What Are the Phases of Clinical Trials?
Clinical trials are usually conducted in phases that build on one another. Each phase is designed to answer certain questions. Knowing the phase of the clinical trial is important because it can give you some idea about how much is known about the treatment being studied. There are pros and cons to taking part in each phase of a clinical trial.
Although there are clinical trials for devices as well as other diseases and treatments, drugs for cancer patients are used in the examples of clinical trial phases described here.
Phase 0 clinical trials: Exploring if and how a new drug may work
Even though phase 0 studies are done in humans, this type of study isn’t like the other phases of clinical trials. The purpose of this phase is to help speed up and streamline the drug approval process.
Phase 0 studies are exploratory studies that often use only a few small doses of a new drug in a few patients. They test to find out whether the drug reaches the tumor, how the drug acts in the human body, and how cancer cells in the human body respond to the drug. The patients in these studies might need extra biopsies, scans, and blood samples as part of the study process.
The biggest difference between phase 0 and the later phases of clinical trials is that there’s no chance the volunteer will benefit by taking part in a phase 0 trial – the benefit will be for other people in the future. Because drug doses are low, there’s also less risk to the patient in phase 0 studies compared to phase I studies.
Phase 0 studies help researchers find out whether the drugs do what they’re expected to do. If there are problems with the way the drug is absorbed or acts in the body, this should become clear very quickly in a phase 0 clinical trial. This process may help avoid the delay and expense of finding out years later in phase II or even phase III clinical trials that the drug doesn’t act as expected to based on lab studies.
Phase 0 studies aren’t used widely, and there are some drugs for which they wouldn’t be helpful. Phase 0 studies are very small, often with fewer than 15 people, and the drug is given only for a short time. They’re not a required part of testing a new drug.
Phase I clinical trials: Is the treatment safe?
Phase I studies of a new drug are usually the first that involve people. The main reason for doing phase I studies is to find the highest dose of the new treatment that can be given safely without serious side effects. Although the treatment has been tested in lab and animal studies, the side effects in people can’t always be predicted. These studies also help to decide on the best way to give the new treatment.
Key points of phase I clinical trials:
- The first few people in the study often get a low dose of the treatment and are watched very closely. If there are only minor side effects, the next few participants may get a higher dose. This process continues until doctors find the dose that’s most likely to work while having an acceptable level of side effects.
- The focus in phase I is looking at what the drug does to the body and what the body does with the drug.
- Safety is the main concern at this point. Doctors keep a close eye on the people and watch for any serious side effects. Because of the small numbers of people in phase I studies, rare side effects may not be seen until later.
- Placebos (sham or inactive treatments) are not part of phase I trials.
- These studies usually include a small number of people (20 to 80).
- Often, people with different types of cancer can take part in the same Phase I study.
- These studies are usually done in major cancer centers.
- These studies are not designed to find out if the new treatment works against cancer.
Overall, phase I trials are the ones with the most potential risk. But phase I studies do help some patients. For those with life-threatening illnesses, weighing the potential risks and benefits carefully is key.
Phase II clinical trials: Does the treatment work?
If a new treatment is found to be reasonably safe in phase I clinical trials, it can then be tested in a phase II clinical trial to find out if it works. The type of benefit or response the doctors look for depends on the goal of the treatment. It may mean the cancer shrinks or disappears. Or it might mean there’s an extended period of time where the cancer doesn’t get any bigger, or there’s a longer time before the cancer comes back. In some studies, the benefit may be an improved quality of life. Many studies look to see if people getting the new treatment live longer than they would have been expected to without the treatment.
Key points of phase II clinical trials:
- Usually, a group of 25 to 100 patients with the same type of cancer get the new treatment in a phase II study. They’re treated using the dose and method found to be the safest and most effective in phase I studies.
- In a phase II clinical trial, all the volunteers usually get the same dose. But some phase II studies do randomly assign participants to different treatment groups (much like what’s done in phase III trials). These groups may get different doses or get the treatment in different ways to see which provides the best balance of safety and effectiveness.
- No placebo (sham or inactive treatments) is used.
- Phase II studies are often done at major cancer centers, but may also be done in community hospitals or even doctors’ offices.
Larger numbers of patients get the treatment in phase II studies, so there’s a better chance that less common side effects may be seen. If enough patients benefit from the treatment, and the side effects aren’t too bad, the treatment is allowed to go on to a phase III clinical trial. Along with watching for responses, the research team keeps looking for any side effects.
