CoChat
Sign Up
Cited by 709Animal testing and alternativesImmunotoxicology and immune responsesVeterinary Pharmacology and Anesthesia

Limitations of Animal Studies for Predicting Toxicity in Clinical Trials

Open access
Van Norman, Gail A.·2019·JACC: Basic to Translational Science
DOI 10.1016/j.jacbts.2019.10.008PMC PMC6978558
Open this paper in CoChat — free accountOpen PDF

Abstract

Animal testing is used in pharmaceutical and industrial research to predict human toxicity, and yet analysis suggests that animal models are poor predictors of drug safety in humans. The cost of animal research is high-in dollars, delays in drug approval, and in the loss of potentially beneficial drugs for human use. Human subjects have been harmed in the clinical testing of drugs that were deemed safe by animal studies. Increasingly, investigators are questioning the scientific merit of animal research. This review discusses issues in using animals to predict human toxicity in pharmaceutical development. Part 1 focuses on scientific concerns over the validity of animal research. Part 2 will discuss alternatives to animal research and their validation and use in production of human pharmaceuticals.

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that animal toxicity testing is a poor predictor of human drug safety, citing low animal-human concordance, high clinical trial failure rates, and cases of severe human harm after animal tests deemed drugs safe. It concludes that animal testing should be abandoned or significantly curtailed in favor of more reliable alternatives, with alternatives to be discussed in Part 2.

Key findings

  • Concordance between animal and human results is low: a 2006 review of 76 animal studies found ~20% were contradicted in humans and only 37% were ever replicated in humans; a review of 221 animal experiments found agreement with human studies just 50% of the time. In 37 chemicals from the U.S. National Toxicology Program, average positive predictive value from mouse to rat was 55.3% for long-term and 44.8% for short-term studies, hovering around 50%—no greater than random chance.
  • Drug development failure rates raise doubts about animal predictivity: about 12% of pharmaceuticals pass preclinical testing to enter clinical trials, only 60% of those complete phase I, and approximately 89% of novel drugs fail human clinical trials, with about one-half of those failures due to unanticipated human toxicity. An analysis of 2,366 drugs concluded animal tests are highly inconsistent predictors of human toxic responses and “little better than what would result merely by chance—or tossing a coin.”
  • Post-approval toxicity is common: of 578 discontinued and withdrawn drugs in Europe and the United States, almost one-half were withdrawn or discontinued in post-approval actions due to toxicity; of 93 post-marketing serious adverse outcomes, only 19% were identified in preclinical animal studies. The most common toxicity types associated with U.S. and European drug withdrawals are hepatic (21%), cardiovascular (16%), hematological (11%), neurological (9%), and carcinogenicity (8%).
  • Costs and delays are substantial: rodent testing in cancer therapeutics adds an estimated 4 to 5 years and $2 to $4 million; registering a single pesticide takes about 10 years and $3 million in required animal studies; animal tests range from 1.5× to >30× as expensive as in vitro testing. A single 2-generation reproductive animal toxicity study averages €318,295 worldwide and €285,842 in Europe (roughly $349,890 and $314,215).

Methods

  • Design: narrative review focused on scientific concerns over the validity of animal research for predicting human toxicity in pharmaceutical development; Part 2 is stated to discuss alternatives.
  • Data: published analyses and reviews of animal-to-human toxicity concordance, drug failure and withdrawal statistics, regulatory and historical examples, and cost estimates; no new primary data are collected.
  • Analysis: narrative synthesis, including use of positive predictive value, negative predictive value, and likelihood ratios to assess the evidentiary value of animal toxicity tests for human outcomes.

Limitations

  • Stated in the paper: no comprehensive reviews of the total overall cost of animal testing in pharmaceutical development appear to exist; even the total number of animals or studies is unknown. The paper also states that a comprehensive study of the accuracy, likelihood ratios, and costs of alternative testing methods compared with animal toxicity testing has not been published, and that the prevalence of human toxicity is unknown once a drug tests positive in animals.
  • Stated in the paper: in some analyses, likelihood ratios could not be determined due to a lack of specificity reporting on the tests.
  • Evident from the text: this is a narrative review rather than a systematic review, it presents no new primary data, and it includes selected historical and contemporary examples; the second part on alternatives is not included in this paper.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.jacbts.2019.10.008

Cites

110 of 110 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

23 of 67 cited sources checked · 3 supported · 1 flagged · accuracy not yet measured

  • Premisecitation

    The most common toxicity types associated with drug withdrawals in the United States and Europe are hepatic (21%), cardiovascular (16%), hematological (11%), neurological (9%), and carcinogenicity (8%).

