Abstract
Safety pharmacology is an essential part of drug development aiming to identify, evaluate and investigate undesirable pharmacodynamic properties of a drug primarily prior to clinical trials. In particular, cardiovascular adverse drug reactions (ADR) have halted many drug development programs. Safety pharmacology has successfully implemented a screening strategy to detect cardiovascular liabilities, but there is room for further refinement. In this setting, we present the INSPIRE project, a European Training Network in safety pharmacology for Early Stage Researchers (ESRs), funded by the European Commission's H2020-MSCA-ITN programme. INSPIRE has recruited 15 ESR fellows that will conduct an individual PhD-research project for a period of 36 months. INSPIRE aims to be complementary to ongoing research initiatives. With this as a goal, an inventory of collaborative research initiatives in safety pharmacology was created and the ESR projects have been designed to be complementary to this roadmap. Overall, INSPIRE aims to improve cardiovascular safety evaluation, either by investigating technological innovations or by adding mechanistic insight in emerging safety concerns, as observed in the field of cardio-oncology. Finally, in addition to its hands-on research pillar, INSPIRE will organize a number of summer schools and workshops that will be open to the wider community as well. In summary, INSPIRE aims to foster both research and training in safety pharmacology and hopes to inspire the future generation of safety scientists.
| Original language | English |
|---|---|
| Article number | 106889 |
| Number of pages | 10 |
| Journal | Journal of Pharmacological and Toxicological Methods |
| Volume | 105 |
| DOIs | |
| Publication status | Published - Sept 2020 |
Keywords
- Safety pharmacology
- Cardiovascular safety liabilities
- Cardio-oncology
- Drug development
- Training and education
- Methods
- Marie Sklodowska-curie actions
- CELL-DERIVED CARDIOMYOCYTES
- CLINICAL-TRIALS
- PRESSURE
- PARADIGM
- RODENTS
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- 10.1016/j.vascn.2020.106889Licence: CC BY
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In: Journal of Pharmacological and Toxicological Methods, Vol. 105, 106889, 09.2020.
Research output: Contribution to journal › Article › Academic › peer-review
TY - JOUR
T1 - INSPIRE
T2 - A European training network to foster research and training in cardiovascular safety pharmacology
AU - Guns, Pieter-Jan D.
AU - Guth, Brian D.
AU - Braam, Stefan
AU - Kosmidis, Georgios
AU - Matsa, Elena
AU - Delaunois, Annie
AU - Gryshkova, Vitalina
AU - Bernasconi, Sylvain
AU - Knot, Harm J.
AU - Shemesh, Yair
AU - Chen, Alon
AU - Markert, Michael
AU - Fernandez, Miguel A.
AU - Lombardi, Damiano
AU - Grandmont, Celine
AU - Cillero-Pastor, Berta
AU - Heeren, Ron M. A.
AU - Martinet, Wim
AU - Woolard, Jeanette
AU - Skinner, Matt
AU - Segers, Vincent F. M.
AU - Franssen, Constantijn
AU - Van Craenenbroeck, Emeline M.
AU - Volders, Paul G. A.
AU - Pauwelyn, Thomas
AU - Braeken, Dries
AU - Yanez, Paz
AU - Correll, Krystle
AU - Yang, Xi
AU - Prior, Helen
AU - Kismihok, Gabor
AU - De Meyer, Guido R. Y.
