The Innovative Medicines Initiative IMI Proposal for the First

The Innovative Medicines Initiative (IMI) Proposal for the First IMI Call October 17, 2007 IMI Call 2008 DRAFT of 17/10/2007 Table of Content 1. 2. 3. 4. 5. 6. 7. 8. 9. PredTox II .................................................................................................................................3 Translational safety biomarkers ...............................................................................................6 Immunogenicity ......................................................................................................................12 Non-genotoxic carcinogenesis...............................................................................................17 Expert systems for in silico toxicity prediction .......................................................................23 Pharmacovigilance .................................................................................................................26 Islet cell research ...................................................................................................................29 Surrogate markers for vascular endpoints.............................................................................32 Genetics and genomics of type 2 diabetes............................................................................34 10. Pain Research........................................................................................................................36 11. Psychiatric disorders ..............................................................................................................41 12. Neurodegenerative disorders.................................................................................................45 13. Severe Asthma.......................................................................................................................51 14. COPD .....................................................................................................................................55 15. Rhinitis....................................................................................................................................61 16. EMRA Hub..............................................................................................................................65 17. Safety sciences training programme .....................................................................................69 18. Pharmaceutical medicine training programme ......................................................................72 19. Integrated medicines development training programme .......................................................78 20. Pharmacovigilance training programme ................................................................................82 Page 2 of 88 PredTox II IMI Call 2008 DRAFT of 17/10/2007 1. PredTox II Improved Predictivity of Non-Clinical Safety Evaluation – PredTox II The project will be build of the existing EU InnoMed Integrated Project “Predictive Toxicology- PredTox” of FP6 which will be accomplished by fall-2008 (for details see: www.innomed-predtox.com/). Goals: • Assess the value of combining results from ‘omics technologies together with the results from conventional toxicology methods for a more informed decision making earlier in preclinical safety evaluation Identification and qualification of novel translational biomarkers of selected toxicities in relevant species for use in non-clinical safety studies Broaden the support in education of scientists within Systems Toxicology Critically review the value of this approach together with Regulatory Authorities with the final goal to integrate new, validated methods into preclinical safety assessment 1 Topic title 2 Project description • • • Research program In vivo animal studies, mainly in rats but also selectively in non-rodent species, using ~10-15 well characterized drug candidates from participating companies and ~10-15 reference compounds. Compounds will be selected based on toxicity findings in liver and/or kidney. Biomarker discovery for regulatory decision making will be based on cross-‘omics comparison as a major part of the evaluations. Special focus based on experience from PredTox-I project: • • Bioinformatics: improved biostatistical models, and novel approaches of data integration with strong emphasis in biological interpretation are to be developed and used Mechanistic Investigations: thorough assessment of generated biological hypotheses and introduction of new technologies as necessary to confirm or reject these hypotheses (e.g. additional assays, in vitro systems, etc). Development of tools, technologies, assays, standards and procedures which can be used by pharmaceutical companies for application in standard toxicity studies and potentially for regulatory decision making Co-operation with other consortia (e.g. C-Path – Preclinical Safety Testing Consortium, Health and Environmental Sciences Institute- HESI) and with the respective IMI programme on translational biomarkers Page 3 of 88 • • PredTox II IMI Call 2008 DRAFT of 17/10/2007 A valid, relational, high quality database for improved predictivity of safety evaluations Novel non-clinical biomarkers Understanding of biological mechanisms underlying the relationship between identified biomarkers and toxicity 3 Key deliverables of the project 4 EFPIA participants in AstraZeneca the project Bayer Healthcare Boehringer Ingelheim Johnson & Johnson Merck Serono Novartis Orion Pharma Roche sanofi aventis Servier Solvay UCB G. Oliver K. Meyer A. Kalkuhl S. Spanhaak J. Harleman F. Dieterle K. Haasio F. Pfannkuch, L. Suter-Dick E. Harpur N. Claude S.Thun-Battersby O. Depelchin The participating companies will have to face annual “in kind” contributions in the order of magnitude of € 200’000 – 400’000. The distribution between the participating companies has to be discussed. Participation of additional companies will decrease the investments, accordingly. 5 Role of EFPIA participants in the project Specifications of study protocols to achieve the aims, i.e. provide samples for biomarker sensitivity and recovery Performance of animal experiments with special analyses (mainly rat, also selectively in non-rodents, adaptive trials involving biopsies, clinical chemistry, histopathology, etc.) Evaluation of samples for transcriptomics (laboratory; staff; costs of reagents, microarrays) Evaluation of samples for proteomics (staff; laboratories; costs of regents and materials) Evaluation of samples for metabonomics (staff; laboratories; costs of regents and materials) Evaluation of immunoassays, immunohistochemistry (IHC), in-situhybridization (ISH) Evaluation of laser-capture micro-dissection and other techniques for subsequent detection of genes or proteins of interest Research-related Project Management Page 4 of 88 PredTox II IMI Call 2008 DRAFT of 17/10/2007 6 Indicative duration of 3 years the project 7 Indicative total in kind contribution from the EFPIA companies 8 Indicative expectations from the public consortium € 10 million Capabilities in histopathological evaluation, tissue microarrays, digital slide scanning and automated image analysis Transcriptomics technologies Quantitative mass spectrometry: LC/MS & GC/MS and 1H-NMR techniques, iTRAQ Proteomic profiling via SELDI, 2D-DIGE analysis Capabilities in quantitative RT-PCR and in-situ hybridization Mechanistic and confirmatory studies Development of assays Provision, hosting, maintenance, and further development of the existing FP6 – InnoMed - PredTox database infrastructure Infrastructure and services for centralized assessment and processing of all data Development of approaches and infrastructure for integrated data analysis, building of biostatistical models based on all experimental data Support in education of scientists within Systems Toxicology Biological interpretation / integration of results Page 5 of 88 Translational safety biomarkers IMI Call 2008 DRAFT of 17/10/2007 2. Translational safety biomarkers Qualification of Translational Safety Biomarkers from Non Clinical to Early Clinical Studies Background: 1. A lack of specific and sensitive mechanistic safety markers and its assay for human samples is often delaying regularly drug development programs. This is especially the case when a histo-pathological signal is seen in preclinical tox studies which cannot be adequately monitored in humans. 2. Furthermore, the predictivity between non-clinical and early clinical studies of currently accepted markers is very poor (e.g. for drug induced vascular injury no translational biomarker is qualified, or markers of fibrosis in different organs are either still only exploratory or have been only used pre-clinically,…) 3. There is no clear process on how to qualify new safety biomarkers for clinical regulatory decision making. They are current attempts within the Predictive Safety Testing Consortium of the C-Path Institute but the primary milestone was driven by the preclinical concept. Since no official process exists yet it is very important to participate to the definition of such a generic process and to test several options before it could be accepted by all parties 4. Three target organs would be selected as examples of critical drug induced pathologies (liver, kidney and vascular) and a subset of markers would be identified from preceding discoveries and/or other pre-clinical qualification exercises (PredToxI, PSTC, ILSI/HESI, …) and their assays developed for human use if not yet available. The selection of the markers would be based on their potential/probable success of becoming a useful translational tool and also in concert with other groups like the PSTC to avoid redundancies and to privilege complementarity. Drug Induced Liver Injury (DILI): The predictability, mechanistic understanding and monitoring for DILI in preclinical and clinical settings are not specific or sensitive enough to distinguish DILI from other causes of liver injury or from adaptive responses to drugs. The biomarkers used now in man and animal species are relatively good at detecting gross hepatocyte dysfunction or cell integrity but are not sensitive or specific enough to distinguish early DILI from other causes of derangement in liver biochemistry or from adaptive hepatic responses, nor can they predict which subjects will recover from those who will go on to develop fulminant liver disease. There is a big need to develop new biomarkers for DILI and also to understand more about predisposing factors for DILI (both genetic and Page 6 of 88 1 Topic title 2 Project description Translational safety biomarkers IMI Call 2008 DRAFT of 17/10/2007 environmental). We also know that many mechanisms triggering DILI can not be mimicked in preclinical studies and a sole validation exercise of biomarker candidates from preclinical projects would exclude potentially important biomarker candidates obtained by back-translation from human samples. A key to the solution of this problem lies in obtaining good quality clinical material from individuals experiencing DILI, as well as from individuals suffering from non-drug related liver injury. Drug Induced Kidney Injury (DIKI) Drug-induced nephrotoxicity is not an uncommon adverse event in drug development affecting various classes of drugs, e.g. in the field of oncology, immune suppression, or antibiotics. Looking at the anatomy and function of the kidney, it is straightforward to understand why. The kidney is basolaterally exposed to xenobiotics circulating in blood but also luminally exposed to these entities, which are filtered and concentrated in the kidney. In many circumstances drug-induced nephrotoxicity as cause of acute kidney injury could be prevented or at least minimized by screening and monitoring with appropriate tools and early intervention. At this time, the main problem is the late identification of acute kidney injury linked to the current standards, i.e. Serum Creatinine and blood urea nitrogen (BUN). These are late indicators of renal injury, which might not be significantly changed until 2/3 of the nephron function has already been lost. During the last years a number of urinary biomarkers have evolved, which monitor the integrity of the kidney and not its function like Serum Creatinine and BUN but they almost all lack clinical validation to be useful for regulatory decision making. Drug Induced Vascular Injury (DIVI) When vascular injuries are detected through histo-pathology in preclinical toxicology studies compounds are most often put on hold since there is no adequate biomarkers to monitor this pathology in Ph I and II human safety trials. Induced vascular injury can involve altered haemodynamic forces (shear stress) on the arterial wall, direct drug induced toxicity or immune mediated injury of endothelium (± medial smooth muscle). Historically the majority of drug-related vascular injury in humans is pathogenetically inflammatory in nature, affecting small arterioles and venules and generally an immune-mediated process is suspected. In preclinical species, endothelial compromise appears as an early event. Drugs that cause altered vasoreactivity (constriction, dilation) administered either acutely or chronically may be factors in lesion induction and remodeling that influence chronic vascular injury. Current biomarkers of vascular injury in humans are non specific and of limited sensitivity and include (CRP, ESR, ANCA, immune complexes). Page 7 of 88 Translational safety biomarkers IMI Call 2008 DRAFT of 17/10/2007 Project plan: Qualification Process: Define different options of a potential generic process for clinical validation of translational safety markers and discuss it with Health Authorities to check its acceptance and the key elements to be focused on during the test period: define current standards/ parameters used in clinical situation to define/monitor a need for treatment or treatment changes define parameters applicable and identifying the population to treat/monitor define the control ranges applicable to these parameters i.e. this means that when the parameter value is out of the control range the treatment / BM application scheme would be applied define whether a recovery i.e. normalization of the parameters to control range is anticipated if not what are the expected range values of a BM for an effective treatment define the clinical utility /value as opposed to clinical use of the BM define a scheme how to assess the clinical utility/value as opposed to current standards define the possible interfering situations / parameters which would influence the control range or the treatment range for each BM or for a combination of BM select mechanistic biomarkers from different non-clinical discovery or qualification exercises (e.g. FP6/PedTox or CPath/PSTC,…) based on their potential for translational use establish assays and sampling protocols in human to get enough diversity of pathological responses to qualify the biomarkers for these responses versus clinical endpoints and with respect to current standards. (analytical and biological validation) conduct baseline human trial studies to understand the variability and control values and define the appropriate control ranges for the different populations under investigation select a subset of adjacent diseases or drugs (based on basic mechanistic understandings) which could influence the biomarker profiles and mislead its interpretation (specificity) - - - - - - DILI specific project plan: Select mechanistic biomarkers for DILI from different non-clinical discovery or qualification exercises for clinical validation, Examples of Page 8 of 88 Translational safety biomarkers markers are: - IMI Call 2008 DRAFT of 17/10/2007 From FP6/PredTox (no candidate biomarkers yet) From PSTC (MDH, GLDH, PNP, PON-1, ) From literature (Cytokeratin 18 [M35 for apoptosis/M60 for necrosis] as structural marker, Liver-specific coagulation factors such as PT as functional markers, Cytokines [pro- and antiinflammatory], LECT-2 [an NKT cell chemokine specific for the liver], Calpain and calpain-specific matrix protein fragments, ALT1/ALT2 isoforms,…) DIKI specific project plan: The new markers cover the integrity of different compartments such as proximal tubules (KIM-1, GST- , Lipocalin-2) or distal tubules (GST- ) but cover also different molecular events such as the integrity of the glomerular filtration barrier (Total Protein) tubular re-absorption processes (Cystatin C, 2-Microglobulin), regeneration processes (KIM1), cell leakage (GST- , GST- ). A number of these markers are currently being qualified for regulatory decision making in pre-clinical settings by the C-Path Predictive Safety Testing Consortium (PSTC) together with the health authorities EMEA and FDA. In clinical settings several of these markers have already been used to diagnose kidney diseases (Total Protein, Kim-1), to monitor allograft rejection (GST- , GST- ), ischemia (Lipocalin-2, Kim-1) or drug-induced nephrotoxicity (Kim-1, GST- , NAG). Yet, a systematical qualification of these markers in clinical setting is still lacking, rendering these marker unusable for regulatory decision making. In the case of biomarkers, for which no assay is available, the development and analytical validation is a prerequisite for the clinical qualification. Hereby, clinical qualification includes assessing control ranges, thresholds, sensitivity and specificity for different patient populations and pathologies. DIVI specific project plan Select mechanistic biomarkers for DIVI from different non-clinical and clinical discovery or qualification exercises like those from PSTC, ABPI and others. Clinical translation of preclinical assays will be explored in early clinical trials. Other examples of potential biomarkers for the vascular system could come from toxicity induced by clotting factor rFXIII as studied recently by Novo-Nordisk. 3 Key deliverables of the project 1. A generic process of clinical validation of translational safety biomarkers. 2. The clinical utility / use of the selected biomarkers to be qualified and whether which utility is worth the effort 3. A set of Biomarkers for drug induced injuries and their assays, both qualified for use in early safety clinical trials. Control ranges and cut-off values for different populations and different clinical utilities. 4. Assays and their performances. Also identification of potential Page 9 of 88 Translational safety biomarkers IMI Call 2008 DRAFT of 17/10/2007 5. 6. 7. 8. assay producer that would be willing to develop and produce the assays A basic understanding how patient specific factors (e.g. diseases, other drugs, …) can influence the biomarkers. A database with human biomarker profiles with a detailed characterization of clinical, individual and drug-specific factors in the context of drug-induced toxicities and diseases A communication/training plan and the target audience to implement effectively the results including monitoring plans to assess successful implementation A biobank of the material collected for clinical validation of biomarker candidates would also be highly suitable for novel biomarker discovery for DILI, DIKI and DIVI, with particular emphasis on biomarkers of predisposition and organ changes in the triggering, progression and resolution phases, utilising genetic, proteomic and metabonomic analysis platforms. This is out of the scope of this call but would provide a unique biobank for biomarker discovery if samples can be made available to study human-specific biomarkers. I. Schuppe Koistinen, M. Steinberg, G. Oliver A. Kalkuhl R. Peck J. Hazelden S. Spanhaak A. Bernareggi J. Vonderscher, F. Dieterle, R. Schmouder M.B. Oleksiewicz, P. Brinck R. Wallis L. Doessegger J.L. Paquet 4 EFPIA participants in the project AstraZeneca Boehringer Ingelheim Eli Lilly GSK Johnson & Johnson Merck Serono Novartis Novo Nordisk Pfizer Roche Solvay 5 Role of EFPIA participants in the project Options for a qualification process: Such a process once officialized and taken up by HAs would facilitate the emergence of new qualified biomarkers largely beyond the scope of this call. Markers having enough pre-validation data giving them a high success probability of being “validatable”. Such markers would improve the predictivity of non-clinical safety studies and have a positive impact on attrition rates and drug development timelines. They will also possibly allow the reduction of animal trials by moving compounds faster to clinical phases Clinical trials and Samples: • • Samples from PhI and II studies Diseased populations (e.g. impaired kidney and liver patients Page 10 of 88 Translational safety biomarkers from regulatory studies) IMI Call 2008 DRAFT of 17/10/2007 Biomarker assays: in house assays and antibodies to enable measurements of the biomarkers 6 Indicative duration of the project 7 Indicative total in kind contribution from the EFPIA companies 4 to 5 years € 21 million for 3 target organs € ca. 7 million per target organ [2 clinical trials with serial sampling and subsequent bioanalysis (4 million) + Sampling and subsequent bioanalysis from on-going Ph.I, II III and IV studies (2.5 million) + assay development (0.5 million)] Options for a qualification process: Such a process once officialized and taken up by HAs would facilitate the emergence of new qualified biomarkers largely beyond the scope of this call. Markers having enough pre-validation data giving them a high success probability of being “validatable”. Such markers would improve the predictivity of non-clinical safety studies and have a positive impact on attrition rates and drug development timelines. They will also possibly allow the reduction of animal trials by moving compounds faster to clinical phases Clinical trials and Samples: • • identify clinical unit that would be the lead in implementing the outcome. clinical units need to develop implementation plans in clinical studies which may include appropriate study populations, characterization of populations, sampling, assessment of current standards, standardization of current standards (including medical assessment), dosing regimens,… academics and clinics may investigate the specificity of the biomarkers with respect to drug induced pathologies but also investigate the utility of biomarkers to diagnose diseases. assays to enable measurements of the biomarkers study the sensitivity and specificity of these assays 8 Indicative expectations from the public consortium • Biomarker assays: • • Biologic/Mechanistic understanding: Academics to perform mechanistic studies to understand the mechanisms of biomarkers but also the potential limitations of the biomarkers Page 11 of 88 Immunogenicity IMI Call 2008 DRAFT of 17/10/2007 3. Immunogenicity Prediction and Minimization of Immunogenicity to Biotherapeutics in Man Background: At this time no reliable prediction methods for immunogenicity of therapeutic proteins in man exist. The proposed project has three goals: 1. Standardize anti-drug antibody analyses. 