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Women’s involvement in clinical trials: Historical perspective and future implications

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Abstract

The importance of considering the differences between the male and female sex in clinical decision-making is crucial. However, it has been acknowledged in recent decades that clinical trials have not always adequately enrolled women or analyzed sex-specific differences in the data. As these deficiencies have hindered the progress of understanding women's response to medications, agencies in the United States have worked towards the inclusion of women in clinical trials and appropriate analysis of sex-specific data from clinical trials. This review outlines the history and progress of women's inclusion in clinical trials for prescription drugs and presents considerations for researchers, clinicians, and academicians on this issue.
Liu KA, DiPietro Mager NA. Women’s involvement in clinical trials: historical perspective and future implications.
Pharmacy Practice 2016 Jan-Mar;14(1):708. doi: 10.18549/PharmPract.2016.01.708
www.pharmacypractice.org (eISSN: 1886-3655 ISSN: 1885-642X)
1
ABSTRACT
*
The importance of considering the differences between the
male and female sex in clinical decision-making is crucial.
However, it has been acknowledged in recent decades
that clinical trials have not always adequately enrolled
women or analyzed sex-specific differences in the data. As
these deficiencies have hindered the progress of
understanding women’s response to medications,
agencies in the United States have worked towards the
inclusion of women in clinical trials and appropriate
analysis of sex-specific data from clinical trials. This review
outlines the history and progress of women’s inclusion in
clinical trials for prescription drugs and presents
considerations for researchers, clinicians, and
academicians on this issue.
Keywords: Clinical Trials as Topic; Patient Participation;
Women's Health; Female; Research; United States
*
Katherine A. LIU. Raabe College of Pharmacy, Ohio
Northern University. Ada, OH (United States). k-
liu@onu.edu
Natalie A. DIPIETRO MAGER. PharmD, MPH. Associate
Professor of Pharmacy Practice. Raabe College of
Pharmacy, Ohio Northern University. Ada, OH (United
States). n-dipietro@onu.edu
BACKGROUND
It is important to understand the underlying
variables contributing to differences between health
outcomes seen in women and men. Although there
are lifestyle, environmental, and behavioral
differences, there are also biological differences at
the molecular and cellular level.
1
These biological
distinctions may contribute to the differences in
clinical outcomes, which can be better understood
through research.
In 2001, the Institute of Medicine published
“Exploring the Biological Contributions to Human
Health: Does Sex Matter?” The Committee on
Understanding the Biology of Sex and Gender
Differences examined biology from the cellular to
the organismal and behavioral levels, and
concluded that differences do occur and can have
important consequences. They concluded that sex
(being male or female) should be recognized as an
important variable in research and increased
knowledge in this area should be cultivated.
1
The
growth of knowledge has become a branch of
science known as sex-based biology and has led to
the differentiation between the terms “sex” and
“gender”. “Sex” refers to the biological origin of men
and women based on chromosomal differences.
1,2
It
determines the physiological processes and organs
of the body beyond reproductive ability.
1,2
“Gender”
describes the self-representation, social, and
cultural views of sex.
1,2
Sex differences can be observed in various disease
states in prevalence, diagnosis, severity, and
outcomes.
2
There are disease states which
disproportionally or differentially affect women.
Diseases which disproportionally affect women
indicate a disease burden that is greater in women
than in men. Examples include breast cancer and
urinary incontinence.
3
Another example is that
among men and women who smoke the same
number of cigarettes, women are 20% to 70% more
likely to develop lung cancer.
4
Diseases may also
present differently in men and women. For example,
women with cardiovascular disease may experience
differences in signs or symptoms.
2
Another example
is sexually transmitted infections, which can affect
women differently in several ways, including
susceptibility, the expression of symptoms, and
potential for long-term complications.
5
In addition, there may be differences in patient
outcomes or responses to treatment between men
and women.
2
There are differences in the
physiology of the sexes that may translate into
differences in pharmacokinetics and/or
pharmacodynamics for specific drugs. It is important
to determine if these differences are clinically
Review
Women’s involvement in clinical trials:
historical perspective and future implications
Katherine A. LIU, Natalie A. DIPIETRO MAGER.
Received (first version): 17-Dec-2015 Accepted: 16-Feb-2016
Liu KA, DiPietro Mager NA. Women’s involvement in clinical trials: historical perspective and future implications.
Pharmacy Practice 2016 Jan-Mar;14(1):708. doi: 10.18549/PharmPract.2016.01.708
www.pharmacypractice.org (eISSN: 1886-3655 ISSN: 1885-642X)
2
relevant, as it may result in differences in safety or
efficacy of prescription products between men and
women.
6,7
The differences between the sexes in circulating
levels of endogenous hormones, such as
testosterone and estradiol, can affect
pharmacokinetic or pharmacodynamic parameters.
Other differences seen between the sexes (e.g.,
weight, muscle mass, body fat, metabolic enzymes,
and plasma proteins) may also impact the
pharmacokinetic parameters of a particular drug.
6,8
Differences in pharmacokinetics of drugs between
the sexes can be related to body composition and
size.
1
Women typically have a lower body weight
than men, so when taking the same dose of a drug,
results in a higher level of drug.
9
Lipophilic agents
may have a larger distribution in females because of
their higher body fat content.
2
Other variations
between the sexes include protein binding,
biotransformation, and even pharmacodynamic
characteristics related to receptor and enzyme
levels.
1
Pharmacodynamic differences between the sexes
have been observed for particular drugs. For
example, women are at increased risk of
experiencing torsades de points, a potentially fatal
arrhythmia, after taking drugs which prolong the QT
interval.
6,7
In addition, acute liver failure as a result
of certain drug exposures has also been reported in
women more often than in men.
6
Although detected pharmacokinetic and
pharmacodynamics differences may not indicate
clinically meaningful outcomes, there are still
differences that may be clinically significant yet
remain unknown.
1,9
In fact, many drugs are
administered as fixed doses instead of based on
weight.
10
An example of a clinically significant
pharmacokinetic difference are dosing
recommendations for zolpidem.
10
It was found that
the same dose in women as in men caused two
times the drug levels due to differences in
metabolism.
10
This accounted for the potential
driving impairment the morning after taking the
medication.
10
In 2014, the U.S. Food and Drug
Administration (FDA) initiated distinct weight-based
dosing for women and men.
10
At that time, zolpidem
was the only medication to have dosing based on
sex.
10
This demonstrates the importance of
recognizing sex as a variable that may contribute to
varying responses to drugs in patients.
Health disparities are also observed between men
and women, which may be due to biological,
cultural, social, or economic factors.
11,12
These
differences represent health outcomes that need to
be addressed in order to successfully reach health
equity in both sexes.
11
It has been recognized that
potential differences by sex should be examined at
multiple levels, from the genetic and cellular level to
the organism level. In addition, potential sex
differences should be studied at all lifestages. It has
been recommended that sex and gender be
examined as separate effects, especially when
considering potential differences in diagnosis and
treatment options between men and women.
Women should be prospectively included and
evaluated through all phases of drug
development.
13
HISTORICAL PERSPECTIVE
Opinions and actions concerning women’s
participation in clinical trials in the United States
(U.S.) have changed through the years as
governmental groups and researchers have best
sought to protect the public’s health, but also try to
better understand how women respond to
prescription drugs (Table 1).
