Interim Clinical Trial Data: Who Can See What, and When?

It has long been a basic principle of randomized clinical trials addressing serious outcomes and/or major public health issues that interim data should be inaccessible to investigators and to industry sponsors, with interim data reviewed on a regular basis by an independent data monitoring committee (DMC). Challenges to this principle may arise when sponsors and/or regulators perceive a need to review interim data while the trial remains ongoing-for example, when a trial is being considered for accelerated approval. In this paper we propose approaches that could minimize the extent of interim data that is made available to others while the trial continues.

A Systematic Review of the Etiology and Neurobiology of Intermittent Explosive Disorder.

Intermittent Explosive Disorder (IED) is characterized by repeated inability to control aggressive impulses. Although the etiology and neurobiology of impulsive anger and impulse control disorders have been reviewed, no systematic review on these aspects has been published for IED specifically. We conducted a systematic search in seven electronic databases for publications about IED, screened by two authors, and retained twenty-four studies for the review.

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.

Modulation of circulating free testosterone fraction by testosterone, dihydrotestosterone, and estradiol during testosterone replacement therapy.

Background: Testosterone, estradiol, and dihydrotestosterone share common ligand binding sites on sex hormone binding globulin and albumin. It is unknown whether and how changes in testosterone, dihydrotestosterone, and estradiol concentrations during testosterone replacement therapy affect free testosterone fraction.

Objective: To determine the effect of changes in testosterone, dihydrotestosterone, and estradiol concentrations on free testosterone fraction during testosterone replacement therapy of men with hypogonadism.

Challenges in designing a randomized, double-blind noninferiority trial for treatment of acne: The SD-ACNE trial.

Background/aims: Excessive use of antibiotics has led to development of antibiotic resistance and other antibiotic-associated complications. Dermatologists prescribe more antibiotics per clinician than any other major specialty, with much of this use for acne. Alternative acne treatments are available but are used much less often than antibiotics, at least partially because dermatologists feel that they are less effective.

Pulmonary Hypertension and Anastrozole (PHANTOM): A Randomized, Double-Blind, Placebo-Controlled Trial.

Inhibition of aromatase with anastrozole reduces pulmonary hypertension in experimental models. We aimed to determine whether anastrozole improved the 6-minute-walk distance (6MWD) at 6 months in pulmonary arterial hypertension (PAH). We performed a randomized, double-blind, placebo-controlled phase II clinical trial of anastrozole in subjects with PAH at seven centers.

Methods for the estimation of direct and indirect vaccination effects by combining data from individual- and cluster-randomized trials.

Both individually and cluster randomized study designs have been used for vaccine trials to assess the effects of vaccine on reducing the risk of disease or infection. The choice between individually and cluster randomized designs is often driven by the target estimand of interest (eg, direct versus total), statistical power, and, importantly, logistic feasibility. To combat emerging infectious disease threats, especially when the number of events from one single trial may not be adequate to obtain vaccine effect estimates with a desired level of precision, it may be necessary to combine information across multiple trials.

Testosterone Treatment and Fractures in Men with Hypogonadism.

Background: Testosterone treatment in men with hypogonadism improves bone density and quality, but trials with a sufficiently large sample and a sufficiently long duration to determine the effect of testosterone on the incidence of fractures are needed.

Methods: In a subtrial of a double-blind, randomized, placebo-controlled trial that assessed the cardiovascular safety of testosterone treatment in middle-aged and older men with hypogonadism, we examined the risk of clinical fracture in a time-to-event analysis. Eligible men were 45 to 80 years of age with preexisting, or high risk of, cardiovascular disease; one or more symptoms of hypogonadism; and two morning testosterone concentrations of less than 300 ng per deciliter (10.

Long-term Outcomes with Spinal versus General Anesthesia for Hip Fracture Surgery: A Randomized Trial.

Background: The effects of spinal versus general anesthesia on long-term outcomes have not been well studied. This study tested the hypothesis that spinal anesthesia is associated with better long-term survival and functional recovery than general anesthesia.

Methods: A prespecified analysis was conducted of long-term outcomes of a completed randomized superiority trial that compared spinal anesthesia versus general anesthesia for hip fracture repair.

Symptomatic benefits of testosterone treatment in patient subgroups: a systematic review, individual participant data meta-analysis, and aggregate data meta-analysis.