2. Improve understanding of critical factors leading to immunogenicity and find ways to minimize them. 3. Optimize and harmonize existing pre-clinical tools to improve the prediction of immunogenicity in man. The administrative and scientific core group of this project will be in contact with the EIP (European Immunogenicity Platform) organized by Christian Ross Pederson, Novo Nordisk to avoid redundancies. The first milestone of this project will be the elaboration of a detailed project plan. Package 1: Long term program to improve the general understanding of the key factors leading to immunogenicity, in order to re-evaluate and substantiate the “risk based approach to immunogenicity”, outlined in the recently released EMEA guideline on immunogenicity: Database: Set-up of a database which is primarily fuelled by the companies of the consortium with immunogenicity relevant data from their biotherapeutic protein development programs. The database should improve the understanding of the predictive value of pre-clinical tools, help select and standardize the most promising predictive tool combinations for different compound classes and help evaluate and develop risk minimization strategies. Data mining will be applied to identify significant factors and patterns favouring the induction of immunogenicity in man (e.g. improved understanding of role of target: receptor vs. soluble molecule). Validation of findings with new compounds. The database may contain the following aspects: • • • • • • • data on immunogenicity in pre-clinical animal model applied in silico or in vitro risk assessment tools humanization and/ or de-immunization cell-based versus soluble target HLA status of target population mode of administration dosing regimen Page 12 of 88 1 Topic title 2 Project description Immunogenicity • • IMI Call 2008 DRAFT of 17/10/2007 immunogenicity data from clinical trials drug properties (percentage of aggregates, proteolytic stability, etc) Standardization program for anti-drug antibody analyses: The assays available for anti-drug Ab analyses show significant interassay variability. Before developing predictive tool sets, it is crucial to standardize the methods currently used to determine the incidences of anti-drug antibodies in clinical settings. For the different drug classes, international teams will conduct inter-assay, inter-laboratory, intercompany variability analyses. Data should be accessible via webinterfaces. Package 2: Improve tools to predict immunogenicity in man, based on > 5 selected compounds In-vitro (pre-condition to pt.4 below): Perform side-by-side comparison of different versions of human APC/ T cell assays. Explore which of the assays, if any, is able to reflect the immunogenic potential seen in clinical studies of > 5 reference drugs, with respect to immunogenicity incidence and HLA restriction of the response, as derived from clinical studies. Reference drugs are primarily those that carry non-human sequences or artificial post-translation modifications. Improve throughput, reproducibility and thereby statistical relevance of data. In-silico: Subject > 5 model drugs which have displayed differential immunogenicity incidences in clinical trials, to in silico screening for HLA-DR associated T cell epitopes by a set of established in silico prediction algorithms. Consensus peptide agretopes side-by-side with the full-length protein drugs are to be tested in APC/ T cell assays as to which of the agretopes qualify as epitopes. Animal models: Evaluate the predictive value of animal models: • • Analyse whether the transgenic mouse model that relies on breakage of tolerance, is dependent on T cells. In case yes, it is not a predictive tool due to MHC II species differences. Analyse mouse models that rely either on human HLA-DR transgenes or human IgG genes or human hematopoietic stem cell transfer for potential to predict relative immunogenicity incl. formulation and production changes. Analyse value of animals to decide between soluble vs cell target. Analyze value of animals to assess clinical consequence of neutralization of endogenous protein. Try to differentiate the predictability for biologics with endogenous homologues versus therapeutic Abs with no endogenous homologues. Try to reduce inter-animal variability which, as yet, is the major limitation. Page 13 of 88 • • • • Immunogenicity IMI Call 2008 DRAFT of 17/10/2007 Stratification: Implement HLA typing as a standard tool in clinical studies and attempt to link immunogenicity incidence with particular HLA-DR allotypes. If applicable, try to validate as stratification biomarker for potential to develop immunogenicity. Package 3: Draw conclusions from findings of package 1 & 2 and prepare recommendations for prediction and minimization of immunogenicity Prediction: Recommend combinations of in silico / in vitro / in vivo prediction tools that are tailor made for individual compound classes like: therapeutic antibodies, therapeutic proteins, new scaffolds, etc.. Design a decision tree that takes into account different risk categories, dependent on indication, mode of administration, dosing scheme etc. Minimization: Inform about and recommend immunogenicity potential/risk minimization strategies based on identified key factors and patterns favouring the induction of immunogenicity in man (if applicable). Recommend for which compound classes (e.g. therapeutic proteins, antibodies) and in which situations (target, disease, etc.) deimmunization adds value and how this could be best achieved; in particular in those cases in which immunogenicity minimization is expected to give rise to decreased potency and in those cases in which there is a risk to induce auto-reactive responses in man unless the therapeutic protein is fully de-immunized. 3 Key deliverables of the project Package 1: Improved understanding of factors leading to immunogenicity, including re-evaluated and substantiated “risk based approach to immunogenicity”, outlined in the recently released EMEA guideline: Database: Consortium-owned data base that compiles immunogenicity relevant data. Database and query tools. The data base should be accessible via a web-interface allowing all participants to use a central on-line resource and to prepare a later publicly accessible database. Standardization program for anti-drug antibody assays: Drug classspecific standardization program in order to improve comparability and quality of data defining immunogenicity positives vs. negatives. Package 2: Improved tools to predict immunogenicity in man, based on > 5 selected compounds In-vitro: 1-2 standardized, quantitative, high throughput (statistically relevant data generation) and clinically validated in vitro APC / T cell activation assays (if applicable).These assays are to be compatible with formulated biologics and cover the 8-10 most frequent HLA-DR Page 14 of 88 Immunogenicity allotypes of the Caucasian population. IMI Call 2008 DRAFT of 17/10/2007 In-silico: 1-2 standardized in silico prediction algorithms that proved to be user-friendly and most reliable (in terms of false-positive promiscuous epitopes) when applied in combination with validated in vitro models (if applicable). Animal models: Consolidated evaluation on the predictive value of different animal models for different types of aspects that are considered to contribute to immunogenicity. Stratification: HLA investigated as potential stratification biomarker for prediction of the individual risk of healthy subjects or patients to develop immunogenicity responses. Package 3: Recommendations for prediction and minimization of immunogenicity based on findings of packages 1 & 2 Prediction: Recommendation to apply combinations of in silico, in vitro and in vivo tools which are tailor-made for mAbs versus non-mAb biologics and that account for risk differences in immunogenicity potential and clinical consequences. Differentiated recommendations will be summarized in focus reviews. Minimization: Consolidated recommendation how to minimize immunogenicity potential/risk for different compound classes to be outlined in a focus review. Consolidated recommendation, whether and how to de-immunize therapeutic Abs versus recombinant non-Ab proteins that give rise to immunogenicity flags in pre-clinical assessment with the tool set described above. 4 EFPIA participants in the project AstraZeneca Bayer Healthcare Boehringer Ingelheim Genzyme Lundbeck Merck Serono Novartis Novo Nordisk Pfizer Roche UCB 5 Role of EFPIA participants in the G. Oliver, J. Sims H.W. Vohr U. Bamberger Y. Xu H. Northeved D. Kramer, B. Ladstetter A. Zaar C. Ross Pedersen, A. Gruhler R. Wallis H. Kropshofer, B. Mueller-Beckmann T. Bourne Different subgroups of IMI participants will concentrate on their respective fields of expertise. Knowledge will be shared with EIP expert group (to align with existing initiatives and to avoid redundancies) and Page 15 of 88 Immunogenicity project will be discussed with health authorities. IMI Call 2008 DRAFT of 17/10/2007 Database: provide the data, evaluation, data mining Standardization: Program proposed in line with EIP including selected drug classes in order to compare immunogenicity assay results between different companies. In-vitro: Shared optimization of an optimized assay platform, comparison of different assays or joint approach with CROs. Highthroughput format of selected assay to be implemented by industry. In-silico: Shared approach with academia. Comparison of currently existing algorithms. Animal models: Participate (provide models to academia and collaborate) 6 Indicative duration of the project 7 Indicative total in kind contribution from the EFPIA companies 4 to 5 years €13 millions Package 1: €3 millions Package 2: € 8 millions Package 3: € 2 millions 8 Indicative expectations from the public consortium Database: Set up ; Data mining Standardization: Potential test partner for validation of standardization procedure In-vitro: Shared optimization of one assay, comparison of different assays or joint approach with CROs. In-silico: Improvement of existing algorithms. Animals models: Optimization of existing and development of new predictive animal models. Page 16 of 88 Non-genotoxic carcinogenesis IMI Call 2008 DRAFT of 17/10/2007 4. Non-genotoxic carcinogenesis Non-genotoxic carcinogenesis: Identification of early markers and molecular classification of tumours 1 Topic title 2 Project description Background: Tumour findings are common endpoints in the preclinical testing of drug candidates in rodent models. Such in vivo carcinogenesis is rarely genotoxic in nature, as directly genotoxic compounds are excluded at an early point in the drug development process by use of in vitro and in vivo assays. However, there exist no sufficiently accurate and well-validated short-term assays to identify non-genotoxic carcinogens, thus necessitating an expensive 2-year rodent bioassay for assessing the carcinogenic risk of such compounds to humans. The applicability of early biomarkers in the assessment of non-genotoxic carcinogenesis in preclinical rodent toxicity studies has thus far not been conclusively established. Even in those cases where candidate biomarkers have been suggested for specific carcinogenic effects, it is unknown whether the biomarkers involved are mechanistically or causally involved in cancer development. Thus, it would be exceedingly valuable to establish the mechanisms by which early biomarkers are linked to tumour formation, and ultimately demonstrate the concept that early biomarkers can reliably and robustly predict later cancer development. Relevant topics for consideration: (1) Epigenetic markers and gene expression Predictive toxicogenomic approaches suggest that molecular profiling technologies can potentially predict non-genotoxic carcinogens in shortterm preclinical toxicity studies and, in addition, provide insights into mechanism of action, thus contributing to the assessment of human cancer risk at a much earlier point in the pharmaceutical development process. More recent investigations indicate that epigenomic alterations (e.g. altered DNA methylation status) may precede the expansion of premalignant cells during the earliest stages of tumourigenesis. Furthermore, the application of both genomic (mRNA and microRNA) & epigenomic profiling approaches to the study of human cancers has demonstrated that there exist molecular subtypes associated with distinct biological processes, disease progression and treatment response. (2) Molecular classification of tumours The intrinsic chemical stability of DNA in both frozen and fixed tissue samples represents a unique opportunity for the application of Page 17 of 88 Non-genotoxic carcinogenesis IMI Call 2008 DRAFT of 17/10/2007 epigenomic and other molecular profiling technologies to “unlock” the extensive preclinical tissue archives generated from carcinogenicity testing within the pharmaceutical industry. The molecular classification of spontaneous versus chemically-induced tumours may be accomplished via combined epigenomic and gene expression profiling of archived rodent tissues from these long-term carcinogenicity studies. Important outputs of such efforts include collation of baseline molecular signatures from spontaneously occurring tumours in aged animals, and the identification of biomarkers which may be applied to the early assessment of non-genotoxic carcinogens. (3) Circulating tumor cells/nucleic acids The presence of tumour-specific circulating cells, nucleic acids and methylated DNA in plasma or serum represent promising biomarkers for the early detection of cancer. The conceptual and technical feasibility of identifying circulating tumour cells in preclinical rodent models has not yet been explored. In addition, the predictive value of tumour-specific circulating nucleic acids and/or methylated DNA in plasma or serum as non-specific surrogate biomarkers of non-genotoxic carcinogenesis should be assessed in preclinical studies. (4) Receptor-mediated carcinogenesis Often, in vivo carcinogenic effects depend upon drug-receptor interactions. For example, PPARαand CAR agonists induce liver tumors in rodents through mechanisms that are not fully elucidated, but require the presence of receptor proteins. Early biomarkers or surrogate endpoints for receptor-mediated carcinogenetic effects may be immensely valuable for increasing speed and reducing volume in preclinical development, as well as to allow bridging from preclinical studies to human trials. (5) Protein markers/in vivo imaging It is well-recognized that neoplastic transformation is associated with changes in intracellular signalling cascades (e.g. protein phosphorylation), as well as changes in transcription factor expression. Accordingly, in some model systems of receptor-mediated carcinogenesis, early protein phosphorylation and transcription factor expression changes may represent biomarkers of carcinogenicity. Recently developed mass-spectrometry-based methods appear quite promising as biomarker identification tools, allowing a Systems Biology approach to the study of complete phospho-proteomes of cells. Multilabelling histopathological approaches, with the potential to localize and quantify a carcinogen receptor as well as a biomarker in relation to preneoplastic lesions, will be useful to evaluate mechanisms and causal effects in cancer development. Finally, in vivo imaging of early preneoplastic lesions in experimental animals constitutes a highly promising approach to shortening carcinogenicity study duration, increasing study power, and reducing the number of experimental animals. Page 18 of 88 Non-genotoxic carcinogenesis IMI Call 2008 DRAFT of 17/10/2007 3 Key deliverables of Deliverables: the project 1. Identify industry-relevant model systems, using small-molecule and biopharmaceuticals, for mechanistic studies of receptor-mediated and/or epigenetic carcinogenic effects, and biomarker identification. 2. Use established models for non-genotoxic carcinogenesis in which candidate biomarkers have already been identified to define the causal relationship between early biomarkers and later cancer development, and investigate the predictive value of the biomarkers across diverse classes of non-genotoxic carcinogens. 3. Compare biomarker findings between preclinical animal models and humans to investigate the potential and robustness of such biomarkers for translation into the clinic. 4. Validate the utility of combining new methodologies for analysis of animal material or live animals for the identification of non-genotoxic carcinogens. 5. Identify novel non-specific and mechanism-based molecular biomarkers for improved cancer risk assessment during late phases of drug development. 6. Generate a unique database of molecular profiles of spontaneous and drug-induced rodent tumours. Impact of the Project: The applicability of early biomarkers in the prediction of non-genotoxic carcinogenesis in preclinical rodent toxicity studies has thus far not been conclusively established for small molecule compounds, and has essentially not been addressed at all for protein/peptide compounds. The main impact of the project will thus be to establish, for the first time, proof of concept that early biomarkers can reliably and robustly predict later cancer development. Early biomarkers of carcinogenicity would be immensely valuable in preclinical development of new compounds, allowing reduction/refinement/replacement of experimental animal use, improved internal selection of superqualifier compounds, fewer delays and attritions during late-phase development, and improved preclinical carcinogenicity safety assessment prior to clinical trials. The development of standardized software tools and procedures for use by pharmaceutical companies and Regulatory Authorities for preclinical safety, human risk assessment, and regulatory decision-making. A collaborative pan-European approach will facilitate access to a wide range of archived tissue resources and molecular profiling databases and also generate a robust framework for ultimate qualification of newly Page 19 of 88 Non-genotoxic carcinogenesis IMI Call 2008 DRAFT of 17/10/2007 identified early biomarkers for non-genotoxic carcinogens. Pooling and sharing of existing archived animal tissue samples for the studies outlined in this call would be well aligned to the 3R’s principle of reduction, refinement & replacement through maximizing the knowledge gained from extensive preclinical carcinogenicity testing programs. Furthermore, the establishment of blood-based surrogate biomarkers such as methylated DNA should ultimately lead to the use of fewer animals in carcinogenicity studies through serial sampling regimes. 4 EFPIA participants AstraZeneca in the project Bayer Healthcare Boehringer Ingelheim Lundbeck Merck Serono Novartis Novo Nordisk Pfizer Solvay UCB G. Oliver H.J. Ahr E. Vock H. Northeved S.O. Mueller, P. Hewitt J. Moogs P. Brinck R. Wallis J.L. Paquet S. Dhalluin Assuming 10 pharma participants in this IMI call, annual “in-kind” contributions would be in the order of magnitude of € 250,000 total. The distribution and exact contribution amounts among the participating companies needs to be clarified. Participation of additional companies will decrease “in-kind” investments accordingly. Specific examples of relevant “in-kind” contributions to this call could include the costs of running carcinogenesis and associated mechanistic studies, provision of existing archived samples from such studies, development of technologies in support of epigenomic profiling assays, development of bioinformatic tools for integration of epigenomic and genomic datasets 5 Role of EFPIA participants in the project Tissue and blood samples from long-term rodent carcinogenicity studies. Tissue and blood samples from short-term mechanistic studies. Evaluation of samples using genome-wide and locus-specific epigenomic profiling technologies including DNA methylation and histone modifications (staff; laboratories; cost of reagents and materials). Evaluation of samples using genome-wide and locus-specific gene expression technologies including Affymetrix microarray and quantitative real-time PCR (staff; laboratories; cost of reagents and materials) Evaluation of samples using molecular pathology tools and assays (e.g. Laser-capture microdissection) for assessing cell-type specific molecular Page 20 of 88 Non-genotoxic carcinogenesis responses to non-genotoxic carcinogens IMI Call 2008 DRAFT of 17/10/2007 Development and application of bioinformatic tools for combining epigenomic and genomic profiling data. Evaluation of samples using clasical immunohistochemistry and in situ hybridization approaches, to correlate carcinogen receptor as well as biomarker expression to sites of tumor formation. Evaluation of potential for translation of preclinical biomarkers to the clinic. Receptor binding studies comparing carcinogenic and non-carcinogenic ligand versions. Phosphoproteome analysis of animal and human cell cultures exposed to model carcinogens. 6 Indicative duration of the project 7 Indicative total in kind contribution from the EFPIA companies 8 Indicative expectations from the public consortium 3 years €2.5 million The Successful Consortium must address the following points: a. Identify and make publicly available knowledge about industry-relevant models for receptor-mediated carcinogenesis, including small molecule as well as protein compounds. b. Gain access to (or generate de novo) high quality samples derived from well-designed studies with model compounds, where the late outcome is known to be cancer in known target organs. c. Using studies mentioned in b, identify early biomarkers, taking into account the known or presumed mechanism of action of the model compound, and the target organs. A variety of techniques can be used for this. d. Explore the causal involvement of the identified biomarkers in later cancer development, using the required techniques. e. Explore the predictive nature of the early biomarkers. It is recognized that this item may not be fully addressable within the duration of this call, due to the complexity and cost of performing long-term animal studies. f. Gain access to and integrate data from appropriate public domain, commercial and in-house molecular profiling databases e.g. CEBS (Chemical Effects in Biological Systems), Human Epigenome Project, Iconix. g. Explore the possibility for tracking outcomes of ongoing rodent carcinogenicity studies following preclinical safety predictions based on Page 21 of 88 Non-genotoxic carcinogenesis IMI Call 2008 DRAFT of 17/10/2007 application of molecular profiling to short term studies. These data should be subsequently made available via appropriate public domain carcinogenicity databases such as the US NTP (National Toxicology Program). Potential public consortium members answering to this call could be safety-oriented organizations, academic institutions, small biotech companies and CROs Page 22 of 88 Expert systems for in silico toxicity prediction IMI Call 2008 DRAFT of 17/10/2007 5. Expert systems for in silico toxicity prediction Development of expert system for in silico toxicity prediction Non-GLP in vivo studies are often unveiling side effect which could have been predicted from the chemistry (either because of cross-target activation or inhibition; or because of straight chemistry-linked toxicities). This would increase the quality of candidate drugs and ensure a lower attrition rate before and during the first GLP animal studies. Approaches: 1. Collect pharmacology-related chemistry (“molecule war-heads”) from known series to build up predictive expert systems for secondary-pharmacology (“off-target toxicity”) prediction. 