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testicular weight and histology that constitute part of the routine toxicology assessment. At such an early stage in the development cycle, the drug is made by a pilot process and is usually in limited supply. The need for twice the amount to conduct a 4-week rather than a 2-week study and for the 10-week male rat fertility study can cause a significant program delay. Removal of this barrier to harmonization is a likely outcome of future discussions on fertility testing. |
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Before entering a female into a clinical study, it is necessary to have completed the entire reproductive program, which consists of studies of fertility (Segment I), teratology (Segment II), and late gestation and lactation (Segment III). This represents approximately a 2-year time frame. Although the U.S. regulations state the need for Segments I and II and the demonstration of efficacy in male patients, where appropriate, before entering females into the program, the present U.S. trend is toward relaxation of the requirements to encourage investigation of the drug in a larger number of females during product development. This trend has probably more to do with the powerful Women's Lobby in the U.S. than any other single factor: there is no equivalent Japanese lobby. |
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Three additional requirements unique to Japan are necropsies in acute toxicity studies, with additional histology where macroscopic abnormalities are detected; an acute toxicity study for identified degradates of the test medication; and antigenicity tests. The last include skin-sensitization and photo-sensitization studies for topical preparations, in addition to the minimum requirement for all medications of active sensitization of guinea pigs, passive cutaneous anaphylaxis in rabbits or guinea pigs, and passive hemagglutination with use of sensitized rabbit serum. |
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Nonclinical data accumulated from studies conducted outside Japan are accepted by the Koseisho provided that they comply with the appropriate regulations [24,25], and that adequate information is supplied regarding the facility and scientists where the studies were conducted. A statement from the program director that the data have been collected and prepared in accordance with Japanese GLP guidelines, or their equivalent, is essential. Japan has mutual recognition of GLP inspections with most other major regulatory agencies. Japan has adhered to GLP [26] since 1983, its data are acceptable internationally, and it accepts all GLP data generated in other major pharmaceutical research countries. |
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A significant point of deviation from the requirements of other agencies is that the majority of the toxicology data contained in a Japanese NDA must be published. Since toxicology data are frequently published in non-peer-review journals, it adds nothing to the quality assurance of these data. The requirement also raises concerns regarding both confidentiality and the possible exploitation of these data to register a copy product by a third party. Also as |
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