    “The most common toxicity types associated with drug withdrawals in the United States and Europe are hepatic (21%), cardiovascular (16%), hematological (11%), neurological (9%), and carcinogenicity (8%) (Figure 2) (20).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [20] Siramshetty B.V. Nickel J. Omieczynski C. WITHDRAWN—a resource for withdrawn and discontinued drugs Nucl Acids Res 44 2016 D1080 D1086 26553801 PMC4702851 source

      The Materials and Methods section (‘Toxicity types’; page unavailable) classifies withdrawn drugs using all five named toxicity types. The Introduction says most drugs were reported withdrawn in the United States and European countries. Our copy does not give the claimed percentages or establish that these are the five most common types in those regions. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
  • Premisecitation

    Of those, only 60% successfully complete phase I trials.

    “Of those, only 60% successfully complete phase I trials (16).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [16] Van Norman G.A. Drugs, devices and the FDA: part 1: an overview of approval processes for drugs J Am Coll Cardiol Basic Trans Science 1 2016 170 179 PMC6113160 30167510 source

      The ‘Phase I trials’ section describes the purpose and size of these trials but gives no completion rate. I searched the indexed copy for ‘60%’ and Phase I success rates; the Figure 1 caption discusses failure rates generally but does not state that 60% complete Phase I. No page numbers were available for these passages. (LLM, conf=0.73)

      Experimental — accuracy not yet measured
  • Premisecitation

    In the first decade of the 21st century, approximately one-third of FDA-approved drugs were subsequently cited for safety or toxicity issues after remaining on the market for a median of 4.2 years.

    “In the first decade of the 21st century, approximately one-third of FDA-approved drugs were subsequently cited for safety or toxicity issues. or a combination of both, including human cardiovascular toxicity and brain damage, after remaining on the market for a median of 4.2 years (22,23).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [22] Lupkin S. One-Third of New Drugs Had Safety Problems After FDA Approval. NPR: Shots: Health News From NPR Available at: https://www.npr.org/sections/health-shots/2017/05/09/527575055/one-third-of-new-drugs-had-safety-problems-after-fda-approval May 9, 2017
    • cites [23] Downing N.S. Shah N.D. Aminawung J.A. Postmarket safety events among novel therapeutics approved by the US Food and Drug Administration between 2001 and 2010 JAMA 317 2017 1854 1863 28492899 PMC5815036 source

      The Results report that 71 of 222 novel therapeutics approved from 2001 through 2010 (32.0%) had a postmarket safety event. The 4.2-year median is the time from approval to the first event among affected therapeutics, not the median time that all approved drugs remained on the market; the paper reports 11.7 years of median market availability overall. Its Results describe cardiovascular safety concerns, but do not identify the cited events as “brain damage.” (LLM, conf=0.88)

      Experimental — accuracy not yet measured
  • Premisecitation

    Review of 37 chemicals in the U.S. National Toxicology Program concluded that toxicities other than carcinogenesis were not reproducible between rats and mice, between sexes, or compared with historic control animals.

    “Review of 37 chemicals studied in the U.S. National Toxicology Program concluded that toxicities other than carcinogenesis were not reproducible between rats and mice, between sexes, or compared with historic control animals.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [12] Wang B. Gray G. Concordance of noncarcinogenic endpoints in rodent chemical bioassays Risk Anal 35 2015 1154 1166 25545328 source

      The clinical-trials section discusses animal safety studies and single-dose toxicity trials, but not a review of 37 National Toxicology Program chemicals. Searches for that review and for reproducibility across rats, mice, sexes, and historic controls found no passage addressing the claim. (LLM, conf=0.75)

      Experimental — accuracy not yet measured
  • Premisecitation

    Isuprel for treatment of asthma caused over 3,500 deaths in Great Britain alone, despite safety in rats, guinea pigs, dog, and monkeys at doses far exceeding those administered in humans.

