Randomized, Multicenter Study to Assess the Effects of Different Doses of Sildenafil on Mortality in Adults With Pulmonary Arterial Hypertension.

Background: Sildenafil, approved for pulmonary arterial hypertension (PAH), has a recommended adult dose of 20 mg TID, with a previously approved 5-mg TID dose by the US Food and Drug Administration. Safety concerns arose because of common off-label use of higher doses, particularly after pediatric data linked higher doses to increased mortality. To assess this, the Food and Drug Administration mandated a study evaluating the effects of various sildenafil doses on mortality in adults with PAH.

Reply letter to "Vaccine effectiveness of recombinant and standard dose influenza vaccines against outpatient illness during 2018-2019 and 2019-2020 calculated using a retrospective test-negative design".

A recent study by Zimmerman et al. (2023) reported non-significant higher relative vaccine effectiveness of recombinant (RIV4) over the standard-dose influenza vaccines (SDIV) against outpatient illness during the 2018-19 and 2019-20 vaccination seasons. We agree with the authors' conclusions and would like to emphasize minimal difference between RIV4 and SDIV using Number Needed to Vaccinate (NNV).

Reply letter to "Immunogenicity and safety of a quadrivalent high-dose inactivated influenza vaccine compared with a standard-dose quadrivalent influenza vaccine in healthy people aged 60 years or older: a randomized Phase III trial".

A recent study reported that the high-dose quadrivalent influenza vaccine provided superior immunogenicity and efficacy versus the standard-dose quadrivalent vaccine in the elderly. However, we need to view these results in terms of public health benefits as well. The Number Needed to Vaccinate (NNV) is an important tool to measure the benefit of a given vaccine.

Performance of Multiple-Batch Approaches to Pharmacokinetic Bioequivalence Testing for Orally Inhaled Drug Products with Batch-to-Batch Variability.

Batch-to-batch pharmacokinetic (PK) variability of orally inhaled drug products has been documented and can render single-batch PK bioequivalence (BE) studies unreliable; results from one batch may not be consistent with a repeated study using a different batch, yet the goal of PK BE is to deliver a product comparison that is interpretable beyond the specific batches used in the study. We characterized four multiple-batch PK BE approaches to improve outcome reliability without increasing the number of clinical study participants. Three approaches include multiple batches directly in the PK BE study with batch identity either excluded from the statistical model ("Superbatch") or included as a fixed or random effect ("Fixed Batch Effect," "Random Batch Effect").

Clinical Bioequivalence of Wixela Inhub and Advair Diskus in Adults With Asthma.

Wixela Inhub is a dry powder inhaler approved as a generic equivalent to Advair Diskus (fluticasone propionate [FP]/salmeterol fixed-dose combination) for patients with asthma or chronic obstructive pulmonary disease (COPD). This study aimed at confirming the local (lung) therapeutic equivalence of both the FP and salmeterol components of Wixela Inhub (test [T]) to Advair Diskus (reference [R]) after inhalation. This randomized, double-blind, double-dummy, placebo-controlled, parallel-group study in patients ≥18 years with mild-to-moderate persistent asthma compared the local therapeutic equivalence (using forced expiratory volume in 1 second [FEV]) of FP/salmeterol (100/50 μg) after inhaled delivery via T and R.

Equivalent Systemic Exposure to Fluticasone Propionate/Salmeterol Following Single Inhaled Doses from Advair Diskus and Wixela Inhub: Results of Three Pharmacokinetic Bioequivalence Studies.

Wixela Inhub was developed to deliver inhaled fluticasone propionate/salmeterol (FP/S) combination as a substitutable generic equivalent to Advair Diskus. These studies aimed to confirm the pharmacokinetic bioequivalence (BE) of FP/S after single doses of Wixela Inhub (test [T]) and Advair Diskus (reference [R]). Three open-label, randomized, two-way crossover, single-dose studies in healthy subjects ( = 66 each) compared the systemic exposure of FP and salmeterol after inhalation from three dose strengths of FP/S (100/50, 250/50, or 500/50 μg) delivered from T and R.

A Dose-Response Study Examining the Use of Methacholine Challenge to Demonstrate Local Therapeutic Equivalence of the Salmeterol Component of Generic Inhaled Fluticasone Propionate/Salmeterol Combination Products.

