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Workshop Summary OVERVIEW On August 30, 2011, the Institute of Medicine hosted a work- shop, Sex-Specific Reporting of Scientific Research, sponsored by the Office of Research on Women’s Health (ORWH) of the National Insti- tutes of Health (NIH).1 The workshop explored the need for sex-specific reporting of scientific results; potential barriers and unintended conse- quences of sex-specific reporting of scientific results; experiences of journals that have implemented sex-specific requirements, including the challenges and benefits of such editorial policies; and steps to facilitate the reporting of sex-specific results. Presenters and participants included current and former editors of scientific journals, researchers, and scien- tists and policymakers from government, industry, and nonprofit organi- zations. Presentations and discussions highlighted the importance to both women and men of having sex-specific data, the problems with sample size and financial constraints for conducting the research, the appropri- ateness of sex-specific analyses, and the limitations of journal policies to change experimental designs. During closing remarks, the planning committee chair summarized some of the individual suggestions dis- cussed for advancing sex-specific reporting as: identifying the sex of 1 The workshop was planned in collaboration with the Institute of Medicine’s Board on Health Sciences Policy and was organized by an independent planning committee whose role was limited to identification of topics and speakers. The present summary was prepared by the rapporteur as a factual summary of the presentations and discussions that took place at the workshop. Statements, rec- ommendations, and opinions expressed are those of individual presenters and participants and are not necessarily endorsed or verified by the National Acade- mies, and they should not be construed as reflecting any group consensus. 1
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2 SEX-SPECIFIC REPORTING OF SCIENTIFIC RESEARCH populations in journal populations, sharing of sex-identified raw data, giving “extra credit” in review to manuscripts that include sex-specific information, and requiring sex-stratified analyses where applicable. INTRODUCTION The number of women participating in clinical trials has in- creased over the last two decades, but women are still underrepresented in clinical trials in general. Some of the overall increase can be attributed to the greater number of women-only trials (of therapies for diseases that affect only women). Even when women are included in clinical trials, the results are often not analyzed separately by sex. On August 30, 2011, the Institute of Medicine (IOM) Board on Population Health and Public Health Practice hosted the workshop Sex- Specific Reporting of Scientific Research. Nancy Adler, professor of medical psychology at the University of California, San Francisco, and workshop chair, cited a recent review of high-impact publications of clinical studies, including clinical trials and prospective cohort studies, of non–sex-specific cancers. It found that women constituted less than 40% of participants (Jagsi et al., 2009). Other research indicates that studies of cardiovascular disease are particularly male-biased. A review of 19 ran- domized controlled cardiovascular trials found that only 27% of the par- ticipants were female and that only 13 of the studies presented sex-based analyses of the data (Kim and Menon, 2009). That bias is often uninten- tional, Adler noted. In designing inclusion criteria, for example, early age of onset of myocardial infarction and chest pain as a presenting symptom will favor the enrollment of men over women (Bairey Merz et al., 2006; Canto et al., 2007; Gurwitz et al., 1992). Similarly, the end points select- ed can lead to bias. Unstable angina, stroke, and unrecognized myocardi- al infarction are more common in women, and if a study does not include these as end points, cardiovascular disease in female participants may be underestimated. Bias in inclusion criteria in human immunodeficiency virus (HIV) studies has also been reported (Gandhi et al., 2005). In addi- tion, there is a substantial male bias in animal models of disease, even for diseases that are more prevalent in women. A recent IOM consensus report, Women’s Health Research: Progress, Pitfalls, and Promise (IOM, 2010, p. 12), found that limitations in the design, analysis, and scientific reporting of health research have slowed progress in women’s health. In-
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WORKSHOP SUMMARY 3 adequate enforcement of recruitment of women and of report- ing data by sex has fostered suboptimal analysis and reporting of data on women from clinical trials and other research. That failure has limited possibilities for identifying potentially important sex or gender differences. New methods and ap- proaches are needed to maximize advances in promoting women’s health. On the basis of that finding, the IOM committee recommended (IOM, 2010, p. 13) that the International Committee of Medical Journal Editors and other editors of relevant journals should adopt a guideline that all papers reporting the outcomes of clinical trials report on men and women separately unless a trial is of a sex-specific condition. . . . The National Institutes of Health should spon- sor a meeting to facilitate the establishment of the guidelines. To address the recommendation, the NIH ORWH requested that the IOM convene a 1-day workshop to explore the benefits of and barri- ers to sex-specific reporting of scientific data. The workshop brought together representatives of academe, industry, government, and research- advocacy organizations and editors of leading scientific and medical journals to consider the need for sex-specific reporting of scientific results; potential barriers to and unintended consequences of sex-specific reporting of scientific results; experiences of journals that have implemented sex-specific re- quirements, including the challenges and benefits of such editorial policies; and steps to facilitate the reporting of sex-specific results. The present report summarizes the presentations and discussions by the expert panelists. The first session focused on why sex-specific reporting is important. Panelists highlighted historical and current events that have hindered or helped to advance the study of women. In the next session, panelists in academe discussed the challenges of collecting, ana- lyzing, and reporting sex-specific data from the researcher’s perspective. That was followed by two panels of leading journal editors who shared their experiences in developing and implementing editorial policies and the implications of sex-specific reporting policies for journals. In the
