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Endometriosis is a chronic disease that requires a suitable, lifelong treatment. To our knowledge, the Vi sanne P ost-approval O bservational S tudy (VIPOS) is to date the largest real-world, non-interventional study investigating hormonal management of endometriosis. We describe women’s experiences of endometriosis in the real world by considering their symptoms and the diagnostic process in their healthcare setting. Overall, 27,840 women were enrolled from six European countries via networks of gynecologists or specialized centers. Of these, 87.8% of women were diagnosed based on clinical symptoms; the greatest and lowest proportions of women were in Russia (94.1%) and Germany (61.9%), respectively. Most women (82.8%) experienced at least one of the triad of endometriosis-associated pain symptoms: pelvic pain, pain after/during sexual intercourse, and painful menstrual periods. The most frequently reported endometriosis-associated symptoms were painful periods (61.8%), heavy/irregular bleeding (50.8%), and pelvic pain (37.2%). Women reported that endometriosis impacted their mood; 55.6% reported feeling “down”, depressed, or hopeless, and 53.2% reported feeling like a failure or having let down family/friends. VIPOS broadens our understanding of endometriosis based on real-world data by exploring the heterogeneity of symptoms women with endometriosis experience and the differences in diagnostic approaches between European countries. Trial registration: ClinicalTrials.gov, NCT01266421; registered 24 December 2010. Registered in the European Union electronic Register of Post-Authorisation Studies as number 1613.

Background In 2009 the Uterine Bleeding and Pain Women's Research Study (UBP-WRS) was conducted interviewing 21,479 women across 8 countries in order to gain patient-based prevalence data on uterine pain and bleeding indications and investigate uterine symptoms and women's treatment experiences. This article shows relevant results of the study for the indication uterine fibroids providing data on self-reported prevalence, symptomatology and management of uterine fibroids. Methods 2,500 women (USA: 4,500 women) in each country (Brazil, Canada, France, Germany, Italy, South Korea, the UK, the USA) completed an online survey. Women included were in their reproductive age (age group 15-49 years; USA: 18-49 years) and had ever experienced menstrual bleedings. Quotas were applied for age, region, level of education and household income of respondents. Variables have been analyzed descriptively and exploratory statistical tests have been performed. Results The self-reported prevalence of uterine fibroids ranged from 4.5% (UK) to 9.8% (Italy), reaching 9.4% (UK) to 17.8% (Italy) in the age group of 40-49 years. Women with a diagnosis of uterine fibroids reported significantly more often about bleeding symptoms than women without a diagnosis: heavy bleedings (59.8% vs. 37.4%), prolonged bleedings (37.3% vs. 15.6%), bleeding between periods (33.3% vs. 13.5%), frequent periods (28.4% vs. 15.2%), irregular and predictable periods (36.3% vs. 23.9%). Furthermore women with diagnosed uterine fibroids reported significantly more often about the following pain symptoms: pressure on the bladder (32.6% vs. 15.0%), chronic pelvic pain (14.5% vs. 2.9%), painful sexual intercourse (23.5% vs. 9.1%) and pain occurring mid-cycle, after and during menstrual bleeding (31.3%, 16.7%, 59.7%, vs. 17.1%, 6.4%, 52.0%). 53.7% of women reported that their symptoms had a negative impact on their life in the last 12 month, influencing their sexual life (42.9%), performance at work (27.7%) and relationship & family (27.2%). Conclusions Uterine fibroid is a common concern in women at fertile age causing multiple bleeding and pain symptoms which can have a negative impact on different aspects in women's life.

