4.2 Rationale and Background:
Oestrogen deficiency, described as a decline in the levels of circulating oestrogens, affects numerous tissues in postmenopausal women, including musculoskeletal, vascular, and urogenital systems (Archer 2010).
Oestrogen deficiency leads to a decrease in vaginal lubrication, which is an early hallmark of vulvar and vaginal atrophy (VVA). Symptoms of VVA include vaginal dryness, burning/itching, dyspareunia, vulvar pruritus, bleeding, particularly associated with sexual activity. VVA is also associated with urinary symptoms including urethral discomfort, frequency, haematuria, urinary tract infection, and dysuria (MacBride, Rhodes et al. 2010).
The prevalence of VVA ranges from 45%-57% (Levine, Williams et al. 2008, Santoro and Komi 2009). Current therapies include systemic oestrogens, local oestrogens and lubricants/moisturisers. Ospemifene is the first non-steroidal selective oestrogen receptor modulator (SERM) approved in the EU for the treatment of moderate to severe symptomatic vulvar and vaginal atrophy (VVA) in post-menopausal women who are not candidates for local vaginal oestrogen therapy .
The SERM class of drugs has been associated with an increased risk of venous thromboembolism (VTE) and cerebrovascular events (CVE). In the ospemifene clinical programme, which followed the Food and Drug Administration (FDA) Guidance for the Treatment of VVA, no increase in the incidence of VTE or CVE in the ospemifene cohort compared to placebo was observed. This Post-Authorisation Safety Study (PASS) is being undertaken to assess the safety of ospemifene in real life over a period of up to seven years in the US and five years in the European Union, EU, ( Spain, Italy and Germany). The PASS will involve comparative analyses between specified cohorts of women in the US and Germany arms of the study, and analyses of off-label use in the EU arms (Spain, Italy and Germany).
4.3 Research Question and Objectives:
Following is the research question of interest which is applicable to the Spain arm of the study:
What is the off-label use among ospemifene patients in Spain?
Additional questions of interest that are studied in other countries within the PASS include:
What is the incidence and risk of various side effects (such as VTE, CVE, endometrial hyperplasia, endometrial cancer, pelvic organ prolapse, urinary incontinence, gall bladder events, atrial fibrillation, renal failure, renal carcinoma, renal adenoma, liver tumours, thymic epithelial tumours, increased triglycerides, and vaginal bleeding) in a cohort of postmenopausal women newly prescribed ospemifene relative to (a) a cohort of postmenopausal women diagnosed with VVA but not treated for their condition with local or systemic oestrogens and (b) a cohort of postmenopausal women newly prescribed other SERM therapies (SERM comparison cohort) being utilised for oestrogen-deficiency conditions (i.e., non-cancer and non-infertility indications) or breast cancer prevention.
The objective of the study in Spain is to assess off-label use among ospemifene patients, including use in patients with vaginal bleeding or signs or symptoms of endometrial hyperplasia and endometrial cancer (contraindications)
4.4 Study Design:
The Spain arm of the PASS is an annual cross-sectional study using electronic medical records (EMR). This protocol addresses only the Spain database study arm, and summarises how off-label use of ospemifene will be investigated. All patients with at least one ospemifene prescription are eligible for the study
In order to minimise bias, new users (initiators) will be identified. A new user is defined as anyone in the database with at least 12 months of medical history and with at least one prescription of ospemifene. The study duration will be up to 5 years from study initiation, and annual data updates will be obtained from each data source. Annual data updates will continue until the earliest of (1) the target sample size being reached, or (2) 5 years elapsing since first EU availability.
4.5 Population:
There will be one study analysis population for the Spain arm of the study.
? Ospemifene Prescribed Population: any patient with a prescription of ospemifene (that is, all patients treated with ospemifene who are enrolled in the database). The use of ospemifene in any patients that are not postmenopausal (aged ?54 years) will be considered as off-label use.
Index Date: The index date (date of cohort entry) will be defined as the date of first ospemifene prescription
Inclusion Criteria: The Ospemifene Prescribed Population will include patients with at least one prescription or dispensation of ospemifene within the study period and at least 12 months of medical history (i.e., enrolment in the database or activity in the health system as a proxy for enrolment) prior to the index date.
Exclusion Criteria: There are no exclusion criteria.
Study Duration: The total study duration will be 5 years from the start of analysis. The maximum patient follow-up will be 5 years in the EU and 7 years in the US.
4.6 Variables:
Patient characteristics, medications, and select medical conditions at initial use of ospemifene. Exposure to ospemifene will be assumed to begin on the date of pharmacy dispensing or prescription, and continue to the date of the last prescription. The occurrence of specific indicators will be assessed if diagnosis or treatment occurs in the period extending from the 12 months preceding the first ospemifene to the date of the final prescription.
4.7 Data Source:
The data source for the Spain arm of the PASS is SIDIAP.
4.8 Study Size:
The Spain arm of the PASS will investigate off-label use of ospemifene: this is a descriptive study with an exploratory analysis (with no comparative component) of all patients with an ospemifene prescription, and therefore sample size calculations in this context can be interpreted as a forecast of patients using ospemifene.
4.9 Data Analysis:
Off-Label Use of Ospemifene
A descriptive analysis will be conducted examining the frequency of use of ospemifene that appears to be outside the indication in the EU label.
Patients who have been prescribed ospemifene will be categorised into three main groups. The first group will be designated ?On label? and patients will be included if there is clear evidence that the woman has a VVA diagnosis, is aged 54 years or over whilst receiving ospemifene prescription, and has no contraindications or off-label indicators. The second patient group will be designated ?Potentially on-label but lacking clear evidence of on-label indication?: all patients in this group will have neither contraindications nor other off-label indicators. The third and final patient group will be designated as ?Apparent off-label use?, and will have either contraindications, or have other off-label indicators.
The frequency distribution of patients by specific contraindication or other off-label indicator will be reported. In addition, an age distribution of patients with off-label indicators will be provided.
Post-Menopausal Women Who Are Not Candidates for Local Oestrogen Use (Restricted Conditions for Local Oestrogen Use)
A frequency distribution of patients prescribed ospemifene who have diagnosis or treatment for at least one of the following will be produced: history of melanoma, active treatment for breast cancer (including adjuvant therapy), history of breast cancer, history of endometrial cancer, porphyria, history of endometriosis and dexterity problems (Parkinson?s disease and/or history of stroke). Number and percentage of patients with conditions/indications which are both restricted for local oestrogen use and off-label/contraindicated for ospemifene will be highlighted.
4.10 Milestones:
The drug (ospemifene) is expected to be initially available in Italy, Spain and later in Germany. Ospemifene received approval from the US Food and Drug Administration (FDA) in 2013. Data collection will conducted annually after ospemifene is commercially available in the first European market. See Table A.1 (Appendices) for study milestones.
