Limitations of Animal Studies for Predicting Toxicity in Clinical Trials: Is it Time to Rethink Our Current Approach?

Abstract

Animal testing is used in pharmaceutical and industrial research to predict human toxicity, and yet analysis suggests that animal models are poor predictors of drug safety in humans. The cost of animal research is high-in dollars, delays in drug approval, and in the loss of potentially beneficial drugs for human use. Human subjects have been harmed in the clinical testing of drugs that were deemed safe by animal studies. Increasingly, investigators are questioning the scientific merit of animal research. This review discusses issues in using animals to predict human toxicity in pharmaceutical development. Part 1 focuses on scientific concerns over the validity of animal research. Part 2 will discuss alternatives to animal research and their validation and use in production of human pharmaceuticals.

Keywords: FDA, U.S. Food and Drug Administration; LR, likelihood ratio; NLR, negative likelihood ratio; NPV, negative predictive value; PLR, positive likelihood ratio; PPV, positive predictive value; animal research; drug development; toxicity; translational research.

Graphical abstract

Figure 1

Failures in Translational Research: Preclinical and Clinical Trials Percentages of drugs that fail in preclinical trials (due to drug toxicity or failure of efficacy in animal testing) and in clinical trials (due drug toxicity or failure of efficacy in human testing) are shown in columns 1 and 2. The third column demonstrates what would happen if animal and human toxicity were closely correlated and therefore drugs with human toxicity were eliminated at the preclinical testing stage by animal toxicity testing (one-half of all drug failures in clinical trials are due to toxicity issues despite safety in animals). Success rates of clinical trials increase from 11.7% overall to approximately 56%.

Figure 2

Toxicity Failures in Pharmaceutical Development

Figure 3

Calculating LR The likelihood that a test showing toxicity in a mouse predicts toxicity in the rat (positive likelihood ratio [PLR]) or that a test showing no toxicity in a mouse predicts nontoxicity in a rat (negative likelihood ratio [NLR]). M⁺R⁺ = toxicity present in both mouse and rat; M⁺R⁻ = toxicity present in mouse but not in rat; M⁻R⁺ = toxicity not present in mouse, but present in rat; and M⁻R⁻ = toxicity not present in mouse and also not present in rat.