There are three phases to complete in the clinical trial process before a sponsor can submit their treatments* to the FDA for consideration to be sold on the market. Each stage of a clinical trial has its own purpose in ensuring that a treatment is safe and effective for use by the public.
Phase 1 Clinical Trial
The purpose of Phase 1 is to ensure that the treatment is safe in humans and to determine how and where it distributes within the body. This testing normally takes place with a small group of healthy volunteers. The trial sponsor monitors for potential “serious adverse events”— that is, any toxic, undesirable, or unwanted effect that causes death or danger to health, like a disability or permanent damage, birth defect, heart attack, or other serious medical condition.
At the end of Phase 1, the results are collected, analyzed, and submitted to the FDA for permission to proceed to Phase 2 Clinical Trials. However, if the results show that the treatment was associated with one or more serious adverse events, then the FDA may not give permission to proceed to Phase 2. Normally, testing of that treatment is discontinued or “drops out” of the running for making it to the market. If the trial meets the primary outcome(s), as defined in the initial study design, then the FDA permits the treatment to proceed to Phase 2 Clinical Trial(s).
Sometimes, a potential for treatment of one disease has already been approved for use in treating another disease (for example, a cancer drug may be tested for treatment of Alzheimer’s or macular degeneration). This is called “repurposing” a drug, and sometimes this may shorten the clinical trial, or permit the acceleration into Phase 2 Clinical Trials, because the Phase 1 safety profile has already been tested in the previous clinical trial.
Phase 2 Clinical Trial
The purpose of a Phase 2 Clinical Trial is to determine the right dosage and effectiveness in treating that particular disease. This testing normally takes place with a larger number of volunteers who have the disease. There are many different ways that a trial sponsor can conduct their trial, but the plan normally involves assigning participants to different treatment groups, where each group can receive different doses or delivery of the treatment. Normally, there is a “control group” that receives either the current standard of care, if another type of treatment is already available on the market for that disease, or a “placebo” treatment, such as a sugar pill or harmless injection that does not contain the treatment.
The health of the group(s) of patients who received the different types of treatment is compared to the control groups. However, if the results show that the treatment did not work better than the current standard of care or even caused acceleration of the disease or other unexpected serious adverse events, the FDA may not give permission to proceed to Phase 3. Normally, testing of that treatment is discontinued or “drops out” of the running for making it to the market.
Phase 3 Clinical Trial
A Phase 3 Clinical Trial involves a much larger group of volunteers and primarily focuses on determining whether the treatment* would be safe and effective for a wide variety of people. The plan normally involves assigning participants to treatment or control groups. There can be more than one treatment group, especially if the treatment involves a combination of drugs or different components. Again, there is a control group that recieves either the current standard of care regiment or a placebo treatment.
After completion of Phase 3 Clinical Trials, the health of the patients who received the different types of treatment are compared to the control groups. If the results show that the treatment did not work better than the current standard of care or even caused acceleration of the disease or other unexpected serious adverse events, the FDA may not give permission to proceed to apply for a New Drug Application (NDA). This special NDA contains all of the discoveries made at every stage of the process (starting from the Basic Research/Drug Discovery through to the results of the Phase 3 Clinical Trials), and is submitted to the FDA for their consideration to approve the sale of the treatment on the market.
Phase 4 Clinical Trial/Post-Market Surveillance/Report Adverse Events
After approval by the FDA and manufacturing of the drug on a large scale by the sponsor, the process enters what is called Phase 4 Clinical Trial/Post-Market Surveillance/Report Adverse Events. For at least the entire time a treatment* is on the market, the FDA monitors for public safety and potential serious adverse events. In particular, the FDA has a service called MedWatch, where health professionals, the sponsor, or anyone in the public can report a serious adverse event they believe is associated with a particular drug or treatment (reports can be made online, by mail or e-mail, or by phone). In addition, there may be mandatory or optional Phase 4 Post-Marketing Clinical Trials to obtain further information about the risks, benefits, and long-term effects, or to test the product in special patient populations. The FDA provides a wide variety of information about all of the drugs currently for sale on the U.S. market (see Sources of Information).
How long does it take to complete each stage?
It can take up to 15 years to bring a product to market and then still require additional post-marketing Phase 4. The timeline for clinical trial phases might look like this:
- Basic Research/Drug Development and Pre-Clinical/Translational Research (combined): 3 to 6 years
- Phase 1, Phase 2, and Phase 3 Clinical Trials (combined): 6 to 7 years
- FDA Review/Manufacturing: 0.5 to 2 years
- Phase 4 Clinical Trial/Post-Market Surveillance/Report Adverse Events: 0.5 to 10 years (at least as long as the drug is on the market); Specific Phase 4 trials are optional and can be of variable length if assigned by the FDA as a requirement for a treatment’s approval. For example, some Phase 4 trials could last 5-10 years in order to see the effect of the treatment on populations of specific concern to the FDA. The post-market surveillance for adverse events begins immediately after the drug is available to the public and continues for at least as long as the drug is available on the market.
* Treatment: Although we are using the word "treatment," clinical trials also involve medical research studies in which people participate as volunteers to test new methods of prevention, screening, and diagnosis of disease.
Sources of Information
U.S. Food and Drug Administration (FDA); National Institutes of Health (NIH); Center for Information & Study on Clinical Research Participation (CISCRP); Pharmaceutical Research and Manufacturers of America (PhRMA); Tufts Center for the Study of Drug Development [Updated Outlook 2010 and original referenced paper (DiMasi, Joseph A., Ronald W. Hansen and Henry G. Grabowski (2003) “The Price of Innovation: New Estimates of Drug Development Costs,” Journal of Health Economics 22(2):151-85, March)]; and a paper comparing the costs of different studies (Morgan, Steve, et al. “The cost of drug development: A systematic review” Health Policy 100 (2011) 4–17).