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4 SEX-SPECIFIC REPORTING OF SCIENTIFIC RESEARCH BOX 1 A Brief History of Inclusion of Women in Clinical Research Funded by the National Institutes of Health Late 1980s: Concerns were first raised that clinical research on condi- tions that affect both women and men was being conducted primarily in a homogeneous white male population but that the results were being applied in medical practice to both men and women of all races. 1990: ORWH was established in NIH to ensure that women are includ- ed in NIH-funded clinical studies. 1993: NIH policies on the inclusion of women and minorities in clinical research became law as a result of the NIH Revitalization Act of 1993 (PL 103-43). The act included four major requirements. NIH must ensure that women and members of minority groups and their subpopulations are included in all human-subjects research; ensure that in phase 3 clinical trials, women and minori- ties and their subpopulations are included in such a way that valid analyses of differences in intervention effect can be performed; not allow cost to be used as an excuse for excluding these groups; and initiate programs and support for outreach efforts to re- cruit these groups into clinical studies. 2000: The U.S. General Accounting Office (GAO; now the Government Accountability Office) reported that NIH had made substantial progress in strengthening and implementing its policy on inclusion of women in clinical trials. SOURCE: Clayton, 2011. final session, members of the workshop planning committee and others reflected on the discussion and summarized the individual suggestions made over the course of the day for advancing sex-specific reporting of scientific research. INCLUSION OF WOMEN IN CLINICAL TRIALS FUNDED BY THE NATIONAL INSTITUTES OF HEALTH On behalf of the workshop sponsor and as background for the discussions, Janine Clayton, deputy director of ORWH, provided a brief history of the inclusion of women in NIH-funded clinical studies (Box 1). Despite the success of NIH efforts to enhance enrollment of women,
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WORKSHOP SUMMARY 5 the law and policy apply only to NIH-funded studies, not to studies done by or supported by other agencies or entities. In addition, NIH cannot require editors and journals to mandate inclusion of analysis by sex in reports of studies. As a result, key health data are not reaching other re- searchers and the public. To begin to address that situation, ORWH established a working group of scientific-journal editors as an ad hoc subgroup of the Advisory Committee on Research on Women’s Health. In 2001, the group issued a statement calling on scientific journals to require that, where appropriate, clinical and epidemiologic studies be analyzed to see whether there is an effect of sex; if there is no effect, that should also be reported. Any statis- tical limitations of such analyses should be made clear. To date, howev- er, very few journals have adopted such a policy. Clayton cited the Journal of the National Cancer Institute (JNCI) as an example of jour- nals that address sex-specific analysis in their instructions for authors. The continuing challenge, Clayton concluded, is to get sex- differences research accomplished and the results reported, from basic through applied research. WHY SEX-SPECIFIC REPORTING IS IMPORTANT Early History Ameeta Parekh, director of research and development in the Of- fice of Women’s Health of the U.S. Food and Drug Administration (FDA), reminded participants that the severe birth defects associated with thalidomide use by pregnant women in the 1960s led to a conserva- tive approach to testing of new drugs in women. In 1977, FDA issued General Considerations for the Clinical Evaluation of Drugs, which stat- ed that “women of childbearing potential should be excluded from the earliest dose-ranging studies.” Although the guidance went on to state that such women could be included in further studies if additional evi- dence had been amassed on the safety or preclinical toxicity of a drug, that exclusion inadvertently led to the underrepresentation or exclusion of women from all clinical trials. The exclusion of women from clinical research was not generally questioned, because sex was not recognized as a variable in health research and was not considered to be a factor that could affect health and illness. In addition, investigators believed that women were more difficult to study because they introduced more varia- bles (for example, hormonal cycles) and were difficult to recruit. The result of not studying women is gaps in our knowledge and understand-
