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FDA Consumer magazine
September-October 2003 Issue
Inside Clinical Trials
Testing Medical Products in People
By Carol Rados
Carolyn Meritt was preparing to undergo a stem cell transplant in 2001 to treat mantle cell lymphoma--a rare cancer of the lymph nodes--when her doctor told her about a clinical trial being conducted by the National Institutes of Health (NIH). He suggested that she consider becoming a participant.
"I didn't even know what a clinical trial was," Meritt says. That was only one of many questions she would need answered before she could decide whether or not to enroll.
But Meritt's white blood counts were rising. She would need treatment soon. She could proceed with the stem cell transplant--the only existing therapy--or, as long as she felt well enough, she could hold out hope and participate in the clinical trial, an option open to her only if she had no prior treatment. But how would she decide?
Predicaments like Meritt's are not uncommon. "We get this kind of call just about every day," says Theresa Toigo, director of the Food and Drug Administration's Office of Special Health Issues (OSHI). "The patients have serious and life-threatening diseases. They're afraid. They want some options, but they're not sure where to go. We try to provide the information patients and their families need to make important decisions in such difficult situations."
What Is A Clinical Trial?
A common thread linking such calls, says Toigo, is clinical trials. Clinical trials, also known as clinical studies, test potential treatments in human volunteers to see if they should be approved for wider use in the general population. A treatment could be a drug, medical device, or biologic, such as a vaccine, blood product, or gene therapy. Potential treatments, however, must be studied in laboratory animals first to determine potential toxicity before they can be tried in people. Treatments having acceptable safety profiles and showing the most promise are then moved into clinical trials.
Although "new" may imply "better," it is not known whether the potential medical treatment offers benefit to patients until clinical research on that treatment is complete. Clinical trials are an integral part of new product discovery and development, and are required by the FDA before a new product can be brought to the market.
The FDA is committed to protecting the participants of clinical trials, as well as providing reliable information to those interested in participating. Recently, unethical behavior on the part of some researchers has shaken the public trust and prompted the federal government to establish regulations and guidelines for clinical research to protect participants from unreasonable risks.
Although efforts are made to control risks to clinical trial participants, some risk may be unavoidable because of the uncertainty inherent in clinical research involving new medical products. It's important, therefore, that people make their decision to participate in a clinical trial only after they have a full understanding of the entire process and the risks that may be involved.
Why Participate in a Clinical Trial?
People volunteer to participate in clinical trials for different reasons. Some volunteer because they want to help advance medical knowledge. Others have tried all available treatments for their condition without success.
In a spring 2000 Harris Poll of cancer clinical trial participants, 76 percent of the respondents said they participated because they believed that the trial offered the best quality of care for their disease. Helping other people and receiving more and better attention for their own specific disease were other reasons cited.
"I was going ahead with the stem cell transplant because I thought I had no other options," Meritt admits. "Part of the reason I decided to do this study was so that maybe what they learned through me would help other people with mantle cell lymphoma." Others enter clinical trials in hopes of finding a potential treatment, after traditional therapies fail.
People should not, however, be tempted to enroll in a clinical trial simply because a potential treatment is being offered free during a study, or because of the promise of money, says David Banks, an FDA pharmacist.
"People lured by compensation may overlook the known risks," Banks says. "Or [they may fail] to adequately appreciate the potential for discovery of serious new side effects during clinical testing of a new treatment." Banks also says that clinical trials "are generally not a means for patients to receive long-term treatment for their chronic disease." Still, he adds, "clinical trials often represent an option to seriously consider."
Who Can Participate?
It's important to test medical products in the people they are meant to help. In the past, most new drug testing had been done on white men. Groups such as women, African-Americans, and Hispanics often were not adequately represented. It's important to test medical products in a wide variety of people because drugs can work differently in people of various ages, races, ethnicity, and gender. The FDA seeks to ensure that people from many different groups are included in clinical trials.
Trial guidelines, or eligibility requirements, are developed by the researchers and usually include criteria for age, sex, type and stage of disease, previous treatment history, and other medical conditions. Some trials involve people with a particular illness or condition to be studied, while others seek healthy volunteers. Inclusion or exclusion criteria--medical or social standards used to determine whether a person may or may not be allowed to enter a clinical trial--help identify appropriate participants and help to exclude those who may be put at risk by participating in a trial.
Volunteering for a clinical trial is no guarantee of acceptance. Similarly, there's no guarantee that an individual in a clinical trial will receive the drug or medical product being studied.
What Happens in a Clinical Trial?
Every clinical trial is carefully designed to answer certain research questions. A trial plan called a "protocol" maps out what study procedures will be done, by whom, and why. Products are often tested to see how they compare to standard treatments or to no treatment. The FDA often provides extensive technical assistance to researchers conducting clinical trials, helping them design better trials that can characterize effects of a new product more efficiently, while reducing risks to those participating in the trials.
