Innovative Medicines Initiative Research Articles

Addressing Pressing Needs in the Development of Advanced Therapies.

The commercial development of advanced therapy medicinal products (ATMPs) represents great opportunity for therapeutic innovation but is beset by many challenges for its developers. Although the ATMP field continues to progress at a rapid pace, evidenced by the increasing number of clinical trials conducted over the past few years, several factors continue to complicate the introduction of ATMPs as a curative treatment for multiple disease types, by blocking their translational pathway from research to the patient. While several recent publications (Trounson and McDonald, 2015; Abou-El-Enein et al., 2016a,b) as well as an Innovative Medicines Initiative consultation (IMI, 2016) this year have highlighted the major gaps in ATMP development, with manufacturing, regulatory, and reimbursement issues at the forefront, there remains to be formulated a coherent strategy to address these by bringing the relevant stakeholders to a single forum, whose task it would be to design and execute a delta plan to alleviate the most pressing bottlenecks. This article focuses on two of the most urgent areas in need of attention in ATMP development, namely manufacturing and reimbursement, and promotes the concept of innovation-dedicated research infrastructures to support a multi-sector approach for ensuring the successful development, entry, and ensuing survival of ATMPs in the healthcare market.

Remote Assessment of Disease and Relapse – Central Nervous System- RADAR-CNS

Remote Assessment of Disease and Relapse in Central Nervous System Disorders (RADAR-CNS) is a major international research project. It aims to develop new ways of measuring major depressive disorder, epilepsy and multiple sclerosis (MS) using wearable devices and smartphone technology. RADAR-CNS aims to improve people’s quality of life and change how depression, epilepsy and MS are managed and treated. Data from mobile devices can give a full picture of a person’s condition at a level of detail which was previously impossible. This offers the potential to detect changes in behavior, sleep, or mood before the individual themselves is aware of it. This could help them to predict or even avoid a relapse. To achieve this, we are creating a pipeline for developing, testing and implementing remote measurement technologies for depression, multiple sclerosis (MS) and epilepsy. Depression, multiple sclerosis and epilepsy are all disorders of the central nervous system. While the symptoms and disability experienced by individuals with each condition are different, they all have a significant effect on people’s wellbeing. For doctors and people with these long-term or chronic conditions, understanding how their disease changes over time can help with its management. But in chronic conditions most of the symptoms and episodes happen outside of the health care environment. Measuring individuals’ symptoms, mood and daily function continuously, could help people gain better insight into their condition. RADAR-CNS receives funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 115902. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation program and EFPIA.

Patient participation in ERS guidelines and research projects: the EMBARC experience.

The European Multicentre Bronchiectasis Audit and Research Collaboration (EMBARC) is a European Respiratory Society (ERS) Clinical Research Collaboration dedicated to improving research and clinical care for people with bronchiectasis. EMBARC has created a European Bronchiectasis Registry, funded by the ERS and by the European Union (EU) Innovative Medicines Initiative Programme.From the outset, EMBARC had the ambition to be a patient-focussed project. In contrast to many respiratory diseases, however, there are no specific patient charities or European patient organisations for patients with bronchiectasis and no existing infrastructure for patient engagement. This article describes the experience of EMBARC and the European Lung Foundation in establishing a patient advisory group and then engaging this group in European guidelines, an international registry and a series of research studies.Patient involvement in research, clinical guidelines and educational activities is increasingly advocated and increasingly important. Genuine patient engagement can achieve a number of goals that are critical to the success of an EU project, including focussing activities on patient priorities, allowing patients to direct the clinical and research agenda, and dissemination of guidelines and research findings to patients and the general public. Here, we review lessons learned and provide guidance for future ERS task forces, EU-funded projects or clinical research collaborations that are considering patient involvement.Educational aimsTo understand the different ways in which patients can contribute to clinical guidelines, research projects and educational activities.To understand the barriers and potential solutions to these barriers from a physician’s perspective, in order to ensure meaningful patient involvement in clinical projects.To understand the barriers and potential solutions from a patient’s perspective, in order to meaningfully involve patients in clinical projects.