2. Same approach as above for pure chemistry-related toxicity (e.g., cationic amphiphilic drugs and phospholipidosis). Expert systems (e.g., Mcase, DEREK, etc…), pharmaco-toxicology database with chemical structures and associated pharmacology/toxicity, from both public domain and pharmaceutical industries would be necessary. Access to MDS Pharma-like in vitro receptor binding assay results would be necessary. Usage and implementation would only require personal computers and experts for running, maintaining and regularly updating the systems. Knowledge Management The requirements depend of course on the data being captured. Due to the 3-5 year time frame an off the shelf solution is recommended (also our in-house solutions would be proprietary). Potential partners would allow the gathering of all relevant information including: • Study Design and collection of sample data and associated information (incl. treatment and sampling schedule), and of experimentally measured observations on samples. Sample data include phenotypic anchors and omics data (incl. transcript, protein and metabolite profiles). Pre-processing of experimental raw data and storage in relation to their corresponding experimental samples (incl. reliable data quality assessment of large amounts of molecular data from all omics technologies). Establishment of relationships for experimental data (incl. crossomics mappings, mappings of different platforms within a given omics technology, and mappings of legacy data with current data to extract maximum value from existing corporate knowledge). Comprehensive statistical analysis and determination of discriminating markers for potential toxic effects. Interpretation and validation of markers in biological context Page 23 of 88 1 Topic title 2 Project description • • • • Expert systems for in silico toxicity prediction IMI Call 2008 DRAFT of 17/10/2007 • • (e.g. specific pathways). Application of sophisticated classification and modeling algorithms to predict compound toxicity and compound mode of action. Reliable documentation of markers to support informed decisions on promotion, termination, or re-evaluation of compounds, based on their comprehensive toxicological signatures. Project Management For Project Management and Data sharing there are a number of webbased tools that can be supported within a company or externally. The objective is to allow project management (timelines/task management), document sharing, discussion forums, automatic communication by email etc. Cheminformatics Regarding the point about in silico models: • Develop knowledge expert systems to feed existing data from known toxicities in in silico database and improve prediction. The design of the study would have to either include many (100s of compounds) that are structurally very different but give similar toxic endpoints or we would need to focus on compounds having similar scaffolds but very different levels of toxicity in order to create algorithms to improve the prediction of toxicity based on chemical structure. Software that would help to do the analysis of such data includes Pipeline Pilot and MCASE. If pre-existing (public or proprietary) Tox/Compound relationships will be included then the appropriate databases (Lhasa DEREK and VITIC) would also be needed. Bioinformatics We would need software for identifying the human orthologues of biomarkers identified in animal studies in order to translate the findings in pre-clinical omics studies to clinical omics studies. Much of this is open source (BLAST etc.) but would perhaps need development and support. 3 Key deliverables of the project PC based expert systems for chemistry and off-target related toxicities prediction. Such in silico models would allow chemist to rapidly check for obvious toxic moieties and allow early discovery toxicologists to assess in the same way off-target potential liabilities. Hence some candidate could be removed early before engaging expensive resources for in vivo studies. 4 EFPIA participants in the project AstraZeneca Bayer Healthcare Boehringer Ingelheim G. Oliver T. Steger-Hartmann E. Vock Page 24 of 88 Expert systems for in silico toxicity prediction IMI Call 2008 DRAFT of 17/10/2007 A. Guzman H. Northeved F. Pognan A. Gruhler R. Wallis W. Muster Esteve Lundbeck Novartis Novo Nordisk Pfizer Roche 5 Role of EFPIA participants in the project UCB • • • 6 Indicative duration of the project 7 Indicative total in kind contribution from the EFPIA companies 8 Indicative expectations from the public consortium S. Dhalluin EFPIA participants will contribute samples form phase I studies and measuring of biomarkers Interpretation and validation of markers in biological context (e.g. specific pathways). Structures and related biological data 3 years €5 million Good mix of toxicology and clinical pharmacology skills and experience, as well as information technology/science skills. Fundamental in silico modelling expertise Page 25 of 88 Pharmacovigilance IMI Call 2008 DRAFT of 17/10/2007 6. Pharmacovigilance Improving and Strengthening the Monitoring of the Safety and benefit/risk of Medicines Marketed in the EU The aim is to facilitate the application of existing data resources and/or to expedite the generation of more, and more reliable, pharmacoepidemiological data for proactive pharmacovigilance and risk management of medicines throughout their life-cycle. Work should be directed towards developing, implementing and/or evaluating new methodologies in pharmacovigilance and pharmacoepidemiology, e.g. signal identification/detection, data mining based on large safety databases, integration of drug utilisation information into pharmacovigilance and/or post-approval benefit: risk optimisation. Work should also focus on establishing and working to common standards, protocols and terminologies. to ensure both transparency and uniformity in the conduct and reporting of studies in this field. Training aspects should be addressed where appropriate (link to E&T call). Successful programs should focus on the establishment of EU-wide Pharmacoepidemiology and Pharmacovigilance collaborations and networking by facilitating/stimulating the collaboration between European Research Groups, and the harmonisation of Health Care Databases and Patient Registries This will increase confidence in the post-marketing monitoring of the benefit/risk balance of EU medicinal products, ultimately facilitating an earlier access of novel medicines to EU patients. It is envisaged that this will be assisted by facilitating access to Pharmacoepidemiology resources to regulatory authorities, pharmaceutical industry and to public-private partnerships. 1 Topic title 2 Project description 3 Key deliverables of the project Proposals should be submitted to deliver one or more of the following: 1. Establish new methods of data collection in pharmacovigilance including methods for collecting data in the natural language and research on how to simplify data collection from reporters whoever they are. 2a. Evaluate methods and develop operational definitions for signal detection and signal evaluation. Determine these methods’ performance characteristics and capacity for early detection of adverse events in spontaneous reports databases If applicable, develop operational standards for screening algorithms and criteria to confirm or refute signals 2b. Evaluate methods and develop operational definitions for signal detection and signal evaluation. Determine these methods’ performance characteristics and capacity for early detection of adverse events and identification of benefits in population-based epidemiologic data sources. If applicable, develop operational standards for screening Page 26 of 88 Pharmacovigilance algorithms and criteria to confirm or refute signals IMI Call 2008 DRAFT of 17/10/2007 2c. Establish methods for graphical expression of the benefit risk profile of the medicinal products presenting evidence from clinical trials, epidemiology studies and spontaneous reports. 3. Investigate and develop standards and processes for interoperability and sharing of European epidemiology data sources to determine their capacity for pharmacovigilance, signal detection, and large epidemiology studies for quantification of benefit and risk outcomes The goal of this collaborative research is to enable a more rapid detection of new Adverse Drug Reactions (ADRs), as well as confirmation of safety and efficacy profiles of individual medicines and therapeutic classes of medicines, under ‘real world’ conditions. It will further help to develop risk management, establish and agree on new scientifically based and tested tools for the benefit/ risk assessment that will be used when establishing the benefit/risk profile of marketed drugs, rapidly investigate purported treatment-related risks and refute spurious associations between drug treatment and adverse events. 4 EFPIA participants in the project AstraZeneca Bayer Healthcare Boehringer Ingelheim Eli Lilly Genzyme GSK Lundbeck Merck Serono Novartis Novo Nordisk Pfizer sanofi aventis Sigma Tau Wyeth 5 Role of EFPIA participants in the project M. Keisu R. Dorow S. Eberle G. Salvator O. de Mol E. J. Swain J.P. Balling F. Weber G. Feutren K. Lollike R. Reynolds G. Danan S. de Santis H. Malone Provision of expertise related to therapeutic area specific items and orphan drug issues Provision of data relative to experience in a number of therapeutic area to the extent that these data are non competitive data (e.g. background rates in disease areas, Medical Information support etc) Participation in projects for refining methods of signal detection based Page 27 of 88 Pharmacovigilance on state of the art expertise Pharmacoepidemiologist resource Statistical expertise IS/IT expertise Project management resource 6 Indicative duration of the project 7 Indicative total in kind contribution from the EFPIA companies 8 Indicative expectations from the public consortium 5 years € 15 million IMI Call 2008 DRAFT of 17/10/2007 Development of analytical methods and algorithms for an enhanced detection and evaluation of safety signals: • • using databases containing spontaneous adverse event reports using claims/health care databases and other large sources of epidemiology data Creation of an infrastructure and services for the integration and interoperability of claims/health care databases across the EU to support: • • pharmacovigilance monitoring and signal detection for single drugs and drug classes large hypothesis-testing epidemiology studies that reflect the specificities of the EU population Development of methods – including graphical expression - for integration of safety profiles across all sources (clinical trials, epidemiology, spontaneous reports) Enhancement of early detection of new adverse drug reactions from marketed products and continuous monitoring of benefit-risk Enhanced accuracy of signal detection and ability to differentiate true safety findings from spurious observations Page 28 of 88 Islet cell research IMI Call 2008 DRAFT of 17/10/2007 7. Islet cell research Islet cell research ß-CELLS Research will focus on molecular, physiological and clinical aspects of ß-cell function, regulation and diagnostics covering various areas: ß-cell dynamics in vitro and in vivo: • • • • • • • Origin and function of novel ß-cells Source of novel ß-cells (stem cells vs. already existing ß-cell lines) Conditions for ß-cell differentiation and proliferation from precursor cells Intestine-pancreas crosstalk ß-Cell apoptosis with research on its mechanisms, prevention and methods of apoptosis measurement in animal models (and in humans) Measurement of ß-cell mass and function in humans (and animal models) by non-invasive methods Genetic and genomic studies for identification of biomarkers for responsiveness to drugs affecting ß-cell proliferation and differentiation Novel animal models to examine ß-cell proliferation in vivo Non-invasive technologies for monitoring of ß-cell mass and function in patients and animal models including biomarkers, imaging and nanotechnological approaches Novel biomarker for ß-cell function and islet regeneration in vivo Establishment of a standardized longitudinal cohort with a predefined population progressing, or not, to diabetes 1 Topic title 2 Project description Novel technologies and tools: • • • • ALPHA CELLS Research will include abnormalities in alpha cell function, alpha/beta cell ratio, and the impact of alpha cell function on metabolic abnormalities in various stages of type 2 diabetes. CROSSTALK OF CELLS IN ISLETS with the special focus on alpha and ß-cells 3 Key deliverables of the project In the islet research field, the project will improve our understanding on the key mechanisms for ß-cell loss in type 1 and 2 diabetes and where research should be focused to reduce ß-cell loss by pharmacological agents. Another area is to enhance understanding on the ß-cell proliferation. This approach could provide novel therapeutic targets. There are already some compounds commercially available, which are Page 29 of 88 Islet cell research IMI Call 2008 DRAFT of 17/10/2007 shown to enhance ß-cell mass in vitro or in vivo in animal models of type 2 diabetes. Special focus will be on the understanding of the role of GI-derived ligands or signals towards the pancreas. For this reason it is important to develop non-invasive ways to measure the ß-cell mass in order to monitor the progression of type 2 diabetes and how the progress can be intervened using novel pharmacological approaches. Maintaining and/or restoring the ß-cell mass will be beneficial for type 2 diabetic patients only, if the ß-cell function is concomitantly improved. Therefore, it is important to develop methods and diagnostic tools to measure the function of novel ß-cells and evaluate the functional maturity of the ß-cells including novel biomarkers and imaging techniques. 4 EFPIA participants in the project AstraZeneca Boehringer Ingelheim Eli Lilly Novartis Novo Nordisk Roche sanofi aventis Servier Solvay H. Wennbo M. Mark T.Hardy, V. Koivisto H. Chen, L. Kjems A. E. Karlsen A. Edgar, J. Mizrahi W. Kraemer A. Ktorza C. Legendre, J. Antel The 9 participating companies need to cover annual “in kind” contributions in the order of € 150’000-250’000. The distribution between the participating companies has to be decided based on the specific research protocols. Participation of the additional companies will decrease the investment accordingly 5 Role of EFPIA participants in the project Specifications of the study protocols to achieve the aims. Preclinical scientific experience Provide their already existing technologies to achieve the objectives of the studies Evaluate the DNA samples and samples for proteomics, other –omics, immunoassays, cell based assays, in vivo studies, biomarkers (staff, laboratories, costs of reagents and materials) Database and informatics support Coordinate input from key stakeholders, where relevant Research-related Project management 6 Indicative duration Up to 5 years Page 30 of 88 Islet cell research of the project 7 Indicative total in kind contribution from the EFPIA companies 8 Indicative expectations from the public consortium € 20 million IMI Call 2008 DRAFT of 17/10/2007 Work closely with EFPIA partners to ensure effective management and coordination of the work to deliver key objectives. Provide novel information on the conditions of ß-cell differentiation and proliferation to be used in further therapeutic developments Identification of biomarkers in order to measure ß-cell mass and function during the course of diabetes and in response diabetes therapies Novel animal models to examine ß-cell proliferation in vivo Non-invasive technologies for monitoring ß-cell function and mass Improve knowledge in islet cell physiology and pathophysiology and the cross talk of islet cells Innovation Novel pathways and targets for the regulation of ß-cell mass with appropriate IP sharing. Page 31 of 88 Surrogate markers for vascular endpoints IMI Call 2008 DRAFT of 17/10/2007 8. Surrogate markers for vascular endpoints Surrogate markers for micro- and macrovascular hard endpoints in clinical trials on diabetes In order to reduce size and timelines for studies evaluating different therapeutically effects on the establishment or progression of micro and/or macrovascular complications research should focus on establishment of validated and scientifically justified biomarkers / surrogate endpoints for micro- and macrovascular hard endpoints in diabetes clinical research. This question can be approached for example by: a) Exploring data and samples from recent and ongoing landmark studies or other major databases define and validate biomarker and /or surrogate endpoints for micro and macro vascular complications b) Assessing specific genotypes as biomarkers and/or surrogate endpoints for micro- and/or macrovascular disease c) Assessing innovative assays and invasive and/or non-invasive imaging technologies to asses use as biomarkers for micro and macrovascular disease. d) Evaluating preclinical biomarkers /surrogate endpoints in different animal models that predicts micro/macrovascular disease in man 1 Topic title 2 Project description 3 Key deliverables of the project The main reason for mortality in type 2 diabetes is CVD and the most feared and disabling outcome of diabetes to patients is microvascular disease. To be able to influence micro and / or macrovascular hard endpoints in diabetes therapy is one of the most important objectives in the treatment of diabetes. However, randomized controlled trials to examine that require long time and are very expensive. For these reasons clinical research is moving away from Europe to low cost countries. To identify surrogate markers would make studies shorter and cheaper and this will improve European competitiveness in this area. For microvascular disease there is also a need for defining mutually agreed surrogate endpoints that can be applied in clinical trials to test for treatment or prevention of microvascular complications 4 EFPIA participants in the project Boehringer Ingelheim Eli Lilly Novartis Novo Nordisk Roche M. Mark V. Koivisto H. Chen A. Dejgaard J. Mizrahi Page 32 of 88 Surrogate markers for vascular endpoints IMI Call 2008 DRAFT of 17/10/2007 C. Legendre Solvay 5 Role of EFPIA participants in the project 6 Indicative duration of the project 7 Indicative total in kind contribution from the EFPIA companies 8 Indicative expectations from the public consortium Pending Up to 5 years € 20 million pending Page 33 of 88 Genetics and genomics of type 2 diabetes IMI Call 2008 DRAFT of 17/10/2007 9. Genetics and genomics of type 2 diabetes Genetics and genomics of type 2 diabetes Preventative and well-tolerated drug therapies are amongst the un-met medical needs in type 2 diabetes (T2D) care. These challenges derive from the variegated pathogenesis of the disease, caused by a combination of genetic susceptibility and environmental factors. Recent advances in genomic research offer a great opportunity to uncover the diverse etiological mechanisms underlying T2D, which could provide the potential to develop effective treatments tailed to individual patients. We are calling for innovative project proposals to develop genomic biomarkers for diabetic subjects that will: a) identify pre-diabetic individuals b) monitor disease progression c) act as efficacy and safety markers for existing and new treatments 1 Topic title 2 Project description 3 Key deliverables of the project DNA polymorphisms, mRNAs, proteins or metabolites associated with disease stage, severeness, treatment efficacy or safety will be identified. These new biomakers will be validated in clinical settings. In the long term, these findings will be applied to treat patients preventively, effectively and safely. Boehringer Ingelheim Eli Lilly Novartis Novo Nordisk Roche Servier M. Mark V. Koivisto H. Chen A. E. Karlsen J. Mizrahi A. Ktorza 4 EFPIA participants in the project Provided the total project cost will be € 20 million during a 5 yr period, the maximal investment for the 6 participating companies will be approximately € 650000/yr for 5 yrs. The final amount depends on the duration and total expense of the project. How the expenses are shared between the companies will be decided. If more companies will participate, the investment per company will decrease accordingly. 