Have you ever taken a common pain reliever like ibuprofen or Tylenol? It’s easy to see it as just a simple pill, but that medicine went on a long journey to get to your cabinet, and it passed through many safety checks across clinical trial phases.
Years ago, it started as just an idea in a lab.
Before it was ever given to a person, it was tested on cells and in animals to get an early look at how it might affect a complex, living body and to catch any unexpected or dangerous side effects. This is critical safety step, know as the pre-clinical stage, is designed to protect human volunteers from serious harm when they later join the first phase of a clinical trial.
The pre-clinical stage can be broken into 5 crucial steps:
Data Gathering
Cells tested first: This is where it all begins. A drug idea, which at this point is just a chemical compound, is tested on living cells or tissues grown in a lab dish. Scientists are trying to answer basic questions:
- Does it hit the right target? If a drug is meant to stop a cancer cell from growing or an immune response from occurring, scientists will put it in a dish with cancer or other cells to see if it actually works as expected.
- Is it toxic to cells? They will also test the compound on healthy cells, like liver or heart cells, to see if it harms them. This is an early warning sign that the drug might be too dangerous.
This part of the process allows researchers to test thousands of potential drug compounds quickly and cheaply, weeding out the ones that don’t work or are obviously harmful without ever needing a living creature.
Animal Studies. If a drug looks promising in the lab, it’s then tested in animals. This is a critical safety check because a living body, with all its complex organs, is very different from cells in a dish. During this step, scientists closely watch how the animal’s body processes the drug and look for any harmful effects to determine a reasonably safe dose. This information is essential to know before a drug could ever be considered safe enough to test in people.
Investigational New Drug Application (IND)
After researchers gather data from cell and animal studies, they approach the FDA to ask for permission to begin trials on humans by submitting what is called an Investigational New Drug (IND) application. This is not an easy task. The researchers must submit a detailed report containing:
- Pharmacology Data- data that describes how the drug was absorbed by the animal’s body, distributed, metabolized (how the body broke down the drug and used the pieces for itself), and how it eventually got rid of the drug.
- Toxicology Data- Data from extensive safety studies that show if the drug affects any organs and to identify potential risks and side effects at various dose levels, such as 1mg vs 2mg of the drug
The FDA begins its Scientific Review
Next toxicologists, pharmacologists, chemists, and doctors from the FDA begin its scientific review. Their main goal is to project human volunteers from unreasonable risk. During this review, they are looking for:
- Is there enough evidence of safety? The reviewers analyze the animal toxicology data to identify the No-Observed-Adverse-Effect Level (NOAEL). This is the highest dose tested in animals that did not produce any significant harmful side effects (they are called adverse events in clinical trials). This NOAEL is the single most important data point for determining a safe starting dose in humans, and we will explain later on how this number is used.
- Is the proposed clinical trial designed to be as safe as possible? The sponsor must not only provide the animal data but also submit a detailed plan, or protocol, for the first human study (Phase I). The FDA reviews this protocol to ensure it has proper safety measures in place, such as how the first human volunteers will be monitored and kept safe.
Calculating a Safe Starting Dose for Humans
The FDA doesn’t simply guess at a safe dose. They use a specific, safety-conscious formula to convert the safe dose from animals to humans:
- Calculate the Human Equivalent Dose (HED): Using the NOAEL (the highest safe dose in animals), the FDA uses a standard method based on body surface area to calculate what the equivalent dose would be in a human.
- Apply a Safety Factor: To be extra cautious, the FDA then takes the Human Equivalent Dose and divides it by a safety factor of at least 10.
- What this means is that they take the highest dose that was safe in animals, convert it to what would be a similar dose for a person, and then divide that dose by at least 10. It’s like finding a safe top speed for a new car and then making the first driver go ten times slower just to be certain nothing goes wrong.
The final number is the Maximum Recommended Starting Dose (MRSD) for the Phase I clinical trial. This 10-fold safety margin accounts for potential differences between animal and human biology and helps ensure the first human dose is well below any level that could be expected to cause harm.
The “30-Day Clock” and the Green Light
After the FDA receives the IND application, a 30-day countdown begins.
- If the 30 days pass without any communication from the FDA, the sponsor is officially given the green light to begin the proposed human trials.
- If the FDA has concerns, they will contact the sponsor and may place a “clinical hold” on the study. This stops the trial from beginning until the sponsor addresses the FDA’s safety concerns to the agency’s satisfaction.
In essence, the FDA acts as a crucial gatekeeper, ensuring that a drug has undergone rigorous safety testing and that the first dose given to a human is calculated to be as safe as possible based on all available scientific evidence. This is the first major safety inspection.
References:
U.S. Food and Drug Administration. (1994, August). E4: Dose-response information to support drug registration. https://www.fda.gov/media/71279/download