Asundexian versus Apixaban in Patients with Atrial Fibrillation.

Background: Stroke prevention with direct-acting oral anticoagulant agents in patients with atrial fibrillation confers a risk of bleeding and limits their use. Asundexian, an activated factor XI (XIa) inhibitor, is an oral anticoagulant that may prevent strokes with less bleeding.

Methods: In a phase 3, international, double-blind trial, we randomly assigned high-risk patients with atrial fibrillation in a 1:1 ratio to receive asundexian at a dose of 50 mg once daily or standard-dose apixaban.

The Case for Access to Data Monitoring Committee Charters.

AbstractClinical trials investigating novel or high-risk interventions often use data monitoring committees (DMCs) to ensure that the participants' best interests are safeguarded. The typical DMC charter describes procedures by which the DMC operates, including important details concerning organizational structure, membership, meeting frequency, statistical monitoring guidelines, and contents of DMC reports for interim review. These charters, however, are not routinely publicly available; in some cases, their access could be important to the interpretation of trial results.

Clinical Study Report and Individual Participant Data Transparency for US Food and Drug Administration-Approved Anticancer Drugs: A Call for Systematic Data Availability.

Unlocking the full potential of clinical trials through comprehensive CSR and IPD sharing can revolutionize cancer care, enhance safety evaluations, and reduce bias in systematic reviews. It is time for all stakeholders to embrace transparency and advance patient-centered outcomes.

Framework of the strengths and challenges of clinically integrated trials: An expert panel report.

The limitations of the explanatory clinical trial framework include the high expense of implementing explanatory trials, restrictive entry criteria for participants, and redundant logistical processes. These limitations can result in slow evidence generation that is not responsive to population health needs, yielding evidence that is not generalizable. Clinically integrated trials, which integrate clinical research into routine care, represent a potential solution to this challenge and an opportunity to support learning health systems.

Factors Associated With Coronary Angiography Performed Within 6 Months of Randomization to the Conservative Strategy in the ISCHEMIA Trial.

Background: ISCHEMIA (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches) did not find an overall reduction in cardiovascular events with an initial invasive versus conservative management strategy in chronic coronary disease; however, there were conservative strategy participants who underwent invasive coronary angiography early postrandomization (within 6 months). Identifying factors associated with angiography in conservative strategy participants will inform clinical decision-making in patients with chronic coronary disease.

Methods: Factors independently associated with angiography performed within 6 months of randomization were identified using Fine and Gray proportional subdistribution hazard models, including demographics, region of randomization, medical history, risk factor control, symptoms, ischemia severity, coronary anatomy based on protocol-mandated coronary computed tomography angiography, and medication use.

Training the Next Generation of Data Monitoring Committee Members: An Initiative of the Heart Failure Collaboratory.

Clinical trials are vital for assessing therapeutic interventions. The associated data monitoring committees (DMCs) safeguard patient interests and enhance trial integrity, thus promoting timely, reliable evaluations of those interventions. We face an urgent need to recruit and train new DMC members.

Hierarchical End Points in Prior Heart Failure Trials and the HEART-FID Trial.

Background: Clinical trials in heart failure (HF) traditionally use time-to-event analyses focusing on death and hospitalization for HF. These time-to-first event analyses may have more limited abilities to assess the probability of benefiting from a therapy, especially if that benefit manifests as improved functional status rather than reduced risk of death or HF hospitalization. Hierarchical end points including clinical outcomes and patient status measures allow for ranked evaluation of outcomes in 1 metric assessing whether patients randomized to intervention or control are more likely to derive an overall benefit while also allowing more patients to contribute to the primary outcome.

Accessibility of clinical study reports supporting medicine approvals: a cross-sectional evaluation.

Objectives: Clinical study reports (CSRs) are highly detailed documents that play a pivotal role in medicine approval processes. Though not historically publicly available, in recent years, major entities including the European Medicines Agency (EMA), Health Canada, and the US Food and Drug Administration (FDA) have highlighted the importance of CSR accessibility. The primary objective herein was to determine the proportion of CSRs that support medicine approvals available for public download as well as the proportion eligible for independent researcher request via the study sponsor.

Real-world evidence for regulatory decision-making: updated guidance from around the world.

Leveraging the value of real-world evidence (RWE) to make informed regulatory decisions in the field of health care continues to gain momentum. Improving clinical evidence generation by evaluating the outcomes and patient experiences at the point-of-care would help achieve the ultimate aim of ensuring that effective and safe treatments are rapidly approved for patient use. In our previous publication, we assessed the global regulatory landscape with respect to RWE and provided a review of the regional availability of frameworks and guidance through May 2021 on the basis of 3 key regulatory elements: regulatory RWE frameworks, data quality guidance, and study methods guidance.

Heterogeneity and Utility of Pharmaceutical Company Sharing of Individual-Participant Data Packages.

