Why Drugs Tested in Mice Fail in Human Clinical Trials

Introduction to drug testing

Drug testing trials are the core of pharmaceutical research. These are done for ensuring the safety and efficacy of new medications before they are allowed to be released to the public [1].

Animal studies are usually carried out prior to human clinical trials. Mice are often chosen due to their physiological similarities to humans in addition to their short life spans and ease of breeding [2]. 

This allows researchers to study the drugs on multiple generations of rats and refine the drug's dosage before advancing to human trials.

Afterwards, human studies are organized in multiple phases, and each phase involves larger scale testing compared to the previous.

Healthy volunteers are often chosen first and then the studies eventually include patients with the target condition, as this is safer for the patients [1].

In this article, we will go into more detail into the use of mice in drug research, its ethical problems and reasons for failure, and how new technologies might shape the future of this practice.

History of Animal Testing in Drug Development

The use of animals in medical research began in ancient Greece in the 4th and 3rd centuries BCE, where physicians used animals to study anatomy, and pathology. It wasn’t until the 19th century, however, that animal testing had risen to prominence in drug development [3].

In the 1880s and 1890s, Emil von Behring isolated the diphtheria toxin and demonstrated successful use to immunize guinea pigs [4]. 

Afterwards, he went on to demonstrate immunity against diphtheria in other animals in 1898. 

Roughly 15 years later, Behring announced such a mix suitable for human immunity which succeeded in protecting from diphtheria.

Starting in the 1960s and 1970s, animal testing became more controversial as animal rights activists raised concerns about the use of animals in research. 

In response, governments around the world passed laws and regulations to protect animals used in research, and an example of this was the Animal Welfare Act passed in the United States in the year 1966 to warrant humane treatment of mice in research [5].

Advantages and limitations of using mice in preclinical studies

Mice are small, easy to handle, and have a short lifespan. This makes mice ideal for studying the effects of drugs over short time periods. However, there are also many limitations to using mice to test drugs.

Advantages

Mice share a significant amount of genetic similarity with humans, making them a useful model for studying human diseases and drug responses. 

Additionally, mice are inexpensive and easy to breed which allows for the provision of large numbers of genetically comparable animals for use in preclinical studies, serving to provide large enough samples to conduct statistical analyses and to also facilitate reproduction. 

Furthermore, many tools have been developed specifically to facilitate drug experiments on mice.

One example is technologies to genetically modify mice to induce specific diseases and study their drug responses [6].

Limitations

Although several merits exist to using mice, it’s still not without its limitations. 

First, mice are known for having a very limited behavioral repertoire, which is the reason why it’s difficult to study complex behaviors or cognitive processes that can only be measured in humans [7]. 

Second, the use of animals in research raises a lot of ethical concerns, which we will expand upon later in this article. 

Third, the success of preclinical studies in mice may not always translate to humans, and this is the reason why large-scale human studies are still required for drug approval.

Differences between mice and humans 

• Mice metabolize drugs a lot quicker and also possess different immune systems [7].
• There are many vital differences in how drugs are absorbed and excreted in mice when compared with humans, which could have a major influence on drug safety [7].
• Mice and humans have significant differences in cognitive and social behavior owing to disparities of anatomical brain structures and/or neurochemical pathways [8].

Reasons for failure of drug trials

Genetic variability

One reason why drugs often fail to pass human trials even after successful testing on mice is that mice are not completely genetically identical to humans. 

This triggers many difficulties when trying to predict how a drug might perform in humans.

Moreover, some of the matching genes can actually function in completely different ways than in humans [9].

Physiological differences

Another reason is that mice have different physiological systems than humans. in addition to varying organ functions [10]. 

For instance, mice are significantly smaller than humans; their basal metabolic rate—the rate of energy usage at rest to maintain vital activities like breathing—is much lower.

Complex diseases in humans that mice cannot replicate

Lastly, current science does not permit us to accurately replicate the pathology of some complex diseases that affect humans, an example of which is Alzheimer's disease [11]. 

Although drug trials have succeeded in treating this condition in mice, there is still no way to cure it in humans.

Case Studies of Drug Failures

One of the most high-profile drug failures in recent years was the Alzheimer's drug aducanumab, developed by Biogen [12]. 

Aducanumab was designed to target beta-amyloid plaques in the brain, which are believed to be a key factor in the pathology of Alzheimer's disease. 

The drug showed promising results in early-stage clinical trials. Despite this, these hopes were shattered in March 2019 when Biogen announced the discontinuation of Aducanumab after an independent data monitoring committee found that the outcomes obtained in mice thus far were unlikely to carry over to humans.

The cancer drug bavituximab, developed by Peregrine Pharmaceuticals, is another example of this.

Bavituximab was designed to bind to phosphatidylserine: a protein found on the surface of cancer cells believed to promote tumor growth and metastasis. 

Likewise, trialing on this drug was stopped after phase III failed to show survival advantages when compared to placebo use.

Ethical concerns

Criticisms of animal testing

The use of animals in research perpetuates the notion that their lives are less valuable than those of humans, reinforcing a speciesist hierarchy that is morally unjustifiable. 

In recent times, scientists as well as ethicists have broadly acknowledged that animals are  indeed capable of experiencing pain [13]. 

In many cases, animals are subjected to invasive procedures and confinement, causing immense suffering.

Alternatives to animal testing

Companies are increasingly looking into alternative ways of testing drugs that can provide reliable data without animal involvement. 

One promising new technique is in-vitro drug experimentation: using human tissues in a controlled laboratory environment to study the effects of drugs. 

