Limitations of Animal Studies for Predicting Toxicity in Clinical Trials

In the paper

“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).”

What the sources say

• Partly supported

  The Materials and Methods section (‘Toxicity types’; page unavailable) classifies withdrawn drugs using all five named toxicity types. The Introduction says most drugs were reported withdrawn in the United States and European countries.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)

  cites [20] Siramshetty B.V. Nickel J. Omieczynski C. WITHDRAWN—a resource for withdrawn and discontinued drugs Nucl Acids Res 44 2016 D1080 D1086 26553801 PMC4702851 sourceExperimental — accuracy not yet measured

In the paper

“Of those, only 60% successfully complete phase I trials (16).”

What the sources say

• ?Could not verify

  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)

  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 sourceExperimental — accuracy not yet measured

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites [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
• Partly supported

  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)

  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 sourceExperimental — accuracy not yet measured

In the paper

“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.”

What the sources say

• ?Could not verify

  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)

  cites [12] Wang B. Gray G. Concordance of noncarcinogenic endpoints in rodent chemical bioassays Risk Anal 35 2015 1154 1166 25545328 sourceExperimental — accuracy not yet measured

In the paper

“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).”

What the sources say

• Partly supported

  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)

  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 sourceExperimental — accuracy not yet measured
• ?Could not verify

  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)

  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 sourceExperimental — accuracy not yet measured

In the paper

“A review of 221 animal experiments found agreement in human studies just 50% of the time—essentially randomly (11).”

What the sources say

• Partly supported

  The Discussion reports agreement for three of six interventions, which supports the 50% figure at the intervention level—not as a rate across 221 individual experiments. The Methodological strengths and weaknesses section says the authors cannot provide a precise estimate of agreement or generalize from six interventions. Our copy does not substantiate the 221 figure or the conclusion that agreement was essentially random. (LLM, conf=0.88)

  cites [11] Perel P. Roberts I. Sena E. Comparison of treatment effects between animal experiments and clinical trials: systematic review BMJ 334 2007 197 203 17175568 PMC1781970 sourceExperimental — accuracy not yet measured

In the paper

“Many concerns regarding reliability of animal models in predicting human toxicity are not based on the scientific underpinnings of interspecies translation, but rather call out collateral, potentially correctable issues, such as technical competence in executing animal research, the soundness of animal research study design, and publication bias (Table 2) (67, 68, 69, 70, 71).”

What the sources say

• ?Not checked — no full text of the sourcecites [67] Bracken M.B. Why animal studies are often poor predictors of human reactions to exposure J R Soc Med 102 2009 120 122 19297654 PMC2746847 source
• Partly supported

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

  cites [68] van der Worp H.B. Howells D.W. Sena E.S. Can animal models of disease reliably inform human studies? PLoS Med 7 2010 e10000245 PMC2846855 20361020 sourceExperimental — accuracy not yet measured
• ?Not matched

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

  cites [69] Greek R. Kramer L.A. How to evaluate the science of non-human animal use in biomedical research and testing: a proposed format for debate Herrmann K. Jayne K. Animal Experimentation: Working Towards a Paradigm of Change Vol. 22 2019 Brill Open Boston, MA 65 87

In the paper

“Using a database of more than 800,000 animal toxicity studies performed for 350 chemicals under rigorous guidelines, a reviewer found toxicity was repeatable just 70% of the time in the same species (45).”

What the sources say

• Partly supported

  In “Abandoned or withdrawn because of false-positive test results” (page unavailable), the paper reports that a repeat guideline animal test identified a toxic compound in 70% of cases. But it describes 800,000 studies associated with 10,000 chemicals in the full database; the repeatability analysis used 350 to 750 chemicals, not 800,000 studies of 350 chemicals. The 70% figure concerns repeat detection of toxic compounds, not overall repeatability of toxicity results. (LLM, conf=0.90)

  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 sourceExperimental — accuracy not yet measured

In the paper

“aspirin (embryo toxicity in rats and rhesus monkeys) (41)”

What the sources say

• Partly supported

  Section 7, under “False positive drug toxicity,” says aspirin produced birth defects in rats and monkeys. It does not identify the monkeys as rhesus monkeys, so the species-specific part of the claim is unsupported. (LLM, conf=0.88)

  cites [41] Wilson J.G. Ritter E.J. Scott W.J. Fradkin R. Comparative distribution and embryotoxicity of acetylsalicylic acid in pregnant rats and rhesus monkeys Toxicol Appl Pharmacol 41 1977 67 78 408942 sourceExperimental — accuracy not yet measured

In the paper

“Compared with the costs of in vitro testing, animal tests range from 1.5× to >30× as expensive (44,45).”

