The timing of preclinical toxicological studies: pharmaceutical company approaches to toxicity testing in support of initial clinical investigations.

The completion of preclinical toxicity studies to support the first administration to humans is a time-critical step in the clinical development of medicines, and is complicated by differences in national regulatory requirements. A questionnaire-based study was carried out in 1994 to ascertain pharmaceutical companies' actual practices and views on an ideal approach to the timing of different types of nonclinical safety studies in relation to clinical investigation. Forty-one companies or their subsidiaries from Europe, Japan, and the United States responded by providing data. A range of preclinical packages were indicated as being used by companies prior to initiating Phase I clinical trials. The selection of studies tended to be based on the recommendations of the regulatory authority of the region in which the respondents were located. Differences were evident regarding the extent of genetic toxicity testing, the duration of repeat-dose toxicity studies, and the need for male fertility testing to support the first single administration of a compound to humans. In an ideal situation, the respondents would have preferred to conduct shorter duration repeat-dose toxicity studies prior to the first single administration to humans than was their actual practice in 1994. A harmonized guideline on the timing of toxicity studies in relation to clinical trials will allow better integration between clinical and nonclinical studies in an international development program. However, the diversity in the responses has demonstrated the need for flexibility in any future guideline.