Phase III clinical trials: Is it better than what’s already available?
Treatments that have been shown to work in phase II studies usually must succeed in one more phase of testing before they’re approved for general use. Phase III clinical trials compare the safety and effectiveness of the new treatment against the current standard treatment.
Because doctors do not yet know which treatment is better, study participants are often picked at random (called randomized) to get either the standard treatment or the new treatment. When possible, neither the doctor nor the patient knows which of the treatments the patient is getting. This type of study is called a double-blind study. Randomization and blinding are discussed in more detail later.
Key points of phase III clinical trials:
- Most phase III clinical trials have a large number of patients, at least several hundred.
- These studies are often done in many places across the country (or even around the world) at the same time.
- Phase III clinical trials are more likely to be offered by community-based oncologists.
- These studies tend to last longer than phases I and II
- Placebos may be used in some phase III studies, but they’re never used alone if there’s a treatment available that works.
As with other studies, patients in phase III clinical trials are watched closely for side effects, and treatment is stopped if they’re too bad.
Submission for FDA approval: New drug application (NDA)
In the United States, when phase III clinical trials show a new drug is more effective and/or safer than the current standard treatment, a new drug application (NDA) is submitted to the Food and Drug Administration (FDA) for approval. The FDA then reviews the results from the clinical trials and other relevant information.
After review, the FDA may ask for more information or even require that more studies be done. This can extend the approval process to more than 5 years.
Or, based on its review, the FDA can decide that the treatment is OK to be used in patients with the type of illness the drug was tested on. In this case, the new treatment often becomes the standard of care, and newer drugs must then be tested against it before being approved. But, in some cases, the clinical trials are still not over and phase IV trials continue.
Phase IV clinical trials: What else do we need to know?
Drugs approved after phase III trials are often watched over a long period of time in phase IV studies. Even after testing a new medicine on thousands of people, the full effects of the treatment may not be known. Some questions may still need to be answered. For example, a drug may get FDA approval because it was shown to reduce the risk of cancer coming back after treatment. But does this mean that those who get it are more likely to live longer? Are there rare side effects that haven’t been seen yet, or side effects that only show up after a person has taken the drug for a long time? These types of questions may take many more years to answer, and are often addressed in phase IV clinical trials.
Key points of phase IV clinical trials:
- Phase IV studies look at drugs that have already been approved by the FDA. The drugs are available for doctors to prescribe for patients, but phase IV studies are needed to answer important questions.
- May involve at most, a few tens of thousands of people.
- This is the safest type of clinical trial because the treatment has already been studied a lot and used in possibly millions of people. Phase IV is looking at safety over time.
- These studies may also look at other aspects of the treatment, such as quality of life or cost effectiveness.
You can get the drugs used in a phase IV trial without enrolling in a study. And the care you would get in a phase IV study is very much like the care you could expect if you were to get the treatment outside of a clinical trial. But in phase IV studies you’re helping researchers learn more about the treatment and doing a service to future patients.
Coloma PM. Phase 0 clinical trials: theoretical and practical implications in oncologic drug development. Open Access Journal of Clinical Trials. 2013;5:119-126.
Doroshaw JH. Phase ‘0’ Clinical Trials in Cancer Drug Development: From Concept to Practice. Slide presentation. Accessed at www.iom.edu/~/media/Files/Activity%20Files/Disease/NCPF/Phase0ClinicalTrialsinCancerDrugDevelopmentFromConcepttoPracticeDoroshow.pdf on May 4, 2016.
Friedman LM, Furberg CD, DeMets DL. Fundamentals of Clinical Trials, 4th ed. 2010. New York, NY: Springer Science + Business Media, LLC.
National Cancer Institute. Phases of Clinical Trials. November 2, 2012. Accessed at www.cancer.gov/about-cancer/treatment/clinical-trials/what-are-trials/phases on May 4, 2016.
Streiner DL, Norman GR. Drug Trial Phases. Community Oncology. 2009;6(1):36-40.
US Food and Drug Administration. Investigational New Drug Application. 04/08/2016. Accessed at www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/InvestigationalNewDrugINDApplication/default.htm on May 4, 2016.
Last Medical Review: May 3, 2016 Last Revised: May 3, 2016