EMEA/CPMP/EWP/519/98 Rev 1 Page 3/6
The EU-guideline on the clinical investigation of oral contraceptives was last issued in 2000. TheCHMP has felt a need to update this guideline in the light of scientific advance and the issuing of otherguidelines on specific related topics.This guideline concerns contraceptives, intended for use by women containing substances with sexsteroid action as active substance(s). It is not only applicable for short-acting oral contraceptivescontaining a gestagen or a combination of gestagen and estrogen, but also for long-acting steroidcontraceptives (e.g. implants, injectables, transdermal systems, intravaginal and medicated hormonereleasing intrauterine devices (IUDs)). Emergency contraceptives are not addressed here.Contraceptives are generally used by healthy individuals for prophylactic/preventive purposes. Theytherefore need to have a very low risk in order to have a favourable risk/benefit balance. They need tohave a well-defined contraceptive efficacy and a well-founded description of risks and adverse eventsto enable the woman and the prescriber to make the best individual choice of contraceptive method.This document should be read in conjunction with the Directive 2001/83/EEC, as amended, and allother relevant guidelines outlined in current and future EU and ICH guidelines especially those on:
Fixed Combination Medicinal Products
The Investigation of Drug Interactions
Good Clinical Practice: Consolidated Guideline (ICH topic E6)
Dose response information to support drug registration (ICH topic E4)
Clinical Safety Data Management (ICH topic E2A and E2B)
Statistical Principles for Clinical Trials (ICH topic E9)This Note for Guidance is intended to assist applicants during the development of hormonalcontraceptive products. It is only guidance; any deviation from guidelines should be explained anddiscussed in the Clinical Overview.
2. CLINICAL-PHARMACOLOGICAL STUDIES2.1 Hormonal activity
The nature and hormonal activity of the steroid(s) and its (their) principal metabolites should bedescribed. Such information may come from receptor binding studies, studies of individualmetabolites in animals (and/or man) and studies of indicators of hormonal activity, such as SHBG (sexhormone binding globulin).Receptor binding studies may give indications on actions other than the estrogenic and gestagenicactions aimed at. Indicators, such as SHBG, may give information on the balance between estrogenicand gestagenic/androgenic effects in women.
2.2 Pharmacological action
The pharmacological action or actions, by which the contraceptive effect is attained, should be known.For sex steroids, such actions include the effect on ovarian function, endometrial mucosa and cervicalsecretion.
2.2.1 Ovarian function
The effects on ovarian function in women with normal ovulatory function should be described.Methods to be used include plasma concentrations of ovarian steroids and gonadotrophins andultrasound of ovaries. At least two cycles should be studied in each woman.These studies will give information on the extent to which ovarian function is suppressed by thesteroids used. Ultrasound investigation will supplement the interpretation of plasma steroiddeterminations. It is important that sampling is so frequent that possible LH (luteinising hormone)peaks or ovulations are not missed and the duration of the luteal phase or estrogen peaks can beregistered.