Lessons learned on the design and the conduct of Post-Authorization Safety Studies: review of 3 years of PRAC oversight.

AIMS: To describe and characterize the first cohort of Post-Authorization Safety Study (PASS) protocols reviewed under the recent European pharmacovigilance legislation. METHODS: A systematic approach was used to compile all publicly available information on PASS protocols and assessments submitted from July 2012 to July 2015 from Pharmacovigilance Risk Assessment Committee (PRAC) minutes, European Medicines Agency (EMA) and European Network of Pharmacovigilance and Pharmacoepidemiology (ENCePP) webpages. RESULTS: During the study period, 189 different PASS protocols were submitted to the PRAC, half of which were entered in the ENCePP electronic register of post-authorization studies (EU-PAS) by July 2015. Those protocols were assessed during 353 PRAC reviews. The EMA published only 31% of the PRAC feedback, of which the main concerns were study design (37%) and feasibility (30%). Among the 189 PASS, slightly more involved primary data capture (58%). PASS assessing drug utilization mainly leveraged secondary data sources (58%). The majority of the PASS did not include a comparator (65%) and 35% of PASS also evaluated clinical effectiveness endpoints. CONCLUSIONS: To the best of our knowledge this is the first comprehensive review of three years of PASS protocols submitted under the new pharmacovigilance legislation. Our results show that both EMA and PASS sponsors could respectively increase the availability of protocol assessments and documents in the EU-PAS. Protocol content review and the high number of PRAC comments related to methodological issues and feasibility concerns should raise awareness among PASS stakeholders to design more thoughtful studies according to pharmacoepidemiological principles and existing guidelines.

Latitude and ultraviolet radiation dose in the birthplace in relation to menarcheal age in a large cohort of French women.

BACKGROUND: Age at menarche is an important determinant of hormonal-related neoplasia and other chronic diseases. Spatial and temporal variations in age at menarche have been observed in industrialised countries and several environmental factors were reported to have an influence. METHOD: We examined geographical variations in self-reported age at menarche and explored the effects of both latitude and ultraviolet radiation (UVR) dose on the onset of menarche in 88,278 women from the French E3N cohort (aged 40-65 years at inclusion). RESULTS: The mean age at menarche was 12.8 years. After adjustment for potential confounders (birth cohort, prematurity, birth weight and length, father's income index, body silhouette in childhood, food deprivation during World War II, population of birthplace, number of siblings, breastfeeding exposure and indoor exposure to passive smoking during childhood), latitude and UVR dose (annual or spring/summer) in county of birth were significantly associated with age at menarche (P(trend) < 0.0001). Women born at lower latitudes or in regions with higher annual or spring/summer UVR dose had a 3- to 4-month earlier menarche than women born at higher latitudes or in regions with lower UVR. On a continuous scale, a 1° increment in latitude resulted in a 0.04-year older age at menarche [95% confidence interval (CI): 0.03, 0.05], whereas a 1-kJ/m(2) increment in annual UVR dose resulted in a 0.42-year younger age at menarche (95% CI: -0.55, -0.29). CONCLUSION: These data further suggest that light exposure in childhood may influence sexual maturation in women.

Dietary intake of vitamin D and calcium and breast cancer risk in the European Prospective Investigation into Cancer and Nutrition.

Studies assessing the effects of vitamin D or calcium intake on breast cancer risk have been inconclusive. Furthermore, few studies have evaluated them jointly. This study is the largest so far examining the association of dietary vitamin D and calcium intake with breast cancer risk in the European Prospective Investigation into Cancer and Nutrition. During a mean follow-up of 8.8 yr, 7760 incident invasive breast cancer cases were identified among 319,985 women. Multivariable Cox proportional hazards regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for pre- and postmenopausal breast cancer risk. Comparing the highest with the lowest quintile of vitamin D intake, HR and 95% CI were 1.07 (0.87-1.32) and 1.02 (0.90-1.16) for pre- and postmenopausal women, respectively. The corresponding HR and 95% CIs for calcium intake were 0.98 (0.80-1.19) and 0.90 (0.79-1.02), respectively. For calcium intake in postmenopausal women, the test for trend was borderline statistically significant (P(trend) = 0.05). There was no significant interaction between vitamin D and calcium intake and cancer risk (P(interaction) = 0.57 and 0.22 in pre- and postmenopausal women, respectively). In this large prospective cohort, we found no evidence for an association between dietary vitamin D or calcium intake and breast cancer risk.

Who seeks primary care for sleep, anxiety and depressive disorders from physicians prescribing homeopathic and other complementary medicine? Results from the EPI3 population survey.

