frequentlyyoung peopleofcollegeage. Bothmales
and females will volunteer as financial remunera-
tion, and a free medical check-up and medical care
play their part in motivation. The young also have
less career and family commitments interfering
with their motivation. Time for studying, reading
and relaxation within an atmosphere of camarad-
erie also contributes to the availability of younger
volunteers, who, because of their age, also tend to
be very healthy. It will readily be appreciated that
most drugs or devices are not unique or life saving
but hopefully an improvement on existing agents,
and indeed this applies to most basic research
experiments. Nearly all drug studies in phase I
are aimed at gathering data on a potentially safe
and possiblyefficacious dose range. Asaresult, itis
often hard to recruit older, more mature women for
these basic types of essential drug development
programs.
What is a representative female
population in phase I?
It has been stated that large numbers of mature
women are volunteering for the new lipid, heart
risk, osteoporosis and arthritis phase 3 studies,
due to their concern that women have been repre-
sented so poorly as subjects in the past. Phase I
studies are of short duration (one to two weeks)
but usually require confinement of the volunteers.
Because of this time commitment, far fewer
mature women volunteer, due to career conflicts
or because they are often burdened unequally
with family management. Those that do volunteer
are generally unattached young female students.
Thus, most female volunteers may not be typical
of a ‘representative’, mature, childbearing popu-
lation (if this can ever be defined).
One alternative, a study design of stratification
by age and sex, would lead to inordinately long
study recruitment times, because the last ‘cell’
(group) always takes a disproportionately long
time to fill. The most obvious way out of the
quandary for phase I testing would be to maintain
a special cadre of ‘safe, standard’ volunteers. How
‘representative’ these much used ‘new-drug volun-
teers’ would become is debatable. For example,
studies in arthritic patients show that these ‘ret-
read’ volunteer patients will differ in their toler-
ance to pain and in their judgment of efficacy
and severity of adverse events, when compared to
drug-study ‘naive’ patients (Coleset al., 1988).
This ‘training effect’ increases with multiple drug
exposure.
By far, the biggest issue of undertaking addi-
tional dosing phase I studies on women is expense.
Most of these studies cost $100–250 thousands
each. Altogether, single, multiple and multiple-
dose ranging studies, with food effect studies and
extra staff costs, could add $5 million to develop-
ment costs and very rarely show a difference which
would prove clinically relevant. Indeed, the differ-
ence may not show up at all in phase I or II gender-
to-gender studies due to other variables, for exam-
ple small numbers, estrogen-cycle levels and OC
levels and drug polymorphism.16.5 Drug handling differences
between males and femalesDue to space limitations, this subchapter cannot
discuss the many reports of apparent gender differ-
ences of psychology, different anatomic brain loca-
tion of functions, skeletal build and muscle-to-fat
mass ratios which might have marginal impact
upon drug activity. But an analysis of 300 FDA
reviewed new drug applications between 1995 and
2000, of 163 that included a gender analysis, 11
drugs showed a greater than 40% difference in
pharmacokinetics between male and female,
though while listed on the product label, were not
accompanied by any variable dosing recommenda-
tions. An analysis of 26 bioequivalence studies
involving both sexes was undertaken by Chen
et al.(2000).
In 39% two data sets (AUC or CMax) difference
of 20% or greater was observed and was reduced to
15% after body weight correction, in men.
In general, the between-gender variations did
not result in obvious pharmacodynamic dose–
response differences, but care must be exercised
in drugs having a steep dose–response curve and/or210 CH16 DRUG DEVELOPMENT RESEARCH IN WOMEN