Designing Health & Biomedical Research

All elements of biomedical research—the basic, applied, or translational research conducted to advance and support the body of knowledge in the field of health research and medicine—should take sex and gender into consideration. This recommendation applies over the wide range of study designs (survey, experimental, clinical trial, field trial, prospective, case/control, and more) and across multiple design aspects (see Health and Medicine Checklist). Important resources when considering research design include: Oertelt-Prigione, S. et al., Sex and Gender Aspects in Clinical Medicine; Schenck-Gustafsson et al., Handbook of Clinical Gender Medicine; and Regitz-Zagrosek, Sex and Gender Differences in Pharmacology. Additional resources: U.S. National Institutes of Health online course: The Science of Sex and Gender in Human Health; the European Curriculum in Gender Medicine online course.

Health research addresses a broad range of factors that affect health of an individual or population, such as protective and risk factors, social determinants of health, environment and resource distribution (see Analyzing Gender). Clinical research, which evaluates the safety and efficacy of medications, devices, diagnostic procedures, and treatment regimens for preventing, treating, diagnosing or relieving symptoms of a disease, generally of individuals requires serious consideration of the study population (selection and eligibility criteria—i.e. sampling)—see Analyzing Sex.

Sampling (Selection or Eligibility Criteria and Recruitment Strategies)
Enrolling a representative sample of the population for whom the study results may be generalized includes: a) determining characteristics which are likely to affect outcomes before initiating the study; and b) employing recruitment strategies that ensure enrollment of sufficient numbers of subjects whether animals or human. The goal is to have adequate statistical power to detect differences in outcomes. Variables with potential clinical significance include:

1. Sex: The epidemiology of many diseases and the safety and efficacy of many diagnostics and treatments differ by sex (see Analyzing Sex). It should not be assumed, even for most standard, approved interventions, that similar effects will be observed in women and men. Substantial harm has resulted when data from single-sex studies (typically male only) has been generalized to both sexes (Kim et al., 2010). Female sex is a risk factor for certain adverse drug reactions, such as torsades de pointes, a life-threatening cardiac arrhythmia (Gupta et al., 2007). Since 1994, U.S. legislation has required that women and ethnic/racial minorities be included in Phase III and subsequent clinical trials (1993 Revitalization Act). Nevertheless,

  • a. Even in clinical trials governed by the NIH Revitalization Act, women remain under-enrolled relative to their representation in the patient population. See, for example, trials for Cardiovascular disease (CVD) below.
  • b. The Revitalization Act does not apply to early-phase medical studies. Specifically, the NIH states that “an NIH-defined ‘clinical trial’ is a broadly based prospective Phase III clinical investigation, usually involving several hundred or more human subjects, for the purpose of evaluating an experimental intervention in comparison with a standard or control intervention or comparing two or more existing treatments” (NIH, 2001). Under this definition, Phase I and II studies are not clinical trials and therefore not subject to the provisions of the Act. When women are not included in Phase I and II, important discoveries related to sex may be missed. For example, a drug that works only in women may not be developed.
  • c. Exclusion of women from clinical trials is not justifiable on the grounds of preventing birth defects or other harm to fetuses.In the 1950s, prescription of thalidomide to pregnant women caused widespread birth defects and stillbirths, which in turn “spurred protectionist research policies which, ironically, often harmed women” (Gorenberg et al., 1991). Current policies strictly regulate pregnant women’s enrollment in clinical trials; enrollment requires that “the risk to the fetus is caused solely by interventions or procedures that hold out the prospect of direct benefit for the woman or the fetus; or, if there is no such prospect of benefit, the risk to the fetus is not greater than minimal and the purpose of the research is the development of important biomedical knowledge which cannot be obtained by any other means” (Department of Health and Human Services, 2001). Similarly strict guidelines apply to enrollment of children in medical research (Code of Federal Regulations, 2009; European Parliament, 2001).

