Financial Characteristics of Outcomes-Based Agreements: What Do Canadian Public Payers and Pharmaceutical Manufacturers Prefer?

OBJECTIVES: This study sought to gain insight into the financial characteristics of outcomes-based agreements (OBAs) considered most suitable to Canadian public payers and pharmaceutical manufacturers, and the rationale for their preferences. METHODS: A total of 17 public payers and pharmaceutical manufacturers participated in semistructured qualitative interviews, which assessed their knowledge of OBAs and their preferred financial characteristics. RESULTS: Payers identified 5 OBA financial models that they considered both acceptable and feasible, in no preferential order: (1) discontinuation of therapy, (2) rebates for nonresponders, (3) free trial period, (4) adjustable pricing, and (5) blended rebate. Payers had a clear preference for short-term OBAs (<1 year), whereas both payers and manufacturers agreed OBAs with longer durations (up to 5 years) would be manageable if appropriately designed. Six key success factors to design suitable and acceptable OBA financial models were identified, including the areas of interim reporting, easily measurable health outcomes, trusted data sources, engaging unbiased third-party data experts, harmonizing OBA billing methods, and the inclusion of budget caps. CONCLUSIONS: Manufacturers and payers showed high level of interest in OBAs and a robust understanding of their potential role in supporting timely market access for patients in need, with the caveat that they need to be carefully designed to provide value. Further opportunities for discussion and engagement between public payers and manufacturers are needed to establish how to implement OBAs at a pan-Canadian level and how individual provinces and territories can incorporate them within their existing governance infrastructures.

Endpoint adjudication in cardiovascular clinical trials.

Endpoint adjudication (EA) is a common feature of contemporary randomized controlled trials (RCTs) in cardiovascular medicine. Endpoint adjudication refers to a process wherein a group of expert reviewers, known as the clinical endpoint committee (CEC), verify potential endpoints identified by site investigators. Events that are determined by the CEC to meet pre-specified trial definitions are then utilized for analysis. The rationale behind the use of EA is that it may lessen the potential misclassification of clinical events, thereby reducing statistical noise and bias. However, it has been questioned whether this is universally true, especially given that EA significantly increases the time, effort, and resources required to conduct a trial. Herein, we compare the summary estimates obtained using adjudicated vs. non-adjudicated site designated endpoints in major cardiovascular RCTs in which both were reported. Based on these data, we lay out a framework to determine which trials may warrant EA and where it may be redundant. The value of EA is likely greater when cardiovascular trials have nuanced primary endpoints, endpoint definitions that align poorly with practice, sub-optimal data completeness, greater operator variability, and lack of blinding. EA may not be needed if the primary endpoint is all-cause death or all-cause hospitalization. In contrast, EA is likely merited for more nuanced endpoints such as myocardial infarction, bleeding, worsening heart failure as an outpatient, unstable angina, or transient ischaemic attack. A risk-based approach to adjudication can potentially allow compromise between costs and accuracy. This would involve adjudication of a small proportion of events, with further adjudication done if inconsistencies are detected.

Applying Laws Across Time: Disentangling the 'Always Speaking' Principles.

Common-law judges frequently claim to apply the 'always speaking' principle. But they recognise that they are not clear on what it means, with Lord Leggatt recently calling the metaphor 'enigmatic'. In this article, I seek to clarify this by showing that the 'always speaking' metaphor is associated with at least four different types of principle, each of which responds to a distinct issue (although there is a common theme: change over time). I explore the origins of the 'always speaking' metaphor, distinguish the four issues and explain how they relate. I argue that it is important to disentangle the four types of 'always speaking' principle, with a focus on distinguishing principles of dynamic (versus originalist) interpretation from principles that empower judges to strain or 'recast' legislation to deal with new developments sensibly. In doing so, I analyse and critique the judgments in the recent UK Supreme Court case of News Corp.

Contract Law When the Poor Pay More.

