“Mice lie and monkeys exaggerate” — on the use of non-human primates in HIV vaccine studies

“We don’t really need any more data from animal trials to continue. If we get human efficacy, we’ve got human efficacy, and that’s what matters.”
"Coronavirus vaccine trials have delivered their first results — but their promise is still unclear."
Nature, May 19, 2020.

“We are so ingrained in trying to cure mice that we forget we are trying to cure humans.”

"In the second decade of the 21st century, it is paradoxical that we know more about animal biology than human biology. If the ultimate goal is to advance human medicine and safety testing, then our species must serve as the quintessential animal model, with human biology as the gold standard."

"The trouble is, labs can't just use whatever animal they have lying around to start testing their shiniest Covid-19 vaccine. Not every animal is susceptible to the virus, and those that are may not show signs of disease. Even if they do get sick, that doesn't mean their symptoms match the ones doctors hope to prevent and treat in humans, which can run the gamut from almost unnoticeable cough to life-threatening lung injury."

“It’s funny how the virus can have such devastation in humans, and then you can give a million particles to a mouse and it’s inert.”

“If you don’t have animals getting sick, it’s hard to know what you’re doing.”

Unfortunately, the rodent FOB and Irwin test do not reliably detect some of the most common adverse events observed in Phase I clinical trials, namely headache, nausea, dizziness, fatigue/somnolence, and pain as these methods were not specifically designed to detect these findings or are not sensitive enough to detect them. This lack of concordance between the standard rodent neurofunctional assessment studies and adverse events in humans is a concern and highlights the need for better and more predictive preclinical tools and models.

“This idea of resistance to change has been a reoccurring topic within CDER/OND for many years. It is particularly relevant to the modernization of toxicology for our staff.”

“We have been talking about toxicologists and their fear of accepting new approaches (e.g., in vitro tests). This issue obviously will be true of any scientist, not just toxicologists.”

“It is difficult for evolving institutional practices to keep pace with revolutionary advances in science and technology.”

“Over the ensuing decades, significant investments in technology development and biomedical research have resulted in many transformative scientific breakthroughs necessary for implementing the NRC vision. However, these advances have yet to be met with a concomitant increase in our ability to more accurately predict the adverse human health effects caused by ubiquitous exposure to xenobiotic chemicals…. This translational impact is attributable, at least in part, to rapid scientific advancements outpacing the change in institutional standards required for their effective utlization. Specifically, legacy test methods … developed using animal models cannot always evaluate the nuances of human pathophysiology and genetic variability important for modern safety risk assessment.”

“Left unaddressed, this growing disparity between new scientific advancement and regulatory policy could soon impede our ability to capitalize on the remarkable knowledge and tools arising from projects such as ToxCast, Tox21, Human Tissue Chips, and the Precision Medicine Initiative.”

Human biochips “will mostly replace animal testing for drug toxicity and environmental sensing, giving results that are more accurate, at lower cost and with higher throughput”

“On the question of human in vivo testing, it is widely held to be unethical to use humans as experimental subjects in the assessment of new medicine safety and efficacy. However, we must recognize that we are in fact doing exactly that. It is established that in excess of 90% of potential medicines that have successfully passed the preclinical testing process fail, on the basis of safety and/or efficacy, when evaluated in human subjects. It is clear that human subjects, be they healthy volunteers or patients, are currently the most powerful contributors to the identification of clinical suitability. The obvious failure of animal-based preclinical testing to ‘weed out’ the unsuitable leaves the eventual human recipient as the real arbiter on this issue. If we cannot do any better than this, then we must acknowledge the key role human subjects play in the process, and consider how best to minimize the possibility of harm to them.”

“We live in an era of unprecedented innovation in pharmaceuticals, diagnostics, medical devices, and food and nutrition science. Such innovation offers unprecedented opportunities to advance and improve public health. It is essential that we at FDA keep pace with these changes, especially the evolving science that underpins them, in order to fulfill our regulatory responsibilities effectively and efficiently.”

“Right now, we spend 15 years and half a million dollars or more in development, the drug gets tested in 10,000 patients and usually fails. You then do statistical number crunching to find the subpopulation that might respond, and if you’re lucky you find it, and then have to repeat the process. These (developments) allow you to take advantage of primary cells and stem cells from patients and you can do it for subpopulations.”

