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What You Need to Know Before Becoming A Human Subject in a Clinical Trial

Health Letter Article, March 2013

Every day, in hospitals, clinics and physicians’ offices across the U.S., hundreds if not thousands of patients are recruited to participate in clinical trials. These trials test new experimental drugs, medical devices and other interventions for a wide range of diseases and disorders, including cancer, heart disease, depression, asthma, infections, diabetes and hypertension, to name just a few.

Before they may enroll someone in a clinical trial, the researchers conducting the trial are required by federal regulations to first obtain the individual’s informed consent. The process for obtaining informed consent involves communicating to the prospective subjects, among other things, the procedures involved in the clinical trial, its risks and benefits, and the alternatives to participating in the study that may be advantageous to the subjects.

To assist readers in making well-informed decisions about whether to participate in clinical trials if invited, this article explains the fundamental difference between clinical care and research and offers guidance on important issues to consider before becoming a human subject in a clinical trial.

Clinical care versus clinical research

When doctors invite their own patients to participate in clinical trials, patients may assume that participation in a trial is simply part of clinical care and is in their best interests. However, participation in research and treatment for a medical condition are not the same. It is important to understand the fundamental differences between clinical care and clinical trial research, between being a patient and being a human subject, and between being a physician and being a researcher.

In the clinical care setting, the physician’s sole responsibility is to act in the best interests of the individual patient. Clinical treatment recommendations and decisions are individually tailored and based solely on the unique characteristics, health needs and desires of each patient. The only goal of clinical care is to provide benefit to the patient.

In contrast, the interventions that a human subject receives in the context of a clinical trial are dictated by a research protocol. This protocol generally determines the medical interventions that the subject will receive — such as the type, dose and frequency of drugs and the type and frequency of medical tests and procedures — without respect to the individual needs of the patient or the customized recommendations of the patient’s physician.

Furthermore, the primary goal of clinical research is not to provide benefit to the individual subject, but rather to answer a scientific question or test a medical hypothesis and ultimately obtain new medical knowledge that may benefit future patients. Thus, in the clinical trial setting, the interests of the individual subject are secondary to the goals of the research.

Some bioethicists have concluded that the only way to effectively minimize the potential for patients to confuse medical research with clinical care is to prohibit physicians from recruiting their own patients into clinical trials for which those physicians are also the researchers. Because such a prohibition has not been adopted, it is very important that patients understand the difference between clinical care and research so that they can make well-informed decisions about whether to enroll in clinical trials.

Important questions

Before agreeing to be a subject in a clinical trial, a patient should be sure to obtain and understand answers to the following key questions:

What is the purpose and phase of the clinical trial?

The purpose of a research study tells you why the clinical trial is being conducted. In general, the purpose is defined by the phase of development the experimental intervention being tested has reached. Clinical studies of new experimental drugs, for instance, are typically divided into three phases, referred to as phase 1, 2 or 3.

Phase 1 clinical trials are studies testing a new drug in humans for the first time. These studies involve exposing a small number of human subjects to a single dose of a new drug and collecting data on short-term toxicity as well as drug metabolism and excretion (how the drug is absorbed, broken down and removed from the body). Phase 1 trials generally enroll healthy adult individuals, but those testing certain types of drugs enroll patients with specific diseases. (For example, phase 1 clinical trials of new chemotherapy drugs for cancer usually involve patients with advanced stages of cancer.)

In phase 1 trials, there are no data from human testing indicating that the drug is safe or effective in those patients for whom it is being developed. The primary purpose of a phase 1 study is to find the highest dose of the drug that does not result in unacceptable toxicity. Data from such trials are used to guide dosing in subsequent phase 2 and
phase 3 trials.

Phase 2 clinical trials of drugs are designed to gather preliminary data on the effectiveness of a new drug in patients with a particular disease or condition, as well as additional information on toxicity and metabolism. These trials usually enroll relatively small numbers of subjects (approximately 40 to 200) and involve exposure to multiple doses of the drug being studied. In some phase 2 trials, all subjects receive the new experimental drug being studied, and there is no control group. In other phase 2 studies, one group of subjects receiving the experimental drug is compared to a control group of similar individuals who are given a different intervention, such as an inactive substance (placebo) or another drug that has been shown to be effective for treating the disease of interest.

When phase 2 trials commence, the researchers generally have little or no information on whether the new experimental drug is useful for treating the intended patient group, and minimal information regarding the drug’s short-term toxicity.