Taking inequality as a key challenge of our time, this article aims to highlight consumer markets, and their underpinning legal ground rules, as important contributors to inequitable wealth distributions. It illustrates how product design, as manifested in contractual terms, can allow firms to evade competition and divert resources upwards along society's wealth distribution curve. It then highlights the contestable legality of certain pricing practices, such as 'contingent charges', and the challenge they pose to fundamental principles of contract law. An in-depth view of the 2015 case of Beavis v ParkingEye argues that the UK Supreme Court has validated contingent pricing models in a manner unsupported by traditional contractual reasoning and unjustified by contemporary market failure analysis. The article asks contract law to confront the reality that it shapes market distributions in economically and politically significant ways, and appeals for greater scrutiny of the contribution of contract law adjudication to inequality.

Risk factor associations with individual myocardial infarction subtypes and acute non-ischemic myocardial injury in the Multi-Ethnic Study of Atherosclerosis (MESA): Design and rationale.

BACKGROUND: Despite different prevalence, pathobiology, and prognosis between etiologically distinct myocardial infarction (MI) subtypes, prospective study of risk factor for MI in large NHLBI-sponsored cardiovascular cohorts is limited to acute MI as a singular entity. Therefore, we sought to utilize the Multi-Ethnic Study of Atherosclerosis (MESA), a large prospective primary prevention cardiovascular study, to define the incidence and risk factor profile of individual myocardial injury subtypes. METHODS: We describe the rationale and design of re-adjudicating 4,080 events that occurred over the first 14 years of follow-up in MESA for the presence and subtype of myocardial injury as defined by the Fourth Universal Definition of MI: MI type 1 to 5, acute non-ischemic myocardial injury, and chronic myocardial injury. The project utilizes a 2-physician adjudication process via examination of medical records, abstracted data collection forms, cardiac biomarker results, and electrocardiograms of all relevant clinical events. Comparison of the magnitude and direction of associations between baseline traditional and novel cardiovascular risk factors with incident and recurrent acute MI subtypes and acute non-ischemic myocardial injury events will be made. CONCLUSIONS: This project will result in one of the first large prospective cardiovascular cohort with modern classification of acute MI subtypes, as well as a full accounting of non-ischemic myocardial injury events, with implications for numerous ongoing and future studies in MESA. By creating precise MI phenotypes, and defining their epidemiology, this project will allow for discovery of novel pathobiology-specific risk factors, allow for development of more accurate risk prediction, and suggest more targeted preventive strategies.

Classification of Heart Failure Events by Severity: Insights From the VICTORIA Trial.

BACKGROUND: Hospitalization due to heart failure (HFH) is a major source of morbidity, consumes significant economic resources and is a key endpoint in HF clinical trials. HFH events vary in severity and implications, but they are typically considered equivalent when analyzing clinical trial outcomes. OBJECTIVES: We aimed to evaluate the frequency and severity of HF events, assess treatment effects and describe differences in outcomes by type of HF event in VICTORIA (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction). METHODS: VICTORIA compared vericiguat with placebo in patients with HF with reduced ejection fraction (< 45%) and a recent worsening HF event. All HFHs were prospectively adjudicated by an independent clinical events committee (CEC) whose members were blinded to treatment assignment. We evaluated the frequency and clinical impact of HF events by severity, categorized by highest intensity of HF treatment (urgent outpatient visit or hospitalization treated with oral diuretics, intravenous diuretics, intravenous vasodilators, intravenous inotropes, or mechanical support) and treatment effect by event categories. RESULTS: In VICTORIA, 2948 HF events occurred in 5050 enrolled patients. Overall total CEC HF events for vericiguat vs placebo were 43.9 vs 49.1 events/100 patient-years (P = 0.01). Hospitalization for intravenous diuretics was the most common type of HFH event (54%). HF event types differed markedly in their clinical implications for both in-hospital and post-discharge events. We observed no difference in the distribution of HF events between randomized treatment groups (P = 0.78). CONCLUSION: HF events in large global trials vary significantly in severity and clinical implications, which may have implications for more nuanced trial design and interpretation. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov (NCT02861534).

Time-dependent event accumulation in a cardiovascular outcome trial of patients with type 2 diabetes and established atherosclerotic cardiovascular disease.