9
Although there is
recognition today of the need to include women
sufficiently in clinical trials, in previous decades the
consideration and inclusion of men overshadowed
women in clinical research design and conduct.
2
This was observed when studying diseases
prevalent in both sexes, where males, frequently of
the Caucasian race, were considered to be the
“norm” study population.
1,2
A type of observer bias,
male bias, in assuming a male’s attitude in
conducting trials was another contributing factor.
2
At
the same time, researchers often thought that
women would have the same response as men
from drugs in clinical trials.
1
They also viewed
women as confounding and more expensive test
subjects because of their fluctuating hormone
levels.
1
Concerns of potential reproductive adverse
effects led to policies and guidelines that considered
pregnant women as a “vulnerable population” and,
subsequently, excluded these women from research
and restricted the ability of women of child-bearing
potential to enroll in trials, especially in early stages
of research.
1,9,14-16
However, potential concerns and public attitudes
about excluding women from important studies such
as the Physicians’ Health Study and the Multiple
Risk Factor Intervention Trial (MRFIT) led to raised
awareness of these issues.
15
A task force on
women’s health from the U.S. Public Health Service
acknowledged in the 1980s that the quality of
knowledge related to women’s health was lacking
due to the exclusion of women in research.
9
Government reports in the 1980s and early 1990s
indicated that women were lacking representation in
federally funded studies and certain diseases that
affect both sexes. Examples of these diseases
included heart disease and Acquired Immune
Deficiency Syndrome (AIDS). Finally in 1992, a
discussion about women in clinical trials lead by the
FDA and the Food and Drug Law Institute
concluded that in order to understand the response
of women to pharmaceutical agents, young women
needed to be included in clinical trials.
9
Discussed below are the history and progress in the
U.S. of inclusion of women of child-bearing potential
in clinical trials for prescription drugs; the
involvement of pregnant women, actions taken by
groups outside of the U.S., preclinical trials, or trials
for other products, such as medical devices, are
outside of the scope of this review.
U.S. Food and Drug Administration
Regulations and guidance documents published by
the FDA concerning women’s participation in
industry-sponsored clinical trials have changed
Liu KA, DiPietro Mager NA. Women’s involvement in clinical trials: historical perspective and future implications.
Pharmacy Practice 2016 Jan-Mar;14(1):708. doi: 10.18549/PharmPract.2016.01.708
www.pharmacypractice.org (eISSN: 1886-3655 ISSN: 1885-642X)
3
significantly over the past half century.
17
After the
tragedies caused by the use of thalidomide in
pregnant women, the FDA issued “General
Considerations for the Clinical Evaluation of Drugs”
in 1977. This guidance document stated that
women of child-bearing potential should be
excluded from Phase 1 and early Phase 2 research,
except if these studies were being conducted to test
a drug for a life-threatening illness. If a drug
appeared to have a favorable risk-benefit
assessment, women could then be included in later
Phase 2 and Phase 3 trials if animal teratogenicity
and fertility studies were finished. The term “child-
bearing potential” was defined widely as any woman
capable of becoming pregnant, including
premenopausal single abstinent women, women
using contraceptives, or women with sterile
partners.
16
Advocacy groups criticized the 1977
FDA guideline by arguing that trial participation
should be focused on a woman’s independence to
make decisions and determine fetal risks during
pregnancy.
9
They noted that women were capable
of helping develop medical knowledge about sex
differences through participating in studies.
9
Retrospectively, the FDA, researchers, and the
majority of the public now view the 1977 guidance
as “rigid and paternalistic, leaving virtually no room
for the exercise of judgment by responsible
research subjects, physician investigators, and
investigational review boards (IRBs)”.
16
Concerns
were voiced that this guidance may have had the
unintended effect of causing a general
underrepresentation of women in drug development
studies.
16
In 1993, FDA reversed the 1977 guidance with
another guidance document entitled “Guidelines for
the Study and Evaluation of Gender Differences in
the Clinical Evaluation of Drugs.” This guidance
lifted the ban of women of child-bearing potential
from participating in early phase research and left
the decision to researchers, IRBs, and women
themselves.
16
The guidance further specified that
clinical trial participants should be representative of
the patient population that is likely to be prescribed
the drug once it is approved. The FDA articulated
the importance of examining differences in safety,
efficacy, pharmacokinetics, and when necessary,
pharmacodynamics among population subsets.
16
In 1998, the FDA issued a final rule entitled
“Presentation of Safety and Effectiveness Data for
Certain Subgroups of the Population in
Investigational New Drug Application Reports and
New Drug Applications”. This regulation specifically
states that New Drug Applications (NDA) must
present safety and efficacy data for important
populations, including sex, age, and racial
subgroups. The FDA has the authority to refuse to
file any NDA that does not analyze the safety and
efficacy data appropriately by sex. The rule also
calls for sponsors to report the demographics of
participants in its clinical trials in Investigational New
Drug Application (IND) annual reports as a means
to alert either party to potential deficiencies in the
NDA submission.
18
In 2000, the FDA promulgated a
final rule, “Investigational New Drug Applications:
Amendment to Clinical Hold Regulations for
Products Intended for Life-Threatening Disease and
Table 1. Significant events in the history of women’s participation in clinical trials in the U.S.
Year Event
1962
Thalidomide tragedy in Europe results in United States Congress to pass the Kefauver-Harris Amendment to
mandate changes in drug development and strengthen the authority of the FDA
1975
National Commission for the Protection of Human Subjects and Biomedical and Behavioral Research promulgates
new rule which includes pregnant women as a vulnerable research subjects
1977
FDA guideline “General considerations for the clinical evaluation of drugs” essentially bans women of child-bearing
potential from participating in early phase clinical research, except for life-threatening conditions
1985
Report from U.S. Public Health Service Task Force on Women’s Health concludes “research should emphasize
disease unique to women or more prevalent in women”
1986
NIH advisory committee recommends to grant applicants that women be included in studies; if women are not
included, clear rationale must be provided
1988
FDA “Guideline for the format and content of the clinical and statistical sections of new drug applications” specifies
the importance of examining data within NDA databases for differences in safety or efficacy in subgroup
populations, including gender
1990 Office of Research on Women’s Health established at the NIH
1993
FDA guideline “Guideline for the study and evaluation of gender differences in the clinical evaluation of drugs”
reverses the 1977 guidance
1993
Congress mandates adequate inclusion of women in NIH-sponsored clinical trials to determine differences between
the sexes
1994 Office of Women’s Health Established at the FDA
1994
IOM report, “Women and health research” calls attention to two forms of historical gender bias in the design and
implementation of clinical trials
1998
FDA regulation “Presentation of safety and effectiveness data for certain subgroups of the population in
investigational new drug application repots and new drug applications” states that NDAs must present safety
and efficacy data by sex; FDA has the authority to refuse to file any NDA that does not analyze the safety and
efficacy data appropriately by sex. Demographics of participants in its clinical trials must also be included in IND
annual reports.
2000
FDA regulation “Investigational new drug applications: amendment to clinical hold regulations for products intended
for life-threatening disease and conditions” gives FDA authority to place a trial for a life-threatening disease or
condition on clinical hold if sponsors exclude men or women only because of reproductive potential.
