The study population in the first safety and tolerability study is usually healthy, adult male and female volunteers aged 18-45 years old, with normal weight in proportion to their height. Since the preclinical reproduction toxicity studies may not have been completed when the first human safety study is performed, women of childbearing potential may be excluded from that study population. However, it is highly recommended that women are included as early as possible in the first human clinical pharmacology studies [9-11].
As a matter of fact, as stated in the ICH Guidance document ICH M3 , there are regional differences across the world in the recommended timing of reproduction toxicity studies to support the inclusion of women of childbearing potential into human trials. The regional differences outlined in ICH M3 are as follows:
• The United States: Women of childbearing potential may be included into carefully monitored trials before the reproduction toxicity studies have been completed. Recommended safety measures include pregnancy testing, the uses of a method of birth control considered as highly effective, and study entry after a verified menstrual period.
• The European Union: The evaluation of embryo-fetal development should be completed prior to Phase I trials, and female fertility before Phase III trials are initiated, in women of childbearing potential.
• Japan: Assessment of female fertility and embryo-fetal development should be completed before women using birth control are included in any type of trial. Permanently sterilized or postmenopausal women may be included into trials before reproduction toxicity studies have been completed, if the appropriate repeated toxicity studies have been performed, where any toxicity related to the female reproductive organs have been evaluated. A male fertility trial should be completed before the Phase III trials are started.
If the target patient population only encompasses a certain specific population, e.g., women for oral contraceptives or hormone-replacement therapy, or drugs for Alzheimer's disease in the elderly, more adequate information could be gathered by performing the early Phase I studies in the intended target population (e.g., women or elderly subjects). In certain cases when the toxicity of the drug is expected to be high, e.g., drugs intended for treatment of cancer, it might be unethical to perform any trials in healthy volunteers, thereby exposing healthy subjects to drugs that may cause undue harm. All these factors should be considered at the time of design of these studies.
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