Real world Outcomes across the AD spectrum for better care: Multi-modal data Access Platform Catherine Reed, Lilly on behalf of ROADMAP consortium 3 rd Nordic conference on Real World Data, 28-29 November 2018, Helsinki @IMI2_ROADMAP 10-Dec-18 I 1
Challenges for AD RWE Available data sources to inform the real world trajectory and impact of AD are limited Lack of consensus on study design and endpoints in real world data sources Lack of AD-related outcomes in medical records relevant across the spectrum of disease Lack of clarity on how best to model of natural history of the disease using real world data sources Pre-clinical AD Prodromal/MCI due to AD Mild AD Dementia Moderate AD Dementia Severe AD Dementia Positive Amyloid PET Imaging Scan and/or Aβ CSF/ Tau changes Asymptomatic/ potential slight memory deficit Memory impairment Multi-domain impairment Severe cognitive impairment No functional impairment Some impairment of complex function (iadls) Functional impairment Behavioural symptoms Some assistance Nursing home/ full time care 10-Dec-18 I 3
Opportunities Leverage existing large diverse and complex data sets Harmonize collation methods and analytical tools Perform pilot studies 10-Dec-18 I 4
What is ROADMAP? Real world Outcomes across the AD spectrum for better care: Multi-modal data Access Platform (ROADMAP) ROADMAP is a private-public partnership (PPP) to explore the usability of all available data sources in the decision-making process Goal is to bring data together for the benefit of individuals with AD and their caregivers 2 year project Nov 2016-Oct 2018 This project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 116020 ( ROADMAP ). This Joint Undertaking receives support from the European Union s Horizon 2020 research and innovation programme and EFPIA. 10-Dec-18 I 5
EFPIA partners ROADMAP Consortium Public partners Associated Data Providers Related projects EMA-NICE/HTA/payers Qualification Pilot use of RWE in AD National/Regional Health Authorities to comprise an Expert Advisory Group (EXAG led by NICE): (1) HTA bodies/payers from different archetypes (2) Regulators (3) Patient Associations 10-Dec-18 I 6
WP8 Ethical, Legal and Social Implications (ELSI) ROADMAP Structure WP1 Project Management Executive Committee (UOXF, EMC, NOVARTIS, Eli Lilly, BIOGEN, NICE, SYNAPSE) WP2 Outcome Definition WP3 Identification, Mapping and Integration of RWE WP4 Disease Modelling and Simulation WP6 Regulatory and HTA Engagement WP5 Health Economics WP7 Communication and Patient/Healthcare/ Provider Engagement 10-Dec-18 I 7
WP2 objectives and methods Classify and prioritise AD-related outcomes according to stakeholder relevance and impact Evaluate what constitutes a meaningful delay in disease progression Systematic review, surveys and focus group workshops Survey target population: patients, caregivers, clinicians, scientists, health economists, HTA representatives, regulatory body representatives, payers, policy makers, industry representatives, advocacy group and charity representatives and ethicists 10-Dec-18 I 8
Final results of WP2 Stakeholder generated lists of priority outcomes 10-Dec-18 I 9
Final results of WP2 Disease progression and outcomes classification matrix At the MCI stage, the following outcomes were deemed very important by a high proportion of respondents. Cognitive abilities (183/238, 76.9%) Independence in complex daily activities (functional abilities) [181/238, 76.1%] Patient quality of life (172/238, 72.8%) At the mild dementia stage, the following outcomes were deemed very important by a high proportion of respondents: Cognitive abilities (170/238, 71.4%) Independence in complex daily activities (functional abilities) [178/238, 74.8%] Patient quality of life (190/238, 79.8%) Neuropsychiatric symptoms (169/238, 71.0%) Quality of their carer s and family s lives (169/238, 71.0%) At the moderate to severe stage, the following outcomes were deemed very important by a high proportion of respondents: Behavioural and neuropsychiatric symptoms (172/238, 72.3% and 174/238, 73.1% respectively) Patient quality of life (180/238, 75.6%) Quality of their carer s and family s lives (202/238, 84.9%) 10-Dec-18 I 10
Summary of gap analysis for priority outcomes At a high level: cognitive abilities, functional abilities and independence, behavioural and neuropsychiatric symptoms, details of therapeutic treatment, and mortality & comorbidities are captured frequently Fewer data sources capture significant disease related life events, medical investigations, use of health care and social services, and patient quality of life A limited number of data sources capture caregiver-oriented outcomes, in particular, outcomes related to the quality of the carer s and family s lives No data available for self-efficacy, personal financial situation, caregiver comorbidities, guardianship measures 10-Dec-18 I 11
WP3: Data source information overview 10-Dec-18 I 12
WP3: Final data source overview Source population Clinical diagnosis Disease severity and progression Cognitive abilities Functional ability and independence Behavioural and neuropsychiatric symptoms Medical investigations Assessments by health care professional Use of healthcare and social services Therapeutic treatment Significant disease-related life events Patient quality of life Quality of the carer s and family s lives Mortality and comorbidity 10-Dec-18 I 13
