Innovative Medicines Initiative Research Articles

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.

The ACTTION Guide to Clinical Trials of Pain Treatments: standing on the shoulders of giants.

The ACTTION Guide to Clinical Trials of Pain Treatments: standing on the shoulders of giants.

Data and knowledge management in translational research: implementation of the eTRIKS platform for the IMI OncoTrack consortium

BackgroundFor large international research consortia, such as those funded by the European Union’s Horizon 2020 programme or the Innovative Medicines Initiative, good data coordination practices and tools are essential for the successful collection, organization and analysis of the resulting data. Research consortia are attempting ever more ambitious science to better understand disease, by leveraging technologies such as whole genome sequencing, proteomics, patient-derived biological models and computer-based systems biology simulations.ResultsThe IMI eTRIKS consortium is charged with the task of developing an integrated knowledge management platform capable of supporting the complexity of the data generated by such research programmes. In this paper, using the example of the OncoTrack consortium, we describe a typical use case in translational medicine. The tranSMART knowledge management platform was implemented to support data from observational clinical cohorts, drug response data from cell culture models and drug response data from mouse xenograft tumour models. The high dimensional (omics) data from the molecular analyses of the corresponding biological materials were linked to these collections, so that users could browse and analyse these to derive candidate biomarkers.ConclusionsIn all these steps, data mapping, linking and preparation are handled automatically by the tranSMART integration platform. Therefore, researchers without specialist data handling skills can focus directly on the scientific questions, without spending undue effort on processing the data and data integration, which are otherwise a burden and the most time-consuming part of translational research data analysis.

Establishing a Framework for the Use of Social Media in Pharmacovigilance in Europe.

The Innovative Medicines Initiative (IMI) WEB-RADR (Web-Recognising Adverse Drug Reactions) project looked at opportunities and challenges in using social media in pharmacovigilance as a rapidly evolving source of large, real-time data, which could provide new information on the actual use of medicines and potential safety issues. Two of the objectives were to develop principles for continuous monitoring of the safety of medicines without overburdening established pharmacovigilance systems and to propose a regulatory framework on the use of social media in pharmacovigilance. As a starting point, a review of existing legal requirements and regulatory guidance on social media use in pharmacovigilance was performed based on a survey conducted in 2014–2015. Furthermore, input from two large stakeholder workshops and evidence gathered from the research performed by WEB-RADR on the analysis of social media data were taken into consideration. Whilst analytical results of WEB-RADR indicated limited value of social media in detecting or confirming signals for a majority of the drugs studied, it is important to establish a regulatory framework for the use of social media in pharmacovigilance. Thus, the screening and reporting of suspected adverse reactions remains an important pillar in monitoring the safety and efficacy of medicines and the identification of new safety issues. Principles as to how social media can be used in pharmacovigilance are absolutely needed to provide clarity to patients, healthcare professionals, medicines regulators and the pharmaceutical industry.Electronic supplementary materialThe online version of this article (10.1007/s40264-019-00811-8) contains supplementary material, which is available to authorized users.

Recommendations on the Use of Mobile Applications for the Collection and Communication of Pharmaceutical Product Safety Information: Lessons from IMI WEB-RADR.

Over a period of 3 years, the European Union’s Innovative Medicines Initiative WEB-RADR (Recognising Adverse Drug Reactions; https://web-radr.eu/) project explored the value of two digital tools for pharmacovigilance (PV): mobile applications (apps) for reporting the adverse effects of drugs and social media data for its contribution to safety signalling. The ultimate intent of WEB-RADR was to provide policy, technical and ethical recommendations on how to develop and implement such digital tools to enhance patient safety. Recommendations relating to the use of mobile apps for PV are summarised in this paper. There is a presumption amongst at least some patients and healthcare professionals that information ought to be accessed and reported from any setting, including mobile apps. WEB-RADR has focused on the use of such technology for reporting suspected adverse drug reactions and for broadcasting safety information to its users, i.e. two-way risk communication. Three apps were developed and publicly launched within Europe as part of the WEB-RADR project and subsequently assessed by a range of stakeholders to determine their value as effective tools for improving patient safety; a fourth generic app was later piloted in two African countries. The recommendations from the development and evaluation of the European apps are presented here with supporting considerations, rationales and caveats as well as suggested areas for further research.

