Gender bias in research: how does it affect evidence based medicine?

Abstract

The evidence basis of medicine may be fundamentally flawed because there is an ongoing failure of research tools to include sex differences in study design and analysis. The reporting bias which this methodology maintains creates a situation where guidelines based on the study of one sex may be generalized and applied to both. In fact, study design in the 1970s in response to sex discrimination legislation made efforts to mix gender within study groups since this was considered the best approach to equality. Although significant social progress has been made since then, the application of the principles behind the legislation to women's health and gender-based research have not been so positive. Those who research gender issues in clinical and laboratory medicine are aware of significant barriers both for researchers and for subjects entering studies. This is one illustration of continuing deep-seated patterns of disadvantage that triggered an equalities review by the UK Cabinet Office in November 2005. For example, research funding for coronary artery disease in men is far greater than for women, yet the at risk population of women, which is an older age group, suffers more morbidity and mortality. The lack of funding for women's disease in effect maintains women's lower economic status. It can also hinder research into gender medicine where significant advances in the diagnosis and management of coronary artery disease have built up from small differences into major gender medicine issues.1 Clinical research also exhibits gender bias in other areas. One of these is in recruitment into clinical trials;2 another is the reporting of gender-related data.3 However, there is a dearth of gender-based clinical research from within the UK. Thus it is pertinent to use studies from North America and Europe where these issues have been investigated. It was in 1994 that the US National Institutes of Health (NIH) issued a guideline for the study and evaluation of gender differences in clinical trials to ensure that the safety and efficacy of drugs would be adequately investigated in the full range of patients who would use the therapy.4 Prior to this policy, women had been excluded from early studies of most drugs—mainly for safety reasons, but this prohibition meant there was little information about the effects of drugs in women. For example, women may have a different drug efficacy or side effect profile to men.5 It was reported in 2005 that eight out of ten prescription drugs were withdrawn from the US market because of women's health issues.6 This represents an enormous waste of research money as a consequence of neglecting gender research. The aims of the NIH guidance were to recruit enough women into studies to be able to allow valid analyses of differences in intervention effect, to evaluate the risks and benefits in women, and to provide opportunities for women to contribute to research through active participation in clinical trials while preventing exposure of a fetus to a toxic drug. Since then, in the USA, women can enter phase one, two and three clinical trials. Furthermore, training for and monitoring adherence to this policy has been undertaken by the NIH through the review process for research funding. However there has not been a dramatic recruitment of women's data into trial results.7 Monitoring for gender in NIH research has been reported from the US Congress Office. In 1997, 94% of grant proposals included women as research subjects.8 This high figure, however, belies the underlying Society for Women's Health Research data that the richest charities (as distinct from government funded bodies) were not progressing with the inclusion of women as researchers and subjects and that only 3% of grant proposals measured sex differences.6 One important methodological barrier appears to be that women using hormonal contraception must be considered as a separate group for purposes of analysis.9 However, even the basic concept of including women, whatever their hormonal status, has been brought into focus by recent studies that identified significant barriers to the inclusion of women in clinical trials. Questions concerning contraceptive use in clinical trials were investigated by an Institutional Board survey. These trials were mainly government sponsored in the years after gender discrimination was outlawed. It was found that certification of contraceptive use was required in 42% of protocols without explanation and in 36% of protocols because of the study drug used.10 Almost 10% of protocols allowed no exclusions for contraceptive use (e.g. celibacy or sexual orientation). In addition, for the inclusion of women, up to four counter-signatures were required in some studies to confirm contraceptive use, whereas for men no signatures were required. The study concluded that access to studies by women created burdens that were disproportionate to men. Aspects of contraceptive requirements for studi