Before a medicine can ever be prescribed to a sick patient, or a new medical device can be implanted in a human body, it must undergo rigorous, exhaustive testing. You cannot simply invent a chemical and give it to a human being. This lecture covers the entire phase that happens before humans are involved. We will break down every single test, why we use animals, what documents must be filed, and the extreme ethical and scientific importance of this process.
To understand where preclinical trials fit in, you must memorize the timeline of how a drug is born and brought to the pharmacy shelves. The process follows a strict, sequential pipeline:
Preclinical studies, routinely known as nonclinical trials, are extensive laboratory tests of novel drugs (new medications), gene therapy solutions, or medical devices. They are universally conducted on animal subjects before any human testing is allowed.
While we absolutely want to know if the drug cures the disease (efficacy), the absolute primary objective of pre-clinical investigations is determining the eventual safety profile of a product. In medicine, the golden rule is "First, do no harm." A drug that cures a headache but destroys the liver will never be allowed into human trials. We use animals to find these deadly side effects early.
The ultimate goal of all this testing is strictly bureaucratic: to gather the sufficient information needed to file an IND.
An IND (Investigational New Drug) application is a massive dossier submitted to a regulatory agency (like the FDA in the USA, or the NDA in Uganda). It is essentially a request asking for legal permission to test the drug on humans. The agency will only say "yes" if the preclinical animal data proves the drug is reasonably safe to administer to humans.
After identifying a potential compound, it is given to animals to expose its whole pharmacological profile (what it does from head to toe). This follows a strict, stepping-stone approach:
Imagine a pharmaceutical company creates 10,000 different chemicals to cure hypertension. They test them in glass tubes, and 500 show promise. They give those 500 to mice. 400 of those chemicals kill the mice. Those are rejected. The remaining 100 are given to dogs. 95 of them cause liver failure in dogs. Those are rejected. As the evaluation progresses, unfavorable compounds get rejected at each step. Ultimately, only a very few (perhaps 5 out of the original 10,000) will ever reach the stage where administration to man is even considered. This massive failure rate is why developing drugs is incredibly expensive.
When a drug is in the preclinical phase, it is subjected to an exhaustive battery of ten distinct types of tests. You must know what each one aims to discover.
These are extremely quick and easy assays designed to determine a simple "yes or no" question: Is a specific pharmacodynamic activity present or absent? We do not care how it works yet; we just want to know if it works.
Before putting a drug into a whole, living, breathing animal, we often test it on specific, isolated parts in a glass dish. These are screening tests for specific properties.
You cannot test a cure for Tuberculosis on a perfectly healthy mouse. You must use utilized animal models that mimic human sickness.
This is pure, unguided observation. Small groups of mice receive the medication in triplicate dosages (e.g., a low dose, a medium dose, and a high dose). Then, the scientists simply sit and watch the mice carefully. Their overt (observable, obvious, outward) effects and any hidden internal effects are heavily monitored.
Elaboration: We are not looking for anything specific; we are looking for everything. Does the mouse start shivering? Does its tail turn blue? Does it fall asleep? Does it become highly aggressive? From these observations, initial hints are derived to build the drug's observed effect profile.
When a screening test discovers that a compound is active, we cannot stop there. We must use more highly intricate and detailed tests to strictly confirm and fully describe the activity.
Let's say our screening test showed a drug stops pain (Analgesic). We must now ask: Does it have analogous (related/similar) activities? We run a test to see if it also reduces fever (Antipyretic properties) and another test to see if it reduces swelling in a rat's paw (Anti-inflammatory properties). If it does all three, we have just discovered a drug that acts exactly like Ibuprofen!
We know the drug lowers blood pressure. But how does it do it? The MOA investigates the exact molecular lock-and-key biology of the drug. An immense effort is made to determine this mode of action.
