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6-month study in two species; a 12-month dog study, and 2-year oncogenicity studies in both rats and mice. All of these studies, with the exception of the oncogenicity studies, will include blood chemistry, hematology, and urine chemistry at study termination and, ideally, at intervals during the dosing period. For a typical 6-month rodent study, 80 animals (10 per sex per group) will be bled and urine collected during week 1 (optional), and at months 1, 3, and 6. For rodent studies, the volume of an interim blood sample rarely exceeds 1.2 mL for rats and, for mice, a terminal sample of <1 mL is not uncommon. With such small volumes it is essential that samples are assayed as soon as possible for blood chemistry in order to avoid concentration artifacts due to evaporation. The small volume of rat blood usually available for hematology evaluation and the instability of coagulation samples dictate the immediate analyses of these samples in order to produce valid results. Consequently, near-animal testing is essential and every facility performing toxicology studies should have immediate access to their own clinical pathology laboratory. |
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B. Clinical Pathology and Clinical Trials |
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The clinical development program of a new pharmaceutical agent traditionally includes three distinctive phases with an increasing number of individuals being progressively exposed to the drug with increasing dose levels and for an increasing duration. The preceding toxicology studies must be adequate to characterise any potential toxic effects and in vitro mutagenicity studies should have been completed prior to initial exposure of the drug to man and the conduct of any clinical trial. |
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Each clinical phase has clear purposes with Phase I trials, usually being performed in a small number of healthy volunteers, targeted at safety assessment and initial tolerance studies. Phase II trials, which include up to 500 patients, are a combination of efficacy and tolerance studies while the final Phase III programs aim to expose 30005000 patients by means of several large multicenter multinational trials. Ethical, medical, and regulatory considerations demand that clinical studies are supported by a recommended program of toxicity studies although the requirements do vary between countries and continents. The European Commission (EC), with up to 15 participating member states, is aiming to produce new legislation controlling certain aspects of clinical trials and pulling together a number of the new guidelines to supplement the GCP guidelines issued in 1991. Changes are necessary since each European Union (EU) country has rules on clinical trial authorisation but they are all different. Satisfying these divergent rules cause developers major problems and starting multicenter, multinational trials can take 6 to 9 months longer in Europe than in the United States. |
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In line with these proposals, the International Conference on Harmonization (ICH) has generated guidelines on the Technical Requirements for the |
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