Practical implications of using real-world evidence (RWE) in comparative effectiveness research: learnings from IMI-GetReal.

In light of increasing attention towards the use of real-world evidence (RWE) in decision making in recent years, this commentary aims to reflect on the experiences gained in accessing and using RWE for comparative effectiveness research as a part of the Innovative Medicines Initiative GetReal Consortium and discuss their implications for RWE use in decision-making.

Competencies: A new currency for continuing professional development

“No research without trained researchers” has become the mantra of the EU-funded Innovative Medicines Initiative (IMI) education and training projects. However, it is often hard to determine the type of training required at different stages of a scientist’s career. The situation is further complicated by the constantly changing environment, e.g. the growth of disruptive technologies, societal expectations of biomedical sciences, the greater need for multi-disciplinary collaborations, and conservative or changing regulatory requirements. This article summarises the experience from a series of five EMTRAIN Public Private Partnership PhD workshops that included both scientific and transferrable skill training. This is followed by an example of a recently developed training programme, including a competency profile, for translational research and medicines development; the C-COMEND teaching programme. The emphasis is on competencies as a new currency for continuing professional development. Finally, this paper describes what we consider to be the next steps required by the scientific community to address solutions to the current training challenges so that society can benefit from the innovations that only science can provide.

EUPATI: Collaboration between patients, academia and industry to champion the informed patient in the research and development of medicines

The value of collaborations and partnerships between different stakeholders to achieve optimum outcomes in the medicines research and development process is being recognised. Historically, there has been a lack of collaboration with patients and many research consortiums consisting mainly of academia and/or industry partners. Although patient experts are able to bring valuable first-hand experience and insights, they might not possess detailed knowledge about medicines research and development to actively participate in the collaboration process. The European Patients’ Academy on Therapeutic Innovation (EUPATI) was established to deliver training to patient experts, and education resources to patient advocates and members of the health-interested public across Europe. EUPATI was launched in February 2012 and is a patient-led Innovative Medicines Initiative (IMI) project, with a multi-stakeholder consortium of patient advocates, academia, industry and not-for-profit organisations. Training and educational materials will be used for capacity building among patients, for educating patient advocates and for informing the health-interested public. The successful uptake of EUPATI’s materials will hopefully translate into a new paradigm of increased patient involvement across the entire medicines research and development process, bringing mutual benefits, including better medicines, to all stakeholders.

Model Description Language (MDL): A Standard for Modeling and Simulation

Recent work on Model Informed Drug Discovery and Development (MID3) has noted the need for clarity in model description used in quantitative disciplines such as pharmacology and statistics. 1-3 Cur ...

Abstract 3786: Multicenter evaluation of technology platforms for the enumeration of circulating tumor cells

