AOG XXXXXXXXXX
Exclusion of Pregnant Women From
Industry-Sponsored Clinical Trials
Kristine E. Shields, MSN, DrPH, and Anne Drapkin Lyerly, MD, MA
OBJECTIVE: The lack of human data available to inform
evidence-based treatment for illness during pregnancy has
led to calls for greater inclusion of pregnant women in
esearch, but the extent of their cu
ent representation is
poorly characterized. Our objective was to measure the
cu
ent exclusion of pregnant women from industry-
sponsored clinical trials as a baseline for future comparison.
METHODS: We compiled data from studies enrolling
women of childbearing potential posted on www.
ClinicalTrials.gov between 1 October 2011 and 31
January 2012. The review was limited to open United
States–based phase IV interventional studies sponsored
y the pharmaceutical industry evaluating treatment of
conditions that may be experienced by but are not lim-
ited to pregnant women and did not involve a medication
classified as potentially teratogenic. If there was no
mention of pregnancy in the inclusion or exclusion
criteria, we contacted a study representative to confirm
that pregnant women could be enrolled.
RESULTS: Of 558 qualifying industry-sponsored studies,
five (1%) were designed specifically for pregnant women.
Of 367 phase IV clinical trials with verified inclusion and
exclusion criteria, XXXXXXXXXX%) excluded pregnant women
and 19 (5%) did not.
CONCLUSION: We found the exclusion of pregnant
women from industry-sponsored clinical trials to be
common practice. Moving beyond reflexive exclusion
and developing thoughtful criteria for inclusion of preg-
nant women in clinical research would likely advance the
evidence base to inform treatment decisions during
pregnancy and lead to better health outcomes fo
women and children.
(Obstet Gynecol 2013;122:1077–81)
DOI: XXXXXXXXXX/AOG.0b013e3182a9ca67
The treatment of medical conditions complicatingpregnancy is challenged by a lack of information
about the safety and efficacy of medications used, o
potentially used, by pregnant women. Generally, what
constitutes the most effective therapy is identified
through systematic research; however, pregnant
women are commonly considered ineligible to partic-
ipate. An unintended consequence is that women and
health care providers are often faced with a lack of
information to inform treatment decisions for obstetric
and nonobstetric complications of pregnancy.
The Institute of Medicine,1 the World Health
Organization,2 the American College of Obstetricians
and Gynecologists,3 and other leaders agree that preg-
nant women should be considered eligible for partic-
ipation in clinical trials. Although there are many
situations in which excluding pregnant from research
is justified, they are often reflexively excluded even
when their inclusion can be ethically and scientifically
justified.4 To address this, the U.S. Food and Drug
Association (FDA) is preparing a draft Guidance fo
Industry entitled “Pregnant Women in Clinical Trials:
Scientific and Ethical Considerations.”5
Although the consequences of
oad-based exclu-
sion of pregnant women have been noted, the extent of
the unde
epresentation of women in research trials is
poorly characterized. The intent of this study was to
measure the cu
ent state of inclusion and exclusion in
industry-sponsored clinical trials and to establish a base-
line against which future measurements of the represen-
tation of pregnant women in research can be compared.
Understanding the patterns and extent of their exclusion
will be critical to setting priorities, anticipating ba
iers,
developing policies, and responding appropriately to
FDA draft guidance and other policy interventions.
From the Office of Ethics, Merck, Whitehouse Station, New Jersey; and the
Department of Social Medicine and the Center for Bioethics, University of North
Carolina, Chapel Hill, North Carolina.
Co
esponding author: Kristine Shields, MSN, DrPH, 17 Stover Park Road,
Pipersville, PA 18947; e-mail: XXXXXXXXXX.
Financial Disclosure
Dr. Shields is employed by and receives a salary, stock, and stock options from
Merck & Co. This article was written independently from her employment at
Merck & Co. and is not meant to represent the views of the company. The othe
author did not report any potential conflicts of interest.
© 2013 by The American College of Obstetricians and Gynecologists. Published
y Lippincott Williams & Wilkins.
ISSN: XXXXXXXXXX/13
VOL. 122, NO. 5, NOVEMBER 2013 OBSTETRICS & GYNECOLOGY 1077
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MATERIALS AND METHODS
Our data were compiled from the list of all studies
enrolling women of childbearing potential posted on
www.ClinicalTrials.gov between 1 October 2011 and
31 January 2012. Because the data on ClinicalTrials.gov
are in the public domain, the Institutional Review
Board of the University of North Carolina at Chapel
Hill classified this study as exempt from approval.
We limited the review to open United States–
ased phase IV interventional studies that included
adult female participants. Because the anticipated
FDA guidance is intended for industry, we limited
our review to studies that were sponsored by pharma-
ceutical, biotech, or medical device companies, esti-
mated in one analysis to be 63% of all studies.6 To be
included, the study must have been evaluating treat-
ment of conditions that may be experienced by but
are not limited to pregnant women and must not have
involved the use of a medication that is in the FDA
pregnancy categories D or X, for which there is pos-
itive evidence of human fetal risk or teratogenicity.
