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Improving Clinical Trial Reporting

Improving Clinical Trial Reporting

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Published by: Sex & Gender Women's Health Collaborative on Aug 28, 2012
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 Mayo Clin Proc. May 2008;83(5):523-525 www.mayoclinicproceedings.com
523
EDITORIAL
For personal use. Mass reproduce only with permission from
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For personal use. Mass reproduce only with permission from
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Dispelling the Myths:Calling for Sex-Specific Reporting of Trial Results
 
EDITORIAL
Address correspondence to Sharonne N. Hayes, MD, Division of Cardiovascu-lar Diseases, Women’s Heart Clinic, Mayo Clinic, 200 First St SW, Rochester,MN 55905 (hayes.sharonne@mayo.edu).
© 2008 Mayo Foundation for Medical Education and Research
E
xclusion of women from clinical trials has its origins inthe centuries-old concept of protecting women andchildren from harm. The logical result of this effort wasthat women of childbearing age were barred from partici-pating in most medical research. Unfortunately, this rea-sonable, if somewhat paternalistic, effort to avoid harmingfetuses by not enrolling pregnant participants in early-phase drug trials was overenthusiastically expanded to avirtual ban on all women in clinical trials. Additional rea-sons given for excluding women from research studiesinclude the real and perceived challenges of “controlling”for cyclic hormonal effects on outcomes and the widelyheld assumption that any results derived from male-onlyresearch could be applied to women.Sex-based medicine traditionally has been thought of asthe study and treatment of conditions affecting only men oronly women, such as reproductive health and sex-specificcancers. Only in the past decade or so have researcherswidely recognized the many biological differences be-tween the sexes. Sex-based differences in natural history of disease, epidemiology, pathophysiology, diagnostic accu-racy of tests, response to therapy, and outcomes have allbeen identified in a range of diseases and conditions previ-ously thought to be “gender neutral.” Despite findings in1985 from the US Public Health Service Task Force onWomen’s Health Issues
1
that excluding women from clini-cal studies had led to a lack of knowledge about women’sbiology and that this deficiency had compromised thehealth of women, male domination in clinical trial enroll-ment continued.To address the deficiency of knowledge about womenand health, in 1993 the National Institutes of Health beganto require that federally funded clinical trials includewomen and minorities unless their exclusion was clearly justified and that trials be designed and carried out in such amanner that sex-specific results (SSRs) could be validlyanalyzed.
2,3
Eight years later, the National Academy of Sciences Institute of Medicine published its report,
 Explor-ing the Biological Contributions to Human Health: DoesSex Matter?
4
This report concluded that sex differencesmust be researched at all levels, from the cells and chromo-somes to whole organisms, if we are to identify the biologi-cal and physiologic differences between women and men.Further, the report states that “Understanding the basis of these sex-based differences [is] important to developingnew approaches to prevention, diagnosis, and treatment.”One important step in this effort to provide the best data forboth sexes is to design clinical trials to include both menand women and to report results by sex.Rogers and Ballantyne
5
in this issue of 
 Mayo ClinicProceedings
review 400 Australian studies published from2003 through 2006. They report that a shocking 6% (23) of the studies did not even list the sex of theparticipants, and half of the investigators of those studies could not supply this informa-tion when asked. Further, 10% of the trials,for unclear or unspecified reasons, did not enroll anywomen, despite studying conditions affecting women. Thatinvestigators can still submit manuscripts without includ-ing the sex of the participants and that journals accept themfor publication without comment is both worrisome andindicative that the vital need for sex-specific research andreporting is still not widely appreciated.Almost three-quarters of the half-million participants inpublished reports were women. On the surface, this factseems reassuring. However, approximately two-thirds of these women were involved in trials studying “female con-ditions,” whereas three-quarters of the men participated inresearch on diseases affecting both men and women. Forexample, 55% (219,865/401,801) of women studied wereenrolled in one of 3 large sex-specific epidemiologicstudies of cervical pathology, hysterectomy rates, and os-teoporosis treatment patterns. The authors refer to this phe-nomenon as “biological essentialism”; that is, research inwomen emphasizes “female issues,” such as pregnancy andreproduction. Thus, this article suggests that much of themedical research in women has a focus similar to that of popular women’s magazines—breasts and sex. Researchinvolving men includes a more diverse range of healthconcerns.The relatively high number of women included in theAustralian clinical trials is also explained by the authors’broad definition of clinical trials. They included articlesbased on registry data, administrative claims databases,and observational trials, which supply valuable informa-tion but require little, if any, additional effort to includewomen. Instead, these studies retrospectively analyze pa-tient information from data sets that happen to includemany female patients. Randomized clinical trials require
