U.S. racial and ethnic participation in global clinical trials by therapeutic areas.

WHAT IS KNOWN AND OBJECTIVE: The discussion about health equity in the United States frequently involves concerns over racial and ethnic minority under-representation in clinical trials and particularly in trials conducted in support of product approvals. The FDA has long worked to encourage diverse participation in clinical trials and through its Drug Trials Snapshots (DTS) program, the U.S. Food and Drug Administration (FDA) has moved to make trial demographic data more accessible and transparent. We conducted a demographic study of U.S. participants in clinical trials for FDA-approved new drugs (new molecular entities [NMEs], and original Biologics License Applications [BLAs]) from 2015 to 2019, as reported in DTS database with a purpose of understanding the extent to which U.S.-based trials used to support product approvals represent the racial and ethnic diversity of the U.S. population by therapeutic area. METHODS: Participant-level trial data were collected by accessing the FDA electronic common technical document (eCTD), for the applications used to publish each Snapshot. The therapeutic area (TA) for each drug was determined by review division assignment. The demographic data were analysed and compared to U.S. census data. RESULTS AND DISCUSSION: We examined 102,596 U.S. participants in trials of new drugs that were approved and presented in Drug Trials Snapshots between 2015 and 2019. White participation ranged from 51% in psychiatric trials to 90% in cardiovascular (CV) trials; Black or African American participation ranged from 5% in medical imaging to 45% in psychiatric trials; Asian participation ranged from 0.75% in CV to 4% in dermatologic trials; and Hispanic or Latino participation ranged from 1% in medical imaging to 22% in infectious diseases and gastroenterology trials. WHAT IS NEW AND CONCLUSION: Our data showed variable representation of racial and ethnic minorities across therapeutic areas at the U.S. sites. Blacks or African Americans were represented at or above U.S. census estimates across most therapeutic areas, while Asians and American Indian or Alaska Natives were consistently underrepresented. Hispanic or Latino participation across most therapeutic areas was below U.S. census estimates, however, more variable, and a sizable proportion of data was missing. The next step is a comparison of trial participation based on disease prevalence and epidemiology, which is a more accurate assessment of trial diversity.

Assessing and communicating heterogeneity of treatment effects for patient subpopulations: Keynote and panel discussion on communicating heterogeneous treatment effects across populations.

How do we communicate nuanced regulatory information to different audiences, recognizing that the consumer audience is very different from the physician audience? In particular, how do we communicate the heterogeneity of treatment effects - the potential differences in treatment effects based on sex, race, and age? That is a fundamental question at the heart of this panel discussion. Each panelist addressed a specific "challenge question" during their 5-minute presentation, and the list of questions is provided. The presentations were followed by a question and answer session with members of the audience and the panelists.

Developing a Charlson Comorbidity Index for the American Indian Population Using the Epidemiologic Data from the Strong Heart Study.

Background: The Charlson Comorbidity Index (CCI) is a frequently used mortality predictor based on a scoring system for the number and type of patient comorbidities health researchers have used since the late 1980s. The initial purpose of the CCI was to classify comorbid conditions, which could alter the risk of patient mortality within a one-year time frame. However, the CCI may not accurately reflect risk among American Indians because they are a small proportion of the U.S. population and possibly lack representation in the original patient cohort. A motivating factor in calibrating a CCI for American Indians is that this population, as a whole, experiences a greater burden of comorbidities, including diabetes mellitus, obesity, cancer, cardiovascular disease, and other chronic health conditions, than the rest of the U.S. population. Methods: This study attempted to modify the CCI to be specific to the American Indian population utilizing the data from the still ongoing The Strong Heart Study (SHS) - a multi-center population-based longitudinal study of cardiovascular disease among American Indians.A one-year survival analysis with mortality as the outcome was performed using the SHS morbidity and mortality surveillance data and assessing the impact of comorbidities in terms of hazard ratios with the training cohort. A Kaplan-Meier plot for a subset of the testing cohort was used to compare groups with selected mCCI-AI scores. Results: A total of 3,038 Phase VI participants from the SHS comprised the study population for whom mortality and morbidity surveillance data were available through December 2019. The weights generated by the SHS participants for myocardial infarction, congestive heart failure, and high blood pressure were greater than Charlson's original weights. In addition, the weights for liver illness were equivalent to Charlson's severe form of the disease. Lung cancer had the greatest overall weight derived from a hazard ratio of 8.308. Conclusions: The mCCI-AI was a statistically significant predictor of one-year mortality, classifying patients into different risk strata X2 (8, N = 1,245) = 30.56 (p = .0002). The mCCI-AI exhibited superior performance over the CCI, able to discriminate between participants who died and those who survived 73% of the time.