Background: Testosterone replacement therapy is known to improve sexual function in men younger than 40 years with pathological hypogonadism. However, the extent to which testosterone alleviates sexual dysfunction in older men and men with obesity is unclear, despite the fact that testosterone is being increasingly prescribed to these patient populations. We aimed to evaluate whether subgroups of men with low testosterone derive any symptomatic benefit from testosterone treatment.

Effectiveness of acceptance and commitment therapy for inpatients with psychosis: Implementation feasibility and acceptability from a pilot randomized controlled trial.

Objective: Acceptance and Commitment Therapy for Inpatients (ACT-IN) with psychosis has been found to be efficacious in previous trials, but its effectiveness has not been studied when implemented by frontline clinicians in routine settings.

Method: In this pilot randomized controlled effectiveness trial, inpatients with schizophrenia-spectrum disorders were randomized to ACT-IN plus treatment as usual (TAU) (n = 23) or a time/attention matched (TAM) supportive condition plus TAU (n = 23) delivered by routine hospital staff. Both conditions received individual and group therapy during inpatient care and completed follow-up phone sessions during the first month post-discharge.

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.

Outcomes with spinal versus general anesthesia for patients with and without preoperative cognitive impairment: Secondary analysis of a randomized clinical trial.

Introduction: The effect of spinal versus general anesthesia on the risk of postoperative delirium or other outcomes for patients with or without cognitive impairment (including dementia) is unknown.

Methods: Post hoc secondary analysis of a multicenter pragmatic trial comparing spinal versus general anesthesia for adults aged 50 years or older undergoing hip fracture surgery.

Results: Among patients randomized to spinal versus general anesthesia, new or worsened delirium occurred in 100/295 (33.

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.

A platform trial design for preventive vaccines against Marburg virus and other emerging infectious disease threats.

Background: The threat of a possible Marburg virus disease outbreak in Central and Western Africa is growing. While no Marburg virus vaccines are currently available for use, several candidates are in the pipeline. Building on knowledge and experiences in the designs of vaccine efficacy trials against other pathogens, including SARS-CoV-2, we develop designs of randomized Phase 3 vaccine efficacy trials for Marburg virus vaccines.

Early Termination of Clinical Trials for Futility - Considerations for a Data and Safety Monitoring Board.

Early Termination of Clinical Trials for FutilityClinical trials may be stopped for futility if there is little or no chance of demonstrating the hoped-for effect. Reasons include evidence of no treatment effect, substantial missing data that would unacceptably undermine trial conclusions, or event rates too low to support meaningful comparisons. This review examines issues faced by DSMBs in such settings.

Adverse cardiovascular events and mortality in men during testosterone treatment: an individual patient and aggregate data meta-analysis.

Background: Testosterone is the standard treatment for male hypogonadism, but there is uncertainty about its cardiovascular safety due to inconsistent findings. We aimed to provide the most extensive individual participant dataset (IPD) of testosterone trials available, to analyse subtypes of all cardiovascular events observed during treatment, and to investigate the effect of incorporating data from trials that did not provide IPD.

Methods: We did a systematic review and meta-analysis of randomised controlled trials including IPD.

Determinants of hospital outcomes for patients with COVID-19 in the University of Pennsylvania Health System.

There is growing evidence that racial and ethnic minorities bear a disproportionate burden from COVID-19. Temporal changes in the pandemic epidemiology and diversity in the clinical course require careful study to identify determinants of poor outcomes. We analyzed 6255 hospitalized individuals with PCR-confirmed SARS-CoV-2 infection from one of 5 hospitals in the University of Pennsylvania Health System between March 2020 and March 2021, using electronic health records to assess risk factors and outcomes through 8 weeks post-admission.

Improving the Approach to Defining, Classifying, Reporting and Monitoring Adverse Events in Seriously Ill Older Adults: Recommendations from a Multi-stakeholder Convening.

Background: Clinical trials are needed to study topics relevant to older adults with serious illness. Investigators conducting clinical trials with this population are challenged by how to appropriately define, classify, report, and monitor serious and non-serious adverse events (SAEs/AEs), given that some traditionally reported AEs (pressure ulcers, delirium) and SAEs (death, hospitalization) are common in persons with serious illness, and may be consistent with their goals of care.

Objectives: A multi-stakeholder group convened to establish greater clarity on and new approaches to address this critical issue.