This has the potential to even yield more extrapolatable data compared to animals. 

Another promising example is computer modeling and simulation, which can anticipate drug impact on the human body algorithmically using existing data.

Role of regulation

Regulatory bodies are responsible for establishing guidelines that govern the use of animals in research.

These regulations often require researchers to justify the use of animals in their experiments, demonstrate that no viable alternatives are available, in addition to minimizing the number of animals used and any suffering they might experience.

Improving preclinical studies

Developing humanized mouse models

Humanized mouse models are created through the introduction of human genes, or cells into mice, creating an organism that can better mimic human biology [14]. 

Various human cells have successfully been engrafted in mice, including immune system components, liver cells, skin tissues and pancreatic islets. 

This enables us to study autoimmune and infectious diseases like HIV, allergic reactions to drugs, and many other medical conditions which were previously impossible to replicate.

Using alternative animal models

While mice have long been the preferred animal model, there are instances where alternative animal models may be more informative.

The zebrafish, a small freshwater fish that has gained popularity in recent years due to its genetic similarity to humans and its transparent embryos, allowing an unparalleled level of head-on and non-invasive examination throughout embryonic development [15]. 

Zebrafish have been used to study a wide range of human diseases, including developmental conditions, cardiovascular diseases, and neurological disorders. 

Their rapid development and ease of genetic manipulation make them an attractive model for high-throughput drug screening and functional genomics studies.

One other plausible model is the fruit fly, or Drosophila melanogaster. 

Although more distantly related to humans than mice or zebrafish, fruit flies have been instrumental in uncovering fundamental principles of neuroscience thanks to their relatively simple nervous system [16]. 

The fruit fly helped to provide us with great insights into the molecular basis of learning, memory, and behavior.

Future of drug development

There is now emerging tech that’s expected to revolutionize the current drug testing landscape. An example of these is personalized medicine [17]. 

As we move away from a one-size-fits-all approach to medicine, researchers will need to develop new methods for testing drugs that account for the unique characteristics of each patient. 

This may involve the use of biomarkers to predict a patient's response to a particular drug or the development of companion diagnostics that can help guide treatment decisions.

Artificial intelligence (AI) and machine learning is another example, which can only be expected to further speed up the pharmaceutical process [18]. 

Companies are increasingly utilizing these to analyze complex data sets and further facilitate drug analysis .

Clinical trials

Role of clinical trials in drug development

Through a series of carefully controlled phases, clinical trials help to ensure that all new drugs are indeed safe for human use and also effective in addressing the targeted disease. 

All data gathered from such trials are required to be submitted for regulatory approval and introduction of all new therapies, ultimately improving patient outcomes, whether this is a shorter recovery time or fewer drug related side effects.

Importance of selecting appropriate patient populations

Ensuring that the study participants are representative of the intended patients helps to minimize potential biases besides ensuring that the results are indeed generalizable to the broader population. 

A crucial step is careful consideration of factors such as age, gender, ethnicity, and any accompanying health conditions, and verifying that the distribution of these factors within the selected participant group is similar to the targeted patients who will ultimately use the treatment.

Ethical considerations

Researchers must adhere to strict ethical guidelines to protect the rights and well-being of trial participants. 

This includes obtaining informed consent from all participants, making sure that they fully understand all the risks and benefits of the trial and are free to withdraw at any time [19]. 

Furthermore, trial conductors must also be transparent in their reporting of trial results, regardless of the outcome, to contribute to our broader scientific understanding and maintain public confidence in the clinical trial process.

Addressing the challenges

One way to address the challenges of drug trials using animal subjects is to ensure that the animals are treated with the utmost care. 

This includes providing them with appropriate housing, nutrition, and medical care.

Another way to address these challenges is to use computer simulations and in vitro testing as alternatives whenever possible [18]. 

These methods could even provide more translatable information, while simultaneously avoiding inflicting any suffering upon animals.

Frequently Asked Questions

Why do most drugs fail after entering clinical trials?

Common reasons why drug trials fail include unforeseen side effects, lack of efficacy, and poor pharmacokinetics: a term that encompasses how drugs are absorbed, distributed, metabolized, and finally excreted in a particular organism. 

The complex nature of human biology makes it difficult to tell in advance if a drug will pass testing despite promising preclinical results.

What are the problems with using mice in research?

Moral challenges, dissimilar disease progression, and varied responses to treatments versus humans are only some of the problems that need to be taken into consideration. 

These disparities can limit the applicability of findings to humans, which is why comprehensive trials on humans are still required before granting approval to a drug.

Why is animal testing not accurate for humans?

Drug success in animals doesn’t always translate to humans due to anatomical and genetic differences between species. 

Furthermore, some human-specific diseases cannot be accurately modeled in animals. 

These disparities create a lot of misleading data, causing potential harm to humans and wasting a lot of resources after drug trialing on humans fails.

Why is animal testing morally wrong?

Opponents consider drug experimentation on animals to be morally wrong due to the harms inflicted upon sentient beings. 

Critics argue that human benefit is not enough justification to subject animals to pain, distress, or even death, especially when alternative research methods might be available or under development.

Conclusion

In recent years, there has been growing concern over the high failure rate of drugs tested in mice that fail to translate to human clinical trials. 

While mice are a valuable tool for preclinical research, they are not a perfect model for human disease due to several biological differences. 

This, compounded with moral dilemmas, is a major hindrance to the pharmaceutical industry, as well as to patients who are eagerly awaiting new treatments for a wide range of diseases.

Technologies, such as in-vitro testing and computational models, are hoped to prove more convenient and widely-used alternatives.

References

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