Age and sex in drug development and testing for adults

Individualization of drug therapy requires that the right drug be administered at the correct dose to patients who are likely to achieve the highest benefit and lowest risk. Female sex and age comprise two important risk factors for altered drug exposure and response. This review summarizes the current state of science for considering age and sex-related factors along the drug development pipeline, from cell culture and animal research through all phases of clinical trials in humans. A set of recommendations is provided to improve standards for integrating age and sex into the study design, analysis, and reporting of pre-clinical and clinical assessment of new molecular entities and biologics in adults. © 2017 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Sex based subgroup differences in randomized controlled trials: empirical evidence from Cochrane meta-analyses

Open debate of existing evidence is the hallmark of science and when used appropriately facilitates innovation and discovery. We thank Wallach, et al. for engaging in a healthy debate about sex and gender science, and agree with their emphasis on the need for clarity to prevent fatal flaws in misunderstanding the conclusion of their paper. We welcome the opportunity for future collaboration by offering the following points:

Sex and Gender Differences in Pharmacology

This is the very first book to deal with sex and gender differences in drug therapy - an increasingly recognized medical need. It starts with an overview on S/G in clinical syndromes and a documentation of the medical and socioeconomic damage caused by gender specific adverse drug effects. Part I covers S/G differences in pharmacokinetics. Researchers will be satisfied by the detailed discussion of the mechanisms of S/G differences in drug effects that represents cutting edge science and includes interaction of drugs with sex hormones, genomic and epigenetic mechanisms. It also covers S/G in drug development, in animal models and clinical development and S/G in drug prescriptions. Part II targets S/G differences in drug effects in cardiovascular, pulmonary, CNS, neuromuscular, neuropsychiatric and metabolic diseases, in cancer, inflammation, and rheumatic diseases, in bacterial and retroviral infections, thrombosis, embolism. New drugs will be discussed.

Sex and Gender Aspects in Clinical Medicine

This book is a concise, easy to read professional text with a focus on practical aspects. All chapters include tables on sex/gender differences in symptoms and management and a series of suggestions to the novice in the field. Chapters are specialty-specific. The focus is not on women’s health, but the presentation of differences in clinical symptoms, management and outcomes in women and men. Gender Medicine strives to employ the knowledge about these differences to improve diagnosis, better understand pathogenesis and advance patient-oriented therapy.

Sex in basic research: concepts in the cardiovascular field.

Women and men, female and male animals and cells are biologically different, and acknowledgement of this fact is critical to advancing medicine. However, incorporating concepts of sex-specific analysis in basic research is largely neglected, introducing bias into translational findings, clinical concepts and drug development. Research funding agencies recently approached these issues but implementation of policy changes in the scientific community is still limited, probably due to deficits in concepts, knowledge and proper methodology. This expert review is based on the EUGenMed project (www.eugenmed.eu) developing a roadmap for implementing sex and gender in biomedical and health research. For sake of clarity and conciseness, examples are mainly taken from the cardiovascular field that may serve as a paradigm for others, since a significant amount of knowledge how sex and oestrogen determine the manifestation of many cardiovascular diseases (CVD) has been accumulated. As main concepts for implementation of sex in basic research, the study of primary cell and animals of both sexes, the study of the influence of genetic vs. hormonal factors and the analysis of sex chromosomes and sex specific statistics in genome wide association studies (GWAS) are discussed. The review also discusses methodological issues, and analyses strength, weaknesses, opportunities and threats in implementing sex-sensitive aspects into basic research.

Sex differences in alcohol use disorder.