Abstract Metastasis represents the deadliest feature of cancer, which is fueled by circulating tumor cells (CTCs) being released into the bloodstream from the primary tumor. In addition to the clinical value of CTC enumeration for metastatic risk assessment, CTCs are considered to be a minimally invasive source for studying the molecular and genetic features of the disease as well as response to anticancer therapy. Given the molecular heterogeneity of CTCs, which includes loss of epithelial surface marker expression, several microfluidic and filtration technology platforms were developed to overcome the limitations of surface marker dependent CTC enrichment. Here we describe the efforts of the Innovative Medicines Initiative (IMI) consortium CANCER-ID (www.cancer-id.eu), which represents a joint undertaking of experts from academia and pharmaceutical industry, in generating comparative data using different CTC enrichment platforms in a multicenter ring trial. To address clinically relevant subtypes of Non-Small Cell Lung Cancer (NSCLC), different NSCLC cell lines were profiled for genetic aberrations (mutations and copy number aberrations), expression of epithelial markers (epithelial cell adhesion molecule (EPCAM) and cytokeratins) as well as cell size. Cell lines were selected to generate spike-in samples using blood of healthy volunteers with informed consent in a centralized way. Analysis was performed by at least three CANCER-ID partners using different CTC enrichment technologies including the Siemens filtration device, the Parsortix PR1, VyCap filtration and the CellSearch system. To ensure quality and comparability of results, CANCER-ID partners established standard operation procedures (SOPs) for pre-analytic sample handling including sample fixation, storage and shipment. Special attention was paid on the development of SOPs for the actual CTC enrichment procedure and the integration of downstream applications including single cell isolation by DEPArray™ followed by Ampli1™ WGA and molecular and genetic characterization of isolated cells. Epitope-independent enrichment by filtration or microfluidic devices was evaluated by using NSCLC cells with substantially different cell size. In addition, comparative data on spike-in samples was generated using the EPCAM-expression dependent CellSearch system, which failed to detect EPCAM-negative tumor cells. In conclusion, the evaluation of different CTC enrichment technologies and the integration of workflows for downstream analysis of single cells blaze the trail for the next phase of IMI’s CANCER-ID, which includes the analysis of real-life NSCLC patient material. This work is supported by IMI JU & EFPIA (grant no. 115749). Citation Format: Sebastian Bender, Merlin V. Lütke-Eversloh, Rui P. Neves, NNikolas H. Stoecklein, Leon W. Terstappen, Barbara Baggiani, Martin H. Neumann, Thomas Krahn, Klaus Pantel, Thomas Schlange, Leonie L. Zeune. Multicenter evaluation of technology platforms for the enumeration of circulating tumor cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3786. doi:10.1158/1538-7445.AM2017-3786

Abstract 1733: Automated identification of circulating tumor cells by image analysis

Abstract In the field of Circulating Tumor Cell (CTC) research many new technologies are emerging to isolate CTCs. Some of them provide accompanying automated image analysis tools that present possible CTCs to the user. Others need fully manual image analysis. For all CTC isolation technologies the definition of a CTC based on the immuno-morphologic criteria is either customized to the specific platform or subjective to the user causing high interreader differences – a problem which may condemn many CTC-based clinical studies to failure. Thus, an important issue that the field is confronted with is the lack of a unified and standardized definition to classify a cellular object as a CTC. This problem is addressed within the European FP7 consortium CTCTrap and the Innovative Medicines Initiative (IMI) consortium CANCER-ID by the development of an open-source image analysis toolbox for CTC identification and enumeration. This toolbox is baptized ACCEPT (Automated CTC Classification, Enumeration and Phenotyping) and can process images generated by various CTC isolation technologies. The main software components are the Marker Characterization, the Full Detection and the Automatic Classification. The Marker Characterization tool aims at quantifying the antigens expressed by previously selected CTCs. The Full Detection tool is based on advanced mathematical methods to reliably detect all objects in the images, visualize the objects in scatter plots and enable the user to classify the cell types by the use of gates or selection of specific objects in the scatter plots or on the actual images. The Automatic Classification tool first detects all objects in the images followed by an automated classification approach that – as a result – presents found CTCs to the user. We demonstrate the effectiveness of these tools on two different datasets. The Marker Characterization tool was tested for Her2 expression on archived CTC images isolated and classified by the CellSearch system from patients with metastatic breast cancer. Investigators from three different institutes were asked to score these cells for Her2 positivity first on the images generated by the CellTracks Analyzer and afterwards using ACCEPT. We show that the improved CTC visualization provided in ACCEPT, combined with several measurements which we extract for each cell, can reduce the inter-user variability. The Full Detection and Automatic Classification tools of ACCEPT were tested on archived samples of patients with castration resistant prostate cancer processed with the CellSearch system as well as on microsieves obtained after filtration of the blood discarded by the CellSearch system. Results were compared with manually scored CTCs and showed the improvement of CTC classification by the availability of quantitative image analysis tools. The Open Source ACCEPT program will be available on the MCBP website (http://www.tnw.utwente.nl/mcbp). Citation Format: Leonie L. Zeune, Guus van Dalum, François-Clément Bidard, Jean-Yves Pierga, Tanja Fehm, Hans Neubauer, Brigitte Rack, Marianna Alunni-Fabbroni, Mateus Crespo, Johann de Bono, Leon W.M.M. Terstappen, Christoph Brune. Automated identification of circulating tumor cells by image analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1733. doi:10.1158/1538-7445.AM2017-1733

