Innovative Medicines Initiative Research Articles

The European Prevention of Alzheimer’s Dementia Programme: Summary outputs post Innovative Medicines Initiative Funding

AbstractBackgroundThe in 2015 initiated European Prevention of Alzheimer’s Dementia (EPAD) programme was funded by the Innovative Medicines Initiative (IMI), a European Union led programme that brought commercial, academic, and third sector organisations together. A key part of the project was the development of the EPAD Longitudinal Cohort Study (LCS) to test existing and develop new disease models regarding the pre‐dementia phases of Alzheimer’s disease (AD). After 2020, the maintenance of the EPAD Dataset and Biorepository was supported from multiple sources, including the Alzheimer’s Association and Gates Ventures. EPAD was the first dataset to be uploaded onto the AD Workbench, directly supporting the development of this key part of the Alzheimer’s Disease Data Initiative (ADDI).MethodEPAD‐LCS data is openly available on the AD workbench, with access being split into 3 domains: Data Only, Biological Samples (CSF, Blood, Saliva, and Urine), and (advanced) MRI data. Access to these data sets is monitored and reported on closely via the AD Workbench. More recently the NTK App developed by Roche Diagnostics has been embedded on the AD Workbench as a free‐to‐use app to ease data analysis from EPAD and other cohorts on the AD Workbench.ResultThe total number of requests for data will be presented grouped by research question domain, geographic location, and academic/commercial split. The outputs from these data requests in terms of academic publications will be presented with a summary of where these findings are pointing towards in terms of new insights in our understanding of preclinical and prodromal AD. Operational aspects will also be presented with regards speed of access from initial enquiry, through application to provision of data and samples.ConclusionThe EPAD‐LCS is a major pan‐European study which has generated vast amounts of data across a comprehensive range of biological, clinical, and epidemiological variables. Access to this data to generate new knowledge is free for anyone and we prioritised rapid access to a data environment that facilitates analysis. Combining the major programmes of EPAD, ADDI and the NTK App has been shown to achieve the core objective of knowledge generation which research participants expect.

The European Platform for Neurodegenerative Diseases (EPND)

AbstractBackgroundBiomarker discovery, development, and validation are reliant on large‐scale analyses of high‐quality samples and data. However, discovery, access, and sharing of data and samples are hindered both by silos that limit collaboration, and by complex requirements for secure, legal, and ethical sharing. The European Platform for Neurodegenerative Diseases (EPND) project aims to address these challenges and accelerate biomarker discovery, development and validation, by building a scalable, sustainable platform for collaboration, data and sample sharing. In this presentation we will give an overview of the design of EPND and the achievements in the first year of this 5‐year project.MethodEPND is a multidisciplinary consortium of 29 public and private partners with expertise on data discovery, ethical, legal and regulatory aspects of data sharing, biomarker studies, stakeholder engagement and sustainability. EPND will leverage existing data and research infrastructures, including the Alzheimer’s Disease Data Initiative (ADDI) AD Workbench, which will allow the platform to connect to a global research network. EPND was launched in November 2021 and is funded by the Innovative Medicines Initiative (IMI, grant agreement number 101034344, epnd.org).ResultIn this first year of the project, the design of the data platform has been finalised. EPND has launched its Cohort Catalogue, which features information on participants, samples and data from 60+ neurodegeneration cohorts, spanning 17 countries and 13 disease areas, and involving over 155,000 patients. In addition to standardised operational procedures on sample selection, biobanking, and data harmonisation, we have also developed a white paper on legal, ethical and regulatory aspects of data and sample sharing. Finally, we have performed case studies on ATN biomarkers in plasma and blood in 350 patients with Alzheimer’s disease, Parkinson’s disease and Lewy body dementia.ConclusionWe initiated a multidisciplinary consortium with the goal to accelerate collaborative research into the discovery and validation of biomarkers, to support development of diagnostics and disease‐modifying therapies for AD and other neurodegenerative diseases.

Motor‐cognitive dual tasking in the clinical setting: a sensitive measure of functional impairment in early Alzheimer’s disease

