The Problem of Animal Studies in Drug Discovery

[Picture Source: SciTech Europa]

Drug discovery is exhausting as it is long, expensive, and risky, but still, it doesn't guarantee whether the discovery is a success or not. From 798 drugs investigated between 1991 and 2015 at 36 academic institutions in the United States, the success rates were 75% at phase I, 50% at phase II, 59% at phase III, and 88% at the new drug application (Takebe, Imai, & Ono, 2018). These numbers clearly show that some discoveries end up with failure. Even more pathetic, this paper also observed a very low success rate in the drug discoveries of the disease in the nervous system. The success rates were 5% at phase I, 4% at phase II, and 3% at phase III. In agreement, Kaitin & Milne (2011) also found that the success rate for neuropsychiatric drug candidates was dramatically lower than 8.2% so we may say that fro these discoveries, mostly they have invested so many times and costs, yet ending up with failures still cannot be denied. Of course, we don't want to waste times and more money, so this problem should be resolved for a better future of drug discoveries. 

One of the reasons why the success rate is low for some cases of drug discoveries is the uncertainty in the translation of preclinical experiments to clinical trials. The uncertainty in the translation means the results from animal studies cannot surely represent what will also happen in human studies. Collins, the director of NIH (National Institutes of Health) gave a warning that 80%-85% of drugs effective in mice are ineffective in humans (Collins, 2013). More real examples, thalidomide is not a teratogen in many animal species, but teratogen in humans (Lepper, Smith, Cox, Scripture, & Figg, 2006) and the monoclonal antibody TGN412 is fine during preclinical studies but life-threatening morbidity during the clinical trials in all six healthy volunteers (Attarwala, 2010). That's why some researchers are questioning the relevancy of animal studies to human studies.

There might be some reasons why the relevancy is low. A paper mentioned that it happened because of the lack of robustness from animal to human studies (Lowenstein & Castro, 2009). Robustness is the ability to withstand various conditions or rigorous testing. How come it will have good robustness when usually the animal studies are conducted in a very narrow set of experimental conditions? Meanwhile, in the context of human, humans are varied by age, genetic, geographic, and so on. Thus, the animal studies should be performed in wider set of experimental conditions in order to mimic the real conditions in human. 

For more details why do we need wider set experimental conditions of animal studies is because of the animals being studied themselves are varied in the term of species and strains that with this, firstly, the animals have a variety of metabolic pathways and drug metabolites, leading to variation in efficacy and toxicity. Secondly, there are variations in the drug dosing schedules and regimens in the animal studies that make the adjustment to the human become more complicated. Thirdly, the animal studies are varied in the case of methods of randomization, choice of comparison therapy (none, placebo, vehicle), and the number of experimental groups that are usually small, so it makes the statistical power becomes inadequate (Pound, Ebrahim, Sanderdock, Bracken, & Roberts, 2004).

As a matter of fact, the failure of the translation is not only occurred when the experiments are poorly designed, conducted, and analyzed as already mentioned earlier, but also due to limited animal models that can fully mimic the disease, even there are some diseases without available animal models at all. As an example, King (2018) mentioned that no animal model for Alzheimer's disease was available. This is because no organisms have the same complexity with human brain as human brain is the most complex brain among all organisms. This may also the reason why the success rate of the drug discovery for neural diseases is very low since it also correlates with human brain that the translation from animal models for Alzheimer's disease. 

In another side, some researchers have moved away studying human diseases from animal study. They refocus and adapt new methodologies to understand biology in humans. The alternatives they are studying are in-vitro testing, computer (in silico) modeling, research with human volunteers, and so on. For the case of in-vitro testing. Harvard's Wyss Institute has created a tool named "organs-on-chips" that as its name, the human cells are grown in a state-of-the-art system on a chip to mimic the structure and functions of human organs and organ system so the chip can be used for studying the disease, drug testing, and toxicity rather than using the animals. Organs on a chip is based on microfluidic technology that has rapidly develope as a powerful tool for numerous applications that one of the applications is for this case. The microfluicdic technology provides articficial testing subject that can resembles the human body in every aspect so this tool has enormous potential to accommodate cells/tissues to create a physiologically relevant environment that animal studies may not able to afford (Sosa-Hernandez et al., 2018).

