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1. There are international differences in regulatory guidelines for the appropriate duration of chronic, two species repeat-dose animal tests for new medicines intended for long-term use in man, ranging from 6 months in Europe to 12 months in Japan and the USA. 2. An adequate data base is necessary to support any challenge to the scientific rationale behind regulatory guidelines with regard to the design, duration and relevance of toxicity tests of new medicines. 3. The Centre for Medicines Research has established an international toxicology data base which has been expanded to enable a comparison of data obtained within 6 months, with information from longer periods, for 154 studies. 4. Although new findings were revealed after 6 months for 9/75 cases for which pathology data are available at 6 and 12 months or longer, and 21/80 with data at 1 or 3 (but not 6 months) and 12 months or longer, in no instance did these influence the decision to drop or further develop the compounds in question. 5. These data suggest that a 6-month period of dosing is all that is routinely required for evaluating the chronic toxic (excluding carcinogenic) potential of a new chemical entity intended for therapeutic use.

A comparative retrospective survey of data from chronic toxicity studies has been carried out on 40 pharmaceutical compounds based on comprehensive information from 19 pharmaceutical companies. The results showed that no new salient toxicological effects were observed in tests of more than 6 months duration excluding carcinogenicity studies. Since no additional information was identified by dosing animals continuously for 12-18 months, the value of prolonging chronic toxicity studies in animals beyond 6 months should be carefully reassessed.

Recommendations for the minimum period of repeated dose administration to animals to support marketing authorization of pharmaceuticals vary from 6 months in the EEC to 18 months in Canada. The value of studies lasting longer than 6 months has not, however, been established. In order to enable retrospective analyses to be carried out, the Centre for Medicines Research has established a toxicology databank containing comprehensive data from repeated dose animal safety evaluation studies on 124 compounds, provided by 21 pharmaceutical companies in Europe (Lumley and Walker 1985a). There are 214 case studies (1 compound tested in 1 species for 1 or more time periods), and in 100 of these tests lasted for longer than 6 months. In 88 long-term studies comparable short-term data are available and these have been analysed to determine what new findings, if any, became apparent after 6 months. The data do not support the need for animal toxicity studies of longer than 6 months, apart from those designed to investigate carcinogenicity. Safety evaluation studies should be of value in predicting adverse drug reactions for man. Unless it can be established that these longer-term studies more accurately define potential target organ effects, the scientific rationale for conventional long-term studies must be questioned.

One method of assessing the contribution of studies of longer than 6 months to a safety evaluation program is to compare retrospectively the findings in toxicity tests carried out for 6 months or less with those observed after 6 months. The Centre for Medicines Research has therefore established a databank comprising animal toxicological data obtained from pharmaceutical companies in Europe. Twenty-one companies have provided data for 124 compounds (214 studies), including 88 studies of 65 compounds where comparable short-term (less than or equal to 6 months) and long-term (greater than 6 months) data are available. The results from the 88 studies show that, excluding the possibility of identifying carcinogens, tests of longer than 6 months have not added to the overall safety evaluation of these compounds.