Pre-Marketing Sources of Data Regarding Reproductive and Developmental Safety of Prenatal Drug Exposures
PRE-MARKETING SOURCES OF DATA
REGARDING REPRODUCTIVE AND DEVELOPMENTAL SAFETY OF PRENATAL DRUG EXPOSURES
The
traditional methods for evaluating drug safety in the pre-marketing phases of
drug development, i.e. animal reproductive and developmental toxicity studies
and randomized clinical trials, have limited application with respect to human
pregnancy.
Reproductive
and developmental toxicity studies conducted in selected animal species provide
the first source of information about potential human risks for a variety of
pregnancy outcomes. Results of these experiments are considered in the context
of existing knowledge about the reproductive or developmental effects of
similar chemical entities and the presence or absence of any theoretical
concerns due to the drug’s mechanisms of action or pharmacologic properties. On
the basis of this overall evaluation, a new drug can be marketed with
reassurances that the animal data do not raise concerns about human pregnancy
exposure, or conversely, with the recommendation that until human data are
available, pregnancy should be avoided (Moore et al., 1995). However, there can be differences in the sensitivity
and human compara-bility of the various animal species that are selected for
toxicity testing; there may be differences in the dose, route of administration
and metabolism in the animal model relative to usual human clinical use; and
maternal toxic effects in the test species may play a role. For these and other
reasons, there are limitations to the predictive value of these pre-clinical
studies for human pregnancy exposures and outcomes (Brent, 1986; Scialli et al., 2004). Thus, human pregnancy
data are ultimately necessary to establish human preg-nancy drug safety.
Clinical
trials are the second traditional method of evaluating drug safety. For obvious
ethical reasons, pregnant women typically are not recruited for trials during
any phase of drug development. If and when unintended pregnancies occur during
the course of a trial or post-marketing study, pregnancy outcomes can provide
useful preliminary information regard-ing the risks of exposure (O’Quinn et al., 1999). However, these data
usually involve a small number of subjects. There is a trend to include larger
numbers of women of childbearing age in clinical trials, and this will
undoubtedly result in a larger number of exposed pregnancies in such trials.
Nevertheless, these numbers are likely to be too small to provide mean-ingful
information.
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