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How Clinical Trials Are Conducted

Many clinical trials are done at major cancer centers and academic research institutions, and the research team may include research scientists, doctors, nurses, social workers, and others.
 

Researchers conduct clinical trials in different settings. Many clinical trials are done at major cancer centers and academic research institutions.

Community-based hospitals, clinics, and doctors’ offices that take part in research also can enroll people in clinical trials. In fact, the National Cancer Institute (NCI) launched the NCI Community Oncology Research Program (NCORP) to bring more clinical trials to community-based practices, where most people receive their cancer care. As a result, some major NCI-funded studies may be available in these settings.

Every clinical trial is led by a head researcher called a principal investigator, who is often a medical doctor. The research team may include research scientists, doctors, nurses, social workers, dietitians, other healthcare professionals, and research coordinators.

Clinical trials can be sponsored (funded) by:

  • government agencies, such as the National Cancer Institute, the Department of Defense, and the Department of Veterans Affairs

  • pharmaceutical, biotechnology, or medical device companies

  • healthcare institutions, such as academic medical centers or health maintenance organizations (HMOs)

  • non-profit organizations or private individuals

The sponsoring organization or company may start the clinical trial and help to oversee and manage it.

The researchers write a detailed plan for how the clinical trial will be done and what they hope to find out. This plan is known as a protocol and is written in fairly technical language. For a therapeutic trial, the protocol includes details about the dose of each treatment and how it will be given, as well as how often and for how long. For other types of trials, the protocol describes the type and timing of interventions that will be studied. Examples might include cancer screening tests, an exercise program, or a medication aimed at reducing treatment side effects. The protocol also lists all the lab work, tests, and other evaluations that will be done to figure out how each person in the trial is reacting to the treatment.

The trial protocol also describes:

  • which patients are, or are not, eligible to take part

  • how many participants there will be

  • how long the trial is expected to last

  • how patients will be protected and kept safe

After the protocol is approved, the researchers can begin asking people to be part of the trial.

 

Randomization, blinding, and placebos

Researchers design clinical trials in different ways to help ensure that the results will be as reliable as possible. The following are examples of three important strategies.

Randomization: Clinical trials usually group participants in one to four different treatment or intervention plans, called “arms.” In a trial with more than one treatment arm, participants are often assigned randomly to one of the arms (meaning by chance, rather than by choice). This is called “randomization” or a “randomized clinical trial.” By randomly assigning participants into treatment arms, researchers can reduce bias, ensure the treatment arms are balanced, and more accurately compare the effectiveness of treatments or other interventions as they follow groups over time.

The simplest form of randomization occurs when there are two study arms. In a therapeutic trial, for example, one group of patients is assigned to receive the new therapy as part of the intervention group, or investigational arm. The other group, called the control group, receives the standard treatment currently in use for their particular diagnosis. However, some trials can have as many as three or four different study arms.

Blinding: Many clinical trials are “double-blinded.” This means that neither the participant nor the researcher knows which treatment plan the participant is following. Results from a randomized, double-blinded trial are often considered more credible than results from a trial that isn't randomized or double-blinded.

In a double-blinded trial, the treatment that you receive is labeled with a code that is known only by a small group of people not involved in your treatment. The code is revealed at the end of the study when the results are evaluated.

Double-blinded clinical trials help researchers see the actual benefits and side effects of a treatment without bias or outside influence. For example, if you and your research team knew that you were receiving a new therapy for breast cancer, there might be a tendency to overestimate the impact it is having. This could influence the study results. Whenever possible, clinical trials are both randomized and double-blinded.

In some cases, clinical trials are single-blinded, meaning that only the researcher knows which treatment you are receiving until the study is over. This also ensures that participants won’t be biased in reporting how they are feeling or what side effects they may be experiencing.

Even if a trial is blinded, you would be able to find out which study arm you are in if there is an urgent medical reason, such as having serious side effects or developing a new health issue that could make it unsafe for you to continue. Also, if it becomes very clear in a study that a new treatment is superior to standard treatment, the trial may be stopped early and unblinded so that everyone can benefit from it.

It's not always possible to conduct a blinded clinical trial, which means that the trial is non-blinded. For example, if participants are on different treatment schedules, such as for radiation or chemotherapy, or if a trial is comparing surgery to another form of cancer treatment, it would be obvious who is receiving which treatment. If researchers are conducting a trial of an intervention such as dietary counseling or physical therapy, participants would also know which group they are in.

Placebos: Many patients are understandably concerned about receiving a placebo, or inactive treatment that resembles the real thing, instead of real treatment. However, it is very rare for placebos to be used alone in cancer clinical trials. It is unethical to withhold treatment from a participant if there is a known effective therapy for the cancer — so you would always at least receive standard treatment. Placebos would only be used if:

  • there is no effective treatment for your form of cancer, and researchers are evaluating whether an investigational therapy is better than no therapy at all

  • researchers are trying to determine if adding a new medication or other substance to standard treatment can improve outcomes. If that’s an oral medication, you could receive an inactive pill that looks like the real thing. However, you would still be getting the current standard treatment for your cancer.

 

Understanding the phases of clinical trials

Clinical trials of a new medication, therapy, or medical device are often conducted in a series of four steps, or phases. If the treatment has already been proven safe for humans, then all four phases are not always necessary.

The phases of clinical trials are not related to the stages of breast cancer (I, II, III, IV). A clinical trial's phase tells you how far along the therapy is in its testing and what the goal of the trial is. People with all stages of breast cancer can be candidates for different clinical trial phases.

Phase I trials: Is it safe?