AbstractBackgroundGait is a complex everyday activity that depends upon supraspinal activity and a host of cognitive functions such as attention and executive functions. As cognition declines in neurodegenerative diseases, the interaction and competition for neuronal resources during motor‐cognitive dual‐tasking (e.g., walking while talking) might be a sensitive measure of subtle functional impairments in early Alzheimer’s disease (AD). Here, we aim to identify gait deficits due to neuronal competition across the AD spectrum.MethodThis investigation is part of the ongoing Remote Assessment of Disease and Relapse – Alzheimer’s Disease (RADAR‐AD) study. We attached three inertial measurement units (accelerometer and gyroscope) to both feet and one hip to assess dual task effects (DTE) assessing gait performance with/without concurrent serial subtraction‐by‐1 task in four groups: 1) amyloid negative healthy controls (HC, N = 59); and 2) amyloid positive preclinical AD (PreAD, N = 30); 3) prodromal AD (ProAD, N = 51); and 4) mild‐to‐moderate AD dementia (MildAD, N = 44) (Table 1). We furthermore investigated associations of DTE with observer‐reported cognition.ResultGroup comparisons showed that dual‐tasking induced lower cadence and increased stance, which were significantly different between HC and ProAD. Several DTE measures of variability differed significantly between PreAD and MildAD, with variability in the path length separating best between PreAD and ProAD (Table 2, Figure 1). DTE measures were associated with observer‐rated divided attention only in the MildAD group.ConclusionNeuronal competition as assessed with motor‐cognitive dual‐tasking, specifically the DTE variability, might reflect functional deficits already in early AD, and could be a valuable additional measure to detect early impairments not captured by cognitive or motor tests alone. Future studies should implement an adaptive cognitive load to improve sensitivity/specificity in early AD stages and investigate the use of sensor technologies in predicting and monitoring changes in gait and fall prevention in later stages of the disease. This work has received support from the EU/EFPIA Innovative Medicines Initiative Joint Undertaking (grant No 806999). www.imi.europa.eu. This communication reflects the views of the RADAR‐AD consortium and neither IMI nor the European Union and EFPIA are liable for any use that may be made of the information contained herein.

Remote assessment of functional impairment in Alzheimer’s disease: results of the RADAR‐AD study

AbstractBackgroundRemote monitoring technologies (RMTs), such as smartphone apps and smartwatches, are changing the way functional and cognitive performance are measured in Alzheimer’s disease (AD). Due to their sensitivity, objectivity, and the option of long‐term and continuous measurement, RMTs have the potential to detect a subtle decline in the earliest stages of AD. Here, we present the results of the European RADAR‐AD project (Remote Assessment of Disease and Relapse – Alzheimer’s disease), which aims to test feasibility, acceptability and validity of RMT measures across all stages of AD, from cognitively normal to mild dementia.MethodFour study groups (amyloid negative healthy controls, and amyloid positive preclinical AD, prodromal AD, mild‐to‐moderate AD) were included in this cross‐sectional study (N = 175). During 8 weeks, participants wore two activity trackers (Fitbit and Axivity) measuring physical activity, heart rate and sleep continuously, and used two interactive smartphone apps (Mezurio and Altoida’s research algorithm: DNS‐MCI) measuring cognition daily/weekly. At baseline, participants underwent extensive neuropsychological, physical examinations, and did two sensor‐based tests (banking app and walk test). Features were extracted for all RMTs (Figure 1) and compared across groups using ANCOVA, with adjustment for relevant confounders. This study is part of an ongoing investigation into high‐end multimodal analyses for real‐world functional performance of continuous RMT data streams.ResultCompliance was high, but decreased with cognitive impairment (feasibility). User experience did not differ between groups but was lower for smartwatches compared to interactive smartphone apps (Table 1) (acceptability). Various individual sensors discriminated symptomatic AD participants from asymptomatic participants (p<0.05), for example the two active apps, but did not discriminate preclinical AD from healthy controls (Table 1) (validity).ConclusionThe RADAR‐AD study provides unique insights in the feasibility, acceptability, and validity of remote monitoring of functional abilities in AD and their potential to differentiate between syndromic stages. This work has received support from the EU/EFPIA Innovative Medicines Initiative Joint Undertaking (grant No 806999) and their associated partners. www.imi.europa.eu. This communication reflects the views of the RADAR‐AD consortium and neither IMI nor the European Union and EFPIA are liable for any use that may be made of the information contained herein.

A multimodal digital biomarker of functional deficits in early‐stage Alzheimer’s disease: results of the RADAR‐AD study

AbstractBackgroundRemote monitoring technologies (RMTs), such as smartphone apps, smartwatches, and in‐home sensors, are rapidly changing the way functional and cognitive performance is measured in Alzheimer’s disease (AD) patients. Here, we present results from the European RADAR‐AD study on the use of multimodal data streams for the identification of functional deficits across all syndromic stages of AD.MethodFour study groups (Healthy controls (HC), preclinical AD (pre. AD), prodromal AD (pro. AD), and mild AD) were included in this cross‐sectional study. The RMT features (gait measures from Timed up and Go (TUG), Dual Task Effect (DTE) using physilog, acoustic features from Speech task in Mezurio, neurocognitive function using Altoida, managing finances with Banking app) with in‐clinic neuropsychological (NP) tests, activities of daily living with Amsterdam IADL and demographics (age, gender, education years) were analyzed for different combinations of the multimodal digital biomarker of disease stage in AD across different pairwise comparisons. The analysis includes data from 175 participants (HC = 67, Pre.AD = 26, Pro.AD = 50, Mild AD = 32) collected for 8 weeks. An extreme gradient boosting (XGBoost) machine learning model was trained to obtain a multimodal biomarker of AD disease stage with repeated cross‐validation (5‐fold with 4 repeats) (Figure 1). This investigation is part of the ongoing RADAR‐AD study.ResultThe multimodal combination of RMTs achieved a mean AUC of > 0.60 in all pairwise comparisons with a mean AUC > 0.65 for HC vs (Pre.AD, Pro.AD and Mild) (Figures 2 and 3). The addition of NP tests increases the performance considerably across all pairwise comparisons except HC vs Pre.AD.ConclusionOur results highlight the advantage of combining RMTs to identify functional deficits in the early stage of AD. In particular, in prodromal and mild AD patients, a combined signal shows much more strength compared to individual tests. This work has received support from the EU/EFPIA Innovative Medicines Initiative Joint Undertaking (grant No 806999). www.imi.europa.eu. This communication reflects the views of the RADAR‐AD consortium and neither IMI nor the European Union and EFPIA are liable for any use that may be made of the information contained herein.

