A Case for Synthetic Data in Regulatory Decision-Making in Europe.

Regulators are faced with many challenges surrounding health data usage, including privacy, fragmentation, validity, and generalizability, especially in the European Union, for which synthetic data may provide innovative solutions. Synthetic data, defined as data artificially generated rather than captured in the real world, are increasingly being used for healthcare research purposes as a proxy to real-world data (RWD). Currently, there are barriers particularly challenging in Europe, where sharing patient's data is strictly regulated, costly, and time-consuming, causing delays in evidence generation and regulatory approvals. Recent initiatives are encouraging the use of synthetic data in regulatory decision making and health technology assessment to overcome these challenges, but synthetic data have still to overcome realistic obstacles before their adoption by researchers and regulators in Europe. Thus, the emerging use of RWD and synthetic data by pharmaceutical and medical device industries calls regulatory bodies to provide a framework for proper evidence generation and informed regulatory decision making. As the provision of data becomes more ubiquitous in scientific research, so will innovations in artificial intelligence, machine learning, and generation of synthetic data, making the exploration and intricacies of this topic all the more important and timely. In this review, we discuss the potential merits and challenges of synthetic data in the context of decision making in the European regulatory environment. We explore the current uses of synthetic data and ongoing initiatives, the value of synthetic data for regulatory purposes, and realistic barriers to the adoption of synthetic data in healthcare.

An analysis of ranibizumab treatment and visual outcomes in real-world settings: the UNCOVER study.

PURPOSE: To describe intravitreal ranibizumab treatment frequency, clinical monitoring, and visual outcomes (including mean central retinal thickness [CRT] and visual acuity [VA] changes from baseline) in neovascular age-related macular degeneration (nAMD) in real-world settings across three ranibizumab reimbursement scenarios in the Middle East, North Africa, and the Asia-Pacific region. METHODS: Non-interventional multicenter historical cohort study of intravitreal ranibizumab use for nAMD in routine clinical practice between April 2010 and April 2013. Eligible patients were diagnosed with nAMD, received at least one intravitreal ranibizumab injection during the study period, and had been observed for a minimum of 1 year (up to 3 years). Reimbursement scenarios were defined as self-paid, partially-reimbursed, and fully-reimbursed. RESULTS: More than three-fourths (n = 2521) of the analysis population was partially-reimbursed for ranibizumab, while 16.4% (n = 532) was fully-reimbursed, and 5.8% was self-paid (n = 188). The average annual ranibizumab injection frequency was 4.1 injections in the partially-reimbursed, 4.7 in the fully-reimbursed and 2.6 in the self-paid populations. The average clinical monitoring frequency was estimated to be 6.7 visits/year, with similar frequencies observed across reimbursement categories. On average, patients experienced VA reduction of -0.7 letters and a decrease in CRT of -44.4 µm. The greatest mean CRT change was observed in the self-paid group, with -92.6 µm. CONCLUSIONS: UNCOVER included a large, heterogeneous ranibizumab-treated nAMD population in real-world settings. Patients in all reimbursement scenarios attained vision stability on average, indicating control of disease activity.

Results from a drug utilization study of extended release quetiapine fumarate prescribed by psychiatrists as treatment for major depressive disorder in selected countries in the European Union.

This multicenter, observational drug utilization (DU) study (NCT01594996) investigated the profile of patients and specialist providers who prescribed extended release quetiapine fumarate (quetiapine XR) for treatment of major depressive disorder (MDD) across five European countries (Germany, Italy, Romania, Spain, and Sweden). A DU data abstraction form captured information on the characteristics of physicians, patients, and drugs utilized in the medical management of depressive episodes in MDD, where the therapeutic regimen included quetiapine XR. Data were reported descriptively. This analysis included 811 patients. Psychiatric histories indicated a burden of severe MDD in these patients. Patient demographics were similar across countries; however, those in Sweden had a younger mean age. Physicians' ratings of the therapeutic effect of prior treatment with antidepressants suggested the need for an add-on treatment for most patients. Overall, 15.7% of patients initiated quetiapine XR treatment as monotherapy. Presence of psychotic symptoms during depressive episodes predicted treatment with higher than recommended doses of quetiapine XR (odds ratio=3.11; 95% confidence interval: 1.6-6.0). This analysis demonstrated similarities in DU across the countries analyzed, largely in accordance with the recommended dose of quetiapine XR as an adjunctive therapy to antidepressants in MDD (50-300 mg/day).

