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EDITORIAL

EDITORIAL

Dispelling the Myths:


Calling for Sex-Specific Reporting of Trial Results

E xclusion of women from clinical trials has its origins in


the centuries-old concept of protecting women and
children from harm. The logical result of this effort was
cal and physiologic differences between women and men.
Further, the report states that “Understanding the basis of
these sex-based differences [is] important to developing
that women of childbearing age were barred from partici- new approaches to prevention, diagnosis, and treatment.”
pating in most medical research. Unfortunately, this rea- One important step in this effort to provide the best data for
sonable, if somewhat paternalistic, effort to avoid harming both sexes is to design clinical trials to include both men
fetuses by not enrolling pregnant participants in early- and women and to report results by sex.
phase drug trials was overenthusiastically expanded to a Rogers and Ballantyne5 in this issue of Mayo Clinic
virtual ban on all women in clinical trials. Additional rea- Proceedings review 400 Australian studies published from
sons given for excluding women from research studies 2003 through 2006. They report that a shocking 6% (23) of
include the real and perceived challenges of “controlling” the studies did not even list the sex of the
for cyclic hormonal effects on outcomes and the widely participants, and half of the investigators of See also
held assumption that any results derived from male-only those studies could not supply this informa- page 536
research could be applied to women. tion when asked. Further, 10% of the trials,
Sex-based medicine traditionally has been thought of as for unclear or unspecified reasons, did not enroll any
the study and treatment of conditions affecting only men or women, despite studying conditions affecting women. That
only women, such as reproductive health and sex-specific investigators can still submit manuscripts without includ-
cancers. Only in the past decade or so have researchers ing the sex of the participants and that journals accept them
widely recognized the many biological differences be- for publication without comment is both worrisome and
tween the sexes. Sex-based differences in natural history of indicative that the vital need for sex-specific research and
disease, epidemiology, pathophysiology, diagnostic accu- reporting is still not widely appreciated.
racy of tests, response to therapy, and outcomes have all Almost three-quarters of the half-million participants in
been identified in a range of diseases and conditions previ- published reports were women. On the surface, this fact
ously thought to be “gender neutral.” Despite findings in seems reassuring. However, approximately two-thirds of
1985 from the US Public Health Service Task Force on these women were involved in trials studying “female con-
Women’s Health Issues1 that excluding women from clini- ditions,” whereas three-quarters of the men participated in
cal studies had led to a lack of knowledge about women’s research on diseases affecting both men and women. For
biology and that this deficiency had compromised the example, 55% (219,865/401,801) of women studied were
health of women, male domination in clinical trial enroll- enrolled in one of 3 large sex-specific epidemiologic
ment continued. studies of cervical pathology, hysterectomy rates, and os-
To address the deficiency of knowledge about women teoporosis treatment patterns. The authors refer to this phe-
and health, in 1993 the National Institutes of Health began nomenon as “biological essentialism”; that is, research in
to require that federally funded clinical trials include women emphasizes “female issues,” such as pregnancy and
women and minorities unless their exclusion was clearly reproduction. Thus, this article suggests that much of the
justified and that trials be designed and carried out in such a medical research in women has a focus similar to that of
manner that sex-specific results (SSRs) could be validly popular women’s magazines—breasts and sex. Research
analyzed.2,3 Eight years later, the National Academy of involving men includes a more diverse range of health
Sciences Institute of Medicine published its report, Explor- concerns.
ing the Biological Contributions to Human Health: Does The relatively high number of women included in the
Sex Matter?4 This report concluded that sex differences Australian clinical trials is also explained by the authors’
must be researched at all levels, from the cells and chromo- broad definition of clinical trials. They included articles
somes to whole organisms, if we are to identify the biologi- based on registry data, administrative claims databases,
and observational trials, which supply valuable informa-
tion but require little, if any, additional effort to include
Address correspondence to Sharonne N. Hayes, MD, Division of Cardiovascu- women. Instead, these studies retrospectively analyze pa-
lar Diseases, Women’s Heart Clinic, Mayo Clinic, 200 First St SW, Rochester,
MN 55905 (hayes.sharonne@mayo.edu). tient information from data sets that happen to include
© 2008 Mayo Foundation for Medical Education and Research many female patients. Randomized clinical trials require

