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requirements [17]. These include the need for single- and repeated-dose studies, reproductive and developmental toxicology, mutagenicity, carcinogenicity, and antigenicity studies. These testing requirements are defined as guidelines and data will not be rejected simply because the methodology employed is not in accordance with Japanese guidelines. However, given the sponsor's inability to discuss the program beforehand with the real decision makers (who sit on the subcommittees and committees), as is readily available with the Food and Drug Administration (FDA), and Japan's failure to recognize formally other protocols, rejection of data not collected in strict adherence to Japanese protocols must be viewed as a distinct risk. Thus, it is difficult to see how one can interpret the guidelines as other than mandates at this time. |
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Guidelines covering general pharmacology studies necessary for a Japanese NDA were published in 1991 [18]. These guidelines present basic concepts and fundamental tests to be applied in general pharmacology studies that should be conducted in the research and development of new drugs with diverse pharmacologic effects. Such tests are conducted to study the desired treatment effect and any unwanted effects that may predict adverse reactions during subsequent human exposure. However, the Japanese guidelines do not simply ask for identification of effects in addition to the desired effect, but specify several specific areas of investigation (Table 2). Also in 1991, the Koseisho issued guidelines on animal pharmacokinetics [19]. In addition to general international requirements, the Japanese guidelines have two routine requirements: determination of the pharmacokinetics of metabolites of the test medication and of the distribution of the medication in the body, assessed by whole-body autoradiography. |
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These additional preclinical needs are not only a challenge for harmonization but are also a potential source for delay in the development program of a new medicinal compound. |
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Agreement was reached at the First ICH on regulatory requirements [4] to abandon the LD50, a test requiring identification of the dose that will be lethal to half the animals tested. This test, of questionable value, will no longer be a |
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| Table 2 General Animal Pharmacology | | Effects on general activity and behavior | | Effects on the central nervous system | | Effects on the autonomic nervous system and smooth muscle | | Effects on the respiratory and cardiovascular systems | | Effects on the digestive system | | Effects on water and electrolyte metabolism | | Other important pharmacological effects |
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