Description of the Call Topics 1. Title 2. Project description 3. Key deliverables of the project 4. EFPIA member companies participating in the project 5. Role of EFPIA participants in the project 6. Duration of the project 7. Total in kind contribution from the EFPIA member companies 8. Expectations from the Applicant consortium (science and budget guideline)
Description of the call topics 2 • IMI research projects will often be multidisciplinary and addressing translational medicine challenges • Integrated approaches between non-clinical and clinical disciplines are often required • The successful Applicant Consortium is expected to include expertise for all aspects of the areas mentioned in the description of the call topics
Call & Evaluation Process Stage 1 Research Agenda Annual Implementation Plan Call definition Call Topics Call Expression of Interest Stage 1: Scientific ≈ 5 months 1 st Peer Review excellence Invitation to Submit Full Project Proposal
Description of the Expression of Interest 1. Scientific Case 1. Approaches to meet the project objectives (2 pages) 2. Composition of the Applicant Consortium (1/2 page per member) 3. Unique features and complementarities of the Consortium (1 page) 4. Summary work plan (2 pages) 2. Declaration of ethical issues (1/2 page) 3. Provisional budget plan 1. Estimated cost per Consortium member 2. Estimated requested IMI contribution Written by the Applicant Consortium: i.e. academia, SMEs, regulators, patients organisations (without EFPIA)
Peer Review Stage 1 • Peer Review Committees – Ad hoc experts relevant to the call topics – EFPIA Consortia co-ordinators participate in evaluation of Expressions of Interest – For 2009 and beyond, Standing Peer Review Committees (one per Pillar of the Strategic Research Agenda) assisted by ad hoc experts • Responsibility – To evaluate science of Expressions of Interest and select the winning Applicant Consortium for each topic
Evaluation of the Expressions of Interest Four categories that will be scored : • Scientific and/or technological excellence • Partnership Case • Quality of the Applicant consortium as a whole • Quality and soundness of the work plan, including budget First two will have thresholds One category that will not be scored : • Any other remarks including ethical issues
Call & Evaluation Process Stage 2 Research Agenda Annual Implementation Plan Call definition Call Topics Call Expression of Interest Stage 1: Scientific ≈ 5 months 1 st Peer Review excellence Invitation to Submit Full Project Proposal Full Project Proposal Stage 2: Feasibility ≈ 3 months and scientific 2 nd Peer Review excellence
Description of the Full Project Proposal • Written jointly by the members of the EFPIA Consortium and the winning Applicant Consortium • Full description of research activities – What, who, when, and how much • Will need a draft Project Agreement before submission – IPR sharing agreed between all partners • Expectation of high probability of success Written by the Full Project Consortium: i.e. academia, SMEs, patients organisations with EFPIA companies
Peer Review Stage 2 • Peer Review Committees – Ad hoc experts relevant to the call topics •Same as reviewed the Expressions of Interest BUT •Addition of experts on ethics as needed •No involvement of EFPIA Consortia co-ordinators – Standing Peer Review Committees foreseen for future years • Responsibility – To evaluate Full Proposals based on science and feasibility
Evaluation of the Full Project Proposal Evaluation will likely include consideration of the following aspects: – Scientific and/or technological excellence – Consistency with the original Expression of Interest • Scope and composition of the consortia – Project implementation plan – Draft Project Agreement – Potential impact of the project results Categories will be graded Excellent, Acceptable (subject to adjustment to points raised), or Non- acceptable
Call & Evaluation Process Research Agenda Annual Implementation Plan Call definition Call Topics Call Expression of Interest ≈ 5 months 1 st Peer Review Stage 1: Scientific excellence Invitation to Submit Full Proposal Full Project Proposal ≈ 3 months Stage 2: Feasibility and 2 nd Peer Review scientific excellence 1. Project Agreement Contract Execution ≈ 2 months 2. Grant Agreement
Tentative timelines for First Call April 30th July 15th May June July August Sept October Nov. Dec. January February Publication of Call Submission period for Expressions of Interest Evaluation Stage 1 Submission period for Full proposals Evaluation Stage 2 Negotiation, signature of Grant Agreements, first payments