Background Pictorial blood loss assessment charts (PBACs) represent the most widely used method to assess menstrual blood loss (MBL) in clinical trials. The aims of this review were to: (1) determine the diagnostic accuracy of PBACs that have been validated against the reference alkaline hematin technique; (2) categorize the pitfalls of using obsolete and nonvalidated charts; (3) provide guidelines for development of a new PBAC or use of an existing chart to measure MBL in clinical trials; and (4) consider the feasibility of using pictorial charts in primary care. Methods A literature review was conducted using Embase and MEDLINE databases. The review identified reports of women with self-perceived or actual heavy menstrual bleeding (HMB), bleeding disorders, abnormal uterine bleeding, leiomyomata (uterine fibroids) or endometriosis, and women undergoing treatment for HMB, as well as those with normal menstrual periods. Data were reviewed from studies that focused on the development and validation of PBACs and from those that used derivative noncertified charts to assess HMB. Results Nine studies reported validation of PBAC scoring systems against the alkaline hematin technique. Across these studies, the sensitivity was 58–97%, the specificity was 7.5–95.5%, the positive and negative likelihood ratios were 1.1–13.8 and 0.14–0.56, respectively, and the diagnostic odds ratio was 2.6–52.4. The cut-off score above which the diagnosis of HMB was made ranged from 50 to 185. Several modifications of these PBACs were used in other studies; however, objective confirmation of their validity was not reported. Overall, there was widespread inconsistency of chart design, scoring systems, diagnostic cut-off limits and post-treatment outcome measures. Conclusions PBACs are best suited to the controlled and specific environment of clinical studies, where clinical outcome parameters are defined. The current lack of standardization precludes widespread use of the PBAC in primary care. Review registration number PROSPERO international prospective register of systematic reviews: CRD42016030083.

Objective To compare the country-specific value sets of the EQ-5D-5L utility index and to evaluate the impact on the interpretation of clinical study results. Six country value sets from Canada, England, Japan, Korea, Netherlands and Uruguay were obtained from literature. In addition, ten crosswalk value sets were downloaded from the EuroQol.org website. Results For each of the 3125 possible health states the difference between the country with the highest index and the country with the lowest index was calculated. The median difference was 0.417 across the health states. When analyzing multinational clinical studies, country-specific value sets should be used to evaluate treatment effects. Additional country-specific analyses are needed.

Background Since the publication over 50 years ago of the alkaline hematin method for quantifying menstrual blood loss (MBL) many new approaches have been developed to assess MBL. The aim of this systematic review is to determine for methods of measuring MBL: ability to distinguish between normal and heavy menstrual bleeding (HMB); practicalities and limitations in the research setting; and suitability for diagnosing HMB in routine clinical practice. Methods Embase®™, MEDLINE®, and ClinicalTrials.gov were screened for studies on the development/validation of MBL assessment methods in women with self-perceived HMB, actual HMB or uterine fibroids, or patients undergoing treatment for HMB. Studies using simulated menstrual fluid and those that included women with normal MBL as controls were also eligible for inclusion. Extracted data included study population, results of validation, and advantages/disadvantages of the technique. Results Seventy-one studies fulfilled the inclusion criteria. The sensitivity and/or specificity of diagnosing HMB were calculated in 16 studies of methods involving self-perception of MBL (11 pictorial), and in one analysis of the menstrual-fluid-loss (MFL) method; in 13 of these studies the comparator was the gold standard alkaline hematin technique. Sensitivity and specificity values by method were, respectively: MFL model, 89, 98%; pictorial blood loss assessment chart (PBAC), 58–99%, 7.5–89%; menstrual pictogram, 82–96%, 88–94%; models/questionnaires, 59–87%, 62–86%, and complaint of HMB, 74, 74%. The power of methods to identify HMB was also assessed using other analyses such as comparison of average measurements: statistical significance was reported for the PBAC, MFL, subjective complaint, and six questionnaires. In addition, PBAC scores, menstrual pictogram volumes, MFL, pad/tampon count, iron loss, and output from three questionnaires correlated significantly with values from a reference method in at least one study. In general, pictorial methods have been more comprehensively validated than questionnaires and models. Conclusions Every method to assess MBL has limitations. Pictorial methods strike a good balance between ease of use and validated accuracy of MBL determination, and could complement assessment of HMB using quality of life (QoL) in the clinical and research setting. Trial registration PRISMA registration number: CRD42016032956 .