For most new drugs, phase 3 clinical trials represent the final level of testing before the drug is considered for approval by the Food and Drug Administration (FDA). These studies, which routinely involve several hundred to several thousand subjects, gather more information about safety and effectiveness by studying the drug in different populations, at different dosages, and sometimes in combination with other drugs. For these trials, there is usually some limited evidence from earlier phase 2 or 3 trials suggesting that the drug may offer some benefit for the intended patient population, but such benefit has not yet been proven.

After a drug is approved by the FDA and is no longer considered experimental for its FDA-approved indication, phase 4 clinical trials will sometimes be conducted. Such studies, performed after a drug’s approval, may be required by the FDA as a condition of approval of the drug, or they may be conducted voluntarily by the drug company. They may be similar in design to phase 3 studies or involve only one study group in which all subjects in the trial receive the specific drug being evaluated. The goal of these studies is to collect more information about a drug’s safety, effectiveness or optimal use in the real-world setting.

Studies of nondrug interventions, such as medical devices or social and behavioral interventions, don’t fall neatly into the same four phases of clinical trials used for developing new drugs. Nevertheless, studies of these other interventions commonly follow a development pathway from early-phase trials, where little is known about the safety and effectiveness of the intervention, to late-phase trials, where more is known. Therefore, before enrolling in any clinical trial, it is important to know where the trial falls in the development timeline.

What will the clinical trial involve and how will it differ from usual care?

Patients considering enrollment in a clinical trial must be provided a detailed description of all procedures and interventions that they will be asked to undergo, and they must be informed about the expected duration of study participation. The study description must identify any procedures that are considered experimental. Ultimately, to make a fully informed decision about whether to enroll in a trial, patients need to clearly appreciate how the interventions and procedures in the clinical trial compare with the treatment and procedures they would otherwise undergo as part of routine clinical care.

Most clinical trials involve three stages. The first stage involves undergoing screening to confirm that an individual meets the criteria for enrollment in the trial. This screening may include undergoing a medical history assessment, physical exam, blood test or tests, biopsy, or imaging study, such as X-ray, ultrasound, or CT or MRI scanning. In some cases, the subject would undergo these same procedures and tests as part of routine clinical care, and in other cases, the testing is solely part of the research.

The second stage of a trial involves receiving the primary study interventions being tested. In studies involving comparisons of different interventions — for example, a new experimental drug for hypertension (high blood pressure) being compared to a standard, FDA-approved hypertension drug or to a placebo — subjects are often randomly assigned to receive one of the two interventions. To minimize the possibility of study bias, many clinical trials use double-blinding, in which neither the subject nor the researcher, who is frequently the subject’s physician, know which intervention the subject is receiving. During this stage of a trial, subjects may be required to undergo additional exams, blood tests, biopsies or imaging studies that may or may not be routinely done if they were not participating in the research.

The third stage of a trial is a follow-up stage after the interventions being studied have been discontinued and the subjects are followed for a period of time, from a number of hours to many years. During this stage, information about the subjects’ clinical status is collected periodically to see how each patient’s disease or disorder responded to the primary study interventions being tested. The subjects again may be required to undergo additional tests and procedures that may or may not be routinely done if they were not enrolled in the research.

What are the risks of the research?

Essentially all clinical trials involve risks of harm or discomfort to the subjects. Too often, the risks of a clinical trial are minimized by the researchers.

There are many potential sources of risk from research, including adverse effects resulting from:

  • the experimental drug, medical device or other intervention being studied (for example, the experimental drug may cause strokes, heart attacks, liver injury or kidney disease);
  • other procedures that the subjects undergo because of the research, such as additional imaging studies, blood tests or biopsies; and
  • substandard treatment, or no treatment, of a potentially serious disease if the subjects are assigned to the control group and receive a placebo or nonstandard treatment regimen.

Women of childbearing age need to know about any risks posed by the research to an embryo or fetus. These may include a risk of birth defects, premature delivery and fetal death.

Some trials also involve washout periods, during which all subjects are taken off some or all medications used to treat the disease of interest for a period of days or weeks prior to being randomized to receive one of the specified study interventions being tested. These washout periods are particularly common in trials of diseases such as hypertension and mental health disorders. Washout periods can expose subjects to adverse events related to inadequate treatment of their underlying disease or disorder. For example, a subject with severe hypertension taken off all blood-pressure medication during a washout period could suffer a stroke or other cardiovascular event due to inadequately controlled blood pressure. Likewise, a subject with schizophrenia taken off antipsychotic medication could experience a severe psychotic episode.