“NCATS aims to get more treatments to more patients more efficiently,” said NCATS Director Christopher P. Austin. “That is exactly why we are supporting the development of human tissue chip technology, which could be revolutionary in providing a faster, more cost-effective way of predicting the failure or success of drugs prior to investing in human clinical trials.”

“When I read the paper, I was stunned by just how bad the mouse data are,” Dr. Fink said. “It’s really amazing — no correlation at all. These data are so persuasive and so robust that I think funding agencies are going to take note.” Until now, he said, “to get funding, you had to propose experiments using the mouse model.”

"If I did something in my academic lab that was wrong 50-60% of the time, even 30% of the time, people would think I was nuts, but that’s how this industry works. We need to change how we approach this."

"We have moved away from studying human disease in humans. We all drank the Kool-Aid on that one, me included." With the ability to knock in or knock out any gene in a mouse — which "can't sue us," Zerhouni quipped — researchers have over-relied on animal data. "The problem is that it hasn't worked, and it's time we stopped dancing around the problem... We need to refocus and adapt new methodologies for use in humans to understand disease biology in humans."

"A major problem in the pharmaceutical industry right now is that the drug development model is actually broken. It just does not work. It takes many, many years to get a drug to market, its incredibly expensive, innumerable animal lives are lost and then the results from animals usually don't predict what happens in humans. So this is a huge cost to the economy and to the pharmaceutical industry."

"The adoption of the precautionary principle by the regulatory authorities and the relative ease with which this burden of proof is accepted by the pharmaceutical industry without attempts to improve the current paradigm has created a stalemate in which animal studies, predictive or not, continue to exist with little room for innovation. Stakeholders in industry, academia, and regulatory agencies, need to critically assess animal studies and discuss their predictive value in all earnestness and with the scientific facts at hand. From this, possibilities based on scientific facts may develop which allow new technologies to be implemented that predict the safety and efficacy of therapeutics equal to or better than animal studies do. A way forward would be for the pharmaceutical industry to share clinical and laboratory data generated at all stages of product development with collaborating stakeholders, to enable a complete and transparent analysis of the predictive value of animal studies for drug development."

"Testing the toxicity of pharmaceutical candidates in lab animals to support the safety for human clinical trials is notoriously unreliable. Often compounds that appear safe in rodents prove to be toxic in humans."

"The use of small and large animals to predict safety in humans is a long-standing but not always reliable practice in translational science. New cell-based approaches have the potential to improve drug safety prediction before use in patients."

"With earlier and more rigorous target validation in human tissues, it may be justifiable to skip the animal model assessment of efficacy altogether.”

"Indeed, because oncology drugs have a success rate of only 5%, it is clear that animal models are only marginally effective."

"Mice are mice, and people are people. If we look to the mouse to model every aspect of the disease for man, and to model cures, we're just wasting our time.... [The mouse] has cost us a new generation of medicines... The vast majority of the money that we spend in clinical trials based on mouse data is completely wasted... We keep getting led down the garden path. We've had thousands of mouse studies of tuberculosis, yet not one of them has ever been used to pick a new drug regimen that succeeded in clinical trials. This isn't just true for TB; it's true for virtually every disease. We're spending more and more money and we're not getting more and more drug candidates."

"We want to migrate away from animal testing. We also want to see drug development become more efficient so that fewer resources are wasted."

"Along the path to marketing, the product is subjected to a series of evaluations to predict its safety and effectiveness and to enable its mass production. Despite extensive investment in basic biomedical science over the past three decades, there has been very little change in the science of the development process. The sophisticated scientific tools used in drug discovery and lead optimization are generally not utilized in the pre- clinical and clinical development stages. Instead, traditional empirical evaluation is used in both animal and human testing. We are using the tools of the last century to evaluate this centurys advances."

"We have learned well how to treat cancer in mice and rats but we still can’t cure people."

"Currently, nine out of ten experimental drugs fail in clinical studies because we cannot accurately predict how they will behave in people based on laboratory and animal studies."

"Consider just one stark statistic: Today, nine out of 10 compounds developed in the lab fail in human studies. They fail, in large part because they behave differently in people than they did in animal or laboratory tests."

"Even when drugs with evidence of anticancer activity in preclinical in vivo models are given at their maximum tolerated doses, they frequently fail to produce useful activity in humans."

"You really have to design the medicine for the species of interest ... You'll find it very rare to find a medicine that will work in both."