    “Isuprel for treatment of asthma caused over 3,500 deaths in Great Britain alone, despite safety in rats, guinea pigs, dog, and monkeys, all of which had received doses far exceeding those administered in humans (2,28).”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [2] Greek R. Pippus A. Hansen L.A. The Nuremberg Code subverts human health and safety by requiring animal modeling BMC Med Ethics 13 2012 16 22769234 PMC3532312 source

      The Discussion (Science – empirical evidence) says 3,500 asthmatics died in Great Britain and reports that high-dose studies in rats, guinea pigs, dogs, and monkeys did not elicit similar results. It does not say *over* 3,500 died or establish that the drug was generally safe in those animals; it compares their doses with commercial metered-dose vials, rather than doses administered to humans. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [28] Stolley P.D. Asthma mortality: why the United States was spared an epidemic of deaths due to asthma Am Rev Respir Dis 105 1972 883 890 5032708 source

      The IN VIVO STUDIES and THE FIRST DOSE DISASTER sections describe animal testing and severe reactions to TGN1412, not Isuprel. Searches for Isuprel, the claimed 3,500 deaths in Great Britain, and the listed test animals found no passage addressing the claim; page numbers were unavailable in our copy. (LLM, conf=0.75)

      Experimental — accuracy not yet measured
  • May combine two claims. 25
  • Classified as probably not a substantial claim. 13

  • May combine two claims.

    Premisecitation

    The average cost of a single, 2-generation reproductive animal toxicity study worldwide is €318,295 and for Europe alone is €285,842, or roughly $349,890 and $314,215, respectively.

    “the average cost of a single, 2-generation reproductive animal toxicity study worldwide is €318,295 and for Europe alone is €285,842 (45), or roughly $349,890 and $314,215, respectively.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [45] Meigs L. Smirova L. Rovida C. Leist M. Hartung T. Animal testing and its alternatives—the most important omics is economics ALTEX 35 2018 275 305 30008008 source

      Section 4 gives the same two euro figures for a two-generation OECD TG 416 study, but assigns them to the opposite regions: €285,842 worldwide and €318,295 in Europe. The citing sentence reverses those assignments. (LLM, conf=0.95)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    TGN1412 was given at 1/500th the dose found safe in animal testing to 6 human volunteers in a phase I trial, rendering them all critically ill within minutes and leaving them all with long-term complications.

    “An antibody to treat human autoimmune disease, TGN1412, was given at 1/500th the dose found safe in animal testing to 6 human volunteers in a phase I trial (30,31), rendering them all critically ill within minutes and leaving them all with long-term complications (32, 33, 34).”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [30] Suntharalingam G. Perry M.R. Ward S. Cytokine storm in phase 1 trial of the anti-CD28 monoclonal antibody TGN1312 N Engl J Med 355 2006 1018 1028 16908486 source
    • cites [31] Dayan C.M. Wraith D.C. Preparing for first-in-man studies: the challenges for translational immunology post TGN1412 Clin Exp Immunol 151 2008 231 234 18190459 PMC2276942 source

      The paper’s Abstract and Table 1 describe TGN1412 as an anti-CD28 antibody tested in a Phase 1 study of healthy volunteers, with a starting dose calculated as a fraction of an animal-derived no-adverse-effect level. They do not give the claimed 1/500th fraction or specify six recipients. The subsequent claims about illness and long-term complications are attached to different citations in the citing sentence, so they are not assessed here. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [32] Attarwala H. TGN1412: from discovery to disaster J Young Pharm 2 2010 332 336 21042496 PMC2964774 source

  • May combine two claims.

    Premisecitation

    Approximately 89% of novel drugs fail human clinical trials, with approximately one-half of those failures due to unanticipated human toxicity.

    “Overall, approximately 89% of novel drugs fail human clinical trials, with approximately one-half of those failures due to unanticipated human toxicity (Figure 1) (17).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [17] Van Norman G.A. Phase II trials in drug development and adaptive trial design J Am Coll Cardiol Basic Trans Science 4 2019 428 437 PMC6609997 31312766 source

      The Abstract (page unavailable) says only 9.6% of drugs entering phase I reach the market, broadly supporting the claim that roughly nine in ten fail. But “Why Drugs Fail in Clinical Trials” (page unavailable) attributes previously unknown toxic side effects to 50% of phase II failures, not to half of failures across all human clinical trials. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Combining organ, length of exposure, and sex, PPV between mice and rats hovered around 50%, which is no greater than random chance.

