Enhancing Diversity and Inclusion in Clinical Trials.

Women and people from most racial and ethnic groups in the United States have historically been under-represented in clinical trials of investigational medical products. Inadequate representation of these groups may lead to an incomplete understanding of the safety and efficacy of new drugs, devices, biologics, and vaccines, and limit the generalizability of trial findings. As a result, new medical products may not be beneficial to all people who need them, and existing inequities in outcomes among various population groups may remain unchanged or worsen, or new disparities may arise. Although much work has focused on study-level strategies, research organizations must make systemic changes to how clinical trials are envisioned and implemented to achieve sustainable support for diversity and inclusion in clinical trials. The Clinical Trials Transformation Initiative (CTTI) conducted interviews with leaders at institutions that conduct clinical trials to explore perspectives on organizational-level practices that promote diversity and inclusion in clinical trials. Leaders described motivations, such as an ethical and moral imperative; organizational practices, such as staff investment and resource allocation; perceived return on investments, such as better science; and deterrents, such as cost and time. The CTTI also convened an expert meeting to discuss the interview findings and provide guidance. We present the interview findings and expert guidance in a framework that describes four key areas-commitment, partnerships, accountability, and resources-on sustaining organizational-level approaches for improving diversity and inclusion in clinical trials, with the ultimate goal of advancing health equity. Institutions who conduct and support clinical trials should implement organizational-level approaches to improve equitable access and diverse patient participation in clinical trials.

Behaviors Related to Medication Safety and Use During Pregnancy.

Background: Most women take medication during pregnancy despite limited scientific evidence on safety. We investigated medication use, including changes in and reasons for changes in use during pregnancy, with attention to medication use in pregnant women with chronic conditions. Materials and Methods: We conducted an online survey of pregnant women aged ≥18 years (n = 1,226). We calculated descriptive statistics for aspects of medication use and performed multivariable logistic regression to examine associations between change in use and chronic conditions. Results: Seventy-nine percent of women took at least one medication during pregnancy. Among those, 63.2% made at least one medication change: 42.0% started, 34.9% stopped, 30.0% missed dose(s), and 18.1% lowered dose(s) from that originally prescribed or recommended. More than a third (36.5%) of women who stopped, lowered, or missed medication did so independent of health care provider advice; 54.0% cited concern about birth or developmental defects as reasons for change. Odds of medication change were higher for women with chronic conditions: digestive conditions-starting (adjusted odds ratio [AOR] = 1.8, 95% confidence interval [CI] = 1.1-2.7), stopping (AOR = 2.1, 95% CI = 1.4-3.3), and lowering (AOR = 2.4, 95% CI = 1.7-3.3) medication; mental health conditions-starting (AOR = 1.6, 95% CI = 1.2-2.2), stopping (AOR = 3.0, 95% CI = 2.3-4.0), or missing (AOR = 2.1, 95% CI = 1.6-2.8) medication; pain conditions-stopping (AOR = 2.9, 95% CI = 2.0-4.2); and respiratory conditions-starting (AOR = 2.0, 95% CI = 1.3-3.1), stopping (AOR = 1.7, 95% CI = 1.1-2.6), and missing (AOR = 2.2, 95% CI = 1.4-3.4) medication. Conclusions: Most pregnant women take medication and many, including those with chronic conditions, change their medication use during pregnancy. Medication change may occur independent of health care provider advice and due to women's safety concerns.

Promoting Clinical Trial Diversity: A Highlight of Select US FDA Initiatives.

Although the population in the United States is diverse, there are disparities in healthcare outcomes in some populations, for example, based on characteristics such as race, ethnicity, sex, gender, age, socioeconomic status, and geographic location. Despite disproportionate healthcare outcomes, certain populations are frequently under-represented in clinical trials intended to support applications requesting US Food and Drug Administration (FDA) approval to market a drug or biologic. Additionally, safety and efficacy of therapeutic products may vary based on intrinsic (e.g., sex, age, race, and ethnicity) and/or extrinsic (e.g., drug interactions and medical practice) factors. Enrolling diverse populations in clinical trials can aid in addressing disparities and better inform the use of medical products in all patients who will use them upon approval. Herein, we outline a few initiatives and activities, such as policy development, regulatory review, regulatory research, and stakeholder engagement, that the FDA has undertaken to promote diversity in clinical trials, to support submission of such information in marketing applications for subgroup analyses, and to communicate information to the public.

Determinants of Hormone Replacement Therapy Knowledge and Current Hormone Replacement Therapy Use.