5 Role of EFPIA participants in the project • • • Clinical trial expertise Clinical supply of marketed products to be tested in the trials Support to analyze the genetic, genomic and other data and to correlate that with the outcome of studies individually for each participating patient Page 34 of 88 Genetics and genomics of type 2 diabetes • • • • • • 6 Indicative duration of the project 7 Indicative total in kind contribution from the EFPIA companies 8 Indicative expectations from the public consortium IMI Call 2008 DRAFT of 17/10/2007 Data collection and analysis Project management Design the clinical studies Recruitment of the patients in collaboration with academic centers and patient organizations Interaction with other key stakeholders as appropriate, such as payer or regulatory authorities To support the European network and to facilitate the collaboration between all the stakeholders 3 to 5 years Up to € 20 million • • • • • Patient samples with extensive phenotypic and clinical characterizations and longitudinal information Knowledge in disease biology and genetics Ability to provide novel medication selectively to responders Avoid giving novel medication to patients, who will not respond or who will have serious adverse effects To give right medication to right patients and a right time Page 35 of 88 Pain Research IMI Call 2008 DRAFT of 17/10/2007 10. Pain Research 1 Topic title 2 Project description Pain research: Biomarkers aimed at more predictive preclinical and clinical paradigms yielding safer and more effective treatments. Rationale: The management and treatment of pain remains unsatisfactory. Existing treatments for chronic pain provide incomplete relief for some patients or carry a side-effect profile that is unacceptable. It is essential to build partnerships between academia and industry across the preclinical and clinical domains to accelerate the development of molecules for treating chronic pain conditions. Notably, we need to improve our understanding of the pathways and mechanisms mediating different kinds of pain, to develop translatable efficacy, pharmacodynamic (PD) and pharmacokinetic (PK) measures in animals and humans, to establish and validate mechanism-based human pain models, to develop robust markers for patient stratification and quantitative pain assessment, so that potential novel analgesics can be efficiently tested and compared in relevant patient groups. Mechanisms involved in generating and sustaining pain: Understanding pain pathways and processes together with how they are modified by current analgesics provides an opportunity to develop better models (both preclinical and human), efficacy and stratification markers, all of which can help develop medicines targeting specific pain mechanisms underlying the pathophysiology. There is a need to understand: 1) how chronic pain is maintained, specifically in neuropathic pain where hyperalgesia and allodynia can persist in the absence of nerve injury. As such, increased insight is needed into the mechanisms underlying central sensitisation and its role in chronic pain; 2) how inflammatory mediators (either peripherally- or centrallyreleased), nociceptive neurone activity and central brain processes are involved in different types of pain; 3) how existing analgesics and NCEs modify inflammatory mediators, neuronal activity and plasticity, and alter function in key brain regions; and 4) the role of genetic factors in mediating and sustaining particular types of pain. Preclinical animal model development: The predictability of available animal models for chronic pain remains limited. There is a particular need for models that are translatable between man and animals, in terms of mechanisms and endpoints. This requires: 1) determination of the most predictive animal models; 2) remove user-bias from accepted models and measures; 3) consider more complex nocifensive behaviour than simple withdrawal reflexes; 4) provide greater coherence with emerging clinical techniques, for example, electrophysiological or imaging approaches; and 5) backtranslation of markers validated in clinical studies of pain into appropriate Page 36 of 88 Pain Research predictive preclinical animal models. IMI Call 2008 DRAFT of 17/10/2007 Develop models and markers to translate pain outcomes and pharmacology between animals and humans: There is a need to develop and validate mechanism-based human models of pain in patients, which could be standardised so that preclinical and clinical data-bases obtained with established analgesics, negative controls and NCEs could be compared, to characterise analgesic mechanisms and their PK/PD markers for preclinical and clinical use. Identifying and characterising functional or ‘wet’ markers that correlate with clinical efficacy will allow early identification of successful new analgesics as well as the ability to perform tailored clinical trials in subgroups of patients most likely to benefit. A thorough understanding of the genetic factors involved in particular types of pain will not only provide potential drug targets but also drive selection of candidate biomarkers. This will require whole genome scan hypothesis-free approaches in well-phenotyped patients. There is a need to identify and validate soluble mechanism-based plasma biomarkers for inflammatory pain and to further develop technologies with the potential to achieve translational pharmacology for CNS-penetrant drugs including, for example, quantitative EEG/evoked potentials, magnetoencephalography (MEG), PET, functional magnetic resonance imaging (fMRI), including arterial spin labelling [ASL], and diffusion tractography. The development of translational methodologies to assess both adequate biomarkers and PK in parallel would increase efficacy in early preclinical and clinical drug development. Objective and quantitative assessments of pain for use in clinical trials: It is important to be able to quantitatively detect analgesic efficacy in order to select the best treatment for a particular type of pain patient. More objective, quantitative measures of patients’ pain are required and may emerge from newer developments in fMRI-determined brain activation of the pain matrix, EEG, MEG or other quantitative physiological responses. Such measures will require validation in randomised controlled trials using standard treatments and NCEs. Additionally there is a critical need to develop databases of wellphenotyped patients to enhance capability to perform clinical trials in these well defined groups. Finally, it is imperative that factors contributing to the placebo effects in analgesic drug trials are investigated in detail as large and variable placebo responses can increase the uncertainty in making definitive assessments of novel analgesic efficacy. Therefore, it is important to improve our understanding of the placebo response in a set of well-characterized patients. Abuse potential: More accurate prediction and understanding of signals of abuse potential Page 37 of 88 Pain Research IMI Call 2008 DRAFT of 17/10/2007 in man is a significant goal in developing novel analgesics, many of which will act directly on brain receptors. The abuse potential of opiates makes this a particular area of concern. Imaging technologies have the potential to identify validated cerebral profiles of the positively reinforcing, psychostimulant properties of drugs of abuse. Proposal structure: Proposals submitted for funding should aim, where possible, to address an aspect of each of the main topics outlined above, ensuring the involvement of both pre-clinical and clinical scientists. An integrated approach employing imaging, electrophysiology, novel clinical measures and/or genetic/biochemical markers is desired. It is envisaged that academic partners will work closely with pharmaceutical partners. 3 Key deliverables of 1. Mechanisms involved in generating and sustaining pain: the project • Find new mechanisms of central and peripheral sensitisation and of neuroplasticity involved in the development and maintenance of chronic pain. • Through well-defined protocols and techniques, discover novel mechanisms of chronic pain in patients, which can be translated back to and further analysed in animal models. • Develop protocols and techniques (e. g., brain imaging) to analyse mechanisms underlying the placebo response in clinical trials on pain. 2. Preclinical animal model development: Develop predictive animal models of chronic/neuropathic pain (includes rheumatoid arthritis-, HIV-, cancer-related pain): • Objective, quantitative and clinically translatable pain measures; • Methods enabling measurement of spontaneous pain; • Development of pain-free animal models of pain (3Rs) (including collateral behavioural markers that do not elicit pain). To this end, amongst others: • Validate novel animal models: e. g. , genetic animal models of type 1 and type 2 diabetes; • Design and validate novel pain measures in animals: • devoid of elicitation of withdrawal reflexes, • demonstrate sensory loss as well as hypersensitivity measures, • aim at eliminating user bias in experimental pain assessment. • Adapt animal models of persistent and neuropathic pain in order to obtain, from anaesthetised rats, measures of fMRI and MRSROIs as CNS signatures/surrogate markers of pain. Develop techniques and methods to measure pain inside the NMR bore. Try to obtain signatures of spontaneous versus stimulus-elicited pain. (This approach should be combined with molecular profiling (genetics, transcriptomics, proteomics or metabonomics). Page 38 of 88 Pain Research IMI Call 2008 DRAFT of 17/10/2007 3. Develop models and markers to translate pain outcomes and pharmacology between animals and humans: Use cerebral electrophysiological (EEG, MEG), brain imaging (fMRI, PET), “wet” biomarkers and molecular profiling (genetics, transcriptomics, proteomics or metabonomics) in animal models and in patients suffering chronic pain in order to identify brain mechanisms underlying chronic pain and to develop well-characterised translatable preclinical/human experimental pain models for decision-making and/or patient stratification. To this end, also improve preclinical-clinical translation of PK/PD data. 4. Objective and quantitative assessments of pain for use in clinical trials: • • Refine and extend experimental clinical methods of objectively measuring pain, such as axonal neuronography (ectopic discharge) and quantitative sensory testing (QST). In collaboration with academic partners, investigate placebo effects in pain clinical trials by detailed review of placebo data provided by industry consortium members. Support prospective studies investigating placebo response. Make different methodologies (e. g., genetic linkage, QST, novel methods) converge. Provide access to a well-managed extensive sample collection of blood/plasma from animal models, healthy volunteers and pain subjects, which can be correlated with treatment and/or disease progression. Conduct small-scale, stratified clinical studies, which can deliver reliable early efficacy signals. 5. Delineate phenotypes of chronic pain patients: • • • 6. Brain imaging methodology that allows objective evaluation of the abuse potential of novel analgesics. 4 EFPIA participants in the project AstraZeneca Boehringer-Ingelheim Eli Lilly Esteve GSK Johnson & Johnson Novartis Orion Pharma Pfizer Roche sanofi aventis UCB M. Segerdahl B. Sommer R. Peck J.M. Vela, A. Fresquet E. Irving, S. Stratton, Z. Ali T. Meert B. Gomez Mancilla M. Hämäläinen, R. Salonen R. McKernan, K. Tan, I. Machin L. Santarelli, G. Vargas B. Scatton M. De Ryck, K. Miller Page 39 of 88 Pain Research IMI Call 2008 DRAFT of 17/10/2007 Wyeth J. Kennedy, M. Pangalos 5 Role of EFPIA participants in the project Pre-clinical and clinical scientific expertise and the sharing of pre-clinical models, human experimental pain data and clinical trial data on nonproprietary compounds. • • • • • • • • • Clinical trial expertise Pain clinical trial placebo data Clinical supply of marketed products Tool molecules (clinical and pre-clinical) Clinical and pre-clinical brain imaging facilities Blood/CSF/biochemical biomarkers Transgenic mouse strains/models Animal models of chronic/neuropathic pain Behavioural measures of chronic/neuropathic pain 6 Indicative duration of the project 7 Indicative total in kind contribution from the EFPIA companies 8 Indicative expectations from the public consortium 5 years €15 million • • • • • • • • • • • • In addition to academic centers, patient organisations, regulators and imaging centers could be part of the consortium Academic center should manage the project Work closely with EFPIA partners to ensure effective management and coordination of work to deliver key objectives Consortium should consist of both preclinical and clinical investigators Excellent scientific track record in area of proposed research Sufficient PhD or post-doctoral researchers to ensure delivery of key objectives in a timely manner Establish a network of expertise through a wide range of laboratories across Europe Innovative approaches to the topics outlined in the proposal Structured proposals highlighting how challenges will be addressed Ability to combine and apply numerous expertise areas e. g., behavioural assessment, brain imaging, electrophysiological and/or biochemical/genetic analysis Infrastructure to house and breed Tg animals Infrastructure to conduct well-controlled preclinical and/or patient studies Page 40 of 88 Psychiatric disorders IMI Call 2008 DRAFT of 17/10/2007 11. Psychiatric disorders 1 Topic title 2 Project description Psychiatric disorders This call focuses on development of platforms that translate efficacy of novel therapy approaches within psychiatric disorders into blood/CSF markers, imaging and/or electrophysiological measures suitable for clinical assessments. The pathophysiological processes and etiologic factors in neurodevelopment disorders have so far proven elusive. Despite a growing understanding of the genetic determinants resulting in neurodevelopmental disorders, development of safe therapies that effectively relieve the cores symptoms or delays the progression of the diseases remains a challenge. The development of preclinical models with sensitive pharmacodynamic markers that are closely linked to the pathophysiology of the disease is essential to improve the validity of preclinical models. Prediction of Treatment Outcome Recent data show a correlation between gene expression (transcription) in human brain tissue and blood cells. This supports the hypothesis that transcription analysis from peripheral blood cells could provide relevant biomarkers for psychiatric disorders and response to treatment. A transcription pattern/metabolite/biomarker profile that predicts a favourable response to active treatments as well as placebo is the ultimate goal. Relevance of Phenotype-Transcription Relationships To facilitate selection of sub populations, transcription profiles/metabolite profile and genetic polymorphism should be related to a clinical phenotype. Therefore, the phenotyping should include a detailed description of symptoms, course of disease, previous and family history, environmental factors such as early and recent life events, medication history and co-medication, including drugs of abuse, personality traits and coping styles. Gene and Metabolite Selection The correlation between peripheral and CNS gene expression, at least for some of the genes, offers the possibility to align CNS transcription patterns in animal disease models with transcription patterns from homogenous patient populations. A similar approach can be used for metabolites. This approach will allow profiling of new compounds in preclinical models and will help advance targets/compounds based on their ability to modify clinically relevant markers in a direction consistent with a meaningful Page 41 of 88 Psychiatric disorders treatment response in humans. Pre-clinical animal model development IMI Call 2008 DRAFT of 17/10/2007 In order to improve the preclinical assessments of putative novel medications, back-translational approaches driven by genetic or clinical observations, including human intermediate phenotype is essential to develop novel animal models more predictive of clinical efficacy. Wherever possible these models should employ endpoints aligned with endpoints used in clinical studies (e.g. PET, MRI, MEG and EEG) and demonstrate similar pharmacology to man such that PK/PD assessment and modelling can be used to support scaling to human efficacy. 3 Key deliverables of Identifications of transcriptional/metabolite/bio- blood markers the project relevant for segmentation and stratification of patient groups Transcription patterns associated with treatment response that can be used to select promising candidate genes for genotyping. Transcription patterns associated with treatment response that can to be used to better understand the disease biology and identify novel treatment targets. Metabolite profiles associated with treatment response to be used to select promising candidate genes for genotyping. Metabolite profiles associated with treatment response to be used to better understand disease biology. Quantification of responses and analysis of correlations between transcription factors/metabolites and phenotype within each indication and drug class will advance understanding of disease biology. Development of animal models that translate systems biology of disease Establish platforms and identify critical molecular signaling pathways involved in the disease progression or modification Develop in vitro systems that validate signaling pathways identified in humans Develop animal model systems and identify phenotypes or endophenotypes correlating to clinical relevant parameters Development of animal models that translate to clinical endpoints Establish correlations between symptoms (e.g. cognition, psychosis) or progression of CNS disease and electrophysiological measure, MRI, blood/CSF measures in humans Establish preclinical models that reflect the identified electrophysiological Page 42 of 88 Psychiatric disorders IMI Call 2008 DRAFT of 17/10/2007 measure, MRI phenotype and blood/CSF measures Identification and validation of pharmacodynamic markers to support regulatory submissions Validate link between disease modification and changes in electrophysiological measure and/or MRI phenotype Develop models of PK/PD relationships on pharmacodynamic markers Identification of novel PET ligands and functional neuroimaging to guide dose selection Establish target occupancy relevance for prediction of clinical efficacy Establish correlation between target occupancy and neuroimaging readouts Establish functional neuroimaging read-outs that are correlated with clinical efficacy to facilitate dose selection when no PET ligand is available Synthesis and structure activity relationship (SAR) of BBB penetrant compounds with appropriate in vitro affinities and pharmacokinetics 11C Labelling of compound Preclinical in vivo validation Toxicological evaluation of radioligand Human PET studies 4 EFPIA participants AstraZeneca in the project Eli Lilly GSK Johnson & Johnson Lundbeck Novartis Orion Pharma Pfizer Roche Servier S. Nyberg F. Boess E. A Irving T. Steckler T. B. Stensbøl D. Umbricht J. Sallinen, R. Salonen R. Mckernan L. Santarelli B. Lockhart, M. Millan Page 43 of 88 Psychiatric disorders IMI Call 2008 DRAFT of 17/10/2007 Solvay Wyeth P. Broqua K. Marquis, M. Pangalos 5 Role of EFPIA participants in the project Analysis of omics data sets and MRI markers in collected samples from academic studies Development of hypotheses on diagnostic/efficacy markers Establish correlations between complex disease relevant markers Confirmation and extension of analyses in large (company-sponsored) studies Evaluation of diagnostic, safety and efficacy markers Explore association between neuroimaging and omics markers Data from subsets of placebo/active control clinical trials Generation and phenotyping of genetically modified animals 6 Indicative duration of the project 7 Indicative total in kind contribution from the EFPIA companies 8 Indicative expectations from the public consortium 5 years €10 to 20 million Page 44 of 88 Neurodegenerative disorders IMI Call 2008 DRAFT of 17/10/2007 12. Neurodegenerative disorders 1 Topic title Neurodegenerative disorders : Bridging pre-clinical-clinical divide 2 Project description Clinical outcome studies in the Neurodegeneration area are notoriously long and expensive. In order to accelerate the successful development of molecules for the treatment of Neurodegenerative disorders, it is essential to improve the predictive value of animal models, identify pharmacodynamic markers of drug response, pharmacodynamic models that allow early prediction of efficacy and markers to aid stratification of the patient population. The success of which will be dependent on the partnership of preclinical and clinical scientists to adopt an integrated approach to ensure effective translation of efficacy from bench to bedside and visa versa. This translational science/medicine approach will allow the rapid identification and accelerated development of successful candidate molecules as well as terminating efforts earlier on those unlikely to offer clinical benefit. Healthy volunteer/Pharmacodynamic (PD) model development Models such as scopolamine challenge, sleep deprivation and diurnal vigilance in the elderly have been used to mimic aspects of memory impairments characteristic of diseases such as Alzheimer’s disease. However the decision making capacity of these models is currently low due to lack of publicly available data (both positive and negative) and validation using a variety of cognitive enhancing agents with different mechanisms of action.. In order to enhance our understanding of the molecular basis of these models and their application to drug discovery it is essential that these models are more rigorously explored using clinically proven memory enhancing agents. Key questions are 1) what is the most sensitive methodology for detecting pharmacodynamic effects in these models? To this end an integrated approach using a diverse range of techniques such as imaging, electrophysiology and cognitive measures will be required. 2) What is the predictive capacity of these models for efficacy in enhancing memory deficits in neurodegenerative disorders. Pharmacodynamic marker development The development of sensitive PD markers that are predictive of clinical benefit within weeks rather than months of treatment may not only reduce sample sizes required to define positive drug effect, but also accelerate progression from PoC to phase 2b/3. However the utility of these in clinical development is currently limited due to lack of extensive validation. Recently a number of promising pharmacodynamic markers such as rCBF, electrophysiology measures (e.g. ERPs), cognitive fMRI, MRS, novel neuropsychological tests, and peptides, inflammatory markers and altered metabolites in CSF or blood have been reported. Changes in many of these markers have been reported with doses of drug that are known to offer clinical benefit in patients, however for each Page 45 of 88 Neurodegenerative disorders IMI Call 2008 DRAFT of 17/10/2007 end point pharmacological validation across different mechanistic targets is limited. There is therefore a need for these endpoints to be more fully validated by investigating the effects of a variety of agents with different mechanisms of action in a given disease population. Key questions are 1) what endpoints are the most sensitive to pharmacodynamic manipulation across a variety of different mechanistic targets? 2) what is the shortest duration of treatment required to detect a response? 