First insights exploring Activities of Daily Living performance captured through activity sensors in a Smart Home Environment as an indicator of cognitive decline: A cross‐sectional Analysis

AbstractBackgroundSmart homes offer a unique potential not only for supporting various users’ needs but also for monitoring their activities. Herein the findings of the RADAR‐AD Smart Home study are presented. Using data from activity sensors installed in a smart home environment simulating real‐life conditions, we aim to detect deficits while performing Activities of Daily Living (ADLs) in three known groups of people in different stages of cognitive decline related to Alzheimer’s Disease (AD).MethodIn a fully equipped Smart Home (https://smarthome.iti.gr/), Fibaro smart plugs (to monitor power consumption), motion‐, door‐, flood‐sensors and panic buttons were installed. During their 24 hour visit, participants [13 Healthy Control (HC), 14 Preclinical AD (PreAD), 13 Prodromal AD (ProAD)] (Table 1) followed a protocol listing a number of ADLs (e.g., meal/beverage preparation) (Table 1). Data collection, feature extraction (i.e., activity duration, number of repetitions) and visualization of ADLs were performed through the CARL data collection and analysis platform for assisted living (https://carl.iti.gr/). (Figure 1). Two‐Way ANOVA and Mann‐Whitney were used to test the statistical significance between the groups.ResultComparing Activity Duration for different ADLs and groups (Figure 2), HC executed the ADLs in less time compared to PreAD and ProAD, while PreAD showed no difference in the majority of the tasks compared to ProAD. Three activities were completed by 50% of the HC, 36% of the PreAD and only 17% of the ProAD. Two‐way ANOVA revealed a statistically significant interaction between the effects of cognitive decline and Activity Duration F(3,106) = 3.504, p = 0.034. Mann‐Whitney analysis for the complex task “Meal Preparation” showed decreased duration for HC compared to PreAD (U = 33.00, p = 0.042) and ProAD (U = 17.00, p = 0.052).ConclusionThe RADAR‐AD Smart Home study provides a proof‐of‐concept for the use of home‐based sensors for investigating ADLs in patients with cognitive decline. This work has received support from the EU/EFPIA Innovative Medicines Initiative Joint Undertaking (grant No 806999). www.imi.europa.eu. This communication reflects the views of the RADAR‐AD consortium and neither IMI nor the European Union and EFPIA are liable for any use that may be made of the information contained herein.

Editorial: Impacts of public-private collaborative research on Alzheimer's disease: the case of the innovative medicines initiative

Editorial: Impacts of public-private collaborative research on Alzheimer's disease: the case of the innovative medicines initiative

Role of Allogeneic Stem Cell Transplantation in Preventing Relapse in Adult BCR::ABL1-like Acute Lymphoblastic Leukemia