Variation in the Plasma Membrane Monoamine Transporter (PMAT) (Encoded by SLC29A4) and Organic Cation Transporter 1 (OCT1) (Encoded by SLC22A1) and Gastrointestinal Intolerance to Metformin in Type 2 Diabetes: An IMI DIRECT Study.

Gastrointestinal adverse effects occur in 20-30% of patients with metformin-treated type 2 diabetes, leading to premature discontinuation in 5-10% of the cases. Gastrointestinal intolerance may reflect localized high concentrations of metformin in the gut. We hypothesized that reduced transport of metformin via the plasma membrane monoamine transporter (PMAT) and organic cation transporter 1 (OCT1) could increase the risk of severe gastrointestinal adverse effects. The study included 286 severe metformin-intolerant and 1,128 metformin-tolerant individuals from the IMI DIRECT (Innovative Medicines Initiative: DIabetes REsearCh on patient straTification) consortium. We assessed the association of patient characteristics, concomitant medication, and the burden of mutations in the SLC29A4 and SLC22A1 genes on odds of intolerance. Women (P < 0.001) and older people (P < 0.001) were more likely to develop metformin intolerance. Concomitant use of transporter-inhibiting drugs increased the odds of intolerance (odds ratio [OR] 1.72, P < 0.001). In an adjusted logistic regression model, the G allele at rs3889348 (SLC29A4) was associated with gastrointestinal intolerance (OR 1.34, P = 0.005). rs3889348 is the top cis-expression quantitative trait locus for SLC29A4 in gut tissue where carriers of the G allele had reduced expression. Homozygous carriers of the G allele treated with transporter-inhibiting drugs had more than three times higher odds of intolerance compared with carriers of no G allele and not treated with inhibiting drugs (OR 3.23, P < 0.001). Use of a genetic risk score derived from rs3889348 and SLC22A1 variants found that the odds of intolerance were more than twice as high in individuals who carry three or more risk alleles compared with those carrying none (OR 2.15, P = 0.01). These results suggest that intestinal metformin transporters and concomitant medications play an important role in the gastrointestinal adverse effects of metformin.

Quantitative contribution of efflux to multi-drug resistance of clinical Escherichia coli and Pseudomonas aeruginosa strains.

BackgroundEfflux pumps mediate antimicrobial resistance in several WHO critical priority bacterial pathogens. However, most available data come from laboratory strains. The quantitative relevance of efflux in more relevant clinical isolates remains largely unknown.MethodsWe developed a versatile method for genetic engineering in multi-drug resistant (MDR) bacteria, and used this method to delete tolC and specific antibiotic-resistance genes in 18 representative MDR clinical E. coli isolates. We determined efflux activity and minimal inhibitory concentrations for a diverse set of clinically relevant antibiotics in these mutants. We also deleted oprM in MDR P. aeruginosa strains and determined the impact on antibiotic susceptibility.FindingstolC deletion abolished detectable efflux activity in 15 out of 18 tested E. coli strains, and modulated antibiotic susceptibility in many strains. However, all mutant strains retained MDR status, primarily because of other, antibiotic-specific resistance genes. Deletion of oprM altered antibiotic susceptibility in a fraction of clinical P. aeruginosa isolates.InterpretationEfflux modulates antibiotic resistance in clinical MDR isolates of E. coli and P. aeruginosa. However, when other antimicrobial-resistance mechanisms are present, inhibition of MDR efflux pumps alone is often not sufficient to restore full susceptibility even for antibiotics with a dramatic impact of efflux in laboratory strains. We propose that development of novel antibiotics should include target validation in clinical MDR isolates.FundInnovative Medicines Initiative of European Union and EFPIA, Schweizerischer Nationalfonds, Swiss National Research Program 72, EU Marie Skłodowska-Curie program. The funders played no role in design, data collection, data analysis, interpretation, writing of the report, and in the decision to submit the paper for publication.

