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wished to include Japan, the inability to use a biochemical marker in place of a late onset endpoint for dose-range-finding studies could add considerable time to the clinical development program or require, as at present, that the dosage be reevaluated in Japan. |
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However, irrespective of conditions met, the requirements to conduct clinical trials defining ADME and administration and dosage within Japan will almost certainly not change in the foreseeable future. This opinion is based on the Japanese declared belief that differences in race, environment, and medical care practice may affect such studies and thus the acceptance of foreign data. The Koseisho and physician establishment quote such differences as the frequency of slow acetylators of isoniazid between Japanese and Caucasians, which, in the case of isoniazid, does result in a different adverse-reaction profile. Although there are few documented examples of such differences, the Japanese position is that such differences cannot be excluded for an NCE and that foreign data may not accurately reflect the true adverse-reaction frequency and severity and thus the benefit-to-risk profile in Japanese. Furthermore, they quite the frequently documented lower daily dosages of prescription medication in Japan than in other countries, such as the United States. In part, this is based on a philosophical difference in the approach to drug development. In the United States, emphasis is placed on the need to develop a sufficiently large dose to ensure substantial efficacy for the patient. The tendency in Japan is to develop a lower dose that will demonstrate a degree of efficacy while minimizing associated side effects. |
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In December 1993 the Koseisho published a Guideline for Clinical Trials of Drugs Used in the Elderly [30]. In general these are consistent with the United States, EU, and ICH guidelines. The one substantial difference is in Paragraph 4.1, which states that before conducting clinical trials in the elderly, it is desirable to examine the pharmacokinetics, the efficacy, and the safety of the drug in nongeriatric patients, that is, those under 65 years of age. It is hoped that the guideline will permit some flexibility since there are circumstances where the studies may reasonably be done in parallel or where the drug is targeted primarily to the elderly and thus these parameters might be investigated in the elderly before, or instead of, a younger age group. The guideline clearly supports the option that pharmacokinetic information can be obtained either through formal studies or the so-called pharmacokinetic screen. The latter has been under discussion since the U.S. FDA discussion paper of 1983 [31]. Although pharmacokinetic screening has some merit, difficulties reside in identifying possible problems after completion of Phase III, plus the logistics of the larger number of assays involved. Generally, it will be more efficient to identify potential age-related differences in Phase II and incorporate dosage alterations, if necessary, into the Phase III program. The ICH guideline on drug evaluation in the elderly has reached Step 5 (Second ICH) and should |
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