While providing 3.1-V dc output across a 500-Ω load from 2.15- (VD) and 3.7-V (REC) peak ac inputs at 13.56 MHz, VD/REC achieved measured PCEs of 70% and 77%, respectively.

The elusive experience of agency.

I here present some doubts about whether Mandik's (2010) proposed intermediacy and recurrence constraints are necessary and sufficient for agentive experience. I also argue that in order to vindicate the conclusion that agentive experience is an exclusively perceptual phenomenon (Prinz, 2007), it is not enough to show that the predictions produced by forward models of planned motor actions are conveyed by mock sensory signals. Rather, it must also be shown that the outputs of "comparator" mechanisms that compare these predictions against actual sensory feedback are also coded in a perceptual representational format.