According to the text, animal models may be considered ethical for psychological research if

1.Taylor K, Gordon N, Langley G, Higgins W. Estimates for worldwide laboratory animal use in 2005. Alternatives to Laboratory Animals 2008;36:327–42. [PubMed] [Google Scholar]

2.Systematic reviews that have been conducted generally reveal the unreliability and poor predictability of animal tests. See Perel P, Roberts I, Sena E, Wheble P, Briscoe C, Sandercock P, et al. Comparison of treatment effects between animal experiments and clinical trials: Systematic review. BMJ 2007;334:197. See also Pound P, Bracken MB. Is animal research sufficiently evidence based to be a cornerstone of biomedical research? BMJ 2014;348:g3387. See Godlee F. How predictive and productive is animal research? BMJ 2014;348:g3719. See Benatar M. Lost in translation: Treatment trials in the SOD 1 mouse and in human ALS. Neurobiology Disease 2007;26:1–13 [PubMed] [Google Scholar]. And see Akhtar AZ, Pippin JJ, Sandusky CB. Animal studies in spinal cord injury: A systematic review of methylprednisolone. Alternatives to Laboratory Animals 2009;37:43–62. [PubMed] [Google Scholar]

3.Mathews RAJ. Medical progress depends on animal models—doesn’t it? Journal of the Royal Society of Medicine 2008;101:95–8. [PMC free article] [PubMed] [Google Scholar]

4.See Shanks N, Greek R, Greek J. Are animal models predictive for humans? Philosophy, Ethics, and Humanities in Medicine 2009;4:2 [PMC free article] [PubMed] [Google Scholar]. See also Wall RJ, Shani M. Are animal models as good as we think? Theriogenology 2008;69:2–9. [PubMed] [Google Scholar]

5.See note 3, Mathews 2008. See also Hartung T, Zurlo J. Food for thought… alternative approaches for medical countermeasures to biological and chemical terrorism and warfare. ALTEX 2012;29:251–60 [PubMed] [Google Scholar]. See Leist M, Hartung T. Inflammatory findings on species extrapolations: Humans are definitely no 70-kg mice. Archives in Toxicology 2013;87:563–7 [PMC free article] [PubMed] [Google Scholar]. See Mak IWY, Evaniew N, Ghert M. Lost in translation: Animal models and clinical trials in cancer treatment. American Journal in Translational Research 2014;6:114–18 [PMC free article] [PubMed] [Google Scholar]. And see Pippin J. Animal research in medical sciences: Seeking a convergence of science, medicine, and animal law. South Texas Law Review 2013;54:469–511. [Google Scholar]

6.For an overview of the harms-versus-benefits argument, see LaFollette H. Animal experimentation in biomedical research In: Beauchamp TL, Frey RG, eds. The Oxford Handbook of Animal Ethics. Oxford: Oxford University Press; 2011:812–18. [Google Scholar]

7.See Jucker M. The benefits and limitations of animal models for translational research in neurodegenerative diseases. Nature Medicine 2010;16:1210–14 [PubMed] [Google Scholar]. See Institute of Medicine. Improving the Utility and Translation of Animal Models for Nervous System Disorders: Workshop Summary. Washington, DC: The National Academies Press; 2013. And see Degryse AL, Lawson WE. Progress towards improving animal models for IPF. American Journal of Medical Science 2011;341:444–9. [PMC free article] [PubMed] [Google Scholar]

8.See Morgan KN, Tromborg CT. Sources of stress in captivity. Applied Animal Behaviour Science 2007;102:262–302 [Google Scholar]. See Hart PC, Bergner CL, Dufour BD, Smolinsky AN, Egan RJ, LaPorte L, et al. Analysis of abnormal repetitive behaviors in experimental animal models In Warrick JE, Kauleff AV, eds. Translational Neuroscience and Its Advancement of Animal Research Ethics. New York: Nova Science; 2009:71–82 [Google Scholar]. See Lutz C, Well A, Novak M. Stereotypic and self-injurious behavior in rhesus macaques: A survey and retrospective analysis of environment and early experience. American Journal of Primatology 2003;60:1–15 [PubMed] [Google Scholar]. And see Balcombe JP, Barnard ND, Sandusky C. Laboratory routines cause animal stress. Contemporary Topics in Laboratory Animal Science 2004;43:42–51. [PubMed] [Google Scholar]

9.Suckow MA, Weisbroth SH, Franklin CL. The Laboratory Rat. 2nd ed. Burlington, MA: Elsevier Academic Press; 2006, at 323.

