Guest Column | January 8, 2024

Animal Testing Isn't Perfect. Is There An Alternative?

By Anke Rosch, Boehringer Ingelheim


When I started my career in drug safety, friends warned me that toxicology is as old as humanity. This would also apply to its methods: many animal experiments, regulations, and a traditional mindset, making the integration of innovative (animal-free) methods impossible. I would like to clear up these outdated prejudices.

Animal Statistics

In the European Union, 10.4 million animals were used for the first time in research and testing in 2019 (down 1.5% vs. 2018), including approximately 6.4 million rodent and 700,000 non-rodent mammals.1 For the United States, no easily accessible data on animal use is available. The United States Department of Agriculture (USDA) reported around 800,000 (up 2.2% vs. 2018)2 laboratory animals used for research under the Animal Welfare Act (AWA)3 in 2019, excluding purpose-bred mice and rats. Carbone4 presented an annual estimate of 111.5 million rodents about the same time, based on data from 16 large American institutions. However, in Europe, only 7% of the total number of animals participated in toxicity and safety testing (down 2% vs. 2018)1 compared to 72% used for research.

Regulatory Considerations

In 1937, mass poisoning in the United States because of the antibiotic Elixir Sulfanilamid (in diethylene glycol) led to the passage of the Food, Drug, and Cosmetic Act in 1938.5 The sedative Contergan (thalidomide),6 dosed to pregnant women, caused severe birth defects and deaths in thousands of children in the 1950s. As a result, the Kefauver-Harris amendments were enacted in 1962, requiring animal testing for drug safety and efficacy. Today, several guidelines thoroughly regulate preclinical drug development, such as ICH M3(R2)7 for human pharmaceuticals, ICH S6R1 for biotechnology-derived products,8 ICH S9 for anticancer pharmaceuticals,9 and ICH S5(R3) for reproductive and developmental toxicity.10

The high attrition rate of new drugs (90%)11 after entering clinical studies despite animal testing led to the release of the FDA Modernization Act 2.0 in 2022.12 This law permits the use of suitable animal-free new approach methodologies (NAMs) instead of mandatory animal studies. Simultaneously, the European Parliament launched a program to eliminate animal studies "as soon as scientifically possible," inspired by a European citizen initiative13 in 2021.14 The reformation of the European Directive 2010/63/EU15,16 on the Protection of Animals for Scientific Purpose is supported by the European Medicines Agency (EMA) and the European Partnership for Alternative Approaches to Animal Testing (EPAA).

Reasons For A Change

The heart of the debate about animal sacrifice for drug development lies in the question of whether animal lives are less valuable than those of humans.

There are many additional reasons to dismiss animal studies. Rodent and non-rodent experiments predicted human toxicity in only 48%17 to 71%18 of drugs. In about 20% of drugs 19 like antibodies and fusion and recombinant proteins, the human-specific mode did not allow extrapolation from animal to potential human immunogenicity. In 2006, six human volunteers had to experience that firsthand by participating in a Phase 1 clinical trial with the CD28 superagonist antibody TGN1412.20 It caused systemic "cytokine storm" and life‑threatening multiorgan failure, even though it had been tested previously in two animal species.21 Forty-five percent11 of novel drug failures in clinical studies are attributed to unanticipated toxicity.22 Only 19% of human serious adverse events post marketing were detected in animals beforehand.22

On the contrary, toxicity in animals is occasionally not predictive for humans and might have prevented approval of promising drugs. Liver and kidney toxicity in cats and dogs or embryo toxicity in rats and monkeys, for instance, would have probably discontinued the pharmaceutical development of paracetamol23 and aspirin,24 respectively.

Paradigm Shift In Preclinical Safety

Carcinogenicity may serve as an example of systemic toxicology testing with high complexity. Therefore, the use of alternative methods is still limited. For genotoxic carcinogens, the guidelines include a standard battery of tests, i.e., the Ames test, the micronucleus test, and the chromosomal aberration assay performed in-vitro or using material from repeated dose animal studies since 1995.25–28

For in-vivo carcinogenicity testing with up to 600 to 800 animals per study,29 the ICH S1B addendum30 released in 2022 describes a novel tiered testing approach. Previous versions requested a two-year (lifetime) carcinogenicity study in rats in association with a two-year or medium-term (six months) study in a second species (mouse or transgenic rasH2 mice, respectively). The addendum now allows omitting the two-year rat carcinogenicity study based on available pharmacological and toxicological data in a weight-of-evidence (WoE) approach. Additionally, regulators enable the implementation of mechanistic in-vitro data. 