3) how do drug exposure ranges required to drive the pharmacodynamic response compare to those required for clinical efficacy? 4) which if any of these PD markers provide good predictive capacity for ultimate clinical efficacy? 5) Can any of these pharmacodynamic endpoints be back-translated to detect pharmacodynamic responses in healthy young or elderly volunteers or indeed animal models. Pre-clinical model development Due to the complexity of neurodegenerative diseases and of the ‘disease models’ currently utilised within neurodegeneration research together with the relative lack of ‘gold standard’ agents, it is generally accepted that there are few validated translatable models of disease. Indeed there are numerous examples where molecules demonstrating excellent efficacy in animal models subsequently fail to demonstrate any clinical efficacy. The reasons for this are far reaching, however, in order to improve the predictive capacity of animal models it is essential that we focus on developing new model paradigms that can be used to provide the necessary PK/PD information required to support dose predictions and translation of efficacy into man. To succeed in this arena is essential to develop novel models which reflect the basic pharmacological activity of the drug in addition to developing models more predictive of clinical efficacy using endpoints utilised in clinical studies. Some key questions are 1) what do we understand about the molecular target activity in preclinical species and man? 2) how is this changed in disease states? 3) how does our drug interact with it’s molecular target in preclinical species and in man? 4) what characteristics of disease progression can we measure in man – can we model and measure these in pre-clinical models using similar end-points? 5) are the endpoints used suitable for establishing a PK/PD relationship? Focus should be placed on back translation from the clinic identifying those aspects of HVT and patient studies that can be taken back to the bench. Ideally pre-clinical studies should therefore be proposed in parallel to the clinical studies outlined above. Using similar standard agents, research programmes should be initiated to develop and validate PD markers/models and disease models, utilising translatable endpoints such as EEG, imaging and ‘omics’ markers. If successful, such models will not only support dose prediction (i.e. PK/PD) and the identification and validation of PD markers/models for use in Phase I studies but also develop models more predictive of clinically efficacy all of which will have a significant impact ion the acceleration of drug development. Proposal structure Proposals submitted for funding within the areas of Alzheimer’s disease, Page 46 of 88 Neurodegenerative disorders IMI Call 2008 DRAFT of 17/10/2007 Multiple Sclerosis and Parkinson’s disease should aim, where possible, to address an aspect of each of the main topics outlined above ensuring the involvement of both pre-clinical and clinical scientists. An integrated approach employing imaging, electrophysiology, novel clinical measures and ‘omics’ markers is desired. 3 Key deliverables of the project Identification of, and pharmacological validation of parallel HVT and preclinical pharmacodynamic models to establish effective exposure ranges and support proof of mechanism studies • • • Characterisation of HVT and preclinical pharmacodynamic models (e.g. sleep deprivation) using clinically validated agents Identification of PD endpoints most sensitive to pharmacological intervention in HVT and preclinical models Identification of model with highest predictive capacity of clinical efficacy Identification and pharmacological validation of novel in vivo animal models • Development, validation and refinement of pre-clinical models using fully translatable endpoints and increased predictive capacity. This will improve the quality and ultimately the utility of preclinical data in drug development reducing the number of studies required to support dose predictions and target validation. Identification and validation of pharmacodynamic markers to support preclinical and early clinical assessment in HVT/disease populations. Validation of imaging, electrophysiology, serum/CSF/urine marker endpoints, and/or novel clinical measures with respect to their utility for assessing pharmacodynamic responses to drug Identification of sensitive PD endpoints to support translation from animal to HVT and from HVT to patients Identification of PD endpoints that most accurately predict clinically efficacious exposure ranges Identification of PD markers to support internal decision making and regulatory submissions The ability to design smaller, stratified clinical studies which deliver early signals of efficacy Access to validated imaging facilities both clinically and preclinically with standardised protocols acceptable for regulatory submissions Integrated approach to translational science/ medicine across academia and industry Development of algorithms for combining diverse data sets such as EEG and cognitive endpoints Access to a well managed extensive sample collection of blood/plasma from animal models, healthy volunteers and patients which can be correlated with treatment and/or disease progression Page 47 of 88 • • • • General • • • • • • Neurodegenerative disorders • IMI Call 2008 DRAFT of 17/10/2007 Standardised and validated protocols and data analysis methods across sites. P. Julin B. Sommer E. A. Irving T. Seckler, T. Meert F. Boess, E. Karran C. Videbæk, T.B Stensbøl J. Luthman B. Gomez-Mancilla R. Mckernan L. Santarelli B. Lockhart P. Broqua K. Miller, G. Bennett M. Pangalos 4 EFPIA participants AstraZeneca in the project Boehringer Ingelheim GSK Johnson & Johnson Eli Lilly Lundbeck Merck Serono Novartis Pfizer Roche Servier Solvay UCB Wyeth Please note that the actual level of contribution has yet to be defined for each EFPIA partner, however the type of contribution has been agreed. 5 Role of EFPIA Participants in the project Investigators will have the opportunity to gain access to: Pre-clinical contributions • • • • • • • • • • Numerous transgenic mouse strains/models e.g. amyloid over expressing mice. Data from ongoing pre-clinical PD model development studies e.g. sleep deprivation Data from ongoing pre-clinical/clinical studies exploring novel Pharmacodynamic/cognitive endpoints e.g. electrophysiological and imaging characterisation of amyloid overexpressing mice Animal models of disease including training in surgical skills, behavioural analysis and histological analysis required to run such assays Archived tissues (CNS and blood) from animal models of disease to support genetic and/or biochemical/molecular analysis of novel biomarkers and correlation with disease onset Access to biochemical biomarkers identified from pre-clinical models that could be replicated for validation in future studies Primate model data e.g. aged primates, primate EAE Biochemical assays developed and validated for use in humans, non-human primate and rodent models e.g beta amyloid assays. Data from animal models characterised/validated with gold standard agents Pre-clinical supplies of registered agents Page 48 of 88 Neurodegenerative disorders • • • IMI Call 2008 DRAFT of 17/10/2007 Supplies of novel NCEs (IP dependent) and pharmacological tools Open/closed platform analysis of samples from pre-clinical studies Data from ongoing clinical studies exploring novel pharmacodynamic/cognitive endpoints – both placebo response and subjects treated with NCEs (IP dependent) or marketed agents Data from ongoing experimental medicine studies investigating HVT models with respect to response to registered cognitive enhancing agents and NCEs. Placebo data sets from various clinical studies across Alzhiemer’s Disease, Multiple Sclerosis and Parkinsons disease Access to ongoing HVT/patient studies being conducted with NCEs where specific cohorts may be committed to imaging studies or samples harvested for biochemical biomarker analysis Clinical supplies of registered agents Supplies of novel NCEs (IP dependent) and pharmacological tools Image analysis expertise/support Clinical trial management expertise/support Access to biochemical biomarkers identified from clinical patient studies that could be replicated for validation in future studies. Open/closed platform analysis of samples from pre-clinical and clinical studies Clinical contributions • • • • • • • • • General Project Management In addition to providing general neurobiological expertise/input into the project, It is envisaged that EFPIA partners will work closely with public partners to ensure effective management and coordination of work to deliver key objectives. 6 Indicative duration 3-5 years of the project 7 Indicative total in kind contribution from the EFPIA companies 8 Indicative expectations from the Public Consortium € 5-7.5 million Deliverables expected from the public sector will vary according to the research proposal, however in general investigators should have/provide : • • • • • Excellent scientific track record in area of proposed research Sufficient PhD or post-doctoral researchers and lab space/equipment to ensure delivery of key objectives in a timely manner Work closely with EFPIA partners to ensure effective management and coordination of work to deliver key objectives Adopt expertise from a wide range of labs across Europe Consortium should consist of both pre-clinical and clinical Page 49 of 88 Neurodegenerative disorders IMI Call 2008 DRAFT of 17/10/2007 investigators each of which will be responsible for delivering on agreed objectives Innovative approaches to the challenges outlined in the proposal Structured proposals highlighting how challenges will be addressed The ability to combine expertise to allow an integrated approach to model development e.g. Combining behavioural assessment, imaging, EEG and/or biochemical/genetic analysis Infrastructure to house and breed Tg animals Infrastructure to conduct well controlled HVT and/or patient studies Access to appropriate HVT or patient groups Access to pre-clinical and clinical imaging/EEG facilities Adopt standardised protocols and analysis methods across laboratories • • • • • • • • Page 50 of 88 Severe Asthma IMI Call 2008 DRAFT of 17/10/2007 13. Severe Asthma 1 Topic title Severe Asthma 2008 call is to build the first step towards an EU Severe Asthma network and will be followed by a subsequent call that completes sections to cover the remaining bottle necks in drug discovery 2 Project description Asthma is an inflammatory disease of the airway with a high health care and patient burden which, despite the availability of effective treatments for patients with mild-moderate disease, has a high unmet need for more effective, convenient and safe therapies, particularly for patients with moderately severe and severe disease. These patients remain symptomatic despite combined treatment with high dose inhaled steroids and other agents such as bronchodilators and some also remain “uncontrolled” even when taking oral corticosteroids for sustained periods of time. These patients are diagnosed by the reporting continued symptoms or lung function impairment despite treatment at GINA step 4 or when receiving treatment at GINA step 5; or when patients have previous history of near-fatal asthma attack(s) whilst on treatment. The terms “difficult asthma” and “refractory asthma” have been coined to cover this patient group. It has been estimated that the 10% of asthmatics with the most severe disease account for up to 50% of the total costs of asthma care. Discovery, research and development of new treatments for patients with asthma, has presented clear challenges which include: • • • • Understanding of the natural history and disease mechanisms in the setting of disease heterogeneity, including its frequent comorbidities Limited availability of preclinical and clinical models to enable translational research, for targets which have not been tested in man to establish safety or efficacy Development of novel agents as maintenance therapies requires considerable investment, requiring long and complex clinical studies Uncertainty regarding which are the relevant outcomes for patients with severe asthma; what is the optimal study follow-up time; and whether measures and results that apply to mild asthma also apply to severe disease The Innovative Medicines Initiative (IMI) strategic agenda recognizes these needs and challenges, giving explicit recommendations for research that speaks to these challenges. The priority research areas identified in the document include: • Increased research into disease mechanisms to provide for truedisease modifying therapeutic opportunities. This would include biochemical and genomic biomarkers to identify patient characteristics associated with different phenotypes Page 51 of 88 Severe Asthma • • • IMI Call 2008 DRAFT of 17/10/2007 Biomarkers of lower airway inflammation, infection, and of associated comorbidities Disease models to further knowledge of pathways driving exacerbations and to enable assessment of intervention Preclinical and clinical models to facilitate translational research of novel agents for asthma, including proof of pharmacology/ mechanism and PK/PD. Strategic usage of animal models for these diseases to identify relevant biomarkers that can be extended to human models in vitro and to in vivo studies of human disease Subsequent review of these recommendations by the pharmaceutical companies supporting this call propose that we build a European Network or “Centre of Excellence” for severe asthma aimed at addressing these needs which fall into three main areas: 1. Disease understanding including epidemiology, adequate disease diagnosis, assessment of severity, phenotyping, biochemical and genomic markers of severe asthma 2. Identification and validation of new preclinical and clinical models to facilitate translational research 3. Measurable outcomes including new tools such as QOL measures that are sensitive to pharmacological interventions and can predict pharmacoeconomic benefit This network should include expertise both with adults and children with severe asthma and will be built through a series of calls during the life of IMI, commencing with a first call in 2008 which will address disease understanding. During 2008 industry colleagues will work with academia, patient groups, regulatory authorities and payors through a series of workshops to define the 2009 calls that will speak to other areas beyond disease understanding and help to build the network or “Centre of Excellence”. Hence the call for 2008 is to build an EU Severe Asthma network focused on disease understanding. The further sections for the centre will be decided after a series of workshops with patients’ groups regulatory authorities payers and leading societies. The intent will be to harness efforts of already established groups who are presently working independently such as ENFUMOSA, BIOAIR and the UK severe asthma network. This can be done through establishment of a common protocol for patient identification and assessment together with a common database or prospective registry which will enable: • • • • Longitudinal patient study and associated sampling for markers of disease progression Multi-disciplinary approach to new technology development to support the identification of markers to support patient selection Multi-disciplinary approach to new technology development to support the identification of early diagnostic, disease progression and drug effect markers Multi-disciplinary approach to new technology development to Page 52 of 88 Severe Asthma IMI Call 2008 DRAFT of 17/10/2007 support the monitoring and follow up of patients with severe disease in Europe Further application of ‘omic’ technologies in a systems context to support biomarker identification Build understanding of aetiology of asthma exacerbations as mechanism to identify new targets and therapeutic approaches Identification of novel targets for pharmacological intervention and biomarkers to assess pharmacological response or predict effects on clinical outcomes including disease progression or for diagnostic purposes Identification of targets relevant to specific phenotypes of severe asthma Understanding of aetiology of asthma exacerbations as mechanism to identify new targets and therapeutic approaches and deliver significant pharmacoeconomic benefits Accurate targeting of an intervention to a particular patient subpopulation A European network, able to collaborate in a standardised manner and focused on the efficiency of delivering safe and effective medicines to patients with severe asthma, contributing to an Integrated global effort to reduce attrition of new medicines. T. Jones P.O. Andersson T. Higenbottam M. Klueglich, T. Glaab C. Brindicci, A. Chiesi D. Myles T. Reiss, R. Vessey P. Lloyd D. Bredenbroker • • 3 Key deliverables of the project Improved understanding of disease, leading to: • • • • • 4 EFPIA participants in the project Allergan Almirall AstraZeneca Boehringer-Ingelheim Chiesi GSK Merck Novartis Nycomed 5 Role of EFPIA participants in the project Pfizer C. Compton • EFPIA colleagues will work with consortia to ensure alignment between research efforts and strategic intent of IMI, in particular the key “bottlenecks”, in order to speed availability of medicines to patients with unmet needs • Technical input related to research and development of novel therapeutics for patients with respiratory disease in context of alignment with research aims • Technical input and resources related to assays, imaging and application of other technologies • Database and informatics support • Project management support • Coordinate input from key stakeholders where relevant eg regulatory authorities, payors Page 53 of 88 Severe Asthma IMI Call 2008 DRAFT of 17/10/2007 3 to 5 years The in-kind contribution is to be decided by the participating companies. For 2008 step one an estimated cost of €1 million and potential full costs of subsequent calls could encompass a total spend of €10 to 20 million. The Successful Consortium must address the following points: • • • • • Proven track record of scientific excellence including publication record that speaks to the intent of the call Clearly stated research proposal with deliverables A track record of successful collaboration and delivery of research projects working with other academic partners and industry colleagues is preferred Clear intent to work with EFPIA partners to make best use of EFPIA resources Innovation 6 Indicative duration of the project 7 Indicative total in kind contribution from the EFPIA companies 8 Indicative expectations from the public consortium Page 54 of 88 COPD IMI Call 2008 DRAFT of 17/10/2007 14. COPD 1 Topic title COPD 2008 call is to build the first step towards an EU COPD network will focus on patient reported outcomes and will be followed by a subsequent call that completes sections to cover the remaining bottle necks in drug discovery 2 Project description Chronic obstructive pulmonary disease (COPD) is the 4th leading cause of death and an increasing cause of chronic disability in the European community, placing a huge and increasing burden on health care resources. The main aetiological factor is tobacco smoking, although the disease does not fully resolve on quitting smoking, with persistence of the inflammatory changes within the airways. Older ex-smokers gain little improvement in lung function after quitting (although they have fewer exacerbations). The condition is characterized by large airway inflammation (bronchitis), destruction of the alveolar septa (emphysema) and small airway narrowing (bronchiolitis). COPD is usually associated with chronic disabling breathlessness that limits exercise tolerance together with recurrent attacks when symptoms acutely worsen. These COPD exacerbations are principally triggered by infections. COPD is often associated with important chronic comorbidities (e.g. chronic heart failure, hypertension, metabolic syndrome, osteoporosis) and systemic effects (skeletal muscle structural changes and dysfunction) that may greatly influence the clinical manifestations of the disease both in baseline conditions and during exacerbations. Treatment is largely symptomatic without influence on the progression of the disease and patients remain disabled and threatened by frequent exacerbations. These unmet needs are major challenges to academic medicine, the pharmaceutical industry and society. Despite major research efforts, current treatments for COPD are based on a limited spectrum of biological effects, many belong to drug classes over 40 years old. New therapeutic approaches take considerable time to demonstrate value sufficient for regulatory approval. Discovery, research and development of new treatments for patients with COPD has presented clear challenges which include: • • • Understanding of natural history and disease mechanisms in the setting of disease heterogeneity, its systemic nature , and associated chronic comorbidities Limited availability of preclinical and clinical models to enable translational research, for targets which have not been tested in man to establish safety or efficacy Development of novel agents to reduce exacerbations and Page 55 of 88 COPD IMI Call 2008 DRAFT of 17/10/2007 disability requires considerable investment, requiring long and complex clinical studies Uncertainty regarding which are the relevant outcomes for patients with COPD. For example what is the optimal definition of an exacerbation? How to record severity and duration? Alternatively how are improvements in activity and functional levels to be demonstrated? To capture the impact of the disease on patients now, demands that patients can be given an opportunity to report their own perceptions. In other chronic disease, for example rheumatoid arthritis, such patient reported outcomes (PRO) are now used as an essential mean of capturing the impact of therapy. In COPD this PRO has lagged behind. Develop treatment strategies for mild disease • • • The Innovative Medicines Initiative (IMI) strategic agenda recognizes these needs and challenges, giving explicit recommendations for research that speaks to these challenges. The priority research areas identified in the document include: • The epidemiology of COPD has been studied but there remain major gaps for our understanding of exacerbations. Similarly those patients at an early and late stage of the disease have been poorly investigated leaving uncertainty as to the relevant therapeutic opportunities Increased research into disease mechanisms to provide for restoring function to the chronically damaged lungs and coaffected organs in COPD. This would include biochemical and