Abstract 5036: Correlation of preclinical antitumor activity of regorafenib in CRC-PDX xenografts with gene expression and clinical parameters of the primary tumor

Abstract Regorafenib is a small molecule inhibitor of multiple transmembrane and intracellular kinases involved in normal cellular functions and in pathologic processes such as oncogenesis, tumor angiogenesis, metastasis, and tumor immunity. Regorafenib is approved for the treatment of patients with metastatic colorectal cancer (CRC) who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if RAS wild-type, an anti-EGFR therapy or with locally advanced, unresectable or metastatic gastrointestinal stromal tumor (GIST) who have been previously treated with imatinib mesylate and sunitinib malate. Recently an overall survival benefit has been shown in patients with hepatocellular carcinoma (HCC) who had previously been treated with sorafenib (RESORCE). OncoTrack is an Innovative Medicines Initiative (IMI) sponsored project with the goal to improve the basis for identification of biomarkers based on the mechanisms of action of therapies approved for this indication. For this purpose, a panel of CRC-PDX xenografts was generated by the OncoTrack project. At the time of the analysis reported here fifty xenografts had been treated with regorafenib at a dose of 10 mg/kg/d or with vehicle for 24 days. The analysis of tumor growth rates (TGR) showed pronounced differences between different tumors and between vehicle and regorafenib treated models. The relative antitumor activity (relative TGR) of regorafenib varied between -0,13 (good response) and 0.0 (no response). Investigations of relative TGR in relationship to (non-) clinical parameters of the primary tumor such as age, gender, sidedness and tumor histology identified a marginally significant (p= 0.04) better response in tumors from younger patients. No other correlations were detected to this end, which may be due to the small sample number. To correlate antitumor activity of regorafenib with gene expression, RNA was isolated from sections of selected vehicle and regorafenib treated xenografts and hybrized on Affymetrix HuGene-2.1_st human transcriptome arrays. Expression profiles were subsequently analyzed using the Random Forests algorithm to identify gene expression signatures predicting response to regorafenib. The best signatures did not perform better than signatures derived after randomizing responses, i.e. no predictive signature could be identified. Further studies with larger samples sizes are necessary to improve the outcome of such an approach; however one should acknowledge that to date no predictive gene signatures could be identified for multikinase inhibitors, which may be intrinsic to their complex mechanism of action. The research reported here received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement 115234 (OncoTrack). Citation Format: Henrik Seidel, Jens Hoffmann, Ralf Lesche, Sylvia Grünewald, David Henderson, Dieter Zopf. Correlation of preclinical antitumor activity of regorafenib in CRC-PDX xenografts with gene expression and clinical parameters of the primary tumor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5036. doi:10.1158/1538-7445.AM2017-5036

METHODOLOGICAL AND LOGISTIC STRATEGIES FOR A LARGE MULTI-CENTER β-AMYLOID PET EUROPEAN PROJECT: AMYLOID IMAGING TO PREVENT ALZHEIMER’S DISEASE (AMYPAD)