BACKGROUND: Estimating cardiovascular (CV) event accrual is important for outcome trial planning. Limited data exist describing event accrual patterns in patients with type 2 diabetes (T2D). We compared apparent CV event accrual patterns with true event rates in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS). METHODS: Centrally adjudicated event dates and accrual rates for a 4-point major adverse CV event composite (MACE-4; includes CV death, nonfatal myocardial infarction, nonfatal stroke, or unstable angina hospitalization), MACE-4 components, all-cause mortality (ACM), and heart failure hospitalization were compiled. We used three graphical methods (Weibull probability plot, plot of negative log of the Kaplan-Meier survival distribution estimate, and the Epanechnikov kernel-smoothed estimate of the hazard rate) to examine hazard rate morphology over time for the 7 outcomes. RESULTS: Plots for all outcomes showed real-time constant event hazard rates for the duration of the follow-up, confirmed by Weibull shape parameters. The Weibull shape parameters for ACM (1.14, 95% CI 1.08-1.21) and CV death (1.08, 95% CI 1.01-1.16) were not sufficiently > 1 as to require non-constant hazard rate models to accurately depict the data. The time lag between event occurrence and event adjudication being completed, the adjudication gap, improved over the course of the trial. CONCLUSIONS: In TECOS, the nonfatal event hazard rates were constant over time. Small increases over time in the hazard rate for fatal events would not require complex modelling to predict event accrual, providing confidence in traditional modelling methods for predicting CV outcome trial event rates in this population. The adjudication gap provides a useful metric to monitor within-trial event accrual patterns. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov NCT00790205.

Evidence of cancer progression as the cause of death in men with prostate cancer in Sweden.

OBJECTIVE: To assess the strength of the evidence indicative of prostate cancer (PCa) progression as the adjudicated cause of death, according to age at death and PCa risk category. PATIENTS AND METHODS: Using data from the Prostate Cancer data Base Sweden, we identified a study frame of 5543 men with PCa registered as the cause of death according to the Cause of Death Register. We assessed the evidence of PCa progression through a review of healthcare records for a stratified sample of 495/5543. We extracted data on prostate-specific antigen levels, presence of metastases on imaging, and PCa treatments, and quantified the evidence of disease progression using a points system. RESULTS: Both no evidence and moderate evidence for PCa progression was more common in men aged >85 years at death than those aged <85 years (29% vs 14%). Among the latter, the proportion with no evidence or moderate evidence for PCa progression was 21% for low-risk, 14% for intermediate-risk, 8% for high-risk, and 0% for metastatic PCa. In contrast, in men aged >85 years, there was little difference in the proportion with no evidence or moderate evidence of PCa progression between PCa risk categories; 31% for low-risk, 29% for intermediate-risk, 29% for high-risk, and 21% for metastatic PCa. Of the 5543 men who died from PCa, 13% (95% confidence interval 5-19%) were estimated to have either no evidence or moderate evidence of PCa progression. CONCLUSIONS: Weak evidence for PCa progression as cause of death was more common in older men with PCa and in those with low-risk PCa. This has implications for interpretation of mortality statistics especially when assessing screening and early treatment of PCa because the beneficial effect of earlier diagnosis could be masked by erroneous adjudication of PCa as cause of death in older men, particular those with localised disease at diagnosis.

A hybrid automated event adjudication system for clinical trials.