Topics for the First Call 1. Improved predictivity of immunogenicity 13m/5y 2. Non-genotoxic carcinogenesis 2.5m/2y plus 10m/3y 3. Expert systems for in silico toxicity prediction 5m/5y 4. Improved predictivity of non-clinical safety evaluation 10m/3y 5. Qualification of Translational safety biomarkers 21m/5y 6. Strengthening the monitoring of benefit/risk 15m/5y EFPIA Commitment: 172.5m 7. Islet cell research 10m/5y Typical project 15m euros 8. Surrogate markers for vascular endpoints 20m/5y Majority 5y duration 5-10 EFPIA partners/project 9. Pain research 7.5m/5y 10. New tools for the development of novel therapies in psychiatric disorders 10m/5y 11. Neurodegenerative disorders 7.5m/5y 12. Understanding severe asthma 12.5m/5y 13. COPD Patient Reported Outcomes 2m/1y plus 8m/5y 14. European Medicines Research Training Network 5m/7y 15. Safety sciences for medicines training programme 3m/5y 16. Pharmaceutical medicine training programme 4m/5y 17. Integrated medicines development training programme 3m/5y 18. Pharmacovigilance training programme 3.5m/5y
The Innovative Medicines Initiative (IMI) http://imi.europa.eu www.imi-europe.org
The Innovative Medicines Initiative (IMI) COFFEE BREAK
The Innovative Medicines Initiative (IMI) QUESTIONS AND ANSWERS
The Innovative Medicines Initiative (IMI) LUNCH BREAK
Launching the 2008 IMI scientific programmes Janez Poto č nik European Commissioner for Science and Research Arthur Higgins EFPIA President, CEO of Bayer HealthCare
The Innovative Medicines Initiative (IMI) An Overview of the 2008 Call Topics Jonathan Knowles Chair, IMI Board IMI Launch, April 30 th 2008
The Research Focus of IMI Discovery Discovery Discovery Preclinical Preclinical Preclinical Translational Translational Translational Clinical Clinical Clinical Pharmaco Pharmaco Pharmaco - - - research research research develop. develop. develop. medicine medicine medicine develop. develop. develop. vigilance vigilance vigilance Knowledge Management Education & Training Benefit/Risk Benefit/Risk Predictive Predictive Predictive Predictive Predictive Predictive Identification Identification Patient Patient Validation of Validation of assessment assessment pharmacology pharmacology pharmacology toxicology toxicology toxicology of biomarkers of biomarkers recruitment recruitment biomarkers biomarkers with regulatory with regulatory authorities authorities Efficacy Efficacy Safety Safety
Efficacy and Safety are often disease specific Identification Predictive Predictive Patient Regulatory pharmacology toxicology and validation of recruitment Risk assessment biomarkers Cancer Brain Disorders Inflammatory Diseases Metabolic Diseases Infectious Diseases
IMI First Call: 18 Call Topics • 5 on safety prediction • 1 on pharmacovigilance • 2 on diabetes • 3 on brain disorders • 2 on pulmonary diseases • 5 on Education & Training
Strong industry commitment # Title Companies In-kind (millions) 1 Improve Predictivity of Immunogenicity 12 €13 2 Non-genotoxic Carcinogenesis 8 €12,5 3 Expert Systems for in silico Toxicity Prediction 10 €5 4 Improved Predictivity of non-clinical Safety Evaluation 11 €10 5 Qualification of Translational Safety Biomarkers 12 €21 6 Strengthening the Monitoring of Benefit/Risk 15 €15 7 Islet Cell Research 11 €10 8 Surrogate Markers for Vascular Endpoints 7 €20 9 Pain Research 12 €7,5 10 New Tools for the Development of Novel Therapies in Psychiatric Disorders 13 €10 11 Neurodegenerative Disorders 14 €7,5 12 Understanding Severe Asthma 10 €12,5 13 COPD Patient Reported Outcomes 9 €10 14 European Medicines Research Training Network 24 €5 15 Safety Sciences for Medicines Training Programme 24 €3 16 Pharmaceutical Medicine Training Programme 24 €4 17 Integrated Medicines Development Programme 24 €3 18 Pharmacovigilance Training Programme 24 €3,5
We cannot do it without the stakeholders Discovery Preclinical Translational Clinical Pharmaco- research develop medicine development vigilance Biopharma Policy Makers Industry Patients SMEs Regulators Healthcare Academia Professionals
The Innovative Medicines Initiative (IMI) http://imi.europa.eu www.imi-europe.org
IMI First Call Topics Philippe Cupers IMI JU European Commission, DG RTD Ian Ragan IMI Advisor to EFPIA
The Innovative Medicines Initiative (IMI) IMI Safety and Pharmacovigilance Calls
The Innovative Medicines Initiative (IMI) IMI Safety Calls Salah-Dine Chibout Head of Exploratory Development Europe Global Head Investigative Toxicology at Novartis
Goals of the IMI Safety Projects • Generate and improve cutting-edge technologies to devop safer drugs for human. • Develop methods and acquire knowhow in Europe to lower the late attrition rate of drugs in development. • Develop better tools for monitoring safety of drugs at all stages of drug development – from discovery through clinical development and registration to routine use of drugs. • The ultimate goal is the improvement of the patients‘ safety and benefit.