‘Amyloid imaging to prevent Alzheimer's disease’ (AMYPAD; www.amypad.org) is a 5-year programme within the Innovative Medicines Initiative (IMI), a joint undertaking between the European Union and the European Federation of Pharmaceutical Industries and Associations (EFPIA). AMYPAD will study the impact of β-amyloid PET imaging on the diagnosis and management of AD, the natural history of amyloid accumulation in the pre-symptomatic stage of AD and the selection of individuals for secondary prevention trials. To this end, a network of ∼20 European PET centres aims to conduct a total of 6000 scans. AMYPAD's work package 2 (WP2) will support these goals by developing an efficient tracer supply strategy, setting-up a clinical imaging network, developing image acquisition, quality control and quantification protocols, and deploying a centralized platform for image transfer, analysis and sharing. Since both NeuraCeq (Piramal Imaging) and Vizamyl (GE Healthcare) will be used in AMYPAD, standardization of β-amyloid load measurements across tracers will be crucial to ensure full comparability of the quantitative outcomes of the project. On top of this, specific sub-studies in WP2 will focus on: 1) accurate determination of amyloid change rates though dynamic PET scanning, 2) further development of the role of PET/MR for β-amyloid imaging, 3) refinement of amyloid quantification methods, and 4) identification of lifestyle and environmental factors affecting amyloid accumulation. Quantitative outcomes in AMYPAD will be expressed in the Centiloid scale (Klunk et al. Alzheimers Dement. 2015) in order to ensure the full comparability across tracers and to enable generalization the project's results. At present, WP2 has designed the tracer distribution strategy, set-up the clinical imaging network, and deployed the platform for image transfer and quantification. AMYPAD will improve our understanding of the utility of β-amyloid PET imaging in both clinical and research contexts and will generate a large amount of image data of high value for research purposes. Through WP2, AMYPAD will apply methodologies for quantitative β-amyloid imaging and will leverage with EPAD (European Prevention of Alzheimer's Dementia) to reconcile the datasets gathered in the context of these two IMI projects and share them with the general scientific community.

EUROPEAN MEDICAL FRAMEWORK FOR ALZHEIMER'S DISEASE

The European Medical Information Framework for AD (EMIF-AD, www.emif.eu) was set-up to facilitate studies on predementia AD by enabling optimal use of existing data cohorts. The EMIF-AD platform aims to provide a catalogue with information on study characteristics of cohort studies, a database platform to store and pool data from different cohorts, and access to data from electronic health registries (EHR). EMIF-AD has developed a number of infrastructural tools: 1) a catalogue with metadata of clinical studies on aging and Alzheimer's disease; 2) a database instance on the tranSMART data platform that stores harmonized subject-level data; 3) a ‘switch-box’ that connects local databases to applications that store or search data; 4) harmonized EHRs using the OMOP data model. The catalogue includes currently information on 46 studies that have enrolled 47.000 subjects. The catalogue is accessible after registration (https://emif-catalogue.eu). The catalogue has been used to select 1000 non-demented subjects for multimodality biomarker studies. The tranSMART data-platform contains harmonized data of 10 cohorts including 4000 subjects with information on cognitive, genetic and biomarkers, including high dimensional -omic data. A number of studies are ongoing in EHR data sets. The EMIF-AD platform facilitates data access, data pooling and collaborative studies on early AD. The platform is open for other cohorts to join. EMIF-AD is funded by the EU/EFPIA Innovative Medicines Initiative (IMI) Joint Undertaking.

CROSS-SECTIONAL TRAJECTORIES OF NEURODEGENERATION, COGNITIVE AND PHYSICAL MARKERS IN COGNITIVELY NORMAL SUBJECTS AGED 60-100 YEARS

Ageing is related to neurodegeneration and decrease in cognitive functioning and physical performance. However, the trajectories of these changes during ageing are still unclear. The aim of this study is to explore the cross-sectional trajectories of neurodegeneration, cognitive functioning and physical performance in a cognitively normal population. We selected 210 subjects aged 60 years and older from the PreclinAD study and 22 subjects from the 90+ Study at the VU Medical Center. All subjects were cognitively normal (Clinical Dementia Rating = 0). Neurodegeneration markers were hippocampal volume on MRI and amyloid binding potential measured with positron emission tomography. Cognitive markers were MMSE, Digit Symbol Substitution Test, CERAD memory test and letter fluency. Markers of physical performance were grip strength and skeletal muscle mass (SMM). All measurements were Z transformed, with negative scores representing worse outcome, using subjects aged 60–65 years as reference group. Non-parametric local spline regression analysis (LOESS) was performed to determine trajectories of changes in each marker over age. Critical age was defined as the age at which the z-score of the ageing marker was significantly lower than that of the 60–65 year old reference group. Subjects had a mean age of 73.1 years (SD=10.1). Critical ages were between 65 and 70 years old, with the exception of letter fluency, which had a critical age of 78 years. The trajectories after the critical age differed between markers. Hippocampal volume showed the steepest decline compared to the reference group whereas amyloid load and SMM plateaued after the age of 85 years. In this cross-sectional study, neurodegeneration, cognitive and physical markers show specific trajectories with ageing. The stabilization of amyloid load and SMM at high age might be due to selection bias towards very old subjects who are resilient towards decline on these measures or who had a higher starting point. The observation that cognitive functioning continued to decline while amyloid load stabilized at high age, may suggest that amyloid pathology is a less important cause for cognitive decline at older ages. This work has received support from the EU/EFPIA Innovative Medicines Initiative Joint Undertaking EMIF grant agreement no. 115372. Cross-sectional trajectories of neurodegeneration, cognitive and physical markers.