2001
IOM report, “Exploring the biological contributions to women’s health: does sex matter?” establishes importance of
sex-based biology.
2010
IOM report, “Women’s health research: progress, pitfalls, and promise” highlights areas of advancement and
remaining deficiencies in women’s health research
FDA= Food and Drug Administration; NIH= National Institutes of Health; IOM= Institute of Medicine
Liu KA, DiPietro Mager NA. Women’s involvement in clinical trials: historical perspective and future implications.
Pharmacy Practice 2016 Jan-Mar;14(1):708. doi: 10.18549/PharmPract.2016.01.708
www.pharmacypractice.org (eISSN: 1886-3655 ISSN: 1885-642X)
4
Conditions.” This regulation gives FDA the authority
to place a trial for a life-threatening disease or
condition on clinical hold if sponsors exclude men or
women only because of reproductive potential. This
rule applies to studies involving patients with the
disease or condition the drug is intended to treat;
the rule does not apply to studies enrolling only
health volunteers.
19
The FDA also has an Office of Women’s Health
(OWH), which was created by the 1994
Congressional mandate. The OWH has two
overarching goals: 1) to protect and advance the
health of women through policy, science, and
outreach and 2) to advocate for the participation of
women in clinical trials and for sex, gender, and
subpopulation analyses. The FDA OWH partners
with other governmental agencies and national
groups to reach out to both the scientific and lay
communities.
20
National Institutes of Health
In response to the 1985 report by the U.S. Public
Health Service Task on Women’s Health, the
National Institutes of Health (NIH) urged the
inclusion of women in clinical trials in 1987.
Congress formalized this through a section of the
NIH Revitalization Act of 1993 titled “Women and
Minorities as Subjects in Clinical Research”. Four
issues were addressed: 1) that the NIH ensure that
women and minorities be included in all clinical
research; 2) that numbers in Phase 3 clinical trials
be sufficient to allow for valid analyses of potential
differences; 3) that these groups could not be
excluded due to trial costs; and 4) that the NIH
create programs and support outreach efforts to
enroll and retain women and minorities in clinical
trials. The NIH does not fund any grant or project
that is out of compliance on one of these four
issues.
21
The NIH also has an Office of Research on
Women’s Health (ORWH), which was established in
1990. The ORWH is charged with increasing
research in areas that affect women, identifying
existing gaps in knowledge, and creating a national
women’s health research agenda for the NIH. The
ORWH ensures women are adequately involved in
NIH-supported research studies. Additionally, the
ORWH establishes programs to increase the
number of women who pursue careers in
biomedical research.
22
Progress of Women in Clinical Trials
When attempting to assess the actual number of
women enrolled in clinical trials, various
investigators have reached different conclusions.
The numbers and percentages can vary depending
on the kinds of trials included in the analyses. For
example, the phase of clinical research assessed,
whether trials for sex-specific conditions were
included in the assessment, and the timeline when
the studies were conducted all influence the
perception of women’s participation in such trials.
23
As a result, some published articles have stated that
women are underrepresented or overrepresented in
clinical trials
23
, while others did not find a systematic
bias against women.
24
The FDA conducted two surveys in the 1980s to
assess women as participants in clinical studies.
The first, published in 1983, looked at 11 pending
NDAs. The FDA determined that the proportion of
men and women in later phase clinical studies was
appropriate (once adjusted for age-related
differences in disease expression) for the proposed
indications. In 1989, FDA examined 20 NDAs and
found that two did not have the right proportion of
men and women in later phase clinical trials.
16
In 1992, the U.S. Government Accountability Office
(GAO) polled all drug manufacturers that obtained
FDA approval for new chemical entities from
January 1988 to June 1991. While women were
included in the Phase 2 and 3 clinical trials for all 53
drugs, they were underrepresented (by GAO
assessment) in trials for about 60% of the drugs.
Trials for 36 of the 53 drugs (68%) included the
minimum number of women suggested by the FDA.
For 25 of the 53 drugs (47%), sponsors examined
whether women and men experienced differential
responses. (It is important to note that many of the
drug studies were conducted and submitted to the
FDA before the 1988 requirement).
25
In this
assessment, no indication was found that women
aged 15 to 49 years constituted a lower percentage
of participants than women in other age groups,
contradicting the notion that the ban on women in
early phase clinical research caused a general lack
of participation of women of child-bearing potential
in late phase clinical trials.
16,25
A study conducted by the Center for Drug
Evaluation and Research (CDER) examined 185
new molecular entities approved by the FDA
between 1995-1999. The authors concluded that
women and men participated in clinical trials at
levels consistent with the prevalence of the disease
state studied. Examination of labeling for these
products revealed that at least 68% contained some
statement about sex.
26
An analysis of 10 prescription drugs that were
withdrawn in the market from 1997-2001 found that
eight posed “greater health risks for women”, mainly
because of adverse drug events due to known
pharmacodynamic differences (e.g.: three drugs
withdrawn due to risk of torsades de pointes) or
because of greater exposure of women to these
drugs (e.g.: four drugs were prescribed to more
women than men).
27
These findings resulted in
another the GAO study. In 2001, the GAO published
“Women Sufficiently Represented in New Drug
Testing, but the FDA Oversight Needs
Improvement.” For this review, the GAO examined
summary documents of the 36 NDAs for new
molecular entities submitted to and approved by the
FDA between August 1998 and December 2000. In
addition, the clinical trials section of 100 randomly-
selected IND annual reports were studied. The GAO
found that about a third of the time, sponsors did not
evaluate and/or present gender analysis in the NDA
summary documents. The GAO also found that
39% of IND annual reports did not include the
necessary demographic data for ongoing clinical
trials. The GAO did find that women constituted the
majority of drug trial participants; the percentage of
Liu KA, DiPietro Mager NA. Women’s involvement in clinical trials: historical perspective and future implications.
Pharmacy Practice 2016 Jan-Mar;14(1):708. doi: 10.18549/PharmPract.2016.01.708
www.pharmacypractice.org (eISSN: 1886-3655 ISSN: 1885-642X)
5
women varied with the stage of clinical research
performed. Women accounted for 22% of
participants in Phase 1 studies and 56% of
participants in Phase 2 and 3 studies. Every NDA
reviewed had enough women in the pivotal studies
for a statistical determination that the drug was
effective in this population.
28
The GAO also
observed shortcomings in the FDA review and
oversight process. The GAO felt that neither the
FDA nor sponsors consistently utilized all of the
sex-specific information available.
28
Three additional studies have been more recently
published in 2011 and 2013. In a study that
evaluated the inclusion and analysis of sex in the
results of federally-funded randomized clinical trials
in nine major medical journals in 2009, researchers
found most studies that were not sex-specific had
an average enrollment of 37% women.
29
However,
64% of the studies did not specify their results by
sex and did not explain why the influence of sex in
their findings was ignored.
29
Also, a small sample of
non-federally funded studies were examined and
found to not be significantly different from the
federally funded studies in analysis and inclusion of
women.
29
Although this study did not examine all
federally funded randomized clinical trials or
compare the prevalence of sex in each disease
state researched, the results indicated that studies
were low in compliance with NIH guidelines
regarding analysis and inclusion of women, and
minimally improved from a similar study conducted
in 2004.