  • In some cases, researchers have applied the strict enrollment regulations (designed to protect pregnant women) to all women of childbearing potential (i.e., all women between menarche and menopause), effectively excluding these women from basic research (Kinney et al., 1981). Such "protectionist" policies can in fact endanger pregnant women, as "new drugs and devices are typically not approved for use" in pregnancy (Baylis, 2010). Even though many clinical trials enroll patient cohorts of an age where most or all women are post-menopausal, women remain underrepresented.
  • women in CVD clinical trials vs deaths               women in CVD clinical trials vs patients

  •  
  • In recognition of this deficiency, the European Medicines Agency (EMEA) has asserted that matching the demographics of a study population to the demographics of patients eligible to receive a given treatment is "an underlying principle of drug development." (EMEA, 2005). In the specific context of cardiovascular diseases, EMEA has emphasized the need for research on possible sex differences in "lipid profile, hormonal status and influence of menopause, body composition, etc.," which may be relevant to understanding why sex differences are observed in prognosis and in the efficacy of diagnostic tests (EMEA, 2006).

2. Reproductive (or Hormonal) State: Both females and males have profound hormonal changes: at puberty, with aging, and for females, across the estrus or menstrual cycle, during and after pregnancy, and during the menopausal transition. These hormonal changes have widespread physiological effects, producing changes in immune function, fluid balance, temperature control, and body composition. Researchers should consider these effects in planning research, and where appropriate (Becker et al., 2005).

  • a. Sample naturally ovulating women at different phases of the menstrual cycle (or female animals at different phases of the estrus cycle—See Case Study: Animal Research).
  • b. Take into account the widespread use (and effects) of exogenous hormones, such as oral contraceptives, menopausal hormones, and androgens.
  • c. Sample women at various points of a pregnancy and post-partum.
  • d. Collect data on early and late peri- and post-menopausal status in studies of middle-aged women.

3. Gendered Behaviors:Gender roles and identities influence disease risk factors as well as treatment and outcomes, so they may need to be considered in biomedical studies. Gendered factors of biomedical significance may include:

  • a. Gendered divisions of labor that expose women and men to different risks. For example, in developed countries, men perform most pesticide application and women perform most household cleaning, and therefore women and men may have contact with different groups of endocrine-disrupting chemicals (see Case Study: Environmental Chemicals).
  • b. Cultural gender norms that create differences in women’s and men’s health behaviors. Gender differences exist in protective behaviors—for example, older men exercise more than age-matched women, and exercise promotes bone health (see Case Study: Osteoporosis). Gender differences also exist in risk behaviors—for example, in Western countries, men are more likely to smoke tobacco (a risk factor for cardiovascular diseases and many cancers), whereas women are more likely to use ultraviolet tanning beds (a risk factor for skin cancer).

4. Factors Intersecting with Sex and Gender:Variables such as age, body composition, and comorbidities often correlate (co-vary) with sex and may confound results if not taken into account. For example, because cardiovascular (CV) events are diagnosed at younger ages in men than in women, and many CV trials have age cut-offs, a smaller proportion of women have been eligible for most CV trials. Further, women who are enrolled in CV trials, such as those of cholesterol-lowering statin drugs, have tended to be older and have more (age-related) co-morbidities than men (Dey et al., 2009). Comparing the results of male-only and female-only CV trials without accounting for age can lead to misinterpretation of trial findings.