OBJECTIVES: To describe and compare patients seeking treatment for sleep, anxiety and depressive disorders (SADD) from physicians in general practice (GPs) with three different practice preferences: strictly conventional medicine (GP-CM), mixed complementary and conventional medicine (GP-Mx) and certified homeopathic physicians (GP-Ho). DESIGN AND SETTING: The EPI3 survey was a nationwide, observational study of a representative sample of GPs and their patients, conducted in France between March 2007 and July 2008. PARTICIPANTS: 1572 patients diagnosed with SADD. PRIMARY AND SECONDARY OUTCOMES: The patients' attitude towards complementary and alternative medicine; psychotropic drug utilisation. RESULTS: Compared to patients attending GP-CM, GP-Ho patients had healthier lifestyles while GP-Mx patients showed similar profiles. Psychotropic drugs were more likely to be prescribed by GP-CM (64%) than GP-Mx (55.4%) and GP-Ho (31.2%). The three groups of patients shared similar SADD severity. CONCLUSION: Our results showed that patients with SADD, while differing principally in their sociodemographic profiles and conventional psychotropic prescriptions, were actually rather similar regarding the severity of SADD in terms of comorbidities and quality of life. This information may help to better plan resource allocation and management of these common health problems in primary care.

Impact of physician preferences for homeopathic or conventional medicines on patients with musculoskeletal disorders: results from the EPI3-MSD cohort.

OBJECTIVE: The objective of this study was to assess the effect of physician practicing preferences (PPP) in primary care for homeopathy (Ho), CAM (Complementary and alternative medicines) with conventional medicine (Mx) or exclusively conventional medicine (CM) on patients with musculoskeletal disorders (MSDs), with reference to clinical progression, drug consumption, side effects and loss of therapeutic opportunity. METHODS: The EPI3-MSD study was a nationwide observational cohort of a representative sample of general practitioners (GP) and their patients in France. Recruitment of GP was stratified by PPP, which was self-declared. Diagnoses and comorbidities were recorded by GP at inclusion. Patients completed a standardized telephone interview at inclusion, one, three and twelve months, including MSD-functional scales and medication consumption. RESULTS: 1153 MSD patients were included in the three PPP groups. Patients did not differ between groups except for chronicity of MSDs (>12 weeks), which was higher in the Ho group (62.1%) than in the CM (48.6%) and Mx groups (50.3%). The twelve-month development of specific functional scores was identical across the three groups after controlling for baseline score (p > 0.05). After adjusting for propensity scores, NSAID use over 12 months was almost half in the Ho group (OR, 0.54; 95%CI, 0.38-0.78) as compared to the CM group; no difference was found in the Mx group (OR, 0.81; 95% CI: 0.59-1.15). CONCLUSION: MSD patients seen by homeopathic physicians showed a similar clinical progression when less exposed to NSAID in comparison to patients seen in CM practice, with fewer NSAID-related adverse events and no loss of therapeutic opportunity.

Plasma phospholipid fatty acid concentrations and risk of gastric adenocarcinomas in the European Prospective Investigation into Cancer and Nutrition (EPIC-EURGAST).

BACKGROUND: Epidemiologic data suggest that diet is a risk factor in the etiology of gastric cancer. However, the role of dietary fatty acids, a modifiable risk factor, remains relatively unexplored. OBJECTIVE: The objective of this study was to determine the association of plasma phospholipid fatty acid concentrations, as biomarkers of exogenous and endogenously derived fatty acids, with the risk of gastric adenocarcinoma in a case-control study nested within the European Prospective Investigation into Cancer and Nutrition-Europe Gastric Cancer (EPIC-EURGAST). DESIGN: Fatty acids were measured by gas chromatography in prediagnostic plasma phospholipids from 238 cases matched to 626 controls by age, sex, study center, and date of blood donation. Conditional logistic regression models adjusted for Helicobacter pylori infection status, BMI, smoking, physical activity, education, and energy intake were used to estimate relative cancer risks. RESULTS: Positive risk associations for gastric cancer were observed in the highest compared with the lowest quartiles of plasma oleic acid (OR: 1.72; 95% CI: 1.01, 2.94), di-homo-γ-linolenic acid (OR: 1.92; 95% CI: 1.10, 3.35), α-linolenic acid (OR: 3.20; 95% CI: 1.70, 6.06), and the ratio of MUFAs to saturated fatty acids, as an indicator of stearoyl-CoA desaturase-1 enzyme activity (OR: 1.40; 95% CI: 0.81, 2.43). An inverse risk association was observed with the ratio of linoleic to α-linolenic acid (OR: 0.37; 95% CI: 0.20, 0.66). CONCLUSION: These data suggest that a specific prediagnostic plasma phospholipid fatty acid profile, characterized mainly by high concentrations of oleic acid, α-linolenic acid, and di-homo-γ-linolenic acid, which presumably reflect both a complex dietary pattern and altered fatty acid metabolism, may be related to increased gastric cancer risk.

