Exploratory analyses of clinical trial data used for health technology assessments: a retrospective evaluation.

Objectives: To examine the validity and statistical limitations of exploratory analyses of clinical trial data commonly requested by agencies responsible for determining which medical products may be financed or reimbursed by a healthcare system.

Design: This was a retrospective review of efficacy and safety analyses conducted for German Health Technology Assessment (HTA) evaluations with a decision date between 2015 and 2020, and an illustrative safety-related exploratory analysis of data from two phase III clinical trials of verubecestat (an anti-amyloid drug whose development was stopped for lack of efficacy) as would be mandated by the German HTA agency.

Results: We identified 422 HTA evaluations of 404 randomised controlled clinical trials.

Global Regulatory Landscape for Aggregate Safety Assessments: Recent Developments and Future Directions.

Notwithstanding successful harmonization efforts, the global regulatory framework governing product safety is complex and continually evolving, as evidenced by additional regional guidance and regulations. In this regulatory review, we provide an overview from both global and regional perspectives. A historical perspective, with a focus on recent developments, enables identification of important long-term trends, such as a shift from single-case medical review of serious adverse events to an interdisciplinary evaluation of aggregate data for the purpose of judging product causality and informing benefit-risk assessments.

Statistical Practices of Safety Monitoring: An Industry Survey.

The Biopharmaceutical Section of the American Statistical Association (ASA) formed a Safety Monitoring Working Group to strengthen collaborations between biostatisticians and safety scientists. The task began by surveying current needs and practices regarding available statistical safety tools and methods, regulatory guidance, and processes needed to support their implementation. The goal is for biostatisticians to become fully engaged safety team members by having the necessary safety skill set including appropriate methodology, regulatory guidance and access to appropriate tools.

Correction: wai, m.g.C., et Al. A review of pinealectomy-induced melatonin-deficient animal models for the study of etiopathogenesis of adolescent idiopathic scoliosis. Int. J. Mol. Sci. 2014, 15, 16484-16499.

The authors wish to make the following corrections to this paper [1]: The first name and surname of the authors were reversed. It should be corrected in the following format (with the surname in bold text):[..

Abnormal response of the proliferation and differentiation of growth plate chondrocytes to melatonin in adolescent idiopathic scoliosis.

Abnormalities in the melatonin signaling pathway and the involvement of melatonin receptor MT2 have been reported in patients with adolescent idiopathic scoliosis (AIS). Whether these abnormalities were involved in the systemic abnormal skeletal growth in AIS during the peripubertal period remain unknown. In this cross-sectional case-control study, growth plate chondrocytes (GPCs) were cultured from twenty AIS and ten normal control subjects.

A review of pinealectomy-induced melatonin-deficient animal models for the study of etiopathogenesis of adolescent idiopathic scoliosis.

Adolescent idiopathic scoliosis (AIS) is a common orthopedic disorder of unknown etiology and pathogenesis. Melatonin and melatonin pathway dysfunction has been widely suspected to play an important role in the pathogenesis. Many different types of animal models have been developed to induce experimental scoliosis mimicking the pathoanatomical features of idiopathic scoliosis in human.

C-TOC (Cognitive Testing on Computer): investigating the usability and validity of a novel self-administered cognitive assessment tool in aging and early dementia.

Introduction: Cognitive Testing on Computer (C-TOC) is a novel computer-based test battery developed to improve both usability and validity in the computerized assessment of cognitive function in older adults.

Methods: C-TOC's usability was evaluated concurrently with its iterative development to version 4 in subjects with and without cognitive impairment, and health professional advisors representing different ethnocultural groups. C-TOC version 4 was then validated against neuropsychological tests (NPTs), and by comparing performance scores of subjects with normal cognition, Cognitive Impairment Not Dementia (CIND) and Alzheimer disease.

Variations in the efficacy of resistant maltodextrin on body fat reduction in rats fed different high-fat models.

Many studies have utilized a variety of methods to induce obesity in rodents, but they often received inconsistent results. The present study intended to use resistant maltodextrin (RMD) as a means to investigate the variations in its efficacy on body fat accumulation under the influence of four high-fat (HF) models of 23% or 40% total fat, comprising soybean oil, lard, and/or condensed milk. Results indicated that integrating condensed milk into the diets could help increase diet intake, boost energy intake, increase weight gain, and enhance fat formation.

A predictive Bayesian approach to the design and analysis of bridging studies.

Pharmaceutical product development culminates in confirmatory trials whose evidence for the product's efficacy and safety supports regulatory approval for marketing. Regulatory agencies in countries whose patients were not included in the confirmatory trials often require confirmation of efficacy and safety in their patient populations, which may be accomplished by carrying out bridging studies to establish consistency for local patients of the effects demonstrated by the original trials. This article describes and illustrates an approach for designing and analyzing bridging studies that fully incorporates the information provided by the original trials.

Safety and tolerability of zoster vaccine in adults ≥60 years old.

Objective: To evaluate the general safety of zoster vaccine (ZV) in adults ≥60 years old.

Patients/methods: Subjects were enrolled in a 1:1 ratio to receive 1 dose of ZV or placebo. Subjects were followed for serious adverse experiences (SAEs) for 42 days (primary follow-up period) and 182 days (secondary follow-up period) postvaccination.

Abnormal melatonin receptor 1B expression in osteoblasts from girls with adolescent idiopathic scoliosis.

