Bridging Preclinical and First-in-Human

It’s no surprise that mice are the standard subjects for preclinical research. They are real living things that have real reactions, both positive and negative, to drugs. They’re also not typically associated with the kind of emotional connection that occurs between humans and large pets like cats and dogs. In other ways, however, they are less than ideal. While their differences with humans and larger animals make preclinical research easier to stomach ethically, those differences also make mice imperfect predictors of how a drug will affect human recipients. As they don’t typically get many of the same diseases as humans outside of preclinical research, it can be hard to reliably use them to determine how drugs will impact those diseases.1

These flaws have led some in the research industry to envision a different approach, one that employs subjects more similar to humans before human clinical trials start. In formulating this approach, they have turned to veterinary clinical trials. When dogs and cats get sick, they’re treated with medicinal compounds, just like humans; and, like the medicine we take, those compounds must go through clinical trials before a vet can prescribe them. But dogs and cats are much more similar to humans than mice physiologically, making it more likely that their reactions to compounds will be more analogous to human reactions. They tend to get similar diseases to humans – and they get them in the course of their natural lives, instead of being artificially given diseases in a laboratory setting, which is the norm in research on mice.1 In Europe, regulators already acknowledge the parallels between animal and human physiology, reasoning that a drug that has been deemed safe and efficacious for humans is probably suitable in veterinary scenarios as well;2 in considering the substitution of veterinary clinical trials for traditional preclinical research on mice, researchers are wondering to what extent the reverse is also true.

Benefit for first-in-human trials

Data gathered in clinical trials on pets could benefit human clinical trials as early as Phase I. Because of the physiological similarities between humans and dogs, for example, that data could allow researchers to begin a Phase I clinical trial with clearer expectations regarding the drug’s safety and dosage profile. A head start like this could shorten timelines in a study phase that often suffers from delays, ultimately leading to budget savings as well.

In first-in-human trials for cancer drugs, the benefit could extend even further. While the similarities in disease between dogs and humans are numerous, perhaps the strongest parallel is in cancer.1 And as Phase I cancer trials recruit sick patients instead of the healthy volunteers typical of Phase I, there is a medical need to work as quickly as possible, in addition to a financial one. In these trials, then, the time savings that can come from more predictive preclinical data, in addition to saving money, can keep patients happier and healthier, thereby reducing the high dropout rates that have long been a challenge for Phase I cancer trials.

Benefits beyond first-in-human trials

These similarities in disease tendencies could also give researchers a jump start on determining drug efficacy in later phases. This could lead to better data accuracy, ultimately lowering the troubling rate of drugs that fail to make it to FDA approval. And some have argued that this kind of shift in preclinical research would even boost the veterinary clinical trials industry. Last year, the Journal of Translational Medicine lamented that the number of veterinary clinical trials currently on record was low, and that those that were underway used small cohorts of subjects. If these trials become more widely recognized as a suitable, or even superior, source of preclinical data, it may spark an uptick in veterinary research.

Of course, this link between animal and human clinical trials is still in its nascent stages. While there has been some success – last year, a cancer drug entered first-in-human clinical trials after proving efficacious in dogs3 – there has also been resistance. Conducting drug trials on pets is significantly more expensive than doing so on mice, and it’s important not to overestimate the extent to which an animal’s reaction to a drug can be expected to mirror a human’s reaction. For these reasons, there has been reluctance in both the private and public sectors to funding these trials.1 Still, many are optimistic that, while this approach creates costs early in the research process, it could strengthen and catalyze clinical trials overall.

1 Grimm, David; Can clinical trials on dogs and cats help people?; Science; 11 August 2016
2 Furdos, Irene; Fazekas, Judit; Singer, Josef; Jensen-Jarolim, Erika; Translating clinical trials from human to veterinary oncology and back; Journal of Translational Medicine; 17 June 2015
3 Weintraub, Arlene; Clinical trials in pets pose both challenges and opportunities; FiercePharma; 15 August 2016

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