10.Flow BL, Jaques JT. Effect of room arrangement and blood sample collection sequence on serum thyroid hormone and cortisol concentrations in cynomolgus macaques (Macaca fascicularis). Contemporary Topics in Laboratory Animal Science 1997;36:65–8.

11.See note 8, Balcombe et al. 2004.

12.See note 8, Balcombe et al. 2004.

13.Baldwin A, Bekoff M. Too stressed to work. New Scientist 2007;194:24.

14.See note 13, Baldwin, Bekoff 2007.

15.Akhtar A, Pippin JJ, Sandusky CB. Animal models in spinal cord injury: A review. Reviews in the Neurosciences 2008;19:47–60. [PubMed] [Google Scholar]

16.See note 13, Baldwin, Bekoff 2007.

17.See note 15, Akhtar et al. 2008.

18.See Macleod MR, O’Collins T, Howells DW, Donnan GA. Pooling of animal experimental data reveals influence of study design and publication bias. Stroke 2004;35:1203–8 [PubMed] [Google Scholar]. See also O’ Neil BJ, Kline JA, Burkhart K, Younger J. Research fundamentals: V. The use of laboratory animal models in research. Academic Emergency Medicine 1999;6:75–82.

19.Crabbe JC, Wahlsten D, Dudek BC. Genetics of mouse behavior: Interactions with laboratory environment. Science 1999;284:1670–2, at 1670. [PubMed] [Google Scholar]

20.See Curry SH. Why have so many drugs with stellar results in laboratory stroke models failed in clinical trials? A theory based on allometric relationships. Annals of the New York Academy of Sciences 2003;993:69–74. See also Dirnagl U. Bench to bedside: The quest for quality in experimental stroke research. Journal of Cerebral Blood Flow & Metabolism 2006;26:1465–78 [PubMed] [Google Scholar].

21.van der Worp HB, Howells DW, Sena ES, Poritt MJ, Rewell S, O’Collins V, et al. Can animal models of disease reliably inform human studies? PLoS Medicine 2010;7:e1000245. [PMC free article] [PubMed] [Google Scholar].

22.See note 20, Dirnagl 2006. See also Sena E, van der Worp B, Howells D, Macleod M. How can we improve the pre-clinical development of drugs for stroke? Trends in Neurosciences 2007;30:433–9. [PubMed] [Google Scholar]

23.See Gawrylewski A. The trouble with animal models: Why did human trials fail? The Scientist 2007;21:44. See also Fisher M, Feuerstein G, Howells DW, Hurn PD, Kent TA, Savitz SI, et al. Update of the stroke therapy academic industry roundtable preclinical recommendations. Stroke 2009;40:2244–50. [PMC free article] [PubMed] [Google Scholar]

24.See note 23, Gawrylewski 2007. There is some dispute as to how vigorously investigators adhered to the suggested criteria. Nevertheless, NXY-059 animal studies were considered an example of preclinical studies that most faithfully adhered to the STAIR criteria. For further discussion see also Wang MM, Guohua X, Keep RF. Should the STAIR criteria be modified for preconditioning studies? Translational Stroke Research 2013;4:3–14 [PMC free article] [PubMed] [Google Scholar].

25.See note 24, Wang et al. 2013.

26.O’Collins VE, Macleod MR, Donnan GA, Horky LL, van der Worp BH, Howells DW. 1,026 experimental treatments in acute stroke. Annals of Neurology 2006;59:467–7 [PubMed] [Google Scholar].

27.See note 5, Mak et al. 2014.

28.See note 5, Mak et al. 2014.

29.See Perrin S. Preclinical research: Make mouse studies work. Nature 2014;507:423–5 [PubMed] [Google Scholar]. See also, generally, Wilkins HM, Bouchard RJ, Lorenzon NM, Linseman DA. Poor correlation between drug efficacies in the mutant SOD1 mouse mode versus clinical trials of ALS necessitates the development of novel animal models for sporadic motor neuron disease. In: Costa A, Villalba E, eds. Horizons in Neuroscience Research. Vol. 5. Hauppauge, NY: Nova Science; 2011:1–39.