29,30
Another study examined the sex-
specific analysis and enrollment of women
compared to the prevalence of women in each
disease population in late-phase clinical trials,
specifically Phase 3 trials, from 2007 to 2009.
31
The
results showed that 64% of disease states had
equal or greater participation based on prevalence.
However, trials related to HIV, hypertension, and
acute coronary syndrome had lower female
enrollment in comparison with prevalence of those
disease states in women. The majority of trials were
found to have at least one type of sex-related
analysis of safety or efficacy.
31
Even though the
study only focused on late-phase clinical trials, it
concluded that the FDA guidance and regulations
and acknowledgment of individualized dosing
procedures produced the increase of sex-specific
analysis of safety and efficacy. Researchers also
noted that enrollment of women in clinical trials
could vary every year depending on the drugs
related to each disease being studied.
31
The results
of these two studies, both with limitations, may
indicate that the inclusion of women in clinical trials
has increased; however, trials are still lacking in
recruiting participants similar to the prevalence in
disease state and in performing sex-specific
analyses. Most recently, the FDA also issued a
report, “Collection, Analysis, and Availability of
Demographic Subgroup Data for FDA-Approved
Medical Products”. For all 30 CDER applications
reviewed from 2011, demographic information by
sex for key clinical trials were available in public
documents, and almost all included subset analysis
data by sex. Information on clinically significant
demographic subset data was included in approved
product labeling. The FDA concluded that, in
general, populations were included in clinical trials
by age and sex in similar numbers to the population
distribution for the disease indications studied.
32
Specific disease states that impact women have
had substantial progress in prevention, diagnosis
and treatment over the years.
3
This includes breast
cancer, cervical cancer, and cardiovascular
disease. Other disease states such as depression,
lung cancer, and Alzheimer’s disease have made
less progress.
3
Looking specifically at
cardiovascular disease, most early research was
conducted on men even though the leading cause
of mortality in women has been cardiovascular
disease since 1989.
3
Trials focusing on the
prevention of cardiovascular disease conducted
only in women have had impact clinically. These
include the Women’s Health Initiative and Women’s
Health Study.
33
Other trials designed for both men
and women include using vitamin D and omega-3
supplements or HMG-CoA reductase inhibitors
(“statins”) for cardiovascular disease prevention.
Specific examples of advancements in the
treatment of women include the comparable use of
beta-blockers and aspirin after myocardial infarction
(MI) in women to men, which was not observed
previously, and the advantage of adding on
pharmacotherapy during percutaneous coronary
intervention.
3
Yet the amount of women enrolled in
clinical trials related to cardiovascular disease in
proportion to its prevalence is still lacking even
though participation has increased.
33
Additionally,
although studies on the intervention for MI and
acute ischemic syndromes have been used
clinically in women, the reliability of their
conclusions because of insufficient statistical power
is uncertain.
33
Subsequently, although the inclusion
of women in cardiovascular research has increased,
understanding of sex differences is still wanting.
3
CURRENT EFFORTS
There are numerous initiatives in the U.S. that
continue to address the issue of women in clinical
trials. While not intended to be comprehensive, the
examples listed below highlight some of the ways
the FDA and NIH remain focused on this issue.
The FDA has several ongoing projects that could
improve the ability to identify sex differences. One is
the Critical Path Initiative, the goal of which is to
modernize drug development through use of
innovative tools and techniques.
13
Through the use
of biomarkers to estimate potential safety or efficacy
outcomes, advanced technologies, applications of
pharmacogenomics, and new trial designs and data
analysis techniques, there may be greater
opportunity to identify subpopulation differences in
response. Additionally, more robust use of
information technology will enable better
characterization of data and better identification of
potential clinical trial participants.
13
The FDA also
has an “Action Plan to Enhance the Collection and
Availability of Demographic Subgroup Data”.
Twenty-seven action items comprise the plan, which
has three main priorities: 1) quality - to improve
collection, reporting, and analysis of demographic
subgroup data; 2) participation - to identify barriers
Liu KA, DiPietro Mager NA. Women’s involvement in clinical trials: historical perspective and future implications.
Pharmacy Practice 2016 Jan-Mar;14(1):708. doi: 10.18549/PharmPract.2016.01.708
www.pharmacypractice.org (eISSN: 1886-3655 ISSN: 1885-642X)
6
to enrollment for members of subgroups and to
implement programs to encourage enrollment; and
3) transparency – to make data by demographic
subgroup more available.
34
One program recently
launched to improve transparency is Drug Trial
Snapshots, available at
http://www.fda.gov/Drugs/InformationOnDrugs/ucm
412998.htm. This consumer-friendly website
provides information on subpopulation involvement
in the pivotal clinical trials for newly-approved drugs
and whether any differences in benefits or risks of
drug use by subpopulation were observed.
35
The
FDA continues to educate and train their staff
regarding reporting, analyzing, and communicating
data by subpopulation, and to partner with industry
and other groups such as the NIH to identify best
practices and overcome barriers.
36
To facilitate enrollment of women in clinical trials,
the NIH has created an Outreach Notebook with five
outreach elements related to population
considerations, outreach preparation, research
agreements, developing evaluations and sustaining
communication.
37
In addition, the Advisory
Committee on Research on Women’s Health’s
(ACRWH) recent biennial report observed progress
in the ORWH’s Strategic Plan of six goals (Table 2)
each with their objectives.
38
Focusing on Goal 1,
which is most related to women in clinical trials, the
ORWH partnered with Institutes and Centers of the
NIH to encourage important research enterprises in
women’s health by co-funding projects in various
medical fields with the NIH and using specific
ORWH programs to review research applications
and research.
38
The ORWH introduced two
programs: the Specialized Centers of Research
(SCOR) on Sex and Gender Factors Affecting
Women’s Health and Building Interdisciplinary
Research Careers in Women’s Health (BIRWCH).
Both serve to develop interdisciplinary research and
careers in women’s health research.
38
CONSIDERATIONS FOR THE FUTURE
There are many potential areas for research in
women’s health. Continued investigations in the
areas of sex-based biology, differences in
healthcare needs between men and women,
recognition and reduction of health disparities
between men and women, and evidence-based
information to assist women while making
healthcare decisions are all areas of need.
1,39
There
are considerations for the enrollment and retention
of women in clinical trials, the design of trials, and
the expectations of journals that may help to close
some of the existing gaps seen today.
While there are thousands of clinical trials enrolling
annually, women are less likely to be aware of or to
participate in clinical trials.
40
There are various
reasons contributing to the lack of participation of
not only women, but also of minorities, in clinical
trials.
37
From past history of unethical research,
apprehension and cynicism towards clinical trials
may exist in communities. The transportation
capability to travel to and from research facilities
may complicate the ability to participate in clinical
studies, especially for those living in rural areas.
Subjects may find that taking time to partake in
these trials may interfere with both family and work
obligations. There also may be “subject burden”
where the constant travel and medical testing may
be exhausting for enrollees.
37
Financial burdens
such as poverty or a low-income status may limit
subjects, especially minorities, from participating.
Furthermore, there are extra challenges with the
addition of diversity in clinical trials relative to
communication and cultural attitudes.
