Scientific and Regulatory Policy Committee Points to Consider Review

Abstract

Standard components of nonclinical toxicity testing for novel pharmaceuticals include clinical and anatomic pathology, as well as separate evaluation of effects on reproduction and development to inform clinical development and labeling. General study designs in regulatory guidances do not specifically mandate use of pathology or reproductive endpoints across all study types; thus, inclusion and use of these endpoints are variable. The Scientific and Regulatory Policy Committee (SRPC) of the Society of Toxicologic Pathology (STP) formed a Working Group to assess the current guidelines and practices on the use of reproductive, anatomic pathology and clinical pathology endpoints in General, Reproductive, and Developmental toxicology studies. The Working Group constructed a survey sent to pathologists and reproductive toxicologists, and responses from participating organizations were collected through the STP for evaluation by the Working Group. The regulatory context, relevant survey results, and collective experience of the Working Group are discussed and provide the basis of each assessment by study type. Overall, the current practice of including specific endpoints on a case-by-case basis is considered appropriate. Points to consider are summarized for inclusion of reproductive endpoints in general toxicity studies, and for the informed use of pathology endpoints in reproductive and developmental toxicity studies.

A brief review of kidney development, maturation, developmental abnormalities, and drug toxicity: juvenile animal relevancy

“…For instance, pups can’t be removed from dams before weanling and sampling of blood or urine volume may not yield quantities sufficient for normal testing clinical determinations. Other concerns might involve the most appropriate type of testing methodology to use and the need for age-matched historical control samples 13 .…”

“…The interest and increased numbers of juvenile animal toxicity tests reflect a growing need to predict chemical hazards in pediatric populations 12 . Juvenile kidney studies are emphasized because of the kidney’s ongoing postnatal periods of development and maturation 13 . Nonclinical study protocols designed to evaluate juvenile kidneys may contain procedures, end-points, and histological requirements that are unique for each study and dependent on the drug under investigation.…”

International Harmonization of Nomenclature and Diagnostic Criteria (INHAND): Nonproliferative and Proliferative Lesions of the Dog

“…A survey by a Working Group of the Scientific and Regulatory Policy Committee of the STP showed that pathologists prefer the terms "immature" and "mature" and also use the term "peripubertal." 145 However, some institutions may only record sexual immaturity since the default is reproductive maturity. The Canine Nonrodent Working Group of the INHAND project recommends that for nonclinical studies the state of sexual maturity should be recorded as "mature" when sexually mature and "immature" or "peripubertal" when sexually maturity has not been reached.…”

“…140 Pathologists usually identify testicular maturation by spermatogenesis (ie, presence of elongating spermatids) and epididymal tail containing spermatozoa. 144,145 Immature prostatic acini have narrow, undeveloped lumina lined by basophilic epithelium that is cuboidal to flattened with a high nuclear to cytoplasmic ratio. 49,143 The amount of connective tissue is relatively higher in the immature prostate than the mature prostate.…”

Histomorphological description of the reproductive system in mated honey bee queens

“…microscopic structures of the queen's reproductive tract and provides a visual example of each structure. Histological evaluation of reproductive histopathology is an essential step in toxicological risk assessment in vertebrate species, especially so in pharmaceutical drug development (Halpern et al, 2016) as well as in theriogenology research. Accordingly, the comprehensive characterization and illustration of normal light microscopic morphology of the entire reproductive tract of the honey bee queen performed in the current study is anticipated to serve as a reference for the future histopathological investigations of reproductive problems affecting honey bee queens.…”