How to improve R&amp;D productivity: the pharmaceutical industry's grand challenge

Paul, Steven M.; Mytelka, Daniel S.; Dunwiddie, Christopher T.; Persinger, Charles C.; Munos, Bernard H.; Lindborg, Stacy; Schacht, Aaron L.

doi:10.1038/nrd3078

Cited by 2,984 publications

(2,159 citation statements)

References 29 publications

(33 reference statements)

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“…We anticipate that the integration of hiPSC‐CMs in early, preclinical stages of drug development is imminent and will be of benefit in: (i) the early detection of cardiotoxic drugs in safety pharmacology assays, which will help reduce the withdrawal of drugs already introduced to the market; (ii) the refinement of drug safety assays, as they are based on human cell models at early stages, which may improve the yield of drug discovery activities by selectively discarding potentially harmful compounds in ‘ quick win, fail fast ’ approaches (Paul et al , 2010); and (iii) reducing the number of animal used for drug testing.…”

Section: Discussionmentioning

confidence: 99%

Integrating cardiomyocytes from human pluripotent stem cells in safety pharmacology: has the time come?

Sala

Bellin

Mummery

2016

British J Pharmacology

107

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Cardiotoxicity is a severe side effect of drugs that induce structural or electrophysiological changes in heart muscle cells. As a result, the heart undergoes failure and potentially lethal arrhythmias. It is still a major reason for drug failure in preclinical and clinical phases of drug discovery. Current methods for predicting cardiotoxicity are based on guidelines that combine electrophysiological analysis of cell lines expressing ion channels ectopically in vitro with animal models and clinical trials. Although no new cases of drugs linked to lethal arrhythmias have been reported since the introduction of these guidelines in 2005, their limited predictive power likely means that potentially valuable drugs may not reach clinical practice. Human pluripotent stem cell‐derived cardiomyocytes (hPSC‐CMs) are now emerging as potentially more predictive alternatives, particularly for the early phases of preclinical research. However, these cells are phenotypically immature and culture and assay methods not standardized, which could be a hurdle to the development of predictive computational models and their implementation into the drug discovery pipeline, in contrast to the ambitions of the comprehensive pro‐arrhythmia in vitro assay (CiPA) initiative. Here, we review present and future preclinical cardiotoxicity screening and suggest possible hPSC‐CM‐based strategies that may help to move the field forward. Coordinated efforts by basic scientists, companies and hPSC banks to standardize experimental conditions for generating reliable and reproducible safety indices will be helpful not only for cardiotoxicity prediction but also for precision medicine.Linked ArticlesThis article is part of a themed section on New Insights into Cardiotoxicity Caused by Chemotherapeutic Agents. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.21/issuetoc

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Section: Discussionmentioning

confidence: 99%

Integrating cardiomyocytes from human pluripotent stem cells in safety pharmacology: has the time come?

Sala

Bellin

Mummery

2016

British J Pharmacology

107

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“…Success rates and time spent by development phase have been widely used as parameters to quantify efficiency in pharmaceutical R&D 373, 374, 375. Current success rates by phase are defined as the number of development compounds that advance to the next phase, divided by the number of compounds that entered the phase from which is subtracted the number of compounds of yet unknown fate, for example, those in ongoing studies.…”

Section: Resultsmentioning

confidence: 99%

The Drug Discovery and Development Industry in India—Two Decades of Proprietary Small‐Molecule R&D

Differding¹

2017

ChemMedChem

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This review provides a comprehensive survey of proprietary drug discovery and development efforts performed by Indian companies between 1994 and mid‐2016. It is based on the identification and detailed analysis of pharmaceutical, biotechnology, and contract research companies active in proprietary new chemical entity (NCE) research and development (R&D) in India. Information on preclinical and clinical development compounds was collected by company, therapeutic indication, mode of action, target class, and development status. The analysis focuses on the overall pipeline and its evolution over two decades, contributions by type of company, therapeutic focus, attrition rates, and contribution to Western pharmaceutical pipelines through licensing agreements. This comprehensive analysis is the first of its kind, and, in our view, represents a significant contribution to the understanding of the current state of the drug discovery and development industry in India.

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“…Current paradigms for testing drug efficacy and toxicity are time‐consuming, ineffective, and expensive 1. One of the main reasons is that the animal models used in drug screening are often ineffective at predicting human responses to candidate drugs 2.…”

Section: Introductionmentioning

confidence: 99%

Label‐Free and Regenerative Electrochemical Microfluidic Biosensors for Continual Monitoring of Cell Secretomes

et al. 2017

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Development of an efficient sensing platform capable of continual monitoring of biomarkers is needed to assess the functionality of the in vitro organoids and to evaluate their biological responses toward pharmaceutical compounds or chemical species over extended periods of time. Here, a novel label‐free microfluidic electrochemical (EC) biosensor with a unique built‐in on‐chip regeneration capability for continual measurement of cell‐secreted soluble biomarkers from an organoid culture in a fully automated manner without attenuating the sensor sensitivity is reported. The microfluidic EC biosensors are integrated with a human liver‐on‐a‐chip platform for continual monitoring of the metabolic activity of the organoids by measuring the levels of secreted biomarkers for up to 7 d, where the metabolic activity of the organoids is altered by a systemically applied drug. The variations in the biomarker levels are successfully measured by the microfluidic regenerative EC biosensors and agree well with cellular viability and enzyme‐linked immunosorbent assay analyses, validating the accuracy of the unique sensing platform. It is believed that this versatile and robust microfluidic EC biosensor that is capable of automated and continual detection of soluble biomarkers will find widespread use for long‐term monitoring of human organoids during drug toxicity studies or efficacy assessments of in vitro platforms.

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How to improve R&D productivity: the pharmaceutical industry's grand challenge

Cited by 2,984 publications

References 29 publications

Integrating cardiomyocytes from human pluripotent stem cells in safety pharmacology: has the time come?

Integrating cardiomyocytes from human pluripotent stem cells in safety pharmacology: has the time come?

The Drug Discovery and Development Industry in India—Two Decades of Proprietary Small‐Molecule R&D

Label‐Free and Regenerative Electrochemical Microfluidic Biosensors for Continual Monitoring of Cell Secretomes

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