Asthma is widely treated using inhaled corticosteroid/long-acting beta agonist (LABA) combinations, for example, fluticasone propionate/salmeterol (FPS) dry powder inhaler, marketed as Advair Diskus. Some regulators require generics to demonstrate local (lung) therapeutic equivalence (LTE) for each component of the FPS reference, ideally with a dose-response within the approved FPS dose range. We sought to develop a methacholine challenge (MeCh) LTE methodology for assessing the LABA (salmeterol) component of FPS.

A Dose-Response Study to Examine the Methodology for Demonstrating the Local Therapeutic Equivalence of the Fluticasone Propionate Component of an Orally Inhaled Combination Therapy of Fluticasone Propionate/Salmeterol Dry Powder.

Asthma is widely treated using inhaled corticosteroid/long-acting beta-agonist combinations, such as fluticasone propionate/salmeterol (FPS) dry powder inhaler. Some regulators require generic medications to demonstrate local therapeutic equivalence (LTE) for each component of the FPS reference product. Fractional exhaled nitric oxide (F) was developed as a possible LTE endpoint for the fluticasone propionate (FP) component of FPS in a randomized, double-blind, crossover study in steroid-naive asthma patients with elevated F (≥45 parts per billion).

Particle size and gastrointestinal absorption influence tiotropium pharmacokinetics: a pilot bioequivalence study of PUR0200 and Spiriva HandiHaler.

Aims: Plasma pharmacokinetics permit the assessment of efficacy and safety of inhaled drugs, and possibly their bioequivalence to other inhaled products. Correlating drug product attributes to lung deposited dose is important to achieving equivalence. PUR0200 is a spray-dried formulation of tiotropium that enables more efficient lung delivery than Spiriva HandiHaler (HH).

A tool to assess the quality of a meta-analysis.

Background: Because meta-analyses are increasingly prevalent and cited in the medical literature, it is important that tools are available to assess their methodological quality. When performing an empirical study of the quality of published meta-analyses, we found that existing tools did not place a strong emphasis on statistical and interpretational issues.

Methods: We developed a quality-assessment tool using existing materials and expert judgment as a starting point, followed by multiple iterations of input from our working group, piloting, and discussion.

Methodological quality of meta-analyses: matched-pairs comparison over time and between industry-sponsored and academic-sponsored reports.

Context: Meta-analyses are regularly used to inform healthcare decisions. Concerns have been expressed about the quality of meta-analyses and, in particular, about those supported by the pharmaceutical industry.

Objective: The objective of this study is to compare the quality of pharmaceutical-industry-supported meta-analyses with academic meta-analyses and of meta-analyses published before and after companies started to disclose their data.

Influence of sildenafil on genital engorgement in women with female sexual arousal disorder.

Introduction: We previously described dynamic, noncontrast magnetic resonance imaging (MRI) of the female genitalia as a reproducible, nonintrusive, objective means of quantifying sexual arousal response in women without sexual difficulties. These studies showed an increase in clitoral engorgement ranging from 50 to 300% in healthy women during sexual arousal.

Aim: This study sought to evaluate the genital arousal response in women with female sexual arousal disorder (FSAD) after administration of sildenafil and placebo.

Selective endothelin-A receptor antagonism reduces proteinuria, blood pressure, and arterial stiffness in chronic proteinuric kidney disease.

Proteinuria is associated with adverse cardiovascular and renal outcomes that are not prevented by current treatments. Endothelin 1 promotes the development and progression of chronic kidney disease and associated cardiovascular disease. We, therefore, studied the effects of selective endothelin-A receptor antagonism in proteinuric chronic kidney disease patients, assessing proteinuria, blood pressure (BP), and arterial stiffness, key independent, surrogate markers of chronic kidney disease progression and cardiovascular disease risk.

Discovery of a selective small-molecule melanocortin-4 receptor agonist with efficacy in a pilot study of sexual dysfunction in humans.

The relevance of the melanocortin system to sexual activity is well established, and nonselective peptide agonists of the melanocortin receptors have shown evidence of efficacy in human sexual dysfunction. The role of the MC4 receptor subtype has received particular scrutiny, but the sufficiency of its selective activation in potentiating sexual response has remained uncertain owing to conflicting data from studies in preclinical species. We describe here the discovery of a novel series of small-molecule MC4 receptor agonists derived from library hit 2.

