The cynomolgus monkey as a model for developmental toxicity studies: variability of pregnancy losses, statistical power estimates, and group size considerations

Abstract

For designing and managing primate developmental toxicity studies, this type of analysis provides an objective tool to facilitate decisions either by supplementing groups with additional pregnant animals or stopping a group because an adverse effect on offspring survival has already been adequately revealed.

Developmental and Reproductive Toxicity Testing

“…An earlier review of the cynomolgus monkey reported abortion rates between 11.7% and 30.2% [54], which seem comparable to more recent observations of 8.8-20.3% cumulative prenatal loss rates [9]. In the context of developmental toxicity evaluation, however, it is important to recognize that-unlike cumulative loss rates-prenatal loss rates among vehicle groups in single studies can be highly variable and range from zero to >40% [28]. Early losses can be difficult to interpret, in part because the GD 18-20 pregnancy is typically diagnosed by the presence of a gestational sac, yet a fetal heartbeat cannot be visualized until 1-2 weeks later.…”

“…Per ICH M3(R2), evaluation of fertility is typically required before initiating phase III trials and/or conducted in parallel with phase II trials. Whereas the guidelines recommend physical mating for evaluation of fertility, this is not being done routinely in NHPs for two main reasons: (1) Typically, fertility rates in macaques are clearly <100% (typically 25-45% per cycle and approximately 60% per animal, preimplantation losses are around 25%) [27], and prenatal losses can be as high as 40% [9,28] and (2) While evaluation of implantation sites is a hallmark of rodent fertility studies, this normal fertility end point is not meaningful in macaques, in which there is normally a single implantation site that is then often lost shortly after implantation. Twin pregnancies/births are extremely rare in macaques, with an overall incidence of twin live births around 0.1% [29,30].…”

“…Infant losses in the first month after delivery range from 12% to 22%, with the possibility of a similar amount of additional infant loss during the first year postpartum [54,56]. A detailed analysis of >700 control pregnancies identified the period until GD 50 (first trimester) and the birth event as the most critical periods for losses in cynomolgus monkeys [28]. A specific analysis performed to explore the influence of initial group size on the potential for data interpretation in macaque studies using the end points of embryo/fetal survival and infant survival until postnatal day 7 indicated that average loss rate until postnatal day 7 was 35% [28].…”

“…A detailed analysis of >700 control pregnancies identified the period until GD 50 (first trimester) and the birth event as the most critical periods for losses in cynomolgus monkeys [28]. A specific analysis performed to explore the influence of initial group size on the potential for data interpretation in macaque studies using the end points of embryo/fetal survival and infant survival until postnatal day 7 indicated that average loss rate until postnatal day 7 was 35% [28]. EFD studies with initial control group sizes of 16 and 20 have an 80% probability of having 13-16 ongoing pregnancies at GD 100, respectively.…”

Developmental and Reproductive Toxicology

“…The duration of the postnatal phase will be dependent on which additional end-points are considered relevant for the pharmacological activity. The numbers of confirmed pregnant cynomolgus monkeys per group should be sufficient to detect threefold increase in pregnancy/ parturition-associated losses with 80% power with 95% confidence interval (Jarvis et al, 2009). The sponsor should justify the study design if other NHP species are used.…”