Topics covered by the Safety Projects • Expert systems for in silico toxicity prediction. • Non-genotoxic carcinogenesis. • Immunogenicity of biotherapeutics in man. • Qualification of translational safety biomarkers. • Improved predictivity of non-clinical safety evaluation (presented by Thomas Singer). • Strengthening the monitoring of benefit/risk assessment (presented by Liz Swain).
Expert Systems for in Silico Toxicity Prediction
Expert Systems for in Silico Toxicity Prediction: - Rationale • In vivo and in vitro studies generate a lot of data that can be used to model prediction of toxicity from the chemistry of the molecule. • Early in silico prediction of such cases would increase the quality of drug candidates and ensure a lower attrition rate before and during the first GLP animal studies. • This would also reduce the number of animals (3Rs) used in preclinical studies necessary to select drug candidates.
Expert Systems for in Silico Toxicity Prediction: - Principle Chemical structure OH & features H O N O N N OH Bibliography Computation Expert system Algorithms N Pharma reports Query about a new structure Toxicity alert New Report Public databases New structure or limited early toxicity study
Expert Systems for in Silico Toxicity Prediction: Deliverables • A toxicological database with high quality in vivo and in vitro data. This repository will form the basis of prediction model development. • Construction of prediction models for selected in vivo endpoints to identify compound liability for target organ toxicity. • A successful outcome will initiate the validation of these prediction models. The validation experience will be shared between companies and with regulators. • Reduction of total animal usage, according to the 3Rs.
Nongenotoxic Carcinogenesis (NGC)
Nongenotoxic Carcinogenesis (NGC): - Rationale • Need to better understand predictive value of rodent bioassay for human cancer risk assessments of pharmaceutical drugs. • Need accurate and well validated early biomarkers that can reliably predict later cancer development. • Exploit recent advances in understanding carcinogenesis to identify early mechanisms and biomarkers of rodent NGC. • 3Rs: gain maximum benefit from animal studies by sharing IMI consortia knowledge and tissue archives.
Nongenotoxic Carcinogenesis (NGC): - Goals & deliverables • 2 year Exploratory Phase – evaluate utility of novel tools & models for identifying mechanisms & biomarkers of rodent NGC. Examples : - Epigenomic profiling of tissues & tumours. - Transgenic & humanised mouse models. - Blood-based surrogate markers (Circulating tumour cells & methylated DNA). • 3 year Confirmatory Phase – validation of mechanistic hypotheses & cause-effect relationships. – predictive value & clinical relevance of biomarkers. – generate novel database for rodent tumour molecular profiles.
Prediction of Immunogenicity
Prediction of Immunogenicity Background • Immunogenicity is the unwanted immune response (anti- drug antibodies) to a Biotherapeutic. • Immunogenicity is key to development of Biotherapeutics, since it affects patient safety, drug efficay and study interpretation. • Unmet need to predict and minimize immunogenicity in man.
Prediction of Immunogenicity Current Issues 1. Limited comparability of immunogenicity data between assays & companies. 2. Amount of data within individual companies too limited – to understand factors or patterns favouring immunogenicity. – to verify predictive tools and minimization strategies. 3. Lack of reliable prediction methods for immunogenicity potential of compound, clinical consequences and susceptibility of patient to develop immunogenicity (stratification). 4. Limited literature and guidance available.
Prediction of Immunogenicity Goals & Deliverables 1. Drug class-specific standardization programme in order to improve comparability and quality of data defining immunogenicity positives vs. negatives. 2. Database of immunogenicity-relevant data of consortium compounds: to identify factors or patterns favouring immunogenicity. • to evaluate value of existing predictive tools and • minimization strategies. 3. Improved tools to predict immunogenicity in man, based on at least 5 selected compounds ( in-silico , in-vitro , animal models and stratification markers). 4. Publish recommendations.
