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Introduction1

“[S]ex … is an important basic human variable that should be considered when designing and analyzing studies in all areas and at all levels of biomedical and health-related research.”

—Institute of Medicine, 2001

Biologically based differences between the sexes impact human development and behavior in both obvious and subtle ways. Sex differences are also apparent across the spectrum of health and disease, impacting not only individual health, but also public health, biomedical research, and healthcare delivery. Researchers have begun to elucidate these differences and their potential impact in areas such as pain and pain perception, infection, longevity, disease incidence and course, and cellular response and inflammation. Studies have shown, for example, that males and females can have markedly different responses to certain medications; in some cases these unexpected differences have led to the recall of products from the market (GAO, 2001). In the current era of translational research and personalized medicine, it is increasingly important to take sex differences into account, so that the potential effects of products and therapies can be more fully understood.

Several high-profile reports from the U.S. Food and Drug Administration (FDA), the National Institutes of Health (NIH), and the Institute of

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This workshop was organized by an independent planning committee whose role was limited to the identification of topics and speakers. This workshop summary was prepared by the rapporteurs as a factual summary of the presentations and discussions that took place at the workshop. Statements, recommendations, and opinions expressed are those of individual presenters and participants, and are not necessarily endorsed or verified by the forum or The National Academies, and should not be construed as reflecting any group consensus. Furthermore, although the current affiliations of speakers and panelists are noted in the report, many qualified their comments as being based on personal experience over the course of a career, and not being presented formally on behalf of their organization (unless specifically noted).



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1 Introduction1 “[S]ex . . . is an important basic human ariable that should be considered when designing and analyzing studies in all areas and at all leels of biomedical and health-related research.” —Institute of Medicine, 2001 Biologically based differences between the sexes impact human devel- opment and behavior in both obvious and subtle ways. Sex differences are also apparent across the spectrum of health and disease, impacting not only individual health, but also public health, biomedical research, and health- care delivery. Researchers have begun to elucidate these differences and their potential impact in areas such as pain and pain perception, infection, longevity, disease incidence and course, and cellular response and inflam- mation. Studies have shown, for example, that males and females can have markedly different responses to certain medications; in some cases these unexpected differences have led to the recall of products from the market (GAO, 2001). In the current era of translational research and personalized medicine, it is increasingly important to take sex differences into account, so that the potential effects of products and therapies can be more fully understood. Several high-profile reports from the U.S. Food and Drug Administra- tion (FDA), the National Institutes of Health (NIH), and the Institute of 1 This workshop was organized by an independent planning committee whose role was limited to the identification of topics and speakers. This workshop summary was prepared by the rapporteurs as a factual summary of the presentations and discussions that took place at the workshop. Statements, recommendations, and opinions expressed are those of individual presenters and participants, and are not necessarily endorsed or verified by the forum or The National Academies, and should not be construed as reflecting any group consensus. Further- more, although the current affiliations of speakers and panelists are noted in the report, many qualified their comments as being based on personal experience over the course of a career, and not being presented formally on behalf of their organization (unless specifically noted). 

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 SEX DIFFERENCES AND IMPLICATIONS Medicine (IOM) have stressed the need to consider the biological differ- ences between males and females in clinical research and product develop- ment (FDA, 1993; IOM, 2001; NIH, 1999). While academically it is clear that sex differences should be taken into consideration when developing research studies, in practice it is unclear when, in the course of research, the most appropriate option would be to invest resources into studying these differences. Characterizing sex differences often requires additional experi- mental groups or clinical protocols, adding to the overall cost and time of the research. This is particularly true for neuroscience research because of the complex nature of the nervous system and mental, neurological, and substance use disorders. In recent years, tremendous advances have been made in the method- ologies available for looking at sex differences, said Rae Silver, professor of natural and physical sciences at Columbia University and cochair of the workshop. A microarray analysis of gene transcripts from various mouse tissues, for example, was used to demonstrate sexually dimorphic gene expression in 72 and 68 percent of genes in liver and adipose tissue, respectively (Yang et al., 2006). In the nervous system, which is the subject of interest for the forum, such genome screening analysis is much more difficult as the brain is heterogeneous and likely to have localized regions or nuclei of sex differences, she said. Imaging technology, such as positron emission tomography, offers another approach that can further understand- ing of sex differences in the brain. As an example, Silver cited a study of sex differences in rates of serotonin synthesis, which showed that the mean rate of synthesis was about 52 percent higher in males than in females (Nishizawa et al., 1997). This may contribute to the lower incidence of unipolar depression in males. SCOPE OF THE WORKSHOP To explore the key principles and strategies that basic and applied researchers are using in the study of sex differences in the neurosciences and in the development of therapies for neurological disorders, the IOM Forum on Neuroscience and Nervous System Disorders convened a work- shop on March 8 and 9, 2010, titled Sex Differences and Implications for Translational Neuroscience Research. The Forum was established in 2005 to foster partnerships among stakeholders in the scientific community and the general public; to enhance understanding of research and clinical issues associated with the brain and nervous system and associated disorders; and to advance effective clinical prevention and treatment strategies. For this workshop, participants from academia, government, the pharmaceutical industry, patient advocacy groups, medical journal publishers, and other

