The 4 Phases of Clinical Trials

Pre-Clinical Development

Before an investigational treatment can be given to people in a clinical trial, sponsors must find out if it might be harmful. They first test the treatment in the lab on cells or animals to see if there are any risks and to prove that it might help patients. Once they have enough information, they ask government regulatory agencies and ethics committees for approval to start clinical trials in humans. [US FDA, Preclinical Research, 2018]

Clinical Development

Before new medical treatments like drugs or medical devices can be used widely, they must first be tested in clinical trials to check if they are safe and work well. The medical treatment being studied is often called an “investigational treatment” because it is not yet approved for use outside of a clinical trial. The information from these clinical trials is then reviewed by government regulatory agencies to see if the investigational treatment should be approved for use.

Most investigational treatments must pass through several stages of research before they can be approved for use. These stages are called “phases.” Each phase has a different purpose and helps answer different questions.

The 4 phases are:

• Phase 1 - Checking safety and dosage
• Phase 2 - Testing effectiveness and side effects
• Phase 3 - Confirming efficacy and comparing to standard treatments
• Phase 4 - Tracking long-term effects after approval

The process is long but important to make sure the treatment works and is safe for people with a certain condition or disease.

Phase 1 clinical trials: Is the treatment safe?

Phase 1 trials check if an investigational treatment is safe in a small group of people, usually fewer than 100. They look for common side effects and find the right dose to use in the next phase. Sometimes, they study a treatment in healthy volunteers or in people with the disease when other treatments are not available or not ideal.

Phase 1 trials study how an investigational treatment behaves in the body and what side effects it might cause. They start with low doses and slowly increase them, watching for harmful side effects. The goal is to find the optimal dose and dosing method (for example, by mouth, infusion into a vein or injection) for treating the condition or disease with the fewest side effects.

Phase 1 trials may also study how the treatment is taken up, moves through, is broken down, and leaves the body. These are called Pharmacokinetic studies. Sometimes these trials check if food or other drugs affect the investigational treatment. Phase 1 trials include many tests, like checking vital signs or blood tests to make sure the treatment is safe.

All this information helps the sponsors design safe plans for the next phases of testing. The main goal of a phase 1 trial is to find safe doses to use in phase 2.

Phase 2 clinical trials: Does the treatment work?

Phase 2 clinical trials usually have more participants, up to several hundred people. They still check the treatment’s safety, but they also start to see if it works for people with the disease or condition.

In these clinical trials, participants who have a specific disease or condition get the study treatment at the safe doses found in phase 1. The research team watches their health and symptoms to see how well the treatment works. For example, researchers may measure tumor size in cancer drug trials or viral load in antiviral medication trials. They also look at specific genes, proteins, or other biological signs (called biomarkers) to study the treatment's effect.

Phase 2 clinical trials give sponsors more information about how safe a treatment is and how well it works before moving to phase 3. Information from phase 2 trials also helps set the goals and research plan for phase 3 studies.

Phase 3 clinical trials: Is it better than what’s already available?

Phase 3 clinical trials collect more information about how safe an investigational treatment is and how well it works. Phase 3 clinical trials usually have many participants, sometimes thousands.

Phase 3 trials will compare an investigational treatment with the current standard-of-care to see if it works as well or better, or has fewer side effects, than what is already available to patients. Some phase 3 trials use a placebo which looks like a treatment but does not have any active product in it. Using a placebo alone without another active treatment (such as standard of care treatment) may not be appropriate in some conditions or diseases.

Phase 3 trials can take many years. Sponsors might study the investigational treatment in different doses or combine the investigational treatment with other treatments. They often study how well it works over a longer time and with different groups of people, like younger or older people and people of different racial and ethnic groups. Participants in these trials should represent the patients who may use the treatment if it gets approved.

Phase 4 clinical trials: What else do we need to know?

While pre-approval trials check safety and efficacy, many questions remain, especially about long-term use. Phase 4 trials watch larger groups of people of different ages, sexes, ethnicities, and with different health conditions. These trials may find side effects that did not show up in smaller, shorter trials. They also look at how the treatment affects patients’ quality of life.

Phase 4 trials might test the treatment for other medical uses, different doses, or new combinations with other treatments. Even though sponsors may want to expand how the treatment is used, safety is still the most important focus.

Summary of clinical trial phases

The 4 phases of clinical trials show the steps for testing investigational treatments thoroughly:

• Phase 1: focuses on safety, dosage and best way to give the treatment in a small number of people
• Phase 2: expands to refine methods, check safety and see how well the treatment works
• Phase 3: large-scale, often international, studies that compare the treatment to the standard-of-care. They provide strong data on risks and benefits
• Phase 4: continues to check safety and gathers real-world data on long-term effects

Each phase builds on the one before, ensuring safety while bringing potential innovative treatments from the lab to patients.

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