Postmenopausal serum sex steroids and risk of hormone receptor-positive and -negative breast cancer: a nested case-control study.

Prediagnostic endogenous sex steroid hormone levels have well established associations with overall risk of breast cancer. While evidence toward the existence of distinct subtypes of breast cancer accumulates, few studies have investigated the associations of sex steroid hormone levels with risk of hormone receptor [estrogen receptor (ER) and/or progesterone receptor (PR)] defined breast cancer. In a case-control study nested within the EPIC cohort (European Prospective Investigation into Cancer and Nutrition), estradiol, testosterone, and sex hormone-binding globulin levels were measured in prediagnostic serum samples from postmenopausal women not using hormone replacement therapy at blood donation. A total of 554 women who developed invasive breast cancer with information on receptor status were matched with 821 control subjects. Conditional logistic regression models estimated breast cancer risk with hormone concentrations according to hormone receptor status of the tumor. Sex steroid hormones were associated with risks of not only ER+PR+ breast cancer [estradiol OR for highest vs. lowest tertile = 2.91 (95% CI: 1.62-5.23), P(trend) = 0.002; testosterone OR = 2.27 (95% CI: 1.35-3.81), P(trend) = 0.002] but also of ER-PR- breast cancer [estradiol OR = 2.11 (95% CI: 1.00-4.46), P(trend) = 0.05; testosterone OR = 2.06 (95% CI: 0.95-4.46), P(trend) = 0.03], with associations appearing somewhat stronger in the receptor-positive disease. Serum androgens and estrogens are associated with risks of both hormone receptor-negative as well as receptor-positive breast tumors. Further research is needed to establish through which molecular pathways, and during which evolutionary stages of development, androgens and estrogens can promote the occurrence of both receptor-positive and -negative clinical breast tumors.

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.

Prediagnostic circulating parathyroid hormone concentration and colorectal cancer in the European Prospective Investigation into Cancer and Nutrition cohort.

BACKGROUND: Parathyroid hormone (PTH) has been proposed to play a promoting role in carcinogenesis. However, no epidemiologic studies have yet directly investigated its role in colorectal cancer (CRC). METHODS: A case-control study nested within the European Prospective Investigation into Cancer and Nutrition cohort was conducted with 1,214 incident, sporadic CRC cases matched to 1,214 controls. Circulating prediagnostic PTH and 25-hydroxy vitamin D [25(OH)D] concentrations were measured by enzyme-linked immunosorbent assays. Detailed dietary and lifestyle questionnaire data were collected at baseline. Multivariable conditional logistic regression was used to estimate the incidence rate ratio (RR) with 95% confidence intervals (95% CI) for the association between circulating PTH and CRC risk. RESULTS: In multivariate analyses [including adjustment for 25(OH)D concentration] with a priori defined cutoff points, high levels of serum PTH (≥65 ng/L) compared with medium PTH levels of 30-65 ng/L were associated with increased CRC risk (RR = 1.41, 95% CI: 1.03-1.93). In analyses by sex, the CRC risk was 1.77 (95% CI: 1.14-2.75) and 1.15 (95% CI: 0.73-1.84) in men and women, respectively (P(heterogeneity) = 0.01). In subgroup analyses by anatomical subsite, the risk for colon cancer was RR = 1.56, 95% CI: 1.03-2.34, and for rectal cancer RR = 1.20, 95% CI: 0.72-2.01 (P(heterogeneity) = 0.21). Effect modification by various risk factors was examined. CONCLUSIONS: The results of this study suggest that high serum PTH levels may be associated with incident, sporadic CRC in Western European populations, and in particular among men. IMPACT: To our knowledge, this is the first study on PTH and CRC. The role of PTH in carcinogenesis needs to be further investigated.

Variation in genes coding for AMP-activated protein kinase (AMPK) and breast cancer risk in the European Prospective Investigation on Cancer (EPIC).

AMP-activated protein kinase (AMPK) is an energy sensing/signalling intracellular protein which is activated by an increase in the cellular AMP:ATP ratio after ATP depletion. Once activated, AMPK inhibits fatty acid synthesis and the Akt-mTOR pathway, and activates the p53-p21 axis. All these molecular mechanisms are thought to play a key role in breast carcinogenesis. We investigated the genetic variability of four genes encoding AMPK (PRKAA1, PRKAA2, PRKAB1 and PRKAB2). Using a tagging approach and selecting SNPs we covered all the common genetic variation of these genes. We tested association of tagging SNPs in our four candidate genes with breast cancer (BC) risk in a study of 1340 BC cases and 2536 controls nested into the European Prospective Investigation into Cancer and Nutrition (EPIC). Given the relevance of AMPK on fatty acid synthesis and the importance of body fatness as a BC risk factor, we tested association of SNPs and body-mass index as well. We observed no statistically significant association between the SNPs in the PRKAs genes and BC risk and BMI after correction for multiple testing.

