Scientific and Regulatory Policy Committee Points to Consider: Histopathologic Evaluation in Safety Assessment Studies for PEGylated Pharmaceutical Products

• Published in: Toxicologic pathology 2018-08, Vol.46 (6), p.616-635
• Main Authors: Irizarry Rovira, Armando R., Bennet, Bindu M., Bolon, Brad, Braendli-Baiocco, Annamaria, Chandra, Sundeep, Fleurance, Renaud, Garman, Robert, Hutto, David, Lane, Joan, Romeike, Annette, Sargeant, Aaron, Zimmerman, Bevin
• Format: Article
• Language: English
• Subjects: Animals; Consumer Product Safety - standards; Drug Evaluation, Preclinical - standards; Drug-Related Side Effects and Adverse Reactions - etiology; Drug-Related Side Effects and Adverse Reactions - pathology; Organ Specificity; Pharmaceutical Preparations - chemistry; Pharmaceutical Preparations - metabolism; Policy Making; Polyethylene Glycols - chemistry; Polyethylene Glycols - pharmacokinetics; Polyethylene Glycols - toxicity; Tissue Distribution; Vacuoles - drug effects; Vacuoles - metabolism; Vacuoles - ultrastructure
• ISSN: 0192-6233; 1533-1601
• DOI: 10.1177/0192623318791801

Colorless, intracytoplasmic vacuoles occur in multiple tissues in animals following repeated administration of polyethylene glycol (PEG)-conjugated molecules. The extent of vacuolation depends on physical characteristics and molecular backbone of the PEG and the dose, product, drug target/pharmacology, and duration of exposure. The collective experience gathered from multiple nonclinical toxicology studies of PEGylated biopharmaceuticals indicates that in general, PEG-related vacuolation is not associated with demonstrable cell and tissue damage or dysfunction and is reversible with sufficient duration of drug-free periods. Existing data are insufficient to predict whether nonclinical animal species differ in their sensitivity to develop PEG-associated vacuoles; however, recent data suggest that there may be species differences. Recent comprehensive reviews have addressed the basic challenges in developing PEGylated pharmaceutical products, including general reference to and description of PEG-associated tissue findings. These manuscripts have identified gaps in our current understanding of PEG-associated vacuolation, including the lack of a widely accepted standardized histological terminology and criteria to record and grade the severity of vacuolation as well as insufficient knowledge regarding the nature of the contents of these vacuoles. The goal of this article is to help address some of the gaps identified above by providing points to consider, including a pictorial review of PEG-associated microscopic findings, when evaluating and reporting the extent, severity, and significance (adversity or lack of adversity) of PEG-associated cytoplasmic vacuolation in safety assessment studies. Note: This Points to Consider article is a product of a Society of Toxicologic Pathology (STP) Working Group commissioned by the Scientific and Regulatory Policy Committee (SRPC) of the Society of Toxicologic Pathology (STP). It has been reviewed and approved by the SRPC and Executive Committee of the STP, but it does not represent a formal best practice recommendation of the Society; rather, it is intended to provide key “points to consider” in designing studies or interpreting data from toxicity and safety studies intended to support regulatory submissions. The opinions expressed in this document are those of the authors and do not reflect views or policies of the employing institutions. Readers of Toxicologic Pathology are encouraged to send their thoughts on these ar