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 INTRODuCTION stakeholders assembled to consider how and when it is most appropriate to study the differences between males and females in neuroscience research, and what the implications are of sex differences for translational neuro- science research. Specific objectives of the workshop were to • briefly outline the public health importance of studying sex differ- ence in the nervous system, in health and sickness, including the potential application to healthcare delivery; • identify the scientific principles that should be considered when designing preclinical experiments that will examine sex differ- ences, including strategies to bridge between preclinical and clinical studies; • discuss when and how sex differences should and should not be considered; • explore the key principles and strategies used by academic clini- cians to effectively use basic research for preclinical and clinical application and study, including approaches used by researchers to decide how and when to consider the potential importance of sex differences; • explore how and when industry considers and addresses studying sex differences, given regulatory guidelines; • examine the advantages, constraints, and implication of performing “valid analysis” versus requiring statistical outcomes between the sexes; and • identify the next steps that will be critical to establishing a set of principles that could be used by a variety of stakeholders in con- sidering when and how to incorporate studying sex differences into translational research efforts. Stevin Zorn, executive vice president for neuroscience research at Lundbeck and cochair of the workshop, charged participants to address the following questions: • How can the pathway of sex differences research, from basic re- search to clinical relevance and ultimately, translation into effective medicines, be made more efficient? • Can the efficiency of diagnostic and treatment strategies be im- proved by choosing diagnostic tests, drugs, and/or dosages that consider sex differences? • Are there instances when the sex difference in effect or accuracy is large?

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 SEX DIFFERENCES AND IMPLICATIONS ORGANIZATION OF THE REPORT The report that follows summarizes the presentations by the expert panelists, and the open panel discussions that took place during the work- shop. This report is not intended to be a scholarly review but a detailed accounting of speaker presentations and commentary by panelists and workshop attendees. An overview of the study of sex differences in biomedical research was provided by experts from four academic institutions and the NIH, and their presentations are summarized in Chapter 2. Discussion focused on the pub- lic health importance of studying sex differences in the nervous system, and the potential application of a stronger understanding of these differences to healthcare delivery. Participants discussed when sex differences should be and should not be considered, and how to design preclinical and clinical studies so that sex-based differences can be evaluated. Chapter 3 provides highlights of four disease/condition-specific panel discussions. Experts discussed the implications of sex differences in trans- lational research in depression, pain and pain perception, sleep medicine, and multiple sclerosis and neuroinflammation. These areas were identified by the planning committee as particularly relevant to the discussion. Issues common across these and other areas of neuroscience research were raised during an overarching discussion following the disease panels. In Chapter 4, representatives from two key neuroscience professional journals discussed the reporting of sex differences in research publications, and current journal policies on analysis by sex in submitted manuscripts. Chapter 5 summarizes the panel discussions of the regulatory and indus- try issues related to sex differences research. Morgan Sheng, vice president of neuroscience at Genentech, gave the keynote address at the workshop, offering an industry view of sex differences in translational neuroscience. Panelists from the FDA, the NIH, and industry discussed the history, guide- lines, and regulations regarding the inclusion of males and females in clini- cal trials, and how and when industry considers and addresses studying sex differences, given current regulatory requirements. Concluding remarks and discussion of practical next steps by par- ticipants are provided in Chapter 6, and the references, list of registered attendees, workshop agenda, and speaker biographies are available in the appendixes.