Melatonin signaling dysfunction has been associated with the etiology of adolescent idiopathic scoliosis (AIS). Genetic analysis has also associated the occurrence of AIS with the MT2 gene. Thus, we determined whether there is abnormality in the protein expression of melatonin receptors (MT) in AIS osteoblasts.

Handling missing data in vaccine clinical trials for immunogenicity and safety evaluation.

In clinical trials, study subjects are usually followed for a period of time after treatment, and the missing data issue is almost inevitable due to various reasons, including early dropout or lost-to-follow-up. It is important to take the missing data into consideration at the study design stage to minimize its occurrence throughout the study and to prospectively account for it in the analyses. There are many methods available in the literature that are designed to handle the missing data issue under various settings.

Effect of a zoster vaccine on herpes zoster-related interference with functional status and health-related quality-of-life measures in older adults.

Objective: To determine the efficacy of a zoster vaccine on herpes zoster (HR)-related interference with activities of daily living (ADLs) and health-related quality of life (HRQL).

Design: Randomized double-blind placebo controlled trial.

Setting: Twenty-two U.

Abnormal proliferation and differentiation of osteoblasts from girls with adolescent idiopathic scoliosis to melatonin.

Melatonin deficiency has been postulated as an etiologic factors in adolescent idiopathic scoliosis (AIS). In previous studies, melatonin was shown to regulate skeletal growth and bone formation in both humans and rats. Although it remains controversial whether there are differences in serum melatonin level between AIS and control subjects, melatonin signaling pathway dysfunction in osteoblasts has been reported in patients with AIS.

Correlation of Risser sign, radiographs of hand and wrist with the histological grade of iliac crest apophysis in girls with adolescent idiopathic scoliosis.

Study Design: A correlation analysis between histologic grade (HG) of iliac crest apophysis and skeletal age assessments.

Objective: To study the correlation between HGs of iliac crest apophysis and the skeletal age of hand and wrist, digital skeletal age (DSA), and Risser sign in the girls with adolescent idiopathic scoliosis (AIS).

Summary Of Background Data: The evaluation of the remaining growth of the patients clinically and radiologically is highly significant in predicting the curve progression and thus influencing the treatment strategy in AIS.

Comparison of the levels of immunogenicity and safety of Zostavax in adults 50 to 59 years old and in adults 60 years old or older.

Zostavax has been shown to be efficacious in the prevention of herpes zoster and generally well tolerated in clinical trials among subjects 60 years old or older. This prespecified combined analysis from two studies compares the levels of immunogenicity and safety of Zostavax in subjects 50 to 59 years old versus those in subjects >or=60 years old. Varicella-zoster virus (VZV) antibody (Ab) titers were measured by glycoprotein enzyme-linked immunosorbent assay at baseline and 4 weeks postvaccination.

A double-blind, randomized, controlled, multicenter safety and immunogenicity study of a refrigerator-stable formulation of Zostavax.

The vaccine Zostavax has been shown to prevent herpes zoster (HZ) and postherpetic neuralgia and is recommended for individuals > or =60 years of age. This study compared the safety and the immunogenicity of a refrigerator-stable formulation (Zostavax refrigerated) with those of the current formulation (Zostavax frozen) in subjects > or =50 years of age. Subjects with a negative history for HZ were randomized 1:1 to receive one dose of either formulation.

Safety and immunogenicity profile of the concomitant administration of ZOSTAVAX and inactivated influenza vaccine in adults aged 50 and older.

Objectives: To evaluate the safety and immunogenicity of ZOSTAVAX administered concomitantly with inactivated influenza vaccine or sequentially in adults aged 50 and older.

Design: Randomized, blinded, placebo-controlled study.

Setting: Thirteen U.

Immunogenicity of Oka/Merck varicella vaccine in children vaccinated at 12-14 months of age versus 15-23 months of age.

Objective: Recent reports suggest that breakthrough varicella may be more common in children when the Oka/Merck varicella vaccine is given at 12-14 months of age than when it is given at older ages. An analysis of 5 postlicensure clinical trials with this vaccine was conducted to evaluate immune response relative to the age of the vaccine recipient.

Methods: In 5 clinical trials, 3771 children, 12 through 23 months of age with no history of varicella, received an injection of varicella vaccine.

Correlation coefficient inference on censored bioassay data.

In vaccine clinical trials, immunologic responses sometimes can not be accurately measured by bioassays. For example, a serial dilution assay usually reports the range of the response instead of the exact value. In some other assays, the measurement is not available if the response is lower than the assay's detection limit.

Measurement of cell-mediated immunity with a Varicella-Zoster Virus-specific interferon-gamma ELISPOT assay: responses in an elderly population receiving a booster immunization.

An interferon-gamma ELISPOT assay has been developed for assessment of cellular immune responses to Varicella-Zoster Virus (VZV) in large, multi-center clinical vaccine trials. We show that the assay performed best when testing peripheral blood mononuclear cells (PBMCs) that had been isolated and then frozen on the same day as blood was drawn, and that freezing PBMCs from blood that was stored overnight before processing resulted in dramatically reduced responses. This assay was used to monitor cell-mediated immunity (CMI) in response to a booster immunization with an investigational live, attenuated VZV vaccine in an elderly population that had been vaccinated 8-10 years previously.