Participation of Women in Clinical Trials Supporting FDA Approval of Cardiovascular Drugs.

BACKGROUND: Concerns exist that women are underrepresented in trials of cardiovascular medications. OBJECTIVES: The authors sought to examine women's participation and the reported safety and efficacy by gender for pivotal cardiovascular disease (CVD) trials submitted to the U.S. Food and Drug Administration (FDA) supporting marketing applications. METHODS: On the basis of publicly available FDA reviews, the authors assessed enrollment of women in trials supporting 36 drug approvals from 2005 to 2015. Prevalence-corrected estimates for the participation of women were calculated as the percentage of women among trial participants divided by the percentage of women in the disease population (participation to prevalence ratio [PPR]), with a range between 0.8 and 1.2 reflecting similar representation of women in the trial and disease population. Sex differences in efficacy and safety were assessed. RESULTS: The proportion of women enrolled ranged from 22% to 81% (mean 46%). The calculated PPR by disease area was within or above the desirable range for atrial fibrillation (0.8 to 1.1), hypertension (0.9), and pulmonary arterial hypertension (1.4); PPR was <0.8 for heart failure (0.5 to 0.6), coronary artery disease (0.6), and acute coronary syndrome/myocardial infarction (0.6). The authors found little indication of clinically meaningful gender differences in efficacy or safety. Gender differences in efficacy or safety were described in labeling for 4 drugs. CONCLUSIONS: Women were well represented in trials of drugs for hypertension and atrial fibrillation, and overrepresented for pulmonary arterial hypertension. Representation of women fell below a PPR of 0.8 for trials in heart failure, coronary artery disease, and acute coronary syndrome. Minimal gender differences in drug efficacy and safety profiles were observed.

Representation of Women and Minorities in Clinical Trials for New Molecular Entities and Original Therapeutic Biologics Approved by FDA CDER from 2013 to 2015.

BACKGROUND: The U.S. Food and Drug Administration (FDA) has made efforts to encourage adequate assessment of women, racial/ethnic minorities, and geriatric participants in clinical trials through regulations and guidance documents. This study surveyed the demographics of clinical trial participants and the presence of efficacy and safety analyses by sex for new drugs approved between 2013 and 2015 by the FDA Center for Drug Evaluation and Research. METHODS: New drug marketing applications submitted to FDA were surveyed for demographic data (sex, race, ethnicity, and age) and the presence of sex-based analyses for efficacy and safety. The Ratio of the Proportion of women in clinical trials for the indicated disease population relative to the estimated Proportion of women in the disease population (PPR) was calculated for new drug indications. RESULTS: Of the 102 new drugs in this cohort (defined as new molecular entity drugs and original therapeutic biologics), sex was reported for >99.9% of trial participants, and women accounted for 40.4% of these participants. An estimated 77.2% of participants were White, 6.4% were Black/African American, and 29.1% were aged ≥65 years. Sex-based analyses for both efficacy and safety were conducted for 93.1% of applications. PPR was calculated for 82 new drugs for a total of 60 indications, of which 50 indications (83.3%) had a PPR ≥0.80. CONCLUSIONS: Sex data are now collected for almost all study participants, and this study shows appropriate sex participation for most new drugs when estimated disease prevalence by sex (PPR) is considered. Therapeutic area and disease indication are important considerations when assessing the sex of participants because variation occurs depending on the disease under study. Some racial minorities, especially Blacks/African Americans, are still not well represented in most drug development programs and remain an area where improvement is needed.

The Food and Drug Administration Office of Women's Health: Impact of Science on Regulatory Policy: An Update.

The U.S. Food and Drug Administration Office of Women's Health (FDA OWH) has supported women's health research for ∼20 years, funding more than 300 studies on women's health issues, including research on diseases/conditions that disproportionately affect women in addition to the evaluation of sex differences in the performance of and response to medical products. These important women's health issues are studied from a regulatory perspective, with a focus on improving and optimizing medical product development and the evaluation of product safety and efficacy in women. These findings have influenced industry direction, labeling, product discontinuation, safety notices, and clinical practice. In addition, OWH-funded research has addressed gaps in the knowledge about diseases and medical conditions that impact women across the life span such as cardiovascular disease, pregnancy, menopause, osteoporosis, and the safe use of numerous medical products.

The mechanoelectrical response of the cytoplasmic membrane of Vibrio cholerae.

Persistence of Vibrio cholerae in waters of fluctuating salinity relies on the capacity of this facultative enteric pathogen to adapt to varying osmotic conditions. In an event of osmotic downshift, osmolytes accumulated inside the bacterium can be quickly released through tension-activated channels. With the newly established procedure of giant spheroplast preparation from V. cholerae, we performed the first patch-clamp characterization of its cytoplasmic membrane and compared tension-activated currents with those in Esherichia coli. Saturating pressure ramps revealed two waves of activation belonging to the ∼1-nS mechanosensitive channel of small conductance (MscS)-like channels and ∼3-nS mechanosensitive channel of large conductance (MscL)-like channels, with a pressure midpoint ratio p0.5MscS/p0.5MscL of 0.48. We found that MscL-like channels in V. cholerae present at a density three times higher than in E. coli, and yet, these vibrios were less tolerant to large osmotic downshocks. The Vibrio MscS-like channels exhibit characteristic inward rectification and subconductive states at depolarizing voltages; they also adapt and inactivate at subsaturating tensions and recover within 2 s upon tension release, just like E. coli MscS. Trehalose, a compatible internal osmolyte accumulated under hypertonic conditions, significantly shifts activation curves of both MscL- and MscS-like channels toward higher tensions, yet does not freely partition into the channel pore. Direct electrophysiology of V. cholerae offers new avenues for the in situ analysis of membrane components critical for osmotic survival and electrogenic transport in this pathogen.