The Clinical Trials Process
Clinical trials provide the most important information used by the U.S. Food and Drug Administration (FDA) to decide whether a new medical treatment shows "substantial evidence of effectiveness," or whether an already approved treatment can be used effectively in new ways (for example, the drug gemcitabine was at first approved as a treatment for pancreatic cancer but was later tested and approved for use in treating certain types of lung cancer).
The FDA must certify that a treatment has shown promise in the laboratory and in animals before human testing can begin. All clinical trials are supervised by an independent board of experts, which ensures that the sponsor of the treatment can stop the study early if major problems develop or if unexpected benefits are found. (See Monitoring the Safety of Clinical Trials.) The potential benefits and risks of any clinical trial must be carefully weighed by the researchers conducting the study and the patients who decide to participate.
Different Kinds of Clinical Trials
Cancer clinical trials can focus on either treatment or prevention. Treatment trials test new ways of curing or relieving the symptoms of cancer in people who have the disease. Prevention trials enroll people who are at increased risk for developing cancer. In some cases, prevention trials test the effectiveness of an intervention such as a change in lifestyle; others test whether a drug can help to prevent cancer. Using drugs in this way is called "chemoprevention."
Most clinical research that tests a new treatment moves in an orderly series of steps, from early phase I clinical trials to more definitive phase III trials. Each kind of clinical trial asks certain crucial questions.
- A phase I trial asks: how does the treatment affect the human body, how should it be given, and what dosage is safe?
- A phase II trial asks: does the treatment do what it's supposed to do, and how well does it work?
- A phase III trial asks: is the new approach better than current medical practice?
Phase I: What Dosage Is Safe?
In phase I treatment trials, a small number of volunteer patients (usually between 15-30) are given the experimental treatment in gradually larger doses to test for any side effects or complications. The researchers conducting the trial will also try to determine what a safe dose would be and how it should be given.
Laboratory studies during this period also yield information about how the treatment is processed in the body - how the drug or biologic itself changes, which organ systems it affects, how long it stays in the body, and how the body gets rid of it. About 70 percent of drugs tested in phase I trials are successful enough to go on to phase II trials. (See the FDA's Table of Drug Testing in Humans.)
Often, cancer patients who decide to participate in phase I trials are no longer benefitting from the standard drugs that are available, or they have a type of cancer for which there is no effective treatment. They may benefit from the treatment they receive in a phase I trial, but the main goal at this early stage is to see how the new treatment affects the body and to determine the right dose and treatment schedule for further testing in phase II studies.
Phase II: Does the Drug Do What It's Supposed to Do?
Phase II treatment or chemoprevention trials test how well a new treatment (or new use of an existing treatment) works against cancer. In addition, by recording information about the treatment's side effects and complications, researchers learn more about its short-term safety.
In phase II trials, people with specific types of cancer or with certain cancer risk factors are given the medication to see whether or not it has a beneficial effect. Each phase II study usually focuses on 30-50 patients. Phase II bridges the information gap between "is the treatment safe?" to "will it actually work in a specific situation?"
People enrolling in phase II trials may find that beneficial effects, when they occur, may still be mixed with side effects and complications that the researchers did not expect. Only about 33 percent of the drugs tested in phase II trials are found safe and effective enough to go on to phase III. (See the FDA's Table of Drug Testing in Humans.)
Phase III: Is the New Approach Better Than Current Medical Practice?
By the time a new cancer approach reaches a phase III clinical trial, it has been shown to be safe at a certain dosage and to be effective against a certain kind of cancer. Now researchers need to figure out whether it is superior to the approaches currently used against that disease. "Superior" can mean that the treatment has a more powerful anti-cancer effect, or that it works just as well but with more acceptable side effects.
To achieve these goals, phase III trials typically enroll several hundred, or even thousands, of people from across the country or around the world. Through a process called randomization, each person is assigned by chance (usually by computer) either to a group that will receive the current standard treatment or a group that will receive the experimental one. Random assignment ensures that participants in the two groups are as similar as possible; only if the groups are similar can their test results be reliably compared to see which approach worked best. Randomization is ethically acceptable because doctors do not know at this point whether the new approach really represents an advance - it might actually work less well than the current standard.
For more information about phase III trials, see Which Study Results Are the Most Helpful in Making Cancer Care Decisions?.
Frequently Asked Questions About Phase III Clinical Trials
- Does the way phase III trials are designed mean I might enter a trial and receive no treatment at all?
As already discussed, it is very rare for a treatment trial to be designed with a control group that receives no treatment at all. This might happen only in cases of cancer where there is no effective treatment available. In the vast majority of cases, all participants receive at least the standard treatment.
Prevention trials are different because they enroll healthy individuals with an identified risk factor or factors for developing a specific type of cancer, to test whether or not a drug shows promise in lowering the cancer's incidence. Thus, since few drugs have yet been shown to reduce the risk of cancer, phase III prevention trials typically include a group that does not receive the drug under investigation and one that does. However, once the prevention trial shows that the new drug has a significant effect in preventing the development of cancer, the sponsor will stop the study to make sure that all participants can receive the new drug.
- How will I know the risks and benefits before I enter the trial?
Before you can can enter a phase I, II, or III trial, you must go through a process called informed consent. During this process, you would be fully informed about the trial through both a written document and an oral discussion, which review what the trial is meant to test, how long it should last, what procedures will be performed, if randomization is involved, and what is known about the possible risks and benefits. So you would know exactly how the trial is designed and what your chances are of being assigned to any one group.
Those who decide to enroll in a study are willing to accept certain risks (some of which may not even be known) to help evaluate a potentially beneficial new treatment or prevention agent. Some people are not comfortable with this and decide not to enroll. Participation is an individual decision, but in all cases it should be an informed decision. (For more information, see A Guide to Understanding Informed Consent.)
- Let's say I'm in group A in a phase III study and all the patients in group B begin to show marked improvement. What happens to me?
All results are carefully monitored during the trial by a Data Safety and Monitoring Committee, whose members are not connected to the trial in any other way. (See Monitoring the Safety of Clinical Trials.) If early results indicate a clear advantage for one of the groups, the sponsor of the study may choose to end the trial early and establish a protocol allowing wider use of the drug before final approval for marketing. If a drug is shown to have a strongly negative effect, the trial is stopped as soon as this is known.
- After the trial is over, can I find out which group I was in?
At the completion of a trial (which may sometimes include follow-up data collection), all patients have access to the results of the study and to information about their own participation. In many cases, however, this information is not available right away. Participants sometimes need to wait for data to be compiled, for other participants to finish their parts of the trial, and for investigators to analyze the results.
- How do I find out about participation in clinical trials?
You should consult first with your attending physician about whether participation in such a study is appropriate for you. He or she may already know of a study or be able to direct you to a nearby resource. One of the best online resources is NCI's searchable database of clinical trials, which includes information, contact names, and phone numbers for clinical trials being conducted nationwide. Many NCI-designated Cancer Centers across the country also offer access to clinical trials.