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

Abstract

The contribution of animal testing in drug development has been widely debated and challenged. An industry-wide nonclinical to clinical translational database was created to determine how safety assessments in animal models translate to First-In-Human clinical risk. The blinded database was composed of 182 molecules and contained animal toxicology data coupled with clinical observations from phase I human studies. Animal and clinical data were categorized by organ system and correlations determined. The 2 × 2 contingency table (true positive, false positive, true negative, false negative) was used for statistical analysis. Sensitivity was 48% with a 43% positive predictive value (PPV). The nonhuman primate had the strongest performance in predicting adverse effects, especially for gastrointestinal and nervous system categories. When the same target organ was identified in both the rodent and nonrodent, the PPV increased. Specificity was 84% with an 86% negative predictive value (NPV). The beagle dog had the strongest performance in predicting an absence of clinical adverse effects. If no target organ toxicity was observed in either test species, the NPV increased. While nonclinical studies can demonstrate great value in the PPV for certain species and organ categories, the NPV was the stronger predictive performance measure across test species andmore » target organs indicating that an absence of toxicity in animal studies strongly predicts a similar outcome in the clinic. These results support the current regulatory paradigm of animal testing in supporting safe entry to clinical trials and provide context for emerging alternate models. - Highlights: • Translational database created to determine animal to human safety concordance. • 182 molecules with animal and clinical data; concordance parameters determined • Positive predictive value of 43%; Negative predictive value of 86% • Absence of toxicity in animal study strongly predicts similar outcome in the clinic. • Database supports animal testing to ensure human safety in the clinic.« less

Authors:
 [1];  [2];  [3];  [4];  [5];  [6];  [7];  [8];  [9]
  1. Comparative Biology and Safety Sciences, Amgen, Thousand Oaks, CA 91320 (United States)
  2. Eli Lilly and Company, Indianapolis, IN 46285 (United States)
  3. Safety Assessment, Genentech, South San Francisco, CA 92056 (United States)
  4. Drug Safety Research and Development, Pfizer, Groton, CT 06340 (United States)
  5. Drug Safety Research and Development, Pfizer, Cambridge, MA 02139 (United States)
  6. IQ Consortium, Washington, DC 20005 (United States)
  7. Preclinical Safety, Sanofi, Bridgewater, NJ 08807 (United States)
  8. GlaxoSmithKline, King of Prussia, PA 19406 (United States)
  9. Nonclinical Development Sciences, Blueprint Medicines, Cambridge, MA 02139 (United States)
Publication Date:
OSTI Identifier:
22722947
Resource Type:
Journal Article
Journal Name:
Toxicology and Applied Pharmacology
Additional Journal Information:
Journal Volume: 334; Other Information: Copyright (c) 2017 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0041-008X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; CLINICAL TRIALS; NERVOUS SYSTEM; PERFORMANCE; RISK ASSESSMENT; SAFETY; SOCIO-ECONOMIC FACTORS; TESTES; TOXICITY

Citation Formats

Monticello, Thomas M., E-mail: tmontice@amgen.com, Jones, Thomas W., Dambach, Donna M., Potter, David M., Bolt, Michael W., Liu, Maggie, Keller, Douglas A., Hart, Timothy K., and Kadambi, Vivek J. Current nonclinical testing paradigm enables safe entry to First-In-Human clinical trials: The IQ consortium nonclinical to clinical translational database. United States: N. p., 2017. Web. doi:10.1016/J.TAAP.2017.09.006.
Monticello, Thomas M., E-mail: tmontice@amgen.com, Jones, Thomas W., Dambach, Donna M., Potter, David M., Bolt, Michael W., Liu, Maggie, Keller, Douglas A., Hart, Timothy K., & Kadambi, Vivek J. Current nonclinical testing paradigm enables safe entry to First-In-Human clinical trials: The IQ consortium nonclinical to clinical translational database. United States. doi:10.1016/J.TAAP.2017.09.006.
Monticello, Thomas M., E-mail: tmontice@amgen.com, Jones, Thomas W., Dambach, Donna M., Potter, David M., Bolt, Michael W., Liu, Maggie, Keller, Douglas A., Hart, Timothy K., and Kadambi, Vivek J. Wed . "Current nonclinical testing paradigm enables safe entry to First-In-Human clinical trials: The IQ consortium nonclinical to clinical translational database". United States. doi:10.1016/J.TAAP.2017.09.006.
@article{osti_22722947,
title = {Current nonclinical testing paradigm enables safe entry to First-In-Human clinical trials: The IQ consortium nonclinical to clinical translational database},
author = {Monticello, Thomas M., E-mail: tmontice@amgen.com and Jones, Thomas W. and Dambach, Donna M. and Potter, David M. and Bolt, Michael W. and Liu, Maggie and Keller, Douglas A. and Hart, Timothy K. and Kadambi, Vivek J.},
abstractNote = {The contribution of animal testing in drug development has been widely debated and challenged. An industry-wide nonclinical to clinical translational database was created to determine how safety assessments in animal models translate to First-In-Human clinical risk. The blinded database was composed of 182 molecules and contained animal toxicology data coupled with clinical observations from phase I human studies. Animal and clinical data were categorized by organ system and correlations determined. The 2 × 2 contingency table (true positive, false positive, true negative, false negative) was used for statistical analysis. Sensitivity was 48% with a 43% positive predictive value (PPV). The nonhuman primate had the strongest performance in predicting adverse effects, especially for gastrointestinal and nervous system categories. When the same target organ was identified in both the rodent and nonrodent, the PPV increased. Specificity was 84% with an 86% negative predictive value (NPV). The beagle dog had the strongest performance in predicting an absence of clinical adverse effects. If no target organ toxicity was observed in either test species, the NPV increased. While nonclinical studies can demonstrate great value in the PPV for certain species and organ categories, the NPV was the stronger predictive performance measure across test species and target organs indicating that an absence of toxicity in animal studies strongly predicts a similar outcome in the clinic. These results support the current regulatory paradigm of animal testing in supporting safe entry to clinical trials and provide context for emerging alternate models. - Highlights: • Translational database created to determine animal to human safety concordance. • 182 molecules with animal and clinical data; concordance parameters determined • Positive predictive value of 43%; Negative predictive value of 86% • Absence of toxicity in animal study strongly predicts similar outcome in the clinic. • Database supports animal testing to ensure human safety in the clinic.},
doi = {10.1016/J.TAAP.2017.09.006},
journal = {Toxicology and Applied Pharmacology},
issn = {0041-008X},
number = ,
volume = 334,
place = {United States},
year = {2017},
month = {11}
}