5.1. Overview of Nonclinical Safety Assessment
The goal of drug development is to identify safe and efficacious treatments for human diseases. Safety and efficacy are assessed through careful evaluation in animal models and in vitro systems (nonclinical setting) and in exposed human populations (clinical setting) throughout drug development and post-marketing. This chapter focuses on the design and analysis of studies that are integral to nonclinical safety assessment.
The objectives in nonclinical safety assessment are to define the toxicity profile of candidate drugs, estimate the margin of safety by understanding the relationship between toxic exposures and efficacious exposures, and provide a judgment on the likelihood that the animal findings can be extrapolated to humans. These assessments are important
prior to candidate selection because they provide internal decision-makers with a probability of technical success for the new compound,
during clinical development because they protect the safety of individuals in clinical trials, and
during the post-marketing phase because they support alternative formulations or clinical indications or further investigation of newly discovered safety issues.
It is beyond the scope of this chapter to consider all questions asked in nonclinical studies; however, a few questions are particularly central to safety assessment. These include:
What dose or plasma exposure of the experimental drug is not associated with any adverse outcome (i.e., the no observed adverse effect level, or NOAEL)?
What dose or plasma exposure of drug does not result in any observed biological effect (i.e., the no observed effect level, or NOEL)?
What is the nature of the dose-response relationship? For example, how steep is the dose-response curve as judged by the difference between the NOAEL and the MTD, or is the response monotonic or nonmonotonic?
What are the target organs of toxicity?
Are the toxicities monitorable? That is, are there antemortem measures that are predictive of tissue pathology?
Are the toxicities reversible?
Most of the studies designed to answer the questions above are mandated by regulatory agencies worldwide. Guidance documents for pharmacology and toxicology are available electronically via the Food and Drug Administration (FDA), European Medicines Agency (EMEA), and the International Conference on Harmonization (ICH) Web sites. These guidance documents assist in determining the relevant single-dose, repeat-dose, genetic toxicity, safety pharmacology (e.g., central nervous system, cardiovascular, and respiratory) studies, immunotoxicity, reproductive/developmental, and carcinogenicity studies as well as the necessary studies to ensure adequate quality of the formulated material (e.g., impurity qualification). Other studies to examine more closely certain mechanisms of toxicity or compound-specific issues are conducted as needed.