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expert reaction to analysis of animal research and approval of therapies for human applications

An analysis published in PLOS Biology looks at animal research and human applications. 


Prof Robin Lovell-Badge FRS FMedSci, Group Leader, Francis Crick Institute, said:

“This is an interesting and valuable meta-analysis of studies concerning animal to human translation, which points out some issues that deserve attention and which may lead to improvements in the pathways from basic research to clinical application.

“The authors are correct to point out that animal research tends to give better understanding of underlying mechanisms, which may lead to better future beneficial interventions, whereas trials in humans are focussed initially on safety and then on efficacy, i.e. the experimental approaches are different, therefore the former should not always lead to immediate cures!  The authors conclusion (in the title) that only 5% of animal-tested interventions led all the way through to regulatory approval for human interventions, seems at first glance rather low – but, given the high number of interventions that are tested, this means a lot do have clinical value, and we should be grateful for this. But it is also worth noting that a significant ‘failure’ rate seems to be encountered in going from RCTs to regulatory approval. In other words, a big problem involves developing treatments in humans and need not have much to do with any possible deficiencies in the animal models being used.

“Moreover, and something not explored in this paper, there are interventions never tested in animals, that may go straight from human cell lines, or which involve more or less subtle alterations to protocols or materials that don’t require any animal research, many of which may also fail, which also goes to show that experiments in humans are fraught with difficulties and have ahigh rate of attrition.

“In addition, there are other reasons why interventions may not progress from RCT to regulatory approval. These include new developments that supersede (or promise to do so) those in trials, and given the costs of trials, especially RCTs, and the challenges in obtaining regulatory approval, which are financial as well as bureaucratic, it is not all surprising if many even promising interventions fall by the wayside.”


The below quotes were gathered by our friends at the Spanish SMC.

Dr Lluís Montoliu, researcher at the National Center for Biotechnology (CNB-CSIC) and CIBERER-ISCIII, said:

“Periodically, studies emerge that aim to provide new data on the eternal question of whether animals are useful for developing therapies that can later be effective in humans. There are studies to suit all tastes. Some studies indicate that the transfer of results from animals to humans is unpredictable, comparable, or entirely different.

“Currently, with growing groups in the population opposing animal experimentation, who systematically appeal to community institutions to try to achieve a ban on these practices, these types of studies aimed at deciphering the usefulness of animal experiments for obtaining effective treatments in humans have gained new and unprecedented interest, especially when the results obtained are negative and, therefore, favorable to those who oppose the continued use of animals in biomedical research.

“We must remember that Directive 2010/63/EU, from which all national European legislations for the protection of animals used in research and teaching are derived, already anticipates that the ultimate goal of the regulation is to end animal experimentation, but adds, when this is scientifically possible. And we are not yet at this point. We still need to go through preclinical analyses in animal models for therapeutic proposals aimed at new treatments, which we want to be safe and effective. Safety and efficacy are first evaluated in animals before being analyzed in subsequent clinical trials. It is no coincidence that the vast majority of Nobel Prizes in Medicine or Physiology have been achieved thanks to animal experimentation.

“We must also bear in mind that we are not indistinguishable from other animals, and each animal model has its advantages and disadvantages in biomedical studies. They are very useful to us most of the time, but there are physiological and metabolic differences for which caution is recommended when comparing and drawing conclusions from the responses obtained in animal models and humans. For example, chocolate is tolerated by humans without problems but can kill a dog, which is unable to process some of its components that become toxic to the animal. Therefore, studies in more than one animal model are often required for the development of gene therapies and vaccines.

“A group of Swiss and British researchers has just published in the journal PLoS Biology the results of analyzing many publications describing preclinical analyses with animals and their subsequent follow-up in patients, in the form of some type of human study, randomized controlled clinical trials, or authorization by regulatory authorities. The strict selection criteria applied to these publications result in only 122 out of the initial 5,228 publications being retained (which may be one of the weakest points of this study, the limited number of cases finally studied). The rest of the study is conducted solely on these 122 publications. These articles describe 54 different human diseases and 367 therapeutic interventions.

