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Clinical Trials: Finding Balance In Randomization

Tom Reynolds

Years ago a prominent cancer researcher asked the provocative question, "Is there any mileage left in the randomized clinical trial?"

Emil J. Freireich, M.D., a leukemia expert at the University of Texas M. D. Anderson Cancer Center in Houston, rejected the conventional view of the randomized trial as the gold standard in clinical research. He compared it instead to an old Tin Lizzy, a car that served long and well but is now fit only for museum or junkyard. Answering his own question in the negative, he laid out ethical objections to randomized trials and asserted that many clinical scientists have abandoned such trials as the best way to gather medical knowledge.



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Dr. Emil J. Freireich

 
Years later, though, that claim appears overstated—or at least premature. The randomized, controlled trial reigns today as firmly as ever, and researchers have been slow to embrace alternatives or even to modify the standard design. But ethical tensions have not disappeared either.

At the heart of the continuing debate is that some are uneasy with physicians relinquishing control over treatment decisions. Traditionally, the welfare of individual patients is a doctor’s chief concern. Physicians are supposed to do their utmost to heal patients, making the best decisions they can about treatment and taking into account each patient’s unique circumstances and values.

Randomized clinical trials, by contrast, demand that the treatment being studied is determined by chance. And if a trial has the desired outcome, and proves one option more effective or less toxic, then some patients (typically half) will have had suboptimal treatment. Their experience will likely benefit future patients with the same disease. But how can it be reconciled with physicians’ professional duty to their patients—not to mention their moral duty to treat other persons as they would like to be treated?

The answer depends largely on the interpretation of two key criteria, equipoise and informed consent, that must be met in an ethical trial. Equipoise is a balance of evidence resulting in uncertainty about which treatment is truly best. Informed consent means patients understand just what they are getting into when they enroll in a trial, and what their alternatives are.

Equipoise

As originally conceived, equipoise implied that doctors can put their patients on a trial in good conscience only if they believe that each treatment is equally likely to prove superior. If they think one treatment is probably better, they should give that treatment in accordance with their professional obligation. But in practice, true equipoise is elusive at best, at least at the individual-physician level. For one thing, a large-scale, randomized trial is unlikely to be done if those mounting the trial do not have some reason to believe the new treatment has an advantage.

In 1987, Benjamin Freedman, Ph.D., an ethicist at McGill University in Montreal, introduced the notion of clinical or community equipoise, which widely influenced thinking about clinical research ethics. If there is "no consensus within the expert clinical community about the comparative merits of the alternatives to be tested," Freedman argued, a trial can be considered ethical.

Justifiably Participate

Physicians who hold opinions favoring one alternative can justifiably participate, recognizing that other equally competent and experienced clinicians hold different views, and that a trial may show these opposing views to be right. Many ethicists and clinical researchers accept this argument, and are comfortable with a trial as long as it addresses an issue that has not been resolved to the general satisfaction of the medical community.

Others reject the notion of community-based equipoise, holding that the physician’s duty to the individual patient overrides all other considerations.

"As a doctor, you’re supposed to be loyal to your patient, to be honest, and to provide that patient with your best judgment," said Samuel Hellman, M.D., a radiation oncologist at the University of Chicago who has written critically about randomized trials. "There’s no contract with the patient that you’re going to serve humanity and that might compromise that patient’s care."



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Dr. Samuel Hellman

 
If a clinical question is so important and the answer so uncertain that a randomized trial is needed, Hellman said, doctors may tell patients about a trial. But unless they truly have no opinion on which treatment is best, to participate in the trial themselves would mean "they have two interests that are at cross-purposes."

But some say today’s clinician–scientists must reconcile those two interests. "American physicians who are trained in good places are socialized to think ‘I have two loyalties, one to my patients and one to the community of science,’" said John C. Fletcher, Ph.D., retired director of the Center for Biomedical Ethics at the University of Virginia, Charlottesville.



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Dr. John C. Fletcher

 
Eliminating Diversity

Critics also fault trials for lumping together diverse groups of patients. Treatment needs to be standardized for trials to be run properly, but this constrains physicians in tailoring therapy to each patient’s needs. Hellman pointed out that a physician may have doubts about the best treatment for the hypothetical "average" patient, but be able in many cases to see which alternative best suits a real, individual patient.

This "lumping" may have scientific drawbacks too. In his 1990 editorial, Freireich noted that "many potentially useful treatments, particularly treatments useful for a small subset of patients, are lost forever in the falsely negative clinical trials designed to compare outcomes for the average patient."