41
Researchers need to address these challenges and
utilize available tools to facilitate enrollment of
women in clinical trials (Table 3). Logistically, clinics
may need to be open at flexible hours or follow-up
may need to be performed at the participant’s
home, rather than at the clinic.
4
Childcare or
transportation should be offered or reimbursed, per
IRB approval. Reaching out to women through IRB-
approved advertising in places such as salons,
gyms, stores, laundromats, and churches may be
helpful. Diverse staff should be recruited, if possible;
all staff should be made aware of the distinct needs
of women in clinical trials. Additional time should be
allotted to review informed consent with women,
considerations for which are described below. Their
contributions should be acknowledged, and
feedback should be gathered from women at the
conclusion of the trial to inform future efforts.
4
Researchers must also have special considerations
when enrolling fertile women. The FDA expects that
women of child-bearing potential enrolled in a
clinical trial will take the necessary precautions to
avoid pregnancy during drug exposure, the length of
which may surpass the actual length of the study.
16
Therefore, women participating in the trials must
have access to counseling and medical care for
contraception.
14,16,42
Investigators must verify that a
woman participating in the trial is not pregnant and
monitor for pregnancy.
14,16,42
As much detail as
possible must be given in the informed consent
document about the potential risks to a fetus from
the investigational drug.
16
If no pertinent data
available, the document should clearly state the
potential for fetal risk. Researchers may also be
Table 2. National Institutes of Health (NIH) Office of Research on Women’s Health (ORWH) strategic plan goals
3
8
Goal 1: Increase sex differences research in basic science studies
Goal 2: Incorporate findings of sex/gender differences in the design and application of new technologies, medical
devices, and therapeutic drugs
Goal 3: Actualize personalized prevention, diagnostics, and therapeutics for girls and women
Goal 4: Create strategic alliances and partnerships to maximize the domestic and global impact of women’s health
research
Goal 5: Develop and implement new communication and social networking technologies to increase understanding and
appreciation of women’s health and wellness research
Goal 6: Employ innovative strategies to build a well-trained, diverse, and vigorous women’s health research workforce
Liu KA, DiPietro Mager NA. Women’s involvement in clinical trials: historical perspective and future implications.
Pharmacy Practice 2016 Jan-Mar;14(1):708. doi: 10.18549/PharmPract.2016.01.708
www.pharmacypractice.org (eISSN: 1886-3655 ISSN: 1885-642X)
7
able to reduce the risk of fetal exposure through
study design.
4
Multiple considerations may complicate the
researcher’s task of designing trials to conduct sex
analysis of their findings.
43
This includes the
difficulty of estimating and recruiting a large enough
sample size to have a sufficient power for subgroup
analyses. This indicates that the percentage of
female subjects is not the only concern. Without
appropriate power, the application of study results is
limited. Researchers also need to look forward to
considering reproductive endocrinology as a
variable in test subjects.
43
The female population in
a study may be further allocated by their hormonal
status, menopausal status. And contraceptive use,
but researchers may not be cognizant about these
endocrine factors. Different statistical methods such
as the Bayesian statistical inference test have been
suggested as better tailored towards sex-analysis
rather than frequentist statistics and null-hypothesis
errors. Consequently the question remains of the
best way to statistically analyze differences between
sexes. Using new methodologies would result in the
necessity of researchers and clinicians to be
educated on the statistical methods to understand
findings. In terms of statistical significance, having
enough women to establish statistical power has not
been successful since the estimation and likelihood
of achieving the sample size needed is difficult.
43
The inexperience of conducting sex-based research
among researchers is an issue as well.
33
Also, new methods of design and analysis
associated with requirements from medical journals
or governmental agencies warrant further
discussion to help ensure consistent sex-specific
analysis of data.
43
For example, journal editors and
editorial associations especially have an ability to
establish policies for authors to consider sex-
analysis when designing and reporting clinical
trials.
43
Revised publishing standards for journals
may also encourage more researchers to analyze
data by sex. Most standard guidelines and editorial
associations for researchers do not require
reporting sex-specific results. The Journal of the
National Cancer Institute became the first journal to
ask authors to, when appropriate, conduct subgroup
analyses by sex and ethnicity in clinical and
epidemiological studies. If there is no difference, it
should be stated in the Results section. Any
editorial policy changes should be carefully
considered to minimize unintended
consequences.
43
Lastly, further advancement of women in clinical
research may require not only the continued
leadership of government agencies, but also input
from other stakeholders such as policymakers,
healthcare professionals, educators, advocacy
organizations, and funding organizations.
33
By
promoting health equity through developing
research requirements for design and analyses of
clinical trials and improving understanding how
clinical outcomes are affected by sex, further
progress in women’s health can be made.
SUMMARY
Many groups, including the FDA, NIH, clinicians,
academia, Congress, industry, and advocacy
groups, have an interest in ensuring appropriate
enrollment of women in clinical trials and sex-
specific analysis of the data. It is critical that data
from women are available when decisions on
dosing, safety, and efficacy of therapeutic agents
are being made. In the U.S., there has been a shift
in philosophy in how to best protect public’s health.
Instead of simply excluding women of child-bearing
Table 3. Selected resources for clinicians, academicians, and researchers
Sex-based Biology
Web-based Training Courses: The science of sex and gender in human health (joint project with the NIH Office of Research on
Women’s Health) Available at https://sexandgendercourse.od.nih.gov/
IOM. “Exploring the biological contributions to women’s health: does sex matter?” 2001. Available at
http://www.nap.edu/catalog/10028/exploring-the-biological-contributions-to-human-health-does-sex-matter
IOM. “Women’s health research: progress, pitfalls, and promise”. 2010. Available at
http://iom.nationalacademies.org/Reports/2010/Womens-Health-Research-Progress-Pitfalls-and-Promise.aspx
Curricula Guides
“Beyond women’s health: incorporating sex and gender differences into graduate public health curricula”. Available at:
http://www.aspph.org/wp-content/uploads/2014/06/Womens-Health-FINAL.pdf
Women’s health curricula: final report on expert panel recommendations for interprofessional collaboration across the health
professions. Available at: http://www.aacn.nche.edu/education-resources/HRSA-Womens-Health-Curricula-Report.pdf
Women’s health curriculum and toolbox jointly developed by American Association of Colleges of Pharmacy and FDA OWH.
Available at http://www.aacp.org/RESOURCES/EDUCATION/WHC/Pages/default.aspx
Women’s Health Resources
Women’s health resources web portal. Available at: http://orwh.od.nih.gov
FDA OWH. Available at: http://www.fda.gov/ForConsumers/ByAudience/ForWomen/default.htm
U.S. Department of Health and Human Services OWH. Available at http://www.womenshealth.gov/index.php
Clinical Trial Materials
NIH Outreach notebook for the inclusion, recruitment and retention of women and minority subjects in clinical research. Available
at http://orwh.od.nih.gov/research/inclusion/pdf/Outreach-Notebook-021315.pdf
NIH outreach toolkit: how to engage, recruit, and retain women in clinical research. Available at http://orwh.od.nih.gov/toolkit/
FDA Women in Clinical Trials. Available at http://www.fda.gov/ForConsumers/ByAudience/ForWomen/ucm118508.htm
The Society for Women’s Health Research and FDA OWH. Dialogues on diversifying clinical trials successful strategies for
engaging women and minorities in clinical trials. Available at:
http://www.fda.gov/downloads/ScienceResearch/SpecialTopics/WomensHealthResearch/UCM334959.pdf
National Institute on Drug Abuse Treatment Clinical Trials Network: Successfully including women in clinical trials, a guide for
researchers. Available at https://www.drugabuse.gov/sites/default/files/womens-brochure_1025-004_508.pdf
FDA= Food and Drug Administration; IOM: Institute of Medicine; NIH= National Institutes of Health; OWH= Office of Women’s Health
Liu KA, DiPietro Mager NA. Women’s involvement in clinical trials: historical perspective and future implications.