AU - Valentin, Jean-Pierre
N1 - Funding Information: INSPIRE is a European Training Network (ETN) in the field of safety pharmacology. INSPIRE has started in January 2020 and will run until December 2023 and is funded through the European Commission's Horizon 2020 Marie Skłodowska-Curie Actions (MSCA) Innovative Training Networks (ITN) programme. The MSCA-ITN programme does not have predefined priority research areas, but relies on scientific proposals submitted, bottom-up, by consortia. The primary focus of ETN projects is to offer a stimulating, multidisciplinary research and training environment for Early Stage Researcher (ESR; i.e., PhD students) fellows, which will enable them to develop a scientific career in industry or academia. ETN consortia are selected by a very competitive evaluation process (success rate < 10%). Selected projects receive a budget to recruit ESR fellows for a period of 36 months. The budget covers the salary of the recruited ESR fellows, as well as a contribution to expenses related to research and training activities. The total budget is proportional to the number of ESR fellows with a maximum of 15 ESR fellows per ETN; this can be up to approximately 4 million € of funding. Matching internal funding may extend the length of the individual ESR projects to increase the likelihood of the ESR fellow to obtain a high quality PhD-degree. ESR fellows have mandatory secondments within the network to access new methodologies and foster knowledge sharing. Furthermore, complementary to the hands-on research programme, INSPIRE includes a training programme tailored to the educational needs of the ESR fellows, consisting of summer schools and workshops, that are open for the wider community. More information on INSPIRE is available through the website ( http//www.inspire-safety-pharmacology.eu ). Funding Information: Safety pharmacology has been shaped by intensive interactions between the pharmaceutical industry and regulatory authorities under the auspices of ICH, eventually leading to a set of guidance documents, such as ICH S7A, ICH S7B, ICH E14, ICH S6, ICH S9 and ICH M3. Further, the Safety Pharmacology Society (SPS) has been an important driver to promote collaboration and provide education in safety pharmacology ( Pugsley et al., 2018 ). SPS's Annual Meeting is a key forum for sharing best practices and discussing future directions of safety pharmacology. SPS provides an educational programme for newcomers and a continuous education track for experienced safety scientists. Moreover, SPS has established the Diplomate in Safety Pharmacology (DSP) programme that certifies the knowledge and skills of qualified safety pharmacologist ( Authier et al., 2015 ). Similarly, the Society of Toxicology (SOT) has been promoting collaboration among toxicologists and safety pharmacologists. Further, a range of initiatives has motivated the field to refine existing assays and to explore new technologies. Probably the best known organization involved with such activities is the Health and Environmental Sciences Institute (HESI) that supports pre-competitive collaborative research involving major safety themes. In particular, HESI's Cardiac Safety Technical Committee (HESI-CSTC) has been a vivid forum for identifying issues commonly faced in the evaluation of cardiovascular safety. HESI-CSTC has started a number of collaborative research projects, such as “The Comprehensive in vitro Proarrhythmia Assay” (CiPA) Initiative. CiPA aims to develop an integrated, mechanism-based approach to proarrhythmia evaluation. While a single hERG channel block by a NCE mostly correlates with QT prolongation in experimental models, it has limited performance for predicting overall clinical proarrhythmia risk, especially when a NCE interferes with multiple cardiac ion channels ( Gintant, Sager, & Stockbridge, 2016 ; Sager, Gintant, Turner, Pettit, & Stockbridge, 2014 ). To overcome this, CiPA proposed to evaluate NCE effects on multiple ion channels beyond hERG (e.g., I Ks , I Na , I Ca,L ) that are then used for in silico reconstruction of cellular cardiac electrophysiological activity. Next, the in silico predictions are compared to experimental data obtained from hiPSC-derived cardiomyocytes - human cells were specifically chosen to exclude potential species-related differences in cardiac electrophysiology ( Fermini et al., 2016 ). CiPA aims to transform the assessment of drug-related proarrhythmia risk, including, but not limited to TdP risk. While initial results from CiPA are promising, further cross-validation against both clinical and preclinical datasets is needed ( Wallis et al., 2018 ). In the validation process, CiPA has gathered data on the robustness of high-throughput methods for cardiac ion channel screening and has included a validation of hiPSC-derived cardiomyocytes assays. Meanwhile, discussions have been initiated with the ICH S7B/E14 Implementation Working Group (IWG) to revise these guidelines through a Questions & Answers process taking into account the latest scientific and technological developments. Other focus areas of HESI-CSTC include the exploration of hiPSC-based assays to assess functional and structural cardiotoxicity, including the identification of