Although it is important that researchers sample sufficient numbers of people of both sexes, single-sex studies may be preferable to mixed-sex studies under the following circumstances:

  • a. Studying conditions affecting only women or men. These are generally disorders of reproductive organs, including sex-specific cancers such as ovarian cancer in women and prostate cancer in men. Other single-sex disorders include menstrual and menopausal conditions, pregnancy and childbirth, and erectile dysfunction.
  • b. Medical diagnostics and interventions already tested extensively in one sex. For example, it was reasonable to study the safety and effectiveness of the HPV vaccine in young men only (Giuliano et al., 2011), after it had been extensively studied in young women (Future II Study Group, 2007). Similarly, many osteoporosis drugs have been studied extensively in women, but have not yet been studied in men.
  • c. Differences (or similarities—i.e., prior studies support no significant differences) in disease development, diagnosis, or treatment are already well understood. In this case, single-sex studies can allow researchers to examine differences within each sex, often through analysis of factors intersecting with sex. For example, the Women’s Ischemic Stroke and Evaluation (WISE) study evaluated angina that was present with no obvious obstructive coronary disease in women only, noting that it is much less common in men, and determined several underlying causes of ischemia (Shaw et al., 2008).

Study design should build in strategies to ensure that women and men enrolled in a study receive similar interventions and are retained at similar high levels, and that comparable data are gathered.

In some cases, retrospective analysis may be performed. For instance, researchers might compare treatment effects in a set of female-only studies of a particular drug and male-only studies of the same drug. Though neither group of studies is able to detect sex differences, a meta-analysis of the two studies might demonstrate such differences. Retrospective analysis is, however, much less reliable than prospective analysis—see Common Pitfalls in Sampling.

Related Case Studies

Works Cited

Allender, A., Scarborough, P., Peto, V., Rayner, M., Leal, J., Luengo-Fernandez, R., & Gray, A. (2008). European Cardiovascular Disease Statistics, 2008 Edition. Brussels: European Heart Network.

Baylis, F. (2010). Pregnant Women Deserve Better. Nature, 465 (7299), 689-690.

Becker, J., Arnold, A., Taylor, J., Young, E., Berkley, K., Blaustein, J., Eckel, L., Hampson, E., Herman, J., Marts, S., Sadee, W., & Steiner, M. (2005). Strategies and Methods for Research on Sex Differences in Brain and Behavior. Endocrinology, 146 (4), 1650-1673.

Cleland, J., Swedberg, K., Follath, F., Komajda, M., Cohen-Solal, A., Aguilar, J., Dietz, R., Gavazzi, A., Hobbs, R., Korewicki, J., Madeira, H., Moiseyev, V., Preda, I., van Gilst, W., Widimsky, J., Freemantle, N., Eastaugh, J., & Mason, J. (2003). The EuroHeart Failure Survey Programme—A Survey on the Quality of Care among Patients with Heart Failure in Europe, Part 1: Patient Characteristics and Diagnosis. European Heart Journal, 24 (5), 442-463.

Code of Federal Regulations (CFR). (2009). Title 45 (Public Welfare), Part 46 (Protection of Human Subjects). Washington, D.C.: Government Publishing Office (GPO).

Department of Health and Human Services (DHHS). (2001). Protection of Human Research Subjects, Code of Federal Regulations (CFR) Title 45, Part 46, Final Rule. United States Federal Register, 66 (219), 56775-56780.

Dey, S., Flather, M., Devlin, G., Brieger, D., Gurfinkel, E., Steg, P., FitzGerals, G., Jackson, E., & Eagle, K. (2009). Sex-Related Differences in the Presentation, Treatment, and Outcomes among Patients with Acute Coronary Syndromes: The Global Registry of Acute Coronary Events. Heart, 95, 20-26.

European Medicines Agency (EMEA). (2006).Committee for Medicinal Products for Human USE (CHMP) Reflection Paper on Gender Differences in Cardiovascular Diseases. London: EMEA.

European Medicines Agency (EMEA). (2005). Gender Considerations in the Conduct of Clinical Trials. London: EMEA.

European Parliament and Council of the European Union. (2001). Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001 on the Approximation of the Laws, Regulations, and Administrative Provisions of the Member States Relating to the Implementation of Good Clinical Practice in the Conduct of Clinical Trials on Medicinal Products for Human Use. Official Journal of the European Communities, L121, 34-44.

Future II Study Group. (2007). Quadrivalent Vaccine against Human Papillomavirus to Prevent High-Grade Cervical Lesions. New England Journal of Medicine, 356 (19), 1915-1927.