Ethical and social implications of using predictive modeling for Alzheimer’s disease prevention: a systematic literature review protocol

IntroductionThe therapeutic paradigm in Alzheimer’s disease (AD) has shifted towards secondary prevention, defined as an intervention aiming to prevent or delay disease onset in pre-symptomatic individuals at risk of developing...

Safety biomarker applications in drug development.

Biomarkers are invaluable drug development tools to assess and monitor safety in early clinical trials especially when exposure margins are limiting for promising therapeutics. Although progress has been made towards identifying and implementing translational safety biomarkers for a number of organ toxicities such as kidney and liver, significant biomarker gaps still exist to monitor toxicities for testis, pancreas, etc. Several precompetitive consortia [e.g., Predictive Safety Testing Consortia (PSTC), Innovative Medicines Initiative (IMI)] are working with industry, academia, government, patient advocacy groups and foundations with a goal to qualify biomarkers such that they can be used in preclinical studies and clinical trials to accelerate drug development. This manuscript discusses the complexities of novel biomarker discovery, validation and international regulatory qualifications intended for clinical trial applications and shares specific examples from Pfizer Research and Development. As safety biomarkers become widely accepted and qualified by the regulatory agencies, they will increasingly be implemented in early clinical trials, play a key role in decision making and facilitate the progression of promising therapeutics from preclinical through clinical development.

Research Collaborations and Quality in Research: Foes or Friends?

Collaboration is the cornerstone of nowadays research. Successful collaborative research and high research quality go hand in hand. Collaborative research needs to build on common and upfront expectations for the quality of its outputs. This is necessary to enable a trustful research environment where all are committed to contribute and can share the rewards. A governance and leadership are critical for this to happen as well as a policy for openness and for effective data sharing. Collaborative research is often large-scale research: to be successful it needs good research practice as an enabler. Collaborative projects are ideal vehicles to promote high research quality, among other by enabling the delivery of results of high external validity and the development and implementation of standards. Robustness of results increases when confirmed by combining different methods and tools and even more when results are obtained while sharing and learning different approaches and languages of science. When doing collaborative research, there is the best opportunity to combine the different experience and expertise of all partners by design to create a more efficient and effective environment conductive for high-quality research. Using as example the public-private partnership type of projects created by the Innovative Medicines Initiative, the chapter covers the key aspects of the complex relationship between collaborative research and quality of research providing insights on the critical factors for delivering both a successful collaboration in research and robust high-quality research outputs.

A Pathogenic Cytokine Network Is Associated with Pro-Inflammatory B Cells in Systemic Lupus Erythematosus Patients

Objective: This report presents translational research showing that a pathogenic cytokine network could stratify systemic lupus erythematosus (SLE) patients associated with B cell dysfunction. Methods: Forty-five patients with SLE and 48 healthy volunteers (HV) were recruited from 10 centers in Europe. Cytokines analyses on patient's sera were performed using the Luminex technology. Autoantibodies measurement was realized on analyzer IDS-iSYS chemiluminescent. Patient's phenotyping was performed on whole blood. Functional profiles were explored using flow cytometry and quantitative RT-PCR. Cytokines in supernatants were measured using a multiplex bead-based assay. Results: To better understand how the cytokine microenvironment could be associated with different disease status in patients, we profiled 12 cytokines using the Luminex technology in serum from 45 SLE patients and 48 HV. We thus documented a unique pathogenic cytokine cluster in a group of patient delineated by CXCL10, IL-6, and IFN-γ. This pathogenic network was associated with pro-inflammatory helper B cells and an increase in systemic autoreactivity. We thus designed an in vitro model to study cytokine networks involved in pro- and anti- inflammatory B-cell functions. We demonstrated that CD4+ CD45RA+ naive T cells (TRA) polarized B cells toward pro-inflammatory B cells defined by a memory-like phenotype and an exacerbated production of CXCL-10, IFN-γ, and IL-2. Conclusion: This composite analysis brings new insights on human B cell functional heterogeneity and, on the other hand, proposes a better stratification of SLE patients according to their functional cytokine microenvironment suggesting that combined biomarkers would be a great value to design new personalized treatments. Clinical Trial Number: Registered on clinicaltrials.gov NCT 02890121 and NCT 02890147. Funding Statement: The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking PRECISESADS under grant agreement n° 115565, resources of which are composed of financial contribution from the European Union's Seventh Framework Program (FP7/2007-2013) and EFPIA companies in kind contribution. Declaration of Interests: The authors declare no competing interests. Ethical Approval Statement: The study was performed in accordance with the Declaration of Helsinki and was approved by ethical committees at each site for respective sub-cohorts. All patients gave their informed consent for participating in the study, which was registered on clinicaltrials.gov NCT 02890121 and NCT 02890147.