    “Combining organ, length of exposure, and sex, PPV between mice and rats hovered around 50%, which is no greater than random chance (12).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [12] Wang B. Gray G. Concordance of noncarcinogenic endpoints in rodent chemical bioassays Risk Anal 35 2015 1154 1166 25545328 source

      The clinical-trials section discusses animal safety studies as a basis for initial human doses, but does not report predictive values between mice and rats. Searches for PPV, organ, exposure duration, sex, and interspecies toxicity found no passage addressing the claimed approximately 50% result or its comparison with chance. Page numbers were not available in our copy. (LLM, conf=0.76)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    BIA-102474-101 caused deep brain hemorrhage and necrosis in all 5 human volunteers during a phase I clinical trial after it was administered in doses that were 1/500th of the safe dose for dogs; one volunteer died.

    “BIA-102474-101, a drug developed for a range of disorders from anxiety to Parkinsonism, caused deep brain hemorrhage and necrosis in all 5 human volunteers during a phase I clinical trial after it was administered in doses that were 1/500th of the safe dose for dogs. One volunteer died (35).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [35] Eddleston M. Cohen A.F. Webb D.J. Implications of the BIA-102474-101 study for review of first-into-human clinical trials Brit J Clin Pharm 81 2016 582 586 PMC4799914 26996741 source

      The clinical-trial section reports deep-brain haemorrhage and necrosis on MRI in five symptomatic participants, one of whom died. The risk-assessment section reports a human dose of 0.67 mg/kg and dog no-observed-adverse-effect levels of 20 and 50 mg/kg/day—not a human dose 1/500th of the dog dose. The paper also describes eight participants in the affected cohort, rather than five volunteers in the trial. (LLM, conf=0.90)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Average positive predictive value from mouse to rat was 55.3% for long-term studies and 44.8% for short-term studies.

    “Average positive predictive value (PPV) from mouse to rat was 55.3% and 44.8% for long-term and short-term studies, respectively.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [12] Wang B. Gray G. Concordance of noncarcinogenic endpoints in rodent chemical bioassays Risk Anal 35 2015 1154 1166 25545328 source

      The Clinical Trials section discusses animal safety studies and human trial phases, but does not report mouse-to-rat positive predictive values. Searches for both percentages and for mouse-to-rat predictive value in long- and short-term studies found no matching passage in our copy. (LLM, conf=0.75)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    An analysis of 2,366 drugs concluded that results from tests on animals (rat, mouse, rabbit) are highly inconsistent predictors of toxic responses in humans and little better than chance.

    “An analysis of 2,366 drugs concluded that “results from tests on animals (specifically rat, mouse and rabbit models) are highly inconsistent predictors of toxic responses in humans, and are little better than what would result merely by chance—or tossing a coin—in providing a basis to decide whether a compound should proceed to testing in humans” (13).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [13] Bailey J. Thew M. Balls M. An analysis of the use of animal models in predicting human toxicology and drug safety Altern Lab Anim 42 2014 189 199 25068930 source

      The supplied passages on phase II and III attrition and false positives discuss clinical-trial results, not animal tests. Searches for 2,366 drugs, rat/mouse/rabbit models, and whether animal tests predict human toxicity found no passage addressing the claim in our copy. (LLM, conf=0.76)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    In a review of 2,366 drugs, including data from rat, mouse, and rabbit, positive likelihood ratios were generally high, but median negative likelihood ratios were very low-1.12 (rabbit), 1.39 (mouse), and 1.82 (rat)-and were of little or no value in excluding human toxicity.

    “In a review of 2,366 drugs, including data from 3 of the most common animal research species—rat, mouse, and rabbit—PLRs were generally high (i.e., there is a likelihood that positive toxicity tests in animals would show toxicity in humans). But median NLRs were very low—1.12 (rabbit), 1.39 (mouse), and 1.82 (rat); in other words, they were of little or no value in excluding human toxicity (13).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [13] Bailey J. Thew M. Balls M. An analysis of the use of animal models in predicting human toxicology and drug safety Altern Lab Anim 42 2014 189 199 25068930 source

      Split into 2 atoms — 0 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 2 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Premisecitation

    The biological sciences have increasingly embraced theories regarding complex systems (e.g., chaos theory and complexity theory) to explain mechanisms in evolution, the biology of cancer, the divergent properties of animal species, as well as the failures of translation of drug therapeutics from animal species to humans.