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6 SEX-SPECIFIC REPORTING OF SCIENTIFIC RESEARCH ing of the differences between men and women with regard to treatments and response. Carolyn Clancy, director of the Agency for Healthcare Research and Quality (AHRQ), added that the first randomized trial of estrogen to prevent heart disease was conducted in the early 1960s in men. The ef- fect of estrogen on heart disease in women was not studied in a random- ized trial until the Women’s Health Initiative, 35 years later. The Need to Study Both Sexes Martha Nolan, vice president for public policy of the Society for Women’s Health Research (SWHR), said that there is a great need to identify biologic and physiologic differences between men and women and to understand the implications of the differences for diagnosis and treatment. She noted, for example, that more women than men take anti- depressants; women respond more slowly and are less likely to achieve an optimal response to treatment for depression; and women are more likely to stop using the medication because of adverse events. There are many other examples of differences that are not fully understood. Female athletes, especially those in contact sports, sustain a higher percentage of concussions during play than male athletes do, but virtually all the litera- ture and mass-media attention is on male football and ice-hockey play- ers. Transplantation of donor organs from females is less successful than transplantation from males. Boys are more likely than girls to receive a diagnosis of peanut allergy early in life, but by the age of 24, more wom- en than men are receiving the diagnosis. Parekh provided further support for the need to study both sexes. Women make up more than 50% of the U.S. population (50.7% accord- ing to the 2010 U.S. Census) and on the average outlive men (80.7 years vs 74.8 years). Many diseases place a heavier burden on women than on men (consider, for example, heart disease, cancer, rheumatoid arthritis, lupus, and osteoporosis); however, treatment guidelines are based largely on data on men. Women also rely more on medical systems than men do and are likely to seek treatment sooner. Jesse Berlin, vice president of epidemiology at Johnson & John- son Pharmaceutical Research and Development, said that sex-specific reporting helps to define the most appropriate population for treatment and to determine whether benefits or harms differ by sex. Differences between the sexes are more than just pharmacokinetic, however. For ex- ample, Berlin cited a recent report that describes sex-specific differences in cell regulatory processes (Mittelstrass et al., 2011).
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WORKSHOP SUMMARY 7 Sex-specific analysis and reporting are not just “women’s health” issues. Better data on women would be better data for everyone, Clancy said. Sex-specific data could allow guidelines to be more specific and allow clinicians to better tailor care to individuals. Speakers also presented examples of the importance of sex- specific differences. One example of critical differences between males and females is drug-induced electrocardiographic changes. Parekh ex- plained that several drugs withdrawn from the market were associated with prolongation of the QT interval (a measure of cardiac repolariza- tion) and torsades de pointes (a potentially fatal form of polymorphic ventricular tachycardia). Women have a longer baseline QT interval and a higher propensity for drug-induced QT prolongation, and they are two to three times more likely to develop torsades than men. The effects of drugs being studied for cardiotoxicity, Parekh said, need to be looked at and understood in both men and women. A more recent example of the importance of sex-based data is A Diabetes Outcome Progression Trial (ADOPT), a randomized controlled trial (RCT) that compared rosiglitazone with metformin and glyburide over several years. The overall fracture rate associated with rosiglitazone use was higher than that associated with glyburide and metformin, but analysis by sex showed that women had a rate of fractures twice that of men (Kahn et al., 2008). As a result, the label for rosiglitazone includes data on the increased fracture risk for women. Raising Awareness of Sex Differences A 1992 GAO review of FDA policies and pharmaceutical- industry practices found that women were not adequately included in clinical studies and that data were not analyzed for sex differences with any consistency, and that consequently there was a lack of understanding of sex differences (GAO, 1992). As a result, Parekh said, FDA issued several new guidance documents and regulations. The 1977 policy that mentioned exclusion of women of childbearing potential was reversed through the 1993 guideline Study and Evaluation of Gender Differences in the Clinical Evaluation of Drugs, which recommended collection and analysis of data on sex differences in effectiveness, adverse effects, pharmacokinetics, and pharmacodynamics. The 1998 investigational new drug (IND) application and new drug application (NDA) regulation, also called the demographic rule, requires NDA submissions to provide safety and effectiveness data and IND submissions to tabulate numbers of participants according to age,
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8 SEX-SPECIFIC REPORTING OF SCIENTIFIC RESEARCH race, and sex. In 2000, FDA issued the clinical-hold rule, which permits FDA to stop IND studies of treatments for life-threatening diseases if women are excluded because of their reproductive potential. Parekh noted that data reported in poster sessions at a recent Drug Information Association meeting indicated that analysis of safety and efficacy data by sex has been increasing—around 75% of clinical trials in 2007–2009 reported analysis by sex—and a review of approved product labels found that nearly all included pharmacokinetic infor- mation by sex. With regard to reporting in the literature, Nolan said that a dec- ade ago the NIH ORWH, in collaboration with SWHR, convened a meet- ing of scientific-journal editors to discuss the development of specific instructions for authors and reviewers about the analysis of clinical-trial data by sex. However, in an informal survey of 11 science journals2 con- ducted by SWHR in 2010, only JNCI and Circulation required reporting of sex differences; the others did not set any sex-specific requirements for authors. Nolan cited several recent articles that draw attention to the need to consider sex differences. In March of 2010, an article in Science re- ported on sex bias in animal models and predicted that reporting would change if journals adopted a common set of guidelines for manuscripts to provide details on the sex of the animals used and required authors to state their rationale for studying