What the sources say

• ?Not matched

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

  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
• Partly supported

  Table 4 (section 4; page not supplied) lists a $30,000 animal test against a $20,000 in vitro test (1.5×), and a $700,000 animal test against a $22,000 in vitro test (about 32×). But it also lists a $1,800 rabbit eye test against a $1,400 in vitro test (about 1.3×), so 1.5× is not the lower end of the comparisons shown. (LLM, conf=0.86)

  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 sourceExperimental — accuracy not yet measured

In the paper

“Regulatory and research leaders are increasingly taking notice of the issue.”

What the sources say

• Supported

  In “Claims about the predictive nature of animal models” (page unavailable), the paper cites a 2007 statement by the U.S. Secretary of Health and Human Services that laboratory and animal studies cannot accurately predict how many drugs will behave in people. “Other voices” describes concern within the scientific community about animal models’ predictive power. Together, these passages support the broad claim that regulatory and research figures are taking notice of the issue. (LLM, conf=0.85)

  cites [62] Shanks N. Greek R. Greek J. Are animal models predictive for humans? Philos Ethics Humanit Med 4 2009 2 19146696 PMC2642860 source
• ?Not checked — no full text of the sourcecites [63] U.S. Food and Drug Administration Press release: FDA issues advice to make earliest stages of clinical drug development more efficient. January 12 2006 U.S. Food and Drug Administration Washington DC source
• ?Not matched

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

  cites [64] Institute of Medicine Committee on the Use of Chimpanzees in Biomedical and Behavioral Research Chimpanzees in Biomedical and Behavioral Research: Assessing the Necessity 2011 National Academic Press Washington, DC 22514816
• ?Not matched

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

  cites [65] Milman O. National Institutes of Health announces end to chimpanzee research. The Guardian Available at: https://www.theguardian.com/us-news/2015/nov/19/national-institutes-health-end-chimpanzee-research November 19, 2015

In the paper

“although a number of studies do demonstrate continued problems with predicting human efficacy (73).”

What the sources say

• Supported

  The section on discordance between human diseases and animal models reports multiple clinical failures after apparent benefits in animals. It also cites a systematic review in which animal and human results agreed only half the time, directly supporting the claim about continued problems predicting human efficacy. (LLM, conf=0.93)

  cites [73] Akhtar A. The flaws and human harms of animal experimentation Camb Q Healthc Ethics 24 2015 407 419 26364776 PMC4594046 source

In the paper

“Despite widespread efforts to improve the quality of methodology in animal studies, however, studies examining whether such measures consistently improve the reliability of animal models in predicting human toxicity have yet to be published”

In the paper

“analysis suggests that animal models are poor predictors of drug safety in humans”

• Also stated in: § Historical Perspective · hedged

  “we need go no farther than the failure rates in drug development to have serious questions about whether animal testing accurately predicts toxicity in human trials.”

In the paper

“Undoubtedly many potentially beneficial drugs have failed animal testing and been lost to patients, even though they would have been both safe and effective (36,37).”

What the sources say

• ?Not checked — no full text of the sourcecites [36] Sankar U. The delicate toxicity balance in drug discovery Scientist 19 2005 32
• ?Not checked — no full text of the sourcecites [37] Gura T. Systems for identifying new drugs are often faulty Science 273 1997 1041 1042 9381203 source

In the paper

“When animal tests falsely identify a safe chemical as “toxic,” the almost certain outcome is abandonment of further development.”

In the paper

“Thalidomide caused devastating phocomelia in an estimated 20,000 to 30,000 infants before it was withdrawn.”

What the sources say

• ?Not matched

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

  cites [29] Schardein J. Drugs as Teratogens 5 1976 CRC Press Cleveland, OH 49

In the paper

“Van Meer et al. (21) found that of 93 post-marketing serious adverse outcomes, only 19% were identified in preclinical animal studies.”

What the sources say

• ?Not checked — no full text of the sourcecites [21] van Meer P.J. Kooijman M. Gispen-de Wied C.C. Moors E.H. Schellekens H. The ability of animal studies to detect serious post marketing adverse events is limited Reg Tox Pharm 64 2012 345 349 22982732 source

In the paper

“However, animal tests failed to reveal significant teratogenicity in 10 strains of rats; 11 breeds of rabbit; 2 breeds of dog; 3 strains of hamsters; 8 species of primates; and various cats, armadillos, guinea pigs, swine, and ferrets (29).”

What the sources say

• ?Not matched

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

  cites [29] Schardein J. Drugs as Teratogens 5 1976 CRC Press Cleveland, OH 49

In the paper

“penicillin (fatal to guinea pigs) (39)”

What the sources say

• ?Not checked — no full text of the sourcecites [39] Cormia F.E. Lewis G.M. Hopper M.E. Toxicity of penicillin for the guinea pig J Invest Dermatol 9 1947 261 267 18918918 source

In the paper

“Drugs that survive clinical trials and attain market approval may still be recalled later due to toxicity identified only after months or years of in-human use.”

