The role of Real-World Data and evidence in oncology medicines approved in EU in 2018-2019

Use of Real-World Data (RWD) has gained the interest of different stakeholders in cancer care. The aim of this study was to identify and describe the use of RWD/RWE during the pre-authorization phase of products authorized by the EMA in 2018 and 2019 (n = 111), with the focus on oncology medicines (n = 24). Information was extracted from the European Public Assessment Report (EPAR) summaries and recorded for 5 stages (11 categories) of the drug development lifecycle (discovery, early development, clinical development, registration/market launch, lifecycle management). Specific chapters of full EPAR were reviewed to substantiate the findings on RWD/RWE use in clinical trial design, efficacy, safety, and effectiveness evaluation. RWD/RWE is present in all stages of the oncology drug development; 100.0 % in discovery, 37.5 % early development, 58.3 % in clinical development, 62.5 % in registration decision and 100.0 % in post-authorization lifecycle management. Examples showed that trial design supported by RWD/RWE included use of open label/single arm studies; efficacy was about using either comparison of results to historical controls, supplying survey data obtained outside the clinical trial or utilizing expert panel advice; safety about including literature findings in evidence; and effectiveness on comparison of trial results of the given product to historical data or existing standard of care. The findings of this study provide specific insights into how RWD/RWE is used in development of cancer therapeutics, how it contributes to regulatory decision making and can guide further policy developments in this field

Use of Real World Data and Evidence in Drug Development of Medicinal Products Centrally Authorized in Europe in 2018-2019

Real-world data/real-world evidence (RWD/RWE) are considered to have a great potential to complement, in some cases, replace the evidence generated through randomized controlled trials. By tradition, use of RWD/RWE in the postauthorization phase is well-known, whereas published evidence of use in the pre-authorization phase of medicines development is lacking. The primary aim of this study was to identify and quantify the role of potential use of RWD/RWE (RWE signatures) during the pre-authorization phase, as presented in the initial marketing authorization applications of new medicines centrally evaluated with a positive opinion in 2018–2019 (n = 111) by the European Medicines Agency (EMA). Data for the study was retrieved from the evaluation overviews of the European Public Assessment Reports (EPARs), which reflect the scientific conclusions of the assessment process and are accessible through the EMA website. RWE signatures were extracted into an RWE Data Matrix, including 11 categories divided over 5 stages of the drug development lifecycle. Nearly all EPARs included RWE signatures for the discovery (98.2%) and life-cycle management (100.0%). Half of them included RWE signatures for the full development phase (48.6%) and for supporting regulatory decisions at the registration (46.8%), whereas over a third (35.1%) included RWE signatures for the early development. RWE signatures were more often seen for orphan and conditionally approved medicines. Oncology, hematology, and anti-infectives stood out as therapeutic areas with most RWE signatures in their full development phase. The findings bring unprecedented insights about the vast use of RWD/RWE in drug development supporting the regulatory decision making

Volumetric high-resolution X-ray phase-contrast virtual histology of breast specimens with a compact laboratory system

The assessment of margin involvement is a fundamental task in breast conserving surgery to prevent recurrences and reoperations. It is usually performed through histology, which makes the process time consuming and can prevent the complete volumetric analysis of large specimens. X-ray phase contrast tomography combines high resolution, sufficient penetration depth and high soft tissue contrast, and can therefore provide a potential solution to this problem. In this work, we used a high-resolution implementation of the edge illumination X-ray phase contrast tomography based on "pixel-skipping" X-ray masks and sample dithering, to provide high definition virtual slices of breast specimens. The scanner was originally designed for intra-operative applications in which short scanning times were prioritised over spatial resolution; however, thanks to the versatility of edge illumination, high-resolution capabilities can be obtained with the same system simply by swapping x-ray masks without this imposing a reduction in the available field of view. This makes possible an improved visibility of fine tissue strands, enabling a direct comparison of selected CT slices with histology, and providing a tool to identify suspect features in large specimens before slicing. Combined with our previous results on fast specimen scanning, this works paves the way for the design of a multi-resolution EI scanner providing intra-operative capabilities as well as serving as a digital pathology system

Impact of information letters on the reporting rate of adverse drug reactions and the quality of the reports: a randomized controlled study