Background Philadelphia-like acute lymphoblastic leukemia (Ph-like ALL) is characterized by the activation of several kinase pathways that promote treatment resistance leading to poor survival of patients at all ages. Despite the use of tyrosine kinase inhibitors in the Ph-like ABL-class subtype (15% Ph-like ALL), there is not a consensus approach for treatment of most patients (JAK-class especially), and the role of allogeneic stem cell transplantation (alloSCT) has scarcely been explored so far (i.e., mandatory vs. MRD-oriented). Objective To assess the outcome of Ph-like patients enrolled in the ongoing ALL19 trial from the Programa Español de Tratamientos en Hematología (PETHEMA) for adults (18-60y) with Ph-negative ALL, and to evaluate the effectiveness of alloSCT in first complete remission (CR). Methods In the ALL19 trial, patients are allocated to alloSCT according both to the end of induction (EOI) measurable residual disease (MRD) level and to high-risk genetic markers such as low-hypodiploidy, KMT2A rearrangement, TP53 biallelic alteration and concomitant deletion of IKZF1 and CDKN2A/B. Therefore, BCR::ABL1-like subtype was not a criteria for early transplantation unless meeting either poor MRD clearance at EOI or concomitant deletion of IKZF1+CDKN2A/B. Patients with MRD≥0.01% on day+35 (EOI) and/or high-risk genetics were assigned to early alloSCT (preceded by 1 cycle of consolidation chemotherapy) while those with good MRD clearance and standard risk genetics received early and delayed consolidation (3 cycles each) and maintenance therapy. Bone marrow or peripheral blood samples were analyzed by G-banding+FISH, SNP array (750K Affymetrix, Thermo Fisher) and next generation sequencing (NGS, with a custom DNA gene panel, Illumina) at diagnosis in 4 reference laboratories. MRD was centrally assessed by next generation flow cytometry with a sensitivity up to 2x10 -6. Results Twenty-four Ph-like out of 248 adult BCP ALL (10%) were detected. Baseline characteristics were similar between Ph-like and the remaining BCP-ALL. Most Ph-like ALL patients showed the JAK-class profile (20/24 [83%]: 17/24 CRLF2 rearrangement[r], 1/24 JAK2r, 1 BLNK::DNTT and 1 JAK2 R683 mutation), 3/24 belonged to the ABL-class subtype (2 ABL2r, 1 NUP214::ABL1) and 1 patient was identified by RNAseq (gene expression profiling similar to BCR::ABL1 ALL) without identifying any rearrangement. Regarding secondary genetic alterations, 17/24 (71%) patients showed the IKZF1 plus profile, 10/23 (43%) harbored JAK2 R683 mutation, 4/23 N/KRAS mutations, 2/23 CRLF2 mutation and 1/23 showed mutations in several genes such as IKZF1, NR3C1 or FLT3, among others. There were no significant differences in the probability of achieving CR between Ph-like and the remaining BCP ALL (15/20 [75%] vs. 137/162 [85%], p=0.334). However, EOI MRD level of Ph-like individuals was significantly poorer (MRD<0.01% Ph-like 4/15 [27%] vs. other BCP-ALL 85/136 [63%], p=0.007). By intention to treat, most Ph-like patients (17/19, 89%) were allocated to alloSCT (vs. 91/153 [59%] in the other BCP-ALL, p=0.011) due to either EOI MRD≥0.01% (9/18), IKZF1+CDKN2A/B concomitant deletions (3/18) or both (6/18). The 2-y overall survival (OS) in both groups was not significantly different (57% [95% CI, 27%-78%] vs. 67% [55%-77%, p=0.304]) (Figure 1). Interestingly, most Ph-like patients died due to treatment-related toxicity (2 transplant-related mortality, 1 CART-related, 1 during induction, 1 in CR and 1 by COVID-19 infection). The 2-y cumulative incidence of relapse (CIR) was also similar (Ph-like 27% [8%-50%] vs. other BCP-ALL 35% [25%-45%], p=0.946) (Figure 1). Conclusions Despite the short follow up of this series, our results show that Ph-like ALL patients have poorer EOI MRD clearance and higher rate of alloSCT realization than the remaining BCP ALL patients, without significant differences in outcome. This suggests that early alloSCT in first CR might overcome the poor prognosis of Ph-like ALL patients. Funding Funded in part by: PI10/01417 y FIS PI19/01183 Ministerio de Salud Carlos III, JCyL_SA118P20, FMM21/002_AP176752021, “La Caixa” Foundation, Pfizer Spain, Fundación PETHEMA. This project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement No IMI001-07. The JU receives support from the European Union's Horizon 2020 research and innovation programme and EFPIA.

Rheumatology tolerance for cure (RTCure) – an IMI project aimed at prevention and cure of RA

The RT Cure project, supported from the Innovative Medicines Initiative (IMI) has been active for 6 years and involved several European and one Australian rheumatology institutions, six major pharma companies and a few small companies. The present report describes the major aims and results of the project which includenew understanding of specificity and regulation a of adaptive immunity that precedes RA and is active in established disease.use this understanding to predict risk for RA and establish registers of at risk for RA cohorts.support for clinical trials aimed at prevention of RA with knowledge and tools for immune surveillance.The progress in these areas, including the support to successful clinical trials for prevention will provide a basis for further development of prevention of RA using increasingly specific immunotherapies.

Electronic health records (EHRs) in clinical research and platform trials: Application of the innovative EHR-based methods developed by EU-PEARL

