from 2000 to 2050, compared to males (45.4%).
Population of women over 65 years will increase
by 24% over 2000–2010 in the United States and
12% in Europe, and even in 2000 women of 80
years outnumbered males by a 2:1 ratio (Source:
United Nations Population Database). In western
countries, 54% of women are of childbearing
potential (15–49 years). Women account for 57%
of physician visits (National Disease and Thera-
peutic Index, 1991). In the age group 20–39 years,
women were found to be the biggest users of anti-
infectives, especially ampicillin and amoxicillin;
antidepressants are prescribed twice as often to
women as to men (Stewart, 1998); and of some
concern was that tetracycline, a known teratogen,
was the eighth most prescribed drug in the 38% of
women of childbearing age (FDA, 1986).
As major users, it might be postulated that
women, including those of childbearing age,
should be the group on which phase I and
phase II dosing (early efficacy and safety) should
be based. Why is this not so? Critics of the
industry, and indeed of the wider research pro-
cess, claim that it is entrenched discrimination
by males, which is disguised as ‘concern and
gallantry’. Critics also point out that both med-
icine and research are dominated by males, who
place research into women’s diseases on the back
burner of their male priorities and only see data,
even on women, from a man’s point of view.
They point to a report by Coale (1991) on the
‘missing 100 million women’ in Asia and the
Indian subcontinent, who are speculated not to
exist because of abortion and medical and nutri-
tional neglect. They also point to the misuse of
science (ultrasound or amniocentesis) for sex
determination.
While these are extreme examples of societal
attitudes, it is true that women have been excluded
from many large, well-published studies, such
as the Physicians’ Health Study of aspirin in
cardiovascular disease (Henrekens, 1989). It is
also true that many early studies of drugs in phases
I and II were conducted in healthy white males
18–40 years old, and the results then extrapolated
to women in phase III studies, primarily aimed at
expanded efficacy and safety. Only recently,
Paul Williams (1996) confirmed that exercise
raised HDL cholesterol in women, many years
later than that reported in men. It is, however, in
most cases, grossly naive to attribute this to delib-
erate ‘male discrimination’ to exclude research on
women.
It is also frequently mentioned that fear of
embryonic malformation, whether or not drug-
related, and subsequent litigation isthe major
determining factor for exclusion of females from
therapeutic and basic research projects. This overly
simple explanation covers up other difficulties,
such as methodology, lack of relevant baseline
information and biochemical variables, both hor-
monal and gender-related. It also ignores the use of
information derived from other groups of women,
those of no childbearing potential, sterile or post-
menopausal, the elderly or children just entering
puberty, where the risk of fetal exposure is non-
existent or minimal.16.2 The dilemmas
Do women respond to medications differently to
men? If so, in what ways and how frequently are
these changes clinically meaningful? Review of
the literature shows some examples of differences
between the sexes in drug handling, particularly
with certain classes of drugs. These will be dealt
with later, but it is important to bear in mind that,
despite some detectable differences, usually no
therapeutically significant differences are seen
(Edwards, 1991). This is unlikely to be due to
lack of compliance, as women are generally more
reliable than men, although compliance does fall
off to 67% over a few weeks for both genders
(Crameret al., 1990). This does not exclude self-
adjustment of dose by female patients, a phenom-
enon seen in both sexes and probably much more
common than reported.
It has also been claimed (because gender data
are rarely mentioned in clinical studies, papers
or reports) that gender differences are not
sought. This presupposes that data are neither
collected nor examined. In fact, the opposite is
much more likely: 94% of surveyed pharmaceu-
tical firms were found to collect gender data in
their studies (Edwards, 1991). The reality is that204 CH16 DRUG DEVELOPMENT RESEARCH IN WOMEN