"Given that many of these investigational anticancer drugs eventually fail, the animal models on which clinical trials are predicated must at best be limited in power, and at worst wildly inaccurate."

"The problem with animal carcinogenicity tests is not their lack of sensitivity for human carcinogens, but rather their lack of human specificity. A positive result has poor predictive value for humans."

"Most of the animal tests we accept have never been validated. They evolved over the past 20 years, and the FDA is comfortable with them."

"It's been well known for maybe two decades that many of these preclinical human cancer models have very little predictive power in terms of how actual human beings — actual human tumours inside patients — will respond ... Preclinical models of human cancer, in large part, stink ... Hundreds of millions of dollars are being wasted every year by drug companies using these [animal] models ..."

"The main causes of failure in the clinic include safety problems and lack of effectiveness: inability to predict these failures before human testing or early in clinical trials dramatically escalates costs. For example, for a pharmaceutical, a 10-percent improvement in predicting failures before clinical trials could save $100 million in development costs per drug."

"The traditional tools used to assess product safety animal toxicology and outcomes from human studies have changed little over many decades and have largely not benefited from recent gains in scientific knowledge. The inability to better assess and predict product safety leads to failures during clinical development and, occasionally, after marketing.”

"Despite some efforts to develop better methods, most of the tools used for toxicology and human safety testing are decades old."

"In the face of these shortcomings, many experts believe the scientific value of the 2-year bioassay is highly limited – barely worth the investments in personnel, animals, money, and time."

"HIV/AIDS [animal] models have not yielded a clear correlate of immunity nor given consistent results on the potential efficacy of various vaccine approaches."

"The standard carcinogen tests that use rodents are an obsolescent relic of the ignorance of past decades."

"Ultimately, the answers to many of our questions regarding the underlying pathophysiology and treatment of stroke do not lie with continued attempts to model the human situation more perfectly in animals, but rather with the development of techniques to enable the study of more basic metabolism, pathophysiology and anatomical imaging detail in living humans."

"Candidate antivirals have been screened using in vitro systems and those with acceptable safety profiles have gone directly into humans with little supportive efficacy data in any in vivo [animal] system. The reasons for this are complex but certainly include the persistent view held by many that there is no predictive animal model for HIV infection in humans."

"We always have a battle on the issue of what to do with the animal data."

"So much evidence has accumulated that chemicals frequently have wholly different effects in animals and humans that officials throughout government and industry often do not act on the studies findings."

"The US National Cancer Institute tested 40,000 plant species on animals for anti-tumor activity. From all this, all positive animal results were useless for humans. A lab handbook concluded, despite 25 years of intensive work and positive results in animals not a single anti-tumor drug emerged from this work."

"We have relied too heavily on animal testing, and we believed in it too strongly. Now, I think we are commencing to realize that what goes on in an animal may not necessarily be applicable to humans."

"The US National Cancer Institute treated mice growing 48 different human cancer with which they had been implanted. They used 12 different drugs which were proven successful in humans, and in 30 cases the drugs were useless in mice."

"The history of cancer research has been a history of curing cancer in the mouse," said Dr. Richard Klausner, director of the National Cancer Institute. "We have cured mice of cancer for decades--and it simply didn't work in humans."

“The extensive animal reproductive studies to which all new drugs are now subjected are more in ...the nature of a public relations exercise than a serious contribution to drug safety."

"The methods of assessing toxicity in animals are largely empirical and unvalidated...It is urgently necessary to know whether the tests as in fact conducted have sufficient predictive value to be justifiable, or whether they are a colossal waste of resources to no good purpose."

"Drugs known to damage the human fetus are found to be safe in 70% of cases when tried on primates."

"...there is no ideal animal model to extrapolate teratogenicity results to human exposure because of species sensitivity and species difference."

"Extrapolating from one species to another is fraught with uncertainty...For almost all of the chemicals tested to date, rodent bioassays have not been cost- effective. They give limited and uncertain information on carcinogenicity, generally give no indication of mechanism of action, and require years to complete. [They are] rarely the best approach for deciding whether to classify a chemical as a human carcinogen."

"Surely not even the most zealous toxicologist would deny that epidemiology, and epidemiology alone, has indicted and incriminated the cigarette as a potent carcinogenic agent, or would claim that experimental animal toxicology could ever have done the job with the same definition."

"Animal studies are done for legal reasons and not for scientific reasons. The predictive value for such studies for man is meaningless which means our research may be meaningless."