Totality of evidence of the effectiveness of repurposed therapies for COVID-19: Can we use real-world studies alongside randomized controlled trials?

Rapid and robust strategies to evaluate the efficacy and effectiveness of novel and existing pharmacotherapeutic interventions (repurposed treatments) in future pandemics are required. Observational "real-world studies" (RWS) can report more quickly than randomized controlled trials (RCTs) and would have value were they to yield reliable results. Both RCTs and RWS were deployed during the coronavirus disease 2019 (COVID-19) pandemic.

Platform trials to evaluate the benefit-risk of COVID-19 therapeutics: Successes, learnings, and recommendations for future pandemics.

Background: In response to the COVID-19 global pandemic, multiple platform trials were initiated to accelerate evidence generation of potential therapeutic interventions. Given a rapidly evolving and dynamic pandemic, platform trials have a key advantage over traditional randomized trials: multiple interventions can be investigated under a master protocol sharing a common infrastructure.

Methods: This paper focuses on nine platform trials that were instrumental in advancing care in COVID-19 in the hospital and community setting.

A Tutorial on Modern Bayesian Methods in Clinical Trials.

Clinical trials continue to be the gold standard for evaluating new medical technologies. New advancements in modern computation power have led to increasing interest in Bayesian methods. Despite the multiple benefits of Bayesian approaches, application to clinical trials has been limited.

Bayesian Strategies in Rare Diseases.

Bayesian strategies for planning and analyzing clinical trials have become a viable choice, especially in rare diseases where drug development faces many challenges and stakeholders are interested in innovations that may help overcome them. Disease natural history and clinical outcomes occurrence and variability are often poorly understood. Standard trial designs are not optimized to obtain adequate safety and efficacy data from small numbers of patients.

U.S. Food and Drug Administration Reasoning in Approval Decisions When Efficacy Evidence Is Borderline, 2013-2018.

Background: The U.S. Food and Drug Administration (FDA) has substantial flexibility in its approval criteria in the context of life-threatening disease and unmet therapeutic need.

Vaccines After an Emergency Use Authorization (EUA): Modern Evidence Generation Approaches.

Every medical product requires additional study even after regulatory approval. We highlight several lines of enquiry to advance our understanding of COVID19 vaccines post authorization: identifying key population segments warranting more study, assessment of efficacy, and of safety data, harmonization of data relating to immune response and developing mechanisms for data and knowledge sharing across countries. We show how innovative trial designs and sources from real world data play a critical role in generating evidence.

Sources of Safety Data and Statistical Strategies for Design and Analysis: Transforming Data Into Evidence.

Background: Safety evaluation is a key aspect of medical product development. It is a continual and iterative process requiring thorough thinking, and dedicated time and resources.

Methods: In this article, we discuss how safety data are transformed into evidence to establish and refine the safety profile of a medical product, and how the focus of safety evaluation, data sources, and statistical methods change throughout a medical product's life cycle.

Sources of Safety Data and Statistical Strategies for Design and Analysis: Real World Insights.

Background: Although randomized controlled clinical trials provide necessary information and serve as the basis for regulatory decision making, a significant gap exists between the evidence these trials provide and what the biomedical community needs. It is recognized that a wealth of data are routinely collected outside clinical trials. Such real-world data (RWD) are not of comparable quality, it does not have similar immunity from bias and confounding as data collected in randomized clinical trials, but it might offer additional understanding of the benefit-risk, provide new insights to different stakeholders, and aid in regulatory decision making.

Logistic Regression Likelihood Ratio Test Analysis for Detecting Signals of Adverse Events in Post-market Safety Surveillance.

The Vaccine Adverse Event Reporting System (VAERS) and other product surveillance systems compile reports of product-associated adverse events (AEs), and these reports may include a wide range of information including age, gender, and concomitant vaccines. Controlling for possible confounding variables such as these is an important task when utilizing surveillance systems to monitor post-market product safety. A common method for handling possible confounders is to compare observed product-AE combinations with adjusted baseline frequencies where the adjustments are made by stratifying on observable characteristics.

The importance of mRNA structure in determining the pathogenicity of synonymous and non-synonymous mutations in haemophilia.

Introduction: Mutational analysis is commonly used to support the diagnosis and management of haemophilia. This has allowed for the generation of large mutation databases which provide unparalleled insight into genotype-phenotype relationships. Haemophilia is associated with inversions, deletions, insertions, nonsense and missense mutations.

Checking distributional assumptions for pharmacokinetic summary statistics based on simulations with compartmental models.

Bioequivalence (BE) studies are an essential part of the evaluation of generic drugs. The most common in vivo BE study design is the two-period two-treatment crossover design. AUC (area under the concentration-time curve) and Cmax (maximum concentration) are obtained from the observed concentration-time profiles for each subject from each treatment under each sequence.

CBER's Experience With Adaptive Design Clinical Trials.

There is considerable interest among pharmaceutical and other medical product developers in adaptive clinical trials, in which knowledge learned during the course of a trial affects ongoing conduct or analysis of the trial. When the FDA released a draft Guidance document on adaptive design clinical trials in early 2010, expectations were high that it would lead to an increase in regulatory submissions involving adaptive design features, particularly for confirmatory trials. A 6-year (2008-2013) retrospective survey was performed within the Center for Biologics Evaluation and Research (CBER) at the FDA to gather information regarding the submission and evaluation of adaptive design trial proposals.