only one sex and the implications of not studying the other (Wald and Wu, 2010). A June 2010 editorial in Nature suggested that funding agencies should require researchers to justify sex inequalities in grant proposals and should favor proposals that include both sexes; that FDA should ensure that physicians and the public are aware of sex differences in drug reactions and dosages; and that medical schools should train physicians in how diseases, symptoms, and drug responses can differ by sex (Putting gender on the agenda, 2010). The editorial also noted that Nature was considering whether to require au- thors to document the sex of animals in published papers. Finally, an ar- ticle in the New England Journal of Medicine in June 2010 noted how the global H1N1 influenza pandemic disproportionately affected preg- nant women and stressed the need for inclusion of pregnant women in clinical trials (Goldkind et al., 2010). 2 Journal of the National Cancer Institute (JNCI), Circulation, JAMA, New Eng- land Journal of Medicine, Endocrinology, American Journal of Physical Medi- cine & Rehabilitation, BMJ, Lancet, Immunology, Gastroenterology, and Urology.
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WORKSHOP SUMMARY 9 The Department of Defense and the Department of Veterans Af- fairs are beginning to examine sex differences, such as how psychologic and physical health conditions affect female soldiers and veterans, Nolan said. These agencies are also reporting when research shows no differ- ence between the sexes. Great strides have been made in raising public awareness about sex-based differences in cardiovascular, muscular, skeletal, and behav- ioral health and disease, but only rarely are medical-care options tailored to the patient’s sex, Nolan said. She suggested that it could take less time for research to be translated into medical practice if major journal pub- lishers required analysis by sex and reporting of differences found or the lack thereof. Barriers to Studying Sex Differences There are both technical and political barriers to advancing knowledge of sex differences. Clancy described an imbalance between the fear of not knowing what the health-related differences between men and women are and the fear that identifying such differences is somehow impolitic or inappropriate. When the fear and concern associated with not knowing overpower concerns about the influence of politics on sci- ence, studying sex differences will become straightforward, she said. There are methodologic challenges to studying population sub- groups, such as males and females. A primary issue in breaking down data by sex is sample size. Berlin asked, Are two separate, adequately powered studies, one in each sex, needed? Or can a single study have sufficient statistical power to detect interaction? Separate studies of men and women risk confounding. Separate studies of men and women might use different doses as in, for example, studies of aspirin and myocardial- infarction prevention. It could then be difficult to tell whether differences in outcome were due to different doses, sex, or other factors. Instead, conducting two studies, each with both men and women, might allow stratification of both studies by sex and provide replication for sex- specific findings. Alternatively, meta-analytic principles could be applied to a program of development and testing. A barrier to meta-analysis is availability of data. Clancy noted that the opportunity to conduct meta-analyses often rests on the goodwill of investigators in sharing data from clinical trials. As data collection has moved from paper to electronic form, the technical barriers to data- sharing have diminished. The unanswered question is who owns the data, particularly when studies have been funded with taxpayer dollars. With
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10 SEX-SPECIFIC REPORTING OF SCIENTIFIC RESEARCH regard to sample size, meta-analysis of clinical data can be a valuable exercise before investment in a large clinical trial—it can help in design- ing trials strategically. Other Groups Although the focus of the workshop was on sex-specific analysis and reporting, some panelists pointed out that race and ethnicity may also be clinically relevant, as may other clinically, genetically, or socially defined characteristics. Berlin cited Freedman and colleagues (1995), who discussed the possibility of finding clinically unimportant but statis- tically significant differences or clinically important but statistically nonsignificant differences and argued against separate results in the ab- sence of a priori evidence of subgroup differences. Berlin argued, how- ever, that such clinical-trial results can point to basic science and the needs for further elucidation. Clancy referred participants to a 2009 Kaiser Family Foundation report, Putting Women’s Health Care Disparities on the Map: Examining Racial and Ethnic Disparities at the State Level.3 The principles being discussed in the present workshop do not refer only to definitions of gen- der and sex but extend to other population groups as well, she stressed. Managing the Data Parekh highlighted several current FDA initiatives, including one focused on standardizing the data that are electronically submitted to FDA so that analysis of data on women and other populations is easier. Clancy raised the concept of a learning health care system whereby medical knowledge is advanced by making use of the substan- tial amounts of data and other information collected every day in the provision of health care. The implementation of electronic health-record systems is a key component of a learning health care system. Many pro- fessional societies and other organizations have created patient-level reg- istries, which offer another method of collecting data. Clancy added that AHRQ is using American Recovery and Reinvestment Act funds desig- nated for comparative-effectiveness research and patient-centered out- comes research to develop “a registry of registries” that will be 3 See http://www.kff.org/minorityhealth/7886.cfm (accessed August 26, 2011).