translational biomarkers ( Pierson et al., 2013 ). Complementary to this programme, the Japan iPS Cardiac Safety Assessment (JiCSA) ( Kanda, Yamazaki, Osada, Yoshinaga, & Sawada, 2018 ) has evaluated the utility of hiPSC cardiomyocytes assays for cardiac safety evaluation. Another initiative of the Japan Safety Pharmacology Society (J-SPS) is the Japan activity for Improvement of Cardiovascular Evaluation by Telemetry system (J-ICET) ( Komatsu et al., 2019 ). Similarly, HESI-CSTC is engaged in a multi-site comparison and cross-validation of the sensitivity and reproducibility of minimally invasive telemetry methods for measuring hemodynamic parameters, including cardiac contractility. The latter has become increasingly important, since some pharmacological mechanisms (e.g., tyrosine kinase inhibitors (TKIs)) may negatively affect cardiac contractility and may predispose patients to heart failure. The Cardiac Safety Research Consortium (CSRC) is another initiative worth mentioning in the setting of cardiovascular ADRs. The CSRC, coordinated by Duke University, was established in 2006 as part of FDA's Critical Path Initiative (CPI) and organizes annual Think Thank meetings and regularly publishes white papers to stimulate research in specific areas of cardiovascular safety. This way, CSRC actively contributed to the design of CiPA. Another important project of CSRC involves the set-up of a data warehouse of ECG signals that can be used for training of automated ECG analysis algorithms. Another CPI consortium is the Predictive Safety Testing Consortium (PSTC) aiming to validate clinical safety biomarkers, especially for drug-related kidney and liver injury. Further, the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ consortium) is worth mentioning. Its Working Group on Non-Clinical to Clinical Translational Safety has established a database for benchmarking various assays used in toxicology and safety evaluation ( Monticello et al., 2017 ). The Innovative Medicines Initiatives 2 (IMI-2) programme also has a number of projects in its portfolio related to toxicology and safety evaluation. IMI-2 is a PPP, funded by the European Commission and equally matched by in kind contribution from the pharma industry, aimed to develop pre-competitive capabilities to accelerate drug development. IMI launches competitive calls on a regular basis. The topics of these calls are defined by members of the European Federation of Pharmaceutical Industries and Associations (EFPIA). Since its conception, IMI has funded over 148 projects, providing 5.3 billion € in funding. IMI-projects cover topics such as improving safety by adopting a systems toxicology approach (e.g., eTOX, TransQST), developing safety biomarkers (e.g., TransBioLine), exploring imaging markers (e.g., SAFE-T, TRISTAN) or enabling hiPSC-derived assays (e.g., EBiSC2). The United Kingdom's National Centre for the Replacement, Reduction and Refinement of animals in research (NC3Rs) is also actively engaging the safety pharmacology community to promote and support research on best practices with respect to implementation of the 3Rs ( Jackson et al., 2019 ; Redfern et al., 2017 ). Given the complexity of the cardiovascular system, the use of animal models in safety pharmacology evaluation is still considered crucial to assess cardiovascular function. Accordingly, the S7A guideline requires in vivo animal experimentation to fulfil regulatory recommendations before first-in-human (FIH) trials. Nevertheless, there are still opportunities to minimize, replace or refine the use of animals or to improve animal welfare during the experimental procedures. Examples of cardiovascular research supported by NC3Rs include in silico modelling of cardiac electrophysiology ( Passini et al., 2017 ), systems biology approaches aimed to develop effective Adverse Outcome Pathways (AOP) for cardiotoxicity ( Margiotta-Casaluci, Dusza, Moreira, Winter, & Prior, 2019 ) and social housing of laboratory animals during telemetry studies to better reflect normal behavioral environments and reduce stress levels of animals during the test procedures ( Prior et al., 2016 ; Skinner et al., 2019 ). Funding Information: The INSPIRE project has received funding from the European Union's Horizon 2020 Research and Innovation Program (H2020-MSCA-ITN program, Grant Agreement: No 858070 ). Funding Information: Safety pharmacology has been shaped by intensive interactions between the pharmaceutical industry and regulatory authorities under the auspices of ICH, eventually leading to a set of guidance documents, such as ICH S7A, ICH S7B, ICH E14, ICH S6, ICH S9 and ICH M3. Further, the Safety Pharmacology Society (SPS) has been an important driver to promote collaboration and provide education in safety pharmacology (Pugsley et al., 2018). SPS's Annual Meeting is a key forum for sharing best practices and discussing future directions of safety pharmacology. SPS provides an educational programme for newcomers and a continuous education track for experienced safety scientists. Moreover, SPS has established the Diplomate in Safety Pharmacology (DSP) programme that certifies the knowledge and skills of qualified safety pharmacologist (Authier et al., 2015). Similarly, the Society