title: The predictivity of preliminary embryo-fetal development (EFD) studies: results of a retrospective survey in Japanese pharmaceutical companies.
abstract: To explore the predictivity of dose range-finding (DRF) studies, we conducted asurvey by sending out questionnaires to 72 Japanese pharmaceutical companies.The survey yielded data for 108 and 85 compounds for which any embryo-fetaldevelopment (EFD) toxicities were observed in the definitive studies in rodentsand non-rodents, respectively. As a result of the analysis, 83% of studies inrodents and 80% in non-rodents showed EFD effects in the DRF studies. Whenfocusing on teratogenicity, 91% of studies in rodents and 100% in non-rodentswere judged "positive" in the DRF studies when all EFD toxicities were used asmarkers. When the effects of both the rodent and non-rodent studies wereevaluated together, the combination predictive value in the DRF studies was 96%for EFD toxicants and 100% for teratogens. To evaluate the influence of theexamination items, the predictive value was analyzed using 54 compounds forwhich full examinations (external, visceral and skeletal examination) wereconducted in both rodent and non-rodent DRF studies. When the results werejudged by including or excluding skeletal and visceral examinations results,the predictive values were not significantly different. In conclusion, theresults of this survey showed that a pair of the DRF studies in the rodents andnon-rodents is useful to increase the predictivity of DRF studies. In additionthe inclusion of observations such as fetal survival, body weight and externalexamination into the DRF studies are important to predict effects in thedefinitive studies.
authors.affiliation: Non-Clinical Evaluation Subcommittee, Drug Evaluation Committee, Japan Pharmaceutical Manufactures Association, Tokyo. noriko-okahashi@ds-pharma.co.jp
authors.forename: Noriko
authors.initials: N
authors.lastname: Okahashi
authors.forename: Takashi
authors.initials: T
authors.lastname: Ikeda
authors.forename: Shuichi
authors.initials: S
authors.lastname: Kai
authors.forename: Shinichi
authors.initials: S
authors.lastname: Komatsu
authors.forename: Hajime
authors.initials: H
authors.lastname: Matsui
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Yamashita
authors.forename: Keiji
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Fumio
authors.initials: F
authors.lastname: Sagami
mesh_terms: D000014:Abnormalities, Drug-Induced; D000818:Animals; D004305:Dose-Response Relationship, Drug; D064420:Drug-Related Side Effects and Adverse Reactions; D047108:Embryonic Development / Q000187:drug effects*; D005313:Fetal Death / Q000139:chemically induced; D047109:Fetal Development / Q000187:drug effects*; D020567:Fetal Weight / Q000187:drug effects; D051379:Mice; D010865:Pilot Projects; D011237:Predictive Value of Tests; D011817:Rabbits; D051381:Rats; D012189:Retrospective Studies; D011795:Surveys and Questionnaires; D013723:Teratogens / Q000145:classification / Q000633:toxicity*; D018675:Toxicity Tests; D015262:Xenobiotics / Q000145:classification / Q000633:toxicity*
chemical_list: D013723:Teratogens; D015262:Xenobiotics