Clinical Trials

August 6, 2011

Clinical trials are a form of medical research involving human participants. What follows is a brief overview about what clinical trials are and why they are done, important considerations for individuals considering participation in clinical trials, and a history of women and clinical trials.

The primary purpose of clinical trials is to determine whether promising new strategies for treatment and/or prevention of illness are safe and effective. Sometimes clinical trials also assess whether other factors—like subtype of illness, co-occurring illnesses, or differences in rates of metabolism in different individuals—influence how safe and effective various treatments and prevention strategies are.

Clinical trials might be testing an experimental drug or medical device that looks promising in laboratory studies and animal studies, but has not yet been tested in humans. Or, they might be testing a new system for delivering a medication already proven to be safe and effective for humans—for example, through an extended-action pill format, nasal preparation, or as an injection. Many clinical trials compare different treatment or prevention strategies to provide information about which is better. For example, a clinical trial may test how a combination of psychotherapy plus medication compares with psychotherapy alone and/or medication alone to help guide treatment decisions for clinical depression; another might compare prophylactic surgery with intensive monitoring and “watchful waiting” for women found to be at high risk for breast cancer to provide information to help guide decisionmaking related to preventing breast cancer.

Clinical trials are generally divided into four phases, or steps along the pathway toward determining safety and efficacy (Table). The four phases are most well defined for medication trials. However, research design has become so complex that many trials do not fit nicely into one of these four phases. Nevertheless, these four phases provide an overview of the processes involved in establishing new treatment and prevention strategies.

Table. Four phases of medication clinical trialsa

Phase I Phase I trials assess safety and toxicity of an experimental agent in healthy volunteers or sometimes in individuals with the medical condition of interest. Phase I trials are only conducted if there are adequate data from laboratory and animal studies to justify trying the experimental agent in humans. Phase I trials generally enroll a small number of research participants and last a relatively short period of time (weeks to months). Experimental agents must pass through each stage to get to the next one.
Phase II Phase II trials test further for safety and start to look for effective doses and other preliminary evidence of efficacy. Phase II trials generally enroll 50 to several hundred individuals and can take up to a couple of years to enroll enough research participants.
Phase III Phase III trials are designed to test for efficacy and also to further assess frequency and severity of side effects. Phase III trials are comparative trials and compare the result from a group of participants receiving the experimental agent with a group receiving a “control” agent, either a standard available treatment or a placebo (a sugar pill). They generally involve random assignment to these different groups—thus research participants do not get to choose which group they will be in. In addition, research participants and the researchers themselves are frequently not allowed to know which group they are in during the course of the trial—a research design aspect known as “blinding” or “masking.” “Randomized, controlled, double-blind” clinical trials are the gold standard for minimizing bias and providing reliable evidence for efficacy. Phase III trials may enroll thousands of individuals and take up to several years to complete enrollment.
Phase IV Phase IV trials are used to inform questions about longer term effectiveness of medications (e.g., how well they perform in regular clinical settings for long periods of time as opposed to the more controlled environment of a phase III clinical trial) and to assess longer term and rarer side effects. Phase IV clinical trials are much less standard in design and depend on the relevant questions being asked.

a

Only phases I—III are required for FDA approval. Phase IV trials are not required for FDA approval. They are conducted after FDA approval to answer remaining important questions.

While there are many different types of clinical trials, one thing they have in common is their ultimate objective: to advance the scientific knowledge upon which treatment and prevention strategies are based. Sometimes, “new” and “promising” experimental treatments or prevention strategies are thought to be better, just because they are new. However, until welldesigned and well-conducted clinical trials are completed, we cannot know if a promising experimental treatment or prevention strategy will be safe and effective. In the United States, companies seeking to market medications or medical devices must get approval from the Food and Drug Administration (FDA). In order to get FDA approval, these companies must provide data from clinical trials showing that the investigational drug or medical device is safe and effective. However, just because a new medication or medical device is approved for marketing, does not mean that it is necessarily safer or more effective than other available treatments. For example, in many medication trials for agents seeking FDA approval, experimental agents are compared with placebo (a sugar pill used to decrease bias in the clinical trial) to show that the experimental agent is safe and effective. Other types of trials directly comparing treatments may be needed to help determine if one is safer or more effective than another and/or if different treatments work better for different individuals.

Even though the primary purpose of clinical trials is to generate new knowledge, individuals sometimes view participation in clinical trials as an important option for accessing promising, albeit unproven and uncertain, alternatives to available treatments. This is especially true for some illnesses for which no good treatments are available. For individuals seeking to participate in clinical trials because of the possibility of personal benefit, and for their loved ones and health care providers helping them to make decisions about whether to participate, it is crucial to understand that participation in a clinical trial may not provide the medical benefits one is hoping for. It is also important for all involved to remember that even if there is a chance of receiving direct medical benefit from participating in a clinical trial, receiving care in a clinical trial is different from receiving treatment outside a clinical trial.