Mayo Clin Proc. • May 2008;83(5):523-525 • www.mayoclinicproceedings.com 523

For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
EDITORIAL

active recruitment and enrollment of participants, and should explain why only subjects of certain ages were
women have been shown to have different, and frequently included or why women were excluded. The guiding prin-
more, barriers to participation in trials than men.6 Random- ciple should be clarity about how and why a study was done
ized clinical trials are considered the best type of scientific in a particular way.”8 Perhaps it is time for this recommen-
evidence, to which observational studies are an important dation to be made a mandate and for journal editors to
complement. After we have answered the experimental either require that manuscripts include sex-specific data to
question about the efficacy of a particular therapy or be considered for review or at least to make such data
procedure in the more idealized randomized trial setting, available online. The “author information” section of Cir-
observational data tell us about its benefit and effective- culation suggests providing “sex-specific and/or racial/
ness in the “real world.” To ensure high-quality evidence- ethnic-specific data when appropriate, in describing the
based health care, we must not only include adequate outcomes of epidemiologic analyses or clinical trials; or
numbers of men and women in research but report SSRs specifically state that no sex-based or racial/ethnic-based
also. This practice is especially important for large obser- differences were present.”9 The Journal of the American
vational studies, as results can help inform our clinical College of Cardiology uses nearly identical wording,10
practice. but substitutes “gender-specific” for “sex-specific.” How-
The data reported by Rogers and Ballantyne on the ever, this requirement is not emphasized to submitting
current state of sex-specific reporting show there is much authors or to journals’ peer reviewers and is not a consis-
room for improvement. Of the studies of men and women tent practice in recent publications, even when female
reviewed, 93% did not provide sex-specific analysis. It is participants are included in sufficient numbers to provide
disappointing to find that, as recently as 2006, sex-specific this reporting.9,10
reporting and rates of inclusion of women in clinical trials It is time to recognize that women are complex biologi-
were still appallingly low. In fact, in large trials involving cal creatures just as are men. All clinical studies should
the study of pharmaceuticals, the percentage of sex-spe- strive to include equal numbers of female and male partici-
cific reporting was a dismal zero. pants or to at least reflect the prevalence of the condition of
We observed the same phenomenon in a recent review interest by sex. In older populations, this could appropri-
of cardiology clinical trials where only 25% of all studies ately include a preponderance of women. A recent analysis
reported results by sex.7 As heart disease is the leading of clinical trials used for Medicare national coverage deci-
cause of death in women, it is dismaying that data from sions found that, although 58% of Medicare beneficiaries
cardiovascular clinical trials are so limited. Unexpected sex- are women, women make up only 25% of participants in
based differences have been found in the epidemiology the clinical trials reviewed.11 Until we are able to make this
of many diseases, such as lung cancer, other non–sex- leap, women will continue to be marginalized in clinical
specific cancers, degenerative joint disease, and depression trials of diseases that affect them in numbers equal to men.
and mental health disorders, leading us to conclude that We hope that this editorial and the work that has pre-
the lack of sex differences should not be assumed and ceded it serve as a clarion call to researchers, authors,
instead must be systematically studied. Further, we agree reviewers, and journal editors to include sex-specific re-
with Rogers and Ballantyne that, because of reporting that porting in all clinical trials that include more than 50 par-
is inconsistent or lacking, these types of analyses to as- ticipants. Analyzing data by sex for conditions or treat-
sess levels of SSRs are quite cumbersome and require ments affecting both men and women is the only way we
intensive literature review and data analysis when done will be able to begin to provide optimal care for all patients
after publication. and is a critical step toward the ultimate goal of “individu-
Heightened awareness among investigators, authors, re- alized medicine.”
viewers, and journal editors of the importance of enrolling
and reporting data for both men and women in clinical Sharonne N. Hayes, MD
trials will inform efforts to achieve optimal care of all Division of Cardiovascular Diseases
patients. The International Committee of Medical Journal Women’s Heart Clinic
Editors8 recommends that investigators describe their se- Mayo Clinic
lection of study participants, including controls, clearly Rochester, MN
(eg, eligibility, exclusion criteria, description of the source
population). The committee states, “Because the relevance Rita F. Redberg, MD, MSc
of such variables as age and sex to the object of research is Division of Cardiology
not always clear, authors should explain their use when Women’s Cardiovascular Services
they are included in a study report; for example, authors University of California, San Francisco