Hormonal therapy and risk of breast cancer in mexican women.

The use of hormonal therapies, including hormonal contraceptives (HC) and postmenopausal hormone replacement therapy (HRT) have been shown to influence breast cancer (BC) risk. However, the variations of these effects among populations and ethnic groups are not completely documented, especially among Hispanic women. We evaluated the association between HC and premenopausal BC risk, and between HRT and postmenopausal BC risk in Mexican women. Data from a Mexican multi-center population-based case-control study ofwomen aged 35 to 69 years were analysed. A total of 1000 cases and 1074 matched controls were recruited between 2004 and 2007. Information on hormonal therapy was collected through a structured questionnaire. Results were analysed using conditional logistic regression models. Overall, HC were used by 422/891 (47.3%) premenopausal women and HRT was used by 220/1117 (19.7%) postmenopausal women. For HC, odds ratios (ORs) for BC were 1.11 (95% confidence interval (CI): 0.82, 1.49) for current users and 1.68 (95% CI: 0.67, 4.21) for ever-users. No clear effect of duration of use was observed. For HRT, the OR for BC was significantly increased in ever users (OR: 1.45; 95% CI: 1.01, 2.08). A non-significant increased risk was observed for combined estrogen/progestin, (OR =  1.85; 95% CI: 0.84, 4.07) whereas no effect was observed for the use of estrogen alone (OR = 1.14; 95% CI: 0.68, 1.91). Our results indicate that, HC had a non-significant effect on the risk of pre-menopausal BC, but suggested that injected contraceptives may slightly increase the risk, whereas HRT had a significant effect on post-menopausal BC in this population. This study provides new information about the effects of HC and HRT on BC risk in a Mexican population, which may be of relevance for the population of Latin America as a whole.

Impact of body mass index on perioperative morbidity, oncological, and functional outcomes after extraperitoneal laparoscopic radical prostatectomy.

OBJECTIVE: To evaluate the impact of obesity on the outcomes of laparoscopic radical prostatectomy. METHODS AND MATERIALS: In a prospective urologic cancer database, 765 patients underwent extraperitoneal laparoscopic radical prostatectomy for localized prostate cancer. The patients were categorized into 3 groups of body mass index (kg/m(2)): <25.0 (n = 276, 30%, "normal weight"), 25.0 to 30.0 (n = 365, 48%, "overweight") and >30.0 (n = 124, 16%, "obese"). We assessed the perioperative, oncological, and functional outcomes in this cohort of patients. Preoperative and postoperative evaluation of continence and erectile function were performed using validated questionnaires. RESULTS: Mean operative time was significantly longer in obese patients (P < .001) and blood loss was also more important (P < .01). The obese patients had the highest likelihood of having aggressive tumors: nonorgan confined prostate cancer (49%, P = .002) and Gleason score ≥ 7 (80%, P = .005). The obese group had the higher positive surgical margins rate (overall: 27%, P = .012; pT2: 20%, P = .02). With a mean follow-up of 38 months, obesity was not an independent predictive factor of biochemical recurrence. At the 12-month follow-up, 85%, 74%, and 72% of normal, overweight, and obese men, respectively, were continent (no pad) (P = .04). At the 12-month follow-up, 57%, 58%, and 40% of normal, overweight, and obese men, respectively, reported an erection sufficient for intercourse (P = .01). CONCLUSION: Laparoscopic radical prostatectomy is a safe and effective procedure in obese men with midterm cancer control. However, obese patients are at higher risk of aggressive disease. Recovery of continence and potency in these patients are significantly lower compared to nonobese men.