30.Traynor BJ, Bruijn L, Conwit R, Beal F, O’Neill G, Fagan SC, et al. Neuroprotective agents for clinical trials in ALS: A systematic assessment. Neurology 2006;67:20–7 [PubMed] [Google Scholar].

31.Sinha G. Another blow for ALS. Nature Biotechnology 2013;31:185 [Google Scholar]. See also note 30, Traynor et al. 2006.

32.See Morales DM, Marklund N, Lebold D, Thompson HJ, Pitkanen A, Maxwell WL, et al. Experimental models of traumatic brain injury: Do we really need a better mousetrap? Neuroscience 2005;136:971–89 [PubMed] [Google Scholar]. See also Xiong YE, Mahmood A, Chopp M. Animal models of traumatic brain injury. Nature Reviews Neuroscience 2013;14:128–42 [PMC free article] [PubMed] [Google Scholar]. And see commentary by Farber: Farber N. Drug development in brain injury. International Brain Injury Association; available at http://www.internationalbrain.org/articles/drug-development-in-traumatic-brain-injury/ (last accessed 7 Dec 2014).

33.Maas AI, Roozenbeek B, Manley GT. Clinical trials in traumatic brain injury: Past experience and current developments. Neurotherapeutics 2010;7:115–26. [PMC free article] [PubMed] [Google Scholar]

34.Schneider LS, Mangialasche F, Andreasen N, Feldman H, Giacobini E, Jones R, et al. Clinical trials and late-stage drug development in Alzheimer’s disease: An appraisal from 1984 to 2014. Journal of Internal Medicine 2014;275:251–83 [PMC free article] [PubMed] [Google Scholar].

35.Seok J, Warren HS, Cuenca AG, Mindrinos MN, Baker HV, Xu W, et al. Genomic responses in mouse models poorly mimic human inflammatory diseases. Proceedings of the National Academy of Sciences USA 2013;110:3507–12. [PMC free article] [PubMed] [Google Scholar]

36.Palfreyman MG, Charles V, Blander J. The importance of using human-based models in gene and drug discovery. Drug Discovery World 2002. Fall:33–40 [Google Scholar].

37.See note 2, Perel et al. 2007.

38.Harding A. More compounds failing phase I. The Scientist 2004 Sept 13; available at http://www.the-scientist.com/?articles.view/articleNo/23003/title/More-compounds-failing-Phase-I/ (last accessed 2 June 2014).

39.See note 5, Pippin 2013.

40.See note 5, Hartung, Zurlo 2012.

41.Wiebers DO, Adams HP, Whisnant JP. Animal models of stroke: Are they relevant to human disease? Stroke 1990;21:1–3. [PubMed] [Google Scholar]

42.See note 15, Akhtar et al. 2008.

43.See note 2, Akhtar et al. 2009.

44.Lonjon N, Prieto M, Haton H, Brøchner CB, Bauchet L, Costalat V, et al. Minimum information about animal experiments: Supplier is also important. Journal of Neuroscience Research 2009;87:403–7. [PubMed] [Google Scholar]

45.Mogil JS, Wilson SG, Bon K, Lee SE, Chung K, Raber P, et al. Heritability of nociception I: Responses of 11 inbred mouse strains on 12 measures of nociception. Pain 1999;80:67–82. [PubMed] [Google Scholar]

46.Tator H, Hashimoto R, Raich A, Norvell D, Fehling MG, Harrop JS, et al. Translational potential of preclinical trials of neuroprotection through pharmacotherapy for spinal cord injury. Journal of Neurosurgery: Spine 2012;17:157–229. [PubMed] [Google Scholar]

47.See note 35, Seok et al. 2013, at 3507.

48.Odom DT, Dowell RD, Jacobsen ES, Gordon W, Danford TW, MacIsaac KD, et al. Tissue-specific transcriptional regulation has diverged significantly between human and mouse. Nature Genetics 2007;39:730–2 [PMC free article] [PubMed] [Google Scholar].

