Heterogeneity in treatment effects across diverse populations.

Differences in patient characteristics, including age, sex, and race influence the safety and effectiveness of drugs, biologic products, and medical devices. Here we provide a summary of the topics discussed during the opening panel at the 2018 Johns Hopkins Center for Excellence in Regulatory Science and Innovation symposium on Assessing and Communicating Heterogeneity of Treatment Effects for Patient Subpopulations: Challenges and Opportunities. The goal of this session was to provide a brief overview of FDA-regulated therapeutics, including drugs, biologics and medical devices, and some of the major sources of heterogeneity of treatment effects (HTE) related to patient demographics, such as age, sex and race. The panel discussed the US Food and Drug Administration's role in reviewing and regulating drugs, devices, and biologic products and the challenges associated with ensuring that diverse patient populations benefit from these therapeutics. Ultimately, ensuring diverse demographic inclusion in clinical trials, and designing basic and clinical research studies to account for the intended patient population's age, sex, race, and genetic factors among other characteristics, will lead to better, safer therapies for diverse patient populations.

Under-representation of racial minorities in prostate cancer studies submitted to the US Food and Drug Administration to support potential marketing approval, 1993-2013.

BACKGROUND: US Food and Drug Administration (FDA) approval of new drugs depends on results from clinical trials that must be generalized to the US population. However, racial minorities are frequently under-represented in clinical studies. The enrollment of racial minorities was compared in key clinical studies submitted to the FDA in the last 10 years in support of potential marketing approval for prostate cancer (PCa) prevention or treatment. METHODS: Patient demographic data were obtained from archival data sets of large registration trials submitted to the FDA to support proposed PCa indications. Six countries/regions were analyzed: the United States, Canada, Australia, Europe, the United Kingdom, and Eastern Europe. Background racial demographics were collected from national census data. RESULTS: Seventeen key PCa clinical trials were analyzed. These trials were conducted in the past 20 years, comprising 39,574 patients with known racial information. Most patients were enrolled in the United States, but there appeared to be a trend toward increased non-US enrollment over time. In all countries, racial minorities were generally under-represented. There was no significant improvement in racial minority enrollment over time. The United States enrolled the largest nonwhite population (7.1%). CONCLUSIONS: Over the past 20 years, racial minorities were consistently under-represented in key PCa trials. There is a need for effective measures that will improve enrollment of racial minorities. With increased global enrollment, drug developers should aim to recruit a patient population that resembles the racial demographics of the patient population to which drug use will be generalized upon approval.

EMBRACE: One Small Story in Lupus-One Giant Challenge in Clinical Trials.

Clinical trials of novel therapeutics in the United States have not been adequately representative of diverse populations, particularly racial and ethnic minorities. The challenges and consequences of underrepresentation in clinical trial recruitment are exemplified by the case of belimumab, a biologic treatment for systemic lupus erythematosus (SLE), a disease that is more prevalent in patients of Black African ancestry and of Hispanic/Latino ethnicity than in other patient populations. Although belimumab was found to be effective in phase 2 and 3 clinical trials in the general population, post hoc analyses of efficacy data in patients of Black African ancestry showed inconsistent results. Consequently, a cautionary statement regarding belimumab use in this population was added to the product label. To alleviate concerns that belimumab may not be safe and effective for patients of Black African ancestry, the Efficacy and Safety of Belimumab in Black Race Patients with SLE (EMBRACE) study was conducted in a post-marketing commitment to the Food and Drug Administration. The study recruited only patients who self-identified as being of Black race; its findings led to the removal of the cautionary labeling of belimumab use in patients of Black African ancestry. Our manuscript highlights the critical lessons learned from the successes and failures of the EMBRACE study. It also provides suggestions for overcoming health disparities, highlighting strategies for conducting well-designed clinical trials to overcome systematic barriers to diversity in recruitment, with a focus on enacting long-term support to ensure equity in the process, products, and benefits from drug development and clinical trials.

Demographic Composition of Select Oncologic New Molecular Entities Approved by the FDA Between 2008 and 2017.