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WORKSHOP SUMMARY 11 functionally interoperable with the clinical-trial registration database, ClinicalTrials.gov. THE RESEARCHER PERSPECTIVE: COLLECTING, ANALYZING, AND REPORTING SEX- SPECIFIC DATA Researchers encounter barriers to the reporting of sex-specific biomedical research results well before the publication stage, said session moderator Jon Levine, director of the Wisconsin National Primate Re- search Center and editor-in-chief of Frontiers in Neuroendocrinology. Challenges emerge in designing experiments, applying for grants, and making the most of limited funding inasmuch as these activities build on the existing knowledge base, which is historically biased toward males. Collecting the Data: Sex in Biomedical Research The Politics of Sex Differences Biases against studying females are embedded in the research culture, and there are numerous misconceptions, said Larry Cahill, pro- fessor of neurobiology and behavior at the University of California, Irvine. In neuroscience, for example, some think that if there is no behav- ioral difference between the sexes, there is no brain difference. It is known, however, that identical behaviors can be manifested through different neurobiologic mechanisms. Others assert that consideration of sex differences makes things more complicated. But analyzing data by sex can sometimes provide clarity. Cahill offered an example of sex differences in brain function from his work on emotional memory. He discovered that the amygdala operates differently in men and the women when they watch the same emotional event; activity in the left-hemisphere amygdala is more pre- dictive of memory of a given event in women, while activity in the right- hemisphere amygdala is more predictive of memory of the same event in men. The greatest obstacle to moving forward, Cahill said, is the pro- found biases that exist against the consideration of sex differences. Such biases may be even greater in studies of the brain. Sex differences in the liver or kidneys are not particularly controversial, but sex differences in the brain can become a political issue. Cahill said that researchers need
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34 SEX-SPECIFIC REPORTING OF SCIENTIFIC RESEARCH guidelines that do not address sex-specific reporting at all, including the Council of Science Editors (which covers science broadly, not only bio- logic science but the physical sciences), the World Association of Medi- cal Editors, the Guideline on Good Publication Practice of the pharmaceutical industry, and the EQUATOR (Enhancing the QUAlity and Transparency Of health Research) network, an umbrella organization that catalogs numerous reporting guidelines, such as CONSORT (Con- solidated Standards of Reporting Trails) for randomized trials and STROBE (STrengthening the Reporting of OBservational studies in Epi- demiology) for observational studies. (The CONSORT and STROBE guidelines cover the majority of the clinical research published in the major journals.) Annals of Internal Medicine does not have a specific policy on sex-specific reporting but follows the ICMJE policy, Laine said, and en- courages authors to follow reporting guidelines, including CONSORT and STROBE. She added that for many years, Annals has indicated in the title and abstract when a study includes only men or only women and indicates in the limitations of the study if data are insufficient to examine potentially relevant sex differences or racial or ethnic differences. Annals does not ask authors to report sex-specific results when the study design is insufficient to enable useful reporting of such results. A journal can put a policy into place, but there has to be a way to implement it. Laine offered clinical-trial registration as a case example: the ICMJE put its registration policy into place before there was any- where for sponsors to register their trials. Similarly, journals could re- quire that studies be powered for subgroup analysis, but that would entail the availability of resources to fund those types of studies. It will not work if the funders, researchers, and journal editors are not aligned. Edi- tors can foster more accurate reporting, but must be careful about making requirements that are not feasible, Laine cautioned. As data-sharing ad- vances, journals may be different a decade from now, and researchers whose studies do not meet some set criteria may move away from tradi- tional journals and publish their results in an open-access setting. Berlin added that a motivation for trial registration was to eliminate publication bias—to make all results available regardless of whether they are posi- tive or negative. He cautioned that a situation in which only studies with sex-specific results are published is not desirable. Another issue is the long pipeline of current high-quality clinical trials, many with long-term followup. These will be coming to comple- tion over the next decade or later, and panelists discussed how any edito- rial policy that affects study design would need to be phased in over an
