Masterstudiengang "Drug Regulatory Affairs"

Master-Thesis

Preclinical toxicity profiles of authorised medicinal products: analysis and comparison between short-term and long-term repeated dose toxicity studies in animals ***

Dr. Alex Savtschenko (Abschlußjahr: 2021)

Summary
Language: English
Currently, regulatory toxicity studies in animals play an important role in the development of new medicinal products and their safety assessment, representing the standard approach to support the marketing authorisation. International harmonisation of the duration of chronic toxicity testing (i. e. studies of six (6) months or longer) in animals had been a protracted process that eventually led to the development and adoption of regulatory guidelines on the recommended periods of repeated dose toxicity studies.
In general, repeated dose toxicity studies up to a maximum duration of six (6) months in rodents and nine (9) months in non-rodents are considered sufficient in the EU in support of marketing authorisation applications for the most medicinal products intended for chronic use. However, several published studies had questioned the added value of chronic toxicity testing of six (6) months or longer duration. This assumption has been challenged in the present analysis to aid in a better understanding of the utility of chronic toxicity studies of six (6) months or longer duration and their relevance for human safety evaluation. Thus, the fundamental objective of the present work was to critically evaluate the feasibility of gaining comparable levels of information from short term (4 to 8 weeks) and subchronic (3 months) repeated dose toxicity studies as with chronic toxicity testing (6 to 12 months).
The data originating from the European public assessment reports (EPAR) published on the website of the European Medicines Agency (EMA) laid the basis for this analysis. In this context, it was confirmed that publicly available sources contain pertinent information generally adequate to provide a reliable framework for drawing conclusions. Overall, toxicity profiles of 51 active substances were identified in the retrieved dataset of 469 EPARs and subsequently analysed in this study. For the key target organ classes examined in this analysis, a significant proportion of toxicity findings was first identified in the short term and/or subchronic repeated dose studies for many pharmaceuticals. Consequently, the results of this analysis and further literature reports support the thrust towards shorter term repeated dose toxicity studies as a growing body of evidence indicates that toxicity testing of one (1) month to three (3) months duration is largely sufficient to characterise the toxicity profile of the most potential drug candidates. Likewise, the evaluated data further strengthened the validity of using two (2) animal species – one rodent and one non rodent.
When comparing findings noted in chronic toxicity studies only with those listed in the summary of product characteristics (SmPC), this review also highlighted the ambiguity in the predictive power of toxic effects from chronic animal studies for the subsequent human safety assessment, demonstrating a degree of over  or underprediction of adverse effects in humans.
While acknowledging certain limitations of this review, the present study has further contributed to a more thorough understanding of the utility and range of abilities of chronic repeated dose toxicity studies, while promoting the development of advanced integrative testing approaches consistent with the principle of the 3Rs (replacement, reduction, and refinement).
Pages: 93
Annexes: 2, Pages: 3