Baricitinib for systemic lupus erythematosus: a double-blind, randomised, placebo-controlled, phase 3 trial (SLE-BRAVE-I).

Background: Baricitinib is an oral selective inhibitor of Janus kinase 1 and 2 approved for the treatment of rheumatoid arthritis, atopic dermatitis, and alopecia areata. In a 24-week phase 2 study in patients with systemic lupus erythematosus (SLE), baricitinib 4 mg significantly improved SLE disease activity compared with placebo. The objective of this trial was to evaluate the efficacy and safety of baricitinib in patients with active SLE in a 52-week phase 3 study.

Interdisciplinary Safety Evaluation for Learning and Decision-Making.

The FDA IND safety reporting Final Rule (21CFR 312.32) applies to all human drugs and biological products being studied under an Investigational New Drug (IND). A sponsor must file an IND safety report for any serious unexpected suspected adverse reaction (SUSAR) of a medicinal product being investigated.

Baricitinib-associated changes in global gene expression during a 24-week phase II clinical systemic lupus erythematosus trial implicates a mechanism of action through multiple immune-related pathways.

Objective: To characterise the molecular pathways impacted by the pharmacologic effects of the Janus kinase (JAK) 1 and JAK2 inhibitor baricitinib in SLE.

Methods: In a phase II, 24-week, randomised, placebo-controlled, double-blind study (JAHH), RNA was isolated from whole blood in 274 patients and analysed using Affymetrix HTA2.0 array.

Adaptation of the robust method to large distributions of reference values: program modifications and comparison of alternative computational methods.

The objective of this research was to compute reference limits using reference values from patients entering pharmaceutical development clinical trials by the nonparametric method and the robust method of Horn and Pesce, with and without outlier exclusion, and compare the methods with respect to influence on the limits. Reference limits were computed for 38 analytes with over 130,000 subjects contributing reference values. Subjects were partitioned into 10 demographic strata for limit computation.

Reference Limits for Outlier Analyses in Randomized Clinical Trials.

Background: Reference limits used in clinical medicine to screen and manage patients are typically developed nonparametrically using reference values from a limited number of healthy subjects using a 95th percentile reference interval. We have evaluated alternative methods of computation and the resulting limits for use in the analyses of treatment-emergent outliers in clinical trials.

Methods: We developed a set of alternative reference limits for 38 laboratory analytes based on alternative statistical methods and assessed their relative performance in clinical trial analysis.

Reporting Adverse Drug Reactions in Product Labels.

Product labels are intended to provide health care professionals with clear and concise prescribing information that will enhance the safe and effective use of drug products. In this manuscript, we offer suggestions to improve product labels. First, we recommend that product labels that include comparator data be changed to include adjusted incidence proportions (or adjusted incidence rates when needed and appropriate) for adverse drug reactions that are somewhat common.

The FDA's Final Rule on Expedited Safety Reporting: Statistical Considerations.

In March 2011, a Final Rule for expedited reporting of serious adverse events took effect in the United States for studies conducted under an Investigational New Drug (IND) application. In December 2012, the U.S.

Seeing is believing: good graphic design principles for medical research.

Have you noticed when you browse a book, journal, study report, or product label how your eye is drawn to figures more than to words and tables? Statistical graphs are powerful ways to transparently and succinctly communicate the key points of medical research. Furthermore, the graphic design itself adds to the clarity of the messages in the data. The goal of this paper is to provide a mechanism for selecting the appropriate graph to thoughtfully construct quality deliverables using good graphic design principles.

Protocol for a mixed-methods study of supplemental oxygen in pulmonary fibrosis.

Background: Little is known about whether or how supplemental oxygen affects patients with pulmonary fibrosis.

Methods/design: A mixed-methods study is described. Patients with pulmonary fibrosis, informal caregivers of pulmonary fibrosis patients and practitioners who prescribe supplemental oxygen will be interviewed to gather data on perceptions of how supplemental oxygen impacts patients.

Prospective safety surveillance of GH-deficient adults: comparison of GH-treated vs untreated patients.

Context: In clinical practice, the safety profile of GH replacement therapy for GH-deficient adults compared with no replacement therapy is unknown.

Objective: The objective of this study was to compare adverse events (AEs) in GH-deficient adults who were GH-treated with those in GH-deficient adults who did not receive GH replacement.

Design And Setting: This was a prospective observational study in the setting of US clinical practices.

Comparison of Bayesian and frequentist meta-analytical approaches for analyzing time to event data.

Using meta-analysis in health care research is a common practice. Here we are interested in methods used for analysis of time-to-event data. Particularly, we are interested in their performance when there is a low event rate.

Meta-analysis of clinical trial safety data in a drug development program: answers to frequently asked questions.

Background: Meta-analyses of clinical trial safety data have risen in importance beyond regulatory submissions. During drug development, sponsors need to recognize safety signals early and adjust the development program accordingly, so as to facilitate the assessment of causality. Once a product is marketed, sponsors add postapproval clinical trial data to the body of information to help understand existing safety concerns or those that arise from other postapproval data sources, such as spontaneous reports.

Planning and core analyses for periodic aggregate safety data reviews.