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WORKSHOP SUMMARY 35 extended period. In the interim, Golub said, it is unlikely that journals would forgo publishing a well-done, informative study that could affect patient care solely because it lacked enough power to permit valid sex- specific reporting. Conversely, journals are not willing to publish poor- quality studies or invalid or meaningless data or analyses. As discussed earlier, the present workshop was designed to con- sider a recommendation in Women’s Health Research (IOM, 2010) that “the International Committee of Medical Journal Editors and other edi- tors of relevant journals should adopt a guideline that all papers reporting the outcomes of clinical trials report on men and women separately un- less a trial is of a sex-specific condition” (IOM, 2010, p. 13). Laine raised several concerns about editorial policies that might be developed on the basis of that recommendation. First, it appears that observational studies are not included. Second, as discussed above, many trials include insufficient numbers of women or men to allow valid comparisons or within-group conclusions. Third, if randomization was not stratified by sex, the results should not be interpreted as causal relationships. Finally, simply reporting sex-specific results does not address the question of whether any of the observed sex differences are due to sex or to con- founding factors. Suggestions from the Editors On the basis of their experiences in implementing editorial poli- cies, the panelists offered a variety of suggestions regarding the inclusion of sex-specific information in scientific publications (summarized in Box 2). It was also suggested that the ICMJE consider adopting a strong- er sex-specific analysis and reporting statement similar to that of JNCI. Laine predicted, however, that ICMJE members would question why only sex was being addressed and not other key factors, such as age, race, ethnicity, and insurance coverage.
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36 SEX-SPECIFIC REPORTING OF SCIENTIFIC RESEARCH LOOKING FORWARD8 In the final session of the workshop, members of the workshop planning committee and others reflected on the recurring themes of the meeting. Clayton noted the intersecting roles of journal editors, govern- ment funding agencies, industry, basic researchers, and others in advanc- ing the understanding of sex differences in health through careful study design, data-sharing, subgroup analysis, and sex-specific reporting of results. Anthony pointed out that major goals of biomedical research are the translation of findings into clinical practice and informing the devel- opment of health policy. FDA’s mandate, for example, is to ensure that the medical products that it regulates are safe and effective in the appro- priate populations. In that regard, profound sex-based differences that affect health and disease in both males and females at the cellular, mo- lecular, and physiologic levels should be considered. Adler pointed out that, despite progress over the last decade, there is still a need for more and better data on sex differences. The focus of the workshop was on how to bring information on sex differences in health to light and specif- ically how journal editors, through editorial policies, could influence how research is reported. BOX 2 Summary of Suggestions by Individual Editors Preclinical Studies The sex of the animals studied should be reported. If only one sex of an animal was studied, this should be indicated in the title of the article. In most cases, the sex of origin of cells used should be reported (exclud- ing, for example, immortalized cell lines, which are highly transformed and for which the sex of the original cells may not be relevant). Both male and female animals should be studied when appropriate; and, when it is possible, both sexes should be studied in the same experi- ment. 8 The topics highlighted in this section are based on closing remarks of members of the workshop planning committee and the session chairs and on the open dis- cussions throughout the workshop. They should not be construed as reflecting any group consensus or endorsement by the IOM.
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WORKSHOP SUMMARY 37 1 Clinical-Study Design Studies should be designed with stratified randomization by sex; strati- fied analyses should not just be conducted post hoc. Simply mandating post hoc subgroup analyses today, on a study that was started 10 years ago, is not necessarily valid, because it will probably violate the random- ization. Studies should be designed with adequate statistical power for sub- group analyses and to test for interactions. In the absence of adequate power, raw data should be archived by sex for future pooling and meta-analysis. One possible criterion for requiring the analysis and reporting of sex- specific results should include an a priori reasonable likelihood that sex- based associations might exist. Clinical-Study Reporting The title and abstract should indicate whether a study involved only men or only women. If the study design allows identification of sex differences, journals should require authors to present these results. If there is an inability to identify sex differences, this should be reported in the discussion of the limitations of the study. Researchers should be allowed to report inconclusive or descriptive sex- specific findings as raw data in electronic-only appendixes to meet NIH and FDA policies. As above, this will make the data available to researchers for conducting meta-analyses. The Role of Editorial Policy Levine reiterated earlier discussions that developing and imple- menting editorial policies regarding the analysis and interpretation of information that has already been obtained is fairly straightforward. Journal editors can set standards in their instructions for authors regard- ing what information is expected to be included in a manuscript. More challenging and perhaps controversial is the development and implementation of editorial policies that ultimately influence how experiments are designed and conducted, including being appropriately powered to allow comparison between the sexes. Workshop participants expressed varied opinions regarding the extent to which a journal policy should stipulate what analyses authors must include. Some participants