INTRODUCTION: In clinical trials, event adjudication is a process to review and confirm the accuracy of outcomes reported by site investigators. Despite efforts to automate the communication between a clinical-data-and-coordination center and an event adjudication committee, the review and confirmation of outcomes, as the core function of the process, still fully rely on human labor. To address this issue, we present an automated event adjudication system and its application in two randomized controlled trials. METHODS: Centrally executed by a clinical-data-and-coordination center, the automated event adjudication system automatedly assessed and classified outcomes in a clinical data management system. By checking clinically predefined criteria, the automated event adjudication system either confirmed or unconfirmed an outcome and automatedly updated its status in the database. It also served as a management tool to assist staff to oversee the process of event adjudication. The system has been applied in: (1) the Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) trial and (2) the New Approach riVaroxaban Inhibition of Factor Xa in a Global trial versus Aspirin to prevenT Embolism in Embolic Stroke of Undetermined Source (NAVIGATE ESUS) trial. The automated event adjudication system first screened outcomes reported on a case report form and confirmed those with data matched to preset definitions. For selected primary efficacy, secondary, and safety outcomes, the unconfirmed cases were referred to a human event adjudication committee for a final decision. In the New Approach riVaroxaban Inhibition of Factor Xa in a Global trial versus Aspirin to prevenT Embolism in Embolic Stroke of Undetermined Source (NAVIGATE ESUS) trial, human adjudicators were given priority to review cases, while the automated event adjudication system took the lead in the Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) trial. RESULTS: Outcomes that were adjudicated in a hybrid model are discussed here. The COMPASS automated event adjudication system adjudicated 3283 primary efficacy outcomes and confirmed 1652 (50.3%): 132 (21.1%) strokes, 522 (53%) myocardial infarctions, and 998 (59.7%) causes of deaths. The NAVIGATE ESUS one adjudicated 737 cases of selected outcomes and confirmed 383 (52%): 219 (51.5%) strokes, 34 (42.5%) myocardial infarctions, 73 (54.9%) causes of deaths, and 57 (57.6%) major bleedings. After one deducts the time needed for migrating the system to a new study, the automated event adjudication system helped to reduce the time required for human review from approximately 1303 to 716.5 h for the Cardiovascular Outcomes for People Using Anticoagulation Strategies trial and from 387 to 196 h for the New Approach riVaroxaban Inhibition of Factor Xa in a Global trial versus Aspirin to prevenT Embolism in Embolic Stroke of Undetermined Source trial. CONCLUSION: The automated event adjudication system in combination with human adjudicators provides a streamlined and efficient approach to event adjudication in clinical trials. To immediately apply automated event adjudication, one can first consider the automated event adjudication system and involve human assistance for cases unconfirmed by the former.

A machine learning approach using endpoint adjudication committee labels for the identification of sepsis predictors at the emergency department.

Accurate sepsis diagnosis is paramount for treatment decisions, especially at the emergency department (ED). To improve diagnosis, clinical decision support (CDS) tools are being developed with machine learning (ML) algorithms, using a wide range of variable groups. ML models can find patterns in Electronic Health Record (EHR) data that are unseen by the human eye. A prerequisite for a good model is the use of high-quality labels. Sepsis gold-standard labels are hard to define due to a lack of reliable diagnostic tools for sepsis at the ED. Therefore, standard clinical tools, such as clinical prediction scores (e.g. modified early warning score and quick sequential organ failure assessment), and claims-based methods (e.g. ICD-10) are used to generate suboptimal labels. As a consequence, models trained with these "silver" labels result in ill-trained models. In this study, we trained ML models for sepsis diagnosis at the ED with labels of 375 ED visits assigned by an endpoint adjudication committee (EAC) that consisted of 18 independent experts. Our objective was to evaluate which routinely measured variables show diagnostic value for sepsis. We performed univariate testing and trained multiple ML models with 95 routinely measured variables of three variable groups; demographic and vital, laboratory and advanced haematological variables. Apart from known diagnostic variables, we identified added diagnostic value for less conventional variables such as eosinophil count and platelet distribution width. In this explorative study, we show that the use of an EAC together with ML can identify new targets for future sepsis diagnosis research.

Central vs site outcome adjudication in the IRIS trial.