Background: In 2009, the Safety Planning, Evaluation and Reporting Team gave detailed recommendations for a well-planned and systematic approach for safety data collection and analysis. Important aspects of this approach included regular reviews of aggregate data by a multidisciplinary team focusing on safety.

Purpose: This article provides information to facilitate the planning and implementation of aggregate data reviews.

Recommendations for safety planning, data collection, evaluation and reporting during drug, biologic and vaccine development: a report of the safety planning, evaluation, and reporting team.

Background: The Safety Planning, Evaluation and Reporting Team (SPERT) was formed in 2006 by the Pharmaceutical Research and Manufacturers of America.

Purpose: SPERT's goal was to propose a pharmaceutical industry standard for safety planning, data collection, evaluation, and reporting, beginning with planning first-in-human studies and continuing through the planning of the post-product-approval period.

Methods: SPERT's recommendations are based on our review of relevant literature and on consensus reached in our discussions.

Comparison of several imputation methods for missing baseline data in propensity scores analysis of binary outcome.

We performed a simulation study comparing the statistical properties of the estimated log odds ratio from propensity scores analyses of a binary response variable, in which missing baseline data had been imputed using a simple imputation scheme (Treatment Mean Imputation), compared with three ways of performing multiple imputation (MI) and with a Complete Case analysis. MI that included treatment (treated/untreated) and outcome (for our analyses, outcome was adverse event [yes/no]) in the imputer's model had the best statistical properties of the imputation schemes we studied. MI is feasible to use in situations where one has just a few outcomes to analyze.

Growth hormone treatment of early growth failure in toddlers with Turner syndrome: a randomized, controlled, multicenter trial.

Context: Typically, growth failure in Turner syndrome (TS) begins prenatally, and height sd score (SDS) declines progressively from birth.

Objective: This study aimed to determine whether GH treatment initiated before 4 yr of age in girls with TS could prevent subsequent growth failure. Secondary objectives were to identify factors associated with treatment response, to determine whether outcome could be predicted by a regression model using these factors, and to assess the safety of GH treatment in this young cohort.

Genotypes and phenotypes in children with short stature: clinical indicators of SHOX haploinsufficiency.

Background: Short stature affects approximately 2% of children, representing one of the more frequent disorders for which clinical attention is sought during childhood. Despite assumed genetic heterogeneity, mutations or deletions of the short stature homeobox-containing gene (SHOX) are found quite frequently in subjects with short stature. Haploinsufficiency of the SHOX gene causes short stature with highly variable clinical severity, ranging from isolated short stature without dysmorphic features to Léri-Weill syndrome, and with no functional copy of the SHOX gene, Langer syndrome.

Growth hormone is effective in treatment of short stature associated with short stature homeobox-containing gene deficiency: Two-year results of a randomized, controlled, multicenter trial.

Background: The short stature homeobox-containing gene, SHOX, located on the distal ends of the X and Y chromosomes, encodes a homeodomain transcription factor responsible for a significant proportion of long-bone growth. Patients with mutations or deletions of SHOX, including those with Turner syndrome (TS) who are haplo-insufficient for SHOX, have variable degrees of growth impairment, with or without a spectrum of skeletal anomalies consistent with dyschondrosteosis.

Objective: Our objective was to determine the efficacy of GH in treating short stature associated with short stature homeobox-containing gene deficiency (SHOX-D).

Effect of growth hormone dose on bone maturation and puberty in children with idiopathic short stature.

Context: GH at 0.22 mg/kg.wk has been shown to have no effect on pubertal onset or pace, whereas GH at 0.

The phenotype of short stature homeobox gene (SHOX) deficiency in childhood: contrasting children with Leri-Weill dyschondrosteosis and Turner syndrome.

Objective: To evaluate the growth disorder and phenotype in prepubertal children with Leri-Weill dyschondrosteosis (LWD), a dominantly inherited skeletal dysplasia, and to compare the findings from girls with Turner syndrome (TS).

Study Design: We studied the auxologic and phenotypic characteristics in 34 prepubertal LWD subjects (ages 1 to 10 years; 20 girls, 14 boys) with confirmed short stature homeobox-containing gene (SHOX) abnormalities. For comparative purposes, we evaluated similar physical and growth parameters in 76 girls with TS (ages 1 to 19 years) and 24 girls with LWD (ages 1 to 15 years) by using data collected from the postmarketing observational study, GeNeSIS.

Safety of growth hormone treatment in pediatric patients with idiopathic short stature.

Context: Recombinant human GH was approved by the United States Food and Drug Administration in 2003 for the treatment of idiopathic short stature (ISS). However, to date, the safety of GH in this patient population has not been rigorously studied.

Objective: The objective of this study was to address the safety of GH treatment in children with ISS compared with GH safety in patient populations for which GH has been approved previously: Turner syndrome (TS) and GH deficiency (GHD).

Growth hormone (GH) treatment to final height in children with idiopathic short stature: evidence for a dose effect.

Objectives: To investigate in an open-label randomized study, the effect of two doses of growth hormone (GH) on final height and height velocity during the first 2 years of treatment of children with idiopathic short stature (mean baseline height standard deviation score [SDS] -3.2).

Study Design: Patients were treated with GH at 0.