Embryo-fetal developmental toxicity study design for pharmaceuticals.
Assessment of potential developmental and reproductive toxicity of human pharmaceuticals is currently guided by the International Conference on Harmonization (ICH) S5(R2) document (available at http://www.ich.org). The studies that assess developmental hazard are generally conducted in rodents and rabbits. Based on the authors' collective experience, adequate designs (including range-finding studies) and the presentation of data for these studies are described in detail. In addition, the suggested initiation and then total duration of these studies in relation to clinical studies that enroll women of childbearing potential are described. Optional parameters that may be included in the studies are discussed, as are study designs that combine assessments of fertility and developmental toxicity. New methods that may replace or enhance current procedures are outlined. The details described herein will assist all laboratories performing these studies, individuals who need to plan for the studies, and regulatory agencies that ultimately review these studies.
Wise
L David
LD
Merck Research Laboratories, West Point, Pennsylvania 19486, USA. ld_wise@merck.com
Buschmann
Jochen
J
Feuston
Maureen H
MH
Fisher
J Edward
JE
Hew
Kok Wah
KW
Hoberman
Alan M
AM
Lerman
Steven A
SA
Ooshima
Yojiro
Y
Stump
Donald G
DG
D000014:Abnormalities, Drug-Induced; D000818:Animals; D017849:Animals, Inbred Strains; D004353:Drug Evaluation, Preclinical; D064420:Drug-Related Side Effects and Adverse Reactions; D047108:Embryonic Development / Q000187:drug effects*; D005260:Female; D047109:Fetal Development / Q000187:drug effects*; D007390:International Agencies; D007391:International Cooperation; D008297:Male; D018811:Maternal Exposure; D051379:Mice; D011817:Rabbits; D051381:Rats; D012107:Research Design; D018675:Toxicity Tests / Q000379:methods*