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Japan; they cover toxicokinetics and when to conduct repeated-dose tissue distribution studies. |
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The former may improve the ability of animal toxicology studies to predict possible adverse events in man; currently their relevance is questioned [23]. Whereas there is general agreement on the registration requirement for single-dose tissue distribution studies there is no consistency regarding the requirement for repeated-dose tissue distribution data. |
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Currently, the Japanese do not require a mammalian cell gene mutation assay. The three tests required for genotoxicity evaluation are a bacterial gene mutation test, in vitro cytogenetics, and in vivo tests for genetic damage. The Japanese regulations clearly state these to be the minimum requirement and encourage additional tests. Thus harmonization will likely be achieved by the Koseisho recommending all four tests as occurs in the United States and EU. |
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In the clinical development of drugs in Japan, before a single-dose human study can be undertaken, a 1-month preclinical toxicology study must be conducted. This is twice as long as the U.S. requirement. The duration of toxicity studies required to support the use of a test drug for varying lengths of human usage in Japan is shown in Table 3. Additionally, before conducting a single-dose male volunteer study in Japan, it is usually necessary to have completed a preclinical male fertility study (Segment 1) that has an in-life phase of 10 or more weeks. Although the guidelines do not require completion of this study before Phase I, the responsible Institutional Review Board (IRB) or the investigator, usually does. The unique Japanese requirement for Segment I male fertility studies before the conduct of single-dose studies on male volunteers in Japan has, as yet, not been resolved by the ICH initiatives. Japanese regulatory circles are aware that the Segment I male fertility study is of poor predictive value. This requirement is unique to Japan, and its value is debatable. The rat, which is used in this study, produces a marked excess of sperm and thus the test is believed by many to be less sensitive than the evaluation of |
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| Table 3 Preclinical Requirements | | Duration of dosing in toxicity study | | Duration of human exposure |
| | 1 month | Single dose or repeat dosage not exceeding 1 week | | 3 months | Repeated dosing exceeding 1 week and to a max. of 4 weeks | | 6 months |  |
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Repeated dosing exceeding 4 weeks and to a maximum of 6 months |
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| | 12 months | |
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Repeated dosing exceeding 6 months or where this is deemed to be appropriate |
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