Does long-acting injectable risperidone make a difference to the real-life treatment of schizophrenia? Results of the Cohort for the General study of Schizophrenia (CGS).

OBJECTIVE: The primary aim of this study was to compare the impact of risperidone long-acting injectable (R-LAI) to other antipsychotics on rates of hospitalisation in real-life settings. METHOD: The Cohort for the General study of Schizophrenia (CGS) followed 1859 patients diagnosed with schizophrenia (DSM-IV) from 177 psychiatric wards of public and private hospitals across France over a mean period of 12months. These patients were ambulatory or had been hospitalised for less than 93days at study entry. Recruitment was stratified for long-acting second-generation antipsychotic use. A multivariate Poisson regression adjusted for confounding with propensity scores and allowing for autocorrelation was used for the calculation of relative rates of hospitalisation with 95% confidence intervals. RESULTS: The mean age of participants was 37.65years, 68.3% were male and 36.7% were hospitalised for less than 93days at study entry. Altogether, participants accumulated 796 hospital stays (53.4 per 100 person-years). R-LAI patients were slightly younger and had been hospitalised more often in the past 12months compared to non-R-LAI users. The adjusted Poisson regression analysis showed R-LAI use to be associated with a lower rate of future hospitalisation: 0.66 [0.46-0.96] compared to non-R-LAI use, and 0.53 [0.32-0.88] compared to use of other LAIs. CONCLUSION: Use of R-LAI was associated with lower rates of hospitalisation compared to non-use of R-LAI.

Risk of osteoporotic fractures after discontinuation of menopausal hormone therapy: results from the E3N cohort.

While current use of menopausal hormone therapy (MHT) reduces the risk of osteoporotic fractures, epidemiologic studies suggest that protection wears off rapidly after discontinuation of treatment. The authors identified 5,589 first osteoporotic fractures (2,235 major osteoporotic fractures) among 70,182 postmenopausal women from the French E3N cohort (1992-2008) and used Cox multivariate proportional hazards regression models to estimate hazard ratios. Persistence of protection against major osteoporotic fractures after MHT discontinuation was only observed when MHT had been used for at least 5 years, with a slightly more important decrease within the 5 years after discontinuation (compared with never use of MHT, hazard ratio = 0.68, 95% confidence interval: 0.50, 0.92) than beyond 5 years (hazard ratio = 0.83, 95% confidence interval: 0.69, 0.99); the P value for homogeneity between the 2 estimates was not significant. Oral estrogen use and transdermal estrogen use conveyed similar estimates in past users. Among current users, the authors confirmed a protective effect of MHT against risk of osteoporotic fractures. These findings, which relied on a number of MHT combinations, suggested that such therapies should be used for 5 years or more for reducing risk of fracture after treatment discontinuation.

Menopausal hormone therapy and breast cancer risk: impact of different treatments. The European Prospective Investigation into Cancer and Nutrition.

Menopausal hormone therapy (MHT) is characterized by use of different constituents, regimens and routes of administration. We investigated the association between the use of different types of MHT and breast cancer risk in the EPIC cohort study. The analysis is based on data from 133,744 postmenopausal women. Approximately 133,744 postmenopausal women contributed to this analysis. Information on MHT was derived from country-specific self-administered questionnaires with a single baseline assessment. Incident breast cancers were identified through population cancer registries or by active follow-up (mean: 8.6 yr). Overall relative risks (RR) and 95% confidence interval (CI) were derived from country-specific Cox proportional hazard models estimates. A total of 4312 primary breast cancers were diagnosed during 1,153,747 person-years of follow-up. Compared with MHT never users, breast cancer risk was higher among current users of estrogen only (RR: 1.42, 95% CI 1.23-1.64) and higher still among current users of combined MHT (RR: 1.77, 95% CI 1.40-2.24; p = 0.02 for combined vs. estrogen-only). Continuous combined regimens conferred a 43% (95% CI: 19-72%) greater risk compared with sequential regimens. There was no significant difference between progesterone and testosterone derivatives in sequential regimens. There was no significant variation in risk linked to the estrogenic component of MHT, neither for oral vs. cutaneous administration nor for estradiol compounds vs. conjugated equine estrogens. Estrogen-only and combined MHT uses were associated with increased breast cancer risk. Continuous combined preparations were associated with the highest risk. Further studies are needed to disentangle the effects of the regimen and the progestin component.

