How Pre-Clinical Research Contributes to Clinical Trial Safety

Objectives and goals

Once a new treatment or a therapy is identified, the primary goal of pre-clinical research is to assess the safety and efficacy in order to determine which are suitable to advance into clinical trials ( human testing). During the pre-clinical stage, researchers must also evaluate all potential adverse reactions (in non-human animals). Pre-clinical research also provides an opportunity to assess how long any therapeutic effects last, as well as whether an intervention is expected to improve quality of life and overall health outcomes. 

Collectively, this data provides invaluable insight to the researchers and the Therapeutic Goods Administration (TGA) into whether or not a certain treatment is likely to be successful at achieving its desired effects prior to advancing to human clinical trials.

Types of preclinical research

In vitro

In vitro, the Latin for “in glass,” means the experiments are performed outside living organisms, such as cells or tissues from an animal or human. So, in vitro preclinical research involves testing drugs in a laboratory setting using cells grown in a Petri dish.

The benefits of in vitro preclinical studies include low cost, shorter duration and fewer ethical considerations. Additionally, these types of studies can test multiple drugs or treatments simultaneously. However, the drawback is that results may not accurately reflect what will happen when a drug is tested on a multi-system living organism. In the preclinical research pipeline, scientists usually test their idea as a first pass in in vitro systems due to above advantages. If the in vitro result of a drug shows a positive outcome, then the research proceeds to in vivo systems. 

 In vivo

In vivo preclinical research uses laboratory animals to study a new drug’s safety and efficacy. Researchers study the behaviour and biological responses of the animals after being exposed to varying doses of the drug, which helps to determine safe dosage levels for humans.

The main benefit of in vivo research is that it is a reliable way to assess the performance of a drug against a disease of interest in  humans. It allows researchers to observe real-time responses in a multi-system environment that cannot be assessed through isolated cells (in vitro). However, its main drawback is the need for large numbers of animals to be used, raising ethical issues.

When is one preferred over the other?

In vitro pre-clinical research  is generally preferred for ethical reasons and as mentioned above this approach is usually the first option and is commonly performed before in vivo research. In this regard, in vitro studies act as a screening platform for quick and cheap first pass outcomes.

But there are drugs, such as protonsil, that have different effects in cell culture and animals. According to the book Science, Research and Animals, “prontosil, has no effect on bacteria in culture; but when prontosil is given to a mouse, it is broken down by the liver into the antibacterial drug sulfanilamide.” Had it not been tested in animals this discovery would not have been possible. 

It is also important to note, that the in vitro approach is unable to capture the effects of the immune system and how this can contribute to the progression of various diseases and impact the efficacy of different drugs.

There is an entire class of anti-cancer drugs (immune checkpoint inhibitors) that are entirely reliant on the activity of the immune system for their effects.

However, in some cases in vitro systems are essential to study disease mechanisms and mechanism of action of drugs. For example, to understand how and why a disease occurs, scientists need to study the very early stages of disease development (before symptoms start). In these situations, in vitro systems allow genetic and other artificial manipulations that are currently not possible to conduct in living animals.

What preclinical research involves

To determine the safety and efficacy of a potential treatment, researchers conduct several studies and tests, including the following:

Pharmacology

Pharmacology is the branch of medicine and biology that studies the effects of drugs on living animals. It is used to understand how a drug works and how it interacts with the organ systems of the body. There are two arms of pharmacology essential for pre-clinical studies: pharmacokinetics and pharmacodynamics.

Pharmacokinetics is the study of how a drug moves through the body and what happens to it as it circulates. In pre-clinical research, pharmacokinetic studies measure the drug’s absorption, distribution, metabolism and excretion in different species.

Pharmacodynamics, however, is the study of how drugs act on cells, tissues and organs to produce a response. Overall, these two arms are essential to understand how a drug is processed and eliminated by the body. When new drugs are developed in pre-clinical research, it is very important to understand the drug’s pharmacokinetic and pharmacodynamic properties to know its safety and effectiveness in patients. This informs the scientists how much and how frequently the drug should be given and how the drug should be administered (e.g. orally or via an injection).

Toxicology

In addition to pharmacology, preclinical research also studies toxicology, which is the study of the adverse effects of drugs. This includes determining safe dosage levels and identifying side effects. Toxicology specifically assesses single-dose toxicity, repeated-dose toxicity and genotoxicity.

Single-dose toxicity is the study of how a drug affects an animal when given once or on a rare occasion. Repeated-dose toxicity is the study of how a drug affects an animal when it’s given repeatedly. It looks at the drug’s possible long-term effects or accumulation in the body’s tissues. Finally, genotoxicity is the study of any changes in genetic materials caused by drugs, such as mutations and chromosomal aberrations. It helps to identify the carcinogenic potential of a drug.

Others

Other aspects pre-clinical studies need to examine are local tolerance, teratogenicity and fertility impact. Local tolerance assesses the effects of a drug when applied to different parts of the body, such as skin, eyes and nose. Teratogenicity studies look at whether a drug can cause congenital disabilities when given to pregnant women. Fertility studies also determine if drugs interfere with reproductive capacity in males or females.

GLP and Biocompatibility

If developing medical devices, good laboratory practice (GLP) and biocompatibility are also necessary. GLP ensures the quality and consistency of results when manufacturing medical devices. Biocompatibility tests measure the potential for a device to cause an immune reaction in patients when implanted, as well as its longevity.

The Future of Pre-Clinical Research

Thanks to technological advancement, pre-clinical research evolves and improves each day, making the drug development pipeline more reliable, efficient and ethical. For example, organs on a chip(OoC) which are systems containing engineered or natural miniature tissues grown inside microfluidic chips. Organoids is another avenue that allows whole organ mimetics to be grown on a Petri dish.   

Here in Australia, Codex Research engineered the perfusion bioreactor technology “to recreate biological environments that mimic human biology, enabling the growth and study of tissues outside living organisms.” The goal is to grow tissue-like structures from human cells that can withstand physical forces like pressure and flow.

Conclusion

Pre-clinical research is an essential part of the therapeutic pipeline as it helps to not only identify potential safety issues of drugs and medical devices before they reach the general public but also studies disease mechanisms to develop new drugs and devices. This type of research involves a variety of safety tests, such as pre-clinical safety studies, teratogenicity testing and fertility effect assessments.

In the future, pre-clinical research is expected to become more highly efficient due to advances in technology, such as 3D models, which can limit the use of animal model systems and provide more targeted treatments with fewer side-effects.

White Coats Foundation is involved in many wonderful initiatives that are helping to improve clinical research awareness. We encourage everyone to learn more about the importance of research and how research outcomes have the potential to impact lives, even our own.