The Role of Histopathology and Clinical Pathology in Integrated Toxicology Reports

During drug development, histopathologists and clinical pathologists play important roles in the evaluation of toxicology studies. Close discussion and collaboration between experts from different fields and the study director is the key to generating a comprehensive toxicology report of high scientific value. In order to accurately reflect all the data in the final report, the study director must integrate all the findings, including PK and expected PD, with the professional opinions of contributing scientists. During the early phase of toxicology studies, contributing clinical and anatomic pathologists use their knowledge and experience of clinical pathology and morphological changes to identify target organ toxicity. This information is then provided to the sponsor for further late phase or GLP toxicology studies.

In QPS Taiwan’s Center for Toxicology and Preclinical Sciences (CTPS), experienced, well-trained clinical- and histopathologists are on-site, full-time. Their immediate availability makes close collaboration among individual contributing scientists and study directors convenient and workable for all studies. Understanding the importance of integrated reports, most sponsors have come to expect such collaboration even for early phase toxicology reports.

In 7-day rodent and non-rodent studies of a drug of known mechanism, the following findings were observed at higher dose levels:

  • Clinical Pathology: Liver - increases in ALT, AST, ALP, γ-GT, T-BIL, D-BIL and CHO
  • Macroscopic Pathology: Liver – discoloration; testis - reduced weight and size
  • Microscopic Pathology: Liver – necrosis; cholestasis and bile duct proliferation; testis – degeneration of seminiferous tubules (findings classified as class effects since these toxicities were well documented in the literature with other drugs in this class)

Following these findings, discussions within the study team, including the sponsor, led to critical modifications regarding future study designs. These included: 1) reduction of the high dose level for the pivotal GLP study, 2) addition of more clinical pathology time points to better monitor and evaluate the reversibility of liver function for the subsequent GLP study, and 3) extension of the recovery phase in order to sufficiently evaluate the reversibility of the observed test article-related testicular effects.



Walter Bee, PhD; VP; Head of Global Safety Assessment and Regulatory Affairs

QPS CTPS Taiwan 
Yasuo Mori, MSc, DABT, DJST, LATG; Associate Director, Toxicology 
Patricia Lin, DVM, DACVP; Director, Pathology 
Chris Tseng, DVM; Head of Clinical Pathology and Veterinary Services 
Charlene Chen, ScD; Senior Director of CTPS

20 years in pharma R&D navigation