BACKGROUND: Central adjudication of outcome events is the standard in clinical trial research. We examine the benefit of central adjudication in the Insulin Resistance Intervention after Stroke (IRIS) trial and show how the benefit is influenced by outcome definition and features of the adjudicated events. METHODS: IRIS tested pioglitazone for prevention of stroke and myocardial infarction in patients with a recent transient ischemic attack or ischemic stroke. We compared the hazard ratios for study outcomes classified by site and central adjudication. We repeated the analysis for an updated stroke definition. RESULTS: The hazard ratios for the primary outcome were identical (0.76) and statistically significant regardless of adjudicator. The hazard ratios for stroke alone were nearly identical with site and central adjudication, but only reached significance with site adjudication (HR, 0.80; p = 0.049 vs. HR, 0.82; p = 0.09). Using the updated stroke definition, all hazard ratios were lower than with the original IRIS definition and statistically significant regardless of adjudication method. Agreement was higher when stroke type was certain, subtype was large vessel or cardioembolic, signs or symptoms lasted > 24 h, imaging showed a stroke, and when NIHSS was ≥3. DISCUSSION: Central stroke adjudication caused the hazard ratio for a main secondary outcome in IRIS (stroke alone) to be higher and lose statistical significant compared with site review. The estimate of treatment effects were larger with the updated stroke definition. There may be benefit of central adjudication for events with specific features, such as shorter symptom duration or normal brain imaging.

Authorship Issues When Articles are Retracted Due to Research Misconduct and Then Resubmitted.

In the last 20 years, there has been a sharp increase in the incidence of retractions of articles published in scientific journals, the majority of which are due to research misconduct. In some cases, researchers have revised and republished articles that were retracted due to misconduct, which raises some novel questions concerning authorship. Suppose that an article is retracted because one of the authors fabricated or falsified some data, but the researchers decide to salvage the useable data, make appropriate revisions, and resubmit the article for publication. If the person who committed misconduct has made a significant contribution to the research reported in the revised paper, should they be named as an author to recognize this contribution or should they be denied authorship because they committed misconduct? This is a challenging issue because it involves the confluence of two research ethics domains that are usually dealt with separately, i.e., resolution of authorship disputes and adjudication of misconduct findings, as well as potential conflicts among norms that underlie authorship practices and misconduct adjudication. In this paper, we (1) describe some actual cases involving articles that were retracted for misconduct and republished; (2) review policies from the International Committee of Medical Journal Editors, Committee on Publication Ethics, and top fifteen biomedical journals to determine whether they provide adequate guidance for cases like these; and (3) analyze the ethical and policy issues that may arise in these situations.

Two Types of Formalism of the Rule of Law.

The aims of this article are twofold: (i) to propose an explanatory framework, focusing on law-making acts, for accounting for whether the formal requirements of the rule of law are fulfilled; and (ii) to propose two further models within this framework. One model, which I call 'rulebook formalism', pertains to Parliament's law-making acts; another model, which I call 'rights formalism', concerns the courts' law-making acts. This distinction results from the different modality of law, ie the different natures of law-making acts. Drawing on speech act theory, I give a general account of the formal requirements as the success conditions of law-making acts. Then, applying this framework, I discuss the formal requirements for Parliament's law-making acts and the courts' law-making acts respectively.

Bayesian analysis of survival data with missing censoring indicators.

In some large clinical studies, it may be impractical to perform the physical examination to every subject at his/her last monitoring time in order to diagnose the occurrence of the event of interest. This gives rise to survival data with missing censoring indicators where the probability of missing may depend on time of last monitoring and some covariates. We present a fully Bayesian semi-parametric method for such survival data to estimate regression parameters of the proportional hazards model of Cox. Theoretical investigation and simulation studies show that our method performs better than competing methods. We apply the proposed method to analyze the survival data with missing censoring indicators from the Orofacial Pain: Prospective Evaluation and Risk Assessment study.

Physician adjudication of angioedema diagnosis codes in a population of patients with heart failure prescribed angiotensin-converting enzyme inhibitor therapy.

PURPOSE: Our objective was to calculate the positive predictive value (PPV) of the ICD-9 diagnosis code for angioedema when physicians adjudicate the events by electronic health record review. Our secondary objective was to evaluate the inter-rater reliability of physician adjudication. METHODS: Patients from the Cardiovascular Research Network previously diagnosed with heart failure who were started on angiotensin-converting enzyme inhibitors (ACEI) during the study period (July 1, 2006 through September 30, 2015) were included. A team of two physicians per participating site adjudicated possible events using electronic health records for all patients coded for angioedema for a total of five sites. The PPV was calculated as the number of physician-adjudicated cases divided by all cases with the diagnosis code of angioedema (ICD-9-CM code 995.1) meeting the inclusion criteria. The inter-rater reliability of physician teams, or kappa statistic, was also calculated. RESULTS: There were 38 061 adults with heart failure initiating ACEI in the study (21 489 patient-years). Of 114 coded events that were adjudicated by physicians, 98 angioedema events were confirmed for a PPV of 86% (95% CI: 80%, 92%). The kappa statistic based on physician inter-rater reliability was 0.65 (95% CI: 0.47, 0.82). CONCLUSIONS: ICD-9 diagnosis code of 995.1 (angioneurotic edema, not elsewhere classified) is highly predictive of angioedema in adults with heart failure exposed to ACEI.