Computer (in silico) modeling, another alternative besides in-vitro testing, allows researcher to study the human biology and the progression of developing diseases without harming the animals through a sophisticated model computer. For example, Quantitative structure-activity relationships (QSAR) that has been developed with an estimation that can accurately predict the ways the new drugs will react in the human body. It was Veith who was pioneering the development of QSAR that through the International QSAR Foundation, he organized some experts with the same value to develop non-animal testing methods (Sullivan, Manupello, & Willet, 2014).

Meanwhile, research with human volunteers, another choice for the alternative, introduced a method called "microdosing" that provides vital information before applying it to the large-scale human trials so with the help from imaging techniques a very small doses of a drug given to the volunteers can be monitored so the way how the drug behaves can be seen in the body. The use of microdose might have prevented the tragedy with TFN1412 mentioned earlier that was life-threatening for the subjects because the microdose study with TGN1412 by systemic dermal application could have determined the amount of antibody without risk to the subjects and even can provide pharmacokinetic and metabolic data relevant to the human species (Langley & Farnaud, 2010).

In summary, as we don't want to waste times and more money on a drug discovery that the success rate is very low, at least there are two choices: to develop wider set of experimental conditions in animal studies or to select the alternative methods without animal testing (in-vitro testing, computer (in silico modeling), and research with human volunteers (microdosing). Whatever it is, of course, we hope a better future for the drug discovery.

(Disclaimer: this is my essay submitted for my master course assignment)



References:

Attarwala, H. (2010). TGN1412: From discovery to disaster. J Young Pharm, 2(3), 332-336.

Collins, F. (2013). Of mice, men and medicine. [http://directorsblog.nih.gov/of-mice-men-and-medicine/comment-page-1/#comment-4902].

Kaitin, K. I., & Milne, C. P. (2011). A dearth of new meds. Sci Am, 305, 16.

King, A. (2018). The search for better animal models of Alzheimer’s disease. Nature (London), 559, S13-S15.

Langley, G., & Farnaud, S. (2010). Microdosing: safer clinical trials and fewer animal tests. Bioanalysis, 2(3), 393-395.

Lepper, E. R., Smith N.F., Cox, M. C., Scripture, C. D., & Figg, W. D. (2006). Thalidomide metabolism and hydrolysis: mechanisms and implications. Curr Drug Metabol, 7, 677–685.

Lowenstein, P. R., Castro M. G. (2009). Uncertainty in the translation of preclinical experiments to clinical trials. Why do most phase III clinical trials fail?. Curr Gene Ther, 9(5), 368–374.

Pound, P., Ebrahim, S., Sandercock, P., Bracken, M. B., & Roberts, I. (2004). Where is the evidence that animal research benefits humans? BMJ, 328, 514–517.

Sosa-Hernández, J. E., Villalba-Rodríguez, A. M., Romero-Castillo, K. D., Aguilar-Aguila-Isaías, M. A., García-Reyes, I. E., Hernández-Antonio, A., & … Iqbal, H. (2018). Organs-on-a-chip module: a review from the development and applications perspective. Micromachines, 9(10), 536.

Sullivan, K. M., Manuppelo, J. R., & Willett, C. E. (2014). Building on a solid foundation: SAR and QSAR as a fundamental strategy to reduce animal testing. SAR and QSAR Environmental Research, 1-9.

Takebe, T., Imai, R., & Ono, S. (2018). The Current Status of Drug Discovery and Development as Originated in United States Academia: The Influence of Industrial and Academic Collaboration on Drug Discovery and Development. Clin Transl Sci, 6, 597–606.