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 ad ministration to humans is a time-critical step in the clinical develop ment of medicines, and is complicated by differences in national regul atory requirements. A questionnaire-based study was carried out in 199 4 to ascertain pharmaceutical companies' actual practices and views on an ideal approach to the timing of different types of nonclinical saf ety studies in relation to clinical investigation. Forty-one companies or their subsidiaries from Europe, Japan, and the United States respo nded by providing data. A range of preclinical packages were indicated as being used by companies prior to initiating Phase I clinical trial s. The selection of studies tended to be based on the recommendations of the regulatory authority of the region in which the respondents wer e located. Differences were evident regarding the extent of genetic to xicity testing, the duration of repeat-dose toxicity studies, and the need for male fertility testing to support the first single administra tion of a compound to humans. In an ideal situation, the respondents w ould have preferred to conduct shorter duration repeat-dose toxicity s tudies prior to the first single administration to humans than was the ir actual practice in 1994. A harmonized guideline on the timing of to xicity studies in relation to clinical trials will allow better integr ation between clinical and nonclinical studies in an international dev elopment program. However, the diversity in the responses has demonstr ated the need for flexibility in any future guideline. (C) 1996 Academ ic Press, Inc.