Seeking harmony: estimands and sensitivity analyses for confirmatory clinical trials.

In October 2014, the Steering Committee of the International Conference on Harmonization endorsed the formation of an expert working group to develop an addendum to the International Conference on Harmonization E9 guideline ("Statistical Principles for Clinical Trials"). The addendum will focus on two topics involving randomized confirmatory clinical trials: estimands and sensitivity analyses. Both topics are motivated, in part, by the need to improve the precision with which scientific questions of interest are formulated and addressed by clinical trialists and regulators, specifically in the context of post-randomization events such as use of rescue medication or missing data resulting from dropouts.

Quantifying the impact of time-varying baseline risk adjustment in the self-controlled risk interval design.

Purpose: The self-controlled risk interval design is commonly used to assess the association between an acute exposure and an adverse event of interest, implicitly adjusting for fixed, non-time-varying covariates. Explicit adjustment needs to be made for time-varying covariates, for example, age in young children. It can be performed via either a fixed or random adjustment.

Letter to the editor by the authors of Exact Calculation of Power and Sample Size in Bioequivalence Studies Using Two One-sided Tests, Pharmaceutical Statistics, DOI: 10.1002/pst.1666.

This article reflects the views of the authors and should not be construed to be those of the US Food and Drug Administration.

National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: III. The 2014 Biomarker Working Group Report.

Biology-based markers to confirm or aid in the diagnosis or prognosis of chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation or monitor its progression are critically needed to facilitate evaluation of new therapies. Biomarkers have been defined as any characteristic that is objectively measured and evaluated as an indicator of a normal biological or pathogenic process, or of a pharmacologic response to a therapeutic intervention. Applications of biomarkers in chronic GVHD clinical trials or patient management include the following: (1) diagnosis and assessment of chronic GVHD disease activity, including distinguishing irreversible damage from continued disease activity; (2) prognostic risk to develop chronic GVHD; and (3) prediction of response to therapy.

Exact calculation of power and sample size in bioequivalence studies using two one-sided tests.

The number of subjects in a pharmacokinetic two-period two-treatment crossover bioequivalence study is typically small, most often less than 60. The most common approach to testing for bioequivalence is the two one-sided tests procedure. No explicit mathematical formula for the power function in the context of the two one-sided tests procedure exists in the statistical literature, although the exact power based on Owen's special case of bivariate noncentral t-distribution has been tabulated and graphed.

Preclinical safety evaluation of human platelets treated with antimicrobial peptides in severe combined immunodeficient mice.

Background: Bacterial sepsis is a complication attributed to room temperature (RT)-stored platelets (PLTs) in transfusion medicine. Antimicrobial peptides (AMPs) are emerging as new therapeutic agents against microbes. We had previously demonstrated bactericidal activity of select synthetic AMPs against six types of bacteria in stored PLTs.

Multiple in silico tools predict phenotypic manifestations in congenital thrombotic thrombocytopenic purpura.

Congenital thrombotic thrombocytopenic purpura (cTTP) is a rare, recessively inherited genetic disorder with varying clinical presentation that is caused by ADAMTS13 mutations. Several studies have found limited associations between ADAMTS13 mutations and cTTP phenotype. The use of in silico tools that examine multiple mutation characteristics may better predict phenotype.

Evaluation of tuberculosis diagnostics in children: 2. Methodological issues for conducting and reporting research evaluations of tuberculosis diagnostics for intrathoracic tuberculosis in children. Consensus from an expert panel.

Confirming the diagnosis of childhood tuberculosis is a major challenge. However, research on childhood tuberculosis as it relates to better diagnostics is often neglected because of technical difficulties, such as the slow growth in culture, the difficulty of obtaining specimens, and the diverse and relatively nonspecific clinical presentation of tuberculosis in this age group. Researchers often use individually designed criteria for enrollment, diagnostic classifications, and reference standards, thereby hindering the interpretation and comparability of their findings.

FDA perspectives on diagnostic device clinical studies for respiratory infections.

Two pathways are described for submission to FDA for clearance of a diagnostic device: a Premarket Application (PMA), which can lead to approval of a diagnostic device, and a Premarket Notification, which can lead to clearance. The latter is often called a 510(k), named for the statute providing for this path. Recent FDA clearance of molecular-based multiplex panels represents the beginning of a new era for the diagnosis of respiratory infections.

Simple sari cloth filtration of water is sustainable and continues to protect villagers from cholera in Matlab, Bangladesh.

A simple method for filtering water to reduce the incidence of cholera was tested in a field trial in Matlab, Bangladesh, and proved effective. A follow-up study was conducted 5 years later to determine whether the filtration method continued to be employed by villagers and its impact on the incidence of cholera. A total of 7,233 village women collecting water daily for their households in Bangladesh were selected from the same study population of the original field trial for interviewing.

Reproductive aging in Japanese quail, Coturnix japonica is associated with changes in central opioid receptors.

Quantitative in vitro autoradiography was used to measure specific mu and delta opioid receptor densities in regions of the Japanese quail, Coturnix japonica, brain that regulates reproductive endocrine and behavioral responses to determine the possible involvement of the opioid system in reproductive decline seen during aging. Densities were measured in selected brain regions of young sexually active (YAM), young photoregressed (YPM), old reproductively senescent (OIM) male, young active (YF), and old senescent female (OF) Japanese quail. Medial and lateral septum (SM, SL), medial preoptic area (POM), and n.