Abstract and Background
Background: The post marketing safety surveillance program for a drug containing a new chemical entity should assess both, the safety outcomes that relate specifically to the targeted population, as well as those that could potentially be related to special pharmacological characteristics of the drug. Active safety surveillance using valid epidemiological study designs has been proven to be a pertinent and reliable method to approach this endeavor.
Methods/Design: The primary objective of the study is to compare incidence rates of serious adverse events in users of all types of newly prescribed oral HRT products. This active surveillance study will assess pertinent cardiovascular outcomes - in particular venous and arterial thromboembolism - and other serious adverse events (SAEs) in new HRT users over a period of several years. One product under surveillance is Angeliq®, which contains the novel progestagen drospirenone (DRSP) combined with estradiol. In addition, all other oral combined HRT products with a novel progestagen or estrogen that will be newly marketed during the study period will be studied. These new HRT products will be compared with established HRT products. The combined cohort will include at least 30,000 women recruited in several European countries. At least 90,000 years of observation are expected from the field work which started in early 2002 and will end around 2008. The participating women will complete a baseline survey using a self-administered questionnaire to describe the baseline risk. After 6 months, 12 months, and then on an annual basis, they will fill out a questionnaire in which they record complaints and events during the use of the prescribed HRTs. All adverse outcomes occurring during the observational period will be evaluated.
Discussion: A complete lifetime medical history, individually validated SAEs over time, and a low loss to follow-up rate are essential for a robust safety assessment. Therefore, the lifetime history of diseases and relevant medications will be documented. Reported SAEs will be validated and analyzed. A four level, multi-faceted follow-up process was established to ensure low loss to follow-up rates (e.g., 3-5% after three years of follow up). Multivariate methods will be used to adjust for confounding.
The safety of a novel drug product containing a new chemical entity should be assessed in an extensive post marketing safety surveillance program. It is also prudent to assess both, the safety outcomes that relate specifically to the targeted population, as well as those that could potentially be related to the special pharmacological characteristics of the novel drug product. Differentiating between the inherent background population risk and a potential incremental risk due to treatment is often challenging. Active safety surveillance using valid epidemiological study designs has been proven to be a pertinent and reliable method to approach this endeavor.
Long-term active safety surveillance of new HRT products has gained particular importance following the intense scientific debate on the risk/benefit profile of HRT products after the publication of the WHI results. The active safety surveillance study proposed in this protocol, the European Active Surveillance Study of Women taking HRT (EURAS-HRT) study, will assess the risk profile of marketed oral combined HRT products, by comparing HRT products that contain novel progestagens with older HRT products. The primary objective of the study is to compare incidence rates of serious adverse events - in particular cardiovascular outcomes - in new users of all types of oral HRT products. This large, multinational, prospective, controlled, non-interventional, long-term cohort study will follow a series of cohorts for a period of seven years. The study is sponsored by Schering AG with an unconditional grant. Study conduct and data analysis are carried out by an independent investigator under the stewardship of an international advisory committee.
One drug product under surveillance in the EURAS - HRT study is Angeliq®, which contains a novel synthetic progestagen drospirenone (DRSP)[2,3] combined with estradiol. In addition, all other oral combined HRT products with a novel progestagen or estrogen that will be newly marketed during the study period will be included in this study. These new HRT products will be compared with established HRT products.
As estrogen/progestagen combinations increase the risk for thrombembolism, all new drug products that contain a novel estrogen or progestagen should be investigated for their influence on venous and arterial thromboembolic events rates. A large, prospective, controlled cohort study of OC users (EURAS OC Study), which compared DRSP-containing OCs users with other OCs users, demonstrated that DRSP is not associated with an increased incidence for thromboembolic events in OC users. However, because OC users are two to three decades younger than the typical HRT user the results of the OC study can only partially be extrapolated to older age groups.
Furthermore, given DRSP's antimineralocorticoide pharmacological characteristics, specific outcomes such as the risk of hyperkalemia and dysrhythmia, and subsequent serious cardiac problems will be assessed in this study. As secondary objective all other outcomes of the long-term observation will be evaluated.
A long-term observational cohort study, which compares rates of adverse events among users of Angeliq® (and other new HRT products) with those among users of other marketed oral HRTs, is an appropriate design to assess long-term risks and benefits under real-life-conditions of drug utilization, i.e. taking into account all possible interactions with co-morbidity and co-treatment which are common in higher age groups. Potential differences between first-time users of an HRT product and users who switch from one preparation to another will be investigated. Moreover, the potential of greater risk during the early period of use (e.g. the first year) will be carefully monitored.
The pilot phase of this surveillance study was started in early 2002, using a cohort of women who visited European physicians who prescribe HRT. This revised protocol reflects the experiences gained in the pilot phase of the study. Further background information and details are available at the study's website.
BMC Womens Health. 2006;6 © 2006 Dinger and Heinemann; licensee BioMed Central Ltd.
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Cite this: European active surveillance study of women taking HRT (EURAS-HRT): study protocol [NCT00214903] - Medscape - Jan 01, 2006.