Importance: The pharmaceutical industry has made substantial investments in developing processes for sharing individual-participant data (IPD) from clinical trials. However, the utility and completeness of shared IPD and supporting documents must be evaluated to ensure the potential for scientific advancements from the data sharing ecosystem can be realized.

Objective: To assess the utility and completeness of IPD and supporting documents provided from industry-sponsored clinical trials.

Training New DMC Members: A Call to Action.

Historically, clinical trialists developed DMC expertise and experience with "on the job training". Clinical trialists have recognized a large and growing gap between the demand and supply of trained DMC members due in part to the huge increase in ongoing clinical trials. A critical need exists to increase the supply of DMC trained clinicians and biostatisticians.

Ferric Carboxymaltose in Heart Failure with Iron Deficiency.

Background: Ferric carboxymaltose therapy reduces symptoms and improves quality of life in patients who have heart failure with a reduced ejection fraction and iron deficiency. Additional evidence about the effects of ferric carboxymaltose on clinical events is needed.

Methods: In this double-blind, randomized trial, we assigned ambulatory patients with heart failure, a left ventricular ejection fraction of 40% or less, and iron deficiency, in a 1:1 ratio, to receive intravenous ferric carboxymaltose or placebo, in addition to standard therapy for heart failure.

Baseline characteristics of patients in the randomized study to investigate the efficacy and safety of ferric carboxymaltose as treatment for heart failure with iron deficiency: HEART-FID trial.

Background: Prior clinical trials have investigated intravenous iron in patients with heart failure (HF) and iron deficiency, but the safety and efficacy of this therapy remains unclear.

Methods: We report the baseline demographics and clinical characteristics of patients enrolled in the HEART-FID study and compare HEART-FID participants with patients within other contemporary clinical trials of patients with HF with reduced ejection fraction (HFrEF), including other intravenous iron trials.

Results: In the 3,065 participants randomized in HEART-FID, median (IQR) age was 69.

Bringing data monitoring committee charters into the sunlight.

Clinical trials investigating novel or high risk interventions, or studying vulnerable participants, often use a data monitoring committee to oversee the progress of the trial. The data monitoring committee serves both an ethical and a scientific function, by protecting the interests of trial participants while ensuring the integrity of the trial results. A data monitoring committee charter, which typically describes the procedures by which data monitoring committees operate, contains details about the data monitoring committee's organizational structure, membership, meeting frequency, sequential monitoring guidelines, and the overall contents of data monitoring committee reports for interim review.

The Data Monitoring Committee: A Collective or a Collection?

In this commentary, we urge that a Data Monitoring Committee (DMC) should operate as a collective, that is, as a unitary whole. In so doing, its recommendations should emerge through a consensus development process, not through a vote of the members. The summary notes of its closed session, that is, its minutes, should report the recommendations of the DMC and, if necessary, the justification for those recommendations; it should not attribute opinions to individual members.

Cause-Specific Mortality in Patients With Advanced Chronic Kidney Disease in the ISCHEMIA-CKD Trial.

Background: In ISCHEMIA-CKD, 777 patients with advanced chronic kidney disease and chronic coronary disease had similar all-cause mortality with either an initial invasive or conservative strategy (27.2% vs 27.8%, respectively).

Impact of Vaccination With the SCB-2019 Coronavirus Disease 2019 Vaccine on Transmission of Severe Acute Respiratory Syndrome Coronavirus 2 Infection: A Household Contact Study in the Philippines.

Background: An exploratory household transmission study was nested in SPECTRA, the phase 2/3 efficacy study of the adjuvanted recombinant protein-based COVID-19 vaccine SCB-2019. We compared the occurrence of confirmed COVID-19 infections between households and household contacts of infected SPECTRA placebo or SCB-2019 recipients.

Methods: SPECTRA participants at 8 study sites in the Philippines who developed real-time reverse transcriptase-polymerase chain reaction (rRT-PCR)-confirmed COVID-19 were contacted by a study team blinded to assignment of index cases to vaccine or placebo groups to enroll in this household transmission study.

Guideline-Directed Medical Therapy Attainment and Outcomes in Dialysis-Requiring Versus Nondialysis Chronic Kidney Disease in the ISCHEMIA-CKD Trial.

Background: Patients with chronic kidney disease (CKD) on dialysis (CKD G5D) have worse cardiovascular outcomes than patients with advanced nondialysis CKD (CKD G4-5: estimated glomerular filtration rate <30 mL/[min·1.73m]). Our objective was to evaluate the relationship between achievement of cardiovascular guideline-directed medical therapy (GDMT) goals and clinical outcomes for CKD G5D versus CKD G4-5.

The Impact of Landscape Changes on Data and Safety Monitoring Board Oversight of Clinical Trials.

Impact of Landscape Changes on DSMB OversightThis Clinical Trials Workshop describes how external factors (or landscape changes) can affect monitoring of an ongoing clinical trial and discusses issues to consider to avoid stopping a trial too early while maintaining equipoise for enrolled participants. Three clinical trials in which DSMBs had to consider the effects of landscape changes on the continued performance of the monitored trial are reviewed.