CORRELATION OF GREY MATTER NETWORK MEASURES IN COGNITIVELY HEALTHY ELDERLY MONOZYGOTIC TWIN PAIRS

Grey matter connectivity is disrupted in Alzheimer's disease (AD), and has been associated with amyloid pathology and cognitive decline in non-demented subjects. The contribution of genetic and environmental factors to grey matter connectivity is currently unknown. To estimate the upper limit of genetic contribution to grey matter connectivity, we examined the similarity of this measure in cognitively healthy elderly monozygotic twin pairs. Monozygotic twin pairs were selected from the EMIF-AD PreclinAD study. Inclusion criteria were age ≥ 60 years and having a delayed recall score less than 1.5 SD of normative data. Single-subject grey matter networks were constructed from structural MRI. Small regions of interest were connected when they showed statistical similarity in cortical grey matter structure. We calculated network size, degree, connectivity density, betweenness centrality, normalized clustering coefficient and normalized path length. Monozygotic twin pair correlations were assessed for each connectivity measure after adjusting for age, gender and total grey matter volume. Since monozygotic twins are genetically identical, within pair correlations reflect the upper limit of genetic contribution to a trait. Correlations analyses were repeated for random (non-twin) pairings of subjects. We included 96 monozygotic twin pairs (n = 192 subjects) (age = 70.2 ± 7.3 years; 112 (58%) females; MMSE = 29.0 ± 1.1). All grey matter network properties were correlated in monozygotic twin pairs (figure 1). The highest correlation was found for network size (0.82, p<0.001) and lowest for connectivity density (0.45, p<0.001). The other correlations were: degree (0.53, p<0.001), betweenness centrality (0.79, p<0.001), normalized clustering coefficient (0.68, p<0.001), normalized path length (0.76, p<0.001). Estimating the correlation in non-twin pairs did not yield any significant results. In cognitively healthy elderly monozygotic twins, we found significant within pair correlations of grey matter connectivity. These data suggest that in addition to a moderate-strong genetic background for grey matter connectivity, also non-genetic factors substantially influence this trait. Future studies will focus on identifying environmental risk factors for grey matter connectivity disruptions and determinants of twin discordance. This work has received support from the EU/EFPIA Innovative Medicines Initiative Joint Undertaking EMIF grant agreement n°115372. Correlation of grey matter connectivity measures in monozygotic twins. Displayed are standardized residuals after correcting for age, gender, total grey matter volume. Betweenness centrality, normalized clustering coefficient and normalized path length were additionally corrected for connectivity density. rMZ = Pearson correlation within monozygotic twin pairs.