    “The biological sciences have increasingly embraced theories regarding complex systems (e.g., chaos theory and complexity theory) to explain mechanisms in evolution, the biology of cancer, the divergent properties of animal species, as well as the failures of translation of drug therapeutics from animal species to humans (75,76).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [75] Miquel P.A. Extended physics as a theoretical framework for systems biology? Prog Biophys Mol Biol 106 2011 348 352 21463648 source
    • cites [76] Soto A.M. Sonnenschein C. Maini P.K. Novle D. Systems biology and cancer Prog Biophys Mol Biol 106 2011 337 346 21843772 PMC4021577 source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Findingnone given

    A comprehensive study of the accuracy, LR, and costs of alternative testing methods compared with animal toxicity testing has not been published.

    “A comprehensive study of the accuracy, LR, and costs of alternative testing methods compared with animal toxicity testing has not been published”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    A 2006 review of 76 animal studies found approximately 20% were contradicted in humans and only 37% were ever replicated in humans.

    “A 2006 review of 76 animal studies, for example, found that approximately 20% were contradicted in humans and only 37% were ever replicated in humans (10).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [10] Hackam D.G. Redelmeier D.A. Translation of research evidence from animals to humans JAMA 296 2006 1731 1732 17032985 source

  • May combine two claims.

    Interpretationreasoning

    Because a drug that shows toxicity in animal models is unlikely to ever undergo human testing, the magnitude of this type of error is unknown.

    “Because a drug that shows toxicity in animal models is unlikely to ever undergo human testing, the magnitude of this type of “error” is unknown.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    When a human-toxic drug is identified as safe by animal testing, the most likely outcome is that the drug will fail in clinical testing, often due to unacceptable adverse human effects, and sometimes harming volunteer research subjects.

    “When a human-toxic drug is identified as “safe” by animal testing, the most likely outcome by far is that the drug will fail in clinical testing, often due to unacceptable adverse human effects, and sometimes significantly harming volunteer research subjects in the process.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Paracetamol is toxic in dogs and cats.

    “paracetamol (toxic in dogs and cats) (40)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [40] Villar D. Buck W.B. Gonzalez J.M. Ibuprofen, aspirin and acetaminophen toxicosis and treatment in dogs and cats Vet Human Toxicol 40 1998 156 162 9610496

  • May combine two claims.

    Premisecitation

    Paglialunga et al. examined translatability of respiratory safety pharmacology studies from animal models to humans and found that PPV and PLR were so low that animal tests provided little value in predicting human toxicity.

    “Paglialunga et al. (56) examined translatability of respiratory safety pharmacology studies from animal models to humans and found that PPV and PLR were so low that animal tests provided little value in predicting human toxicity.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [56] Paglialunga S. Morimoto B.H. Clark M. Friedrichs G.S. Translatability of the S7A core battery respiratory safety pharmacology studies: preclinical respiratory and related clinical adverse events J Pharmacol Toxicol Methods 2019 Jun 5 [E-pub ahead of print] 31173885 source

  • May combine two claims.

    Premisecitation

    Rodent testing in cancer therapeutics adds an estimated 4 to 5 years to drug development and costs $2 to $4 million.

    “Rodent testing in cancer therapeutics adds an estimated 4 to 5 years to drug development and costs $2 to $4 million.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [43] Humane Society International Limitations of Animal Tests. Humane Society International Available at: https://www.hsi.org/news-media/limitations-of-animal-tests/ February 24, 2019

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The 2019 West Coast Regional Safety Pharmacology Society Meeting discussed concerns about the lack of concordance between animal and human safety studies, including lack of canine and human concordance for proarrhythmia risks of new cardiovascular drugs and the failure of animal research to predict drug-related risks in the human central nervous and respiratory systems.

    “The 2019 West Coast Regional Safety Pharmacology Society Meeting discussed concerns about the lack of concordance between animal and human safety studies, including lack of canine and human concordance for proarrhythmia risks of new cardiovascular drugs and the failure of animal research to predict drug-related risks in the human central nervous and respiratory systems (60,61).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [60] Abi-Gerges N. McMahon C. Vargas H. The west coast regional safety pharmacology society meeting update: filling in the translational gaps in safety assessment J Pharmacol Toxicol Methods 98 2019 106582 31077805 source
    • cites [61] Ewert L. Aylott M. Deurinck M. The concordance between nonclinical and phase I clinical cardiovascular assessment from a cross-company data sharing initiative Toxicol Sci 142 2014 427 435 25246669 source

  • May combine two claims.

    Premisecitation

    Lichtfield examined 6 drugs studied in animal models and found that rats and dogs demonstrated PPVs for human response of 0.49 and 0.55, respectively, essentially random chance.