49.Horrobin DF. Modern biomedical research: An internally self-consistent universe with little contact with medical reality? Nature Reviews Drug Discovery 2003;2:151–4. [PubMed] [Google Scholar]

50.Vassilopoulous S, Esk C, Hoshino S, Funke BH, Chen CY, Plocik AM, et al. A role for the CHC22 clathrin heavy-chain isoform in human glucose metabolism. Science 2009;324:1192–6. [PMC free article] [PubMed] [Google Scholar]

51.See Guttman-Yassky E, Krueger JG. Psoriasis: Evolution of pathogenic concepts and new therapies through phases of translational research. British Journal of Dermatology 2007;157:1103–15 [PubMed] [Google Scholar]. See also The mouse model: Less than perfect, still invaluable. Johns Hopkins Medicine; available at http://www.hopkinsmedicine.org/institute_basic_biomedical_sciences/news_events/articles_and_stories/model_organisms/201010_mouse_model.html (last accessed 10 Dec 2014). See note 23, Gawrylewski 2007. See note 2, Benatar 2007. See note 29, Perrin 2014 and Wilkins et al. 2011. See Cavanaugh S, Pippin J, Barnard N. Animal models of Alzheimer disease: Historical pitfalls and a path forward. ALTEX online first; 2014 Apr 10. And see Woodroofe A, Coleman RA. ServiceNote: Human tissue research for drug discovery. Genetic Engineering and Biotechnology News 2007;27:18 [Google Scholar].

52.Lane E, Dunnett S. Animal models of Parkinson’s disease and L-dopa induced dyskinesia: How close are we to the clinic? Psychopharmacology 2008;199:303–12. [PubMed] [Google Scholar]

53.See note 52, Lane, Dunnett 2008.

54.See note 5, Pippin 2013.

55.Bailey J. An assessment of the role of chimpanzees in AIDS vaccine research. Alternatives to Laboratory Animals 2008;36:381–428. [PubMed] [Google Scholar]

56.Tonks A. The quest for the AIDs vaccine. BMJ 2007;334:1346–8 [PMC free article] [PubMed] [Google Scholar].

57.Johnston MI, Fauci AS. An HIV vaccine—evolving concepts. New England Journal of Medicine 2007;356:2073–81. [PubMed] [Google Scholar]

58.See Rossouw JE, Andersen GL, Prentice RL, LaCroix AZ, Kooperberf C, Stefanick ML, et al. Risks and benefits of estrogen plus progestin in healthy menopausal women: Principle results from the Women’s Health Initiative randomized controlled trial. JAMA 2002;288:321–33 [PubMed] [Google Scholar]. See also Andersen GL, Limacher A, Assaf AR, Bassford T, Beresford SA, Black H, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: The Women’s Health Initiative randomized controlled trial. JAMA 2004;291:1701–12 [PubMed] [Google Scholar].

59.Lemere CA. Developing novel immunogens for a safe and effective Alzheimer’s disease vaccine. Progress in Brain Research 2009;175:83. [PMC free article] [PubMed] [Google Scholar].

60.Allen A. Of mice and men: The problems with animal testing. Slate 2006 June 1; available at http://www.slate.com/articles/health_and_science/medical_examiner/2006/06/of_mice_or_men.html (last accessed 10 Dec 2014).

61.Attarwala H. TGN1412: From discovery to disaster. Journal of Young Pharmacists 2010;2:332–6 [PMC free article] [PubMed] [Google Scholar].

62.See Hogan RJ. Are nonhuman primates good models for SARS? PLoS Medicine 2006;3:1656–7 [PMC free article] [PubMed] [Google Scholar]. See also Bailey J. Non-human primates in medical research and drug development: A critical review. Biogenic Amines 2005;19:235–55. [Google Scholar]

63.See note 4, Wall, Shani 2008.

64.Lemon R, Dunnett SB. Surveying the literature from animal experiments: Critical reviews may be helpful—not systematic ones. BMJ 2005;330:977–8. [PMC free article] [PubMed] [Google Scholar]

65.Roberts I, Kwan I, Evans P, Haig S. Does animal experimentation inform human health care? Observations from a systematic review of international animal experiments on fluid resuscitation. BMJ 2002;324:474–6 [PMC free article] [PubMed] [Google Scholar].