For instance: A new anti-hypertensive drug is proven to lower blood pressure in dogs. Scientists will run cellular tests to find out if it is acting as a calcium channel blocker (relaxing the vessel walls), an ACE inhibitor (stopping a specific hormone), an alpha-blocker, or a beta-blocker (slowing the heart rate). Understanding how it works is mandatory before human use.
This is the search for unintended side effects across the entire body. The effects of drugs on the main organ systems (including the neurological/brain, cardiovascular/heart, respiratory/lungs, and renal/kidneys) are studied absolutely regardless of the drug's primary activity.
Elaboration: If you invent a cream to cure athlete's foot, you might think you only need to test it on the skin. Systemic pharmacology says "No." You must still test what happens if the drug enters the blood and hits the heart, the lungs, and the kidneys. If your foot cream accidentally causes a heart attack, the drug will be rejected.
This test deals strictly with mathematics and numbers. It examines:
Note: The lecture slides repeat "dose-response relationship and maximal effects" under this heading, which traditionally falls under pharmacodynamics. However, to fully grasp PK, you must understand it as the study of what the body does to the drug.
In preclinical PK, scientists track the chemical in the animal's blood over time to understand ADME: Absorption (does it get into the blood from the stomach?), Distribution (does it reach the brain or stay in the fat?), Metabolism (how fast does the animal's liver destroy it?), and Excretion (is it peed out in 2 hours or 2 days?). They compare this kinetic efficacy with existing drugs.
This is arguably the most important preclinical step. It purposely seeks to harm or kill the animals to find the exact boundary of safety.
You cannot conduct these tests in a messy, disorganized basement. All of these preclinical tests are legally required to be conducted in strict accordance with Good Laboratory Practice (GLP).
GLP is a rigidly enforced standard operating procedure. It specifically refers to a quality system governing research laboratories and organizations.
The entire purpose of GLP is to try to absolutely ensure the uniformity, consistency, reliability, reproducibility, quality, and integrity of non-clinical safety tests for chemicals (including pharmaceuticals) applicable to man, animals, and the environment.
It covers everything from testing basic physicochemical properties (how a chemical dissolves in water) all the way through acute and chronic toxicity testing.
Imagine a researcher tests a drug on a rat. The rat dies. The researcher throws the rat in the trash and writes in his notebook, "The rat survived and is very healthy." Without GLP, the company might submit fake data to the government, and humans would die during clinical trials. GLP forces laboratories to keep permanent, unalterable logs, maintain calibrated equipment, record cage temperatures, and prove exactly who fed the animals and when. It ensures the data is 100% trustworthy and has total scientific integrity.
Once all testing is done, the pharmaceutical company (the "sponsor") must compile all the data into the IND (Investigational New Drug) application. This must be submitted to the Agency (like the FDA or NDA) and fully approved before the start of any human studies.
The IND must explicitly include details on all potential risks based on the data gathered from the toxicological and pharmacologic investigations in animals.
(Note: Rats and dogs are the most common animals used for these fundamental safety testing requirements.)
The sponsor must provide adequate, undeniable information about the pharmacological and toxicological studies (involving laboratory animals or in vitro glass tests). Based entirely on this data, the sponsor must legally conclude that it is reasonably safe to conduct the proposed human clinical investigations.
This section is broken down into two main parts:
The FDA and NDA have highly strict guidance publications outlining how to comply with these standards. The application must include:
Finally, as drug development moves further into the future, the sponsor is legally expected to submit informational modifications containing any new safety-related data that arises.
Why spend millions of dollars and years of time on rats and dogs before ever touching a human? There are three fundamental pillars:
In the 1950s, a drug called Thalidomide was sold to pregnant women for morning sickness. At the time, preclinical testing on pregnant animals (reproduction and fetus toxicity testing) was not strictly required. The drug was completely safe for adults, but caused severe, horrifying birth defects in over 10,000 babies (missing limbs). Because of this tragedy, modern preclinical trials are ethically and legally mandatory to ensure we never give an untested chemical to humans again.
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