Low pretreatment total testosterone (< 3 ng/mL) predicts extraprostatic disease in prostatectomy specimens from patients with preoperative localized prostate cancer.

OBJECTIVE: • To investigate the relationship between pretreatment testosterone levels and pathological specimen characteristics, by prospectively examining serum androgen concentrations in a well-studied cohort of patients who underwent radical prostatectomy (RP) for localized prostate cancer. PATIENTS AND METHODS: • A total of 107 patients with clinically localized prostate cancer had an assay of total testosterone before laparoscopic RP at our institution. • The results were classified into two groups based on the total serum testosterone: group1, < 3 ng/mL; group 2, ≥ 3 ng/mL. • Student's t-test was used to compare continuous variables, and Fisher's exact test or the chi-squared test was used to compare categorical variables. • Survival curves were established using the Kaplan-Meier method and compared using the log-rank test. In all tests, P < 0.05 was considered to indicate statistical significance. RESULTS: • All patients had localized prostate cancer based on digital rectal examination (DRE) and preoperative magnetic resonance imaging (MRI). Groups 1 and 2 were similar in terms of age, body mass index, preoperative co-morbidities (cardiovascular and diabetes mellitus), clinical stage of prostate cancer and preoperative PSA levels. • In pathological specimens, low total testosterone (< 3 ng/mL) was an independent risk factor for high Gleason score (> 7) and for locally advanced pathological stage (pT3 and pT4). • Higher preoperative testosterone correlated with disease confined to the gland. • There was no association between serum testosterone levels and surgical margin status, on the one hand, and biochemical recurrence on the other. CONCLUSION: • Low serum testosterone appears to be predictive of aggressive disease (Gleason score >7 and extraprostatic disease, pathological stage > pT2) in patients who underwent RP for localized prostate cancer.

Menopausal hormone therapy and risk of endometrial carcinoma among postmenopausal women in the European Prospective Investigation Into Cancer and Nutrition.

Estrogen-only menopausal hormone therapy (HT) increases the risk of endometrial cancer, but less is known about the association with other types of HT. Using Cox proportional hazards regression, the authors examined the association of various types of HT with the risk of endometrial cancer among 115,474 postmenopausal women recruited into the European Prospective Investigation into Cancer and Nutrition between 1992 and 2000. After a mean follow-up period of 9 years, 601 incident cases of endometrial cancer were identified. In comparison with never users of HT, risk of endometrial cancer was increased among current users of estrogen-only HT (hazard ratio (HR) = 2.52, 95% confidence interval (CI): 1.77, 3.57), tibolone (HR = 2.96, 95% CI: 1.67, 5.26), and, to a lesser extent, estrogen-plus-progestin HT (HR = 1.41, 95% CI: 1.08, 1.83), although risks differed according to regimen and type of progestin constituent. The association of HT use with risk was stronger among women who were older, leaner, or had ever smoked cigarettes. The finding of a strong increased risk of endometrial cancer with estrogen-only HT and a weaker association with combined HT supports the hypothesis that progestins have an attenuating effect on endometrial cancer risk. The increased risk associated with tibolone use requires further investigation.

Postmenopausal hormone therapy and asthma onset in the E3N cohort.