BACKGROUND: Spontaneous reporting of adverse drug reactions (ADRs) is an important method for pharmacovigilance, but under-reporting and poor quality of reports are major limitations. The aim of this study was to evaluate if repeated one-page ADR information letters affect (i) the reporting rate of ADRs and (ii) the quality of the ADR reports. METHODS: All 151 primary healthcare units in the Region Västra Götaland, Sweden, were randomly allocated (1:1) to an intervention (n = 77) or a control group (n = 74). The intervention consisted of one-page ADR information letters administered at three occasions during 2008 to all physicians and nurses in the intervention units. The number of ADR reports received from the 151 units was registered, as was the quality of the reports, which was defined as high if the ADR was to be reported according to Swedish regulations, that is, if the ADR was (i) serious, (ii) unexpected, and/or (iii) related to the use of new drugs and not labelled as common in the Summary of Product Characteristics. A questionnaire was administered to evaluate if the ADR information letter had reached the intended recipient. RESULTS: Before the intervention, no significant differences in reporting rate or number of high quality reports could be detected between the randomization groups. In 2008, 79 reports were sent from 37 intervention units and 52 reports from 30 control units (mean number of reports per unit ± standard deviation: 1.0 ± 2.5 vs. 0.7 ± 1.2, P = 0.34). The number of high quality reports was higher in intervention units than in control units (37 vs. 15 reports, 0.5 ± 0.9 vs. 0.2 ± 0.6, P = 0.048). According to the returned questionnaires (n = 1,292, response rate 57%), more persons in the intervention than in the control group had received (29% vs. 19%, P < 0.0001) and read (31% vs. 26%, P < 0.0001) an ADR information letter. CONCLUSIONS: This study suggests that repeated ADR information letters to physicians and nurses do not increase the ADR reporting rate, but may increase the number of high quality reports

Impact of information letters on the reporting rate of adverse drug reactions and the quality of the reports: a randomized controlled study

BACKGROUND: Spontaneous reporting of adverse drug reactions (ADRs) is an important method for pharmacovigilance, but under-reporting and poor quality of reports are major limitations. The aim of this study was to evaluate if repeated one-page ADR information letters affect (i) the reporting rate of ADRs and (ii) the quality of the ADR reports. METHODS: All 151 primary healthcare units in the Region Västra Götaland, Sweden, were randomly allocated (1:1) to an intervention (n = 77) or a control group (n = 74). The intervention consisted of one-page ADR information letters administered at three occasions during 2008 to all physicians and nurses in the intervention units. The number of ADR reports received from the 151 units was registered, as was the quality of the reports, which was defined as high if the ADR was to be reported according to Swedish regulations, that is, if the ADR was (i) serious, (ii) unexpected, and/or (iii) related to the use of new drugs and not labelled as common in the Summary of Product Characteristics. A questionnaire was administered to evaluate if the ADR information letter had reached the intended recipient. RESULTS: Before the intervention, no significant differences in reporting rate or number of high quality reports could be detected between the randomization groups. In 2008, 79 reports were sent from 37 intervention units and 52 reports from 30 control units (mean number of reports per unit ± standard deviation: 1.0 ± 2.5 vs. 0.7 ± 1.2, P = 0.34). The number of high quality reports was higher in intervention units than in control units (37 vs. 15 reports, 0.5 ± 0.9 vs. 0.2 ± 0.6, P = 0.048). According to the returned questionnaires (n = 1,292, response rate 57%), more persons in the intervention than in the control group had received (29% vs. 19%, P < 0.0001) and read (31% vs. 26%, P < 0.0001) an ADR information letter. CONCLUSIONS: This study suggests that repeated ADR information letters to physicians and nurses do not increase the ADR reporting rate, but may increase the number of high quality reports

A compact system for intraoperative specimen imaging based on edge illumination x-ray phase contrast

