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Although postmarketing studies conducted in population‐based databases often contain information on patients in the order of millions, they can still be underpowered if outcomes or exposure of interest is rare, or the interest is in subgroup effects. Combining several databases might provide the statistical power needed. A multi‐database study (MDS) uses at least two healthcare databases, which are not linked with each other at an individual person level, with analyses carried out in parallel across each database applying a common study protocol. Although many MDSs have been performed in Europe in the past 10 years, there is a lack of clarity on the peculiarities and implications of the existing strategies to conduct them. In this review, we identify four strategies to execute MDSs, classified according to specific choices in the execution: (A) local analyses , where data are extracted and analyzed locally, with programs developed by each site; (B) sharing of raw data, where raw data are locally extracted and transferred without analysis to a central partner, where all the data are pooled and analyzed; (C) use of a common data model with study‐specific data, where study‐specific data are locally extracted, loaded into a common data model, and processed locally with centrally developed programs; and (D) use of general common data model, where all local data are extracted and loaded into a common data model, prior to and independent of any study protocol, and protocols are incorporated in centrally developed programs that run locally. We illustrate differences between strategies and analyze potential implications.

Purpose: Postmarketing drug safety surveillance relies upon measures of disproportionate reporting in spontaneous reporting systems. It has been hypothesized that products or events reported frequently may "mask" signals. Methods: We analyzed the masking effect of vaccines in pediatrics in the EudraVigilance database by conducting disproportionality analysis in the full database (containing vaccine exposures) and in a restricted set (excluding vaccine exposures). We measured performance of the reporting odds ratio (ROR) in both data sets using a pediatric-specific drug reference set and in the absence of a reference set. We assessed masking effects across age groups and conducted a classification tree (CART) analysis. Results: Removal of vaccines decreased the ROR values both in negative and positive controls. Exceptions were drug-event combinations including outcomes frequent in vaccine reports. When restricted to positive control associations, removal of vaccine-related events resulted in increased ROR values for events commonly reported following vaccination. For events rarely associated with vaccination, ROR values decreased for all age groups, especially infants. Analysis in the absence of a reference set showed decrease in ROR following vaccine removal and CART revealed that change in ROR with vaccine removal depended upon age and proportion of reports including a vaccine. Conclusions: Removal of vaccines for signal detection in a pediatric population has an impact on ROR, dependent upon the reporting frequency of the event of interest in combination with vaccines. We recommend stratification by age and removal of vaccine exposures if the investigated adverse drug reactions include those typically reported in association with vaccines for the age strata.

SummaryAim Evaluating the public health impact of regulatory interventions is important but there is currently no common methodological approach to guide this evaluation. This systematic review provides a descriptive overview of the analytical methods for impact research. Methods We searched MEDLINE and EMBASE for articles with an empirical analysis evaluating the impact of European Union or non-European Union regulatory actions to safeguard public health published until March 2017. References from systematic reviews and articles from other known sources were added. Regulatory interventions, data sources, outcomes of interest, methodology and key findings were extracted. Results From 1,246 screened articles, 229 were eligible for full-text review and 153 articles in English language were included in the descriptive analysis. Over a third of articles studied analgesics and antidepressants. Interventions most frequently evaluated are regulatory safety communications (28.8%), black box warnings (23.5%) and direct healthcare professional communications (10.5%). 55% of studies measured changes in drug utilisation patterns, 27% evaluated health outcomes and 18% targeted knowledge, behaviour, or changes in clinical practice. Unintended consequences like switching therapies or spill-over effects were rarely evaluated. Two thirds used before-after time series and 15.7% before-after cross-sectional study designs. Various analytical approaches were applied including interrupted time series regression (31.4%), simple descriptive analysis (28.8%) and descriptive analysis with significance tests (23.5%). Conclusion Whilst impact evaluation of pharmacovigilance and product-specific regulatory interventions is increasing, the marked heterogeneity in study conduct and reporting highlights the need for scientific guidance to ensure robust methodologies are applied and systematic dissemination of results occurs.

Purpose In drug safety, there is a lack of guidance on how prioritization of safety issues should be performed. The aim of this literature review is to provide an overview of criteria used for signal prioritization and of the associated decision support frameworks. Methods A search strategy was constructed to identify relevant articles in Medline/Embase databases from the period from 1 January 1995 to 31 August 2015. The prioritization criteria were extracted and classified in relevant categories. Results From an initial set of 63 articles, 11 were retained for full review. The articles mentioned 48 criteria used in the prioritization process, with a median of six criteria per study [range: 1–16]. More than half of the criteria (63%), referred to strength of evidence while 19% related to public health impact, 14% to general public and media attention and 4% to novelty of the drug event association. Fifteen criteria were tested for predictive value with 11 showing positive results, most of them from the strength of evidence category. Six decision-making frameworks are presented, which incorporate criteria from various categories. Five of these frameworks were tested against expert decisions or by other means, but only in one database each and for a limited set of products. Conclusions There is a wide range of prioritization criteria described in the literature; however, few of them demonstrated predictive value. Many criteria with predictive value were related to strength of evidence category and to novelty. There were few attempts at integrating different criteria in decision support frameworks. Five of the frameworks were tested for validity and showed usefulness, while at least three are already in use for prioritization. Copyright © 2016 John Wiley & Sons, Ltd.

X-ray photoelectron spectroscopy, magnetization and magnetic susceptibility of MnPd1–xSbx are reported. The substitution of Pd by Sb leads to drastic changes both in the crystallographic and electronic structure, with remarkably modifications in the magnetic properties of the investigated systems. The most important feature of the XPS spectra is the well-defined magnetic exchange splitting of the Mn 3s core levels of all investigated alloys, giving a direct evidence of the existence of local magnetic moments in the Anderson's sense confined on Mn sites. (© 2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim)

X-ray photoelectron spectroscopy, magnetization and magnetic susceptibility of MnPd3–xSbx are reported. The substitution of Pd by Sb leads to drastic changes both in the crystallographic and electronic structure, with remarkable modifications in the magnetic properties of the investigated samples. (© 2006 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim)

The Raman spectrum of 2-formylfuran in the liquid phase shows pairs of bands whose temperature and solvent dependence behavior can be interpreted in terms of cis–trans conformational equilibrium. Density functional theory (DFT) calculations performed at the BPW91/6–311+G* and B3LYP/6–311+G* theoretical levels show that the trans-isomer is more stable than the cis-isomer by 2.81 and 3.12 kJ mol−1, respectively. The theoretical ΔH values obtained at these theoretical levels [2.99 kJ mol−1 (BPW91) and 3.2 kJ mol−1 (B3LYP)] are very close to the experimental value ΔH = 2.52 kJ mol−1 determined from the plots of logarithmic relative intensities of the band pairs 1673/1692, 1477/1465 and 1396/1371 cm−1 of these isomers against reciprocal temperature. The surface-enhanced Raman spectrum of 2-formylfuran in silver colloid suggests the chemisorption of this molecular species on the silver surface both through the ring oxygen and the oxygen atom of the substituent group, the cis-form being preferred in the adsorption state. The adsorbed molecules are oriented perpendicular or least tilted with respect to the silver surface. Copyright © 2003 John Wiley & Sons, Ltd.