the greatest users of these medications, should not
study recruitment members be biased in their
favor? However, some of the psychotropic CNS
drugs also have animal data – and a few, even some
human data – suggesting an increased teratogenic
potential (Physician’s Desk Reference, 1991;
Jefferson et al., 1987). There is no consistent
evidence of class teratogenicity (Elia et al.,
1987), but there is a high association of fractured
hips with the use of psychotropic medicines, even
when corrected for women’s greater age-related
hip fracture rate (Rayet al., 1987). One of the
commonest causes of the elderly being admitted
to institutional care is urinary incontinence.
Women have been found to be more susceptible
than men to medications that can cause inconti-
nence to occur (Dioknoet al., 1986).
Adverse event differences
There is increasing evidence that gender is a risk
factor in adverse reactions with female patients at
1.5–1.7-fold greater risk than men (Rademaker,
2002). Although it is true that women take more
medicines than men, but of 8 of 10 prescription
drugs removed from the market, women suffered
more serious adverse reactions. At least four of
these were taken in equal numbers by both genders
(General Accounting Office, 2001).
One of the most striking differences between
male and female responses to drugs is the finding
reported by Martinet al.(1998) in 513 608 patients
with serious adverse events, which occurred in
43.2% males and 55.7% females when adjusted
for age. In women of all ages, Tranet al.(1998)
also reported that, in findings from records of 2367
patients, female patients were at twice greater risk
of adverse reactions than males. More than one
agent was reported to be responsible in 50% of
female patients versus 33.1% of all male patients.
Drugs in both genders most likely to cause an
adverse event were anti-infectives (60.4%) and
nervous system agents (21.5%) (Martin et al.,
1998). The commonest events were skin-related
reactions (49%). It is possible that bare arms and
exposed legs in women may cause more phototoxic
reactions than in men; nonetheless, this cannot be
said of nervous system agents. Clearly, these two
classes of agents need special gender exploration in
clinical development.
Women also have a higher risk of developing
drug-induced cardiac arrhythmia (Ebert et al.,
1998) and life-threatening torsades de points
arrhythmia may occur with drugs such as antihis-
tamines, antibiotics or antipsychotics, making it
important that Cardiac QT studies be conducted
in volunteers of both genders (Woolsey, 2005).16.6 Government agency
and industry actions on
gender-related researchThe Public Health Service Task Force on
Women’s Health Issues (1985) and the National
Institutes of Health (NIH) Guide (1989) both
recommended that biomedical and behavioral
research should be expanded to ensure emphasis
on conditions unique to, or most prevalent in,
women of all age groups: ‘in addition, studies
are needed to study the metabolism and disposi-
tion of drugs and alcohol by age and gender’. The
National Institute for Drug and Alcohol Abuse
(NIDAA) (1990) policy provides detailed, almost
affirmative-action instructions for the inclusion of
women and minorities into study designs, accord-
ing to their prevalence in the diseases being
studied.
Since 1988, the FDA has requested tabulations
of gender, age and racial distributions in NDA
submissions. Many of their senior officials, for
example Drs. Peck and Temple, had forcefully
stated that women should be included in drug
development studies. Indeed, the 1977 guideline,
General Consideration for the Clinical Evaluation
of Drugs, included a policy for the inclusion of
women of childbearing potential in clinical trials
but excluded them, in general, from phase I and
early phase II studies, with exceptions for life-
saving or life-prolonging treatments. Childbearing
potential was strictly defined as ‘any woman cap-
able of becoming pregnant’, including women
using reversible contraceptive precautions and
those with vasectomized partners.16.6 GOVERNMENT AGENCY AND INDUSTRY ACTIONS ON GENDER-RELATED RESEARCH 213