ObjectiveElectronic Health Record (EHR) systems are digital platforms in clinical practice used to collect patients’ clinical information related to their health status and represents a useful storage of real-world data. EHRs have a potential role in research studies, in particular, in platform trials. Platform trials are innovative trial designs including multiple trial arms (conducted simultaneously and/or sequentially) on different treatments under a single master protocol. However, the use of EHRs in research comes with important challenges such as incompleteness of records and the need to translate trial eligibility criteria into interoperable queries. In this paper, we aim to review and to describe our proposed innovative methods to tackle some of the most important challenges identified. This work is part of the Innovative Medicines Initiative (IMI) EU Patient-cEntric clinicAl tRial pLatforms (EU-PEARL) project’s work package 3 (WP3), whose objective is to deliver tools and guidance for EHR-based protocol feasibility assessment, clinical site selection, and patient pre-screening in platform trials, investing in the building of a data-driven clinical network framework that can execute these complex innovative designs for which feasibility assessments are critically important. MethodsISO standards and relevant references informed a readiness survey, producing 354 criteria with corresponding questions selected and harmonised through a 7-round scoring process (0–1) in stakeholder meetings, with 85% of consensus being the threshold of acceptance for a criterium/question. ATLAS cohort definition and Cohort Diagnostics were mainly used to create the trial feasibility eligibility (I/E) criteria as executable interoperable queries. ResultsThe WP3/EU-PEARL group developed a readiness survey (eSurvey) for an efficient selection of clinical sites with suitable EHRs, consisting of yes-or-no questions, and a set-up of interoperable proxy queries using physicians’ defined trial criteria. Both actions facilitate recruiting trial participants and alignment between study costs/timelines and data-driven recruitment potential. ConclusionThe eSurvey will help create an archive of clinical sites with mature EHR systems suitable to participate in clinical trials/platform trials, and the interoperable proxy queries of trial eligibility criteria will help identify the number of potential participants. Ultimately, these tools will contribute to the production of EHR-based protocol design.

Sharing Medical Big Data While Preserving Patient Confidentiality in Innovative Medicines Initiative: A Summary and Case Report from BigData@Heart.

Sharing individual patient data (IPD) is a simple concept but complex to achieve due to data privacy and data security concerns, underdeveloped guidelines, and legal barriers. Sharing IPD is additionally difficult in big data-driven collaborations such as Bigdata@Heart in the Innovative Medicines Initiative, due to competing interests between diverse consortium members. One project within BigData@Heart, case study 1, needed to pool data from seven heterogeneous data sets: five randomized controlled trials from three different industry partners, and two disease registries. Sharing IPD was not considered feasible due to legal requirements and the sensitive medical nature of these data. In addition, harmonizing the data sets for a federated data analysis was difficult due to capacity constraints and the heterogeneity of the data sets. An alternative option was to share summary statistics through contingency tables. Here it is demonstrated that this method along with anonymization methods to ensure patient anonymity had minimal loss of information. Although sharing IPD should continue to be encouraged and strived for, our approach achieved a good balance between data transparency while protecting patient privacy. It also allowed a successful collaboration between industry and academia.

Safety and immunogenicity of the two-dose heterologous Ad26.ZEBOV and MVA-BN-Filo Ebola vaccine regimen in infants: a phase 2, randomised, double-blind, active-controlled trial in Guinea and Sierra Leone

This study assessed the safety and immunogenicity of the Ad26.ZEBOV and MVA-BN-Filo Ebola virus (EBOV) vaccine regimen in infants aged 4-11 months in Guinea and Sierra Leone. In this phase 2, randomised, double-blind, active-controlled trial, we randomly assigned healthy infants (1:1 in a sentinel cohort, 5:2 for the remaining infants via an interactive web response system) to receive Ad26.ZEBOV followed by MVA-BN-Filo (Ebola vaccine group) or two doses of meningococcal quadrivalent conjugate vaccine (control group) administered 56 days apart. Infants were recruited at two sites in west Africa: Conakry, Guinea, and Kambia, Sierra Leone. All infants received the meningococcal vaccine 8 months after being randomly assigned. The primary objective was safety. The secondary objective was immunogenicity, measured as EBOV glycoprotein-binding antibody concentration 21 days post-dose 2, using the Filovirus Animal Non-Clinical Group ELISA. This study is registered with ClinicalTrials.gov (NCT03929757) and the Pan African Clinical Trials Registry (PACTR201905827924069). From Aug 20 to Nov 29, 2019, 142 infants were screened and 108 were randomly assigned (Ebola vaccine n=75; control n=33). The most common solicited local adverse event was injection-site pain (Ebola vaccine 15 [20%] of 75; control four [12%] of 33). The most common solicited systemic adverse events with the Ebola vaccine were irritability (26 [35%] of 75), decreased appetite (18 [24%] of 75), pyrexia (16 [21%] of 75), and decreased activity (15 [20%] of 75). In the control group, ten (30%) of 33 had irritability, seven (21%) of 33 had decreased appetite, three (9%) of 33 had pyrexia, and five (15%) of 33 had decreased activity. The frequency of unsolicited adverse events was 83% (62 of 75 infants) in the Ebola vaccine group and 85% (28 of 33 infants) in the control group. No serious adverse events were vaccine-related. In the Ebola vaccine group, EBOV glycoprotein-binding antibody geometric mean concentrations (GMCs) at 21 days post-dose 2 were 27 700 ELISA units (EU)/mL (95% CI 20 477-37 470) in infants aged 4-8 months and 20 481 EU/mL (15 325-27 372) in infants aged 9-11 months. The responder rate was 100% (74 of 74 responded). In the control group, GMCs for both age groups were less than the lower limit of quantification and the responder rate was 3% (one of 33 responded). Ad26.ZEBOV and MVA-BN-Filo was well tolerated and induced strong humoral responses in infants younger than 1 year. There were no safety concerns related to vaccination. Janssen Vaccines & Prevention and Innovative Medicines Initiative 2 Joint Undertaking. For the French translation of the abstract see Supplementary Materials section.