ObjectiveThe substitution of an in-study control population with a historical control (HC) population is considered a viable option for reducing the necessary recruitment of control patients. However, it is necessary to evaluate whether this method is applicable to studies on indications targeting endometriosis-associated pelvic pain (EAPP). This study aims to evaluate the potential bias in the results of an EAPP study with an HC arm.MethodsFor this case study, we re-evaluated data from a randomised, placebo-controlled trial using dienogest daily to treat EAPP with an HC arm based on data from a second randomised, placebo-controlled trial in the same indication. Propensity Score (PS) matching was used to match between the treatment and HC arm on all baseline variables. To evaluate the effect of matching on the introduced bias, we evaluated efficacy parameters with the full treatment and control group, as well as the matched group.ResultsThe difference between means (placebo minus treatment) in change in pain, as measured on the Visual Analogue Scale from baseline to end of treatment, deviates in the comparison treatment/pool of HC (7.15 (0.22 to 14.08)) from the overall in-study group (reference: 11.89 (6.06 to 17.73)). After PS matching on the baseline variables, the difference between means (11.79 (4.09 to 19.5)) is close to the reference.ConclusionsUsing HC with PS matching has proven to be useful in the setting of treating EAPP, while emphasis must be given to the selection mechanism and the underlying assumptions. This case study has shown that even for studies which are very similar in design, heterogeneity and between-study variations are present. With the use of an HC arm, it was possible to reproduce similar results than in the original study, while the PS matching improved the comparability considerably. For the main endpoint, PS matching could reproduce the original study results.Trial registration numberNCT00225199, NCT00185341

Background Large-scale linkage of international clinical datasets could lead to unique insights into disease aetiology and facilitate treatment evaluation and drug development. Hereto, multi-stakeholder consortia are currently designing several disease-specific translational research platforms to enable international health data sharing. Despite the recent adoption of the EU General Data Protection Regulation (GDPR), the procedures for how to govern responsible data sharing in such projects are not at all spelled out yet. In search of a first, basic outline of an ethical governance framework, we set out to explore relevant ethical principles and norms. Methods We performed a systematic review of literature and ethical guidelines for principles and norms pertaining to data sharing for international health research. Results We observed an abundance of principles and norms with considerable convergence at the aggregate level of four overarching themes: societal benefits and value; distribution of risks, benefits and burdens; respect for individuals and groups; and public trust and engagement. However, at the level of principles and norms we identified substantial variation in the phrasing and level of detail, the number and content of norms considered necessary to protect a principle, and the contextual approaches in which principles and norms are used. Conclusions While providing some helpful leads for further work on a coherent governance framework for data sharing, the current collection of principles and norms prompts important questions about how to streamline terminology regarding de-identification and how to harmonise the identified principles and norms into a coherent governance framework that promotes data sharing while securing public trust.

Background Endometriosis is a common, chronic, impactful condition in women of reproductive age. In the absence of established sensitive and specific biomarkers, disease severity is determined by patient-reported symptoms and impacts. This article details the development of two new patient-reported outcome (PRO) measures designed to assess efficacy endpoints in clinical studies: The Endometriosis Symptom Diary (ESD) and the Endometriosis Impact Scale (EIS). Methods The ESD and EIS were developed according to best practice and scientific standards (including the Food and Drug Administration (FDA) PRO Guidance) and with extensive input from women with surgically-confirmed endometriosis. Research included: a review of published qualitative literature; concept elicitation interviews in the US, Germany and France ( n  = 45) to explore the experiences of women with endometriosis and to inform ESD and EIS development; and cognitive interviews in the US and Germany ( n  = 31) to assess relevance and understanding of the ESD and EIS and usability of administration using an electronic handheld device. The FDA and the European Medicines Agency (EMA) as well as PRO and clinical experts were consulted throughout the process. Results Pelvic pain was identified as the most frequent, severe and bothersome symptom for women with endometriosis. Pain was reported to be greatest during menstruation (dysmenorrhea) and during or after sexual intercourse (dyspareunia). Pain resulted in significant impairments in physical activities, work/study, social/leisure activities, household activities and sexual functioning. All women highlighted the emotional impact of endometriosis. Descriptions of pain and associated impacts were largely consistent across participants from the US and Europe, with the most notable differences being the words used to describe the location of pain (e.g., ‘pelvis’ vs. ‘abdomen’). Testing during cognitive interviews indicated that the ESD and EIS were well understood and consistently interpreted. Furthermore, all participants found the ePRO devices easy to use and no issues regarding visual presentation, selection of responses or navigation were identified. Conclusions Evidence from extensive qualitative research supports the content validity of the ESD and EIS as patient-reported measures of the disease-defining symptoms of endometriosis and the associated impact on women’s lives. Future research will seek to establish the measurement properties of the measures.

