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regulatory requirement for new medicines in the United States, EU, or Japan. The Japanese guidelines were the first to be amended, in accordance with this agreement, in August 1993. It was recommended that the LD50 be replaced by increasing dose tolerance studies in two rodent species by both the recommended (usually oral) and intravenous routes. If the compound has very poor solubility, the peritoneal route may be substituted for the intravenous. These studies will result in the use and sacrifice of significantly fewer animals. |
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Although comment has not, as yet, appeared in the official regulatory guidelines, it is understood that Japan no longer requires single-dose studies in non-rodents. This is an important step, since this requirement was unique to Japan. |
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While the value of repeated-dose testing beyond 6 months has been questioned [20], such testing is a regulatory requirement for a number of agencies, including the FDA and the Koseisho. In Japan, repeated-dose testing for 12 months is required only for new medicines expected to be administered to humans for periods in excess of 6 months [17]. At the First ICH there was consensus that 12-month toxicity studies in rodents could be reduced to 6 months where carcinogenicity studies are required. Encapsulated in the Japanese guidelines, 6-month repeated-dose toxicity studies have been accepted by the agencies of all three regions. Although the FDA continues to demand 12-month repeated-dose toxicity studies in the nonrodent, Japan like the EU accepts a 6-month duration. |
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A regulatory requirement that is more rigorously adhered to in Japan than elsewhere is the need to establish a nontoxic dose within the framework of the toxicity studies. |
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With regard to reproductive toxicology, as a consequence of the First ICH, it was agreed among the United States, EU, and Japan to recommend mutual recognition of their respective current guidelines. However, there were high hopes of a tripartite proposal of harmonisation [21,22]. Prior to the Second ICH a tripartite, harmonized guidelines on reproductive toxicology achieved Step 4 status and has been incorporated into the local regulations of all three regions soon. This is a very significant achievement. |
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Currently the three regions lack uniformity for selection of dosage, the requirements for carcinogenicity studies, exceptions to these requirements, and requirements when the route of administration or chemical form is altered. The rationale and criteria for carcinogenicity testing made progress between the First and Second ICH and guidelines (ICH Step 5) on dose selection for such studies are now available. Additionally, guidelines for when carcinogenicity studies are needed are currently at Step 2 in the process. Although these measures will not propose answers to all the problems, they do go a long way towards this end and are encouraging. |
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Two further documents presented at the Second ICH have now reached Step 5 and are likely to alter the preclinical requirements for registration in |
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