Translational Safety Biomarkers Qualification
Translational Safety Biomarkers Qualification Background • A lack of specific and sensitive blood and urine tests (= peripheral biomarkers ) for safety monitoring. • Example : A histopathology safety signal is seen in preclinical toxicity studies but there is no adequate monitoring method available in humans = lost opportunity to further explore clinical development and potential human health benefits of this drug.
Translational Safety Biomarkers Qualification Background • 3 target organs will be selected, which are criticial for drug-induced injury: • Kidney: Current standards (Serum Creatinine, BUN) are only increased when 50-60% of the kidney function is lost. • Liver: Current standards (AST, ALT, Bilirubin) are not specific and do not predict, who will recover and who will develop fulminant liver disease. • Vascular System: There are currently no biomarkers to monitor drug-induced vascular injury in human.
Translational Safety Biomarkers Qualification Goals • To evaluate utility of preclinical safety biomarkers for monitoring organ safety in humans. • To develop assays and devices for clinical application of safety biomarkers. • To compile enough evidence to qualify safety biomarkers for regulatory decision-making in clinical drug development in co-operation with the health authorities. • To gain evidence for how safety markers may also be used in the diagnosis of diseases.
Translational Safety Biomarkers Qualification Key Milestones and Deliverables • Define clinical qualification processes for safety biomarker qualification in clinical development with health authorities. • Define the needs for new clinical biomarkers compared to current standards and features/criteria to be met. • Select biomarkers from different discovery exercises (e.g. PredTox, PSTC) and develop assays / devices for human use. • Establish baseline values and their variability in healthy subjects. • Define and run protocols to measure the performance of these biomarkers against current standards in clinical trials with expected drug- induced injuries and in patients with relevant diseases. • Establish a common database to be able to build up on any new dataset upcoming in the future and to share with health authorities. • Qualify appropriate markers for regulatory decision making together with health authorities.
The Innovative Medicines Initiative (IMI) Improved Predictivity of Non-clinical Safety Evaluation Dr. Thomas Singer, D.A.B.T. Global Head of Non-Clinical Safety F. Hoffmann-La Roche Ltd.
Research Focus • Combined application of well-known toxicological endpoints (histopathology, clinical chemistry) and novel technologies (toxicogenomics, metabonomics and proteomics) to evaluate hepatotoxicity and nephrotoxicity • In depth data analysis within and across platforms and studies • Investigation of the underlying molecular mechanisms of toxicity and performance of confirmatory mechanistic experiments
Project Plan • Short-term in vivo animal studies, mainly in rats but also selectively in non-rodent species, using – ~10-15 drug candidates from companies and – ~10-15 reference compounds • Biomarker discovery and non-clinical qualification for regulatory decision making
Expectations from an Applicants Consortium • Morphology /histopathology methods and expertise • Transcriptomics technologies • Latest metabonomics methodologies • State-of-the-art capabilities in proteomics • Capacities of mechanistic and confirmatory studies • Information Technology and Data Evaluation – Hosting and maintenance of the necessary IT infrastructure – Integrated data analysis • Expertise in biological interpretation / integration of results • Expertise in education of scientists within Systems Toxicology • Representatives from the Regulatory Authorities
Pre-existing Experience and Rationale • EU FP6 InnoMed Project – with PredTox Project – Precurser for all IMI projects in terms of stakeholder collaboration • InnoMed-PredTox to be accomplished by Jan-2009 • Output of value for pertinent topic/project • Discovery and qualification of non-clinical safety biomarkers is the first step in a multistage procedure to develop new safety markers for humans /patients • Project outcome (markers) to feed into the “Qualification of Translational Safety Biomarkers” project
The Innovative Medicines Initiative (IMI) Priority Areas for Research to Strengthen the Monitoring of Benefit: Risk of Medicines Liz Swain Director of Medical Governance Operations and R&D Policy at GlaxoSmithKline
Background • EMEA and European Commission are jointly working to facilitate the availability of innovative medicines to patients • Essential to have a thorough post-marketing surveillance system of marketed products to ensure a positive benefit: risk balance
Background • Pharmacovigilance tended to be a reactive process focussing on spontaneous reporting • Often insufficient to allow meaningful assessment due to under-reporting and poor data quality