Phase I trials, sometimes called first-in-human trials, are the first clinical trials to test a new treatment in people. Preclinical studies in petri dishes and animals have usually been done before phase I trials begin. In the United States, before a phase I trial can begin, the FDA must approve an investigational new drug application (IND), which includes results from previous studies and detailed information about the new treatment, such as its ingredients and how it is made. Phase I trials are relatively small, with about 15 to 50 people participating.

In phase I trials, researchers are figuring out:

  • the best way to give a new treatment (such as by injection or as a pill)

  • the highest dose that can be given safely, without serious side effects

Researchers closely monitor the participants and adjust the dose a little at time until they find the amount that works the best with acceptable side effects. This dose is usually the one used for further testing.

Everyone in a phase I trial receives the study treatment; no placebos (inactive treatments) are used. Although participants may benefit from the therapy, the main goal of a phase I trial is to find the safest dose, not to figure out if the treatment is effective.

Generally, phase I trials involve the most risk because so little is known about how the therapy works in humans. People who have a form of breast cancer that is very difficult to treat, or who have tried other treatments that weren’t successful, may decide to take part in phase I trials. These are usually offered at major cancer centers that do large amounts of research.

Phase II trials: Does it work?

Phase II trials look at how effective a new treatment is. Phase II trials are slightly larger than phase I trials and usually involve 25 to 200 people. Researchers start with the dose and method of giving the new treatment that were found to be best in phase I trials. The phase II participants are given the new treatment and the researchers watch to see if the treatment has benefits. Depending on the goals of the research, benefits the researchers look for may include:

  • the tumor(s) get smaller

  • the cancer stops growing

  • longer time before the cancer comes back

  • longer survival time

  • better quality of life

Some phase II trials randomly assign people into different groups that get different doses of the treatment or receive the treatment in different ways. If a certain percentage of participants benefit from the treatment and the side effects are still acceptable, the new treatment may go on to a phase III trial. In some cases, positive results from a randomized phase II trial may be enough for a new treatment to be approved.

Phase III trials: Is it better than what we have now?

Phase III trials compare the safety and effectiveness of a new treatment to the current standard of care. Phase III trials are usually large — some involve thousands of participants — and are done at many places in the United States and around the world, including cancer centers, community hospitals, and doctors’ offices.

A phase III trial is the last step a new treatment goes through before the FDA considers approving it for general use.

In a phase III trial, participants are usually randomly assigned to receive the current standard treatment or the new treatment. If possible, the trial is double-blinded so that neither the researchers nor the participants know who's getting which treatment.

In some cases, a phase III trial may look at whether adding a new medication to the current standard of care is better than using the standard treatment alone. In that case, one group may receive a placebo in addition to standard treatment, while the others would receive the new treatment combination. A placebo is never used alone if there is an effective treatment available for your cancer. In some cases, patients in the placebo group may be switched over to the other group if the new treatment combination is proving more effective.

Just as in phase I and phase II trials, phase III trial participants are watched closely for any serious side effects. Treatment is stopped if side effects are too dangerous or difficult to manage. The trial also may be stopped early if the new treatment or treatment being tested is clearly better than the standard of care.

In the United States, when phase III clinical trials (or sometimes phase II trials) show a new treatment is more effective or safer than the current standard of care, a new drug application (NDA) is submitted to the Food and Drug Administration (FDA) for approval. The FDA reviews the results from the clinical trials and other relevant information.

Based on the review, the FDA decides whether to approve the treatment for use in patients with the illness the drug was tested on. If approved, the new treatment often becomes a standard of care option, and newer drugs may be tested against it before they can subsequently be approved.

If the FDA decides that more evidence is needed to show that the new treatment's benefits outweigh its risks, it may ask for more information or require that more studies be done.

Phase IV trials: Are there any other uses or benefits?

Phase IV trials may be done after a treatment has been approved for use by the FDA. They can involve hundreds or thousands of people. The goal is to track people over time to find out if the treatment offers benefits or produces long-term side effects that weren't studied or seen in the phase II or phase III trials.

 

How long clinical trials take

Clinical trials can vary widely in how long they take. A phase I trial can last several months to a year, while a phase II trial can last for a couple of years. Phase III trials can enroll and then follow patients for many years. Even if the new treatment is shown to work better than the standard treatment, researchers often continue to follow participants. It can take up to 10 years or more for a new treatment to progress from a phase I trial to widespread use in patients.

Clinical trials of new approaches to reduce the risk of cancer or improve cancer screening can also take many years, as researchers must follow participants to figure out if an intervention lowered their cancer risk or increased the odds of earlier detection.

Supportive care and symptom management trials tend to move more quickly, as they look at whether interventions such as medication, dietary changes, or exercise improve quality of life or reduce side effects for people with cancer.

 

Faster approvals for promising treatments

The U.S. FDA has a number of programs to speed up review and approval for new treatments that show clear promise in clinical trials or are clearly superior to standard therapies. Examples include:

  • Fast track, which speeds up the FDA review process for therapies that show advantages over standard treatments (such as better outcomes and fewer side effects)

  • Breakthrough therapy designation, which enables researchers with a promising therapy in early-phase clinical trials to work closely with the FDA to speed up the process of drug development

  • Accelerated approval, which could make a treatment available before phase III trials are completed if it shows promise based on lab tests, imaging, symptom improvement, or some other marker

  • Priority review, which can help speed up the approval process for a new treatment after the research is completed and has proven its effectiveness or superiority to standard treatments

— Last updated on January 13, 2022, 4:07 PM

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