of Toxicology (SOT) has been promoting collaboration among toxicologists and safety pharmacologists. Further, a range of initiatives has motivated the field to refine existing assays and to explore new technologies. Probably the best known organization involved with such activities is the Health and Environmental Sciences Institute (HESI) that supports pre-competitive collaborative research involving major safety themes. In particular, HESI's Cardiac Safety Technical Committee (HESI-CSTC) has been a vivid forum for identifying issues commonly faced in the evaluation of cardiovascular safety. HESI-CSTC has started a number of collaborative research projects, such as “The Comprehensive in vitro Proarrhythmia Assay” (CiPA) Initiative. CiPA aims to develop an integrated, mechanism-based approach to proarrhythmia evaluation. While a single hERG channel block by a NCE mostly correlates with QT prolongation in experimental models, it has limited performance for predicting overall clinical proarrhythmia risk, especially when a NCE interferes with multiple cardiac ion channels (Gintant, Sager, & Stockbridge, 2016; Sager, Gintant, Turner, Pettit, & Stockbridge, 2014). To overcome this, CiPA proposed to evaluate NCE effects on multiple ion channels beyond hERG (e.g., IKs, INa, ICa,L) that are then used for in silico reconstruction of cellular cardiac electrophysiological activity. Next, the in silico predictions are compared to experimental data obtained from hiPSC-derived cardiomyocytes - human cells were specifically chosen to exclude potential species-related differences in cardiac electrophysiology (Fermini et al., 2016). CiPA aims to transform the assessment of drug-related proarrhythmia risk, including, but not limited to TdP risk. While initial results from CiPA are promising, further cross-validation against both clinical and preclinical datasets is needed (Wallis et al., 2018). In the validation process, CiPA has gathered data on the robustness of high-throughput methods for cardiac ion channel screening and has included a validation of hiPSC-derived cardiomyocytes assays. Meanwhile, discussions have been initiated with the ICH S7B/E14 Implementation Working Group (IWG) to revise these guidelines through a Questions & Answers process taking into account the latest scientific and technological developments. Other focus areas of HESI-CSTC include the exploration of hiPSC-based assays to assess functional and structural cardiotoxicity, including the identification of translational biomarkers (Pierson et al., 2013). Complementary to this programme, the Japan iPS Cardiac Safety Assessment (JiCSA) (Kanda, Yamazaki, Osada, Yoshinaga, & Sawada, 2018) has evaluated the utility of hiPSC cardiomyocytes assays for cardiac safety evaluation. Another initiative of the Japan Safety Pharmacology Society (J-SPS) is the Japan activity for Improvement of Cardiovascular Evaluation by Telemetry system (J-ICET) (Komatsu et al., 2019). Similarly, HESI-CSTC is engaged in a multi-site comparison and cross-validation of the sensitivity and reproducibility of minimally invasive telemetry methods for measuring hemodynamic parameters, including cardiac contractility. The latter has become increasingly important, since some pharmacological mechanisms (e.g., tyrosine kinase inhibitors (TKIs)) may negatively affect cardiac contractility and may predispose patients to heart failure. The Cardiac Safety Research Consortium (CSRC) is another initiative worth mentioning in the setting of cardiovascular ADRs. The CSRC, coordinated by Duke University, was established in 2006 as part of FDA's Critical Path Initiative (CPI) and organizes annual Think Thank meetings and regularly publishes white papers to stimulate research in specific areas of cardiovascular safety. This way, CSRC actively contributed to the design of CiPA. Another important project of CSRC involves the set-up of a data warehouse of ECG signals that can be used for training of automated ECG analysis algorithms. Another CPI consortium is the Predictive Safety Testing Consortium (PSTC) aiming to validate clinical safety biomarkers, especially for drug-related kidney and liver injury. Further, the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ consortium) is worth mentioning. Its Working Group on Non-Clinical to Clinical Translational Safety has established a database for benchmarking various assays used in toxicology and safety evaluation (Monticello et al., 2017). The Innovative Medicines Initiatives 2 (IMI-2) programme also has a number of projects in its portfolio related to toxicology and safety evaluation. IMI-2 is a PPP, funded by the European Commission and equally matched by in kind contribution from the pharma industry, aimed to develop pre-competitive capabilities to accelerate drug development. IMI launches competitive calls on a regular basis. The topics of these calls are defined by members of the European Federation of Pharmaceutical Industries and Associations (EFPIA). Since its conception, IMI has funded over 148 projects, providing 5.3 billion € in funding. IMI-projects cover topics such as improving safety by adopting a systems toxicology approach (e.g., eTOX, TransQST), developing safety biomarkers (e.g., TransBioLine), exploring