NAMs for non-genotoxic carcinogen testing such as the cell transformation assay31 or a genomic biomarker panel32 to predict rodent carcinogenicity are validated by an OECD established expert group33–35 for regulatory integration.36

From 2015 to 2019, FDA approved new drug applications based on 109 carcinogenicity studies, including at least 65,341 rats and mice. The novel approach promises a 46% reduction in this animal number.37

In the 1980s, several FDA approved drugs (Seldane/terfenadine and Hismanal/astemizole)38 made it into the headlines when a potentially fatal polymorphic ventricular arrhythmia (Torsade de Pointes) occurred in humans. The delay in cardiac repolarization by inhibition of the rapidly activating delayed rectifier potassium current Ikr or hERG (human-ether-a-go-go) channel associated with prolongation of the QT interval was held responsible. As a result, the Committee for Proprietary Medicinal Products (CPMP) published an early guideline on the evaluation of ventricular repolarization39,40 in 1997. The more detailed ICH S7B guidance41 released in 2005 declared a preclinical in-vitro hERG and an in-vivo QT assay, such as in telemetrized animals, as mandatory.

One hundred percent of the responders from surveyed pharmaceutical companies performed in-vivo telemetry studies42 in the following years. Twenty-six percent of the responders even implemented proarrhythmia models such as the methoxamine-treated rabbit and the chronically atrioventricular blocked dog42 that were, however, totally rejected by 62% of scientists. In 2013, a "think tank"43 sponsored by the Cardiac Safety Research Consortium (CSRC), Health and Environmental Sciences Institute (HESI), and FDA confirmed that Ikr inhibition is not the only reason for Torsade de Pointes. A 3R-compliant new testing strategy development was started by the comprehensive in-vitro proarrhythmia assay (CiPa) initiative for updating the S7B and E14 guidelines. The ICH E14/S7B Q&As44 were released in 2022 with the primary aim of waiving thorough QT studies by providing additional preclinical information without increasing the use of animals for drug development. Two years before release, the number of stand-alone telemetry studies had decreased to 77% and 70% using dogs and minipigs or monkeys ("frequently and always"),45 respectively, presumably for the benefit of jacket telemetry measurements in toxicity studies.

Nowadays, preclinical data supplementing the hERG and in vivo assay will consist of animal‑free methods such as the assessment of drug effects on multiple ion channels46 with subsequent in-silico modeling47,48 by the updated O'Hara–Rudy cell model and on human iPSC-derived cardiomyocytes.49 Furthermore, it is recommended to perform a more detailed investigation of drug effects already in Phase 1 studies associated with plasma concentration-QTc modeling.50


I agree that animal experiments cannot entirely predict human outcomes in clinical studies. Differences in metabolic pathways, toxicokinetic profile, drug metabolites, receptor distribution, and sensitivity to adverse effects are responsible. However, often the focus is rather on the failures of animal studies and not on the potential harm that humans could have faced if one hadn't conducted them. For drug safety, guidelines restrict flexibility and extend timelines for drug development but ensure well-powered studies with controlled animal numbers. Reasons for increased animal usage in research may lie in a lack of harmonization. Multiple scientific groups all over the world work competitively on the same promising topic with divergent and often underpowered studies. A systematic meta-analysis of results could reduce the need for animal testing.

Despite the existence of guidelines for safety testing, scientists and regulators have not hesitated to initiate a paradigm shift to bring toxicology into the 21st century. NAMs are stepwise taken up into regulatory testing strategies following validation against animal studies. The mindset of toxicologists got an upgrade with technologies such as adverse outcome pathways (AoPs),51 read-across,52 microphysiological systems (organ-on-a-chip and 3D organ constructs),53 and artificial intelligence.54 However, a biological system is not only the sum of its functions but also of synergies among them.

Replacing animals entirely in toxicology studies by in-vitro methods still seems too risky because it oversimplifies their complexity. I strongly believe that we can achieve further reduction of animal numbers in research and development. I regret having to say that we probably must perform a certain defined number of animal studies for the investigations of adverse effects resulting from interaction between different organs and physiological systems. Integration of further endpoints will significantly refine these studies and make other studies obsolete. Supplementary NAMs might reduce their number as well. The challenge is bridging the gap between traditional and modern toxicologists to benefit from each other's expertise for the animals' sake.


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Anke Rosch is a board-certified pharmacologist and toxicologist working at Boehringer Ingelheim Pharma GmbH & Co. KG. A doctor of veterinary medicine, she has more than 20 years of experience in the pharmaceutical industry and has special expertise in safety pharmacology. Anke can be reached at