Current nonclinical testing paradigm enables safe entry to First-In-Human clinical trials: The IQ consortium nonclinical to clinical translational database

Monticello, Thomas M.; Jones, Thomas W.; Dambach, Donna M.; Potter, David M.; Bolt, Michael W.; Liu, Maggie; Keller, Douglas A.; Hart, Timothy K.; Kadambi, Vivek J.

doi:10.1016/j.taap.2017.09.006

Cited by 115 publications

(75 citation statements)

References 16 publications

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“… 6 The use of two phylogenetically unrelated animal species may increase the likelihood of detection of adverse effects in humans. 13 Reviews of nonclinical data indicate that nonrodent data identify toxicities additional to those detected in rodents for packages supporting FIH trials, 11 , 14 , 15 whereas a specific analysis of 20 anticancer compounds found that the rodent and nonrodent were equally sensitive for detection of human adverse events. 16 Comparisons of target organ toxicities from short-term (≤3 months) and long-term (≥3 months) dosing studies also found it equally likely that the rodent and nonrodent species detected new or increased severity toxicities.…”

Section: Why Do We Use Two Species In Regulatory Toxicology Studies?mentioning

confidence: 99%

Reviewing the Utility of Two Species in General Toxicology Related to Drug Development

et al. 2018

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As part of the safety assessment of new drugs, the use of two species (a rodent and a nonrodent) for regulatory toxicology studies is the typical approach taken for small molecules. For biologics, species selection is dictated by pharmacological relevance, and single species toxicology packages (typically using the nonhuman primate) are common. The UK National Centre for the Replacement, Refinement, and Reduction of Animals in Research and the Association of the British Pharmaceutical Industry are collaborating on a project to review the utility of two species in regulatory toxicology studies, with the aim to explore whether there are wider circumstances when data from a single species could be sufficient to enable safe progression in humans. An international working group consisting of 37 representatives from pharmaceutical and biotechnology companies, contract research organizations, academia, and regulatory bodies is coordinating a large-scale data sharing exercise to examine the potential for changes in current practice to reduce the number of species used for nonclinical safety testing at different stages of development. The challenge will be to determine whether two species toxicology adds significant value or whether in some instances data from a single species are sufficient (across a broader range of molecules than is currently the case) without compromising human safety.

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Section: Why Do We Use Two Species In Regulatory Toxicology Studies?mentioning

confidence: 99%

Reviewing the Utility of Two Species in General Toxicology Related to Drug Development

et al. 2018

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“…Surveys have also been cited suggesting that pharmaceutical companies only do animal research to satisfy regulators [ 72 ]. On the other hand, industry studies suggest that results from animals are imprecise, but still useful predictors of the likelihood of adverse outcomes in clinical trials [ 73 , 74 ]. Since the reliability and usefulness of animal results differs based on circumstances (e.g., species and organ) [ 73 ], the pharmaceutical company that developed the drug is best-placed to summarise the role of animal research for an individual drug.…”

Section: Ethical Health Consumerismmentioning

confidence: 99%

“…On the other hand, industry studies suggest that results from animals are imprecise, but still useful predictors of the likelihood of adverse outcomes in clinical trials [ 73 , 74 ]. Since the reliability and usefulness of animal results differs based on circumstances (e.g., species and organ) [ 73 ], the pharmaceutical company that developed the drug is best-placed to summarise the role of animal research for an individual drug. However, care must be taken by regulators when reviewing these statements because there have been cases of researchers selectively reporting data from animal research that results in ineffective or unsafe compounds proceeding to clinical trials [ 75 , 76 ] just as regulators must take care to ensure clinical trials are well designed [ 77 ].…”

Section: Ethical Health Consumerismmentioning

confidence: 99%

Justifiability and Animal Research in Health: Can Democratisation Help Resolve Difficulties?

Khoo

2018

Animals

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Simple SummaryScientists justify animal use in medical research because the benefits to human health outweigh the costs or harms to animals. However, whether it is justifiable is controversial for many people. Even public interests are divided because an increasing proportion of people do not support animal research, while demand for healthcare that is based on animal research is also rising. The wider public should be given more influence in these difficult decisions. This could be through requiring explicit disclosure about the role of animals in drug labelling to inform the public out of respect for people with strong objections. It could also be done through periodic public consultations that use public opinion and expert advice to decide which diseases justify the use of animals in medical research. More public input will help ensure that animal research projects meet public expectations and may help to promote changes to facilitate medical advances that need fewer animals.AbstractCurrent animal research ethics frameworks emphasise consequentialist ethics through cost-benefit or harm-benefit analysis. However, these ethical frameworks along with institutional animal ethics approval processes cannot satisfactorily decide when a given potential benefit is outweighed by costs to animals. The consequentialist calculus should, theoretically, provide for situations where research into a disease or disorder is no longer ethical, but this is difficult to determine objectively. Public support for animal research is also falling as demand for healthcare is rising. Democratisation of animal research could help resolve these tensions through facilitating ethical health consumerism or giving the public greater input into deciding the diseases and disorders where animal research is justified. Labelling drugs to disclose animal use and providing a plain-language summary of the role of animals may help promote public understanding and would respect the ethical beliefs of objectors to animal research. National animal ethics committees could weigh the competing ethical, scientific, and public interests to provide a transparent mandate for animal research to occur when it is justifiable and acceptable. Democratic processes can impose ethical limits and provide mandates for acceptable research while facilitating a regulatory and scientific transition towards medical advances that require fewer animals.

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“…Prior to drug trials in humans, extensive preclinical studies are conducted to examine efficacy and toxicity [3]. In addition to animal models, alternative translational approaches, especially in silico computational models, are widely used to refine drug development design, and reduce the size and duration of clinical series [4].…”

Section: Introductionmentioning

confidence: 99%

A compound attributes-based predictive model for drug induced liver injury in humans

Liu

Gao

2020

PLoS ONE

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Drug induced liver injury (DILI) is one of the key safety concerns in drug development. To assess the likelihood of drug candidates with potential adverse reactions of liver, we propose a compound attributes-based approach to predicting hepatobiliary disorders that are routinely reported to US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). Specifically, we developed a support vector machine (SVM) model with recursive feature extraction, based on physicochemical and structural properties of compounds as model input. Cross validation demonstrates that the predictive model has a robust performance with averaged 70% of both sensitivity and specificity over 500 trials. An independent validation was performed on public benchmark drugs and the results suggest potential utility of our model for identifying safety alerts. This in silico approach, upon further validation, would ultimately be implemented, together with other in vitro safety assays, for screening compounds early in drug development. OPEN ACCESSCitation: Liu Y, Gao H, He YD (2020) A compound attributes-based predictive model for drug induced liver injury in humans. PLoS ONE 15(4): e0231252.

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Current nonclinical testing paradigm enables safe entry to First-In-Human clinical trials: The IQ consortium nonclinical to clinical translational database

Cited by 115 publications

References 16 publications

Reviewing the Utility of Two Species in General Toxicology Related to Drug Development

Reviewing the Utility of Two Species in General Toxicology Related to Drug Development

Justifiability and Animal Research in Health: Can Democratisation Help Resolve Difficulties?

A compound attributes-based predictive model for drug induced liver injury in humans

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