insignificant. Theoretically, because of weight dif-
ferences, women may receive more medication
than men for a standard dose when adjusted to
mg kg^1. Greater effects might be expected from
the range of normal weights rather than from the
effects of gender.
Clinically significant gender effects have been
reported with CNS, anti-inflammatory and cardio-
vascular drugs. It is suggested that women continue
to be enrolled into most drug study programs, but
that greater thought be given to obtaining ‘repre-
sentative’ numbers in the early program planning
stage. For drugs intended mainly or entirely for
women, even phase I testing in women should be
usually considered. Single-dose testing, even in
women of childbearing potential, poses minimal
risk if done early in the cycle, with adequate pre-
cautions and ‘consort’ consent to short sexual
abstinence. Alternatively, women with tubal liga-
tion could be enrolled for these small studies.
‘Representative’ could be twofold: a reflection of
the percentage of women suffering from the disease,
or a ‘reasonable or sufficient’ number to show clini-
cally significant differences in efficacy or safety in
the main efficacy and safety studies; alternatively,
conducting at least one study just in women in phase
III. What is a ‘clinically significant effect’ would
depend on the drug and disease, but effects with a
less than 15% difference get harder to detect and
generally will be less meaningful. Again, women of
childbearing potential could be included, depending
on the age/prevalence of the disease. Women using
OCs may be compared not only with males but also
with non-OC users. OC and drug interaction studies
are currently required for most drugs.
Early embryo drug exposure and the potential
liability for any damage continues to influence
industry, agencies and some research workers. It
must be recognized that, if an agent has human
teratogenic potential, it is better to detect this
before it achieves the marketplace. Unfortunately,
this is unlikely to be detected because the small
numbers of women becoming pregnant in any
NDA program make it impossible to detect drug-
induced effects from spontaneous birth defects.
Data in women are needed and the possibility is
suggested of an expanded National Register along
the lines of the International Clearing House for
Birth Defects Monitoring to follow up the expected
small number of embryos exposed and a Compen-
sation Panel in the event of proven damage, funded
by an excise tax, as with vaccines.
Finally, with all the great strides being made to
unravel the human genome and determine the gene
structures and their influence, we are much nearer
to tailoring drugs to match male and female differ-
ences, and with enhanced computer power, this
chapter may become moot.Acknowledgments
The author wishes to acknowledge that much of
this chapter was supported by a grant from the NIH
branch, Office of Protection from Research Risks
($805).Recommended reading
DiMasi JA, Hansen RUS, Grabowski, HG. 2003.
The price of innovation: new estimates of drug
development costs.J. Health Econ. 22 : 151–158.
Mastroianni AC, Faden R, Federman D (eds).
(1994).Women and Health Research: Ethical and
Legal Issues of Including Women in Clinical Stu-
dies.Academy Press.References
Abel JG, Sellers EM, Naranjo CA,et al.1979. Inter and
intrasubject variation in diazepam free faction.Clin.
Pharmacol. Ther. 26 : 247–55.
Abernathy DR, Greenblatt DJ. 1981. Impairment of
antipyrine metabolism by low dose oral contracep-
tive steroids.Clin. Pharm. Ther. 29 : 106–110.
Allen MD, Greenblatt DJ. 1981. Comparative protein
binding of diazepam and desmethyldiazepam.
J. Clin. Pharmacol. 21 : 219–223.
Bello M. 1989. Liability crisis disrupts, distorts mater-
nity care.Natl. Res. Counc. New Rep. 39 : 6–9.
Berger JS, Roncaglion MG, Avanzini F,et al.2006.
Asperin for the primary prevention of cardiovascular
events in woman and men: a sex specific meta
analysis of randomized controlled trials. JAMA
294 : 306–313.218 CH16 DRUG DEVELOPMENT RESEARCH IN WOMEN