A scalable tool for adjudication of time sensitive cases during COVID-19 pandemic.

BACKGROUND: During the COVID-19 pandemic, prioritization of care and utilization of scarce resources are daily considerations in healthcare systems that have never experienced these issues before. Elective surgical cases have been largely postponed, and surgery departments are struggling to correctly and equitably determine which cases need to proceed. A resource to objectively prioritize and track time sensitive cases would be useful as an adjunct to clinical decision-making. METHODS: A multidisciplinary working group at Emory Healthcare developed and implemented an adjudication tool for the prioritization of time sensitive surgeries. The variables identified by the team to form the construct focused on the patient's survivability according to actuarial data, potential impact on function with delay in care, and high-level biology of disease. Implementation of the prioritization was accomplished with a database design to streamline needed communication between surgeons and surgical adjudicators. All patients who underwent time sensitive surgery between 4/10/20 and 6/15/20 across 5 campuses were included. RESULTS: The primary outcomes of interest were calculated patient prioritization score and number of days until operation. 1767 cases were adjudicated during the specified time period. The distribution of prioritization scores was normal, such that real-time adjustment of the empiric algorithm was not required. On retrospective review, as the patient prioritization score increased, the number of days to the operating room decreased. This confirmed the functionality of the tool and provided a framework for organization across multiple campuses. CONCLUSIONS: We developed an in-house adjudication tool to aid in the prioritization of a large cohort of canceled and time sensitive surgeries. The tool is relatively simple in its design, reproducible, and data driven which allows for an objective adjunct to clinical decision-making. The database design was instrumental in communication optimization during this chaotic period for patients and surgeons.

A case study of ascertainment bias for the primary outcome in the Strategies to Reduce Injuries and Develop Confidence in Elders (STRIDE) trial.

BACKGROUND/AIM: In clinical trials, there is potential for bias from unblinded observers that may influence ascertainment of outcomes. This issue arose in the Strategies to Reduce Injuries and Develop Confidence in Elders trial, a cluster randomized trial to test a multicomponent intervention versus enhanced usual care (control) to prevent serious fall injuries, originally defined as a fall injury leading to medical attention. An unblinded nurse falls care manager administered the intervention, while the usual care arm did not involve contact with a falls care manager. Thus, there was an opportunity for falls care managers to refer participants reporting falls to seek medical attention. Since this type of observer bias could not occur in the usual care arm, there was potential for additional falls to be reported in the intervention arm, leading to dilution of the intervention effect and a reduction in study power. We describe the clinical basis for ascertainment bias, the statistical approach used to assess it, and its effect on study power. METHODS: The prespecified interim monitoring plan included a decision algorithm for assessing ascertainment bias and adapting (revising) the primary outcome definition, if necessary. The original definition categorized serious fall injuries requiring medical attention into Type 1 (fracture other than thoracic/lumbar vertebral, joint dislocation, cut requiring closure) and Type 2 (head injury, sprain or strain, bruising or swelling, other). The revised definition, proposed by the monitoring plan, excluded Type 2 injuries that did not necessarily require an overnight hospitalization since these would be most subject to bias. These injuries were categorized into those with (Type 2b) and without (Type 2c) medical attention. The remaining Type 2a injuries required medical attention and an overnight hospitalization. We used the ratio of 2b/(2b + 2c) in intervention versus control as a measure of ascertainment bias; ratios > 1 indicated the likelihood of falls care manager bias. We determined the effect of ascertainment bias on study power for the revised (Types 1 and 2a) versus original definition (Types 1, 2a, and 2b). RESULTS: The estimate of ascertainment bias was 1.14 (95% confidence interval: 0.98, 1.30), providing evidence of the likelihood of falls care manager bias. We estimated that this bias diluted the hazard ratio from the hypothesized 0.80 to 0.86 and reduced power to under 80% for the original primary outcome definition. In contrast, adapting the revised definition maintained study power at nearly 90%. CONCLUSION: There was evidence of ascertainment bias in the Strategies to Reduce Injuries and Develop Confidence in Elders trial. The decision to adapt the primary outcome definition reduced the likelihood of this bias while preserving the intervention effect and study power.