genomic biomarkers to identify patient characteristics associated with different phenotypes The pathobiology of exacerbations is similarly poorly understood. For example biomarkers of lower airway inflammation, chronic colonization and associated co-morbidities, both during periods of stability and exacerbations, would be of value Access to cellular components of the lungs and co-affected organs from COPD patients is a major limiting step in drug development ~ identification of therapeutic targets and drug optimizing requires the study of the cellular and molecular mechanisms of the disease Preclinical and clinical models to facilitate translational research of novel agents for COPD, including proof of pharmacology/ mechanism and PK/PD. Strategic usage of animal models for these diseases to identify relevant biomarkers that can be extended to human models in vitro and to in vivo studies of human disease Disease models to further knowledge of pathways driving exacerbations and to enable assessment of intervention ~ mixed smoking and infection models • • • • • Subsequent review of these recommendations by the pharmaceutical companies supporting this call propose that we build a European Network or “Centre of Excellence” for COPD aimed at addressing these Page 56 of 88 COPD needs which fall into three main areas: • IMI Call 2008 DRAFT of 17/10/2007 • • New tools including QOL measures that are sensitive to pharmacological interventions and can predict pharmacoeconomic benefit ~ especially for the quantification of exacerbations and functional performance Disease understanding including epidemiology, disease phenotype, biochemical and genomic markers Identification and validation of new preclinical and clinical models to facilitate translational research This network will be built through a series of calls during the life of IMI, commencing with a first call in 2008 that speaks to outcome measures for exacerbations and functional performance. During 2008 colleagues from the pharmaceutical industry will work with academia, patient groups, regulatory authorities and payors through a series of workshops to define the 2009 calls that will speak to other areas beyond disease understanding and help to build the network or “Centre of Excellence”. Hence the call for 2008 is to build an EU COPD network focused initially on outcome measures with special reference to patient reported outcomes. The further sections for the centre will be decided after a series of workshops with patients’ groups regulatory authorities payers and leading societies. The intent will be to harness efforts of already established groups who are presently working independently on patient reported outcomes. This can be achieved through linking in with the EMEA and building an alliance with the FDA Exacerbation Patients Reported Outcome Tool work (EXACTPRO) that is entering the second year of validation in 2008. Establishment of a European wide definition of exacerbations and develop PRO for exacerbations, activity levels and breathlessness: • • • • • • Longitudinal patient study and associated questionnaire development using individual PDA or Blackberry delivered questionnaires Multi-disciplinary approach to new technology development to support the identification of markers to support patient selection Multi-disciplinary approach to new technology development to support the monitoring and optimal care of patients Multi-disciplinary approach to new technology development to support the identification of early diagnostic, disease diagnosis, assessment of severity, and progression and drug effect markers Working with the Regulatory authorities to ensure that validation is optimal and with Patient and Payor groups to ensure that the PRO captures the essential measurements of the patients needs Build understanding of aetiology of COPD exacerbations as mechanism to identify new targets and therapeutic approachesNew tools including QOL measures that are sensitive to pharmacological interventions and can predict pharmacoeconomic benefit ~ especially for the quantification of exacerbations and functional performance Disease understanding including epidemiology, disease Page 57 of 88 • COPD IMI Call 2008 DRAFT of 17/10/2007 • phenotype, biochemical and genomic markers Identification and validation of new preclinical and clinical models to facilitate translational research This network will be built through a series of calls during the life of IMI, commencing with a first call in 2008 that speaks to outcome measures for exacerbations and functional performance. During 2008 colleagues from the pharmaceutical industry will work with academia, patient groups, regulatory authorities and payors through a series of workshops to define the 2009 calls that will speak to other areas beyond disease understanding and help to build the network or “Centre of Excellence”. Hence the call for 2008 is to build an EU COPD network focused initially on outcome measures with special reference to patient reported outcomes. The intent will be to harness efforts of already established groups who are presently working independently on patient reported outcomes. This can be achieved through linking in with the EMEA and building an alliance with the FDA Exacerbation Patients Reported Outcome Tool work (EXACTPRO) that is entering the second year of validation in 2008. Establishment of a European wide definition of exacerbations and develop PRO for exacerbations, activity levels and breathlessness: • • • • • • 3 Key deliverables of the project Longitudinal patient study and associated questionnaire development using individual PDA or Blackberry delivered questionnaires Multi-disciplinary approach to new technology development to support the identification of markers to support patient selection Multi-disciplinary approach to new technology development to support the monitoring and optimal care of patients Multi-disciplinary approach to new technology development to support the identification of early diagnostic, disease diagnosis, assessment of severity, and progression and drug effect markers Working with the Regulatory authorities to ensure that validation is optimal and with Patient and Payor groups to ensure that the PRO captures the essential measurements of the patients needs Build understanding of aetiology of COPD exacerbations as mechanism to identify new targets and therapeutic approaches Improved understanding of disease and ability to understand the effects of novel interventions on patient reported outcomes, which address key stakeholders needs (including patients, physicians, regulators and payors) leading to: • • • • Identification of novel tools that can be administered daily to patients to quantify the patients perceptions of the severity and duration of exacerbations and functionality/activity levels To explore the use of new technology for home capture of daily data that can be transferred electronically to the database Identification of targets relevant to specific phenotypes and comorbidities of severe COPD Understanding of aetiology of COPD exacerbations as Page 58 of 88 COPD IMI Call 2008 DRAFT of 17/10/2007 mechanism to identify new targets and therapeutic approaches and deliver significant pharmacoeconomic benefits Accurate targeting of an intervention to a particular patient subpopulation A European network, able to collaborate in a standardised manner and focused on the efficiency of delivering safe and effective medicines to patients with COPD, contributing to an Integrated global effort to reduce attrition of new medicines T. Jones P.O. Andersson T. Higenbottam M. Klueglich, F. Gantner C. Brindicci, A. Chiesi D. Myles T. Reiss, R. Vessey P. Lloyd D. Bredenbroker C. Compton N. Gozzard EFPIA colleagues will work with consortia to ensure alignment between research efforts and strategic intent of IMI, in particular the key “bottlenecks”, in order to speed availability of medicines to patients with unmet needs Technical input related to research and development of novel therapeutics for patients with respiratory disease in context of alignment with research aims Technical input and resources related to assays, imaging and application of other technologies Database and informatics support Project management support Coordinate input from key stakeholders where relevant e.g. regulatory authorities, payors • • 4 EFPIA participants in the project Allergan Almirall AstraZeneca Boehringer-Ingelheim Chiesi GSK Merck Novartis Nycomed Pfizer UCB • 5 Role of EFPIA participants in the project • • • • • 6 Indicative duration of the project 7 Indicative total in kind contribution from the EFPIA companies 8 Indicative expectations from the public consortium 3 to 5 years The in-kind contribution is to be decided by the participating companies. For 2008 step one an estimated cost of €1 million and potential full costs of subsequent calls could encompass a total spend of €10 to 20 million. The Successful Consortium must address the following points: • • • Proven track record of scientific excellence including publication record that speaks to the intent of the call Clearly stated research proposal with deliverables A track record of successful collaboration and delivery of Page 59 of 88 COPD IMI Call 2008 DRAFT of 17/10/2007 research projects working with other academic partners and industry colleagues is preferred Clear intent to work with EFPIA partners to make best use of EFPIA resources Innovation • • Page 60 of 88 Rhinitis IMI Call 2008 DRAFT of 17/10/2007 15. Rhinitis 1 Topic title Rhinitis 2008 call is to build the first step towards an EU rhinitis network will focus on disease knowledge and will be followed by a subsequent call that completes sections to cover the remaining bottle necks in drug discovery 2 Project description Rhinitis has a very high prevalence - the European Communities Respiratory Health Survey (ECRHS) II estimated that nasal allergies, including hay fever, affected nearly 30% of European adults during 1998 to 2003 (estimated 123.5 million cases in 2005). However, the impact on those who suffer from the disease is significantly under-appreciated. Allergic rhinitis and non-allergic rhinitis are currently not well differentiated by physicians and are treated with the same medications; it is noteworthy that over 60% of patients remain incompletely controlled despite access to both over the counter and prescription medicines. There are three main reasons for this poor control: 1. Inappropriate use of medication (e.g. only used once the symptoms are apparent) 2. Incomplete prevention or treatment of symptoms by current medications 3. Limited disease understanding, including knowledge of the gold standards for diagnosis and assessment of severity, different phenotypes (e.g. allergic vs. non-allergic) and pathophysiological mechanisms driving the disease In addition, given the high degree of co-morbidity of allergic rhinitis with other airways disease, in particular asthma and sinusitis, we need to understand the relationship between these diseases and the underlying pathophysiology and pathobiology in order to better manage patients. Hence improving our disease understanding is key to identifying relevant targets for patients with different disease phenotypes and our ability to develop better therapies for rhinitis. Non-allergic rhinitis: Whilst it is recognised that there are both allergic and non-allergic drivers of rhinitis symptoms, they are not well differentiated by physicians and are treated with the same medications. Non-allergic mechanisms, for which there are no adequate treatments, drive a proportion of symptoms in over 50% of the rhinitis population. There is also evidence that non-allergic drivers of rhinitis symptoms increase in their importance with age (in contrast to the impact of allergic drivers of symptoms, which decrease with age). Multiple different nonallergic rhinitis phenotypes exist, but they are poorly characterised and understood. Allergic rhinitis: Whilst specific immunotherapy offers the possibility of reducing the onset of symptoms, it is limited in its clinical utility. An increased understanding of the immunological and inflammatory Page 61 of 88 Rhinitis IMI Call 2008 DRAFT of 17/10/2007 mechanisms that induce symptoms in allergic rhinitis could enable further therapeutic advances with the potential of preventing the onset of symptoms and allergic disease. The Innovative Medicines Initiative (IMI) strategic agenda speaks to these needs and challenges, giving explicit recommendations for research. The priority research areas identified in the document include: • Increased research into disease mechanisms to provide for truedisease modifying therapeutic opportunities. This would include development of standardised criteria for diagnosis and assessment of severity and biochemical and genomic biomarkers to identify patient characteristics associated with different phenotypes Biomarkers of airway inflammation Disease models to further knowledge and to enable assessment of intervention Preclinical and clinical models to facilitate translational research of novel agents for allergic rhinitis, including proof of pharmacology/ mechanism and PK/PD. Strategic usage of animal models for these diseases to identify relevant biomarkers that can be extended to human models in vitro and to in vivo studies of human disease • • • Subsequent review of these recommendations by the pharmaceutical companies supporting this call propose that we build a European Network or “Centre of Excellence” for Rhinitis aimed at addressing these needs which fall into three main areas: 1. Disease understanding including epidemiology, diagnosis, assessment of severity and phenotyping, biochemical and genomic markers 2. Identification and validation of new preclinical and clinical models to facilitate translational research 3. Identification of outcome measurements, including new tools including QOL measures that are sensitive to pharmacological interventions and can predict pharmacoeconomic benefit This network will be built through a series of calls during the life of IMI, commencing with a first call in 2008 which addresses disease understanding. During 2008 industry colleagues will work with ERS, patient groups, regulatory authorities and payors through a series of workshops to define the 2009 calls that will speak to other areas beyond disease understanding and help to build the network or “Centre of Excellence” Hence the call for 2008 is to build a European Network to better define and characterize rhinitis and address areas where our lack of disease understanding is limiting our ability to identify novel therapies. The further sections for the centre will be decided after a series of workshops with patients’ groups regulatory authorities payers and leading societies. Page 62 of 88 Rhinitis IMI Call 2008 DRAFT of 17/10/2007 The proposal is to develop a common protocol for patient identification and assessment together with a common database or prospective registry which will enable: • • • • • Better understanding of disease epidemiology, including interactions between allergic and non-allergic rhinitis and other airways disease Longitudinal patient study and associated sampling for markers of disease progression Multi-disciplined approach to new technology development to support the identification of markers to support patient selection. Multi-disciplined approach to new technology development to support the identification of early diagnostic, disease progression and drug effect markers. Further application of ‘omic’ technologies in a systems context to support biomarker identification Identification of novel targets for pharmacological intervention and biomarkers to assess pharmacological response or predict effects on clinical outcomes including disease progression or for diagnostic purposes Identification of targets relevant to specific phenotypes of allergic rhinitis Accurate targeting of an intervention to a particular patient subpopulation A Unique European network, able to collaborate in a standardised manner and focused on the efficiency of delivering safe and effective medicines to patients with rhinitis, contributing to an Integrated global effort to reduce attrition of new medicines.. T. Jones P.O. Andersson T. Higenbottam M. Klueglich, T. Glaab C. Brindicci, A. Chiesi D. Myles T. Reiss, R. Vessey P. Lloyd D. Bredenbroker 3 Key deliverables of the project Improved understanding of disease, leading to: • • • • 4 EFPIA participants in the project Allergan Almirall AstraZeneca Boehringer-Ingelheim Chiesi GSK Merck Novartis Nycomed 5 Role of EFPIA participants in the project Pfizer C. Compton • EFPIA colleagues will work with consortia to ensure alignment between research efforts and strategic intent of IMI, in particular the key “bottlenecks”, in order to speed availability of medicines to patients with unmet needs • Technical input related to research and development of novel Page 63 of 88 Rhinitis IMI Call 2008 DRAFT of 17/10/2007 therapeutics for patients with respiratory disease in context of alignment with research aims Technical input and resources related to assays, imaging and application of other technologies Database and informatics support Project management support Coordinate input from key stakeholders where relevant eg regulatory authorities, payors • • • • 6 Indicative duration of the project 7 Indicative total in kind contribution from the EFPIA companies 8 Indicative expectations from the public consortium 3 to 5 years The in-kind contribution is to be decided by the participating companies. For 2008 step one an estimated cost of €1 million and potential full costs of subsequent calls could encompass a total spend of €10 to 20 million. The Successful Consortium must address the following points: • • • • • Proven track record of scientific excellence including publication record that speaks to the intent of the call Clearly stated research proposal with deliverables A track record of successful collaboration and delivery of research projects working with other academic partners and industry colleagues is preferred Clear intent to work with EFPIA partners to make best use of EFPIA resources Innovation Page 64 of 88 EMRA Hub IMI Call 2008 DRAFT of 17/10/2007 16. EMRA Hub 1 Topic title 2 Project description Coordination and administration of European Medicines Research Academy (EMRA) The scope of EMRA is to establish a pan-European platform of excellence for education and training, covering the whole lifecycle of a medicine, from research to pharmacovigilance. EMRA will: • Build upon existing universities and higher education institutions in Europe by identifying excellent centres within the various disciplines of medicines R&D and stimulate collaboration between these centres. This excellence is seen in a global context Be the academic arm of the Innovative Medicines Initiative Provide education & training support to remove bottlenecks in the medicines R&D process in support of the Innovative Medicines Initiative Establish multiple public-private partnerships within E&T within graduate, doctoral and postdoctoral education and training Encourage the professional development of motivated individuals to embark PhD programmes Organise a business course for all IMI PhD fellows (planned 480) to strengthen the fellow’s insight in creation of knowledge, knowledge leadership and market economic aspects of their research. Through the IMI PhD programme the PhD fellows should be acquainted with both the academic and the industry environment Establish a network of IMI PhD fellows to strengthen the interdisciplinary interaction Ensure added value of IMI E&T activities compared to other similar activities on an European level Facilitate mobility between academia, industry and regulators Have contacts to all stakeholders, academia, industry, regulators, patient organisations and others. • • • • • • • • • EMRA will be hosted by one of the participating universities as a central co-ordinating unit (the hub) at a location characterised by high-quality industry contacts and recognised science. The host university should have proven capabilities for international networking on E&T. The host university should satisfy the following criteria for EMRA institutions: • • • • The university or higher education institution must satisfy the criteria for a Marie-Curie training site The university or higher education institution must have implemented a quality system for the education provided The universities or higher education institution must have a research school with a sound and institutionalised programme in which students are trained to become independent researchers Proven record of administering this research school with multiple Page 65 of 88 EMRA Hub IMI Call 2008 DRAFT of 17/10/2007 • • • • • partners including public-private partnership Proven record of regional/European collaboration (internationalisation) Proven record for handling of IPR issues, innovation and technology transfer Proven record for multiple and co-funded collaborations with industries and industry consortia Each PhD thesis is assessed through a qualified review involving external reviewers, i.e. from outside the CoE. Tuition at PhD level must enable participation of English speaking international students The EMRA hub is the contact point for EMRA and the unit administrating the network. The tasks for the hub are: • Secretariat for EMRA o Organise the EMRA network of existing universities and higher education institutions in Europe within the various disciplines of medicines R&D o Establish and organise the EMRA council o Organisation of meetings for EMRA Council IMI Education & Training programmes o Coordination of the training programmes within IMI E&T o Establish and maintain a system for quality control of training programmes within IMI o IMI PhD programme: Organise a business course for all IMI PhD fellows (planned 480) to strengthen the fellow’s insight in creation of knowledge, knowledge leadership, Innovation, strategy, IPR, ethics and market economic aspects of their research Establish a network of IMI PhD fellows to strengthen the interdisciplinary interaction Networking o Organise a quality control system for the participating institutions, i.e. a “peer review” process o Stimulate sharing of experiences between the participating universities o Stimulate establishment multiple public-private partnerships within E&T o Mapping of European universities to identify new potential members of the network o Establish contacts to relevant existing networks o Facilitate interaction and mobility between academia, industry and regulators o Stimulation of trans-disciplinary E&T to open the scientific “silos” o Address the language barrier, facilitate the use