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The FDA removes animal testing requirement for drug candidates

    TransCure bioServices’ CEO Patrick Nef shares his thoughts on what the changes will mean for drug development

    In December 2022, the U.S. House of Representatives gave the final sign-off on the FDA Modernization Act 2.0, changing the face of drug development forever. Now, preclinical testing of drug candidates on non-relevant animals is no longer required for FDA approval. But the safety and efficacy of drug candidates must still be determined before they are administered to humans in phase 1, 2 or 3 clinical trials.

    Although no longer legally required, animal models can still be used to develop an Investigational New Drug (IND) package for FDA approval. However, the changes mean that non-animal-based models, such as in vitro and in silico methods, can be used instead. So, what does this mean for the future of preclinical studies?

    Dr. Patrick Nef, President and Chief Executive Officer of TransCure bioServices SAS, gives his thoughts on the future of drug development in light of the new legislation. Patrick has over 30 years’ experience in R&D and early drug development spanning academia, the biotechnology industry, pharmaceutical companies, and not-for-profit public-private partnership foundations. In 2012, Patrick co-founded TransCure bioServices SAS in France, developing human immune system (HIS) and human liver mouse disease models and CRO services for immuno-oncology, infectious, inflammation and liver diseases.

    Q.) What do the new FDA regulations mean for drug developers?

    A.) This is a very positive change. Many animal models, physiologically, aren’t human-relevant to the treatment that is being studied. How to treat a patient suffering from schizophrenia, for example, can’t be predicted in any animal model. Going forward with the new FDA regulations, developers don’t have to tick unnecessary boxes by performing preclinical testing in models that bear no relevance to the human disease. You do still have to check that your drug candidate is safe up to a certain dosage, though, and that it is efficacious.

    Q.) How do you see this change affecting drug discovery and development?

    A.) It depends on the industry. Traditional drug development by large pharmaceutical companies is like a mammoth walking in the snow — it goes step by step — very slowly. This means that it’ll be years before the new FDA regulations are integrated by large pharmaceutical organizations, allowing them to develop an IND filing (or package) that gives enough data for the drug to be considered safe and efficacious by the regulators.
    The scene is very different when it comes to biotherapeutics — biological products, proteins, peptides, or antibodies. These therapeutics pose very little risk to humans when injected, and they are usually well tolerated. I imagine there will be a minimal preclinical safety package for these products, so biotech companies are more likely to be affected by the FDA changes sooner than large pharma.

    Q.) What alternative models are available for researchers to use?

    A.) There is a whole host of tools available that can support preclinical drug development — in vitro, in silico, and in chemico testing, for example. While these tests are relatively good for determining the safety or toxicity levels of your drug candidate, efficacy is where it hurts. Once you reach clinical phase 2 or 3 with your candidate, you often realize that the treatment doesn’t work against the disease progression or symptoms the way you were hoping it would.
    Even with superb in vitro data, for example using an actual human tumor sample, it might not reconstitute the tumor macro or microenvironment like that found in a cancer patient. So, these models often fail to be predictive of the efficacy in humans.

    Q.) What role do you think animal models will play in future preclinical studies?

    A.) Essentially, what drug developers really want to build is a data package that best indicates the human-relevant efficacy of their preclinical drug candidate. I believe there’ll be a big shift by companies to spend part of their preclinical budget on more relevant animal models, like those that predict human disease progression. So, they’ll favor in vivo pharmacology animal models, especially those that are highly predictive of human disease progression, as they provide a meaningful way to select the best preclinical candidate for their clinical studies.
    As an organization, we’ll provide more services using human immune system and liver mouse models that are truly able to recapitulate human disease progression, making them highly predictive for efficacy and safety. These so-called chimeric mice have human immune cells, human hepatocytes, and can include human cancer cells or human viruses like HIV and HBV, for example. What this means is that we can reproduce more accurate human-human interactions similar to the ones you’d find in a patient.

    Q.) What disease areas will chimeric human-mouse models shine the brightest in?

    A.) Human immune system mouse models are perfect for preclinical drug candidates that target or educate the human immune system to fight cancer, inflammation, or infection. These models also highlight the main safety issues that you need to present to the regulatory bodies by mimicking what is going to happen in the patient. And with human-specific hepatocyte mouse models, you can more accurately predict the toxicity level of the drug you are exposing the mouse to, as it’ll metabolize the drug as if it were a human.
    All these chimeric human-mouse models can mimic inflammation, cancer, or infectious diseases caused by HIV and HBV, so are ideal to select the best preclinical candidates based on your human predictive in vivo pharmacology data package. As long as you’re choosing the most relevant animal models for your drug mode of action, they can be predictive for both efficacy and safety.

    Q.) What do you see for the future of drug discovery and development?

    A.) I think that regulatory bodies will be a lot closer to the actual scientific breakthroughs and what new advancements mean, giving them a better understanding of how to protect and cure patients in clinical studies. For example, drug developers believe that follow-up drugs, or me-too drugs, with slightly different formulations pose little safety risk. But that’s not necessarily true, and even today, there is complete retesting of safety for these types of drugs — they’re being treated as if they’re unknown entities.

    The picture is the same with biosimilars. The way you produce them can create some side products or introduce contaminants, or they may behave differently in different buffers. So, regulators are asking for developers to prove the safety of these preclinical candidates by doing the whole submission from scratch.

    Ultimately, as a drug developer, you want to be sure that your drug candidate is safe and efficacious before it enters human volunteers, and so will receive approval from the FDA, the EMA (European Medicines Agency) and clinicians. Drug developers, therefore, must focus on bringing a package where both human-relevant safety and efficacy have been thoroughly addressed. Human immune and liver system mouse models will be key in providing this predictive data and helping developers move the best new drug candidates forward.

    A brighter future for preclinical studies

    The FDA Modernization Act 2.0 moves drug development in the right direction. While the regulations have the potential to shake up the industry, changes are likely to be slowly implemented. Proving the human-relevant efficacy of a preclinical candidate, as well as its safety in humans, will remain as crucial as ever to progress the most promising drugs and secure FDA approval.

    Preclinical chimeric human immune and liver system mouse models will be a vital tool to help scientists present more convincing data packages. Developers will be able to select the best preclinical candidates, gain higher rates of regulatory approval, and ultimately deliver safe and more effective treatments for patients.

    To learn more about humanized immune system mouse models and their applications, please contact us.