    “Lichtfield (57) examined 6 drugs studied in animal models and found that rats and dogs demonstrated PPVs (for human response) of 0.49 and 0.55, respectively, essentially random chance.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [57] Lichtfield J.T. Jr. Symposium on clinical drug evaluation and human pharmacology. XVI. Evaluation of the safety of new drugs by means of tests in animals Clin Pharmacol Ther 3 1962 665 672 14465857 source

  • May combine two claims.

    Premisecitation

    Bailey et al. found that the presence of toxicity in a species sometimes added evidentiary weight to the risk of toxicity in another, but the reverse was not true: negative toxicity tests in animals did not significantly increase the probability that a toxic test would also be negative in humans, and a lack of toxicity in any species would not reliably indicate a probable lack of toxicity in any其他

    “Bailey et al. (14) found that the presence of toxicity in a species sometimes added evidentiary weight to the risk of toxicity in another, but the reverse was not true: negative toxicity tests in animals did not significantly increase the probability that a toxic test would also be negative in humans, and a lack of toxicity in any species would not reliably indicate a probable lack of toxicity in”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [14] Bailey J. Thew M. Balls M. Predicting human drug toxicity and safety via animal tests: can any one species predict drug toxicity in any other, and do monkeys help? Altern Lab Anim 43 2015 393 403 26753942 source

  • May combine two claims.

    Premisecitation

    Ganciclovir was delayed for more than a year due to lack of animal studies and finally approved after a 4-year delay.

    “but the FDA delayed clinical trials for more than a year due to lack of animal studies. The drug was finally approved after a 4-year delay (42).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [42] Buhles W.C. Compassionate use: a story of ethics and science in the development of a new drug Monticello M. Perspectives and Biology in Medicine Vol. 54 2011 Johns Hopkins University Press Baltimore, MD 304 315 21857123 source

  • May combine two claims.

    Premisecitation

    In canine models, PPV and PLR for human toxicity were not correlated with one another; NLR were low, indicating that the dog provided little evidentiary weight to ruling out toxicity in humans.

    “The investigators also examined canine models and found that PPV and PLR for human toxicity were not correlated with 1 another: NLR were low, indicating that the dog provided little evidentiary weight to ruling out toxicity in humans (52).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [52] Bailey J. Thew M. Balls M. An analysis of the use of dogs in predicting human toxicology and drug safety Altern Lab Anim 2013 335 350 24329742 source

  • May combine two claims.

    Interpretationreasoning

    Once a drug tests positive for toxicity in animals, it is rarely tested against humans, and the prevalence of human toxicity remains unknown.

    “Once a drug tests positive for toxicity in animals, it is rarely tested against humans, and the prevalence of the real condition the test is being used to “detect”—human toxicity—remains unknown.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationreasoning

    Increasingly, scientific organizations and government regulatory agencies are recognizing that alternative methods may replace animal testing and improve the flow and safety of new therapeutics to human use.

    “Increasingly, scientific organizations and government regulatory agencies are recognizing that alternative methods may replace animal testing and improve the flow and safety of new therapeutics to human use.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Interpretationnone given

    The quality of methodology in an individual experiment cannot be extrapolated to the question of whether animal experimentation as a whole is invalid, merely to whether the individual experiment is yielding true results.

    “The quality of methodology in an individual experiment cannot be extrapolated to the question of whether animal experimentation as a whole is invalid, merely to whether the individual experiment is yielding true results.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

    Interpretationreasoning

    To determine whether animal modeling is reliable in current science, one needs to use modern scientific knowledge and examine modern methodology to determine whether animal modeling is predictive of human outcomes today.

    “To determine whether animal modeling is reliable in current science, we need to use modern scientific knowledge and examine modern methodology to determine whether animal modeling is predictive of human outcomes today.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationnone given

    The invalidity of using certain specific animals does not necessarily rule out animal models as a whole.

    “The invalidity of using certain specific animals does not necessarily rule out animal models as a whole.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable). May combine two claims.

    Interpretationreasoning

    Examination of the published data raises significant questions about whether animal toxicity testing is reliable and should be abandoned or at least significantly curtailed in favor of other potentially more reliable methods.

