Aggregate IND Safety Reporting for Smaller Companies and Programs.

The United States (US) Food and Drug Administration (FDA) Investigational New Drug (IND) Final Rule (US FDA, Final rule: Investigational new drug safety reporting requirements for human drug and biological products and safety reporting requirements for bioavailability and bioequivalence studies in humans, 2010) applies to all human drugs and biological products being studied under an IND. The Final Rule specifies that a sponsor must file an IND safety report for any Suspected Unexpected Serious Adverse Reaction (SUSAR) of a medicinal product being investigated. To make a proper SUSAR classification, sponsors need to go beyond conventional Data Monitoring Committees (DMCs) with an interdisciplinary effort, using all relevant data (including data outside clinical trials), to make judgments on the possibility of serious adverse events being caused by the study drug-rather than the underlying condition of the patient or a concomitant therapy.

Validation of a Modified National Eye Institute Grading Scale for Corneal Fluorescein Staining.

Purpose: Validation of the novel Lexitas modified NEI scale for use in assessment of corneal fluorescein staining.

Patients And Methods: A series of 18 illustrations and 14 clinical photographs depicting varying severity levels of corneal fluorescein staining were assessed by 3 independent examiners. Regions of the cornea were graded for staining severity based on 3 different grading scales: the original NEI staining scale (density-based scoring; 0-3 scale), a structured version of the NEI scale (dot-count scoring; 0-3 scale), and the Lexitas modified NEI staining scale (0-4 scale with half-point increments).

GEECORR: A SAS macro for regression models of correlated binary responses and within-cluster correlation using generalized estimating equations.

Background And Objectives: Generalized estimating equations (GEE) provide population-averaged model inference for longitudinal and clustered outcomes via a generalized linear model for the effect of explanatory variables on the marginal mean, while intra-cluster correlations are ordinarily treated as nuisance parameters. Software to richly parameterize and conduct inference for complex correlation structures in the marginal modeling framework is scarce.

Methods: A SAS macro, GEECORR, has been developed for the analysis of clustered binary data based on GEE to include additional estimating equations for modeling pairwise correlation between binary variates as a function of covariates.

Safety and Effectiveness of Tenofovir Alafenamide in Usual Clinical Practice Confirms Results of Clinical Trials: TARGET-HBV.

Background: Nucleos(t)ide analogues, with a proven record of safety and efficacy, have been the therapy of choice for over a decade for the treatment of chronic hepatitis B. The approval of tenofovir alafenamide (TAF) in 2016 provided an additional treatment option.

Aims: The aim of this study was to evaluate the characteristics and clinical outcomes of patients treated with TAF in usual clinical practice.

Discovery of an Orally Efficacious Positive Allosteric Modulator of the Glucagon-like Peptide-1 Receptor.

The identification of LSN3318839, a positive allosteric modulator of the glucagon-like peptide-1 receptor (GLP-1R), is described. LSN3318839 increases the potency and efficacy of the weak metabolite GLP-1(9-36)NH to become a full agonist at the GLP-1R and modestly potentiates the activity of the highly potent full-length ligand, GLP-1(7-36)NH. LSN3318839 preferentially enhances G protein-coupled signaling by the GLP-1R over β-arrestin recruitment.

A Real-World Observational Cohort of Patients with Hepatocellular Carcinoma: Design and Rationale for TARGET-HCC.

This study describes the design of the TARGET-hepatocellular carcinoma (HCC) cohort and descriptive characteristics of the patient population at diagnosis among those who were enrolled in the cohort across academic and community clinical centers. TARGET-HCC is a 5-year, longitudinal, observational cohort of patients with HCC receiving care in usual clinical practice. Redacted clinical information, obtained from medical records, captures the natural history and management of the disease, including the safety and efficacy of treatment interventions used in usual clinical practice.

Patient Characteristics and Outcomes of 11 721 Patients With Coronavirus Disease 2019 (COVID-19) Hospitalized Across the United States.

Background: As coronavirus disease 2019 (COVID-19) disseminates throughout the United States, a better understanding of the patient characteristics associated with hospitalization, morbidity, and mortality in diverse geographic regions is essential.

Methods: Hospital chargemaster data on adult patients with COVID-19 admitted to 245 hospitals across 38 states between 15 February and 20 April 2020 were assessed. The clinical course from admission, through hospitalization, and to discharge or death was analyzed.

Lean Americans With Nonalcoholic Fatty Liver Disease Have Lower Rates of Cirrhosis and Comorbid Diseases.

Background & Aims: Nonalcoholic fatty liver disease (NAFLD) is typically associated with obesity. Little is known about the prevalence of cirrhosis in patients with NAFLD and a normal body mass index (BMI).

Methods: We determined prevalence of cirrhosis, cardiovascular disease (CVD), and metabolic abnormalities among participants in all BMI categories in the TARGET-NASH study.

High-alert medication administration and intravenous smart pumps: A descriptive analysis of clinical practice.

Background: The Institute for Safe Medication Practices (ISMP) describes high alert medications (HAM) as medications that represent a heightened risk of patient harm when used in error. IV smart pumps with dose error reduction systems (DERS) were created to help address medication administration errors. Compliance with DERS provides a measure of how accurately a hospital uses smart pump technology to reduce IV medication error.

Fox sightings in a city are related to certain land use classes and sociodemographics: results from a citizen science project.

Background: Red foxes (Vulpes vulpes L.) have become successful inhabitants of urban areas in recent years. However, our knowledge about the occurrence, distribution and association with land uses of these urban foxes is poor, partly because many favoured habitats are on private properties and therefore hardly accessible to scientists.

Understanding the influence of individual variables contributing to multivariate outliers in assessments of data quality.

