devices, for many experimental drugs (perhaps 9
out of 10 tested in man) will never achieve the
marketplace.
The potential for pregnancy while
on a trial drug
What is the risk of pregnancy occurring in a study
participant while a new drug is being developed?
The author is not aware of any published figures,
but from the author’s experience in industry and
from questions to colleagues, pregnancy does
occur during drug development, even in those
patients apparently takingadequatecontraceptive
precautions. A typical NDA database for most
drugs will involve between 2000 and 4000 patients,
of which perhaps one-third are female and exposed
to study medication. It is not surprising, therefore,
that given an average failure rate of the contra-
ceptive pill of 2%, or even with the most stringent
compliance, a failure fate of 0.5/100 women years
will result in occasional pregnancy (Trussellet al.,
1990). Other methods, such as the diaphragm,
condoms and IUDs, can carry even higher failure
rates, depending on whether ‘usual’ or ‘perfect
compliance’ calculation of 18–6%, 12–2% and
3–0.5%, respectively, are used (Trussellet al.,
1990). If we assume an average NDA database of
4000 patients, one-third or more female, it is likely
that half of these will be females of childbearing
potential (the other half being postmenopausal or
elderly). Thus, approximately 660 females of
childbearing potential may be exposed to the
drug, the comparator or a placebo. In the best
circumstances of perfect contraceptive compli-
ance, in a one-year exposure and at a 0.5% failure
rate, 3.3 fetuses are likely to be exposed. With a
‘typical compliance’ of the contraceptive pill, a 3%
failure ratewould leave about 19 fetuses exposed to
experimental entities, one-third of which would be
lost due to spontaneous miscarriage.
Few patients would be exposed for a full year,
but more typically only between two weeks and
three months of study medication. Given all the
above assumptions, between 0.8 and 5 early
embryos will be exposed in a full drug develop-
ment program. From the author’s personal experi-
ence of over 30 years in industry, an average of two
children are born exposed to a new chemical entity.
This is most likely to occur in phase III studies,
which have many more patients and are often of
longer duration. Currently, pharmaceutical firms,
with the agreement of the FDA, follow up all
possible exposures until any resultant child is 12–
14 years of age, and a full medical examination
(including a full neurological workup) is done at
yearly intervals.The potential for teratogenic damage
during drug study programsAs previously mentioned, the best sources for the
actual figures for the above calculations reside
within the FDA but may, as alluded, be inaccessible.
In recent years, figures given by the Agency, for
example in elderly drug-testing studies, appear to
have been hand-tallied rather than garnered from
composite computer access. However, the agency is
now involved in a large effort to ‘mine’ data across
therapeutic classes, some of which, with meta-
analysis, will provide data which individual drug
programsnevercould,norweredesignedtoshow.In
time, the ability to access data across drugs and
across drug classes will grow as more firms put in
computer-assisted NDAs (CANDAs) in appropriate
and compatible programs and formats. What is the
risk of a fetus being damaged during an ‘average’
NDA drug development program? Obviously small.
Clearly, toxic but ‘life-saving’ treatment will carry a
heavy embryotoxic risk; anticancer, anti-AIDS
drugs and fetal intrauterine surgical procedures are
obvious examples, but the clear-cut risks involved
are usually deemed acceptable. A more subtle judg-
ment call involves the development of antiepileptic
drugs. Let us look at two examples. It has been
estimated that exposure of pregnant women to nor-
mal therapeutic doses of valproic acid may give rise
to 1% fetal abnormality rate involving the neural
tube (Lindhaut and Schmidt, 1986) – 10 times the
natural incidence. Many of these defectsare correct-
able with modern surgical techniques. Exposure to
phenobarbitone also has a reported higher incidence
of cleft lip and palate defects (Frederick, 1973): most
are surgically correctible. If used in combination,16.3 THE PHANTOM FETUS 207