BACKGROUND: Alcohol use disorder (AUD) is a common and disabling mental disorder associated with a significant burden of medical consequences and high socioeconomic costs. Although a growing number of studies support the existence of sex differences in several aspects of alcohol consumption and AUD, the majority of investigations have been conducted in men. OBJECTIVE: This article was aimed at reviewing sex differences in AUD, focusing on epidemiology, neurobiology, pharmacokinetics, susceptibility to medical consequences, and treatment. RESULTS: Although AUD is more prevalent in men, the number of women with AUD is rapidly increasing, especially in adolescents. Women show a higher vulnerability to medical consequences induced by alcohol consumption, including alcohol-related liver disease, cardiomyopathy, and breast cancer. This observation is only partly explained by the sex differences observed in the pharmacokinetics of alcohol. Women also show an accelerated progression from the first use of alcohol to the onset of AUD and appear to be at higher risk of alcohol-medication interactions. Although AUD women are less likely to seek treatment than men, they achieve better results through dedicated programs taking into account the special needs of female patients. However, findings on the efficacy and safety of medications used to treat AUD mostly come from studies in which women were largely underrepresented. CONCLUSION: The sex differences observed suggest the urgent need to conduct studies recruiting adequate numbers of female subjects, to increase knowledge of sex differences in AUD, and to develop personalized and evidence-based approaches of prevention and treatment of AUD in women.

Gender and cardiovascular diseases : Why we need gender medicine

Gender medicine is concerned with the question of why diseases are expressed differently in the genders. It takes differences between men and women into account, which are often neglected by traditional medicine. Sex differences can also be found in cardiovascular diseases; therefore, risk factors for cardiovascular diseases have a different significance depending on the sex. Diabetic diseases tend to promote the occurrence of coronary heart disease (CHD) more strongly in women than in men. Myocardial infarctions affect women 10 years later than men and young women are often treated too late, possibly because myocardial infarction is consider to be a "male disease". The number of cases of coronary syndrome is significantly increasing, particularly in young women. Some of the diseases which predominantly occur in women are takotsubo cardiomyopathy, microcirculation disorders and spontaneous coronary artery dissection. Pharmacological treatment of CHD is principally the same in men and women but attention must be paid to differences in the pharmacokinetics of important drugs. Coronary dilatation has comparable effects in both men and women but more complications occur in women. Cardiac failure with impaired left ventricular systolic function affects more men than women in the Western world but the opposite is true for cardiac failure with preserved left ventricular ejection fraction. Hypertrophic and dilatative cardiomyopathies are more frequent in men. Many of the drugs used to treat cardiac failure have different actions in men and women. Too little attention is paid to the pharmacokinetics and pharmacodynamics in women when testing active agents; however, awareness of the differences that need to be considered is growing.

Mechanistic Pathways of Sex Differences in Cardiovascular Disease

Major differences between men and women exist in epidemiology, manifestation, pathophysiology, treatment, and outcome of cardiovascular diseases (CVD), such as coronary artery disease, pressure overload, hypertension, cardiomyopathy, and heart failure. Corresponding sex differences have been studied in a number of animal models, and mechanistic investigations have been undertaken to analyze the observed sex differences. We summarize the biological mechanisms of sex differences in CVD focusing on three main areas, i.e., genetic mechanisms, epigenetic mechanisms, as well as sex hormones and their receptors. We discuss relevant subtypes of sex hormone receptors, as well as genomic and nongenomic, activational and organizational effects of sex hormones. We describe the interaction of sex hormones with intracellular signaling relevant for cardiovascular cells and the cardiovascular system. Sex, sex hormones, and their receptors may affect a number of cellular processes by their synergistic action on multiple targets. We discuss in detail sex differences in organelle function and in biological processes. We conclude that there is a need for a more detailed understanding of sex differences and their underlying mechanisms, which holds the potential to design new drugs that target sex-specific cardiovascular mechanisms and affect phenotypes. The comparison of both sexes may lead to the identification of protective or maladaptive mechanisms in one sex that could serve as a novel therapeutic target in one sex or in both.