Pharmacy Practice 2016 Jan-Mar;14(1):708. doi: 10.18549/PharmPract.2016.01.708
www.pharmacypractice.org (eISSN: 1886-3655 ISSN: 1885-642X)
8
potential from participation in early phase research,
it is now recognized that risk can be mitigated by
responsible research practices. Although history
has displayed a lack of representation of women in
clinical trials, U.S. governmental agencies have
sought to establish guidelines, policies, and
organizations to encourage researchers to increase
the quality of women’s health research. Through
these efforts, the medical field will be able to identify
sex differences, which includes the response of
medications relative to safety and efficacy, to
carefully direct clinical decisions. While there are
still barriers and questions that continue to be
addressed, women’s health research continues to
advance.
CONFLICT OF INTEREST
The authors have no conflict of interest with this
article. No funding was provided.
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... Population external validity of a randomized controlled trial (RCT) is defined as the extent to which the results of a trial can be generalized from a specific sample to a target population [1]. For many years, the population external validity of RCTs was compromised due to the inclusion of mainly male participants, while women were underrepresented [2,3]. When applying gender-unbalanced RCTs to real-life clinical settings, concerns arise as treatment dosing and effects may not be similar between the predominantly male RCT population and women patients [2,3]. ...
... For many years, the population external validity of RCTs was compromised due to the inclusion of mainly male participants, while women were underrepresented [2,3]. When applying gender-unbalanced RCTs to real-life clinical settings, concerns arise as treatment dosing and effects may not be similar between the predominantly male RCT population and women patients [2,3]. Drug effects may vary between the sexes according to body composition and size and pharmacokinetic or pharmacodynamic parameters [3,4]. ...
... When applying gender-unbalanced RCTs to real-life clinical settings, concerns arise as treatment dosing and effects may not be similar between the predominantly male RCT population and women patients [2,3]. Drug effects may vary between the sexes according to body composition and size and pharmacokinetic or pharmacodynamic parameters [3,4]. This may lead to inappropriate dosing and inaccurate estimation of side effects in women and, ultimately, to overall less qualitative patient care and suboptimal clinical treatment outcomes for women patients. ...
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Background Although regulatory changes towards correcting the underrepresentation of women in randomized controlled trials (RCTs) occurred (National Institutes of Health 1994), concerns exist about whether an improvement is taking place. In this systematic review and meta-analysis, we aimed to assess the inclusion rates of women in recent RCTs and to explore the potential barriers for the enrollment of women. Methods RCTs published in 2017 examining any type of intervention in adults were searched in PubMed and Cochrane Library. The following predefined medical fields were included: cardiovascular diseases, neoplasms, endocrine system diseases, respiratory tract diseases, bacterial and fungal infections, viral diseases, digestive system diseases, and immune system diseases. Studies were screened independently by two reviewers, and an equal number of studies was randomly selected per calendric month. The primary outcome was the enrollment rate of women, calculated as the number of randomized women patients divided by the total number of randomized patients. Rates were weighted by their inverse variance; statistical significance was tested using general linear models (GLM). Results Out of 398 RCTs assessed for eligibility, 300 RCTs were included. The enrollment rate of women in all the examined fields was lower than 50%, except for immune system diseases [median enrollment rate of 68% (IQR 46 to 81)]. The overall median enrollment rate of women was 41% (IQR 27 to 54). The median enrollment rate of women decreased with older age of the trials’ participants [mean age of trials’ participants ≤ 45 years: 47% (IQR 30–64), 46–55 years: 46% (IQR 33–58), 56–62 years: 38% (IQR 27–50), ≥ 63 years: 33% (IQR 20–46), p < 0.001]. Methodological quality characteristics showed no significant association with the enrollment rates of women. Out of the 300 included RCTs, eleven did not report on the number of included women. There was no significant difference between these studies and the studies included in the analysis. Conclusions Women are being inadequately represented, in the selected medical fields analyzed in our study, in recent RCTs. Older age is a potential barrier for the enrollment of women in clinical trials. Low inclusion rates of elderly women might create a lack of crucial knowledge in the adverse effects and the benefit/risk profile of any given treatment. Factors that might hinder the participation of women should be sought and addressed in the design of the study.
... For instance, evidence suggests that women and men may make decisions differently and, thus, the same enrolment process may yield different enrolment rates by sex. 31,32 In addition, greater flexibility in study structures and processes to cater for the different preferences and needs of women and men may promote gender equality among participants in clinical trials. 33 Limitations ...
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... In the past, women were underrepresented in clinical trials and sex-disaggregated results were often not published (95). Current clinical study guidelines recommend that trials include an adequate demographic characterization of the patient/target population, including a representative sex distribution, and that analyses of safety and efficacy data will be stratified on sex, as one cannot assume the absence of sexual dimorphism in the effects of vaccination/drugs (96,97). ...
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... Medical research has historically been androcentric 1,2 ; most research has been performed on the bodies of the average male and generalized to females. [3][4][5] There is evidence to suggest that globally, this sex and gender gap in health research is ongoing 6 and a recent cross-sectional analysis highlighted a specialty-based sex and gender gap in Australian health research. ...
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Background: The androcentric history of medicine and medical research has led to an ongoing sex and gender gap in health research and education. Sex and gender gaps in research and education may translate into real-life health inequities for women. This study aimed to explore the experiences of female patients with chronic health conditions in the Australian health system, considering existing sex and gender gaps in medicine. Methods: This qualitative study used semistructured in-depth interviews with a sample of adult women with chronic conditions in Australia. Thematic analysis was undertaken, guided by Braun and Clarke. Software NVivoX64 assisted in the management of the data. Coding was performed before grouping into subthemes and central themes. To allow for potential researcher biases, the principal researcher engaged in the practice of reflexivity, including the writing of detailed notes during analysis. Results: Twenty adult Australian women with chronic conditions were interviewed. Diagnoses were varied and included Ehlers-Danlos syndrome, chronic fatigue syndrome, functional neurological disorder, and inflammatory bowel disease. Four central themes emerged: diagnostic difficulties; spectrum of health care experiences; understanding medical complexity; and coping with symptoms. Conclusions: Women with chronic conditions in Australia report pain, fatigue, and suffering that significantly impacts upon their daily lives. There was a shared experience of feeling that the pain and suffering of women was dismissed or not taken seriously. Many women expressed trauma because of their experiences in health care and often this led to a fear of accessing health services. The participants highlighted a need for more knowledge, understanding, and empathy from health care practitioners.