imaging markers (e.g., SAFE-T, TRISTAN) or enabling hiPSC-derived assays (e.g., EBiSC2). The United Kingdom's National Centre for the Replacement, Reduction and Refinement of animals in research (NC3Rs) is also actively engaging the safety pharmacology community to promote and support research on best practices with respect to implementation of the 3Rs (Jackson et al., 2019; Redfern et al., 2017). Given the complexity of the cardiovascular system, the use of animal models in safety pharmacology evaluation is still considered crucial to assess cardiovascular function. Accordingly, the S7A guideline requires in vivo animal experimentation to fulfil regulatory recommendations before first-in-human (FIH) trials. Nevertheless, there are still opportunities to minimize, replace or refine the use of animals or to improve animal welfare during the experimental procedures. Examples of cardiovascular research supported by NC3Rs include in silico modelling of cardiac electrophysiology (Passini et al., 2017), systems biology approaches aimed to develop effective Adverse Outcome Pathways (AOP) for cardiotoxicity (Margiotta-Casaluci, Dusza, Moreira, Winter, & Prior, 2019) and social housing of laboratory animals during telemetry studies to better reflect normal behavioral environments and reduce stress levels of animals during the test procedures (Prior et al., 2016; Skinner et al., 2019).The INSPIRE project has received funding from the European Union's Horizon 2020 Research and Innovation Program (H2020-MSCA-ITN program, Grant Agreement: No 858070). Publisher Copyright: © 2020 The Authors
PY - 2020/9
Y1 - 2020/9
N2 - Safety pharmacology is an essential part of drug development aiming to identify, evaluate and investigate undesirable pharmacodynamic properties of a drug primarily prior to clinical trials. In particular, cardiovascular adverse drug reactions (ADR) have halted many drug development programs. Safety pharmacology has successfully implemented a screening strategy to detect cardiovascular liabilities, but there is room for further refinement. In this setting, we present the INSPIRE project, a European Training Network in safety pharmacology for Early Stage Researchers (ESRs), funded by the European Commission's H2020-MSCA-ITN programme. INSPIRE has recruited 15 ESR fellows that will conduct an individual PhD-research project for a period of 36 months. INSPIRE aims to be complementary to ongoing research initiatives. With this as a goal, an inventory of collaborative research initiatives in safety pharmacology was created and the ESR projects have been designed to be complementary to this roadmap. Overall, INSPIRE aims to improve cardiovascular safety evaluation, either by investigating technological innovations or by adding mechanistic insight in emerging safety concerns, as observed in the field of cardio-oncology. Finally, in addition to its hands-on research pillar, INSPIRE will organize a number of summer schools and workshops that will be open to the wider community as well. In summary, INSPIRE aims to foster both research and training in safety pharmacology and hopes to inspire the future generation of safety scientists.
AB - Safety pharmacology is an essential part of drug development aiming to identify, evaluate and investigate undesirable pharmacodynamic properties of a drug primarily prior to clinical trials. In particular, cardiovascular adverse drug reactions (ADR) have halted many drug development programs. Safety pharmacology has successfully implemented a screening strategy to detect cardiovascular liabilities, but there is room for further refinement. In this setting, we present the INSPIRE project, a European Training Network in safety pharmacology for Early Stage Researchers (ESRs), funded by the European Commission's H2020-MSCA-ITN programme. INSPIRE has recruited 15 ESR fellows that will conduct an individual PhD-research project for a period of 36 months. INSPIRE aims to be complementary to ongoing research initiatives. With this as a goal, an inventory of collaborative research initiatives in safety pharmacology was created and the ESR projects have been designed to be complementary to this roadmap. Overall, INSPIRE aims to improve cardiovascular safety evaluation, either by investigating technological innovations or by adding mechanistic insight in emerging safety concerns, as observed in the field of cardio-oncology. Finally, in addition to its hands-on research pillar, INSPIRE will organize a number of summer schools and workshops that will be open to the wider community as well. In summary, INSPIRE aims to foster both research and training in safety pharmacology and hopes to inspire the future generation of safety scientists.
KW - Safety pharmacology
KW - Cardiovascular safety liabilities
KW - Cardio-oncology
KW - Drug development
KW - Training and education
KW - Methods
KW - Marie Sklodowska-curie actions
KW - CELL-DERIVED CARDIOMYOCYTES
KW - CLINICAL-TRIALS
KW - PRESSURE
KW - PARADIGM
KW - RODENTS
U2 - 10.1016/j.vascn.2020.106889
DO - 10.1016/j.vascn.2020.106889
M3 - Article
C2 - 32565326
SN - 1056-8719
VL - 105
JO - Journal of Pharmacological and Toxicological Methods
JF - Journal of Pharmacological and Toxicological Methods
M1 - 106889
ER -