SGSI project at CNAF

The Italian Tier1 center is mainly focused on LHC and physics experiments in general. Recently we tried to widen our area of activity and established a collaboration with the University of Bologna to set-up an area inside our computing center for hosting experiments with high demands of security and privacy requirements on stored data. The first experiment we are going to host is Harmony, a project part of IMI’s Big Data for Better Outcomes programme (IMI stands for Innovative Medicines Initiative). In order to be able to accept this kind of data we had to make a subset of our computing center compliant with the ISO 27001 regulation. In this article we will describe the SGSI project (Sistema Gestione Sicurezza Informazioni, Information Security Management System) with details of all the processes we have been through in order to become ISO 27001 compliant, with a particular focus on the separation of the project dedicated resources from all the others hosted in the center. We will also describe the software solutions adopted to allow this project to accept in the future any experiment or collaboration in need for this kind of security procedures.

European Prevention of Alzheimer’s Dementia Longitudinal Cohort Study (EPAD LCS): study protocol

IntroductionThe European Prevention of Alzheimer’s Dementia (EPAD) project is funded initially by the Innovative Medicines Initiative and has been established to overcome the major hurdles hampering drug development for secondary...

1387. Phase I Study to Evaluate the Safety and Pharmacokinetics (PK) of Single and Multiple Ascending Doses (SAD/MAD) of Intravenous (IV) Minocycline in Healthy Adult Subjects