We chose to investigate enrollment in phase IV
studies because studies of pregnant women would best
e conducted after initial testing had established low
isk of toxicity and teratogenicity in animal tests and
efficacy in the general population. Having established
these data points, phase IV trials are potentially the
most appropriate and least controversial for inclusion
of pregnant women. Phase IV trials are conducted
using drugs that have already received regulatory
approval and are cu
ently on the market. They
evaluate drug interactions, long-term effectiveness,
use in populations other than those for which the
drug was initially approved, and other characteristics.7
In addition, FDA pregnancy risk categories for the
study drugs in phase IV trials are available to help
assess the appropriateness of exclusion of pregnant
women. Given these characteristics, phase IV studies
epresent those most likely to enroll pregnant women
and thus to establish the most permissive baseline
from which to characterize inclusion.
The ClinicalTrials.gov database was queried
using the search function of the web site for the terms:
“open studies,” “interventional studies,” “location in
the United States,” “studies with female participants,”
“adult age group (18–65),” “phase 4,” and “funded by
industry.” Variables such as sponsor, drug or device
or procedure, condition undergoing study, and exclu-
sion criteria from each study retrieved by the query
were manually transposed to an Excel worksheet. The
FDA pregnancy categories for all drug products were
ascertained and transcribed from www.PDR.net, the
electronic version of the Physicians’ Desk Reference from
PDR Network, a leading publisher of drug labeling
information.8
Those studies evaluating the treatment of medical
conditions that could not be experienced by pregnant
women were excluded, as were studies found to be
using medications in FDA pregnancy category D
(positive evidence of human fetal risk but benefits of
use may outweigh the risk) or category X (positive
evidence of animal or human fetal risk and the risk of
use clearly outweighs the potential benefit). If there
was no mention of pregnancy in the inclusion o
exclusion criteria, we contacted a study representative
y e-mail or telephone to discern whether pregnant
women could be enrolled and, if not, the reason fo
their exclusion.
RESULTS
Application of the search criteria retrieved a total of
559 industry-sponsored studies from the Clinical-
Trials.gov web site over the course of this 4-month
period. Of these, one trial (a trial for hemophilia lim-
ited to males) was excluded, resulting in a total of 558
clinical trials available for study.
Of these 558, five studies limited enrollment to
pregnant women and 98 were found to appropriately
exclude pregnant women based on the following
criteria: 74 trials utilized at least one drug in FDA
pregnancy category D or X; the age range criteria in
17 studies precluded childbearing potential; and the
topic of seven studies precluded pregnancy at enroll-
ment, including four on menopause, two on con-
traception, and one on lactation. Of the remaining
455 clinical trials that could potentially enroll women
of childbearing potential, 301 specifically excluded
pregnant women, one specifically did not exclude
pregnant women, and 153 made no mention of preg-
nancy in the inclusion or exclusion criteria posted on
ClinicalTrials.gov.
One might expect that, if pregnancy was not
mentioned in the exclusion criteria, pregnant women
could be included. To test that assumption, we
attempted to contact study personnel from all 153 of
these studies by telephone, by e-mail, or both. Eighty-
eight did not respond to the request for information.
Of the 65 studies for which clarification about whethe
pregnant women could be included was obtained,
47 (72%) excluded pregnant women and 18 (28%) did
not exclude them from enrollment in the study.
Justifications for the pregnancy exclusion elicited
from study personnel included that the condition
undergoing study had a low prevalence in pregnant
women, that there was not yet enough safety data, that
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pregnant women are considered by FDA to be
a “vulnerable population,” and that pregnancy was
“normally always an exclusion criteria [sic].” One
esearcher commented, “no glaucoma treatments
have been approved for use in pregnant women so
[excluding them] was a no-
ainer.”
Overall, of 558 qualifying industry-sponsored
studies, only five were designed specifically fo
pregnant women (a rate of approximately 1%). Of
the 367 phase IV clinical trials for which we had
specific inclusion and exclusion criteria about preg-
nancy, XXXXXXXXXX%) excluded pregnant women and
19 (5%) did not exclude pregnant women from
enrollment (5% is a lower limit based on the 88
studies with unknown exclusion criteria) (Fig. 1).
A range of medical conditions that could occur in
pregnant women was noted in the phase IV studies
evaluated. These included, for example, epilepsy,
depression, arthritis, peripheral artery disease, human
immunodeficiency virus, and schizophrenia. All of the
conditions being evaluated by the clinical trials in ou
study could occur in pregnant women, although
treatment of some, like knee replacement, might be
safely postponed until the completion of the preg-
nancy; however, treatment of others would be impor-
tant to the ongoing health of a pregnant woman and
her fetus.
The topics of the five studies that were limited to
women who were pregnant or intending to become
pregnant were all pregnancy-related conditions. We
found no studies designed specifically to evaluate the
treatment of nonobstetric illness during pregnancy.
Acknowledging that the small number of studies
that allowed enrollment of pregnant women (n519)
precludes robust statistical analysis, we compared the
characteristics of studies that excluded pregnant
women with those that permitted their enrollment
(Table 1). In approximately 80% of the studies in both
groups, the purpose of the trial was to evaluate treat-
ment as opposed to preventive, diagnostic, or support-
ive care. Regardless of whether they included o
excluded pregnant women,