    “Although animal toxicity testing has been the stalwart basis of “ensuring” safety of in-human clinical testing and use, examination of the published data raises significant questions about whether it is reliable and should be abandoned or at least significantly curtailed in favor of other potentially more reliable methods.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Animal toxicity testing has been the stalwart basis of “ensuring” safety of in-human clinical testing and use.
    • Rests on an assumption: The published data on animal toxicity testing are sufficient to assess its reliability.
    • Rests on an assumption: Animal models are used to predict human toxicity.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The Interagency Coordinating Committee on Validation of Alternative Methods and the National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods were established in 1997 to coordinate the development, validation, acceptance, and harmonization of alternative toxicological test methods throughout the U.S. government and have as a part of their mission theex-

    “The Interagency Coordinating Committee on Validation of Alternative Methods and the National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods were established in 1997 to coordinate the development, validation, acceptance, and harmonization of alternative toxicological test methods throughout the U.S. government (85) and have as a part of their mission”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [85] U.S. ICCVAM Interagency Coordinating Committee on Validation of Alternative Methods. Research Triangle Park, NC: U.S. ICCVAM, 2019 Available at: https://www.niehs.nih.gov/health/materials/interagency_coordinating_committee_on_the_validation_of_alternative_methods_508.pdf

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Interpretationreasoning

    Historical use of animal modeling is a poor measure of the validity of current experimentation and methods.

    “Historical use of animal modeling is a poor measure of the validity of current experimentation and methods.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    There is data suggesting that in vitro testing and other methods are significantly faster and less expensive than animal models.

    “however, there is data suggesting that in vitro testing and other methods are significantly faster and less expensive than animal models (42,44).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [42] Buhles W.C. Compassionate use: a story of ethics and science in the development of a new drug Monticello M. Perspectives and Biology in Medicine Vol. 54 2011 Johns Hopkins University Press Baltimore, MD 304 315 21857123 source
    • cites [44] Humane Society International Costs of Animal and Non-animal Testing. Humane Society International Available at: https://www.hsi.org/news-media/time_and_cost/ October 23, 2012

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A 2019 spending bill passed by the U.S. House of Representatives includes a directive to the National Institutes of Health to accelerate the replacement of nonhuman primates in research with alternative research models.

    “A 2019 spending bill passed by the U.S. House of Representatives includes a directive to the National Institutes of Health to accelerate the replacement of nonhuman primates in research with alternative research models (83).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [83] Reardon S. U.S. Lawmakers Propose Plan to Reduce Primate Research at the National Institutes of Health. Nature Available at: https://www.nature.com/articles/d41586-019-01511-0?utm_source=twt_nnc and utm_medium=social and utm_campaign=naturenews and sf212424116=1 May 9, 2019 32382118 source

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    The existence of alternatives to animal research does not address whether continued use of animal models is scientifically valid, regardless of alternative methods.

    “This argument does not address whether continued use of animal models is scientifically valid, regardless of alternative methods”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    Alternatives to animal research exist or are developing in many areas of medical research, but in many instances such alternatives do not exist.

    “Whereas alternatives to animal research exist or are developing in many areas of medical research, in many instances such alternatives do not exist.”
    Quote in the paperNot a substantial claim
33 of 33

  • The paper relies on this without support.

    Animal testing is used in pharmaceutical and industrial research to predict human toxicity.

    “Animal testing is used in pharmaceutical and industrial research to predict human toxicity”

  • The paper relies on this without support.

    Animal toxicity testing has been the stalwart basis of “ensuring” safety of in-human clinical testing and use.

    “Although animal toxicity testing has been the stalwart basis of “ensuring” safety of in-human clinical testing and use”

  • The paper relies on this without support.

    The published data on animal toxicity testing are sufficient to assess its reliability.

    “examination of the published data raises significant questions about whether it is reliable”

  • The paper relies on this without support.

    Animal models are used to predict human toxicity.

    “reliability of animal models in predicting human toxicity”
4 of 4

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • The absence of pharmacokinetic exposure control confounds interpretation of cross-species concordance because toxicities observed in animal models at high doses may not represent risks at clinically relevant efficacious doses.

    “The absence of pharmacokinetic exposure control further confounds interpretation, as toxicities observed in animal models, often at high doses, may not accurately represent risks relevant to clinical settings with relevant efficacious doses (Van Norman, 2019).”