“The study’s conclusions are that 50% of animal studies progress to human studies, and 40% progress to randomized controlled clinical trials. These figures are significantly higher than those usually published by this type of study. However, only 5% of animal studies progress to obtain the corresponding regulatory approval. They also conduct a meta-analysis and conclude that there is concordance in the positive results in animal models and humans in 86% of cases. The median waiting time between animal studies and human studies, randomized controlled trials, or approvals by authorities is set at 5, 7, and 10 years, respectively.

“To explain the low rate (5%) of animal studies that reach approval in humans, they propose two possible explanations:

  • Either the requirements for randomized controlled clinical trials are very strict, causing some potentially promising animal studies to fail to overcome this barrier;
  • Or there are limitations in the design of both animal experiments and human trials. The authors lean towards the second option. And I agree with this interpretation.

“The regulatory pressure of the 3Rs (replacement, reduction, and refinement) ensures a focus on maintaining animal welfare, but it can force, in some cases, suboptimal experimental designs, which may include perhaps fewer individuals per experimental group or fewer experimental groups than would be objectively necessary (for example, conducting experiments only with males and not including females in the analyses, something highly discouraged). The standardization of environments and animals (mostly inbred, if we talk about mice) usually presented as an advantage, can also be a source of problems, given that it is obvious that humans live in diverse environments and are generally not inbred. All this can produce results in animals that are not robust enough and, therefore, generate therapeutic expectations that later are not confirmed in humans. The same occurs with the first Phase I/II clinical trials, with extraordinary costs, which may not have the adequate design or the necessary statistical power to draw conclusive results.

“Animal experiments remain necessary in biomedicine to advance the development of therapies to treat diseases that affect both animals and us, humans. But surely, we should try to improve experimental designs, both at the preclinical and clinical levels, to increase the percentage of animal studies that are confirmed in humans.”


Jordi Gracia-Sancho, Research Professor at IDIBAPS-Hospital Clínic de Barcelona and Scientific Director of CIBEREHD – Carlos III Health Institute, said:

“In the field of liver disease research, we are aware of the intrinsic limitations of animal models. However, we believe that they remain essential for understanding both the mechanisms of action of new drugs, as well as for better understanding the pathophysiology of diseases affecting the liver.

“Regarding this article, I believe that we should take its conclusions with caution as the type of analysis performed is based on an evaluation of already published review articles (it is not based on directly analysing and comparing original preclinical and clinical articles) and, therefore, there may be some bias derived from the conclusions or opinions of the authors of these reviews.

“Translational researchers must continue to work to improve and optimise the animal models used in biomedical research, always following the highest ethical standards in the treatment and care of animals. In the case of the study of liver disease, we must continue to develop models that better mimic the disease in humans, including adult models, that include both sexes, and that mimic the disease both cellularly and pathophysiologically to that of humans.”


Francisco Javier Cubero, Professor of Immunology in the Department of Immunology, Ophthalmology and ENT of the Complutense University of Madrid, member of the Gregorio Marañón Health Research Institute of Madrid and the Networked Biomedical Research Center for Liver and Digestive Diseases (CIBEREHD), said:

“In biomedicine, research and understanding of the pathophysiological mechanisms that cause disease is fundamental to the development of effective treatments. However, the translation of results obtained in the laboratory to the patient’s bedside has been and remains disappointing, as this timely study confirms.

“On the one hand, experimental animal models do not recapitulate the full heterogeneity of human disease nor the lifestyle, genetic predisposition or environmental factors that condition the response to a drug. On the other hand, clinical trials focus on the response to a therapeutic intervention rather than on the analysis of mechanisms.

“Therefore, improving experimental design and incorporating other variables into clinical trials is crucial for improving the success rates of translating experimental therapies to humans.”



‘Analysis of animal-to-human translation shows that only 5% of animal-tested therapeutic interventions obtain regulatory approval for human applications’ by Benjamin Ineichen et al. was published in PLOS Biology at 7pm UK time on Thursday 13 June.





Declared interests

Lluís Montoliu regularly uses animal models in his research on rare diseases and is a promoter of the COSCE agreement for transparency in animal experimentation in Spain.

Jordi Gracia-Sancho: no interests

Francisco Javier Cubero: no interests

Robin Lovell-Badge: I have no conflicts to declare

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