Regular medical treatment is meant to provide personalized help to the individual seeking treatment; clinical trials are designed to answer scientific questions. “Treatments” used in clinical trials are intended to benefit future patients and society as a whole by advancing medical knowledge. Individual research participants may or may not receive medical benefit from the experimental interventions and “treatment” administered as part of a clinical trial. Interestingly, however, some researchers contend that just being in a welldesigned clinical trial is good for individuals because they receive better care than is available outside of a clinical trial, and clinical outcomes of individuals in trials are better than those of individuals receiving regular medical care—and there are studies trying to assess whether these contentions are supported by evidence. Nevertheless, while it may be true that some individuals do receive medical benefit from their participation in clinical trials, this certainly is not always the case. Thus, such benefit may best be thought of as a “side effect” of clinical trial participation that some participants experience. And it is important to remember that providing individualized medical benefit to each participant in a clinical trial is not the main purpose of the trial.

Many individuals participate in clinical trials because they see participation as providing hope for medical benefit, even with all of the uncertainty involved. Some participate because of the desire to contribute to medical science and help future patients. Others participate because they feel a sense of camaraderie from being with other individuals with the same medical condition being closely monitored and cared for by a team of experts: the research physicians and nurses. Most participants in research have multiple motivations for considering research participation; for example, some might hope to benefit, but also understand that their participation helps to advance science and may help future patients, even though they themselves may not directly benefit from being in the trial.

While it is natural for individuals to have many different motivations for considering enrollment in a clinical trial, it is crucial that individuals have enough information and time to make an informed decision about whether or not to enroll. Although research undergoes review for its science and its ethics, a clinical trial that is determined to be appropriate to conduct may not be appropriate for or acceptable to every individual. For example, it is widely held that in order to be ethical, clinical trials must satisfy a requirement known as “clinical equipoise”—that is, a genuine uncertainty and lack of consensus exists within the medical community about whether the investigational treatment is as good as or better than standard treatment or placebo, when no effective treatment is available. However, even clinical trials that comply with this ethical standard still have features that depart substantially from standard medical practice. To increase scientific rigor, treatment alternatives (or placebo) are frequently randomly assigned to participants, participants and the research team are typically blind to which alternative is received, and protocol-driven limitations may be placed on the types and doses of interventions. Clinical trials generally do not allow the flexibility for individualized clinical decision-making that patients might be used to in working with their own personal physicians.

In addition, clinical trials may include research procedures that impose discomforts or risks for harm to participants who are not compensated by personal diagnostic or therapeutic benefits; instead, they are justified by the importance of the knowledge from the study. For example, participation in some trials may include medication washout periods, biopsies, overnight hospital stays, imaging studies with radiation exposure, blood draws, and questionnaires—not because something will be learned that will benefit the participant, but because they are needed to generate data necessary to test study hypotheses. Individuals who participate in clinical trials are closely monitored by the research team for adverse events that might be linked to their participation in the trial, and it is expected that their participation will be stopped by the research team if it looks like they are experiencing significant adverse events as a result of participating in the research. However, despite the fact that clinical trials are designed and reviewed to minimize risks of harm and the fact that there is close monitoring of the participants, some individuals may be harmed by their participation in a clinical trial—either by a research procedure or by the experimental intervention itself. These risks are on top of the risk of not receiving medical benefit from participating in a clinical trial. After all, clinical trials are conducted to see how well the experimental intervention works and if it is safe in humans.

For all these reasons, individuals considering participating in a clinical trial are encouraged to find out as much information about what it means to participate in clinical trials generally and what it would mean to participate in the particular trial they are considering. This process of gathering information and making decisions is referred to as the “informed consent process.”

During the informed consent process, individuals should carefully read the consent form and any other information the research team has available to give them. Individuals should feel free to ask any and all questions they have about the research study, including who is funding the study and whether or not the researchers have a financial stake in the outcome of the study, if they desire this information. Individuals should also feel free to consult with their own personal health care providers and their family and friends about this decision. Books and pamphlets are available that offer more information about clinical trials and suggestions for important questions to ask when considering participation in one. Two such general resources published in 2002 are: Should I Enter a Clinical Trial? A Patient Reference Guide for Adults with a Serious or LifeThreatening Illness, a report by the Emergency Care Research Institute (ECRI), a nonprofit health services research organization committed to improving quality, safety, and cost-effectiveness of health care; and Informed Consent: The Consumer’s Guide to the Risks and Benefits of Volunteering for Clinical Trials, by Getz and Borfitz (full citations in Suggested Reading at the end of this entry).