BackgroundCarbapenem-resistant Acinetobacter baumannii infections are defined by the WHO as a critical threat. IV minocycline is approved in the United States for treatment of Acinetobacter infections at doses up to 200 mg BID. This study investigated safety and PK of single and multiple doses of IV minocycline, including doses higher than approved in the United States.MethodsThis was a randomized, double blind, placebo-controlled, SAD/MAD study of 6 doses (100–600 mg) of IV minocycline. Healthy adult subjects received a single dose of minocycline or placebo on Day 1, and 15 doses BID starting on Day 4. Safety was assessed throughout the study. Serial blood and urine samples were collected for PK assessment.ResultsSixty-nine healthy subjects were randomized, 49 were included in the PK analysis. No serious adverse events (AEs) occurred; 55 subjects (79.9%) reported study drug-related AEs; dizziness 40 (58.0%) and nausea 34 (49.3%) were the most common. All related AEs were mild except for seven subjects with moderate nausea and/or dizziness. Dosing in the 400 mg cohort was discontinued due to AEs, therefore MAD escalation was stopped. Subsequent cohorts were escalated for SAD and loading dose only.SAD Mean (SD) PK ParametersDose (mg)100200300400500600 N 888889Cmax (mg/L)0.99 (0.2)1.89 (0.4)3.35 (1.2)4.93 (1.8)4.36 (0.9)7.03 (2.4) T 1/2 (h)11.05 (2.1)13.70 (2.3)16.62 (3.9)17.55 (2.1)14.44 (2.7)17.27 (3.6)AUC0-∞(mg*h/L)9.73 (1.4)25.90 (6.9)39.16 (13.8)63.64 (18.2)53.76 (20.3)83.00 (29.4)Cl (L/h)10.48 (1.8)8.21 (2.2)8.28 (2.1)6.71 (1.7)10.25 (3.0)8.07 (2.8)Vss (L)156 (36.7)148 (36.6)158 (45.4)142 (38.0)179 (46.5)153 (52.8)AUC, area under the drug concentration–time curve; Cmax, maximum observed drug concentration; T1/2, half-life; Cl, plasma clearance; Vss, volume of distribution at steady state. N, number of subjects.ConclusionSingle IV doses of minocycline up to 600 mg were tolerated reasonably well, but the maximum tolerated multi-dose was 300 mg BID. Most common AEs were mild nausea and dizziness with evidence of increasing incidence but not increasing severity with increasing dose. Exposure increased in a dose proportional fashion with exception of the 500 mg dose. The dosage regimen selected for further studies will be a 600 mg loading dose followed by 300 mg BID.Disclosures O. A. Cornely, Innovative Medicines Initiative Joint Undertaking: Grant Investigator, Grant recipient. A. MacGowan, Merck: Commercial grant, Research support; Paratek: Commercial grant, Research support; VenatoRx: Commercial grant, Research support; Bayer: Commercial grant, Research support; Achaogen: Commercial grant, Research support; AiCuris: Collaborator and Commercial grant, Grant recipient and Research support; Polyphor: Commercial grant, Research support; Pfizer: Commercial grant, Research support; Roche: Commercial grant, Research support; Melinta: Industrial partner, Research support; MedImmune (AZ): Industrial partner (IMI), Research support; NIHR England: Grant Investigator, Grant recipient; MRC (UK): Grant Investigator, Grant recipient; Innovate UK: Grant Investigator, Grant recipient. Newton Fund (FCO): Grant Investigator, Grant recipient. S. K. Cammarata, Melinta Therapeutics, Inc.: Employee, Salary. K. Fusaro, Melinta Therapeutics: Employee, Salary. J. S. Loutit, The Medicines Company: Employee and Shareholder, Salary

Detection and prevalence of carbapenem-resistant Gram-negative bacteria among European laboratories in the COMBACTE network: a COMBACTE LAB-Net survey

Antimicrobial resistance (AMR) represents a global public health threat that jeopardises the progress medicine has made over the last century. To confront AMR, the Innovative Medicines Initiative (IMI) has supported the development of a large network of hospitals and laboratories in Europe as part of the New Drugs for Bad Bugs (ND4BB) programme and the COMBACTE projects. COMBACTE LAB-Net conducted a pilot survey on distribution and usage of carbapenem resistance detection methods among laboratories in the COMBACTE network in two clinical trials as part of the COMBACTE-CARE project. The survey was sent out to 211 laboratories in 20 European countries between May 2015 and June 2017. Answers were collected from 165 laboratories (78%). Sixty laboratories (36%) reported an outbreak of carbapenem-resistant (CR) Enterobacteriaceae during one of the two years preceding the completion of the survey. High rates of CR Acinetobacter spp. above 50% were reported by 74 laboratories (47%), particularly in the Western Balkan countries where the rates were sometimes higher than 90%. Apart from determining the antimicrobial susceptibility of isolates, laboratories also used various methods, such as Matrix Assisted Laser Desorption Ionization - Time of Flight (MALDI-TOF), Carbapenemase Nordmann-Poirel (Carba NP) test or molecular methods, to detect CR Gram-negative bacteria. The survey resulted in the selection of sites with high resistance rates that successfully recruited many patients in the EURECA observational clinical trial.

Quality management for academic laboratories: burden or boon? Professional quality management could be very beneficial for academic research but needs to overcome specific caveats.