66.See note 60,Allen 2006. See also Heywood R. Target organ toxicity. Toxicology Letters 1981;8:349–58 [PubMed] [Google Scholar]. See Fletcher AP. Drug safety tests and subsequent clinical experience. Journal of the Royal Society of Medicine 1978;71:693–6. [PMC free article] [PubMed] [Google Scholar]

67.See note 60, Allen 2006. See note 5, Pippin 2013. See also Greek R, Greek J. Animal research and human disease. JAMA 2000;283:743–4 [PubMed] [Google Scholar].

68.See note 60, Allen 2006. See also note 5, Leist, Hartung 2013.

69.Food and Drug Administration. Development & approval process (drugs); available at http://www.fda.gov/Drugs/DevelopmentApprovalProcess/ (last accessed 7 Dec 2014). See also http://www.fda.gov/drugs/resourcesforyou/consumers/ucm143534.htm (last accessed 7 Dec 2014).

70.Drug discovery pipeline. IRSF; available at http://www.rettsyndrome.org/research-programs/programmatic-overview/drug-discovery-pipeline (last accessed 24 Sept 2014).

71.See note 60, Allen 2006.

72.Follow the yellow brick road. Nature Reviews Drug Discovery 2003;2:167, at 167.

73.See note 5, Pippin 2013.

74.For data on aspirin, see Hartung T. Per aspirin as astra … Alternatives to Laboratory Animals 2009;37(Suppl 2):45–7 [PubMed] [Google Scholar]. See also note 5, Pippin 2013. For data on penicillin, see Koppanyi T, Avery MA. Species differences and the clinical trial of new drugs: A review. Clinical Pharmacology and Therapeutics 1966;7:250–70 [PubMed] [Google Scholar]. See also Schneierson SS, Perlman E. Toxicity of penicillin for the Syrian hamster. Proceedings of the Society for Experimental Biology and Medicine 1956;91:229–30. [PubMed] [Google Scholar]

75.See note 67, Greek, Greek 2000.

76.Oral bioavailability of blockbuster drugs in humans and animals. PharmaInformatic. available at http://www.pharmainformatic.com/html/blockbuster_drugs.html (last accessed 19 Sept 2014).

77.Sams-Dodd F. Strategies to optimize the validity of disease models in the drug discovery process. Drug Discovery Today 2006;11:355–63 [PubMed] [Google Scholar].

78.Zurlo J. No animals harmed: Toward a paradigm shift in toxicity testing. Hastings Center Report 2012;42. Suppl:s23–6 [PubMed] [Google Scholar].

79.There is no direct analysis of the amount of money spent on animal testing versus alternatives across all categories; however, in 2008 the Chronicle of Higher Education reported that funding of research involving animals (under basic research) of the National Institute of Health (NIH) remained steady at about 42 percent since 1990. See Monastersky R. Protesters fail to slow animal research. Chronicle of Higher Education 2008:54. In 2012, NIH director Francis Collins noted that the NIH’s support for basic research has held steady at 54 percent of the agency’s budget for decades. The remainder of the NIH’s budget is heavily funded toward clinical research, suggesting that preclinical human-based testing methods are much less funded. See also Wadman M. NIH director grilled over translational research centre. Nature News Blog 2012 Mar 20. Available at http://blogs.nature.com/news/2012/03/nih-director-grilled-over-translational-research-center.html (last accessed 5 Mar 2015). There is no data that suggests that the NIH’s funding of animal experimentation has decreased. A 2010 analysis estimates that at least 50 percent of the NIH’s extramural funding is directed into animal research; see Greek R, Greek J. Is the use of sentient animals in basic research justifiable? Philosophy, Ethics, and Humanities in Medicine 2010;5:14 [PMC free article] [PubMed] [Google Scholar].

80.For a helpful discussion on animal pain, fear, and suffering, see DeGrazia D. Taking Animals Seriously: Mental Lives and Moral Status. New York: Cambridge University Press; 1996:116–23. [Google Scholar]

81.See Akhtar A. Animals and Public Health: Why Treating Animals Better Is Critical to Human Welfare. Hampshire, UK: Palgrave Macmillan; 2012:chap. 5.