Researchers must exercise special care in obtaining informed consent from people perceived as vulnerable to coercion, such as the mentally retarded. Extending that idea, some critics have argued that having a life-threatening illness, coupled with the power imbalance in the doctor–patient relationship, can itself make people vulnerable. Patients may seek to please their doctor through compliance. They may feel helpless and unwilling to question the doctor’s judgment.

Christopher Daugherty, M.D., an oncologist at the University of Chicago, pointed out that while vulnerability is a concern, the flip side is that it would be paternalistic for doctors to presume seriously ill patients are incapable of weighing the options and making good decisions for themselves. So a failure to disclose all options to a patient, including entering a trial, could be considered unethical.

Daugherty said studies are needed to explore the many variables that could compromise informed consent. One troubling question is patients’ motivation to enter trials. Rather than accepting that two alternatives are in equipoise, many patients may enroll in hope of getting a new treatment they can get only in a trial. If randomized to the control arm, they are likely to be unhappy and may drop out. This problem has led in some cases to special programs allowing patients access to "experimental" therapies outside trials.

Logical Inconsistency

Walter M. Robinson, M.D., a pediatrician at Children’s Hospital in Boston, detects a logical inconsistency in the way informed consent is mandated. In the March 11, 1999, New England Journal of Medicine, Robinson and colleagues pose the question, why is it that randomization always requires informed consent, while therapeutic innovations outside a trial—essentially uncontrolled experiments—do not?

"Why should informed consent hinge on randomization?" Robinson asked in an interview. "From the patient’s point of view, risk is the concern, not randomization." On one hand, the authors argue, informed consent could ethically be waived in certain cases, making it easier to do randomized trials of interventions where patients are unlikely to know or care about alternatives, and are not specifically asked for consent anyway. These might answer many questions in hospital practice, Robinson said, such as the best way to wean patients off a ventilator, or the most effective type of hand soap for preventing infection.

Practicing Informed Consent

On the other hand, he said, ad hoc experiments like off-label use of drugs should call for patients’ consent whether used in or out of a trial, because the risk is the same in either case.

Don Marquis, Ph.D., an ethicist at the University of Kansas in Lawrence, suggests that the resolution to the randomization dilemma lies in the way physicians regard, and practice, informed consent. In the Aug. 26, 1999, New England Journal of Medicine, he argues that true informed consent includes discussion both of the physician’s own preferences and recommendations, however uncertain, and the option of enrolling in a trial. This is because one of the roles of a physician is to inform the patient about all reasonable options, including participation in randomized studies.

Fletcher agreed, saying that failure to inform a patient about appropriate trials is a breach of ethics. "If I know that well-respected experts disagree, and there is a well-designed randomized trial, my duty as a physician–scientist is to tell my patients about the option of entering the trial," he said. "But if I have a preference, the patient deserves to know that preference—and also to know that it is undoubtedly biased."

He believes physicians rarely engage patients in a thorough, balanced informed-consent discussion. Reasons include time pressures, ignorance of trial options, and self-interests that may sway doctors either for or against enrollment. And no one knows what effect such open discussions would have on recruitment: Will patients still enroll in a trial if they know their own physician has a preference, however subjective?

Ethical Tensions

Some investigators argue that if ethical tensions cannot be eliminated from randomized trials, they might at least be reduced by minimizing the number or the duration of patients getting suboptimal therapy. One innovation has long been standard practice: an independent monitoring board that can call for stopping a trial if one treatment clearly looks better or too toxic.

Proponents of alternative trial design say other strategies exist but are rarely used. For example, in unbalanced randomization, more patients are put on one arm when there is a strong suggestion it will prove superior. In "play the winner" designs—most feasible when treatment response is immediate—the probabilities of getting each treatment change based on how previous patients have fared. And sequential designs allow the number of patients randomized to vary based on interim results, meaning fewer patients may be needed compared with fixed sample size designs.

Andrew Avins, M.D., an internist at the VA Medical Center in San Francisco, discussed alternative methods in the December 1998 Journal of Medical Ethics. Avins accepts the fact that patients often join trials hoping to get into the experimental group, and argues that efforts should be made to maximize the number who do.

"When you have really good reason to believe that something might be more effective, and patients are coming into a trial because they want access to it, isn’t it in everyone’s interest to give patients a greater opportunity of getting it?" he asked. "To me it’s a no-brainer, and yet the reactions have been extraordinarily negative."

Avins described entrenched resistance within the research community to alternatives like unbalanced randomization and said proposals for studies using unconventional designs are at a disadvantage in competition for funding. "I don’t think the world is ready" to embrace alternatives, he said.



             
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