PRECLINICAL SAFETY & TOXICITY TESTING
All drugs are toxic in some individuals at some dose. Seeking to cor-rectly define the limiting toxicities of drugs and the therapeutic index comparing benefits and risks of a new drug is an essential part of the new drug development process. Most drug candidates fail to reach the market, but the art of drug development consists of effective assessment and management of risk versus benefit and not total risk avoidance.Candidate drugs that survive the initial screening procedures must be carefully evaluated for potential risks before and during clinical testing. Depending on the proposed use of the drug, pre-clinical toxicity testing includes most or all of the procedures shown in Table 5–1. Although no chemical can be certified as completely “safe” (free of risk), the objective is to estimate the risk associated with exposure to the drug candidate and to consider this in the context of therapeutic needs and likely duration of drug use.The goals of preclinical toxicity studies include identifying potential human toxicities, designing tests to further define the toxic mechanisms, and predicting the most relevant toxicities to be monitored in clinical trials. In addition to the studies shown in Table 5–1, several quantitative estimates are desirable. These include the no-effect dose—the maximum dose at which a speci-fied toxic effect is not seen; the minimum lethal dose—the small-est dose that is observed to kill any experimental animal; and, if necessary, the median lethal dose (LD50)—the dose that kills approximately 50% of the animals. Presently, the LD50 is estimated from the smallest number of animals possible. These doses are used to calculate the initial dose to be tried in humans, usually taken as one hundredth to one tenth of the no-effect dose in animals.
It is important to recognize the limitations of preclinical test-ing. These include the following:
1. Toxicity testing is time-consuming and expensive. Two to 6 years may be required to collect and analyze data on toxicity before the drug can be considered ready for testing in humans.
2. Large numbers of animals may be needed to obtain valid pre-clinical data. Scientists are properly concerned about this situ-ation, and progress has been made toward reducing the numbers required while still obtaining valid data. Cell and tis-sue culture in vitro methods and computer modeling are increasingly being used, but their predictive value is still lim-ited. Nevertheless, some segments of the public attempt to halt all animal testing in the unfounded belief that it has become unnecessary.
3. Extrapolations of therapeutic index and toxicity data from animals to humans are reasonably predictive for many but not for all toxicities. Seeking an improved process, a Predictive Safety Testing Consortium of five of America’s largest pharma-ceutical companies with an advisory role by the Food and Drug Administration (FDA) has been formed to share internally developed laboratory methods to predict the safety of new treatments before they are tested in humans. In 2007, this group presented to the FDA a list of biomarkers for early kid-ney damage.
4. For statistical reasons, rare adverse effects are unlikely to be detected in preclinical testing.