Embryo-fetal development study

The critical period for the induction of hypospadias by finasteride in rats is Days 16 to 17 of gestation (Clark et al., 1990a). It is unlikely that other agents would have a much earlier critical period since testosterone synthesis, which is required for the development of the penile urethra, begins in the rat on Day 15 of gestation (Habert and Picon, 1984). Thus, if treatment in the embryo-fetal development study... 

Food consumption Toxicokinetics For fertility studies In-life observations Terminal and necroscopic evaluations For embryo-fetal development studies In-life observations... 

The combined fertility and embryo-fetal development study is described as a two study design in the ICH S5(R2) guideline (1) and is anticipated for use in rodents (usually rat but also the mouse) embryo-fetal development must still be evaluated in a second, nonrodent, species. 

However, combining different phases of the reproductive cycle into a single study design increases the risk of an adverse event compromising the evaluation of subsequent stages, e.g., any impact on fertility of the male or female could result in too few litters for the embryo-fetal development evaluation. Under such circumstances, a separate embryo-fetal development study would have to be scheduled with the associated added cost and use of animals. Further, a separate embryo-fetal development study is recommended if the test item is poorly tolerated with repeated dosing in order to limit the duration of the administration period. 

Embryo fetal Development Studies in Nonhuman Primates... 

Synopsis of parameters collected in cynomolgus and marmoset monkeys embryo fetal development studies... 

French Jet al (2010) Use of magnetic resonance imaging (MRI) and micro-computed tomography (micro-CT) in the morphological examination of rat and rabbit fetuses from embryo-fetal development studies. Reprod Toxicol 30 292-300... 

The embryo-fetal development study aims to detect adverse effects on pregnant females (i.e., maternal toxicity) and on the development of embryos and fetuses (i.e., embryo-fetal death, altered growth, and structural changes) consequent to exposure of the female during organogenesis. 

Historically, embryo-fetal development studies were mandatory to support inclusion of women of childbearing potential (WOCBP) in clinical trials. More recently, it has become admissible under appropriate circumstances to include WOCBP in early clinical trials before performing the embryo-fetal toxicity studies, provided that effective contraception is used. In Japan and Europe, data from adequately designed preliminary embryo-fetal toxicity studies, with as few as six females per group, may be used to support the inclusion of WOCBP in short-term clinical trials (18). The predictivity of such preliminary mammalian studies has not been established (see below), but it could be argued that they may be less predictive than alternative methods such as FETAX. We therefore expect FETAX to play an evermore important role in pharmaceutical development in the future. 

Cappon GD, Fleeman TL, Rocca MS, et al. Embryo/fetal development studies with hydroxypropyl methylcellulose acetate succinate (HPMCAS) in rats and rabbits. Birth Defects Res (Part B) 2003 68 421. 

Reproductive toxicology, usually embryo/fetal development studies in two species, are required in Europe and Japan if women of child-bearing potential are included. Not required in the US for some early trials. Mutagenicity-m vitro tests for mutagenicity and chromosome damage. 

Rabbit New Zealand White, SPF, Oryctolagus cuniculus female Reproductive studies including range finding studies in pregnant rabbits, embryo-fetal development study, teratogenecity studies... 

---