Mahalanobis distance is often recommended to identify patients or clinical sites that are considered unusual in clinical trials. Patients extreme in one or more covariates may be considered outliers in that they reside some distance from the multivariate mean, which can be thought of as the center of the data cloud. Less often discussed, patients whose data are believed to be "too good to be true" are located near the centroid as inliers.

The insensitive dormouse: reproduction skipping is not caused by chronic stress in .

Entire populations of edible dormice () can skip reproduction in years without mast seeding of deciduous trees (particularly beech or oak seed), because juveniles require high-calorie seeds for growth and fattening prior to hibernation. We hypothesized that, in mast failure years, female dormice may be forced to spend larger amounts of time foraging for low-quality food, which would increase their exposure to predators, mainly owls. This may lead to chronic stress, i.

Rethinking the Clinically Based Thresholds of TransCelerate BioPharma for Risk-Based Monitoring.

Background: The quality of data from clinical trials has received a great deal of attention in recent years. Of central importance is the need to protect the well-being of study participants and maintain the integrity of final analysis results. However, traditional approaches to assess data quality have come under increased scrutiny as providing little benefit for the substantial cost.

Sources of Safety Data and Statistical Strategies for Design and Analysis: Postmarket Surveillance.

Background: Safety data are continuously evaluated throughout the life cycle of a medical product to accurately assess and characterize the risks associated with the product. The knowledge about a medical product's safety profile continually evolves as safety data accumulate.

Methods: This paper discusses data sources and analysis considerations for safety signal detection after a medical product is approved for marketing.

Sources of Safety Data and Statistical Strategies for Design and Analysis: Clinical Trials.

Background: There has been an increased emphasis on the proactive and comprehensive evaluation of safety endpoints to ensure patient well-being throughout the medical product life cycle. In fact, depending on the severity of the underlying disease, it is important to plan for a comprehensive safety evaluation at the start of any development program. Statisticians should be intimately involved in this process and contribute their expertise to study design, safety data collection, analysis, reporting (including data visualization), and interpretation.

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.

Discovery of LY3104607: A Potent and Selective G Protein-Coupled Receptor 40 (GPR40) Agonist with Optimized Pharmacokinetic Properties to Support Once Daily Oral Treatment in Patients with Type 2 Diabetes Mellitus.

As a part of our program to identify potent GPR40 agonists capable of being dosed orally once daily in humans, we incorporated fused heterocycles into our recently disclosed spiropiperidine and tetrahydroquinoline acid derivatives 1, 2, and 3 with the intention of lowering clearance and improving the maximum absorbable dose (Dabs). Hypothesis-driven structural modifications focused on moving away from the zwitterion-like structure. and mitigating the N-dealkylation and O-dealkylation issues led to triazolopyridine acid derivatives with unique pharmacology and superior pharmacokinetic properties.

Intravenous Smart Pump Drug Library Compliance: A Descriptive Study of 44 Hospitals.

Background: Although intravenous (IV) smart pumps with built-in dose-error reduction systems (DERS) can reduce IV medication administration error, most serious adverse events still occur during IV medication administration. Sources of error include overriding DERS and manually bypassing drug libraries and the DERS.

Methods: Our purpose was to use the Regenstrief National Center for Medical Device Informatics data set to better understand IV smart pump drug library and DERS compliance.

The Discovery, Preclinical, and Early Clinical Development of Potent and Selective GPR40 Agonists for the Treatment of Type 2 Diabetes Mellitus (LY2881835, LY2922083, and LY2922470).

The G protein-coupled receptor 40 (GPR40) also known as free fatty acid receptor 1 (FFAR1) is highly expressed in pancreatic, islet β-cells and responds to endogenous fatty acids, resulting in amplification of insulin secretion only in the presence of elevated glucose levels. Hypothesis driven structural modifications to endogenous FFAs, focused on breaking planarity and reducing lipophilicity, led to the identification of spiropiperidine and tetrahydroquinoline acid derivatives as GPR40 agonists with unique pharmacology, selectivity, and pharmacokinetic properties. Compounds 1 (LY2881835), 2 (LY2922083), and 3 (LY2922470) demonstrated potent, efficacious, and durable dose-dependent reductions in glucose levels along with significant increases in insulin and GLP-1 secretion during preclinical testing.

EXPLORATORY PLASMA BIOCHEMISTRY REFERENCE INTERVALS FOR URAL OWLS (STRIX URALENSIS, PALLAS 1771) FROM THE AUSTRIAN REINTRODUCTION PROJECT.

The Ural owl (Strix uralensis) is the biggest forest-living owl in Austria; however, it became extinct in Austria through poaching and habitat loss more than half a century ago. The birds examined in the present study were breeding pairs from the reintroduction project with the aim of determining exploratory plasma biochemistry reference intervals in Ural owls and evaluating the amount of biological variation between seasons, sexes, and ages. A total of 45 birds were sampled, including 13 adult males, 14 adult females, and 18 juvenile birds.

Using Contour Plots to Assess the Sensitivity of Clinical Trial Design Assumptions.

Background: Sample size calculations are an important part of the design of any clinical trial. These calculations ensure a sufficient number of patients to detect a clinically meaningful difference between 2 treatments with high probability (ie, power). Perhaps less-often discussed, the sample size exercise is important so that resources are not wasted studying too many observations to test a particular hypothesis.

Identification of potent and selective retinoic acid receptor gamma (RARγ) antagonists for the treatment of osteoarthritis pain using structure based drug design.

A series of triaryl pyrazoles were identified as potent pan antagonists for the retinoic acid receptors (RARs) α, β and γ. X-ray crystallography and structure-based drug design were used to improve selectivity for RARγ by targeting residue differences in the ligand binding pockets of these receptors. This resulted in the discovery of novel antagonists which maintained RARγ potency but were greater than 500-fold selective versus RARα and RARβ.