Study design for development of novel safety biomarkers of drug-induced liver injury by the translational safety biomarker pipeline (TransBioLine) consortium: a study protocol for a nested case–control study

A lack of biomarkers that detect drug-induced liver injury (DILI) accurately continues to hinder early- and late-stage drug development and remains a challenge in clinical practice. The Innovative Medicines Initiative’s TransBioLine consortium comprising academic and industry partners is developing a prospective repository of deeply phenotyped cases and controls with biological samples during liver injury progression to facilitate biomarker discovery, evaluation, validation and qualification.In a nested case–control design, patients who meet one of these criteria, alanine transaminase (ALT) ≥ 5 × the upper limit of normal (ULN), alkaline phosphatase ≥ 2 × ULN or ALT ≥ 3 ULN with total bilirubin > 2 × ULN, are enrolled. After completed clinical investigations, Roussel Uclaf Causality Assessment and expert panel review are used to adjudicate episodes as DILI or alternative liver diseases (acute non-DILI controls). Two blood samples are taken: at recruitment and follow-up. Sample size is as follows: 300 cases of DILI and 130 acute non-DILI controls. Additional cross-sectional cohorts (1 visit) are as follows: Healthy volunteers (n = 120), controls with chronic alcohol-related or non-alcoholic fatty liver disease (n = 100 each) and patients with psoriasis or rheumatoid arthritis (n = 100, 50 treated with methotrexate) are enrolled. Candidate biomarkers prioritised for evaluation include osteopontin, glutamate dehydrogenase, cytokeratin-18 (full length and caspase cleaved), macrophage-colony-stimulating factor 1 receptor and high mobility group protein B1 as well as bile acids, sphingolipids and microRNAs. The TransBioLine project is enabling biomarker discovery and validation that could improve detection, diagnostic accuracy and prognostication of DILI in premarketing clinical trials and for clinical healthcare application.

O.4.2-8 Gait differences between adults with COPD and healthy controls: systematic review and metaanalyses

Abstract Purpose Fall risk is increased in adults with COPD. Although gait is an important risk factor for falls, hospitalisations, and mortality, the available literature shows inconsistencies on whether gait differs between adults with COPD and healthy controls. The aim of this study was to identify differences in digitally-measured gait characteristics during laboratory tests between adults with COPD and healthy controls. Methods As part of the Mobilise-D project (https://www.mobilise-d.eu), we conducted a systematic review built upon a previous scoping review (Polhemus, A. et al. npj Digit. Med. 2021). The search was updated in July 2021. Teams of two reviewers independently screened articles and extracted data. Meta-analyses were performed in studies not considered at a high risk of bias. Results Twenty-five studies were included. Gait speed was studied in 17 studies (68%), step length in 9 (36%), step time in 7 (28%), cadence in 6 (24%) and step width in 5 (20%). Meta-analyses revealed that adults with COPD walked with a lower self-selected speed and top speed than healthy controls. There was a trend towards a lower step length, lower cadence and higher step time at a self-selected walking speed in adults with COPD compared to healthy controls. Step width was similar for both groups. Conclusion Adults with COPD exhibit slower gait than healthy controls. This could contribute to the increased fall risk in adults with COPD. Support/Funding Source This work was supported by the Mobilise-D project that has received funding from the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement No. 820820.

O.5.2-7 Listening to the patients’ voice: a conceptual framework of the walking experience

Abstract Purpose Walking is crucial for an active and healthy ageing, but it changes with age and in the presence of diverse health conditions, such as non-communicable diseases and injuries. So far, conceptual frameworks of walking have not included the impact of these conditions and individuals’ lived experiences on their walking. Thus, we aimed to identify and synthesize evidence describing the walking experience from the perspective of individuals living with highly prevalent walking-impairing conditions of diverse aetiology (i.e., Parkinson’s disease, multiple sclerosis, chronic obstructive pulmonary disease, heart failure, hip fracture, frailty and sarcopenia). Methods We conducted a systematic review and meta-ethnography of qualitative evidence, following appropriate guidance. Results Out of 2,552 unique records, 117 were deemed eligible for the meta-ethnographic synthesis. We identified seven common themes that explain the experience of walking: (1) becoming aware of the walking experience, (2) the walking experience as a link between individuals’ activities and sense of self, (3) the physical walking experience, (4) the mental and emotional walking experience, (5) the social walking experience, (6) the context of the walking experience, and (7) behavioral and attitudinal adaptations resulting from the walking experience. Conclusion We proposed a framework that describes the interplay between these themes, providing a conceptualization of walking that is grounded in the experiences of individuals recovering from a hip fracture or living with other walking-impairing health conditions, and that may be used to set priorities and improve patient centricity in clinical practice, research and public health initiatives. Support/Funding Source This work was supported by the Mobilise-D project that has received funding from the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement No. 820820. This JU receives support from the European Union’s Horizon 2020 research and innovation programme and the European Federation of Pharmaceutical Industries and Associations (EFPIA).