Joint effects of dietary vitamin D and sun exposure on breast cancer risk: results from the French E3N cohort.

BACKGROUND: Ecological studies have suggested that vitamin D production through ultraviolet (UV) solar irradiance could reduce breast cancer (BC) risk. Although studies restricted to dietary vitamin D intake have provided inconsistent results, little is known about the relationship between pre- and postmenopausal BC and combined intakes from diet, supplements, and sun exposure. METHODS: Cox proportional hazards regression models evaluated the association between vitamin D intakes, mean daily ultraviolet radiation dose (UVRd) at the place of residence and risk of BC among 67,721 women of the French E3N cohort. All analyses were stratified on menopausal status taking into account important confounders including calcium consumption. RESULTS: During 10 years of follow-up, a total of 2,871 BC cases were diagnosed. Dietary and supplemental vitamin D intakes were not associated with BC risk; however, in regions with the highest UVRd, postmenopausal women with high dietary or supplemental vitamin D intake had a significantly lower BC risk as compared with women with the lowest vitamin D intake (HR = 0.68, 95% CI: 0.54-0.85, and HR = 0.57, 95% CI: 0.36-0.90, respectively). CONCLUSION: Our results suggest that a threshold of vitamin D exposure from both sun and diet is required to prevent BC and this threshold is particularly difficult to reach in postmenopausal women at northern latitudes where quality of sunlight is too poor for adequate vitamin D production. IMPACT: Prospective studies should further investigate associations between BC risk, vitamin D status and sunlight exposure.

Serum 25(OH) vitamin D and risk of breast cancer: a nested case-control study from the French E3N cohort.

BACKGROUND: High 25-hydroxyvitamin D [25(OH)D] serum concentrations have been found to be associated with reduced breast cancer risk. However, few studies have further investigated this relationship according to menopausal status, nor have they taken into account factors known to influence vitamin D status, such as dietary and serum calcium, parathyroid hormone, and estradiol serum levels. METHODS: We designed a nested case-control study within the French E3N cohort. Cases were women diagnosed with incident breast cancer (n = 636). Controls (n = 1,272) were matched with cases on age, menopausal status at blood collection, age at menopause, and center and year of blood collection. Multivariate logistic regression models were established. RESULTS: We found a decreased risk of breast cancer with increasing 25(OH) vitamin D(3) serum concentrations (odds ratio, 0.73; 95% confidence interval, 0.55-0.96; P trend = 0.02) among women in the highest tertile. We also observed a significant inverse association restricted to women under 53 years of age at blood sampling [odds ratio (T(3) versus T(1)), 0.60; 95% confidence interval, 0.37-0.98; P trend = 0.04]. In premenopausal women, the risk was also decreased, although not significantly. CONCLUSION: Our findings support a decreased risk of breast cancer associated with high 25(OH) vitamin D(3) serum concentrations, especially in younger women, although we were unable to confirm a direct influence of age or menopausal status. IMPACT: Randomized intervention trials with vitamin D supplementation are required to confirm its benefits on breast cancer risk, but the maintenance of adequate vitamin D levels should be encouraged by public health policy.

Vitamin D receptor and calcium sensing receptor polymorphisms and the risk of colorectal cancer in European populations.

Increased levels of vitamin D and calcium may play a protective role in colorectal cancer (CRC) risk. It has been suggested that these effects may be mediated by genetic variants of the vitamin D receptor (VDR) and the calcium sensing receptor (CASR). However, current epidemiologic evidence from European populations for a role of these genes in CRC risk is scarce. In addition, it is not clear whether these genes may modulate CRC risk independently or by interaction with blood vitamin D concentration and level of dietary calcium intake. A case-control study was conducted nested within the European Prospective Investigation into Cancer and Nutrition. CRC cases (1,248) were identified and matched to 1,248 control subjects. Genotyping for the VDR (BsmI: rs1544410; Fok1: rs2228570) and CASR (rs1801725) genes was done by Taqman, and serum vitamin D (25OHD) concentrations were measured. Conditional logistic regression was used to estimate the incidence rate ratio (RR). Compared with the wild-type bb, the BB genotype of the VDR BsmI polymorphism was associated with a reduced risk of CRC [RR, 0.76; 95% confidence interval (CI), 0.59-0.98). The association was observed for colon cancer (RR, 0.69; 95% CI, 0.45-0.95) but not rectal cancer (RR, 0.97; 95% CI, 0.62-1.49). The Fok1 and CASR genotypes were not associated with CRC risk in this study. No interactions were noted for any of the polymorphisms with serum 25OHD concentration or level of dietary calcium. These results confirm a role for the BsmI polymorphism of the VDR gene in CRC risk, independent of serum 25OHD concentration and dietary calcium intake.