Since the oral contraceptive guideline was issued in April 1987, Japanese pharmaceutical firms have been asking physicians to perform clinical studies of the low-dose OCs. At present, eight products from six companies are under clinical development. Ethinyl estradiol (30-35 micrograms per tablet) as an estrogen component is common to all the test drugs. The progestin component in each OC is norethindrone, levonorgestrel, or desogestrel. Phase I clinical studies on small numbers of healthy volunteers showed that they could tolerate the test drugs without any serious complaints. The effects on endocrine systems, including the inhibition of ovulation, were also examined. Pharmacokinetic parameters of active ingredients were comparable to those of Western women, and no substantial difference seemed to exist between Japanese and Western women. As an example, the results of phase I studies of OJK-777 (Ortho-Novum 7/7/7) are mentioned. Phase III clinical studies, which are "open studies," are now under progress with more than 3,000 women. The major objectives are to examine (1) how well the drugs are tolerated, and the dropout rates; (2) the effects on cycle control, especially bleeding patterns; (3) effects on the cardiovascular system, including coagulation and lipid metabolism; (4) effects on hormone secretions. Although some women have been taking the test drugs for more than 12 cycles, overall statistics are not yet available, because the guideline requires long-term administration (for more than 24 cycles). However, some characteristic features observed thus far are discussed.
PIP: Japan began oral contraceptive (OC) clinical studies after 1987 when the government requested studies of 2400 menstrual cycles and a minimum of 100 patients for 12 cycles and 20-30 patients for 24 cycles. 3 monophasic, 1 biphasic, and 4 triphasic drugs were tested from 6 companies and all contained ethinyl estradiol with different progestins (norethindrone, levonorgestrel, or desogestrel). In phase I, the purpose was to examine the pharmacological effects and shortterm safety of all 8 drugs among a small number of healthy volunteers and a comparison of results with Western women. Phase II was eliminated. Phase III involved examination of toleration of the drug, dropout rate, effects on cycle control such as bleeding patterns, metabolism, and effects on hormone secretion. In phase I, Ortho Novum 7/7/7 was administered at 3 dose levels for 1 menstrual cycle and the results were toleration and minimal side effects. Some experienced bleeding, spotting, and breakthrough bleeding. Suppression of ovulation was successful. In phase III, 40 medical schools, 174 hospitals, and 200 investigators enrolled 648 patients of which 117 withdrew. Interim results among women 22-42 years show no adverse effects either in self- reports or laboratory tests. There were nuisance side effects such as nausea, weight gain, and headache, and some amenorrhea and bleeding during different cycles. There is a high continuation rate and patient satisfaction. Results from the full sample are still pending.