Individuals who consider participating in clinical trials should know that the decision whether or not to participate should be voluntary and a decision against participation should not affect their ability to get the medical care that is available to them otherwise. Also, after enrolling in a clinical trial, individuals are free to decide at any time during their participation that they wish to leave the clinical trial for any reason and instead receive standard treatment from their own health care providers. It is important to remember that we all owe a debt of gratitude toward individuals who volunteer for clinical trials, for it is the only way to get the evidence that many of us rely on to assess how safe and effective various treatment and prevention strategies are.

The dual concerns of safety and effectiveness sometimes compete with one another and create a dilemma related to the question, “Who ought to be allowed to participate in research as a research subject?” The history of women as research participants in clinical trials highlights the dilemma. While there are many regulations governing research with human participants, this has only been the case for the past 30 years. Prior to this, many pregnant women took the medications thalidomide and diethylstilbestrol (DES) before it was discovered that these medications caused birth defects and other health problems for the children who were exposed to the medications in utero. In 1977, resulting in part from these discoveries, the FDA barred pregnant women and women of childbearing potential from participating in early phase clinical trials assessing medications. The reasoning behind this policy was that early phase trials rarely provide benefit and have the potential to seriously harm the fetus. Although the FDA policy was limited to early phase studies, concerns about possible harms and legal liability translated into clinical trials that routinely excluded pregnant women and, in many cases, women of childbearing potential. Similar concerns also seemed to sway investigators from studying illnesses or medical conditions primarily affecting pregnant women or women of childbearing potential. This led to a period of time in which most clinical trials included primarily men or postmenopausal women. And this practice continued because it was widely believed in the scientific community—a community made up largely of men—that potential differences between women and men were scientifically and clinically unimportant. Now, we know that there are important differences between women and men, for example, in drug metabolism and in prevalence of various medical disorders. Thus, these guidelines— which were originally intended to limit the harm done in clinical research—had the ironic effect of limiting new knowledge about women and their health issues.

In the late 1980s and early 1990s, both the National Institutes of Health (NIH) and the FDA issued policies and guidelines requiring that women of childbearing age be included in later phase research and that analyses be conducted to assess differences between men and women with regard to safety and efficacy of experimental treatments. The NIH created an Office of Research on Women’s Health to promote research aimed at improving the health of women and to oversee the implementation of the NIH policy on inclusion of women in NIHsupported research. The FDA also has an Office of Women’s Health which funds research and educational efforts to enhance women’s health. It also works to ensure that clinical trials over which the FDA has jurisdiction include sufficient numbers of women to assess safety and efficacy of medications and devices seeking FDA approval.

Even though clinical trials have started to include women in sufficient numbers to provide information about safety and efficacy of treatments for women, there are not always sufficient numbers of individuals with other characteristics that potentially affect the safety and efficacy of medications and medical devices. For example, there are differences in drug metabolism among various ethnic groups that may not be picked up in clinical trials because there are not enough individuals from an ethnic group participating in a trial. Also, many clinical trials exclude individuals with co-occurring illnesses or who are on other medications from participation in the trial, and thus there is no information about whether the medications and/or devices studied are safe and effective in individuals with these co-occurring illnesses or when taken with other medications. Postmarketing surveillance of FDA-approved medications and devices can help answer some of these questions that are left unanswered by the approval process. In addition, postmarketing surveillance may uncover information about safety that leads an approved medication to be pulled off the market because data in a larger number of individuals, some with characteristics that were not included in previous clinical trials, show that it is not as safe as it originally seemed.

While postmarketing surveillance provides important information, it cannot substitute for information gathered from well-designed clinical trials. However, most information about use of medications during pregnancy and breast-feeding is garnered from surveillance data from pregnant and breast-feeding women who take medication after it is approved, rather than from clinical trials due to continued worries about exposing fetuses and breast-feeding infants to risks of harm in clinical trials. The paucity of reliable information lead women and their physicians to shy away from using medications during pregnancy or breast-feeding, to use lower doses of medications when they are needed, and to use older medications which seem to be safer based on reasoning that they have been around long enough that serious problems would have already shown up. However, though concern over taking medication while pregnant and/or breast-feeding is understandable, in many cases, not treating or inadequately treating a medical condition is equally concerning and raises questions that are currently unanswerable. Various federal agencies are working together to gather better systematic data on outcomes from women who have taken medications while pregnant and/or breast-feeding as well as to promote clinical research aimed at answering these types of questions related to maternal health.

We are starting to see the benefits of the concerted steps taken to improve the situation generated by many years of neglect regarding women in clinical trials research. While there is still room for improvement, these policies and programs have contributed greatly to enhancing the medical knowledge base for women.

SEE ALSO: Diethylstilbestrol, Discrimination, Disparities in Women’s Health and Health Care, History of Women’s Health in the United States, Informed consent, Thalidomide, Women’s Health Initiative

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