In the paper

“However, many highly beneficial drugs would have failed animal testing and would never have been brought to market, except that they were developed before animal testing was required (38).”

What the sources say

• ?Not checked — no full text of the sourcecites [38] Koppanyi T. Avery M.A. Species differences and the clinical trial of new drugs: a review Clin Pharmacol Ther 7 1966 250 270 5327179 source

In the paper

“Similar results were found for nonhuman primates and dogs (14).”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“About 12% of pharmaceuticals pass preclinical testing to enter clinical trials (15).”

What the sources say

• ?Not matched

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

  cites [15] American Pharmaceutical Review Preclinical Development: The Safety Hurdle Prior to Human Trials. American Pharmaceutical Review Available at: https://www.americanpharmaceuticalreview.com/Featured-Articles/187349-Preclinical-Development-The-Safety-Hurdle-Prior-to-Human-Trials/ April 30, 2016

In the paper

“immunogenic responses in animals do not predict immunogenicity in humans (15,25, 26, 27).”

What the sources say

• ?Not matched

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

  cites [15] American Pharmaceutical Review Preclinical Development: The Safety Hurdle Prior to Human Trials. American Pharmaceutical Review Available at: https://www.americanpharmaceuticalreview.com/Featured-Articles/187349-Preclinical-Development-The-Safety-Hurdle-Prior-to-Human-Trials/ April 30, 2016
• ?Not checked — no full text of the sourcecites [25] McDougal A.J. Preclinical development [CDER]: biological therapeutics for cancer treatment. Paper presented to iSBTc Oncology Biologics Development Primer; February 28, 2008; Gaithersburg, MD Available at: https://sitc.sitcancer.org/meetings/am08/primer08_oncology/presentations/3_mcdougal.pdf
• ?Not checked — no full text of the sourcecites [26] De Groot A.S. Moise L. Prediction of immunogenicity for therapeutic proteins: state of the art Curr Opin Drug Discov Devel 10 2007 332 340 17554860

In the paper

“About 26% of chemicals demonstrated contradictory results on repeat testing in the same species.”

What the sources say

• ?Not checked — no full text of the sourcecites [50] Browne P. Judson R.S. Casey W.M. Kleinstreuer N.C. Thomas R.S. Screening chemicals for estrogen receptor bioactivity using a computations model Environ Sci Technol 49 2015 8804 8814 26066997 source

In the paper

“Reproducibility of animal studies within species, even when carried out under rigorous protocols, is questionable.”

In the paper

“Compassionate human use of ganciclovir demonstrated efficacy and safety in treating acquired immunodeficiency syndrome–related cytomegalovirus retinitis in more human patients than would generally be required for a phase I clinical trial, but the FDA refused to license it due to lack of animal studies.”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“Later analysis of 3,000 drugs found that tests inferring no toxicity in any 1 species, including nonhuman primates, have no evidentiary weight with regard to toxicity in any other species (14).”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“For industrial toxicity testing, it takes about 10 years and $3 million to complete all required animal studies to register a single pesticide (43).”

What the sources say

• ?Not matched

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

In the paper

“Furthermore, discordant results sometimes ranged over 3 orders of magnitude within the same species (50).”

What the sources say

• ?Not checked — no full text of the sourcecites [50] Browne P. Judson R.S. Casey W.M. Kleinstreuer N.C. Thomas R.S. Screening chemicals for estrogen receptor bioactivity using a computations model Environ Sci Technol 49 2015 8804 8814 26066997 source

In the paper

“Sensitivity, specificity, PPV, and NPV are all strongly affected by the prevalence of the condition they test for and are therefore of limited value in assessing the reliability of a test when the prevalence of the condition is unknown.”

In the paper

“A 1990 analysis of the toxicities of 24 drugs abandoned during human clinical trials demonstrated that 16 had no animal model toxicity correlation (58).”

What the sources say

• ?Not matched

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

  cites [58] Lumley C. Clinical toxicity: could it have been predicted? Premarketing experience Lumley C. Walker S. Animal Toxicity Studies: Their Relevance for Man 1990 Quay Publishing London, UK 49 56

In the paper

“Lack of animal tests has also caused deleterious delays in critical drug approvals.”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“Indeed, Knight (72) could find no review of animal research studies that rated a majority of the experiments as having “good” methodological quality.”

What the sources say

• ?Not checked — no full text of the sourcecites [72] Knight A. Systematic reviews of animal experiments demonstrate poor human clinical and toxicological utility Altern Lab Anim 35 2007 641 659 18186670 source

In the paper

“At this time, the FDA generally still requires submission of preclinical animal data in investigational new drug applications (5).”

What the sources say

• ?Not matched

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

  cites [5] U.S. Food and Drug Administration Investigational New Drug (IND) Application. U.S. Food and Drug Administration Available at: https://www.fda.gov/drugs/types-applications/investigational-new-drug-ind-application October 5, 2017