Race, ethnicity, sex, and age are demographic factors that can influence drug exposure and/or response, and can consequently affect treatment outcome. We evaluated demographic subgroup enrollment patterns in new therapeutic products approved by the US Food and Drug Administration (FDA) for the treatment of select cancers-breast, colorectal, lung, and prostate-that have comparative differences in morbidity and/or mortality among some demographic subgroups. In submissions of products approved between 2008 and 2013, participants (n = 22,481) were white (80%), from outside the United States (74%), between 17 and 64 years old (59%), and men (56% and 53%, including and excluding sex-specific indications, respectively). In pivotal trials of products approved between2014 and 2017, participants (n = 3,612) were white (71%), between 17 and 64 years old (61%), and men (48% and 63%, including and excluding sex-specific indications, respectively). The US-relevant minority populations were under-represented. A broader representation of patient subgroups in clinical trials may contribute to better understanding of exposure and/or response variability, and consequently help personalize drug therapy.

Clinical trials recruitment planning: A proposed framework from the Clinical Trials Transformation Initiative.

Patient recruitment is widely recognized as a key determinant of success for clinical trials. Yet a substantial number of trials fail to reach recruitment goals-a situation that has important scientific, financial, ethical, and policy implications. Further, there are important effects on stakeholders who directly contribute to the trial including investigators, sponsors, and study participants. Despite efforts over multiple decades to identify and address barriers, recruitment challenges persist. To advance a more comprehensive approach to trial recruitment, the Clinical Trials Transformation Initiative (CTTI) convened a project team to examine the challenges and to issue actionable, evidence-based recommendations for improving recruitment planning that extend beyond common study-specific strategies. We describe our multi-stakeholder effort to develop a framework that delineates three areas essential to strategic recruitment planning efforts: (1) trial design and protocol development, (2) trial feasibility and site selection, and (3) communication. Our recommendations propose an upstream approach to recruitment planning that has the potential to produce greater impact and reduce downstream barriers. Additionally, we offer tools to help facilitate adoption of the recommendations. We hope that our framework and recommendations will serve as a guide for initial efforts in clinical trial recruitment planning irrespective of disease or intervention focus, provide a common basis for discussions in this area and generate targets for further analysis and continual improvement.

Personalized medicine and Hispanic health: improving health outcomes and reducing health disparities - a National Heart, Lung, and Blood Institute workshop report.

Persons of Hispanic/Latino descent may represent different ancestries, ethnic and cultural groups and countries of birth. In the U.S., the Hispanic/Latino population is projected to constitute 29% of the population by 2060. A personalized approach focusing on individual variability in genetics, environment, lifestyle and socioeconomic determinants of health may advance the understanding of some of the major factors contributing to the health disparities experienced by Hispanics/Latinos and other groups in the U.S., thus leading to new strategies that improve health care outcomes. However, there are major gaps in our current knowledge about how personalized medicine can shape health outcomes among Hispanics/Latinos and address the potential factors that may explain the observed differences within this heterogeneous group, and between this group and other U.S. demographic groups. For that purpose, the National Heart, Lung, and Blood Institute (NHLBI), in collaboration with the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), and the Food and Drug Administration (FDA), held a workshop in which experts discussed (1) potential approaches to study medical treatments and health outcomes among Hispanics/Latinos and garner the necessary evidence to fill gaps of efficacy, effectiveness and safety of therapies for heart, lung, blood and sleep (HLBS) disorders and conditions--and their risk factors; (2) research opportunities related to personalized medicine to improve knowledge and develop effective interventions to reduce health disparities among Hispanics/Latinos in the U.S.; and (3) the incorporation of expanded sociocultural and socioeconomic data collection and genetic/genomic/epigenetic information of Hispanic/Latino patients into their clinical assessments, to account for individual variability in ancestry; physiology or disease risk; culture; environment; lifestyle; and socioeconomic determinants of health. The experts also provided recommendations on: sources of Hispanic/Latino health data and strategies to enhance its collection; policy; genetics, genomics and epigenetics research; and integrating Hispanic/Latino health research within clinical settings.

Innovative approaches in drug development.

This is the white paper on Innovative Approaches in Drug Development developed by the Biotechnology Industry Organization's (BIO) Clinical Trial Designs Workgroup. As recognized by the Food and Drug Administration's Critical Path Opportunities Report, the need to develop and apply innovative approaches to create new trial designs and clinical development programs is rapidly on the rise. Such novel approaches hold tremendous potential in the ability to refine mechanisms lying at the fundamental core of product safety and efficacy. The paper addresses the opportunities, challenges in pre-clinical and clinical trial design innovations; emphasizes the importance of safety database; and makes recommendations for carrying out the innovative approaches. The views expressed here in are solely those of the authors and do not reflect the official views of the Biotechnology Industry Organization.