BACKGROUND: Epidemiological studies have suggested that female hormones might play a role in asthma and that menopausal hormone therapy (MHT or hormone replacement therapy (HRT)) might increase the risk of asthma in postmenopausal women. The only prospective study addressing this issue reports an increase in the risk of developing asthma which was similar for oestrogen alone and oestrogen/progestagen treatment. METHODS: The association between the use of different types of MHT and the risk of asthma onset in postmenopausal women was investigated prospectively from 1990 to 2002 by biennial questionnaires as part of the French E3N cohort study. Asthma onset was considered to be the time of medical diagnosis of asthma cases occurring during the follow-up of women who were asthma free at baseline. Cox proportional hazards models were used, adjusting for potential confounding factors. RESULTS: Among 57 664 women free of asthma at menopause, 569 incident cases of asthma were identified during 495 448 years of follow-up. MHT was related to an increased risk of asthma onset (HR=1.20, 95% CI 0.98 to 1.46) among recent users. The increase in risk of asthma onset was only significant among women reporting the use of oestrogen alone (HR=1.54, 95% CI 1.13 to 2.09) particularly in never smokers (HR=1.80, 95% CI 1.15 to 2.80) and women reporting allergic disease prior to asthma onset (HR=1.86, 95% CI 1.18 to 2.93). A small increase in the risk of asthma onset associated with the use of oestrogen/progestagen was also observed in these subgroups. CONCLUSION: Postmenopausal use of oestrogen alone was associated with an increased rate of newly diagnosed asthma in menopausal women.

Serum cholesterol level, use of a cholesterol-lowering drug, and breast cancer: results from the prospective E3N cohort.

Metabolic syndrome, including low HDL cholesterol, has been associated with an increased breast cancer risk, whereas little is known of the relationship with total cholesterol. Cox proportional hazards regression models were performed to evaluate the association between self-reported total serum cholesterol, cholesterol-lowering drugs, and risk of breast cancer in 69 088 women from the French E3N cohort study. A total of 2932 cases of primary invasive breast cancer were reported during 12 years of follow-up. Compared with women with low/normal serum cholesterol (<6.6 mol/l), users of cholesterol-lowering drugs had a significantly decreased breast cancer risk [hazard ratio (HR): 0.79, 95% confidence interval (CI): 0.68, 0.93]. There was no variation in HRs according to the menopausal status. In strata defined by the hormone receptor status of the tumor, the risk reached statistical significance only for the estrogen-positive and progesterone-positive receptor subtype (HR: 0.64, 95% CI: 0.50, 0.82). A high cholesterol without cholesterol-lowering drug use was not associated with breast cancer risk (HR: 0.99, 95% CI: 0.85, 1.15) in the entire population. Our result concerning cholesterol-lowering drugs is consistent with studies showing that hypolipidemic molecules are effective in inhibiting cancer cell growth proliferation. Further studies should investigate whether these findings apply to all classes of cholesterol-lowering drugs.

Progestagens use before menopause and breast cancer risk according to histology and hormone receptors.

In a previous study, we found a positive association between premenopausal use of progestagens and breast cancer risk. We conducted the present study to assess the risk of breast cancers defined by their histology and hormone receptors status. We evaluated the association between progestagen-only intake (except for mini pills) before menopause and after the age of 40 years and invasive breast cancer risk in 67,057 women participating in the French E3N cohort study. Histologically confirmed invasive breast cancers (2,264) were identified through biennial self-administered questionnaires completed from 1992 to 2002. Risk estimates were calculated using the Cox proportional hazard model. We found an increased risk of lobular carcinoma associated with premenopausal use of progestagens among both current and past users [hazard ratio (HR), 1.51; 95% confidence interval (95% CI), 1.02-2.24 and HR, 1.38; 95% CI, 1.08-1.75, respectively]. Among current users, the use of progestagens for 4.5 years or more was associated with an increased risk of estrogen receptor-positive/progesterone receptor-positive carcinomas (HR, 1.68; 95% CI, 1.05-2.68), whereas current use of progestagens for <4.5 years was associated with an increase in the estrogen receptor-positive/progesterone receptor-negative carcinoma risk (HR, 1.61; 95% CI, 1.05-2.46). The premenopausal use of progestagens after the age of 40 years may be preferentially associated with the risk of lobular breast cancer and differentially affect the risk of breast cancer according to the hormone receptor status.

Carbohydrate intake, glycemic index, glycemic load, and risk of postmenopausal breast cancer in a prospective study of French women.

