Preclinical Studies in Drug Development

If I were to show you a vial of liquid and said that it was a cure for STXBP1 and I wanted to inject your child with it, what would be your reaction? 

At first you might be excited, but soon you would probably be asking a lot of questions, like:  What exactly is in the vial? How does it work? What evidence do you have that it works? Where did you get it? And, importantly, is it safe? 

All are excellent questions. And these, and similar questions, are what preclinical studies are designed to answer. In very broad terms a preclinical study is any study that is not performed in people. In more specific terms, preclinical studies refer to a phase in drug development.

The Drug Development Process

The drug development process is long and regulated. What I mean by regulated is that there are agencies, like the Food and Drug Administration (FDA), that require specific types of data be collected about a drug before it can be tested in people. Generally, drug development includes a drug discovery phase, during which drug candidates are identified, a preclinical phase where drug candidates are tested to determine if they work and if they are safe, and clinical trial phases where drug candidates are tested for safety and efficacy in people. This process is summarized in Figure 1.

There are two basic categories of drugs. Chemical drugs are small-molecule medicines that can be taken orally or that may be administered in various other forms, such as injection, infusion, transdermal patch, or inhalant. Biologic drugs are proteins, antibodies, peptides, most gene therapies, and some vaccines that are usually injected or infused. These two categories of drugs have different regulatory requirements due to the way they are made and how the body processes them once they are administered to a person. The table below summarizes some major differences between these two drug classes.

The drug discovery phase begins in the laboratory of either a university researcher or a pharmaceutical company. Someone has new insight in a disease process and how this might be used to treat the disease or may have a new technology, such as gene editing, that might be useful in treating a disease. From this starting point potential drug candidates are developed. Drug discovery can take years of research and include a multitude of studies, including the development of animal and/or cell models of the disease and initial testing of drug candidates in these models.

For example, I spent several years at the University of Pittsburgh doing drug discovery research. Our team of scientists would identify a neurological condition, like chronic pain, that we thought we might be able to treat. We would design and construct different gene therapy drugs that we thought might be useful. We tested these drugs, first in cells and then in animal models, and identified which drugs appeared to work best. All of this work is intended to provide what is called ‘proof-of-concept’, that is, proof that your drug candidate, or candidates, have the potential to treat the disease or condition.

Preclinical Studies in Drug Development

Once a drug candidate is identified, it enters the preclinical phase of drug development. This usually involves a set of studies designed to address specific concerns from regulatory agencies like the FDA or European Medicines Agency, or EMA. 

There are many different preclinical studies that can be, or are required, by regulatory agencies that need to be performed, but they tend to address two basic concerns: 1) drug dosing, and 2) drug safety.

It may seem to be an obvious point, but it is important to identify a biologically active dose for a drug. This is a dose of the drug that will have an effect on the disease you are trying to treat. It is also important to identify the best way to administer the drug. For example, will it be taken by mouth (swallowed), injected into the blood or body tissues, applied to the skin, or inhaled. 

This may seem simple but can be difficult to determine. For chemical drugs and some biologic drugs like antibodies, you need to know how long it takes a drug to become effective once it is taken, and how long a drug remains in the body once it is taken (these types of drugs are naturally removed from the body over time). This information can tell you how often you need to take the drug to maintain an effective dose in the body (for example, once per day, twice per week, once per month). For gene therapy drugs, it is important to know where it goes in the body, that is, its biodistribution, as this might tell you about potential side effects. Since all of this work is ‘preclinical’ it is done in animals and the results used to make a ‘best guess’ at what doses should be tested in people.

The major concern of preclinical studies is safety. There are many studies performed to determine the safety of a drug candidate. For example, does a drug cause cancer, does it cause a DNA mutation, does cause damage to the heart, brain, lungs, kidneys, etc. and at if so at what doses. Some studies examine the potential long term toxic effects of the drug or if the drug has an adverse effect on reproduction or on the development of an embryo or fetus. Other studies focus on environmental impacts that the drug might have or any negative impacts that drug might have with other drugs a person might be taking. These are called drug-to-drug interactions. Still other studies look for potential toxic compounds that might have been introduced into a drug product during its manufacturing process. 

All these safety studies are types of studies that regulatory agencies might require before they would allow a drug candidate to be tested in a person, though the exact type of safety studies required depends on the type of drug being tested. 

The point of all these preclinical studies is to reduce uncertainty. There are inherent risks associated with any drug, what preclinical studies do is reduce the uncertainty of what those inherent risks might be. 

To accomplish this, it is important that preclinical studies be performed on model systems – animal and cellular models – that represent the intended patient population, and what is tested is representative of the final drug that would be used in people. 

For example, for a STXBP1 drug, some preclinical studies might be run in zebrafish or mouse models of STXBP1 to help define what doses improve behavioral outcomes, but certain safety studies might better be conducted in animals more representative of humans in size and physiology, such as pigs or nonhuman primates.

Ultimately, all the preclinical studies that are performed increase our confidence that a new drug candidate will likely be safe and hopefully effective when it is finally tested in people.