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38 SEX-SPECIFIC REPORTING OF SCIENTIFIC RESEARCH also discussed how any clinical-journal editorial policy that affects study design may need to be phased in over a long period, inasmuch as clinical studies that are already under way may be years away from completion and publication. Levine reminded participants that several editors stressed that the design and analysis of studies are not likely to change simply because editors change reporting requirements. Journals can encourage change by making very clear what they consider to be the standards for sex-specific reporting, but there needs to be a culture shift within science. In that re- gard, there is a key role for federal agencies and other funders in shaping research culture to embrace consideration of sex differences as part of sound study design. For example, when reviewing grant proposals, NIH and other funders could consider whether criteria for sex-specific analy- sis are met (for example, whether a study includes both males and fe- males, is powered for valid subgroup analysis, or justifies the study of only one sex). Adler pointed to earlier discussions that there are clearly other subgroups that may be relevant to consider, such as race and ethnicity. However, issues of sample size are more challenging with multiple groups and there is much greater evidence of the biological effects of sex than of race. The need for research that will allow for a better under- standing of racial and ethnic differences in health and treatment effects does not diminish the need for sex-specific analyses, nor is it tied to it. Levine discussed the issue, raised earlier by participants, of con- sideration of sex in studies that use animals, because these studies help to elucidate mechanisms and inform drug-development studies in humans. It was suggested that editorial policies for basic-science journals be “more of a carrot policy than a stick policy.” That is, the value added in the review process by a stated policy of sex-specific reporting should be stressed, and reviewers should be advised to consider the inclusion of sex-specific information as a desirable attribute of a manuscript. The cur- rency of scientific work is publication, and it was suggested that this ap- proach will feed back to the design of experiments as researchers begin to understand that manuscripts that include sex-specific information and analyses, or a clear justification for studying only one sex, will be re- viewed more favorably. Levine also mentioned, as noted earlier by some participants, that there is no editorial body of basic-science journal editors comparable with the ICMJE for clinical journals.
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WORKSHOP SUMMARY 39 Statistical Power for Subgroup Analysis Anthony summarized earlier discussions pointing out that for clinical studies, issues of statistical power are paramount. But in a resource-limited research environment, larger samples do not constitute a feasible solution for enabling valid subgroup analysis. Instead, new study designs and advanced statistical methods may help reap the most reward from patient participation in clinical trials. It was suggested that when there is insufficient power to analyze sex differences within a study, it may be possible to combine data from various studies and con- duct meta-analysis or apply advanced statistical methods, such as the use of Bayesian inference. Golub also cautioned about the potential for type II errors by publishing comparisons by sex that do not show a significant difference. If a study is not adequately powered to look for such differ- ences, then a study showing no differences is meaningless. Summary of Participants’ Suggestions for Advancing Sex-Specific Reporting Adler discussed four themes that she thought reflected the sug- gestions for advancing sex-specific reporting discussed by others over the course of the day. First, Adler noted the earlier discussions related to identifying the sex of populations in journal publications, including listing the sex of origin of cells and tissues, the sex of animals in basic and preclinical re- search, and the sex of participants in observational research and in clini- cal trials. If only one sex is studied, noting that in the title of the paper would be helpful. Adler suggested that having summary data, similar to what Golub presented, published annually would be helpful. Second, she reiterated the advantages of sharing sex-identified raw data, noting that if a study is not sufficiently powered for subgroup analysis, sex-identified raw data could be made available, either as a supplement or on a website, to facilitate meta-analyses (with the neces- sary caution to avoid overinterpretation of the raw data). Third, referring back to the discussion of using a “carrot policy” by giving “extra credit” in review to manuscripts that include sex- specific information, Adler pointed out that editors could make it clear that including sex-specific information will enhance a paper’s chances of publication.