Background: The use of hormone replacement therapy (HRT) to treat menopausal symptoms has declined since the early 2000s, and little is known about the contemporary determinants of use in the United States. We aim to understand women's knowledge of HRT as a treatment of menopausal symptoms and to assess the factors associated with HRT use. Materials and Methods: Weighted multivariate logistic regression models evaluated the correlates of high HRT knowledge and current HRT use among a sample of 2,548 women aged ≥45 years who participated in an online survey between August 2019 and May 2020. Results: In total, 82% of the women surveyed reported experiencing one or more menopausal symptoms, yet only 10.5% reported using HRT. Only 33% reported high HRT knowledge. The odds of reporting high HRT knowledge increased with increasing age. Racial, ethnic minority women were less likely to report high HRT knowledge (adjusted odds ratio [AOR] = 0.69; 95% confidence interval [CI] = 0.5-0.9). Hispanic and non-Hispanic women of other racial and ethnic groups were less likely to use HRT compared with non-Hispanic White women (AOR = 0.3; 95% CI = 0.1-0.6) (AOR = 0.4; CI = 0.2-0.9), respectively. Women experiencing irregular periods were less likely to report current HRT use (AOR = 0.1, 95% CI = 0.4-0.7). Compared with past users, never users appeared to be more risk averse, and reported concern over HRT risks and side effects as reasons for nonuse. Conclusions: Many factors impact women's perceived HRT knowledge level and to a lesser extent HRT use. Future research should better define the most important factors influencing decisions to use HRT for symptom relief.

Eligibility criteria and clinical trials: An FDA perspective.

INTRODUCTION: Randomized clinical trials are regarded as the gold standard for evaluating the effectiveness and safety of interventions. The US Food and Drug Administration (FDA) has made efforts to promote inclusive eligibility criteria. The objective of this study is to identify common trends in eligibility criteria and identify patterns of exclusion criteria among different diseases. METHODS: The authors evaluated the inclusion and exclusion criteria of 38 pivotal clinical trials representing 38 novel drugs approved between 2014 and 2017. Additionally, the authors reviewed the demographic characteristics of participants enrolled across 38 trials. RESULTS: Eighty two percent of trials in our study excluded participants based on hepatic related criteria and 79% trials excluded participants based on renal related criteria and specific infectious diseases. For trials in conditions that affected both men and women, there were no exclusions based on gender and race. More than 90% of trials excluded pregnant, lactating women and women not on adequate contraception. Of the 36,644 patients enrolled in trials for which both men and women were eligible, 62% were men. CONCLUSIONS: The most frequent exclusion criteria were pregnancy, lactation/breastfeeding, renal and hepatic abnormalities, and specific infectious diseases. The preponderance of men in our study likely indicates that factors other than exclusion criteria affect enrollment. The lower representation of women may have been influenced by two large cardiovascular trials that included 75% men. Our study marks an important step in the ongoing efforts of the Agency to increase inclusivity in clinical trials by understanding common clinical trial eligibility criteria patterns.

The safety of asthma medications during pregnancy and lactation: Clinical management and research priorities.

Asthma is one of the most common underlying diseases in women of reproductive age that can lead to potentially serious medical problems during pregnancy and lactation. A group of key stakeholders across multiple relevant disciplines was invited to take part in an effort to prioritize, strategize, and mobilize action steps to fill important gaps in knowledge regarding asthma medication safety in pregnancy and lactation. The stakeholders identified substantial gaps in the literature on the safety of asthma medications used during pregnancy and lactation and prioritized strategies to fill those gaps. Short-term action steps included linking data from existing complementary study designs (US and international claims data, single drug pregnancy registries, case-control studies, and coordinated systematic data systems). Long-term action steps included creating an asthma disease registry, incorporating the disease registry into electronic health record systems, and coordinating care across disciplines. The stakeholders also prioritized establishing new infrastructures/collaborations to perform research in pregnant and lactating women and to include patient perspectives throughout the process. To address the evidence gaps, and aid in populating product labels with data that inform clinical decision making, the consortium developed a plan to systematically obtain necessary data in the most efficient and timely manner.

Progress and opportunities for women in clinical trials: A look at recent data and initiatives from the U.S. FDA.

Recruiting and retaining diverse populations in clinical research is critically important. Over the years, we have seen improvements in the representation of women in clinical trials submitted in FDA marketing applications, and we are encouraged by the potential for new strategies to further their representation.

Advancing the Use of Mobile Technologies in Clinical Trials: Recommendations from the Clinical Trials Transformation Initiative.

Mobile technologies offer the potential to reduce the costs of conducting clinical trials by collecting high-quality information on health outcomes in real-world settings that are relevant to patients and clinicians. However, widespread use of mobile technologies in clinical trials has been impeded by their perceived challenges. To advance solutions to these challenges, the Clinical Trials Transformation Initiative (CTTI) has issued best practices and realistic approaches that clinical trial sponsors can now use. These include CTTI recommendations on technology selection; data collection, analysis, and interpretation; data management; protocol design and execution; and US Food and Drug Administration submission and inspection. The scientific principles underpinning the clinical trials enterprise continue to apply to studies using mobile technologies. These recommendations provide a framework for including mobile technologies in clinical trials that can lead to more efficient assessment of new therapies for patients.