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The prevalence, incidence, and severity of a wide variety of diseases and ailments are significantly influenced by the significant disparities that occur between the sexes. The way that men and women react to pharmacological treatment also varies. Therefore, it is crucial to comprehend these reactions in order to conduct risk assessment correctly and to develop safe and efficient therapies. Even from that limited vantage point, the manner and timing of our drug usage might have unintended and unanticipated consequences. There are sex-specific differences in the incidence and mortality of certain malignancies. One of the most important discoveries in cancer epidemiology is the gender inequalities. Cancer incidence differences between the sexes are thought to be regulated at the genetic and molecular levels and by sex hormones like oestrogen. Differences based on sex and gender are among the least investigated factors impacting cancer susceptibility, progression, survival, and therapy response despite their established importance in clinical care. The molecular mechanisms underlying sex differences in particular are poorly known, hence the majority of precision medicine approaches employ mutational or other genetic data to assign therapy without taking into account how the patient's sex may affect therapeutic efficacy. In patients receiving chemotherapy, there are definite gender-dependent disparities in response rates and the likelihood of side effects. This review explores the influence of sex as a biological variable in drug effects or toxicity in oncology.
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Objective: Electroconvulsive therapy (ECT) is the most effective treatment for patients with severe major depressive disorder (MDD). Given the known sex differences in MDD, improved knowledge may provide more sex-specific recommendations in clinical guidelines and improve outcome. In the present study we examine sex differences in ECT outcome and its predictors. Methods: Clinical data from 20 independent sites participating in the Global ECT-MRI Research Collaboration (GEMRIC) were obtained for analysis, totaling 500 patients with MDD (58.6 % women) with a mean age of 54.8 years. Severity of depression before and after ECT was assessed with validated depression scales. Remission was defined as a HAM-D score of 7 points or below after ECT. Variables associated with remission were selected based on literature (i.e. depression severity at baseline, age, duration of index episode, and presence of psychotic symptoms). Results: Remission rates of ECT were independent of sex, 48.0 % in women and 45.7 % in men (X2(1) = 0.2, p = 0.70). In the logistic regression analyses, a shorter index duration was identified as a sex-specific predictor for ECT outcome in women (X2(1) = 7.05, p = 0.01). The corresponding predictive margins did show overlapping confidence intervals for men and women. Conclusion: The evidence provided by our study suggests that ECT as a biological treatment for MDD is equally effective in women and men. A shorter duration of index episode was an additional sex- specific predictor for remission in women. Future research should establish whether the confidence intervals for the corresponding predictive margins are overlapping, as we find, or not.
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Abstract To promote health equity within the United States (US), randomized clinical trials should strive for unbiased representation. Thus, there is impetus to identify demographic disparities overall and by disease category in US clinical trial recruitment, by trial phase, level of masking, and multi-center status, relative to national demographics. A systematic review and meta-analysis were conducted using MEDLINE, Embase, CENTRAL, and ClinicalTrials.gov, between 01/01/2008 to 12/30/2019. Clinical trials (N = 5,388) were identified based on the following inclusion criteria: study type, location, phase, and participant age. Each clinical trial was independently screened by two researchers. Data was pooled using a random-effects model. Median proportions for gender, race, and ethnicity of each trial were compared to the 2010 US Census proportions, matched by age. A second analysis was performed comparing gender, race, and ethnicity proportions by trial phase, multi-institutional status, quality, masking, and study start year. 2977 trials met inclusion criteria (participants, n = 607,181) for data extraction. 36% of trials reported ethnicity and 53% reported race. Three trials (0.10%) included transgender participants (n = 5). Compared with 2010 US Census data, females (48.3%, 95% CI 47.2–49.3, p
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Objective To determine whether gender and menopausal status moderates the response to antipsychotic medication in patients with schizophrenia. Methods We analyzed data of 22 short-term placebo-controlled registration trials of antipsychotic medications, which included 5,231 patients with schizophrenia. We applied two-step individual patient data meta-regression analyses to establish the influence of gender and menopausal status on treatment response in mean difference in symptom severity and difference in response (>30% symptom reduction). Analyses were performed both with and without correction for (negative) baseline symptom severity. Results Antipsychotic treatment is associated with larger mean symptom reduction in women than in men with schizophrenia. The number need to treat (NNT) for a response in women was 6.9, in men 9.4. Although we found an age by gender effect, the gender by treatment effect was independent of premenopausal status and baseline (negative) symptom severity. Conclusion In the treatment of schizophrenia we found evidence of a higher response to antipsychotic medication in women relative to men. We found no evidence that this effect was driven by menopausal status, or baseline (negative) symptom severity. Despite the impact of gender and age on effect size in acute antipsychotic treatment, efficacy was clinically relevant in all subgroups.
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The requirement to establish safety of drugs prior to marketing has been in place since 1938 by the US Food, Drug and Cosmetic Act and is by no means a new concept. The efficacy regulations were enacted in 1962 via the Kefauver-Harris Amendment and the drug approval process has evolved thereafter. The assessment of safety and efficacy of drug products is made by pharmaceutical companies during drug development, which then goes through a regulatory review by the US FDA for the determination of market approval or nonapproval. The drug development and regulatory approval processes have endured close ongoing scrutiny by regulatory bodies, the public, US Congress and academic and private organizations and, as a result, have ensured continual refinement. Over the years, evidence has been emerging on varied drug responses in subgroup populations, and the underlying biology associated with age, race and sex as demographic variables have been examined. The resulting growing knowledge of disease burden, treatment response and disparate outcomes has generated opportunities to streamline and improve treatment outcomes in these populations. This article discusses the historical context of women's participation in clinical drug trials submitted to the FDA for regulatory review and approval purposes. The inadvertent consequences of women's exclusion or inadequate representation in past clinical trials and the evidentiary basis for understanding sex differences are also evaluated. Advances in the US regulatory processes to address treatment outcomes that are tied to the topic of this paper, specifically, adverse drug effects in women, are also discussed.
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The National Institutes of Health (NIH) Revitalization Act of 1993 requires that NIH-funded clinical trials include women and minorities as participants; other federal agencies have adopted similar guidelines. The objective of this study is to determine the current level of compliance with these guidelines for the inclusion, analysis, and reporting of sex and race/ethnicity in federally funded randomized controlled trials (RCTs) and to compare the current level of compliance with that from 2004, which was reported previously. RCTs published in nine prominent medical journals in 2009 were identified by PubMed search. Studies where individuals were not the unit of analysis, those begun before 1994, and those not receiving federal funding were excluded. PubMed search located 512 published articles. After exclusion of ineligible articles, 86 (17%) remained for analysis. Thirty studies were sex specific. The median enrollment of women in the 56 studies that included both men and women was 37%. Seventy-five percent of the studies did not report any outcomes by sex, including 9 studies reporting <20% women enrolled. Among all 86 studies, 21% did not report sample sizes by racial and ethnic groups, and 64% did not provide any analysis by racial or ethnic groups. Only 3 studies indicated that the generalizability of their results may be limited by lack of diversity among those studied. There were no statistically significant changes in inclusion or reporting of sex or race/ethnicity when compared with 2004. Ensuring enhanced inclusion, analysis, and reporting of sex and race/ethnicity entails the efforts of NIH, journal editors, and the researchers themselves.