The clinical trial team includes doctors and nurses as well as other health care professionals. This team checks the health of the participant at the beginning of the trial and assesses whether that person is eligible to participate. Those found to be eligible--and who agree to participate--are given specific instructions, and then monitored and carefully assessed during the trial and after it is completed.
Done at hospitals and research centers around the country, clinical trials are conducted in phases. Phase 1 trials try to determine dosing, document how a drug is metabolized and excreted, and identify acute side effects. Usually, a small number of healthy volunteers (between 20 and 80) are used in Phase 1 trials.
Phase 2 trials include more participants (about 100-300) who have the disease or condition that the product potentially could treat. In Phase 2 trials, researchers seek to gather further safety data and preliminary evidence of the drug's beneficial effects (efficacy), and they develop and refine research methods for future trials with this drug. If the Phase 2 trials indicate that the drug may be effective--and the risks are considered acceptable, given the observed efficacy and the severity of the disease--the drug moves to Phase 3.
In Phase 3 trials, the drug is studied in a larger number of people with the disease (approximately 1,000-3,000). This phase further tests the product's effectiveness, monitors side effects, and, in some cases, compares the product's effects to a standard treatment, if one is already available. As more and more participants are tested over longer periods of time, the less common side effects are more likely to be revealed.
Sometimes, Phase 4 trials are conducted after a product is already approved and on the market to find out more about the treatment's long-term risks, benefits, and optimal use, or to test the product in different populations of people, such as children.
Phase 2 and Phase 3 clinical trials generally involve a "control" standard. In many studies, one group of volunteers will be given an experimental or "test" drug or treatment, while the control group is given either a standard treatment for the illness or an inactive pill, liquid or powder that has no treatment value (placebo). This control group provides a basis for comparison for assessing effects of the test treatment. In some studies, the control group will receive a placebo instead of an active drug or treatment. In other cases, it is considered unethical to use placebos, particularly if an effective treatment is available. Withholding treatment (even for a short time) would subject research participants to unreasonable risks.
The treatment each trial participant receives is often decided by a process called "randomization." This process can be compared to a coin toss that is done by computer. During clinical trials, no one likely knows which therapy is better, and randomization assures that treatment selection will be free of any preference a physician may have. Randomization increases the likelihood that the groups of people receiving the test drug or control are comparable at the start of the trial, enabling comparisons in health status between groups of patients who participated in the trial.
In conjunction with randomization, a feature known as "blinding" helps ensure that bias doesn't distort the conduct of a trial or the interpretation of its results. Single-blinding means the participant does not know whether he or she is receiving the experimental drug, an established treatment for that disease, or a placebo. In a single-blinded trial, the research team does know what the participant is receiving.
A double-blind trial means that neither the participant nor the research team knows during the trial which participants receive the experimental drug. The patient will usually find out what he or she received at a pre-specified time in the trial.
Meritt participated in an NIH study of a vaccine and chemotherapy combination in previously untreated mantle cell lymphoma. Following more than a year of medical treatment through the study, her cancer went into remission.
What Are the Risks?
Some treatments being studied can have unpleasant, or even serious, side effects. Often these are temporary and end when the treatment is stopped. Others, however, can be permanent. Some side effects appear during treatment, and others may not show up until after the study is over. The risks depend on the treatment being studied and the health of the people participating in the trial. All known risks must be fully explained by the researchers before the trial begins. If new risk information becomes available during the trial, participants must be informed.
"I didn't tolerate the drugs well," says Leslie Garelick of Olney, Md., referring to the two rounds of experimental chemotherapy she received as a participant in a clinical trial of a breast cancer treatment. Because her white blood cell counts were dangerously low, she was forced to skip some of the scheduled trial treatments. On the advice of her doctor, the 30-year-old mother of two withdrew from the trial and received standard treatment for breast cancer. Even though she quit the study, Garelick's experience gave the research team information about tolerance to the drug being tested.
How Are People Protected?
Most clinical trials are federally regulated with built-in safeguards to protect participants. Today, the Office for Human Research Protections (OHRP) in the Department of Health and Human Services (HHS) leads the department's programs for the protection of human research participants, and oversees human protection in HHS-funded research.
"It's important that we have the rapport with the public that allows them to trust us with this program," says Bernard A. Schwetz, D.V.M., Ph.D., acting director of the OHRP. He adds, "Without people willing to participate, there won't be any clinical trials."
The FDA has authority over clinical trials for drug, biologic and medical device products regulated by the agency. This authority includes studies that are HHS-funded (with joint oversight by the FDA and the OHRP), as well as studies that are solely funded by industry or by private parties. Many clinical trials are not subject to FDA regulation but are monitored by the institution sponsoring the trial, such as a hospital. (See "Institutional Review Boards".)
To help protect the rights and welfare of volunteers and verify the quality and integrity of data submitted for review, the FDA performs inspections of clinical trial study sites and anyone involved in the research, says David A. Lepay, M.D., Ph.D., director of the FDA's Good Clinical Practice Program. Lepay says that the quality of clinical trials has improved markedly since the agency started inspecting them back in 1977.
