adverse effects; also, information on ‘target
organs’ (organs likely to be most affected or
harmed) is usually predictable but unconfirmed at
this point. Generally, as a result of animal studies, it
is thought that the effect of drugs on reproductive
function in males is less than that in females and
only affects the sperm viability or, rarely, the size
and function of the testicles, which is usually
reversible. This is unduly optimistic, as one report
by Yazigi, Odem and Polakoski (1991) suggest that
spermatozoa may not be immobilized or destroyed
by cocaine, but may interact, and the spermatozoa
themselves have the potential to act as an active
transport mechanism for drugs, pesticides and even
environmental chemicals to the unfertilized ovum.
They may also alter the genetic makeup of either
spermatozoa or ovum. In addition, spermatozoa
can be made sluggish by calcium channel blockers,
leading to male infertility while on medication.
Hence, the European guidelines call for male ani-
mal testing prior to start of phase II.
The blastocyst (early embryo) is relatively resis-
tant to damage in the first seven days, for up to 75%
of cells can be destroyed before tissue differentia-
tion and the embryo can still survive. What might
happen if garden pesticides, or house builders’
formaldehyde containing glue and chemicals, are
combined into the genetic material? If it is ever
confirmed, then we may have the inkling of what
makes up the 65% of the ‘unknown’ causes of
developmental defects mentioned by Wilson
(1972). If it could be shown that the synthetic
chemicals are incorporated into the blastocyst,
the field of male phase I testing would be trans-
formed, as would that of genetic counseling.
Testing facilities
Largely because early testing of drugs occurred in
males rather than females, for reasons discussed
above, most commercial and hospital units devoted
to human pharmacology testing were set up to deal
with a unisex population. They ran one gender
study at a time, usually male, in 1993. Sleeping
and bathroom facilities in the units’ dormitory
accommodations did not provide for mixed gender
groups. These were minor but not inexpensive
attentions but were quickly adopted following the
publication of theFDA Guidelines for the Study
and Evaluation of Gender Differences in the Clin-
ical Evaluation of Drugs(Federal Register, 1993).Standardizing for the menstrual cycle
(phase I and early phase II)Of much greater concern is the issue of standardiz-
ing the drug administration to the menstrual cycle.
Women of childbearing age do not all have
cycles for the same length of days; variations of
24–36-day cycles are not unusual between and
within the same women. Thus, unless controlled
by OCs, women volunteers could not start and
finish in a study all together. Indeed, if OCs were
used to standardize cycles, the issue of how really
representative ofallwomen of childbearing age
this artificial hormone-boosted group might be
would be debatable. Evidence suggests that even
low-dose contraceptives can affect metabolism
(Abernathy and Greenblatt, 1981). The logistics
of running phase I single-dose and multiple-dose
ranging studies while controlling for a natural
menstrual cycle are truly horrendous, both for the
phase I testing units and for the volunteer. The
duration of any study would be extended by at
least one month (the time required for the last
patient’s cycle to start), and each patient volunteer
would have to be measured separately because of
the different days of her cycle. A small but fre-
quently argued point is timing. Which is the pre-
ferred day in the cycle for single-dose studies? And
for a multiple-dose study (usually only 10–14 days
long), which segments of the cycle should be cov-
ered? This may seem academic, but in those clini-
cally significant drug classes where womens’
responses to drug handling are different to those
of men because of biochemical hormone effects
(not just gender), then the timing of drug dosing
and measurement would be critical.Too many young volunteer studies
Many volunteer studies, especially at commercial,
academic and university clinical units, include16.4 INDUSTRY PRACTICE: FACTORS IN PHASE I AND EARLY 209