Post- -marketing marketing pharmacovigilance pharmacovigilance – – a challenging a challenging Post and labour labour- -intensive process intensive process and • Reporting process is voluntary • Reporting process is voluntary… …difficult to assess whether there are difficult to assess whether there are excess reports of a particular adverse event - excess reports of a particular adverse event - no denominator or no denominator or control group, signal vs. noise. control group, signal vs. noise. • Traditionally focused on individual cases • Traditionally focused on individual cases - - no systems no systems- -based tools for based tools for signal detection/evaluation or quantitative analysis signal detection/evaluation or quantitative analysis • Nonetheless this is important safety information which is used t • Nonetheless this is important safety information which is used to make o make decisions decisions
The Importance of Proactive Pharmacovigilance
Observations of Current Situation by IMI Pharmacovigilance Stakeholder Group • A wealth of epidemiological data on drug exposure and outcomes is available in the EU, but – No central repository of such data – Different data sources do not communicate – Data cannot be combined • Systems and networks for pharmacovigilance are used for regulation, not for research • Methods of pharmacovigilance have remained unchanged for two decades • Risk minimisation methods are not yet available for testing • Effectiveness of risk communication is put into question
Proposals from IMI Pharmacovigilance stakeholder group • Optimisation of data resources and strengthening of evidence base in pharmacovigilance • Development and strengthening of methodologies and networks of pharmacovigilance • Development of novel methods of risk prediction and benefit : risk assessment • Training and education of Health Care Professionals and patients (see training and education call)
What are we aiming to improve? • Goal is to increase confidence in the post- marketing monitoring of benefit: risk of EU medicinal products , ultimately facilitating an earlier access of novel medicines for the benefit of EU patients • Scope is to optimise data resources and strengthen the evidence base through development of methodologies and networks in the EU
Opportunities for Research to Strengthen the Monitoring of Benefit:Risk of Medicines • Establish new methods of pharmacovigilance data collection • Evaluate methods and develop operational definitions for • signal detection and evaluation in spontaneous reports databases, and • population-based epidemiologic data sources • Establish methods for graphical expression and comparison of the benefit : risk profile of medicinal products • Investigate and develop standards and processes for interoperability of European epidemiology data sources
Research = Patient Benefit
The Innovative Medicines Initiative (IMI) http://imi.europa.eu www.imi-europe.org
The Innovative Medicines Initiative (IMI) IMI Efficacy Calls
The Innovative Medicines Initiative (IMI) Diabetes Calls: Islet cell research Surrogate markers for vascular endpoints Veikko Koivisto, MD, PhD Eli Lilly & Co April 30th , 2008
Diabetes Call Topics • Islet Cell Research: Improving Beta Cell Function and Identification of Biomarkers for Treatment Monitoring in Diabetes • Surrogate Markers for Vascular Endpoints : Surrogate Markers for Micro- and Macrovascular Hard Endpoints to Shorten Clinical Trials in Diabetes
Islet Cell Research I • Focus – Beta cell dynamics in vitro and in vivo – Cross talk of beta cells with other cell types in islets and with other tissues or organs • EFPIA Participants (n=10) - Astra Zeneca, Boehringer Ingelheim, Eli Lilly, MSD, Novartis, Novo Nordisk, Roche, Sanofi Aventis, Servier, Solvay
Islet Cell Research II • Beta cell dynamics in vitro and in vivo – Origin, source and function of novel beta cells – Conditions for beta cell proliferation and differentiation from precursor cells – Genetic and genomic studies for identification of biomarkers – Beta cell apoptosis: its mechanisms, prevention, measurement • Novel technologies, tools, approaches – Novel animal models or in silico tools – Novel biomarkers for beta cell function and islet regeneration – Non-invasive technologies for monitoring beta cell mass - Imaging, nanotechnologies, biomarkers
Islet Cell Research III • Cross talk with beta cells and other cell types – Abnormalities with alpha cell function, alpha/beta cell ratio – Interaction between islet cells and gastrointestinal tract • Key deliverables – Generation of tools – Identification and validation of biomarkers and novel mechanism and targets for diagnosis and therapy – Knowledge on • mechanism of beta cell loss in type 1 and type 2 diabetes • beta cell proliferation and differentiation
Surrogate Markers for Vascular Endpoints I • Focus – To find ways to shorten clinical trials on hard vascular endpoints in diabetes – Retrospective: Analyse data in already performed or ongoing clinical trials – Prospective approach: Perform novel trials to search and validate the surrogate markers • EFPIA Participants (n=8) - Boehringer Ingelheim, Eli Lilly, Novartis, Novo Nordisk, Pierre Fabre, Roche, Servier, Solvay
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