Use cases Work Package 3 Research purpose Data source Location Validation of the pre-symptomatic AD model 4C and BBACL studies The Netherlands PPSW & H70 studies Sweden SIDIAP dementia diagnosis validation study SIDIAP & ReDeGi Spain Validation of the MMSE model IPCI The Netherlands SIDIAP Spain PPSW & H70 studies Sweden EDAR European multicentre study ICTUS European multicentre study Memento France Girona cohort Spain Copenhagen database Denmark Pilot study: estimation costs of dementia Amsterdam dementia cohort The Netherlands DESCRIPA European multicentre study ICTUS European multicentre study Validation of the time to institutionalization model ADNI AIBL ICTUS 4C study USA Australia European multicentre study The Netherlands Mapping of quality of life instruments Actifcare The Netherlands LeARN The Netherlands Validation of Danish dementia trajectories - - BESIDE: Identifying care transitions and NIVEL-PCD The Netherlands durations of different care trajectories of persons with dementia, and investigation of hospitalization Statistics Netherlands The Netherlands Dutch Hospital Data registry The Netherlands 10-Dec-18 I 14
Use Case: Estimation duration of AD stages * Estimate the age-specific duration of AD disease stages Preclinical Prodromal Mild dementia Moderately severe dementia Examine the influence of setting (clinical vs research), gender, APOE genotype, and CSF tau Data from 6 prospective cohort studies N=438 preclinical AD N=729 prodromal AD N=2169 probable AD-type dementia Multistate model analysis with four AD stages and death as the end stage * Collaboration European Brain Council, Amsterdam UMC and Maastricht University 10-Dec-18 I 15
Use Case: Estimation duration of AD stages* * Lisa Vermunt et al in preparation 10-Dec-18 I 16
Guidelines for combining RCT, cohort, and EHR based data for RWE in AD Generalized Guidelines Use Case specific examples 10-Dec-18 I 17
WP4: Disease progression modelling Disease Trajectories Analysis Pharmacological interventions External validation of disease progression models 10-Dec-18 I 20
Validation model selection Review of disease progression models yielded 43 studies with 62 different models Three models selected for external validation: Handels MMSE model Novartis Presymptomatic time-course model Eli Lilly s PenTAG/GERAS institutionalization model 10-Dec-18 I 21
MMSE model Developed model validation pipeline Fill in TRIPOD checklists Specify SAP Extract data locally (Jerboa) Generate validation results (R script, Remote Research Environment) Applied pipeline to variety of data sources EHRs (IPCI, SIDIAP), population cohort (Gothenburg), memory clinics (Girona, MEMENTO, ICTUS, EDAR) Results indicate poor to moderate prediction for individual cases Also applied pipeline to development cohort (Kungsholmen) Results show moderate prediction for individual cases 10-Dec-18 I 22
Conclusions Validation pipeline works Standardizes analysis of multiple external data sources Reduces workload of database custodians Handles anonymization and data-sharing issues Increases transparency and repeatability Poor to moderate individual MMSE predictions on validation sets (but also on development set!) Apart from model, other factors may affect performance Selection bias, AD dementia criteria, length of follow-up, 10-Dec-18 I 24
WP5- economic modelling SLR on resource use and costs for people with pre-dementia or dementia SLR on HRQoL of people with pre-dementia and dementia SLR on economic models for AD Stakeholder preferences for an AD economic model Mapping algorithms from real world outcomes to preference based measures: QOL-AD to EQ-5D Economic evaluation of new technologies for use in AD: a model specification guide Research plan for prospective data requirements, model development and validation 10-Dec-18 I 25
Stakeholder preferences for AD economic models Flexible for patient and caregiver perspectives Acceptability of outcomes linked with uncertainty management Health care and patient costs key from HTA perspective Earlier stages of AD have greatest uncertainty AD is complex one modelling approach may not be feasible Restrictions on model development due to limited data 10-Dec-18 I 26
Aims of Work Package 6 Mechanism for engagement with regulators, HTA agencies and payers To ensure regulatory + HTA perspectives are taken into account in project outputs and deliverables Developing a real-world evidence strategy for Alzheimer s disease/dementia: Guidance on the potential use of RWE for AD from the regulatory, HTA, and payer perspectives 10-Dec-18 I 27
Work Package 6: Workstreams ROADMAP Expert Advisory Group (EXAG) Experts from regulatory/hta backgrounds representing different European countries Quarterly meetings by teleconference / face-to-face (6 meetings in total) Discussion, feedback and input on project outputs and activities: AD priority outcomes Disease stage definitions Disease-progression and economic modelling Approaches for real world data collection 10-Dec-18 I 29
Lessons learned: Priority outcomes Lack of validated outcomes in the early disease stages Establish accepted outcomes for Regulators/HTAs/Payers which are able to demonstrate prevention/delayed onset of AD Importance of caregiver-relevant outcomes 10-Dec-18 I 30
Gaps in RWE sources relating to different outcome measures/instruments Lack of standardisation in the collection of real-world data Limitations in the use of RWE to demonstrate effectiveness of a treatment BUT Role for RWE in supporting disease progression and health economic modelling assumptions: Correlation between disease stages and endpoints Caregiver impacts Information on regional/national settings Lessons learned: Real-world evidence in AD 10-Dec-18 I 31
Learnings Collaboration builds strength Data integration possibilities Engagement with stakeholders is win-win Data access challenges even with partners 2 year ambitious timeline for RWE work Opportunities for greater coordination across IMI AD projects unexplored e.g. disease progression modelling 10-Dec-18 I 34
What next? Phase 2 Phase 1 highlights the need for more quality data for modelling purposes Opportunity for global multi-stakeholder dialogue on RWE needs and strategy in AD Collaboration to develop common model for RWE generation and integration in AD across the disease spectrum Importance of aligning on common data set of priority measures relevant to demonstrate value of new interventions 10-Dec-18 I 35
Thank you 10-Dec-18 I 36