A placebo-controlled study investigating the efficacy and safety of the phosphodiesterase type 5 inhibitor UK-369,003 for the treatment of men with lower urinary tract symptoms associated with clinical benign prostatic hyperplasia.

Objectives: To evaluate the efficacy and safety of the phosphodiesterase type 5 inhibitor UK-369,003 for the treatment of lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) in men with and without erectile dysfunction (ED).

Patients And Methods: This was a multicentre, double-blind, placebo- and active-controlled, parallel-group study conducted across 45 centres in North and South America, Europe, and Australia. In all, 418 men aged ≥ 40 years with a clinical diagnosis of BPH, an International Prostate Symptom Score (IPSS) of ≥ 13, and maximum urinary flow rate (Q(max) ) of 5-15 mL/s for a voided volume of > 150 mL were stratified into two groups (with and without ED) and randomized to one of seven treatment groups, i.

A placebo-controlled exploratory study investigating the efficacy and safety of the phosphodiesterase type 5 inhibitor UK-369,003 for the treatment of men with storage lower urinary tract symptoms associated with a clinical diagnosis of overactive bladder.

Objectives: To evaluate the efficacy and safety of the phosphodiesterase type 5 inhibitor, UK-369,003 modified release (MR), for the treatment of storage lower urinary tract symptoms (LUTS) in men with and without erectile dysfunction (ED).

Patients And Methods: This was a multicentre, double-blind, placebo-controlled, parallel-group study conducted across 50 centres in North and South America, Europe and Australia. In all, 310 men aged ≥ 18 years with a clinical diagnosis of overactive bladder (OAB; voiding frequency ≥ 8 times/24 h, urgency episode frequency once or more per 24 h and a mean voided volume of <300 mL) and maximum urinary flow rate of >5 mL/s in a voided volume of >150 mL were stratified into two groups (with or without ED) and randomized to one of five treatment groups (10, 25, 50 or 100 mg UK-369,003; or placebo once a day) for 12 weeks.

How do pharmaceutical companies approach data from sexual health studies for regulatory agencies?

We briefly outline the importance of statistical input into clinical trial research in the pharmaceutical industry and in interactions with regulatory agencies, with particular concentration on the role of the statistician in projects on sexual health during Phases 2 and 3 of clinical trials required in bringing new drugs to the market.

Modeling and simulation of sexual activity daily diary data of patients with female sexual arousal disorder treated with sildenafil citrate (Viagra).

Purpose: To develop a model to explore the dose-response of sildenafil citrate in patients with female sexual arousal disorder (FSAD) based on telephone sexual activity daily diary (TSADD) data obtained in double-blind, placebo controlled clinical studies.

Materials: Data were available on 614 patients with FSAD. A parametric model (Weibull distribution) was developed to describe the probability density function of the time between sexual events.

Efficacy of sildenafil citrate (Viagra) in men with premature ejaculation.

Objectives: Premature ejaculation (PE) is the most common ejaculatory dysfunction. We assessed the efficacy of sildenafil to increase the time to ejaculation, improve ejaculatory control, and decrease the postejaculatory erectile refractory time in men with PE.

Design And Methods: The main study was an 8-week, double-blind, placebo-controlled, parallel group study in men between 18 and 65 years of age with diagnosed PE.

The use of the sexual function questionnaire as a screening tool for women with sexual dysfunction.

Aim: To determine if the validated Sexual Function Questionnaire (SFQ), developed to assess efficacy in female sexual dysfunction (FSD) clinical trials, may also have utility in identifying target populations for such studies.

Methods: Data from five clinical trials and two general population surveys were used to analyze the utility of the SFQ as a tool to discriminate between the presence of specific components of FSD (i.e.

Safety and efficacy of sildenafil citrate for the treatment of female sexual arousal disorder: a double-blind, placebo controlled study.

Purpose: We evaluated the efficacy and safety of sildenafil citrate in spontaneously or surgically postmenopausal women with female sexual arousal disorder (FSAD).

Materials And Methods: Sildenafil (a 50 mg dose adjustable to 100 or 25 mg) was evaluated in a 12-week, double-blind, placebo controlled study in 202 postmenopausal women with FSAD who had protocol specified estradiol and free testosterone concentrations, and/or were receiving estrogen and/or androgen replacement therapy. Patients were excluded if emotional, relationship or historical abuse issues contributed significantly to sexual dysfunction.