of English to increase mobility of not only students and tutors, but also textbooks and other teaching materials o Stimulate the use of the Bologna architecture utilising the ECTS system Page 66 of 88 • • EMRA Hub o IMI Call 2008 DRAFT of 17/10/2007 Concurrent identification and update of new scientific and technology developments and rapid implementation of corresponding training courses - Assessment of current availability of expertise in new and emerging fields of technology (e.g. toxicogenomics and other ‘omics, combinatorial chemistry, systems biology, nanobiotechnology etc.) across the EU and elsewhere Upgrading o Support association of members to improve their level of quality with the aim to become full members of the network of excellent universities • Reference: Innovative Medicines Initiative, Strategic Research Agenda, version 2.0 pp100-110 especially key objectives and management of EMRA on page 105 ff. 3 Key deliverables of Establishment of the EMRA hub to handle the tasks described above the project • Creation and organisation of the EMRA consisting of excellent institutions in Europe • Quality control of training programmes within IMI implemented • All IMI PhD fellows to have completed business course • Network of IMI PhD fellows established • “Peer review” process established and running • Cases of better practice sharing and public-private partnerships established • Proven networking and collaboration among the participating institutions • Examples of “upgrading” of associated institutions • Free rotation of IMI fellows and students among the participating institutions 4 EFPIA participants in the project AstraZeneca GSK Novartis Novo Nordisk Pfizer Roche Solvay 5 Role of EFPIA participants in the project 6 Indicative duration of the project 7 Indicative total in Wyeth • • • • C. Sundstedt M. Skingle, J. Lahuerta D. Limoges J. Dirach J. Graham R. Imhof C. Kruse R. Baranello A consultative role in the set up of EMRA Input from industry on business course Lecturers for the courses Support to IMI PhD programme for PhD fellows in the companies 7 years € 3 to ? million, dependent on the number of PhD Page 67 of 88 EMRA Hub kind contribution from the EFPIA companies IMI Call 2008 DRAFT of 17/10/2007 Cost of EFPIA employee’s participation in course development • • • • • • Senior staff members to be members of faculty for lecturing and as assessors Preparation for lectures Travelling and accommodation in connection with lectures Development of case studies Sharing existing relevant in-house training programmes and/or educational materials Hosting courses/modules, lecture rooms & facilities Final figures depends on the design of the programme and will be established by the final consortium 8 Indicative expectations from the public consortium The successful consortium must address the following points: • • • • • • • • • A plan to organise the European Medicines Research Academy including the initial core institutions Outline of the structure and viability/solidity of the public consortium Plan to set up and deliver the programme Outline of the content of the business course Each consortium partner to specify their contribution (managerial/organisational and scientific input) and funding from IMI (in €) to set up the programme Innovative, realistic ideas on organisation of the programme Proposed time lines for program set-up Indication whether this partnership shall be a temporary or a permanent one Promotion of the programme to relevant potential participants The public consortium must consist of a least 2 partners in at least 2 EU member states. Page 68 of 88 Safety sciences training programme IMI Call 2008 DRAFT of 17/10/2007 17. Safety sciences training programme 1 Topic title 2 Project description Safety Sciences for Medicines Training Programme Safety scientists with a much broader spectrum of knowledge than the traditional toxicologist are much needed. The future safety scientist will have to integrate knowledge accumulated from many safety-relevant disciplines (for example primary and secondary pharmacology, drug metabolism & kinetics, functional genomics, safety pharmacology, mammal anatomy, embryology and physiology, patho-physiology, physical chemistry, animal and clinical toxicology, cellular biology, biochemistry, with all their specialist branches) if they are to excel in modern risk assessment and risk management. The safety scientist should bridge from classical pharmaceutical toxicology to human safety pharmacology. • The task is to establish a programme to train scientists holding a degree in life sciences to become knowledgeable in the fields necessary to perform a holistic evaluation of the safety of a new medicine by evaluating and linking animal and human/patient safety data. The programme should be developed by a consortium of experienced academic course providers with a proven record. The consortium may include commercial course providers. The programme should utilise established courses providing the necessary content and new courses developed by the consortium The programme should satisfy the need of stakeholders, especially in industry and regulatory agencies The programme should be open to scientists working in industry, academia or regulatory agencies Faculty should consist of teachers from academia/industry/regulatory The programme should be modular to ensure flexibility and to cope with future scientific development The programme should include a combination of lectures and workshops and should enable distance learning assuming that participants continue their normal work Each topic to be completed with an assignment related to a concrete safety issue (e.g. a case from the student’s institution) The total programme should comprise 60 ECTS equivalent to the workload of a full-time student during one academic year, however it should be possible to enlist on a part time basis to complete the programme within 2 to 3 years Option for scientists to pursue or complete single topics / modules (continuing professional development) The programme should be completed with appropriate assessment resulting in a diploma and should be developed to recognition as a master degree Page 69 of 88 • • • • • • • • • • • Safety sciences training programme • • • • • • 4 EFPIA participants in the project GSK Merck Serono Novartis Novo Nordisk Pfizer Roche 5 Role of EFPIA participants in the project IMI Call 2008 DRAFT of 17/10/2007 3 Key deliverables of the project A programme/curriculum for multidisciplinary training of scientists involved in the safety evaluation of medicines in development A European Network of Faculties (universities and private institutions) able and willing to support the project Establishment of programme More than 50 participants in programme At least 20 participants completed full programme A process for an European accreditation of such programme L.A. Cornes, C. Sundstedt M. Skingle P. J. Kramer D. Limoges J. Dirach H. Sterz, J. Graham F. Pfannkuch AstraZeneca Wyeth R. Baranello • Input to industry need for course content • Lecturers for the courses • 1-2 participating employees paid for from each participating EFPIA company • In house mentors for the company’s students • Providing case studies • Providing short term tutoring programs in an industry environment 5 years € 2.5 to 3 million • • • • • • • • • • Cost of EPIA employee’s participation in course development Senior staff members to be members of faculty for lecturing and as assessors Preparation for lectures Travelling and accommodation in connection with lectures Development of case studies Sharing existing relevant in-house training programmes and/or educational materials Facilitate training by creating/maintaining recognised “training positions” in the companies with adequate support of in-house mentors Hosting courses/modules, lecture rooms & facilities Fees for employees participating in programme Travel and accommodation for employees on programme 6 Indicative duration of the project 7 Indicative total in kind contribution from the EFPIA companies Final figures depends on the design of the programme and will be established by the final consortium Page 70 of 88 Safety sciences training programme IMI Call 2008 DRAFT of 17/10/2007 8 Indicative expectations from the public consortium The Successful Consortium must address the following points: • • • • • • • • • Outline of the structure and viability/solidity of the public consortium Plan to set up and deliver the programme Outline of the content of the course modules and pre-requisites for accreditation of the programme Each consortium partner to specify their contribution (managerial/organisational and scientific input) and funding from IMI (in €) to set up the programme Innovative, realistic ideas on organisation of the programme, e.g. distance learning facilities, flexibility, on-the-job training Indication of a fee to be paid by the course participants per module based on a break-even basis calculation Proposed time lines for program set-up Indication whether this partnership shall be a temporary or a permanent one Promotion of the programme to relevant potential participants The public consortium must consist of a least 2 partners in at least 2 EU member states. Page 71 of 88 Pharmaceutical medicine training programme IMI Call 2008 DRAFT of 17/10/2007 18. Pharmaceutical medicine training programme 1 Topic title 2 Project description Pharmaceutical Medicine Training Programme Improving professional effectiveness by promoting education and training in Pharmaceutical Medicine throughout the European Union, in order to address the present needs and future competitive demands of highly qualified professionals (physicians and other life science graduates) in this key area of expertise. This is to be accomplished by the harmonised activity of existing and new courses in pharmaceutical medicine. A network of academic centres should be established. These should deliver foundation and advanced educational programmes, employing state of the art educational methodology to include quality management of the processes and outcomes. External validity and appropriateness of the contents, as well as practical applicability of the educational programmes must be ensured. A more detailed description of the project proposed is described below: Pharmaceutical Medicine (PM) is a medical scientific discipline concerned with the discovery, development, evaluation, registration, monitoring and medical aspects of marketing of medicines for the benefit of patients and the public health. PM is an interdisciplinary field. Although the role of physicians is necessary, important and not interchangeable, many other professionals with different background (Pharmacy, Biological and Health Sciences, etc.) currently practice in this area of expertise in the pharmaceutical industry and allied industries (e.g. CROs), regulatory bodies and other institutions. Education and training (E&T) in PM has been of paramount importance to ensure professional competence and enhance the value of the PM specialist. Currently a number of post-graduate courses in PM exist around Europe. Many of these courses were established by the national associations of PM in collaboration with local universities, see www.ifapp.org. E&T in PM is also provided in Europe as in-house activities in many pharmaceutical companies, and commercial and non-commercial providers offer courses of various contents and duration. Although these are valuable activities, they cannot be considered as comprehensive, structured, widely available and quality assessed educational activities as the courses mentioned before. The specific objectives of the project, over a 4-year period, can be grouped chronologically as follows: Phase 1 (Years 1-2): Designing the best E&T product Page 72 of 88 Pharmaceutical medicine training programme IMI Call 2008 DRAFT of 17/10/2007 Mapping and producing an inventory of existing courses. Define E&T needs (for the industry, regulatory agencies, students, etc.) for Europe (various regions). Review of educational programmes and resources matched according to needs. Design of the programme, at various levels (foundation, advanced, high, Continuing Medical Education/Continuing Professional Development, CME/CPD): contents, delivery, tuition, assessment, collaboration with industry and other parties (Regulatory Authorities). The principles ruling this initial process are building on existing practice, flexibility (modular approach), efficiency of the use of resources, harmonisation, transportability of credits and a pan-European scope following Bologna criteria for European Higher Education Area. Also important, is the integration of this project with other in-parallel E&T initiatives for other professionals (pre-clinical medicines developers, safety scientists, etc.) to allow for transdisciplinary cross-fertilisation and enlarging the scope of applicability of the various programmes. Quality in the whole process is to be ingrained in all aspects of the programme developed: from content to implementation and assessment. Rating high among the priorities of this initial phase will be setting up quality criteria for all activities and aiming for a high quality curriculum the completion of which could lead to the award of a Master (60 ECTS) degree of Advanced Studies in Drug Development Sciences. Phase 2 (Years 1-4): Implementing the best E&T solution through a European network of E&T elements: existing and new courses, other outreach facilities and collaboration with pharmaceutical industry and regulatory agencies. The programmes, perhaps following a pilot, will be delivered in a harmonised fashion to cater for perceived needs: • • • • • Foundation education in PM at the postgraduate level Advanced education and practical training Elective courses/programmes in areas requiring particular expertise Comprehensive high-quality programme (Master) Specific E&T initiatives for other professionals involved in activities governed by Pharmaceutical Medicine (e.g. GCP for research teams in drug clinical trials) The project aims to significantly expand the number of participants in E&T in the various activities, by reaching persons currently experiencing difficulties in access (e.g. those located in Central and Eastern Europe). Improvement in the quality, regarding a best fit to needs and continuous improvement process, will also rate high in the implementation phase. Finally, the implementation activities will provide a basis to establish PM as a separate medical specialty throughout Europe. 3 Key deliverables of the project • • • • A network of established academic centres using harmonised contents and similar educational and assessment methods, accredited by an external body New academic centres in European areas where needed (likely new accession countries) A common Pharmaceutical Medicine Syllabus A common and widely-acceptable training scheme in Page 73 of 88 Pharmaceutical medicine training programme IMI Call 2008 DRAFT of 17/10/2007 • • • • Pharmaceutical Medicine (basic and advanced) for physicians and non physicians A CME/CPD programme Distance learning materials Training programme for investigators to include GCP First cohorts of students started on the programmes A more detailed description of the project key deliverables proposed is provided below following the chronology of the two proposed phases: • A Coordinating Board, comprised of members belonging to the various stakeholders of E&T in Pharmaceutical Medicine in Europe, ensuring the external validity and practical application of the proposals, as well as the adequacy of contents and solutions proposed Map of existing E&T training resources in Europe Analysis of E&T needs in PM in Europe. Matching with existing resources. Gap-analysis and plans to solve any discrepancies. A description of the most adequate educational programmes and training schemes at foundation, advanced, and elective levels, high qualification (Master) and CME/CPD Harmonised contents (standard Syllabus - modules) and suitable educational methods. Adequate and validated assessment methods. Definition of adequate E&T requirements in PM, at the various levels, in relation to specialist recognition status in Europe Pool of resources: teachers and materials. Quality management of these. Accreditation criteria and implementation. Outreach (e-learning) programmes, methods and materials Criteria for selection and assessment of training positions within the pharmaceutical industry, regulatory authority and others Quality management criteria and guide for implementation. Accreditation process and implementation. A network of established university post-graduate courses in PM delivering programmes in a harmonised fashion, using similar educational and assessment methods and employing accepted quality management methods to include accreditation. Where required, establishing new centres of similar characteristics (e.g. Central and Eastern Europe) Organization of advanced workshops. The scientific organization (choice of topics and speakers) will be provided centrally. The workshops will be organized in different European cities with rotation from one year to the other. Topics may include: optimization of early drug development, novelties in clinical trials, current issues in bioethics and evolution of the pharmaceutical market… These advanced workshops are intended for course participants to complement basic modules as well as for the CPD of recognized pharmaceutical physicians. E-learning tool for training clinical investigators: A course will be developed complying with the syllabus published by the Page 74 of 88 • • • • • • • • • • • • • Pharmaceutical medicine training programme IMI Call 2008 DRAFT of 17/10/2007 European Science Foundation in 2001 with a focus on GCP and containing chapters on the design of clinical trials, the ethical and regulatory aspects, the organization and conduct of clinical trials and data analysis and publication. This course will be made available to the European medical and paramedical community. 4 EFPIA participants in the project AstraZeneca GSK Novartis Novo Nordisk Pfizer Wyeth 5 Role of EFPIA participants in the project C. Sundstedt J. Lahuerta, M. Skingle D. Limoges J. Dirach J. Graham R. Baranello The success of the proposed project largely resides in maintaining the existing good collaboration between E&T activities provided by academic courses and pharmaceutical companies belonging to EFPIA. It goes without saying that the expertise of PM resides in the clinical research, Medical and Regulatory departments of these companies and in other support industries (CROs), as well as within the Regulatory Authorities. In fact, many companies have their own training schemes covering areas related to PM. Therefore the role of EFPIA participants in this project needs to be considered as a partnership between them and the stake-holders of the proposals. EFPIA participants will contribute to the project in several ways. Promoting E&T in PM among their employees by allowing them to devote time off work to undertake the appropriate programmes described in the proposal. This is probably the most important contribution to be made because of the numbers of employees that are potentially to benefit from these programmes and, at the end of the day, who could make a difference in improving the competitiveness of Drug Development in Europe, by translating this E&T received in daily good decisions. Thus, top-down commitment and bottom-up interest are essential in the success of this project. R&D, Medical, Regulatory and Human Resource directors, as well as Centres of Excellence, need to be aware of this project and give the appropriate support and recognition of achievement. This is a true partnership and companies will likewise benefit of counting on a better trained and more effective staff, particularly in key areas as drug development and Pharmaceutical Medicine at large. Paying the tuition fees of the courses for employees. Cost to undertake the appropriate courses may be a significant access barrier to some staff, one impeding them to benefit from E&T in PM. In countries where no local course exists, the problem is compounded with additional cost of travelling and extended time off-work. These aspects need to be objectively but generously considered by employers against the benefits of having well-trained efficacious employees. Page 75 of 88 Pharmaceutical medicine training programme IMI Call 2008 DRAFT of 17/10/2007 Allowing senior members of their staff time off work to serve as educators or assessors of the proposed educational programmes. Education needs to be provided by those who know. Therefore, it is no surprise that adequate educators in the courses will come, at least in part, from the pharmaceutical industry. The importance of the time and effort these people, usually senior staff members, provide to the courses they teach, needs to be adequately recognised by their companies. Moreover, these activities should be considered part of the employment commitments. Sharing resources of their existing in-house training programmes with a “common house” of educational materials and personnel in Pharmaceutical Medicine. Many pharmaceutical companies (and other support industries or regulatory authorities) have extensive educational materials that they use in-house only. Some of these refer to proprietary matters or company-only procedures but a large number of materials are generic and could be shared among others for the purpose of education. This simple initiative, creating a pool of shared materials, would greatly benefit all, in particular those in countries or organisations with less opportunities, and contribute to the joint goal of improving E&T in PM across Europe. Facilitating training in Pharmaceutical Medicine by creating/maintaining recognised “training positions” in their own structures with adequate support of in-house mentors. One important aspect that pharmaceutical companies need to address to contribute to this project is providing training opportunities for their staff (and perhaps for outside trainees) as part of their organisation. These also require some of its senior members taking the role of mentors and tutors. To do this effectively, the training positions need to form part of a wider educational structure (such as that currently enforced in the Higher Medical Training Scheme in the UK) and in close collaboration with an academic body, supporting the activity of the tutors. It could be further envisaged that short-time periods of training for academicians could be offered in some departments of a pharmaceutical company, in order for them to gain adequate “hands-on” knowledge of a discipline not practised outside this environment. 