A significant number of patients receiving breast-conserving surgery (BCS) for invasive carcinoma and ductal carcinoma in situ (DCIS) may need reoperation following tumor-positive margins from final histopathology tests. All current intraoperative margin assessment modalities have specific limitations. As a first step towards the development of a compact system for intraoperative specimen imaging based on edge illumination x-ray phase contrast, we prove that the system\u27s dimensions can be reduced without affecting imaging performance. We analysed the variation in noise and contrast to noise ratio (CNR) with decreasing system length using the edge illumination x-ray phase contrast imaging setup. Two-(planar) and three-(computed tomography (CT)) dimensional imaging acquisitions of custom phantoms and a breast tissue specimen were made. Dedicated phase retrieval algorithms were used to separate refraction and absorption signals. A \u27single-shot\u27 retrieval method was also used, to retrieve thickness map images, due to its simple acquisition procedure and reduced acquisition times. Experimental results were compared to numerical simulations where appropriate. The relative contribution of dark noise signal in integrating detectors is significant for low photon count statistics acquisitions. Under constant exposure factors and magnification, a more compact system provides an increase in CNR. Superior CNR results were obtained for refraction and thickness map images when compared to absorption images. Results indicate that the \u27single-shot\u27 acquisition method is preferable for a compact CT intraoperative specimen scanner; it allows for shorter acquisition times and its combination of the absorption and refraction signals ultimately leads to a higher contrast. The first CT images of a breast specimen acquired with the compact system provided promising results when compared to those of the longer length system

Longitudinal realist evaluation of the dementia PersonAlised care team (D-PACT) intervention: protocol

BACKGROUND: Different dementia support roles exist but evidence is lacking on which aspects are best, for whom and in what circumstance, and on their associated costs and benefits. Phase 1 of the Dementia PersonAlised Care Team programme (D-PACT), developed a post-diagnostic primary care-based intervention for people with dementia and their carers and assessed the feasibility of a trial. AIM: Phase 2 of the programme aims to 1) refine our programme theory on how, when and for whom the intervention works and 2) evaluate its value and impact. DESIGN & SETTING: A realist longitudinal mixed-methods evaluation will be conducted in urban, rural, and coastal areas across Southwest and Northwest England where low-income groups or ethnic minorities (eg, South Asian) are represented. Design was informed by patient, public and professional stakeholder input and Phase one findings. METHOD: High volume qualitative and quantitative data will be collected longitudinally from people with dementia, carers and practitioners. Analyses will comprise: 1) realist longitudinal case studies; 2) conversation analysis of recorded interactions; 3) statistical analyses of outcome and experience questionnaires; 4 a) health economic analysis examining costs of delivery; 4b) realist economic analysis of high-cost events and 'near misses'. All findings will be synthesised using a joint display table, evidence appraisal tool, triangulation and stakeholder co-analysis. CONCLUSION: Our realist evaluation will describe how, why and for whom the intervention leads (or not) to change over time; it also demonstrates how a non-randomised design can be more appropriate for complex interventions with similar questions or populations

How well do computer-generated faces tap face expertise?

The use of computer-generated (CG) stimuli in face processing research is proliferating due to the ease with which faces can be generated, standardised and manipulated. However there has been surprisingly little research into whether CG faces are processed in the same way as photographs of real faces. The present study assessed how well CG faces tap face identity expertise by investigating whether two indicators of face expertise are reduced for CG faces when compared to face photographs. These indicators were accuracy for identification of own-race faces and the other-race effect (ORE)-the well-established finding that own-race faces are recognised more accurately than other-race faces. In Experiment 1 Caucasian and Asian participants completed a recognition memory task for own- and other-race real and CG faces. Overall accuracy for own-race faces was dramatically reduced for CG compared to real faces and the ORE was significantly and substantially attenuated for CG faces. Experiment 2 investigated perceptual discrimination for own- and other-race real and CG faces with Caucasian and Asian participants. Here again, accuracy for own-race faces was significantly reduced for CG compared to real faces. However the ORE was not affected by format. Together these results signal that CG faces of the type tested here do not fully tap face expertise. Technological advancement may, in the future, produce CG faces that are equivalent to real photographs. Until then caution is advised when interpreting results obtained using CG faces

A compact system for intraoperative specimen imaging based on edge illumination x-ray phase contrast

“This is an author-created, un-copyedited version of an article accepted for publication/published in Physics in Medicine & Biology. IOP Publishing Ltd is not responsible for any errors or omissions in this version of the manuscript or any version derived from it. The Version of Record is available online at https://doi.org/10.1088/1361-6560/ab4912