ACROSS-SESSION REPRODUCIBILITY OF AUTOMATIC WHITE MATTER HYPERINTENSITIES SEGMENTATION: A EUROPEAN MULTI-SITE 3T STUDY

PharmaCOG is an industry-academic European project aimed at identifying reliable biomarkers that are sensitive to disease progression in patients with mild cognitive impairment. Several automated methods for quantitative assessment of white matter hyperintensities (WMH) have been recently developed (for a review see Caligiuri, 2015). However, the longitudinal reproducibility of these approaches has been poorly investigated. Here we present preliminary work aimed at evaluating the across-session test-retest reproducibility of the automated WMH quantification computed with SPM12 (Schmidt, 2012) on a group of healthy elderly subjects. Eleven 3T MRI sites (Siemens, GE, Philips) participated across Italy, Spain, France, Germany, Greece and The Netherlands. The acquisition protocol includes one 2D FLAIR sequence: acceleration factor in the range of 1.5 to 2 where possible (GRAPPA, SENSE and ASSET in Siemens, Philips and GE systems, respectively), 0.9x0.9x4mm3, with TE/TR/TI as recommended by the ADNI project (Jack, 2008). Five local healthy volunteers (55–90 years) per site were scanned in two sessions a week apart. The segmentation of WMH was performed using lesion segmentation tool (LST) version 2.0.15 (Schmidt, 2012) with optimized parameters and applying the longitudinal correction. The WMH volume and number of lesions reliability for each subject was computed evaluating test-retest absolute differences relative to the mean. Visual assessment indicates good segmentation results. The WMH volume was comparable across sites (Kruskal–Wallis, p=.143) and was around 1.6 ml (SD=2.9). The reproducibility error of total WMH volume averaged across sites was 2.3% (SD= 7.0) while that reported for the lesion number was 1.9% (SD=7.0). None of the WMH volume reproducibility metrics showed MRI site effects (Kruskall-Wallis test, p>.185). Despite the differences of MRI scanner configurations across our 11 sites we found consistent WMH volumes and lesion count reliability. Our findings suggest that the WMH volume may be a reliable longitudinal marker in multisite studies. Pharmacog is funded by the EU-FP7 for the Innovative Medicine Initiative (grant n°115009).

Enabling personalized medicine in Europe by the European Commission's funding activities.

Personalized medicine (PM) is an emerging approach to prevention, diagnosis, treatment and care. It helps to address the challenge of the aging of the population, an increase in chronic disease and increasing healthcare costs. The EU is developing policies to move toward PM. This is underpinned by a sustained and significant investment starting in 2010. So far, a total of €3.2 billion has been invested in PM research across the medical innovation cycle 'from bench to bedside'. This investment has come from the research framework programs FP7 and Horizon 2020. About a third of the total investment has been made in the context of the Innovative Medicines Initiative, the largest public-private partnership in life sciences globally.

Series: Pragmatic trials and real world evidence: Paper 4. Informed consent

The GetReal consortium of the Innovative Medicines Initiative aims to develop strategies to incorporate real-world evidence earlier into the drug life cycle to better inform health care decision makers on the comparative risks and benefits of new drugs. Pragmatic trials are currently explored as a means to generate such evidence in routine care settings. The traditional informed consent model for randomized clinical trials has been argued to pose substantial hurdles to the practicability of pragmatic trials: it would lead to recruitment difficulties, reduced generalizability of the results, and selection bias. The present article analyzes these challenges and discusses four proposed alternative informed consent models: integrated consent, targeted consent, broadcast consent, and a waiver of consent. These alternative consent models each aim at overcoming operational and methodological challenges, while still providing patients all the relevant information they need to make informed decisions. Each consent model, however, relies on different attitudes toward the principle of respect for persons and the related duty to inform patients as well as represents different views on whether the common good demands moral duties from patients. Such normative consequences of modifying consent requirements should be at least acknowledged and ought to be assessed in light of the validity of empirical claims.

Thoughtflow: Standards and Tools for Provenance Capture and Workflow Definition to Support Model-Informed Drug Discovery and Development.

Pharmacometric analyses are complex and multifactorial. It is essential to check, track, and document the vast amounts of data and metadata that are generated during these analyses (and the relationships between them) in order to comply with regulations, support quality control, auditing, and reporting. It is, however, challenging, tedious, error‐prone, and time‐consuming, and diverts pharmacometricians from the more useful business of doing science. Automating this process would save time, reduce transcriptional errors, support the retention and transfer of knowledge, encourage good practice, and help ensure that pharmacometric analyses appropriately impact decisions. The ability to document, communicate, and reconstruct a complete pharmacometric analysis using an open standard would have considerable benefits. In this article, the Innovative Medicines Initiative (IMI) Drug Disease Model Resources (DDMoRe) consortium proposes a set of standards to facilitate the capture, storage, and reporting of knowledge (including assumptions and decisions) in the context of model‐informed drug discovery and development (MID3), as well as to support reproducibility: “Thoughtflow.” A prototype software implementation is provided.

