For decades, the requirements for determining the toxicological profile of a new chemical entity (NCE) through a safety assessment study were well-defined. But advances in research brought about novel entities, bringing new challenges to toxicology testing.
Biopharmaceuticals introduced many of these challenges in the 1980s. Half-lives for these larger molecules were measured in days, not minutes or hours. Existing guidelines were inappropriate as a result and traditional study designs/approaches had to be reconsidered. Details such as animal model selection, dosing frequency, duration of dosing and recovery periods were rethought and regulatory agencies issued “points to consider.” In 1997, harmonized guidelines (ICH S6) were issued that better defined biologics and provided guidance on the relevance of certain studies within a development program. The guidelines were a significant step forward, but there were many areas of ambiguity. The lack of clarity drove industry to default to NCE approaches, which in hindsight weren’t always the most appropriate.
We have learned a great deal since biopharmaceuticals were introduced, such as the importance of selecting pharmacologically relevant models, the importance of immunogenicity determinations in correlation with the exposure evaluation as well as study finding interpretation. We also know that the risks and significance of immunogenic responses should be considered as well as the immunomodulatory potential. In 2011, these and other considerations were incorporated into an addendum to the ICH S6 guidelines (ICH S6R1).
Recent advances in technology have also led to changes in study designs. In the clinic, for instance, cardiovascular changes can be monitored in humans during clinical research and/or under some cardiac disease conditions using devices such as Holter monitors to capture heart rates and wave forms. Advancements in technology have also led to non-invasive telemetry devices, which use radio transmission to capture cardiovascular hemodynamic parameters in animal models and can now be used within a toxicology study. In a toxicology study, these telemetry devices can be more appropriate in some instances, such as with biopharmaceuticals where the monitoring of effects following repeat administration is more relevant. In addition to these advances, more translational biomarkers are being validated as the use of pharmacologically relevant species presents more opportunities to monitor these clinically relevant endpoints. Many labs, including Charles River, are finding ways to monitor pharmacodynamics and adverse modulations related to exaggerated pharmacology.
Advances with in vitro assays are helping greatly in the characterization of new molecules. Their optimization and improved sensitivity are also supporting the application of the 3Rs (Replacement, Refinement and Reduction). At Charles River, we’re reducing the use of animals in studies using minimal blood volumes and microsampling techniques in clinical pathology and pharmacokinetics/toxicokinetics. Microsampling has gained significant momentum recently and may perhaps become the default procedure in the future. The continued development of animal models is also an important area of focus. Multiple factors influence responses to treatments, including genetic variability, health status as well as environmental, emotional and psychological factors.
Over the years, knowledge sharing has increased through conferences, consortiums and committees. Such collaborative efforts have generated publications, databases and case studies that will likely facilitate the industry’s increased awareness of “personalized medicine,” where practitioners use an individual’s genetic profile to prevent, diagnose and treat disease. This sharing of knowledge should advance research and development forward and help overcome future obstacles in toxicology testing.