Development and validation of an interpretable machine learning-based calculator for predicting 5-year weight trajectories after bariatric surgery: a multinational retrospective cohort SOPHIA study

Weight loss trajectories after bariatric surgery vary widely between individuals, and predicting weight loss before the operation remains challenging. We aimed to develop a model using machine learning to provide individual preoperative prediction of 5-year weight loss trajectories after surgery. In this multinational retrospective observational study we enrolled adult participants (aged ≥18 years) from ten prospective cohorts (including ABOS [NCT01129297], BAREVAL [NCT02310178], the Swedish Obese Subjects study, and a large cohort from the Dutch Obesity Clinic [Nederlandse Obesitas Kliniek]) and two randomised trials (SleevePass [NCT00793143] and SM-BOSS [NCT00356213]) in Europe, the Americas, and Asia, with a 5 year follow-up after Roux-en-Y gastric bypass, sleeve gastrectomy, or gastric band. Patients with a previous history of bariatric surgery or large delays between scheduled and actual visits were excluded. The training cohort comprised patients from two centres in France (ABOS and BAREVAL). The primary outcome was BMI at 5 years. A model was developed using least absolute shrinkage and selection operator to select variables and the classification and regression trees algorithm to build interpretable regression trees. The performances of the model were assessed through the median absolute deviation (MAD) and root mean squared error (RMSE) of BMI. 10 231 patients from 12 centres in ten countries were included in the analysis, corresponding to 30 602 patient-years. Among participants in all 12 cohorts, 7701 (75·3%) were female, 2530 (24·7%) were male. Among 434 baseline attributes available in the training cohort, seven variables were selected: height, weight, intervention type, age, diabetes status, diabetes duration, and smoking status. At 5 years, across external testing cohorts the overall mean MAD BMI was 2·8 kg/m2 (95% CI 2·6-3·0) and mean RMSE BMI was 4·7 kg/m2 (4·4-5·0), and the mean difference between predicted and observed BMI was -0·3 kg/m2 (SD 4·7). This model is incorporated in an easy to use and interpretable web-based prediction tool to help inform clinical decision before surgery. We developed a machine learning-based model, which is internationally validated, for predicting individual 5-year weight loss trajectories after three common bariatric interventions. SOPHIA Innovative Medicines Initiative 2 Joint Undertaking, supported by the EU's Horizon 2020 research and innovation programme, the European Federation of Pharmaceutical Industries and Associations, Type 1 Diabetes Exchange, and the Juvenile Diabetes Research Foundation and Obesity Action Coalition; Métropole Européenne de Lille; Agence Nationale de la Recherche; Institut national de recherche en sciences et technologies du numérique through the Artificial Intelligence chair Apprenf; Université de Lille Nord Europe's I-SITE EXPAND as part of the Bandits For Health project; Laboratoire d'excellence European Genomic Institute for Diabetes; Soutien aux Travaux Interdisciplinaires, Multi-établissements et Exploratoires programme by Conseil Régional Hauts-de-France (volet partenarial phase 2, project PERSO-SURG).

How can patient preferences be used and communicated in the regulatory evaluation of medicinal products? Findings and recommendations from IMI PREFER and call to action.

