the incidence of anticonvulsant teratogenic effects
are increased (Lindhautet al., 1984). Would either
of these drugs be developed in today’s litigious
atmosphere? Its doubtful. But both drugs are valu-
able in many circumstances; they may be the only
drugs suitable for some patients and, indeed,
frequently can be life-saving. Certainly, maternal
status epilepticus is very injurious to the fetus,
often resulting in miscarriage or premature birth.
The incidence of neonatal abnormalities in
mothers taking anticonvulsant treatment is 70/
1000 live births (Frederick, 1973). This is
2.4 times the ‘spontaneous rate’ in the general
population (29 abnormalities/1000 live births).
Thus, even using a known ‘low-incidence’ terato-
gen could cause 40 additional cases/1000 live
births, but to determine that accurately would
require many thousands of female patient expo-
sures to be detectable against the ‘spontaneous’
background incidence.
So, back to the opening question. What is the
likelihood of detecting low-incidence, drug-
induced congenital effects in a drug development
program? With our presumed database of 4000
patients, only 0.8–5 fetuses would be exposed to
a background ‘spontaneous’ risk of 2.9%. Each
program could carry a 1 in 33 to 1 in 6 chance of
a single ‘spontaneous’ abnormality occurring. If
the drug or procedure should have low teratogenic
activity (at the level of an anticonvulsant), this risk
rises to 1 in 14 to 1 in 2.5 that a child will be born
with a congenital abnormality in any drug devel-
opment program. Both ‘spontaneous’ or drug-
induced abnormalities may occur, for example
a neural tube defect. Thus, on a single-case basis,
the abnormalities will be indistinguishable for
drug causality. This, in turn, can lead to litigation,
and certainly to a reference in the package label
insert.
Wilson has estimated that both drugs and envir-
onmental chemical exposures only account for
2–3% of developmental defects in man (Wilson,
1972).Thus, a product-label reference of such an
occurrence will be undeserved at least 97% of
the time, but also may be the first signal of a
teratogenic risk. It may now be appreciated why
this 2–3% risk is termed the ‘phantom fetus’
and also why the difficulty indisproving liability
dominates the mainstream concerns of research,
regulatory authorities and industry alike. This
‘ghost risk’ creates ‘discrimination’ against female
patients in drug research. This ‘ghost’ must be
exorcised and contained; possible solutions will
be discussed later.16.4 Industry practice: factors
in phase I and early
phase II testingMedical journalist Paul Cotton (1990) asked, in a
thought-provoking article, is there still too much
extrapolation from data on middle-aged white
men? Inspection of the demographics of recent
NDAs will give us numbers to debate; however,
these data are not readily accessible. Most phase I
testing is still undertaken in healthy young males,
and even for phase I testing of new contraceptives
hormonal for women. Why this occurs is multi-
faceted.Timing of mutagenicity fertility
and teratogenicity testingThe complete battery of tests with full histology
and the development of a final report can take as
long as two years. In general, only some of the
mutagenicity studies are completed, and perhaps
one- to three-month reports of animal testing are
available when male phase I dosing volunteer stu-
dies commence. All animal studies do not com-
mence at the same time but are usually sequential.
Some, such as postexposure weaning and subse-
quent second-generation drug effect studies, will
be time-consuming and expensive. Often, if muta-
genicity tests, for example Ames’ test or mouse
lymphoma test, are positive (Ames test has 30%
false-positive rate), then females will be excluded
until more data are collected. Thus, only limited
data are available prior to the first human exposure
(for further reference Federal Register, 1994,
1996).
Volunteer dose-ranging studies will, by design,
include high enough doses to provoke unpleasant208 CH16 DRUG DEVELOPMENT RESEARCH IN WOMEN