Use of Mobile Devices to Measure Outcomes in Clinical Research, 2010-2016: A Systematic Literature Review.

BACKGROUND: The use of mobile devices in clinical research has advanced substantially in recent years due to the rapid pace of technology development. With an overall aim of informing the future use of mobile devices in interventional clinical research to measure primary outcomes, we conducted a systematic review of the use of and clinical outcomes measured by mobile devices (mobile outcomes) in observational and interventional clinical research. METHOD: We conducted a PubMed search using a range of search terms to retrieve peer-reviewed articles on clinical research published between January 2010 and May 2016 in which mobile devices were used to measure study outcomes. We screened each publication for specific inclusion and exclusion criteria. We then identified and qualitatively summarized the use of mobile outcome assessments in clinical research, including the type and design of the study, therapeutic focus, type of mobile device(s) used, and specific mobile outcomes reported. RESULTS: The search retrieved 2,530 potential articles of interest. After screening, 88 publications remained. Twenty-five percent of the publications (n = 22) described mobile outcomes used in interventional research, and the rest (n = 66) described observational clinical research. Thirteen therapeutic areas were represented. Five categories of mobile devices were identified: (1) inertial sensors, (2) biosensors, (3) pressure sensors and walkways, (4) medication adherence monitors, and (5) location monitors; inertial sensors/accelerometers were most common (reported in 86% of the publications). Among the variety of mobile outcomes, various assessments of physical activity were most common (reported in 74% of the publications). Other mobile outcomes included assessments of sleep, mobility, and pill adherence, as well as biomarkers assessed using a mobile device, including cardiac measures, glucose, gastric reflux, respiratory measures, and intensity of head-related injury. CONCLUSION: Mobile devices are being widely used in clinical research to assess outcomes, although their use in interventional research to assess therapeutic effectiveness is limited. For mobile devices to be used more frequently in pivotal interventional research - such as trials informing regulatory decision-making - more focus should be placed on: (1) consolidating the evidence supporting the clinical meaningfulness of specific mobile outcomes, and (2) standardizing the use of mobile devices in clinical research to measure specific mobile outcomes (e.g., data capture frequencies, placement of device). To that aim, this manuscript offers a broad overview of the various mobile outcome assessments currently used in observational and interventional research, and categorizes and consolidates this information for researchers interested in using mobile devices to assess outcomes in interventional research.

Differences in insulin secretion and sensitivity in short-sleep insomnia.

OBJECTIVE: Short-sleep insomnia is associated with increased risk of diabetes. The role of altered insulin secretion and action in this association is poorly understood. DESIGN: Observational study. SETTING: Academic clinical research center. PARTICIPANTS: Nondiabetic individuals with insomnia (mean [standard deviation] age 48 [9] y, body mass index 25.6 [3.9] kg/m(2)) with ≤ 6 h (short sleep, n = 14) and > 6 h of sleep (n = 14) during overnight laboratory polysomnography. MEASUREMENTS AND RESULTS: Standard oral glucose testing was used to assess glucose tolerance, beta-cell function (homeostasis model assessment [HOMA-B]; second-phase insulin secretion) and insulin resistance (HOMA-IR; insulin sensitivity index). There was no significant difference in hemoglobin A1C and fasting or 2-h blood glucose concentrations between sleep groups. Short-sleep insomnia sufferers had lower fasting and postchallenge serum insulin concentrations associated with lower estimates of fasting and glucose-stimulated insulin secretion, and increased insulin sensitivity. CONCLUSIONS: Individuals with short-sleep insomnia appear to have higher indices of systemic insulin sensitivity and secrete less insulin without changes in overall glucose tolerance.

TPMT, UGT1A1 and DPYD: genotyping to ensure safer cancer therapy?

The Food and Drug Administration (FDA) has approved label changes for two anticancer drugs, 6-mercaptopurine (6-MP) and irinotecan, to include pharmacogenetic testing as a potential means to reduce the rate of severe toxic events. Comprehensive evaluation of the clinical benefit and cost effectiveness of screening strategies with these tests has not been completed. However, the FDA decided that evidence indicates sufficient benefit to warrant informing prescribers, pharmacists and patients of the availability of pharmacogenetic tests and their possible role in the selection and dosing of these anticancer agents. Reviewing the gene-drug-phenotype relationships of 6-MP, irinotecan and 5-fluorouracil reveals properties of these relationships that lead to a clinically useful pharmacogenetic test. Research in the near future should clarify the role of pharmacogenetic testing in reducing the risk of severe toxicity and determine how these same tests might identify a subset of patients who should safely receive higher doses of treatment to derive the same benefit as the rest of the patient population.