How has the Covid19 pandemic impacted the courts of law? Evidence from Brazil.

We provide empirical insight into the consequences of the Covid19 pandemic for the administration of justice. Drawing on a comprehensive monthly panel of Brazilian labor courts and using a difference-in-difference approach, we show that the pandemic has had a large and persistent deleterious effect on adjudicatory efficacy, leading to a massive decrease in the clearance rate and an increase in court backlogs. The pandemic has affected how courts dispose adjudication cases, expectedly causing a plummeting in the share of disputes resolved via trial hearings and, less predictably, exerting a temporally non-linear effect on the share of in-court settlements. Notably, we find no evidence of an effect of the pandemic on efficacy in enforcement. Although the pandemic led to an increase in the share of new filings requiring enforcement, any effect on the relative use of enforcement to execute court-ordered payments has been intermittent and temporary. The intensity of the pandemic has been an important moderating factor.

Myocarditis in the Setting of Cancer Therapeutics: Proposed Case Definitions for Emerging Clinical Syndromes in Cardio-Oncology

Recent developments in cancer therapeutics have improved outcomes but have also been associated with cardiovascular complications. Therapies harnessing the immune system have been associated with an immune-mediated myocardial injury described as myocarditis. Immune checkpoint inhibitors are one such therapy with an increasing number of case and cohort reports describing a clinical syndrome of immune checkpoint inhibitor­associated myocarditis. Although the full spectrum of immune checkpoint inhibitor­associated cardiovascular disease still needs to be fully defined, described cases of myocarditis range from syndromes with mild signs and symptoms to fatal events. These observations in the clinical setting stand in contrast to outcomes from randomized clinical trials in which myocarditis is a rare event that is investigator reported and lacking in a specific case definition. The complexities associated with diagnosis, as well as the heterogeneous clinical presentation of immune checkpoint inhibitor­associated myocarditis, have made ascertainment and identification of myocarditis with high specificity challenging in clinical trials and other data sets, limiting the ability to better understand the incidence, outcomes, and predictors of these rare events. Therefore, establishing a uniform definition of myocarditis for application in clinical trials of cancer immunotherapies will enable greater understanding of these events. We propose an operational definition of cancer therapy-associated myocarditis that may facilitate case ascertainment and report and therefore may enhance the understanding of the incidence, outcomes, and risk factors of this novel clinical syndrome.

Cost-benefit of outcome adjudication in nine randomised stroke trials.

BACKGROUND: Central adjudication of outcomes is common for randomised trials and should control for differential misclassification. However, few studies have estimated the cost of the adjudication process. METHODS: We estimated the cost of adjudicating the primary outcome in nine randomised stroke trials (25,436 participants). The costs included adjudicators' time, direct payments to adjudicators, and co-ordinating centre costs (e.g. uploading cranial scans and general set-up costs). The number of events corrected after adjudication was our measure of benefit. We calculated cost per corrected event for each trial and in total. RESULTS: The primary outcome in all nine trials was either stroke or a composite that included stroke. In total, the adjudication process associated with this primary outcome cost in excess of £100,000 for a third of the trials (3/9). Mean cost per event corrected by adjudication was £2295.10 (SD: £1482.42). CONCLUSIONS: Central adjudication is a time-consuming and potentially costly process. These costs need to be considered when designing a trial and should be evaluated alongside the potential benefits adjudication brings to determine whether they outweigh this expense.