Toxicological Sciences, Vol 49, 143-155, Copyright © 1999 by Society of Toxicology
JJ DeGeorge, LL Meyers, M Takahashi and JF Contrera
At the present time, there are no uniform standards for the duration of
non-rodent chronic toxicity studies. The European Union (EU) requires a
6-month non-rodent study. In Japan, a 6-month study is sufficient for most,
but not all, compounds. The U.S. Food and Drug Administration (FDA)
maintains its standard duration of 12 months for non-rodents, with 6-month
studies accepted for some clinical indications on a case- by-case basis. To
achieve harmonization on the duration of non-rodent toxicity studies, each
member regulatory region (EU, U.S., and Japan) of the International
Conference on Harmonization (ICH) collected non- rodent studies with
significant new toxicological findings that had occurred after 6 months. An
ICH expert working group was organized that included representatives from
the regulatory authorities of each ICH region, to jointly review all
available case studies for the purpose of arriving at a consensus on the
best duration time for non-rodent toxicity studies. Eighteen case studies
were identified and evaluated (16 original cases plus 2 additional FDA
cases); most of the toxicities identified fell into the following
categories: (1) toxicities identified at 6 months; (2) toxicities observed
at 12 months, which were absent or considered isolated and not noteworthy
findings at 6 months; (3) drug-related deaths or morbidity that occurred
between 6 and 12 months, with a pattern of toxicity that permitted the
interpolation of findings to an intermediate interval between 6 and 12
months; and (4) a shift in the dose response for toxicity with increasing
duration of drug exposure. Of the 18 cases evaluated, 11 supported a
study-duration of 9-12 months, 4 supported a duration of 12 months, and the
3 remaining cases indicated that a 6-month study would be adequate. The
working group concluded that there was sufficient evidence to support a
harmonized 9-month duration for non-rodent toxicity studies, which would be
applicable for most categories of pharmaceuticals.
ARTICLES
The duration of non-rodent toxicity studies for pharmaceuticals. International Conference on Harmonication (ICH)
FDA Center for Drug Evaluation and Research, Office of Review Management, Rockville, MD 28057, USA.
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