    From A large-scale concordance study of toxicity findings across preclinical species and humans for small molecules and biologics (2026) · cites this paper as Van Norman, 2019

    The Historical Perspective section reports poor concordance between animal and human toxicity findings. But our copy does not identify a lack of pharmacokinetic exposure control as the confounder or say that toxicities seen in animals at high doses may be irrelevant at clinically efficacious doses. The Price of Wrong Decisions instead gives examples of animals appearing safe at doses far above those that harmed humans; no page numbers were provided. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • These events often lack precise analogs in animal models, are subject to broad etiologic variability, or are under-detected due to behavioral and physiological differences across species.

    “These events often lack precise analogs in animal models, are subject to broad etiologic variability, or are under-detected due to behavioral and physiological differences across species (Van Norman, 2019; Lu et al., 2023; Wu et al., 2023).”

    From A large-scale concordance study of toxicity findings across preclinical species and humans for small molecules and biologics (2026) · cites this paper as Van Norman, 2019

    The Historical Perspective and Growing Scientific Criticism sections (page unavailable) report that animal studies often fail to predict human toxicities, supporting the general point that animal models may not capture human events. They do not establish that the events have broadly variable etiologies or are under-detected because of behavioral and physiological differences across species. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • Such limitations align with broader critiques of the challenges in predicting certain human toxicities from animal studies, especially for nuanced functional and neurobehavioral endpoints.

    “Such limitations align with broader critiques of the challenges in predicting certain human toxicities from animal studies, especially for nuanced functional and neurobehavioral endpoints (Van Norman, 2019).”

    From A large-scale concordance study of toxicity findings across preclinical species and humans for small molecules and biologics (2026) · cites this paper as Van Norman, 2019

    The Abstract and Conclusions question whether animal studies reliably predict human toxicity. Growing Scientific Criticism specifically reports failures to predict drug-related risks in the human central nervous system, but the paper does not identify nuanced functional or neurobehavioral endpoints as especially difficult to predict. The copy provides section labels but no page numbers for these passages. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Removing toxicity failures does not produce a 56% clinical-trial success rate

    Major

    The figure says the toxicity-related failures are eliminated before clinical trials, not converted into successful trials. With an 11.7% success rate and roughly half of the 89% failures removed, the success rate among the remaining trials would be about 21%, not 56%.

  • The stated effect of an NLR below one reverses its earlier definition

    Minor

    The paper defines the NLR as indicating a decrease in the probability that a condition exists after a negative result. It later says an NLR below one decreases the probability that the condition is absent-the opposite direction.

  • Likelihood ratios are said to multiply both probabilities and odds

    Minor

    The paper first says to calculate the change by multiplying the pre-test probability by the likelihood ratio, but later says the calculation requires converting probabilities to odds and back. Those are different calculations: likelihood ratios multiply odds, not probabilities.

3 of 3

Cited works that were retracted

Works this paper cites that were later retracted, from the retraction notices publishers deposit. Major when the notice came out before this paper was published.

  • Cites a retracted work: 10.1093/nar/gkv1192

    Info

    The cited work was retracted; the date of the notice is not on record.

    Cited work 10.1093/nar/gkv1192 · retraction date not known · this paper published 2019-11

1 of 1

Cites

1 retracted

Flagged first, then by citations

8 of the 118 references couldn’t be matched to a known paper.

Research works printed but not linked: 2

  1. Schardein, 1976, 5, 49
  2. Sankar, 2005, The delicate toxicity balance in drug discovery, Scientist, 19, 32

Cited by

Sorted by citations

Related

Authors
Van Norman, G. A.
Venue
JACC: Basic to Translational Science
Publisher
Elsevier BV
Published
2019-11
Volume
4
Issue
7
Pages
845-854
ISSN
2452-302X (ISSN-L)
DOI
10.1016/j.jacbts.2019.10.008
PMC
PMC6978558
OpenAlex
W2990376563
Semantic Scholar
a2a9d2d371770e1ed07ef2f37ee2de2649caa0c0
Cited by
709
References
118
Citations by year
2026: 105 · 2025: 143 · 2024: 155 · 2023: 103 · 2022: 104 · 2021: 59 · 2020: 20
FWCI
56.78
Type
journal article
Language
en
Open access
Licence
Locations
  • JACC Basic to Translational Science (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by-nc-nd)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Topics
  • Health Sciences › Veterinary › Small Animals › Animal testing and alternatives
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotoxicology and immune responses
  • Health Sciences › Veterinary › Small Animals › Veterinary Pharmacology and Anesthesia
Keywords
animal experimentation, animal models, drug safety, translational research, alternatives to animal testing, clinical trials, drug development, drug approval delays

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-07.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-07.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review