While the term “clinical trial” was coined in 1947, the first experiments that could be considered a clinical trial were performed by Scottish physician James Lind in 1747 as he sought to find the cause of scurvy by testing remedies on a group of sailors.
Today’s clinical trials are, naturally, far more sophisticated than those 18th century studies, but the crux remains the same: Simply put, clinical trials are research studies that involve people. Cancer clinical trials—and, by extension, breast cancer clinical trials—help answer many questions relating to cancer treatment and care. As such, they are an integral part of the research process and the only way to translate new research into clinical practice to improve current patient care.
Here we discuss breast cancer clinical trials (though the concepts described apply to most clinical trials): what kinds of questions they ask, how they are designed to answer these questions, what their phases mean, and more.
Clinical trials are used across the breast cancer care continuum—from studying ways to prevent the disease to testing specific drugs to treat it. As such, there are several different types of trials and breast cancer research studies.
Treatment trials may test novel drugs alone or new combinations of treatments. These trials can also study methods to: improve the efficacy of existing drugs; manage a treatment’s symptoms, side effects, effective dosage, and timing; or increase the efficacy of radiation or surgical intervention. Breast cancer vaccine trials also fall under this category.
Researchers may test behavioral interventions (such as diet or exercise), risk assessment tools, or drugs to see if they can decrease breast cancer risk in prevention trials.
Screening trials investigate new imaging techniques or methods to improve interpretation of existing techniques. They can also refine the timing and application of genetic screening and evaluate breast cancer risk assessment methods.
Researchers conduct survivorship trials assessing ways to improve quality of life both during and after treatment by decreasing patients’ risk of adverse side effects or by improving side effect management after treatment.
Epidemiological trials study trends in breast cancer risk by enrolling large numbers of people and following them over many years. These studies may examine what genes or environmental factors contribute to an increased risk of breast cancer. Or they may chart people and families with and without cancer to uncover clues that may inform individual and population-level risk.
Health services trials examine the health care system’s effectiveness by studying how people access services and how those services influence patient outcomes. In addition, these trials may look at health care cost and how financial toxicity affects outcomes and quality-of-life issues.
Most clinical trials, particularly those that involve drugs, are a culmination of years of basic research and the final phase of a multi-step process. Long before drugs are used in patients, scientists work to understand how they affect cancer cells and determine potential side effects through laboratory experiments on cells and models that mimic a tumor’s environment. Scientists and clinicians (doctors who care for patients) then work hand in hand to test these findings in people with a disease and assure new drugs/treatments or procedures have a positive impact on their care and are safe.
A cancer clinical trial is usually designed and initiated by a principal investigator and their research team, who develop a protocol that outlines every aspect of the trial including:
In designing a clinical trial, investigators and their teams may have other aspects to consider as well.
For example, they may have to determine if a control group (volunteers that do not have breast cancer) or a placebo (an innocuous substance given instead of the study drug) is needed to answer the study questions. If a placebo is employed, the trial staff will randomize who receives the placebo. In a single-blind study, only the trial staff will know which volunteers get the placebo; whereas in a double-blind study, only the pharmacist (and not the staff or volunteers) knows who was assigned the placebo to prevent study groups from being treated differently.
In the U.S., clinical trial protocols must be approved by the institution conducting the trial (a.k.a. the trial site) as well as the federal Food and Drug Administration (FDA) in the case of trials that test potential treatments. At the trial site, the protocol is reviewed by an institutional review board (IRB). This step ensures that people’s rights and safety are protected both before the study starts and as it proceeds. In addition to assessing the study design’s safety, an IRB considers factors such as whether it’s ethical to ask volunteers to take part in the investigational treatment, intervention, or other approach.
If a drug is involved, the drug developer or clinical trial sponsor must submit an Investigational New Drug (IND) application to the FDA for approval before the trial starts. Trial sponsors can be a medical institution, pharmaceutical company, foundation, or a federal agency (such as the FDA, National Institutes of Health, National Cancer Institute, Department of Defense, or Department of Veterans Affairs).
Regulatory requirements ensure that all health professionals involved follow the strict rules put forth by the FDA and that volunteers are treated as safely as possible. Under these careful guidelines, breast cancer research studies are performed throughout the U.S. in cancer centers, hospitals, medical centers, community hospitals, or clinics, and a single trial can be conducted in multiple sites (see trial networks below).
Clinical trials occur in a series of phases with each building on the results of the one before. If a drug or intervention is successful in one phase, it will move to the next.
Phase 1 trials are primarily focused on assessing the safety and efficacy of a drug in humans and involve a small group of about 20-80 healthy people or those with the disease that receive the study drug for the first time. The process goes on for several months with the goal of answering key questions: Is the drug safe at the effective dose? What is the best way to deliver the drug (i.e., orally, intravenously, etc.)? Are there any severe adverse effects?
If the drug meets a pre-determined criteria for success, it will move to phase 2, where hundreds of people with the disease are enrolled. This phase lasts for several months to two years to further evaluate if the drug is safe and effective. Approximately 70 percent of drugs make it to this phase.
Phase 3 studies are significantly larger and longer in duration, typically involving thousands of patients over several years. They continue to examine the treatment’s efficacy and monitor adverse reactions over a much longer period. Approximately 33 percent of drugs make it to this phase. In addition, phase 3 trials may compare a treatment to standard-of-care therapies and collate information to allow the new drug to be used safely.