EMBO Reports (2018) e47143 Basic and translational biomedical research explores biological and pathophysiological mechanisms with the aim of developing novel therapies, preventive measures, and diagnostics to improve human health. Disappointingly, however, most new therapies fail when they are tested in clinical trials. Although the causes of this “translational attrition” are diverse and often rooted in the complexity of the underlying biology, it has also become clear that methodology is a major issue. The “translational roadblock”, along with what has been dubbed a “reproducibility crisis” [1], has fueled discussions about the reliability and reproducibility of biomedical research in general. There is strong evidence that weaknesses in planning, conducting, analyzing, and (non)reporting of research [2], as well as misidentification or contamination of reagents, biologicals, and cell lines [3], are prevalent factors. Meta‐research has shown that these problems can lead to an inflation of effect size and false positives and consequently decrease the reproducibility and predictiveness of research results. At the same time, the increasing methodological complexity combined with the immense proliferation in research outputs greatly complicates the production and evaluation of reliable evidence. Pressure to publish and hypercompetition for resources further compromise the robustness and rigor of research. Arguably, basic and translational biomedical research has a quality problem. In the 1970s, US cars had major quality problems. By comparison, Japanese cars were much more reliable. The introduction of rigorous quality management in the production process was largely credited for this competitive advantage, which helped the Japanese car industry to dominate the market for decades to come. By now, most industries, including US car manufacturers, the health and pharmaceutical industries as well as clinical medicine, have established sophisticated quality management systems (QMS) on which they spend several percent of their budget. Clearly, these investments pay off as companies …

Development of an Infrastructure for the Prediction of Biological Endpoints in Industrial Environments. Lessons Learned at the eTOX Project.

In silico methods are increasingly being used for assessing the chemical safety of substances, as a part of integrated approaches involving in vitro and in vivo experiments. A paradigmatic example of these strategies is the eTOX project http://www.etoxproject.eu, funded by the European Innovative Medicines Initiative (IMI), which aimed at producing high quality predictions of in vivo toxicity of drug candidates and resulted in generating about 200 models for diverse endpoints of toxicological interest. In an industry-oriented project like eTOX, apart from the predictive quality, the models need to meet other quality parameters related to the procedures for their generation and their intended use. For example, when the models are used for predicting the properties of drug candidates, the prediction system must guarantee the complete confidentiality of the compound structures. The interface of the system must be designed to provide non-expert users all the information required to choose the models and appropriately interpret the results. Moreover, procedures like installation, maintenance, documentation, validation and versioning, which are common in software development, must be also implemented for the models and for the prediction platform in which they are implemented. In this article we describe our experience in the eTOX project and the lessons learned after 7 years of close collaboration between industrial and academic partners. We believe that some of the solutions found and the tools developed could be useful for supporting similar initiatives in the future.

PMU100 - MAPPING BENEFIT-RISK DECISION-MAKING PROCESSES AND IDENTIFYING DECISION POINTS WITH THE POTENTIAL TO INCLUDE PATIENT PREFERENCE INFORMATION THROUGHOUT THE MEDICAL PRODUCT LIFECYCLE

Patient preference information (PPI) has not been effectively integrated in decision-making throughout the medical product lifecycle (MPLC). A first step requires an understanding of existing processes and decision points to know how to incorporate PPI to improve patient-centric decision making. The aims were to: 1) identify the decision-making processes and decision points throughout the MPLC for stakeholders, and 2) determine which decision points have potential to include PPI. A 3-step approach was conducted, including a scoping literature review identifying relevant white and grey literature, validation meetings with stakeholders to confirm decision-making processes, and semi-structured interviews with representatives of 3 stakeholder groups (industry n=24, regulatory n=22, HTA n=24). The literature review was conducted using five scientific databases, and interviews were conducted within seven different European countries and the US. Six decision points were identified for industry decision-making process: 1) Select & prioritize targets and leads; 2) Prioritize studies; 3) Prioritize assets; 4) Optimize & Prioritize assets; 5) Regulatory Submission & Launch; and 6) Manage MPLC & Prioritize opportunities. Four decisions points for the regulatory decision-making process: 1) Submission and validation; 2) Scientific opinion; 3) Orphan designation; and 4) Commission decision. Six decision points for HTA decision-making: 1) Filtration; 2) Prioritization; 3) Appraisal; 4) Filtration II; 5) Prioritization II; and 6) Appraisal II. PPI is currently not considered required information to be submitted for decision-making, but has the potential to be included at most key decision points. Currently, PPI is not considered as obligatory information to submit for any of the MPLC decision points, nor is it a pre-set criterium for decision-making. PPI is considered an important component by most stakeholders to inform future decision-making across the MPLC. Acknowledgement: This work received support from the EU/EFPIA Innovative Medicines Initiative [2] Joint Undertaking PREFER grant n° 115966