"Between FDA, the help of other government agencies, the review by Institutional Review Boards, the required monitoring of studies by industry or private sponsors, and the required oversight and reporting by investigators and their staff," Lepay says, "a lot of people are looking out for the research subject's safety."
What Is Informed Consent?
The FDA requires that potential participants be given complete information about the study. This process is known as "informed consent," and it must be in writing. (See "Information Required for Informed Consent".)
The informed consent process provides an opportunity for the researcher and patient to exchange information and ask questions. Patients invited to enter a trial are not obligated to join, but can consent to participate if they find the potential risks and benefits acceptable. A consent form must be signed by the participant prior to enrollment and before any study procedures can be performed.
Participants also have the right to leave a study at any time. At the same time, people need to know that circumstances may arise under which their participation may be terminated by the researcher, without their consent.
For example, Schwetz says that sometimes it becomes evident early on that a trial is not working and researchers know they are not going to get enough meaningful information to make continuation worthwhile. In addition, if an unexpected change occurs in the health status of a participant, such as toxic effects or sudden kidney problems that may have developed, it "would not be in the best interest of the patient to continue, and certainly not consistent with what the investigator is trying to study," he says. In any case, the circumstances must be described in the consent document.
Where To Get Information on Clinical Trials
It is often difficult for patients to learn about opportunities to participate in clinical trials. Doctors and patient advocacy groups can be valuable resources for patients in search of clinical trial information. Newspapers, particularly in large cities, often carry clinical trial recruitment advertisements. A call to the relevant department at nearby university medical centers can lead to information about clinical trials currently recruiting patients.
The Web site ClinicalTrials.gov also provides patients, family members, health care professionals, and members of the public easy access to information on clinical trials for a wide range of diseases and conditions. The NIH, through its National Library of Medicine, has developed this site in collaboration with all NIH institutes and the FDA.
The site currently contains information on about 8,200 clinical studies sponsored by the NIH, other federal agencies, and the pharmaceutical industry in over 99,000 locations worldwide. Studies listed in the database are conducted primarily in the United States and Canada, but include locations in about 90 countries. ClinicalTrials.gov gives information about a trial's purpose, who may participate, locations, and phone numbers for more details. In addition, a glossary is available that will help people become familiar with the most common clinical trial terms.
The Bottom Line
While it's true that clinical trials offer no guarantees, when standard treatments fail, or none exist, clinical research trials sometimes can offer hope. People can reduce the confusion and uncertainty that often comes with deciding whether or not to participate in a clinical trial by obtaining all the information available on various Web sites, through phone calls, within FDA, HHS, and NIH offices, and from patient advocacy organizations.
The bottom line: Know and understand the different types of trials, which questions to ask, and your rights as a trial participant. Find out what risks there may be, and determine what level of risk you are willing to accept before you agree to enroll in a clinical trial for medical research.
For More Information
FDA's Office of Special Health Issues
(301) 827-4460 or (888) INFO-FDA (463-6332), select 3 for directory information and ask to be connected to the Office of Special Health Issues
www.fda.gov/oashi/home.html
Cancer Information Service
(800) 4-CANCER (422-6237)
www.cancer.gov/clinical trials
AIDS and HIV trials
(800) 874-2572
www.aidsinfo.nih.gov
Patient advocacy groups
www.cancer.gov/cancerinfo/make-a-difference
Institutional Review Boards
Clinical trial procedures are reviewed by Institutional Review Boards (IRBs). These boards are composed of at least five members that include scientists, doctors and lay people, and they must approve every clinical trial taking place within their jurisdiction--usually a hospital. The purpose of an IRB review is to ensure that appropriate steps are taken to protect the rights and welfare of participants as subjects of research. If the risks to participants are found to be too great, the IRB will not approve the research or it will specify changes that must be made before the research can be done.
IRBs also review participant inclusion and exclusion requirements to be sure that appropriate people have been identified as eligible for the trial. They often look at how and where recruitment for clinical trials will occur. IRBs review the adequacy of the informed consent document to ensure that it includes all the elements required by law, and that it is at an appropriate reading level and understandable to study participants.
Information Required for Informed Consent
The FDA requires that people be told:
That the study involves research of an unproven drug, biologic (such as a vaccine, blood product, or gene therapy) or device
The purpose of the research
How long the participant will be expected to participate in the study
What will happen in the study and which parts of the study are experimental
Possible risks or discomforts to the participant
Possible benefits to the participant
Other procedures or treatments that might be advantageous to the participant instead of the treatment being studied
That the FDA may look at study records, but the records will be kept confidential
Whether any compensation and medical treatments, if any, are available if the participant is injured, what those treatments are, where they can be found, and who will pay for the treatment
The person to contact with questions about the study, participants' rights, or if the participant gets hurt
That participation is voluntary and that he or she can quit the study at any time without penalty or loss of benefits to which the participant is otherwise entitled.
(Infographic by Renée Gordon)
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