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Koseisho would expect the drug to have been studied in approximately 500 patients, with at least 50 having been on therapy for 12 months and with at least 100 over 65 years of age. Special postmarketing surveillance arrangements exist to identify rarer adverse reactions. In an attempt to address the lack of consensus on duration of exposure and patient numbers required to evaluate safety of an NCE, the ICH has produced guidelines that have now reached Step 5. Japan has agreed with the United States and EU that, for chronic-use therapy, 300600 patients should be treated for a minimum of 6 months and that no fewer than 100 patients should have been treated for at least 1 year. While the United States and EU feel, based on retrospective data, that a total of 1500 cases is acceptable, the Japanese have pressed for a prospective evaluation before reaching final decision, since their retrospective data are not compatible with that collected in the United States and EU. Such data should be available by 1996. The reviewing committees of the PAB presently consider that data on 1000 patients (with a range of 500 to 1500 or more for vaccines and oral contraceptives) would be appropriate to evaluate the safety within the NDA for an NCE. |
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The clinical development program is divided into three phases. The guidelines state that, in an ethical and scientific clinical program, the data generated in each phase should be carefully evaluated before permitting progression to the next phase. Phase I consists of a single rising-dose study, a short multiple-dose study, and a food-interaction study. Although the Japanese PAL does not mandate a food-interaction study for all oral medications, it is clearly recommended that such a study be carried out before the commencement of Phase II. |
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Phase II consists of a prepilot study, a pilot study, and a dose-ranging study. The prepilot study is not mentioned in any of the guidelines but is carried out at the instigation of the supervisory investigator with the objective of familiarizing the investigators with the NCE before commencing the full pilot study. For products already investigated outside of Japan and for which data are available, this step is generally omitted. The pilot study is considered to be a probe for efficacy, safety, and initial dosage evaluation and is conducted as an open, dose-escalation trial of 6- to 8-weeks' duration in about 30 to 40 patients. This is followed by the dose-range-finding study, which is often double blind, but may be conducted as an open study, in a maximum of 100 outpatients for 8 to 12 weeks. The value of both the prepilot and pilot studies before the dose-ranging study has been questioned. Although the Japanese clinical trial guidelines refer to early double-blind studies, they are advised only when possible. |
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On the other hand, during Phase III, strong emphasis is placed on double-blind comparative studies with registered compounds having similar indications. A double-dummy approach to blinding is not uncommon as it obviates |
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