PMU103 - INCORPORATING PSYCHOLOGICAL CONSTRUCTS INTO PATIENT PREFERENCE STUDIES: WHICH YOU SHOULD CONSIDER INCLUDING IN YOUR NEXT STUDY?

In healthcare decision-making, patients need to deliberate on specific risks, benefits, and preferences of different healthcare options. When eliciting patient preference (PP), it is necessary to identify, measure, and account for psychosocial constructs that may influence the construction and interpretation of PPs. This study aimed to identify: 1) Psychological constructs that could influence the construction of PP and explain PP heterogeneity; 2) Motivational factors for selecting psychological constructs to be measured in PP studies. We conducted a systematic review to identify psychological constructs affecting the construction and heterogeneity of PP. A list of motivational factors for identifying and selecting psychological constructs to be measured in PP studies was also developed. A total of 29 constructs were detected and categorized in these six categories: 1) cognition, 2) motivation, 3) individual differences, 4) emotion and mood, 5) health belief and 6) well-being and social support. Based on the strength of available evidence, these constructs were categorized into three class of recommendations: 1) Class I: constructs that should be measured in PP studies; 2) Class II: constructs that are reasonable to be measured in PP studies; 3) Class III: constructs that are not yet reasonable to be measured in PP studies. To help stakeholders to select psychological constructs relevant to their specific aim, the constructs were organized into 1) Constructs that may explain PP heterogeneity; 2) Constructs that may influence the formation process of preferences. Understanding PP heterogeneity is important for both product development and evaluation. This study indicates which psychological constructs influence PP and how healthcare stakeholders can measure them in PP studies. This work received support from the EU/EFPIA Innovative Medicines Initiative [2] Joint Undertaking PREFER grant n° 115966.

PSY202 - THE OCCUPATIONAL HAZARDS OF MEASURING RISK TOLERANCE: CONVERGENT VALIDITY IN PREFERENCE ELICITATION.

Given there is no consensus about the best way to elicit patients’ preferences, this study empirically test the consistency of responses to two different preference elicitation methods. Such research has been encouraged by the FDA and is one of the key motivators of the Innovative Medicine Initiative funded Patient Preferences in Benefit-Risk Assessments during the Drug Life Cycle project (PREFER). Two methods, thresholding and adapted swing weighting (ASW), were adopted to elicit patients’ minimum acceptable benefit (MAB) for pegvaliase, a treatment for phenylketonuria (PKU). Both elicitation methods used the same attributes and associated levels: the ability to lower phenylalanine (Phe) levels, and the likelihood of experiencing allergic reactions. To enable the reasons for differences in MAB obtained from these two exercises the participants were asked to outline their rational for their choices. Patients would require a minimum likelihood of 22.67% (ASW) to 34.4% (thresholding) of achieving a Phe level less 360 μmol/L before they would tolerate the risks. This is less than the benefit generated by pegvaliase. There was no relationship between MAB and patient’s current Phe level, perception of PKU control, or satisfaction with treatment. Seven participants had their MAB increase significantly between the ASW and the thresholding exercise. In four cases, this was explained by their refusal to take an injectable, which was an aspect highlighted in the introduction to the thresholding but not in the ASW exercise. The insight generated by both methods supported patients would be willing to take pegvaliase despite its risks, and both methods drew the same conclusions with regards to treatment preference. Also, this study highlights the impact of the elicitation format and framing of questions on the elicited trade-offs. The introduction of the treatment characteristic could explain most of the discrepancies between the MABs in the two exercises.