Giuliano, A., Palefsky, J., Goldstone, S., Moreira, E., Penny, M., Aranda, C., Vardas, E., Moi, H., Jessen, H., Hillman, R., Chang, Y., Ferris, D., Rouleau, D., Bryan, J., Marshall, D., Vuocolo, S., Barr, E., Radley, D., Haupt, R., & Guris, D. (2011). Efficacy of a Quadrivalent Human Papilloma Virus (HPV) Vaccine against HPV Infection and Disease in Males. New England Journal of Medicine, 364 (5), 401-411.

Gorenberg, H., & White, A. (1991). Off the Pedestal and Into the Arena: Toward Including Women in Experimental Protocols. New York University Review of Law and Social Change, 19, 205-246.

Gupta, A., Lawrence, A., Krishnan, K., Kavinsky, C., & Trohman, R. (2007). Current Concepts in the Mechanishs and Management of Drug-Induced QT Prolongation and Torsade de Pointes. American Heart Journal, 153 (6), 891-899.

Institute of Medicine (IOM). (2010). Women’s Health Research: Progress, Pitfalls, and Promise. Washington, D.C.: National Academies Press.

Johnson, B., Shaw, L., Pepine, C., Reis, S., Kelsey, S., Sopko, G., Rogers, W., Mankad, S., Sharaf, B., Bittner, V., & Merz, C. (2006). Persistent Chest Pain Predicts Cardiovascular Events in Women without Obstructive Coronary Artery Disease: Results from the National Institutes of Health (NIH)-National Heart, Lung, and Blood Institute (NHLBI)-sponsored Women's Ischaemia Syndrome Evaluation (WISE) Study. European Heart Journal, 27 (12), 1408-1415.

Kim, A., Tingen, C., & Woodruff, T. (2010). Sex Bias in Trials and Treatment Must End. Nature, 465 (7299), 688-689.

Kim, E., Carrigan, T., & Menon, V. (2008). Enrollment of Women in National Heart, Lung, and Blood Institute (NHLBI)-Funded Cardiovascular Randomized Controlled Trials Fails to Meet Current Federal Mandates for Inclusion. Journal of the American College of Cardiology, 52, 672-673.

Kinney, E., Trautmann, J., Gold, J., Vesell, E., & Zelis, R. (1981). Underrepresentation of Women in New Drug Trials: Ramifications and Remedies. Medicine and Public Issues, 95 (4), 495-499.

Müller-Nordhorn, J., Binting, S., Roll, S., & Willich, S. (2008). An Update on Regional Variation in Cardiovascular Mortality within Europe. European Heart Journal, 29 (10), 1316-1326.

NIH Policy and Guidelines on The Inclusion of Women and Minorities as Subjects in Clinical Research – Amended, October, 2001.

Oertelt-Prigione, S.& Regitz-Zagrosek, V. (Eds.) (2012). Sex and Gender Aspects in Clinical Medicine. London: Springer Verlag.

Regitz-Zagrosek, V. (Ed.) (2012). Sex and Gender Differences in Pharmacology. London: Springer Verlag.

Ridker, P., Cook, N., Lee, M., Gordon, D., Gaziano, J., Manson, C., Hennekens, H., & Buring, J. (2005). A Randomized Trial of Low-Dose Aspirin in the Primary Prevention of Cardiovascular Disease in Women. New England Journal of Medicine, 352 (13), 1293-1304.

Schenck-Gustafsson, K., DeCola, P., Pfaff, D., Pisetsky, D. (Eds.) (2012). Handbook of Clinical Gender Medicine. Basel: Karger, 2012.

Stramba-Badiale, M. (2010). Women and Research on Cardiovascular Diseases in Europe: A Report from The European Heart Health Strategy (EuroHeart) Project. European Heart Journal, 31 (14), 1677-1685.

 

 

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