Assessing the risks posed by a clinical trial requires considering the various interventions and procedures that are solely a function of research participation, as well as estimating both the probability and severity of the adverse events that may result from those interventions. The probability of a particular adverse event may range from extremely rare to very likely. Likewise, the severity of a particular adverse event may range from mild (for example, slight dry mouth) to extremely severe, life-threatening or even fatal.

Frequently, because of limited prior testing of a particular new experimental drug or medical device, the exact probability of a particular adverse event occurring is unknown. Moreover, potential subjects need to recognize that a particular treatment or research intervention may involve unforeseeable risks. The likelihood that a clinical trial involves such unforeseeable risks is highest in early-phase studies (that is, phase 1 and early phase 2 trials) due to limited knowledge of safety at these points. For example, last year, a phase 2 clinical trial testing an experimental drug for hepatitis C infection unexpectedly resulted in severe heart failure and death in some subjects. Because of these unforeseen adverse events, the manufacturer terminated the development program for the drug.

What are the alternatives to being in the clinical trial?

Patients considering enrollment in a clinical trial must be informed of appropriate alternative procedures or courses of treatment, if any, that may benefit them. For many diseases and disorders, there are standard, state-of-the-art treatments available. Patients should be informed of these treatments.

In some clinical trials, different FDA-approved drugs or combinations of FDA-approved drugs are being compared for the treatment of a particular disease. This is particularly common in clinical trials testing new treatment regimens for cancer. Many patients choose to enroll in such clinical trials hoping that they will be randomly assigned to the study group receiving the “newest” regimen or drug being evaluated. For such trials, patients should ask the researchers or their own physicians whether they can receive one of the drugs or drug combinations being tested without enrolling in the clinical trial.

Finally, for some patients considering enrollment in clinical trials of interventions for advanced, terminal illnesses, one alternative that may be advantageous to patients is supportive, palliative care.

What are the benefits, if any, to participating in the research?

The potential benefit to subjects that may result from participation in clinical trials is highly variable across trials. Too often, researchers overstate the potential benefits of research, and subjects have unreasonable expectations about them.

For some trials, particularly phase 1 trials in healthy volunteers (who are usually paid for their participation), there is no medical benefit. For patients with a particular disease or disorder being studied, the potential for benefit is lowest in early-phase studies. In fact, as a general rule, subjects in early-phase studies probably are more likely to experience harm than clinically significant benefits.

The prospect of benefit for individual subjects in phase 3 trials is higher than earlier-phase studies, but the degree of benefit is unknown and may be minimal compared with the benefits of routine medical care unrelated to the trial. Indeed, the goal of such trials is to determine what benefit, if any, the experimental interventions provide for treating the disease or disorder of interest.

Ideally, if the trial is well designed and conducted, the researchers will gain important new knowledge that will benefit future patients.

What are your rights as a research subject?

Prospective research subjects must be informed that participation in research is completely voluntary and that refusal to participate will not result in any penalty or loss of benefits to which they are otherwise entitled. For example, patients invited to enroll in a clinical trial can’t be threatened with loss of health care benefits if they opt not to participate in the research.

Similarly, patients who enroll in clinical trials are free to discontinue participation at any time without penalty or loss of benefits. Furthermore, while the researchers may recommend that subjects wishing to discontinue participation undergo certain tests and procedures to ensure a safe and orderly withdrawal from a trial, subjects are under no obligation to adhere to those recommendations.

Subjects also have a right to be informed about any new information or findings about the drug or device that develop during the course of a trial that may relate to the subjects’ willingness to continue participation. For example, if during the course of a clinical trial, researchers discover that an experimental new drug has a risk of causing severe liver failure, subjects in the trial should be promptly informed of this new risk information so that they can reassess whether they want to continue participation.

Advice for readers

Before enrolling in a clinical trial, you should discuss each of the above questions, in detail, with the researchers. You should ask for a copy of the consent form for the trial and ideally, if time permits, go home and take time to discuss the proposed trial with family, friends or your primary care doctor. Thoughtfully consider whether enrollment in the research is the right choice for you. You also may want to do some independent online research to learn more about the proposed research interventions as well as the currently available treatment options for your disease or condition. Once you are comfortable that you understand the research and have considered all your options, only then should you decide whether participating in a clinical trial is right for you.

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