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 1–4, several quantitative estimates are desirable. These include the no-effect dose—the maximum dose at which a specified toxic effect is not seen; the minimum lethal dose—the smallest 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 in a test group. 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 testing. 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 preclinical data. Scientists are properly concerned about this situation, and progress has been made toward reducing the numbers required while still obtaining valid data. Cell and tissue culture in vitro methods and computer modeling are increasingly being used, but their predictive value is still limited. Nevertheless, some segments of the public attempt to halt all animal testing in the unfounded belief that it has become unnecessary.
3.
Extrapolations of toxicity data from animals to humans are reasonably predictive for many but not for all toxicities.
4.
For statistical reasons, rare adverse effects are unlikely to be detected in preclinical testing.
TABLE 1–4 Safety tests.
A very small fraction of lead compounds reach clinical trials, and less than one third of the drugs studied in humans survive clinical trials and reach the marketplace. Federal law in the USA and ethical considerations require that the study of new drugs in humans be conducted in accordance with stringent guidelines. Scientifically valid results are not guaranteed simply by conforming to government regulations, however, and the design and execution of a good clinical trial require interdisciplinary personnel including basic scientists, clinical pharmacologists, clinician specialists, statisticians, and others. The need for careful design and execution is based on three major confounding factors inherent in the study of any drug in humans.
A. The Variable Natural History of Most Diseases
Many diseases tend to wax and wane in severity; some disappear spontaneously, even, on occasion, cancer. A good experimental design takes into account the natural history of the disease by evaluating a large enough population of subjects over a sufficient period of time. Further protection against errors of interpretation caused by disease fluctuations is sometimes provided by using a crossover design, which consists of alternating periods of administration of test drug, placebo preparation (the control), and the standard treatment (positive control), if any, in each subject. These sequences are systematically varied, so that different subsets of patients receive each of the possible sequences of treatment.
B. The Presence of Other Diseases and Risk Factors