Phases of Clinical Trials

Differences in phase 1, phase 2, and phase 3 medical research studies

The phases of clinical trials have different purposes and goals. Phase 1 clinical trials are the first tests done on humans and are designed to answer the question, "Is the treatment safe and what is the best dose?" Phase 2 trials focus more on determining whether the treatment works, and phase 3 trials often compare a new treatment against the best treatment currently available. After a phase 3 clinical trial a medication or procedure may receive FDA approval. After a drug is FDA approved, it may be studied in a stage 4 trial to see if it is effective in another situation, such as whether a drug works for a different type of cancer. Prior to being tested in humans in phase 1 trials, new treatments undergo extensive evaluation and are often studied both in cells in the lab and in animal models.

Unfortunately, due to lack of awareness, and sometimes the myths of clinical trials, only a fraction of people who are eligible for clinical trials—and might benefit—are enrolled.

Phases of Clinical Trials

There are three different phases of clinical trials with different purposes, beginning with the first use of a drug or treatment on humans, and finishing with approval for general public use by the FDA. There is also an additional phase of clinical trials in which a drug or procedure approved for one condition is evaluated for another. It's important to note that each phase of a clinical trial is a separate research study.

Types of Clinical Trials

In addition to phases, there are different types of clinical trials. The type of trials most people are familiar with are those that evaluate treatments, such as the use of a chemotherapy drug, but other types are very important as well. These include prevention trials, screening trials that look at better ways to detect disease, diagnostic trials, and quality of life trials. It's important to be aware of both the phase and the type of a clinical trial you may be considering.

Phase 1 Clinical Trials

Phase 1 clinical trials are the first tests done on humans for an experimental drug or treatment.

Testing Before Phase 1 Clinical Trials

Before a drug or procedure enters a phase 1 trial it undergoes extensive evaluation. For example, research may begin by identifying potential targets to treat, research find molecules that can "hit" the target, research to determine which molecule works best, and then further study of the best molecule to make it as effective as possible with the fewest side effects possible.

After this testing is done, preclinical testing is performed. This can include evaluation both in cancer cells grown in the lab (cellular testing) and animal testing. This evaluation can further define the potential effectiveness of a drug as well as identify potential side effects.

Purpose: Is the Treatment Safe and What Dose Should Be Used

When the drug is then first studied in humans in a phase 1 trial, only a small number of people, perhaps 10 to 30, are included. People who receive the drug are carefully monitored to determine the safety of the drug as well as the optimal dose.

Phase 1 Clinical Trials are Changing

In the current era of precision medicine, the potential benefit of a phase 1 clinical trial for an individual is changing. In the past, it was often unlikely that a new drug would change the course of a person's disease to a significant degree, and phase 1 trials were often thought of as "last ditch efforts" and a way a person could help to advance medicine. At the current time, especially with the newer targeted therapies, this has changed radically. Drugs that enter phase 1 trials have often been carefully designed to target a specific abnormality in cancer cells that has been identified in a particular patient. When this is the case, the chance that the drug will also be effective is a significant, and many people with cancer are currently alive only because of their participation in phase 1 clinical trials.

Phase 2 Clinical Trials

After a drug or treatment is found to be relatively safe in a phase 1 trial, it is tested in a phase 2 trial. Unlike phase 1, which will include patients with different types of cancer, phase 2 will focus on patients with just one type of cancer.

Purpose: Does the Treatment Work?

Phase 2 clinical trials are focused on determining whether a treatment is effective, though important information is often gained about its safety as well. With precision medicine, information on effectiveness may already be noted during phase 1 trials, and phase 2 trials allow researchers to look not only at effectiveness, but whether there are differences in the efficacy of a drug among different groups of people. For example, looking at a larger group of people researchers may note that a drug works better in one sex or another, if it works better in younger people or older people, and much more.

Phase 3 Clinical Trials

Phase 3 trials are the final phase of clinical trials before a drug or procedure can be evaluated for FDA approval. These studies involve larger numbers of patients, often thousands.

Purpose: Is the Treatment Better Than Standard Treatment?

The purpose of phase 3 trials is to compare the effectiveness of a treatment to the current standard of care treatment. Further information is also gained on safety with these studies.

Phase 3 trials are usually “double-blind” studies; meaning that neither the patient nor the investigator knows which treatment is being used. If the experimental treatment is found to be either superior or inferior to the standard treatment, these studies are usually stopped early to allow individuals to receive the best treatment possible.

An example might be to test a less invasive surgery for lung cancer to see if either the survival rate is higher than traditional surgery, or if the new surgery has fewer side effects and complications than the traditional (standard) surgery.

The "endpoint" of a phase 3 trial is not always an improvement in survival or reduction in symptoms. Instead, it may be found that the experimental treatment has fewer side effects (less toxicity), or is more convenient to use (oral vs. intravenous administration, etc.).

Phase 4 Clinical Trials

After a drug has been approved for general use, a phase 4 trial may be done to look at the safety of a drug or procedure over time, or to look at other uses for the drug such as for a different stage of cancer (such as the use of a drug as an adjuvant treatment along with surgery for an early stage cancer though the drug is approved for metastatic cancer) or another type of cancer. Other phase 4 clinical trials are postmarketing studies providing further information on effectiveness with "real-world" data. These studies often involve thousands of patients.

Pre-Clinical Trials

It's important to take a moment to mention preclinical trials, or the studies that are done before a drug every gets to a phase 1 trial. These early studies are extensive, and most substances that are evaluated never reach even a stage 1 clinical trial. There are two primary types of studies.

Laboratory Studies

Many studies are done essentially in a dish in the lab. These studies may be done, however, on human cells. Cancer cells can be isolated and grown so that drugs can be tested. These studies are referred to as in vitro tests, in contast to in vivo tests which are done in humans. Some results of these transmit to humans, but many do not. The body is very complex, and there may be a number of pathways involved in the greater picture that would lend a drug ineffective that appears to work very well in the lab on isolated cancer cells.

Animal Studies

After studies in lab dishes, substances that may be effective in treating disease are then often tested in rodents. This is the story behind the guinea pig comments you may here. While it is very helpful to test drugs first in animals (most people would rather have a drug first tested on mice than on their child), what occurs in a mouse doesn't necessarily translate to what will happen in humans. There can be differences in both the effectiveness of a substance and the side effects experienced.

Importance of Clinical Trials

There are many myths about clinical trials, judging from the common cartoons portraying guinea pigs or rats on a treadmill. These medical studies are, in fact, the only way that any new treatments become available for the treatment of cancer or any other diseases.

How important these trials can be not just for the population as a whole, but for their potential for individuals, can be emphasized by illustrating what has happened with lung cancer in recent years. The newer targeted therapies are designed to target specific molecular abnormalities unique to a particular tumor. The abnormality may be present in only a minority of lung cancers, in some cases, less than one percent or less, but due to the precise action of a drug, may hold the potential to control and otherwise aggressive or terminal cancer. Many people who have participated in phase 1 clinical trials studying these targeted medications are alive only because they participated in the trial.

A Word From Verywell

The only way that newer and better medications and procedures become available for use by the public, is through evaluation in clinical trials. With many cancers, the National Cancer Institute now recommends asking whether or not a clinical trial may be an option.

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