Working Together to Address Women's Health in Research and Drug Development: Summary of the 2017 Women's Health Congress Preconference Symposium.

Historically, women have been underrepresented in clinical research, requiring physicians to extrapolate medical recommendations for women from clinical research done in cohorts consisting predominantly of male participants. While government-funded clinical research has achieved gender parity in phase-3 clinical trials across many biomedical disciplines, improvements are still needed in several facets of women's health research, such as the inclusion of women in early-phase clinical trials, the inclusion of pregnant women and women with physical and intellectual disabilities, the consideration of sex as a biological variable in preclinical research, and the analysis and reporting of sex and gender differences across the full biomedical research continuum. The National Institutes of Health (NIH) Office of Research on Women's Health and the Office of Women's Health of the U.S. Food and Drug Administration (FDA) cosponsored a preconference symposium at the 25th Annual Women's Health Congress, held in Arlington, VA in April, 2017, to highlight gains made and remaining needs regarding the representation of women in clinical research, to introduce innovative procedures and technologies, and to outline revised policy for future studies. Six speakers presented information on a range of subjects related to the representation of women in clinical research and federal initiatives to advance precision medicine. Topics included the following: the return on investment from the NIH-funded Women's Health Initiative; progress in including women in clinical trials for FDA-approved drugs and products; the importance of clinical trials in pregnant women; FDA initiatives to report drug safety during pregnancy; the NIH-funded All of Us Research Program; and efforts to enhance FDA transparency and communications, including the introduction of Drug Trials Snapshots. This article summarizes the major points of the presentations and the discussions that followed.

Neuroprotective effects of hyperbaric oxygen treatment in experimental focal cerebral ischemia are associated with reduced brain leukocyte myeloperoxidase activity.

OBJECTIVE: Hyperbaric oxygen (HBO) reduces cerebral infarct size after middle cerebral artery occlusion (MCAO) in rats through an unknown mechanism. In other forms of injury, cellular protection with HBO is associated with diminished infiltration of polymorphonuclear neutrophils (PMN). We hypothesized that HBO given prior to or after MCAO reduces PMN infiltration into the brain, and that decreased PMN infiltration is associated with improved functional and anatomic outcome. METHODS: Forty rats underwent MCAO and were randomized to pretreatment with HBO (3 ATA) immediately prior to (n=13), or posttreatment immediately after surgery (n=12), or to control (air 1 ATA) (n=15). Five rats underwent sham surgery. Neurologic outcome was measured at 24 h in all animals. Brain myeloperoxidase (MPO) activity (n=22) and infarct volume (n=23) were determined. RESULTS: MPO activity was significantly higher in controls (mean 0.28, 95% C.I. 0.17-0.38) than in the HBO pretreatment group (0.12, 0.08-0.16), HBO posttreatment group (0.16, 0.13-0.19), and the sham group (0.02, -0.02 to 0.05). HBO treated animals also had better neurologic outcomes (pretreatment 1.5, 0.9-2.1, posttreatment 2.6, 2.0-3.2) and smaller infarcts (pretreatment 27%, 18-37%, posttreatment 28%, 19-37%) than controls (neurologic outcome 3.7, 3.1-4.4, infarct volume 39%, 30-48%). Neurologic outcomes correlate better with MPO activity (R(2)=0.75) than with infarct volume (R(2)=0.25). CONCLUSION: These data confirm the neuroprotective effects of HBO in cerebral ischemia and suggest that the mechanism of this action may involve inhibition of PMN infiltration in the injured brain.