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There is increasing concern among many in the medical arena about the extent to which the effects of treatment, either good or bad, apply to specific subgroups of individuals. Women comprise one of the most frequently considered 'subgroups' of patients. In the 1980s, much political attention was focused on concerns about equity in the research enterprise. In this paper, we briefly describe the statutory approaches to achieving equity in research, beginning with The NIH Revitalization Act of 1993. We go on to describe clinical, methodological and political factors affecting these discussions. We conclude that the controversy over the inclusion of women in clinical trials probably stems, in part, from theoretical concerns about gender differences in treatment effects and, in part, by legitimate fears of exposing fetuses to investigational drugs. However, we believe that the broader issue centres on biological factors, possibly defined by genes or gene expression, that may directly or indirectly modify the effect of specific treatments on specific individuals. A growing concern of physicians, regulators, healthcare policy makers and patients is the extent to which the effects of treatment, both good and bad, apply to specific subgroups. Do results of clinical trials apply consistently and equally across all clinically meaningful subclasses of patients enrolled in the studies? Can the results of those studies be extrapolated to patients or types of patients who did not participate in the original research? Reliable data on these issues are rarely available at the time of drug approval and are more difficult to generate once the drug is on the market and readily available.
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Several years ago regulatory authorities requested to include women in all phases of clinical drug development in order to thoroughly investigate potential gender differences in the pharmacokinetics and pharmacodynamics of newly developed therapeutic agents. Since then, numerous reports have been published that evaluate the potential existence and impact of gender differences on all aspects of clinical pharmacology. With regard to pharmacokinetics, differences in absorption rate and duration have been reported for several drugs, but generally lack to have major clinical relevance. Differences in oral bioavailability, however, seem to be more important and are usually caused by sex differences in the activity of major intestinal and hepatic metabolic enzymes. Distributional differences have also been identified for numerous compounds. Although the majority of these findings were merely weight effects as women generally have a lower body weight, some of the gender-specific distribution differences persisted after normalization for weight. Possible explanations are differences in body composition between men and women and/or physiological changes during the menstrual cycle as well as differences in plasma protein binding secondary to hormonal characteristics. Frequent and sometimes clinically relevant gender differences could be identified for drug elimination processes and were predominantly linked to the sex-specific expression of metabolic enzyme systems, e.g. CYP3A4 and CYP1A2. In contrast, gender-related differences in renal elimination are generally only of minor importance. With regard to pharmacodynamics, gender differences have been observed in baseline characteristics as well as in drug response, which might both, at least in part, be the consequence of modulation by sex hormones. Some of the most striking examples identified were in pain therapy and perception, glucose management and arrhythmia susceptibility. Since clinical endpoints of efficacy and toxicity are often difficult to monitor and are frequently substituted by surrogate markers that might increase variability and thus mask gender effects, sex-specific differences in pharmacodynamic characteristics can often remain uncovered and further intensive research in this area seems imperative. For the majority of investigated drugs in the past few years, however, no or only very minor gender differences could be detected in pharmacokinetics and/or pharmacodynamics. In addition, the clinical significance of those gender differences identified seem very limited and was only very rarely linked to treatment success or failure. Hence, it is undoubtedly necessary to include women in the clinical drug development process, but it seems questionable whether women of child-bearing capability should be exposed to potential risks in early phase I clinical trials.
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Even though slightly over half of the U.S. population is female, medical research historically has neglected the health needs of women. However, over the past two decades, there have been major changes in government support of women's health research--in policies, regulations, and the organization of research efforts. To assess the impact of these changes, Congress directed the Department of Health and Human Services (HHS) to ask the IOM to examine what has been learned from that research and how well it has been put into practice as well as communicated to both providers and women. Women's Health Research finds that women's health research has contributed to significant progress over the past 20 years in lessening the burden of disease and reducing deaths from some conditions, while other conditions have seen only moderate change or even little or no change. Gaps remain, both in research areas and in the application of results to benefit women in general and across multiple population groups. Given the many and significant roles women play in our society, maintaining support for women's health research and enhancing its impact are not only in the interest of women, they are in the interest of us all. © 2010 by the National Academy of Sciences. All rights reserved.
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This paper describes a Women's Health Initiative workshop on promoting adherence and retention in randomized clinical trials among ethnic minority women, participants of lower socioeconomic status, and older women. Workshop objectives were: (1) to increase knowledge of demographic and cultural characteristics of diverse groups, (2) to increase awareness of how diversity can affect interactions in clinical research, (3) to explore how research staff behavior can influence adherence and retention, and (4) to increase knowledge of strategies to enhance adherence and retention in special populations. The workshop emphasized the importance of understanding beliefs, values, and experiences that are common in diverse groups of individuals, while at the same time recognizing and respecting individual differences that result from varying life circumstances and experiences. We discuss strategies to increase cultural competence, reduce stereotypes and discrimination, and create a culturally relevant and sensitive research environment.
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Background: Biological sex differences may contribute to differential treatment outcomes for therapeutic products. This study tracks women's participation in late-phase clinical trials (LPCTs), where efficacy and safety of drugs and biologics are evaluated, of new molecular entity (NME) drugs and biologics approved by the U.S. Food and Drug Administration (FDA) in 2007-2009. Furthermore, presentations of sex-based analyses were assessed from the FDA reviews. Methods: New drug applications (NDAs) and biologics license applications (BLAs) were accessed from the U.S. FDA database and evaluated for women's participation in LPCTs. Sex-based analyses for efficacy and safety contained in FDA reviews were surveyed. Ratios for women's LPCT participation (PROPORTION OF STUDY SUBJECTS) to their proportion in the disease population were calculated for each approved therapeutic product and grouped into therapeutic categories. Results: Sex-specific (n=5) and pediatric (n=3) drug applications were excluded. Women's participation in LPCTs was 39%, 48%, and 42% in NDAs (n=50) and 49%, 62%, and 58% in BLAs (n=11) for 2007, 2008, and 2009, respectively. Sixty-four percent of NDAs and 91% of BLAs had participation to proportion ratios of ≥0.80. Seventy-four percent of NDA reviews and 64% of BLA reviews included safety and efficacy sex analysis. Ninety-six percent of NDA reviews and 100% of BLA reviews included efficacy sex analysis. Conclusion: Women's participation in LPCTs averaged 43% for NDAs and 57% for BLAs in 2007-2009 and varied widely by indication. As a comparison, the 2001 U.S. Government Accountability Office (GAO) reported 52% of women's participation for drug clinical trials in1998-2000 and an FDA study reported 45% for BLAs approved from 1995 to 1999. This study showed that sex-analysis of both safety and efficacy in NDA has increased to 74% since the GAO report of 72%, while those for BLAs increased to 64% from 37% reported for therapeutic biologics approved in 1995-1999. Knowledge of disease prevalence and participation in clinical trials provides an understanding of recruitment and retention patterns of patients in these trials.
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Studying sex and gender differences is critical to understanding diseases that affect women solely, disproportionately or differently from men. Although inclusion of both sexes is essential in clinical research, advanced technology and analysis methods offer tools to define complex biological and physicochemical differences and improve prevention, diagnosis and treatments for diseases in women and men. This paper identifies the potential for biomarker development, pharmacogenetics and bioinformatics in research under the FDA Critical Path Initiative.Section editor:Janet Woodcock – Food and Drug Administration, Rockville, Maryland, USA