Objective: Patients have unique insights and are (in-)directly affected by each decision taken throughout the life cycle of medicinal products. Patient preference studies (PPS) assess what matters most to patients, how much, and what trade-offs patients are willing to make. IMI PREFER was a six-year European public-private partnership under the Innovative Medicines Initiative that developed recommendations on how to assess and use PPS in medical product decision-making, including in the regulatory evaluation of medicinal products. This paper aims to summarize findings and recommendations from IMI PREFER regarding i) PPS applications in regulatory evaluation, ii) when and how to consult with regulators on PPS, iii) how to reflect PPS in regulatory communication and iv) barriers and open questions for PPS in regulatory decision-making. Methods: PREFER performed six literature reviews, 143 interviews and eight focus group discussions with regulators, patient representatives, industry representatives, Health Technology Assessment bodies, payers, academics, and clincians between October 2016 and May 2022. Results: i) With respect to PPS applications, prior to the conduct of clinical trials of medicinal products, PPS could inform regulators' understanding of patients' unmet needs and relevant endpoints during horizon scanning activities and scientific advice. During the evaluation of a marketing authorization application, PPS could inform: a) the assessment of whether a product meets an unmet need, b) whether patient-relevant clinical trial endpoints and outcomes were studied, c) the understanding of patient-relevant effect sizes and acceptable trade-offs, and d) the identification of key (un-)favorable effects and uncertainties. ii) With respect to consulting with regulators on PPS, PPS researchers should ideally have early discussions with regulators (e.g., during scientific advice) on the PPS design and research questions. iii) Regarding external PPS communication, PPS could be reflected in the assessment report and product information (e.g., the European Public Assessment Report and the Summary of Product Characteristics). iv) Barriers relevant to the use of PPS in regulatory evaluation include a lack of PPS use cases and demonstrated impact on regulatory decision-making, and need for (financial) incentives, guidance and quality criteria for implementing PPS results in regulatory decision-making. Open questions concerning regulatory PPS use include: a) should a product independent broad approach to the design of PPS be taken and/or a product-specific one, b) who should optimally be financing, designing, conducting, and coordinating PPS, c) when (within and/or outside clinical trials) to perform PPS, and d) how can PPS use best be operationalized in regulatory decisions. Conclusion: PPS have high potential to inform regulators on key unmet needs, endpoints, benefits, and risks that matter most to patients and their acceptable trade-offs. Regulatory guidelines, templates and checklists, together with incentives are needed to foster structural and transparent PPS submission and evaluation in regulatory decision-making. More PPS case studies should be conducted and submitted for regulatory assessment to enable regulatory discussion and increase regulators' experience with PPS implementation and communication in regulatory evaluations.

Co-design and its consequences: developing a shared patient engagement framework in the IMI-PARADIGM project

Abstract Whilst patient engagement (PE) activities have become increasingly prevalent in development of medicines, collaborating actors have different perspectives on the goals of PE and its added value. In the production of PE standards and frameworks, the significance of these differences tends to be minimised. Boundary objects have been shown to mediate knowledge exchange between multiple social worlds, thereby playing an important role in participatory technology governance processes. In this article, we draw on boundary objects to learn from the process of co-designing a PE monitoring and evaluation (M&E) framework within the Innovative Medicines Initiative–Patients Active in Research and Dialogues for an Improved Generation of Medicines (IMI-PARADIGM) consortium (2018–20). As facilitators of PARADIGM’s co-design process, we report on the challenges encountered in developing a practicable M&E framework that serves a variety of needs and interests. We argue these challenges of co-design reflect a negotiation of different frames throughout, thereby providing insight into how such work may contribute to addressing the challenge of knowledge integration in institutional medicines development settings.

Achieving consensus on the language of obesity: a modified Delphi study

Obesity is recognized by the World Health Organization as a chronic disease. As such, it should be referred to using the language of chronic diseases, with correct and established terminology and definitions. This study was designed to map the current language used to discuss obesity and to compare this with the standard language used for chronic disease. We performed a modified Delphi study to identify the language of chronic disease that is being used in the context of obesity, and to identify discrepancies and potential use of inadequate language with respect to the standard language used for chronic diseases. Participants (n=24) were identified from relevant stakeholder groups and desk research, and included patients, healthcare professionals, policymakers, researchers, industry, and payers (social insurers) of 18 nationalities/regions in Europe, North/South America, and South Africa. Participants were enrolled between 20.10.2020 and 30.10.2020. The study comprised two rounds of qualitative surveys. In Round 1, participants responded to six open-ended questions. Round 2 comprised 38 statements based on key terms/themes identified in Round 1 and covered the definition, causes, progression, treatment, management, and complications of obesity. Consensus was defined as ≥70% participant agreement on a statement. All participants completed Round 1 and 23 participants completed Round 2. In Round 2, consensus was reached for 28 of the 38 statements. Participants reached a consensus regarding the use of statements that acknowledge the heterogeneous nature of obesity, but not on the use of statements that: defined obesity based on body mass index; regarded psychological, physical, or physiological factors among the main causes of obesity; or implied that weight loss should be the aim of obesity treatment. This study uses expert consensus to provide insight into the language used to describe obesity as a chronic disease, and forms the basis for a unified language of obesity. Innovative Medicines Initiative, Novo Nordisk A/S.

It pays to promote joint PhD programmes between academia and the private sector

The prosperity of a country is closely related to its level of education to fuel research and innovation. Doctoral graduates have attained the highest education level and should be the key players in research and innovation. The number of doctoral graduates is increasing rapidly in most/many countries, but is less well correlated to changes in prosperity of a country.The innovative medicines initiative (IMI) was established to help Europe strengthen its position in biomedical research and development. During its planning stage IMI observed large gaps in the scientific interaction between academia and industry in Europe, and that undergraduate students were not realizing the career opportunities within biomedical R&D. A major objective for the education and training section of IMI, the European Medicines Research Training Network (EMTRAIN, http://www.emtrain.eu), has therefore been to work out a framework for public private partnership PhD (PPP-PhD) and to create a cohort of networking, industry-aware scientists.