BACKGROUND: Diets high in carbohydrates may result in chronically elevated insulin concentrations and may affect breast cancer risk by stimulation of insulin receptors or through insulin-like growth factor I (IGF-I)-mediated mitogenesis. Insulin response to carbohydrate intake is increased in insulin-resistant states such as obesity. OBJECTIVE: We sought to evaluate carbohydrate intake, glycemic index (GI), and glycemic load (GL) and subsequent overall and hormone-receptor-defined breast cancer risk among postmenopausal women. DESIGN: A prospective cohort analysis of dietary carbohydrate and fiber intakes was conducted among 62 739 postmenopausal women from the E3N French study who had completed a validated dietary history questionnaire in 1993. During a 9-y period, 1812 cases of pathology-confirmed breast cancer were documented through follow-up questionnaires. Nutrients were categorized into quartiles and energy-adjusted with the regression-residual method. Cox model-derived relative risks (RRs) were adjusted for known determinants in breast cancer. RESULTS: Dietary carbohydrate and fiber intakes were not associated with overall breast cancer risk. Among overweight women, we observed an association between GI and breast cancer (RR(Q1-Q4): 1.35; 95% CI: 1.00, 1.82; P for trend = 0.04). For women in the highest category of waist circumference, the RR(Q1-Q4) was 1.28 (95% CI: 0.98, 1.67; P for trend = 0.10) for carbohydrates, 1.35 (95% CI: 1.04, 1.75; P for trend = 0.01) for GI, and 1.37 (95% CI: 1.05, 1.77; P for trend = 0.003) for GL. We also observed a direct association between carbohydrate intake, GL, and estrogen receptor-negative breast cancer risk. CONCLUSIONS: Rapidly absorbed carbohydrates are associated with postmenopausal breast cancer risk among overweight women and women with large waist circumference. Carbohydrate intake may also be associated with estrogen receptor-negative breast cancer.

Use of different postmenopausal hormone therapies and risk of histology- and hormone receptor-defined invasive breast cancer.

PURPOSE: We previously found that the risk of invasive breast cancer varied according to the progestagen component of combined postmenopausal hormone therapy (CHT): progesterone, dydrogesterone, or other progestagens. We conducted the present study to assess how these CHTs were associated with histology- and hormone receptor-defined breast cancer. PATIENTS AND METHODS: We used data from the French E3N cohort study, with 80,391 postmenopausal women followed for a mean duration of 8.1 years; 2,265 histologically confirmed invasive breast cancers were identified through biennial self-administered questionnaires completed from 1990 to 2002. The relative risks (RRs) were estimated using Cox proportional hazards models. RESULTS: Compared with postmenopausal hormone therapy (HT) never-use, ever-use of estrogen+progesterone was not significantly associated with the risk of any breast cancer subtype, but increasing duration of estrogen+progesterone was associated with increasing risks of lobular (P = .06) and estrogen receptor-positive/progesterone receptor-negative (ER+/PR-; P = .02). Estrogen+dydrogesterone was associated with a significant increase in risk of lobular carcinoma (RR, 1.7; 95% CI, 1.1 to 2.6). Estrogen+other progestagens was associated with significant increases in risk of ductal and lobular carcinomas (RR, 1.6; 95% CI, 1.3 to 1.8; and 2.0; 95% CI, 1.5 to 2.7, respectively), of ER+/PR+ and ER+/PR- carcinomas (RR, 1.8; 95% CI, 1.5 to 2.1; and 2.6; 95% CI, 1.9 to 3.5, respectively), but not of ER-/PR+ or ER-/PR- carcinomas (RR, 1.0; 95% CI, 0.5 to 2.1; and 1.4; 95% CI, 0.9 to 2.0, respectively). CONCLUSION: The increase in risk of breast cancer observed with the use of CHTs other than estrogen+progesterone and estrogen+dydrogesterone seems to apply preferentially to ER+ carcinomas, especially those ER+/PR-, and to affect both ductal and lobular carcinomas.