Following phase 3 trials, approximately 25 to 30 percent of drugs/treatments are approved by the FDA. Researchers may continue to track a drug’s safety in the general population for many more years through phase 4 trials in several thousand volunteers. These extended studies allow researchers to collect more information to optimize and improve a drug’s use.
Most clinical trials follow the sequential phases as outlined above. However, as scientific advances are made, trial investigators adapt and explore new ways to conduct trials. For example, the groundbreaking I-SPY 1 and 2 trials in breast cancer, supported in part by BCRF, revolutionized the randomized clinical trial model—making it more effective and streamlined.
The I-SPY trials run on an “adaptive” clinical trial model that employs a master protocol for the trial’s regulatory framework but allow multiple treatments to be assessed in the same study. Specifically, if endpoints are not met, agents are removed from the study and replaced without requiring investigators to halt enrollment or resubmit the entire clinical trial protocol for regulatory review. This saves valuable time by ensuring the trial does not have to start all over again.
The innovation of I-SPY 1/2 transformed the way investigators approach clinical trial design and continues to impact development of other cutting-edge trials.
Volunteer safety is the major consideration in FDA and IRB regulations to promote well-designed and well-conducted clinical trials. However, as in routine medical care, trial participation may involve some risk—particularly if the trial is evaluating a new treatment or procedure. For instance, a drug may not be as effective as currently available therapies; there may be unexpected side effects that require medical attention or extra tests that may be uncomfortable or time-consuming; or a new treatment can prove effective for only a small group of participants.
If you are considering enrolling in a clinical trial, the research protocol will contain an “informed consent” document that details the trial and its specific risks. All participants must review and sign this document. Don’t be afraid to ask questions. A clinical trial team member can further discuss the study’s risk and benefits, time commitment, cost (for the treatment and even other related expenses such travel), and how participation in the study may affect your daily life.
As you weigh the practical considerations and logistics of joining a clinical trial, it’s also worth noting what you—and future generations—may stand to gain.
Volunteers get access to new treatments, procedures, or interventions before they are widely available, all while being monitored closely by healthcare professionals. For people diagnosed with advanced breast cancer or types such as triple-negative that lack many targeted treatments, clinical trials can also provide new lines of treatment after others have been exhausted. And, broadly, clinical trials are the only way to improve care for future patients, so your participation could provide crucial new knowledge.
Clinical trials typically aim to enroll as many patients as possible but Black women are woefully underrepresented, meaning that new insights may not apply to them. Breast cancer trialists and organizations are addressing this inequity and seeking new ways (such as mobile health platforms) to reach underrepresented communities, inform patients about available trials, and provide tools to gain access. For example, the Metastatic Breast Cancer Alliance (MBCA) conducted the BECOME (Black Experience of Clinical Trials and Opportunities for Meaningful Engagement) initiative, which reached out to Black patients with metastatic breast cancer to find practical and actionable ways to help them participate in clinical trials.
Your doctor or oncologist is most familiar with your medical history, breast cancer, and previous treatments. Therefore, they are a good source for information about breast cancer clinical trials that may be beneficial for you, or they can reach out to a specific trial’s principal investigator to see if you fit the eligibility criteria.
Since clinical trials may not be offered at every treatment facility, researchers are devising ways to reach and enroll more patients. Because of the pandemic, there’s been an explosion in telehealth procedures—including those to connect potential participants with relevant clinical trials—so don’t automatically dismiss a trial that isn’t nearby.
Anyone can search for clinical trials using Clinicaltrials.gov, a database of privately and publicly funded clinical studies. Other resources are available to help find breast cancer clinical trials (such as BreastCancerTrials.org), as well as those specific for TNBC, metastatic breast cancer (MBC; here and here), or ductal carcinoma in situ (DCIS), to name a few. Groups such as the Cancer Support Community, a division of Gilda’s Club, and even a trial network or site itself may offer travel assistance and support groups for patients who get involved in a trial. Others, like MBCA offer clinical trial matching services.
Several large cancer clinical trial networks also promote awareness of and participation in cancer clinical trials and have innovated how such studies are conducted.
The BCRF-supported Translational Breast Cancer Research Consortium (TBCRC), for example, runs breast cancer clinical trials across the continuum of the disease—from DCIS to MBC—at 18 institutions in 13 states and the District of Columbia. Networks like TBCRC provide a centralized hub for clinical trial development so that a single protocol can be implemented widely. This provides a major advantage: Results from multiple sites and potentially hundreds of volunteers can be pooled—yielding a more accurate answer to the trial question. For researchers to get a better picture of how effective a treatment will be, the more data the better.
BCRF is proud to help support a number of these collaborative networks, including TBCRC, SWOG, ECOG-ACRIN Cancer Research Group, the Coalition of Cancer Cooperative Groups, the Alliance for Clinical Trials in Oncology, the National Surgical Adjuvant Breast and Bowel Project, and the Breast International Group.
Groundbreaking scientific advances are possible because people volunteer to participate in clinical research. Through rigorous testing, these studies provide new insights into breast cancer diagnosis, screening, prevention, treatment, and survivorship. Clinical trials are critical to improving outcomes and ensuring that future patients can live longer, healthier lives.
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