Impact of sex and gender on the efficacy of antiplatelet therapy: the female perspective

Ischemic heart disease is the single leading cause of death and a significant cause of morbidity among women in industrialized countries. Current guidelines recommend antiplatelet therapy as the main cornerstone for the prevention and treatment of cardiovascular disease. Unfortunately, evidence is emerging that the response to antiplatelet drugs differs according to sex, although the biological basis for this gender disparity is unknown. In order to explain the epidemiological data showing a more severe clinical expression of cardiovascular disease in addition to adverse outcomes despite optimal pharmacological and interventional approaches in women compared to men, differences in platelet reactivity related to sex and gender are currently under investigation. In this report, we review available data from clinical trials of antiplatelet drugs administered for primary and secondary prevention, focusing on the underenrollment of female subjects in interventional randomized studies and weak community awareness of the impact of cardiovascular disease on life expectancy in women. Based on our findings, the development of real gender-oriented evidence-based guidelines for antiplatelet use in the setting of cardiovascular disease is urgently required.

Mainstreaming sex and gender analysis in public health genomics

BACKGROUND: The integration of genome-based knowledge into public health or public health genomics (PHG) aims to contribute to disease prevention, health promotion, and risk reduction associated with genetic disease susceptibility. Men and women differ, for instance, in susceptibilities for heart disease, obesity, or depression due to biologic (sex) and sociocultural (gender) factors and their interaction. Genome-based knowledge is rapidly increasing, but sex and gender issues are often not explored. OBJECTIVE: To explore the implications of a sex and gender analysis for PHG. METHODS: We explore genome-based knowledge in relation to sex and gender aspects using depression as an example, gender equality, and the intersection of sex and gender with other social stratifiers such as ethnic background or socioeconomic status. RESULTS: We advocate a sex- and gender-sensitive genomics research agenda alongside studies that provide sex-disaggregated data rather than controls based on sex. Such a research agenda is needed to guide research on how genomics is understood and perceived by men and women across groups, and for the equitable and responsible translation of such knowledge into the public health domain. CONCLUSIONS: Including sex and gender analysis in PHG research will not only shed more light on phenomena such as diseases with a higher prevalence in either men or women, but will ultimately lead to gendered innovations by way of exploring how gendered and cultural environments increase or safeguard genetic predispositions.

Scientific excellence in applying sex- and gender-sensitive methods in biomedical and health research

Despite regulations, the attention paid to sex and gender in biomedical and health research is far from optimal. Researchers often recognize the importance of incorporating sex and gender issues in general but fail to see the applicability to their own research. This can have severe consequences and impedes gender equity in healthcare. More hands-on approaches are needed that stimulate scientists to integrate sex and gender aspects into their research. The present work is based on the contents of a workshop developed by the authors that serves as such a hands-on method. It aims at familiarizing a broad range of scientists in the field of biomedical and health research with the basics of conducting sex- and gender-sensitive research. In addition to clarifying concepts, it serves to provide a general introduction to sex- and gender-sensitive methods. To this end, challenges in pitfalls conducting sex- and gender-sensitive research, originally identified in the social sciences, are translated to the practice of biomedical and health research. Implications and applicability to all areas of biomedical and health research are shown by providing illustrative examples. Finally, a tool is presented that allows for the detection of sex and gender bias throughout all phases of the research process and shows how this bias can be overcome through sex- and gender-sensitive (1) relevance checking, (2) literature search, (3) formulation of research questions and hypotheses, (4) research methods and sample, (5) data analysis and interpretation, (6) reporting, and (7) conclusions and recommendations.

Sex Differences Research, Precision Medicine, and the Future of Women's Health

The National Institutes of Health's (NIH) commitment to improving health outcomes for women and men through rigorous science has been compromised by the lack of basic science evidence obtained from female animals. To correct this limitation, in June 2015 the NIH announced expectations that "sex," as a biological variable, be included into research design and analysis in studies of vertebrate animals and humans (NOT-OD-15-102). Scientists must take the responsibility to implement this directive. However, in doing so, there is a risk that attention could be restricted to only studies of direct comparison between female/women and male/men. By contrast, understanding how sex influences health and disease needs to take a programmatic approach that includes the study of sex-specific conditions. A programmatic approach will assure the advancement of knowledge to improve women's health.