Toxicology guidelines, study requirements

GLP regulations require confirmation of the potency of all formulations used in nonclinical studies. Furthermore, current ICH guidelines also require toxicokinetic data (i.e. animal pharmacokinetics determined at one or more time points during a nonclinical toxicology study). Both the potency and the toxicokinetic assays require an analytical method to determine the parent drug... 

In Japan, there has been harmonization with the other regions in the area of toxicology (animal studies) the Japanese Ministry of Health, Labor and Welfare (MHLW) accepts appropriate foreign animal data and animal safety studies performed according to ICH guidelines. Indeed, Japan has played a major role, and its then current fertility and reproductive animal studies requirements have been adopted by the other two regions. 

The registration process has inexorably slowed. In the re-proposed toxicology guidelines, in addition to the major new test requirements, applicants are now directed to submit much of their original or raw data which was, in times past, only presented in summary. We have estimated that in one long-term rat study, including the tabulation and summarization of data, individual data points may exceed 500,000. 

These procedures outlined are not all-encompassing and should serve only as guidelines. Additionally, the end use of the extract (i.e., biochemical studies, analytical methodology, toxicological studies) will have a large effect on the required purity of the final product. Some uses need only water extraction while others need a more rigorous clean-up procedure with methods outlined in Chapter 3. 

The nature, timing, and extent of the initial nonclinical toxicology effort must be consistent with the clinical development plan that it must support. The ICH guidelines further specify the extent and duration of nonclinical studies that are required to initiate or continue clinical studies. Therefore, it is important that the clinical development plan, at least the initial stages, be clearly delineated so that clinical studies are not delayed owing to the lack of appropriate nonclinical studies. 

Toxicokinetics has become a critically important component of any nonclinical program (see discussion in Section 14.10). Current ICH guidelines require the determination of animal pharmacokinetics at all dose levels administered on at least 2 days (beginning and end) during a nonclinical toxicology study.5 Similarly, this requires the development of a validated analytical method for the determination of parent drug (and possible major metabolites). 

Guideline Section 2 specifies that only mammalian species are to be used in the studies to be described. The rat is noted as being generally the most practical choice. A second species is traditionally required, and the rabbit is the preferred choice. Other species or a second rodent species may be used on a case-by-case basis. Note 5 associated with Section 2 points out that a single species can be sufficient if kinetic, pharmacological, and toxicological data show it to be a relevant model for the human. However such a complete set of data are very rarely available prior to the time such studies are needed. 

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