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 Mayo Clin Proc. May 2008;83(5):523-525 www.mayoclinicproceedings.com
524
EDITORIAL
For personal use. Mass reproduce only with permission from
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.
For personal use. Mass reproduce only with permission from
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.
active recruitment and enrollment of participants, andwomen have been shown to have different, and frequentlymore, barriers to participation in trials than men.
6
Random-ized clinical trials are considered the best type of scientificevidence, to which observational studies are an importantcomplement. After we have answered the experimentalquestion about the efficacy of a particular therapy orprocedure in the more idealized randomized trial setting,observational data tell us about its benefit and effective-ness in the “real world.” To ensure high-quality evidence-based health care, we must not only include adequatenumbers of men and women in research but report SSRsalso. This practice is especially important for large obser-vational studies, as results can help inform our clinicalpractice.The data reported by Rogers and Ballantyne on thecurrent state of sex-specific reporting show there is muchroom for improvement. Of the studies of men and womenreviewed, 93% did not provide sex-specific analysis. It isdisappointing to find that, as recently as 2006, sex-specificreporting and rates of inclusion of women in clinical trialswere still appallingly low. In fact, in large trials involvingthe study of pharmaceuticals, the percentage of sex-spe-cific reporting was a dismal zero.We observed the same phenomenon in a recent reviewof cardiology clinical trials where only 25% of all studiesreported results by sex.
7
As heart disease is the leadingcause of death in women, it is dismaying that data fromcardiovascular clinical trials are so limited. Unexpected sex-based differences have been found in the epidemiologyof many diseases, such as lung cancer, other non–sex-specific cancers, degenerative joint disease, and depressionand mental health disorders, leading us to conclude thatthe lack of sex differences should not be assumed andinstead must be systematically studied. Further, we agreewith Rogers and Ballantyne that, because of reporting thatis inconsistent or lacking, these types of analyses to as-sess levels of SSRs are quite cumbersome and requireintensive literature review and data analysis when doneafter publication.Heightened awareness among investigators, authors, re-viewers, and journal editors of the importance of enrollingand reporting data for both men and women in clinicaltrials will inform efforts to achieve optimal care of allpatients. The International Committee of Medical JournalEditors
8
recommends that investigators describe their se-lection of study participants, including controls, clearly(eg, eligibility, exclusion criteria, description of the sourcepopulation). The committee states, “Because the relevanceof such variables as age and sex to the object of research isnot always clear, authors should explain their use whenthey are included in a study report; for example, authorsshould explain why only subjects of certain ages wereincluded or why women were excluded. The guiding prin-ciple should be clarity about how and why a study was donein a particular way.”
8
Perhaps it is time for this recommen-dation to be made a mandate and for journal editors toeither require that manuscripts include sex-specific data tobe considered for review or at least to make such dataavailable online. The “author information” section of 
Cir-culation
suggests providing “sex-specific and/or racial/ethnic-specific data when appropriate, in describing theoutcomes of epidemiologic analyses or clinical trials; orspecifically state that no sex-based or racial/ethnic-baseddifferences were present.”
9
The
 Journal of the AmericanCollege of Cardiology
uses nearly identical wording,
10
but substitutes “gender-specific” for “sex-specific.” How-ever, this requirement is not emphasized to submittingauthors or to journals’ peer reviewers and is not a consis-tent practice in recent publications, even when femaleparticipants are included in sufficient numbers to providethis reporting.
9,10
It is time to recognize that women are complex biologi-cal creatures just as are men. All clinical studies shouldstrive to include equal numbers of female and male partici-pants or to at least reflect the prevalence of the condition of interest by sex. In older populations, this could appropri-ately include a preponderance of women. A recent analysisof clinical trials used for Medicare national coverage deci-sions found that, although 58% of Medicare beneficiariesare women, women make up only 25% of participants inthe clinical trials reviewed.
11
Until we are able to make thisleap, women will continue to be marginalized in clinicaltrials of diseases that affect them in numbers equal to men.We hope that this editorial and the work that has pre-ceded it serve as a clarion call to researchers, authors,reviewers, and journal editors to include sex-specific re-porting in all clinical trials that include more than 50 par-ticipants. Analyzing data by sex for conditions or treat-ments affecting both men and women is the only way wewill be able to begin to provide optimal care for all patientsand is a critical step toward the ultimate goal of “individu-alized medicine.”Sharonne N. Hayes, MDDivision of Cardiovascular DiseasesWomen’s Heart ClinicMayo ClinicRochester, MNRita F. Redberg, MD, MScDivision of CardiologyWomen’s Cardiovascular ServicesUniversity of California, San Francisco

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