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40 SEX-SPECIFIC REPORTING OF SCIENTIFIC RESEARCH Fourth, Adler mentioned earlier discussions about requiring sex- stratified analyses. She reminded participants that it was noted that re- quiring identification of sex-specific information is easier to implement than requiring sex-specific analyses, but possibly less effective than re- quiring them. Editorial policies that require sex-stratified analysis would affect how studies are designed and conducted, not only how they are reported. The ultimate goal would be a culture change in scientific re- search that embraces sex as a key variable for analysis. CLOSING REMARKS Clayton offered closing comments on behalf of the workshop sponsor. The purpose of research is to inform, she said, and, for those involved in health research, to increase knowledge about human biology and to foster development of evidence-based health policy and clinical care. Journal editors, Clayton pointed out, are uniquely positioned as gatekeepers for much of the scientific knowledge that reaches the public domain. They have the power to advance appropriate consideration of sex differences, she said, acknowledging that the term appropriate is subject to interpretation and that “one size does not fit all.” Journal edi- tors and editorial bodies, such as the ICMJE, can set standards for the inclusion of sex-related information in manuscripts submitted to their publications, including the sex of origin of tissues and cells and the sex of animals and humans in preclinical and clinical studies. They are also in a position to set guidelines to encourage authors to think about analy- sis and reporting of sex differences. Clayton reiterated that NIH requires the inclusion of women and minorities, as scientifically appropriate, in all clinical research that is supported by NIH. For a phase 3 clinical trial, if an evidence review re- veals a likelihood of a sex-based difference, the study must be designed to allow comparisons between males and females, and the results must be provided to NIH in the final progress report. However, NIH does not have any control over what is published in the scientific literature. To- gether, the scientific community needs to find ways to ensure that this information gets out so that it can be helpful to researchers, clinicians, and policy-makers, she said. Funding is more limited than at other times, so scientists should also be efficient in collecting as many data as possi- ble from studies. She concluded by noting that patients who participate in trials are relying on researchers to get the maximum information from clinical research.
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42 SEX-SPECIFIC REPORTING OF SCIENTIFIC RESEARCH Goldkind, S. F., L. Sahin, and B. Gallauresi. 2010. Enrolling pregnant women in research—lessons from the H1N1 influenza pandemic. N Engl J Med 362(24):2241-2243. Goodman, S. N. 1999. Toward evidence-based medical statistics. 2: The Bayes factor. Ann Intern Med 130(12):1005-1013. Gurwitz, J. H., N. F. Col, and J. Avorn. 1992. The exclusion of the elderly and women from clinical trials in acute myocardial infarction. JAMA 268(11):1417-1422. IOM (Institute of Medicine). 2010. Women’s Health Research: Progress, Pit- falls, and Promise. Washington DC: The National Academies Press. IOM. 2011. Sex Differences and Implications for Translational Neuroscience Research: Workshop Summary. Washington, DC: National Academies Press. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. 1988. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS- 2. Lancet 2(8607):349-360. Jagsi, R., A. R. Motomura, S. Amarnath, A. Jankovic, N. Sheets, and P. A. Ubel. 2009. Under-representation of women in high-impact published clinical cancer research. Cancer 115(14):3293-3301. Kahn, S. E., B. Zinman, J. M. Lachin, S. M. Haffner, W. H. Herman, R. R. Holman, B. G. Kravitz, D. Yu, M. A. Heise, R. P. Aftring, and G. Viberti. 2008. Rosiglitazone-associated fractures in type 2 diabetes: An analysis from A Diabetes Outcome Progression Trial (ADOPT). Diabetes Care 31(5):845-851. Kent, D., and R. Hayward. 2007a. When averages hide individual differences in clinical trials. American Scientist 95(1):60-68. Kent, D. M., and R. A. Hayward. 2007b. Limitations of applying summary re- sults of clinical trials to individual patients: The need for risk stratification. JAMA 298(10):1209-1212. Kim, E. S., and V. Menon. 2009. Status of women in cardiovascular clinical trials. Arterioscler Thromb Vasc Biol 29(3):279-283. Mittelstrass, K., J. S. Ried, Z. Yu, J. Krumsiek, C. Gieger, C. Prehn, W. Roemisch-Margl, A. Polonikov, A. Peters, F. J. Theis, T. Meitinger, F. Kronenberg, S. Weidinger, H. E. Wichmann, K. Suhre, R. Wang-Sattler, J. Adamski, and T. Illig. 2011. Discovery of sexual dimorphisms in metabolic and genetic biomarkers. PLoS Genet 7(8):e1002215. NIH (National Institutes of Health). 2011. Monitoring Adherence to the NIH Policy on the Inclusion of Women and Minorities as Subjects in Clinical Research: Comprehensive Report: Tracking of Human Subjects Research As Reported in Fiscal Year 2009 and Fiscal Year 2010. Washington, DC: HHS and NIH. Putting gender on the agenda. 2010. Nature 465(7299):665. Sleight, P. 2000. Debate: Subgroup analyses in clinical trials: Fun to look at— but don’t believe them! Curr Control Trials Cardiovasc Med 1(1):25-27.
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WORKSHOP SUMMARY 43 Wald, C., and C. Wu. 2010. Biomedical research. Of mice and women: The bias in animal models. Science 327(5973):1571-1572. Wong, J. B. 2011. What are my chances? Presentation at Sex-Specific Reporting of Scientific Research: A Workshop. Institute of Medicine, Washington, DC. Zucker, I., and A. K. Beery. 2010. Males still dominate animal studies. Nature 465(7299):690.
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