524 Mayo Clin Proc. • May 2008;83(5):523-525 • www.mayoclinicproceedings.com

For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
EDITORIAL

1. Public Health Service Task Force on Women’s Health Issues. Women’s 7. Blauwet LA, Hayes SN, McManus DN, Redberg RF, Walsh MN. Low
Health: Report of the Public Service Task Force on Women’s Health Issues. rate of sex-specific result reporting in cardiovascular trials. Mayo Clin Proc.
Public Health Rep. 1985;100(1):73-106. 2007;82(2):166-170.
2. US Department of Health and Human Services. NIH Guide for Grants 8. International Committee of Medical Journal Editors. Uniform Require-
and Contracts. Vol 19, No. 28; July 27, 1990. http://grants.nih.gov/grants ments for Manuscripts Submitted to Biomedical Journals: Writing and Edit-
/guide/historical/1990_07_27_Vol_19_No_28.pdf. Accessed March 31, 2008. ing for Biomedical Publication. http://www.icmje.org/. Accessed March 31,
3. US Department of Health and Human Services, National Institutes of 2008.
Health. NIH guidelines on the inclusion of women and minorities as subjects in 9. Kosiborod M, Inzucchi SE, Krumholz HM, et al. Glucometrics in pa-
clinical research. Federal Register. 1994;59:14508-14513. http://www.hhs tients hospitalized with acute myocardial infarction: defining the optimal out-
.gov/ohrp/humansubjects/guidance/59fr14508.htm. Accessed March 31, 2008. comes-based measure of risk. Circulation. 2008 Feb 26;117(8):1018-1027.
4. Institute of Medicine (US) Committee on Understanding the Biology of Epub 2008 Feb 11.
Sex and Gender Differences. Wizemann TM, Pardue M-L, eds. Exploring the 10. Lee SW, Park SW, Kim YH, et al. Drug-eluting stenting followed by
Biological Contributions to Human Health: Does Sex Matter? Washington, cilostazol treatment reduces late restenosis in patients with diabetes mellitus:
DC: National Academy Press; 2001. the DECLARE-DIABETES Trial (A Randomized Comparison of Triple Anti-
5. Rogers WA, Ballantyne AJ, Australian Gender Equity in Health Re- platelet Therapy With Dual Antiplatelet Therapy After Drug-Eluting Stent
search Group. Exclusion of women from clinical research: myth or reality? Implantation in Diabetic Patients). J Am Coll Cardiol. 2008;51(12):1181-
Mayo Clin Proc. 2008;83:536-542. 1187.
6. Ross S, Grant A, Counsell C, Gillespie W, Russell I, Prescott R. Barriers 11. Dhruva SS, Redberg RF. Variations between clinical trial participants
to participation in randomised controlled trials: a systematic review. J Clin and Medicare beneficiaries in evidence used for Medicare national coverage
Epidemiol. 1999;52(12):1143-1156. decisions. Arch Intern Med. 2008;168(2):136-140.

Mayo Clin Proc. • May 2008;83(5):523-525 • www.mayoclinicproceedings.com 525

For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.

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