6 Indicative duration of the project 7 Indicative total in kind contribution from the EFPIA companies 4 years €4 million • • • • • • Cost of EFPIA employees’ participation in project and courses’ development EFPIA senior employees to be members of faculty for lecturing and as assessors Preparation of lectures Travelling and accommodation related to lectures/students’ assessment Development of study cases Sharing existing relevant in-house training programmes and/or Page 76 of 88 Pharmaceutical medicine training programme IMI Call 2008 DRAFT of 17/10/2007 • • • • educational materials Facilitate training by creating/maintaining recognised “training positions” in the companies with adequate support of “in-house” mentors Hosting course/modules, lecture rooms and facilities Paying course fees of employees Paying travel and accommodation of employees participating in training programme. Final figures will depend on the design of the programme and will be established be the designated consortium 8 Indicative expectations from the public consortium The Successful Consortium should address the following issues related to the proposed programme: • • • • • • • • Define the structure and viability/solidity of the public consortium Plan to design and implement the programme Outline the content of the programme and requisites for quality assurance measures Each consortium partner to specify their particular contribution (managerial/organisational and scientific input) and funding from IMI (in €) to set up the programme Innovative, realistic ideas to be built in the proposed programme, e.g. distance learning facilities, flexibility, on-the-job training, to maximise existing resources Indication of a fee to be paid by the programme participants based on a “break-even base” calculation Indication as to whether partnership will be a temporary or permanent one Promotion of the programme to the relevant potential partners The public consortium must consist of at least 2 partners in at least two EU member states Page 77 of 88 Integrated medicines development training programme IMI Call 2008 DRAFT of 17/10/2007 19. Integrated medicines development training programme 1 Topic title 2 Project description Integrated Medicines Development Training Programme for nonspecialists An integrated overview of the medicines development process, including ethics, scientific methodology, regulatory requirements, assessments of risk and benefit, intellectual property matters, business skills and understanding of the business environment is needed by many stakeholders who are more or less involved in the process of medicines development. Examples are: journalists, patients, members of ethics committees, venture capitalists, and politicians with a special interest in health, research, environmental, or industrial matters and others. Especially representatives from patient organisations should benefit from this knowledge to enable them to make a more strategic and considered input to medicines development. Further, a more in-depth understanding of the processes is needed for professionals more directly involved, e.g. SME personnel, project managers, general mangers etcetera. A modular course to provide an overview of the medicines development process including regulatory, health economy and ethics requirements should be developed. The course is intended to provide an overview for people who are not directly involved in the research. Specific modules should be directed towards members of ethics committees and patient organisations. The programme could comprise of 2 tracks: • • A short track (approximately one week duration, summer school format) to train journalists, patients, ethics committees, venture capitalists, etcetera. A long track (modular concept, over several months, e.g. lectures/workshops over a couple of days once or twice monthly) for professionals from various origins: basic biology, toxicology, clinical research, regulators, managers, to give them a comprehensive, 'helicopter view' of drug development and changing their specialist profile into a multidisciplinary, managerial profile. For both tracks, mixing participants from different skills/background in the same courses would add value through enhancing interdisciplinary interaction. Further, the faculty of the courses should reflect this too. The modules could be: • Target identification: basic molecular and cell biology and Page 78 of 88 Integrated medicines development training programme IMI Call 2008 DRAFT of 17/10/2007 • • • • • • biochemistry, 'omics', high throughput technology, systems biology, bioinformatics and in silico models Target validation: in vitro and in vivo models, imaging and biomarker identification Toxicity - safety - pharmacovigilance- risk management and communication of benefit-risk Basic clinical pharmacology, translational medicine Clinical trials in the EU including critical differences to other regions of the world (a short version of this module could also be used for investigator training to pan EU trials - over one or two weeks). o study design, methodology phase 1 to 4 (including innovative designs), validation and use of biomarkers, systematic reviews, meta-analyses o data management, biostatistics o roles and responsibilities, cost o recruitment and investigation of patients o ethics, regulatory affairs, insurance, adverse event evaluation and reporting o conduct and monitoring of the study, GCP, quality assurance Legal, regulatory framework, intellectual property Health economy, outcomes drug market and financial aspects of drug life cycle Programme should be planned in English, but should be transferable to other EU languages Programme to be developed by a consortium of a least 2 partners in at least 2 EU member states. 3 Key deliverables of the project Short track course for non-scientific audience • • • • • • • • 4 EFPIA participants in the project GSK Novartis Novo Nordisk Pfizer A programme for the course A European Network of Faculties (universities and private institutions) able and willing to support the course More than 100 participants completed the course Administration of courses A programme for the course A European Network of Faculties (universities and private institutions) able and willing to support the course More than 100 participants completed the course Administration of courses C. Sundstedt M. Skingle, J. Lahuerta D. Limoges J. Dirach J. Graham Page 79 of 88 Long track course for professionals AstraZeneca Integrated medicines development training programme IMI Call 2008 DRAFT of 17/10/2007 C. Kruse Solvay 5 Role of EFPIA participants in the project Wyeth R. Baranello • Input from industry to course content • Lecturers for the courses • 1-2 participating employees paid for from each participating EFPIA company • In house mentors for the company’s students • Providing case studies and material from in house courses and presentations • Providing short term tutoring programs in an industry environment 3 years € 2.5 to 3 million • • • • • • • • • Cost of EPIA employee’s participation in course development Senior staff members to be members of faculty for lecturing and as assessors Preparation for lectures Travelling and accommodation in connection with lectures Development of case studies Sharing existing relevant in-house training programmes and/or educational materials Hosting courses/modules, lecture rooms & facilities Fees for employees participating in programme Travel and accommodation for employees on programme 6 Indicative duration of the project 7 Indicative total in kind contribution from the EFPIA companies Final figures depends on the design of the programme and will be established by the final consortium 8 Indicative expectations from the public consortium The Successful Consortium must address the following points: • • • • • • • • • • Outline of the structure and viability/solidity of the public consortium Plan to set up and deliver the programme Outline of the content of the course modules and pre-requisites for accreditation of the programme Each consortium partner to specify their contribution (managerial/organisational and scientific input) and funding from IMI (in €) to set up the programme Innovative, realistic ideas on organisation of the programme, e.g. distance learning facilities, flexibility, on-the-job training Indication of a fee to be paid by the course participants per module based on a break-even base calculation Proposed time lines for program set-up Relevance to the various stakeholders Indication whether this partnership shall be a temporary or a permanent one Promotion of the programme to relevant potential participants Page 80 of 88 Integrated medicines development training programme • IMI Call 2008 DRAFT of 17/10/2007 Ability of the proposed programme to be transferred/translated from English-speaking participants to other EU languages The public consortium must consist of a least 2 partners in at least 2 EU member states. Page 81 of 88 Pharmacovigilance training programme IMI Call 2008 DRAFT of 17/10/2007 20. Pharmacovigilance training programme 1 Topic title Pharmacovigilance Training Programme 2 Project description In the past, pharmacovigilance has tended to be a reactive process concentrating on very few data resources, mostly spontaneous reporting. This is limited by under-reporting, as well as by data quality, which is often insufficient to allow a meaningful assessment. In more recent times there has been a dramatic shift to a much more proactive approach, involving a broader evidence base and a widening of expertise, resources and methodologies. Moreover, there is increasing interest in coordinating and analysing the wealth of data already available in the EU on the use of medicines, both in clinical trials as well as the general practice and hospital settings. Therefore, current emphasis is on a range of disciplines, and not just conventional pharmacovigilance. These newly-targeted disciplines include advanced epidemiology, biostatistics, drug utilisation, pharmacoepidemiology and use of large automated population-based exposure-outcome databases. There is thus a pressing need to expand the knowledge of pharmacovigilance professionals in order to support proactive pharmacovigilance and risk management of medicines throughout their life-cycle. This should be achieved by customised education and training programmes for professionals working within pharmaceutical companies and regulatory agencies. Shorter training courses should be directed towards journalists, venture capitalists, patients, health care professionals, etc who require a basic understanding of the principles of contemporary pharmacovigilance. There is a need for pharmacovigilance training and research at 3 levels 1. A Short overview course on risk communication for journalists, venture capitalists, patients, health care providers, etc. who need an introduction to pharmacovigilance, including its strengths and weaknesses. This will include an understanding of the different measures of risk and the factors that may confound their interpretation, of the inherent risks associated with a disease and of the beneficial and undesirable effects of medicines, 2. A Masters training programme focussing on the methodologies and tools used in contemporary pharmacovigilance should be developed to train professionals in industry and regulatory agencies who hold a degree in life sciences, 3. A PhD project or programme to identify current gaps, and assess and develop methods for benefit-risk communication.. The research will be used to develop best practices and principles to improve upon existing methods and tools used for communication. • The programme should be developed by a consortium of experienced academic course providers with a proven record. The Page 82 of 88 Pharmacovigilance training programme IMI Call 2008 DRAFT of 17/10/2007 consortium may include commercial course providers, • • The programme should utilise established courses providing the necessary content and new courses developed by the consortium, The programme should be open to scientists working in industry, academia or regulatory agencies and the short course should be open to all stakeholders, Faculty should consist of teachers from academia/industry/regulatory, The programme should satisfy the need of stakeholders, especially in industry and regulatory agencies, The programme should be modular to ensure flexibility and to cope with future scientific development, The programmes should include a combination of lectures and workshops and should enable distance learning assuming that participants continue their normal work, Each topic to be completed with an assignment related to a concrete safety issue (e.g. a case from the student’s institution), The total programme should comprise 60 ECTS equivalent to the workload of a full-time student during one academic year, however it should be possible to enlist on a part time basis to complete the programme within 2 to 3 years, Option for scientists to pursue or complete single topics / modules (continuing professional development). • • • • • • • The programme should be completed with appropriate assessment resulting in a diploma and should be developed to recognition as a Masters degree. The Masters programme The following list of topics to be addressed is intended to set the scope for the programme, not to set limitations for the innovative thinking of the consortium. For the Masters Programme, topics should address: Pharmacovigilance • • • • Historical perspective of drug safety and pharmacovigilance, General principles of assessing drug safety: pre-clinical investigations, clinical trials (Phase I-IV), observational studies, spontaneous reporting, Definitions in pharmacovigilance, Classification of adverse drug reactions, mechanisms (including Page 83 of 88 Pharmacovigilance training programme IMI Call 2008 DRAFT of 17/10/2007 • • • • • • • interactions), predisposing factors, consequences, Causality assessment, Strengths and limitations of spontaneous notification systems, Detection and evaluation of safety signals, and the use of Eudravigilance, Description of the Pharmacovigilance System and Pharmacovigilance Inspections, Roles and responsibilities of the Qualified Person in Pharmacovigilance, Regulatory environment in EU and elsewhere, Specific topics, e.g. o special populations: children, elderly, pregnant women, o pharmacovigilance of biological products, including vaccines, o products acting on the immune system, o pharmacovigilance of oncological products, o pharmacovigilance of products acting on the central nervous system, o pharmacovigilance and genomics. Objectives, definition and principles of pharmacoepidemiology, Definition and measurement of events and exposure, Source of data and indicators of drug exposure, Incidence and incidence rates, Definition and calculation of different risk measures, Risk determinants, confounding factors, effect modifiers, Strengths and limitations of matching, adjustments, multivariate analyses, regression, Concept, parameters and analysis of the cohort approach, Concept, parameters and analysis of the case-control approach, Other types of study design: transversal, ecological, case crossover, case-cohort, nested case-control, self-controlled case series, others, Meta-analyses, Critical appraisal of pharmacoepidemiological studies, Development of a study protocol, Regulatory aspects including ethical issues, Conduct of a pharmacoepidemiological study. Technical aspects: data structure, coding, retrieval and linkage, Types of databases: Public health and administration, drug utilisation and prescription databases, Data requirements for drug safety and retrospective studies, MEdDRA and other terminologies Major EU databases (GPRD, EPIC, IMS, THIN, etc), Automated Signal Detection (including statistical analyses), Record linkage: Study designs and data analyses (e.g. nested case-control, case cross-over, etc) - strengths and limitations, Page 84 of 88 Advanced pharmacoepidemiology • • • • • • • • • • • • • • • • • • • • • • Databases & electronic registries for drug safety Pharmacovigilance training programme • • • Examples and Case Studies. IMI Call 2008 DRAFT of 17/10/2007 Risk management, including risk minimisation Principles of risk management o What risks can and cannot be managed, o Medication errors and product development, ICH E2E pharmacovigilance planning o Safety specifications, o Pharmacovigilance Planning, including tools for investigating safety concerns, EU Risk Management Plan o Legislation, o Content, o Situations when required, Risk minimisation o Available tools for risk minimisation, o Opportunities and limitations within Europe, Building an EU Risk Management Plan, Risk management in specific situations (e.g. pediatric use marketing authorisations, biosimilars, etc.). Benefit-risk assessment, Perceptions of risks and benefits: psycho-sociological aspects of values attached to risks and benefits, influence of factors such as drug indication, perceived severity of disease, demographics and other characteristics, Communication channels: characteristics and effectiveness depending on target audience (patients, HCP, media, public health authorities, etc), Technical aspects of communication (language, print, presentation, internet messages, etc.), Principles of Good Communication in the field of benefit-risk, Recommendations on Direct Health Care Professional Communication, Experience with benefit-risk communication: review of examples and methods used to-date and their effectiveness; impact of the SmPC. • • • • Benefit -risk communication • • • • • • • The PhD project or programme The PhD project or programme should conduct research to identify current gaps, and assess and develop best practices for benefit-risk communication from industry and regulatory agencies to healthcare professionals, patients and other stakeholders (e.g. payers, the media, etc.). The programme will address methods for delivering concise, evidence-based and understandable information. The research activity shall include testing of the effectiveness of current communication tools, review of published literature related to communication of risks, assessment of the impact of current communications, and consultation with experts in the areas of public communication and social science. The project could be approached in several phases, with the initial phase Page 85 of 88 Pharmacovigilance training programme IMI Call 2008 DRAFT of 17/10/2007 focussing on selection of communication tools to be evaluated in the project. 3 Key deliverables of Short overview course for non-scientific audience the project • A programme for the course, • A European Network of Faculties (universities and private institutions) able and willing to support the course, • More than 100 participants completed the course. Training programme on contemporary pharmacovigilance for professionals • • • • • • • • • • A programme/curriculum for multidisciplinary training of scientists involved in pharmacovigilance, A European Network of Faculties (universities and private institutions) able and willing to support the project, Establishment of programme, More than 50 participants in programme with at least 20 completed full programme, A process for an European accreditation of such programme. Project description(s) for PhD project(s), Each PhD project should involve the co-operation of a university, a regulatory authority, a PhD fellow and an EFPIA company, Two supervisors will guide the industrial PhD fellow, one from the university (primary supervisor) and one from the enterprise, The PhD fellow(s) should spend approximately 50% of the time in industry and 50% in academia or regulatory authorities, The PhD fellow is employed by the company on a full-time basis. PhD project or programme See principles for the IMI PhD programme in the IMI Strategic Research Agenda, page 107, www.imi-europe.org. 4 EFPIA participants AstraZeneca in the project GSK Novartis Novo Nordisk Pfizer Wyeth 5 Role of EFPIA participants in the project • • • • • Lecturers for the courses 1-2 participating employees paid for from each participating EFPIA company In house mentors for the company’s students Providing case studies Page 86 of 88 C. Sundstedt E.J. Swain, M. Skingle D. Limoges J. Dirach J. Graham R. Baranello Input to industry need for course content Pharmacovigilance training programme IMI Call 2008 DRAFT of 17/10/2007 • • • • 6 Indicative duration of the project 7 Indicative total in kind contribution from the EFPIA companies 5 years Providing short term tutoring programs in an industry environment Industrial supervisor for PhD fellow(s) Administration of PhD salary Facilities for PhD fellows € 3 to 3,5 million • • • • • • • • • • PhD: • • • • 50% of the standard PhD salary Industry bench costs, i.e. location, use of apparatus etc. Administration of salary, employment contract etc Industry supervisor Cost of EPIA employee’s participation in course development Senior staff members to be members of faculty for lecturing and as assessors Preparation for lectures Travelling and accommodation in connection with lectures Development of case studies Sharing existing relevant in-house training programmes and/or educational materials Facilitate training by creating/maintaining recognised “training positions” in the companies with adequate support of in-house mentors Hosting courses/modules, lecture rooms & facilities Fees for employees participating in programme Travel and accommodation for employees on programme Final figure depends on the design of the programme and will be established by the final consortium 8 Indicative expectations from the public consortium The Successful Consortium must address the following points: • • • • • • • • Outline of the structure and viability/solidity of the public consortium Plan to set up and deliver the programme Outline of the content of the course modules and pre-requisites for accreditation of the programme Each consortium partner to specify their contribution (managerial/organisational and scientific input) and funding from IMI (in €) to set up the programme Innovative, realistic ideas on organisation of the programme, e.g. distance learning facilities, flexibility, on-the-job training Indication of a fee to be paid by the course participants per module based on a break-even basis calculation Proposed time lines for program set-up Indication whether this partnership shall be a temporary or a Page 87 of 88 Pharmacovigilance training programme IMI Call 2008 DRAFT of 17/10/2007 • permanent one Promotion of the programme to relevant potential participants The public consortium must consist of a least 2 partners in at least 2 EU member states. 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