The enhanced pre‐ and postnatal study for nonhuman primates: Update and perspectives

Abstract

The enhanced pre- and postnatal (ePPND) study design has been developed in response to new scientific knowledge and subsequent guideline changes, that is, ICH M3(R2) and ICH S6(R1). The design changes were basically driven by the experiences obtained during preclinical development of biopharmaceuticals. The ePPND concept typically does not apply to pharmaceuticals. In essence, the ePPND design is a PPND study in which key elements of an embryofetal development (EFD) study are being investigated in newborns and infants rather than in the fetus. The current relevant nonhuman primate model is the cynomolgus monkey. The ICH S6(R1) has reached step 4 during June 2011 and provides detailed recommendations on various parameters and the conduct of an ePPND study. By the time this article is written, it appears that for monoclonal antibodies, the ePPND study is the preferred approach although ICH S6(R1) also leaves options for modified EFD and PPND study concepts. Our data also demonstrate that social housing is feasible for developmental toxicity studies in the cynomolgus monkey model.

Developmental and Reproductive Toxicity Testing

“…TK, toxicokinetic samples; BW, body weight collection; other, any other study parameter. Reproduced from Weinbauer et al [5] with permission.…”

“…On the other hand, in our experience, fetal measurements continue to be included in some ePPND studies. A large variety of parameters for the evaluation of infant development is available [5,9]. Recommended end points for an ePPND study are offspring viability and survival, neurobehavioral test battery, external malformations, skeletal effects (e.g., by radiography), and, ultimately, visceral morphology at necropsy.…”

“…In that case, a specific EFD study can be omitted, as per ICH M3(R2) [3] and ICH S6(R1), since the placental transfer of large molecules is assumed to be low during first trimester (organogenesis) and evaluation of potential external, visceral, and skeletal developmental abnormalities can be incorporated into the design of the PPND study as a postnatal assessment; this integrated design is known as an enhanced PPND (ePPND) study [4,5] and is described in detail in ICH S6(R1). ICH S6(R1) also acknowledges that functional fertility studies using NHPs are not routine if the NHP is the only pharmacologically relevant species and that reproductive parameters incorporated into chronic repeat-dose toxicity studies using sexually mature animals are appropriate in most instances.…”

The Development of Therapeutic Monoclonal Antibodies: Overview of the Nonclinical Safety Assessment

“…Alternatively, the enhanced PPND (ePPND) study design can be considered that combines both the EFD and PPND into one study [40]. The ePPND study allows for the evaluation of pregnancy outcome, viability, and external malformations at birth following a natural delivery.…”

Toxicity Testing in the 21st Century: Challenges and Perspectives

“…Due to the often exclusive species specificity of monoclonal antibodies, the nonhuman primate is in many cases the only relevant species for nonclinical safety assessment. Some areas for optimization have been identified [13,14] and some practical measures such as the inclusion of safety pharmacology endpoints in toxicology studies or the implementation of the so-called enhanced Pre-and Postnatal Development (ePPND) study design [15,16] in regulatory guidance documents, are already in place. Both approaches eliminate the need for stand-alone safety pharmacology or embryo-fetal development studies and thus reduce the number of animals used.…”