Effect of appropriate combination therapy on mortality of patients with bloodstream infections due to carbapenemase-producing Enterobacteriaceae (INCREMENT): a retrospective cohort study

The best available treatment against carbapenemase-producing Enterobacteriaceae (CPE) is unknown. The objective of this study was to investigate the effect of appropriate therapy and of appropriate combination therapy on mortality of patients with bloodstream infections (BSIs) due to CPE. In this retrospective cohort study, we included patients with clinically significant monomicrobial BSIs due to CPE from the INCREMENT cohort, recruited from 26 tertiary hospitals in ten countries. Exclusion criteria were missing key data, death sooner than 24 h after the index date, therapy with an active antibiotic for at least 2 days when blood cultures were taken, and subsequent episodes in the same patient. We compared 30 day all-cause mortality between patients receiving appropriate (including an active drug against the blood isolate and started in the first 5 days after infection) or inappropriate therapy, and for patients receiving appropriate therapy, between those receiving active monotherapy (only one active drug) or combination therapy (more than one). We used a propensity score for receiving combination therapy and a validated mortality score (INCREMENT-CPE mortality score) to control for confounders in Cox regression analyses. We stratified analyses of combination therapy according to INCREMENT-CPE mortality score (0-7 [low mortality score] vs 8-15 [high mortality score]). INCREMENT is registered with ClinicalTrials.gov, number NCT01764490. Between Jan 1, 2004, and Dec 31, 2013, 480 patients with BSIs due to CPE were enrolled in the INCREMENT cohort, of whom we included 437 (91%) in this study. 343 (78%) patients received appropriate therapy compared with 94 (22%) who received inappropriate therapy. The most frequent organism was Klebsiella pneumoniae (375 [86%] of 437; 291 [85%] of 343 patients receiving appropriate therapy vs 84 [89%] of 94 receiving inappropriate therapy) and the most frequent carbapenemase was K pneumoniae carbapenemase (329 [75%]; 253 [74%] vs 76 [81%]). Appropriate therapy was associated with lower mortality than was inappropriate therapy (132 [38·5%] of 343 patients died vs 57 [60·6%] of 94; absolute difference 22·1% [95% CI 11·0-33·3]; adjusted hazard ratio [HR] 0·45 [95% CI 0·33-0·62]; p<0·0001). Among those receiving appropriate therapy, 135 (39%) received combination therapy and 208 (61%) received monotherapy. Overall mortality was not different between those receiving combination therapy or monotherapy (47 [35%] of 135 vs 85 [41%] of 208; adjusted HR 1·63 [95% CI 0·67-3·91]; p=0·28). However, combination therapy was associated with lower mortality than was monotherapy in the high-mortality-score stratum (30 [48%] of 63 vs 64 [62%] of 103; adjusted HR 0·56 [0·34-0·91]; p=0·02), but not in the low-mortality-score stratum (17 [24%] of 72 vs 21 [20%] of 105; adjusted odds ratio 1·21 [0·56-2·56]; p=0·62). Appropriate therapy was associated with a protective effect on mortality among patients with BSIs due to CPE. Combination therapy was associated with improved survival only in patients with a high mortality score. Patients with BSIs due to CPE should receive active therapy as soon as they are diagnosed, and monotherapy should be considered for those in the low-mortality-score stratum. Spanish Network for Research in Infectious Diseases, European Development Regional Fund, Instituto de Salud Carlos III, and Innovative Medicines Initiative.

EUropean prospective cohort study on Enterobacteriaceae showing REsistance to CArbapenems (EURECA): a protocol of a European multicentre observational study

IntroductionThe rapid worldwide spread of carbapenem-resistant Enterobacteriaceae (CRE) constitutes a major challenge. The aim of the EUropean prospective cohort study on Enterobacteriaceae showing REsistance to CArbapenems (EURECA), which is part...