How To Improve Preclinical Studies

As of December, 2022, the U.S. Food and Drug Administration (FDA) no longer requires that new medicines be tested on animals. The European Medicines Agency (EMA), as well as many other regulators around the world, are also working to minimize the use of animals in drug development. 

The tide is turning. But non-animal models, including computational, biochemical, or cell-based systems, are still relatively new. In some cases, these new approach methodologies (NAMs) can outperform animal models. For the time being, however, our industry is still heavily reliant on animal testing. And while it can be helpful, it’s also inefficient, expensive, and time-consuming. And the data produced doesn’t always reflect how a drug substance will behave inside a human. 

As we wait for non-animal models to improve, there are a number of things that researchers can do to improve the quality of the data gathered during in vivo testing, starting with how in vitro tests are currently conducted.

Common Issues With In Vitro Testing

Technology has come a long way, but drug developers still face common challenges during in vitro testing that can hamper the effectiveness of subsequent animal trials:

• 2D cell cultures and animal cells don’t replicate the complexity of tissues inside the human body 
• Standard toxicity assays are often inaccurate 
• Without the presence of important drug transporters or enzymes, it’s very difficult to predict how a drug will be absorbed, metabolized, and excreted (ADME)
• In vitro testing is known for inconsistencies and cross-contamination issues
• Cell lines used are often altered or lack diversity 
• How drugs are often dissolved for in vitro testing is not representative of how drugs are dissolved in the human body
• It’s difficult to simulate and assess more long-term effects in the body

Recommended Advancements for Improved Prototype Formulation

The drug development process will never be without risk. Cost will always be an important consideration, and preclinical studies may never provide the type of ironclad data that a pharmaceutical investor is hoping to see. However, just a few strategic improvements made in this phase of development are relatively low-hanging fruit, and they tend to pay off. 

For example, not all drug developers use in vitro models that match regulatory expectations. And sometimes, that mismatch necessitates having to conduct additional animal studies. 

Organs-on-a-chip technology (which attempts to simulate more complex organs like the liver or the heart) is still evolving. But preclinical researchers have also found success using 3D cell cultures (cells that are allowed to grow in all directions), organoids (scaled-down versions of human organs), and multiple cell types grown together (co-culture systems) to better predict toxicity, metabolism, and potential side effects.

Of course, which, if any, of these recommendations would be most valuable depends on the drug substance in question, as well as the condition and patient population it’s intended to treat. So while many biotechs hesitate to partner with a skilled formulator early on in the process, that’s often when a CDMO can save their clients the most money without increasing risk.

Scientific Drawbacks to In Vivo (Animal) Testing 

We very much hope at Corealis that in our lifetimes, technology can replace the need for animal testing. It’s ethically concerning, and the results are sometimes woefully inaccurate for the following reasons. 

1. Pharmacokinetics and Pharmacodynamics Are Fundamentally Different in Animals

Pharmacokinetics (PK) refers to how a drug moves into and through the body; pharmacodynamics (PD) refers to how a drug affects the body. 

Both PK and PD can be very different in animals. They have different GI tracts, and, therefore, different capacities to absorb and excrete drug substances. Those differences can often mean that animal models are poor predictors of drug safety. Incidentally, this is one reason why 30% of clinical trials fail due to unexpected toxicity — a risk that preclinical studies are supposed to address.

2. Laboratory Conditions Introduce Other Variables

While we scientists like to think of a lab and a laboratory experiment as a neutral, impartial setting, they are anything but for animals used in preclinical research. 

We know that stress can significantly impact an animal’s metabolism, immune response, and overall health and behavior. So, it can be difficult to isolate the effects of a drug substance compared to the effects of prolonged stress, confinement, and an artificially controlled diet. 

3. Laboratory Animals Don’t Reflect Natural Diversity

Many lab animals are bred to be genetically homogeneous in an effort to reduce variables. Unfortunately, that lack of genetic diversity has also contributed to high clinical trial failure rates. 

4. Studies Often Have a Limited Duration

While many human diseases are chronic, lab studies are typically short-term, which means that longer-term effects will often go undetected. 

5. The Same Diseases Often Affect Animals Differently

Generally speaking, even animals that experience the same diseases we do will experience them very differently, especially when it comes to chronic degenerative diseases that many researchers are trying to treat. 

Technological Advances That Can Help Predict a Drug’s Absorption Profile

At Corealis, we are connecting with scientists from Kanadevia Corp and Innoreal to discuss how their novel predictive dissolution technology can help our clients reduce cost, save time, and eliminate unnecessary animal testing. 

The technology may still be in its infancy, but as I mentioned earlier, regulators are already indicating that they’ll be receptive to its use in some projects. 

But as this technology continues to advance, there are other things that skilled formulators can do to bridge the gap between animal and human digestive and excretory systems. 

How To Avoid Common Issues When Transitioning to Human Trials

Because animals — especially small rodents — eliminate drugs far more quickly than humans, skilled formulators can sometimes account for some of these differences during testing. For example, a drug’s half-life can be lengthened in rodents to better mimic the human excretory process. 

Additionally, while animal trials typically will include testing different doses, testing how frequently a dose is given is far less common. However, some drugs tend to work much better when they achieve a certain concentration over a period of time. 

When dosage interval testing is included, many researchers have found that they get more valuable data about which PK and PD factors are critical to a treatment’s efficacy. Omitting this type of testing can adversely affect clinical trial results. 

Getting the Data You Need Without Sabotaging Your Budget

In many other industries, outsourcing a part of your business can add cost. In ours, where risk and reward can both be significant, a skilled CDMO that’s been in the business for quite some time will, almost by definition, understand how to reduce the first and maximize the latter.  

And, in many cases, depending on the drug substance and the condition you’re hoping to treat, a CDMO might also find good opportunities to potentially cut back on the number of tests or prototypes, for example, without adding significant risk. 

That’s certainly what we do for our clients, so they can make informed decisions throughout preclinical studies and beyond. Ultimately, making oral solid dosage (OSD) drug development faster, more profitable, and a more rewarding process for all involved is what we’ve focused on since 2005. 

Haven’t heard of us before? That happens! We’re not the biggest CDMO in the business, but that means we can always offer our clients our “A-team”. You’re welcome to check out our upcoming event schedule to find good opportunities to connect with us, or click the link below to learn more about our formulation development services!