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Animal safety studies can miss a harmful response that appears in people, but that does not mean animal research is useless or that animal testing alone caused every volunteer injury. The 2006 TGN1412 trial and the fialuridine (FIAU) case show how species differences can leave serious human risks undetected; the BIA 10-2474 trial is a separate warning whose mechanism remains uncertain in the evidence reviewed here.
How can animal testing fail to predict what a drug will do in people?
A drug can behave differently across species because the biology it acts on is not identical. The U.S. Food and Drug Administration’s April 2026 report identifies differences in disease state, target biology, pharmacokinetics, metabolism, and idiosyncratic or off-target responses as factors that can limit how well animal studies predict human responses. A study can therefore be competently conducted and still fail to reveal a human-specific danger.
That is one kind of failure, not the only one. Risk can also be missed or worsened through how evidence is interpreted, how a first dose is selected, how volunteers are monitored, or how a trial is conducted. Those factors must be assessed separately: an injury after a trial does not, by itself, prove that animal studies caused it or that animals could have predicted it.
The FDA’s April 2026 report says that “over 90% of drugs that appear safe in animals fail to receive FDA approval.” The report attributes the main reasons to safety and/or efficacy problems that become apparent in human trials and cites a 2023 narrative review. This is not a claim that more than 90% fail because animal tests are wrong; failure to show adequate benefit is also part of the stated explanation.
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What the best-documented cases show
These incidents differ in drug type, human harm, evidence source, and what they can establish about animal prediction. The table separates those distinctions rather than treating every clinical-trial disaster as the same kind of failure.
| Case | Drug and trial | Human outcome | What the evidence says about prediction | Evidence and principal lesson |
|---|---|---|---|---|
| TGN1412, also called theralizumab | CD28 superagonist antibody; first-in-human trial in 2006 | All six healthy volunteers who received the drug developed life-threatening reactions. | NIBSC found that a modified human-cell assay reproduced the dramatic response, while the corresponding assay using monkey blood cells did not. It attributed the difference to subtle differences in how human and monkey white blood cells processed the drug. | NIBSC’s institutional follow-up; a direct example of a species-related biological response not captured by the monkey-cell assay. |
| Fialuridine (FIAU) | Antiviral nucleoside analog; human clinical trials | Major hepatic and pancreatic toxicity occurred in people. | The National Academies committee found that comprehensive animal studies offered no evidence from which the major human toxicity could have been anticipated. | Institute of Medicine / National Academies retrospective review (1995); a translational limit, alongside a caution about how possible earlier clinical signals are interpreted. |
| BIA 10-2474 | FAAH inhibitor; first-in-human trial in January 2016 | A secondary review describes severe neurological harms and one death. | The evidence considered here does not establish a definitive mechanism or verify detailed findings against the official investigation. | 2016 secondary review; event context is relevant, but proposed explanations should not be treated as established causes. |
TGN1412: a human-cell response that the monkey-cell assay missed
NIBSC reports that it checked the trial material and found it identical to the material used in the preclinical work. In its follow-up, a modified assay using human cells reproduced the dramatic reaction, whereas the corresponding monkey blood-cell assay did not. NIBSC’s account concludes: “for this drug, monkey studies would never predict the catastrophic reactions suffered by the human volunteers.” That conclusion is specific to TGN1412, not a general verdict on animal studies.
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The MHRA investigation statement, in a version reproduced by the third-party site Animal Research Information, described the result this way: “In this case the resulting activity seen in humans was not predicted from apparently adequate pre-clinical testing.” The reproduction is dated April 5, 2006; it is not the regulator’s statement hosted directly by the MHRA.
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NIBSC says its work informed later European rules for first-in-human trials and new in-vitro assays. The case demonstrates why human-relevant assays can add evidence that an animal model does not provide; it does not establish that any one assay can rule out every dangerous reaction.
Rank #3
FIAU: comprehensive animal studies still left a major human toxicity unexplained
The National Academies’ committee reviewed FDA task-force work on hepatic and pancreatic toxicity. It judged the animal studies comprehensive, yet found no evidence in them from which the major human toxicity could have been anticipated. FIAU is therefore a documented example of a serious gap between animal findings and human outcomes, rather than proof that the animal work was simply absent or inadequate.
The clinical record also illustrates how hard it can be to interpret a possible safety signal. The review reports that 24 of 79 patients in three earlier studies had a peak-to-baseline AST or ALT increase greater than three at some point during therapy or follow-up. The committee specifically did not consider that variable a valid measure of drug-induced hepatotoxicity. It must not be read as 24 confirmed cases of drug-induced liver injury.
BIA 10-2474: serious harm, but no definitive mechanism established here
A 2016 secondary review describes severe neurological harms and one death in the January 2016 first-in-human BIA 10-2474 trial. The account considered here does not independently verify detailed findings against the official investigation or establish a definitive cause. The event belongs in a discussion of first-in-human trial risk, but it cannot responsibly be used to claim that a particular animal-test failure caused the injuries.
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- They show that reassuring animal findings are not a guarantee of human safety. TGN1412 supplies an observed human-versus-monkey assay contrast, while the National Academies’ FIAU review found no animal evidence that anticipated the major human toxicity.
- They do not show that animal studies have no value. The FDA says animal studies can predict some toxicities, while recognizing that species differences limit prediction of all human responses.
- They do not establish that animal testing alone caused the injuries. A trial outcome may involve biological differences, study interpretation, dose selection, monitoring, or trial conduct. The evidence summarized for these cases does not assign every contributing factor or support a single explanation across them.
- They do not make every retrospective signal proof of harm. The FIAU committee’s caution about AST or ALT changes shows why a measured abnormality should not be equated automatically with drug-induced injury.
How safety assessment is changing
The FDA’s April 2026 report describes a weight-of-evidence approach: evaluating relevant evidence together rather than treating one study or method as a complete answer. It also discusses new approach methodologies, including human organ-on-chip systems, computational modeling, AI, and advanced in-vitro assays, as ways to improve human-relevant insight.
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These methods are developing tools, not a demonstrated guarantee of safe trials and not evidence that animal testing has already been universally replaced. NIBSC’s TGN1412 follow-up illustrates one practical role for human-cell testing: it revealed a response that the corresponding monkey-cell assay did not reproduce. The larger challenge is to combine suitable methods and interpret their limits before exposing people to a candidate drug.
Further reading
The National Academies’ Review of the Fialuridine (FIAU/FIAC) Clinical Trials (1995) provides the institutional review of the animal studies and clinical records discussed above.
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