Background The Patient-Reported Outcomes Measurement Information System (PROMIS) Sleep Disturbance v1.0 item bank (27 items) measures sleep disturbances. Rather than the full item bank, an 8-item short form (PROMIS SD SF 8b) or computerized adaptive testing (CAT) can be used. This study compares the performance of the PROMIS SD SF 8b with two CAT algorithms in postmenopausal women. Methods This is a secondary analysis of data collected for the original psychometric testing of the PROMIS Sleep Disturbance item bank, in a sub-sample of women aged ≥55. A graded response model (GRM) was fitted for the item bank, then simulations evaluated the performance of CAT algorithms and the short form, in terms of root mean square error (RMSE) versus the latent trait estimate derived from the full bank. Two CAT algorithms were tested: CAT1 (stop once standard error <0.3 or 12 items administered) and CAT2 (stop once 8 items administered). Convergent and divergent hypotheses for validity were tested through correlations with the Pittsburgh Sleep Quality Index (PSQI) and Epworth Sleepiness Scale (ESS). Known-groups comparisons were made between those with and without self-reported sleep disorder. Results A sample of 337 women was analyzed. Unidimensionality and item-level fit to the GRM was supported; however, the local independence assumption was violated. The CAT1 algorithm showed 4.18 items on average, with a minor decrease in performance (higher RMSE value) compared to CAT2 or the PROMIS SD SF 8b. Administering 8 items adaptively (CAT2) compared to fixed (PROMIS SD SF 8b) performed similarly (RMSE difference = 0.001). Reliability exceeded 0.90 across most of the latent trait for all approaches. Correlations with the PSQI and ESS were largely as hypothesized, with minor differences in coefficient values between the approaches (all within 0.05). Women reporting a sleep disorder had greater sleep disturbance than those who did not ( p  < 0.001 for all). Conclusions The results of this study support using the PROMIS Sleep Disturbance item bank in postmenopausal women. The choice of PROMIS SD SF 8b versus CAT can largely be driven by practical reasons (respondent burden and operational complexity) rather than concerns of differential reliability and validity.

We developed a composite symptom score (CSS) representing disease-related symptom burden over time in patients with malignant pleural mesothelioma (MPM). Longitudinal data were collected from an open-label Phase IIB study in which 239 patients completed the validated MD Anderson Symptom Inventory for MPM (MDASI-MPM). A blinded, independent review committee of external patient-reported outcomes experts advised on MDASI-MPM symptoms to include in the CSS. Through iterative analyses of potential symptom-item combinations, 5 MPM symptoms (pain, fatigue, shortness of breath, muscle weakness, coughing) were selected. The CSS correlated strongly with the full MDASI-MPM symptom set (0.92–0.94) and the Lung Cancer Symptom Scale-Mesothelioma (0.79–0.87) at each co-administration of the scales. The CSS also had good sensitivity to worsening disease and global quality-of-life ratings. The MDASI-MPM CSS can be used as an outcome in MPM clinical trials, including in responder analyses and at the individual patient level. It is brief enough to administer frequently, including electronically, to better capture symptom trajectories during and after a trial and in clinical practice. As a single score, the CSS addresses multiplicity issues that can arise when several symptoms increase due to worsening disease. Our process can be adapted to produce a CSS for other advanced-cancer trials.