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(The online version of this article appears in two parts. Click here to go to part one.)

IN the University of Virginia Cancer Center's clinical-trials library Roger Cohen lifts a large looseleaf binder off a bookshelf packed with identical-looking volumes and flips through page after page of forms filled out by hand -- the required record-keeping for one patient in one study. Physicians are reimbursed by insurance companies for neither the extra paperwork nor the time necessary to obtain "informed consent" -- from a minimum of fifteen minutes or so to the twelve hours one pediatric oncologist spent explaining a trial to a child's family. And doctors other than the chief investigator typically receive no credit or career advancement for their participation.

Karen Parks, the clinical-research coordinator at the University of Virginia, is responsible for submitting data to regulators and documenting progress. "We've also started marketing for doctors," she says, showing a colored sheet listing more than fifty trials by category. Though the effort is intended to make doctors more aware of available trials and to facilitate enrolling patients, many physicians at the center still don't participate.

"Doctors won't say they don't believe in clinical trials," Cohen says. "It's like saying you don't believe in God. They just don't enroll patients." In fact, 80 percent of patients are enrolled by just 10 percent of doctors. Physicians are troubled by the same uncertainty that troubles patients, but they do not like to acknowledge it. "You walk in someplace Friday night," one physician said in a survey of oncologists, "and somebody is sick and they need treatment; the last thing they want to hear is, 'Well, maybe this treatment is best and maybe that treatment is best and we don't know.' That isn't going to win you any friends."

Though patients are increasingly likely to question their doctors, Charles Myers explains, dangerously ill people have traditionally wanted what the medical literature calls "the omnipotent servant." Doctors are loath to relinquish their freedom to make decisions individually for patients, which a trial protocol restricts. "My patients come to me because of my experience" is a frequent explanation for a physician's nonparticipation. "But there's a whole literature on the abysmal track record of doctors using their own experience," Myers laments. Trials proponents can reel off case after case in which accepted treatments proved wrong. In the 1940s castration plus estrogen was used to try to cure prostate cancer, but a randomized trial in the 1950s showed that patients taking estrogen died sooner. A famous study in the 1980s showed that men taking the drugs then universally prescribed to correct an abnormal heartbeat had almost three times as great a risk of dying after a heart attack as those on a placebo. Proponents also decry doctors' -- and patients' -- unsubstantiated assumption that in cancer treatment more is always better. Though many studies prove that more-punishing treatments (administering the drug combination CMF -- cyclophosphamide, methotrexate, and five-fluorouracil -- to breast- cancer patients for twelve months instead of six, for example) do not necessarily benefit patients, some doctors still avoid enrolling patients in studies that may seem to treat them less aggressively than is usual.

The medical literature shows that physicians are often prisoners of their firsthand experience: their refusal to accept even conclusive studies is legendary. Willie Andersen, a gynecologic oncologist at the University of Virginia, believes in clinical trials and enrolls patients in them but still has to struggle against the power of his own experience. Andersen says that despite trials showing the drug Topotecan to be effective against ovarian cancer, he rarely chooses it because he has never had good luck with it himself. "I think, 'The last time, that lady got so sick,'" he says. "Bias is very hard. It's easier when you're dealing with test tubes and experimental animals, but when it's real people looking you in the eye, you get wrapped up in their hopes and your hopes for their hopes, and it's hard."

In our talks Roger Cohen was initially critical of nonparticipating doctors as unscientific or getting a "free ride" by using trial results without contributing. But after several days of my questioning him about these doctors' problems, his tone softened. "I understand," he said, "how people of good intentions might not want to enroll patients: they are genuinely too busy; they get no academic credit; the hypotheses are formulated by anonymous committees; and trials are intrusive and disruptive to one's practice, greatly prolong and intensify the patient experience (in some good but also some unpleasant ways), and introduce still more uncertainty and vulnerability into an uncertain and vulnerable situation -- having cancer in the first place." What motivates Cohen, he says, is that half of cancer patients die, usually within a year, and death rates have scarcely budged in thirty years. "Those two facts mean that for me the only ethical way to practice medicine is through clinical trials. I do not know another way out of the box."

SEVERAL times a year Cohen will try to persuade a patient's insurance company to cover the costs of a trial. "I have found," he says, "that if one is reasonable, patient, gives timely notice of one's plans, is respectful, and buttresses the argument with data and articles, the answer is usually yes. Screaming at them does not work."

The temptation to scream must sometimes be great. Insurers, including Medicare, have often refused to reimburse for care in a trial even when the patient would receive the identical treatment outside the trial. And they object that trials may require additional expensive procedures, to establish a patient's eligibility or just to collect data. They also worry about the expense of treating side effects. Moreover, although doctors may assert that trials cost no more, they lack data to prove this. Political pressure has resulted in a number of initiatives, including a landmark agreement reached in February between the National Institutes of Health and the American Association of Health Plans, which represents HMOs. The trade group will encourage member HMOs to pay the routine care costs for patients in NIH-sponsored trials as long as they are not significantly higher than costs for standard treatment. United Healthcare has already agreed to cover these costs for any of its six million covered members who enroll in trials sponsored by the Coalition of National Cancer Cooperative Groups.

On the government side, several studies to make cost comparisons and efforts to mandate coverage are now under way. The American Society of Clinical Oncology and a host of patient-advocacy groups have joined together to support the Medicare Cancer Clinical Trial Coverage Act of 1997, sponsored by Senators Jay Rockefeller and Connie Mack, which calls for a pilot study to compare routine cancer-patient costs for Medicare beneficiaries who are enrolled in cancer clinical trials with those for beneficiaries who are not. The NCI is conducting similar studies with Kaiser/Permanente and the Mayo Clinic.

In his 1998 State of the Union Address President Clinton urged research funding "so that ours will be the generation that finally wins the war against cancer." To this end the National Cancer Institute plans to devote $425.5 million of its proposed $3.191 billion 1999 budget to widen the clinical-trials bottleneck in several ways: by increasing the number of patients in trials (the goal is a fivefold increase by 2003), by creating additional NCI cancer centers, by further developing an electronic database for doctor and patient information, and by lessening the burdens on doctors -- for example, by funding positions for data managers. The NCI will also direct an all-out education effort at the medical community and the public.

No one suggests that every patient should enroll in a trial or that every trial is worthwhile. But patients should be able to make an informed choice. With a patient-advocacy structure to guide them, they are more likely to inspire vigilance against trials tainted by bias or self-interest. Scrutiny by patient-advocacy groups may help to identify those trials that are well designed and will answer important questions. A "Summit on Clinical Trials" held last July, near Washington, D.C., brought together advocates, leading cancer investigators, and representatives of government and drug companies to address some of these issues. The strategies they agreed on include setting standards for quality trials and working to raise participation from two to three percent of adult cancer patients to 10 to 15 percent. Simply amassing more patients will not solve all the problems of the trials process, but large, representative, and timely studies ought to produce more-conclusive and earlier results.

As I left the University of Virginia, Roger Cohen told me that he had tried that morning, unsuccessfully, to persuade the young father with kidney cancer to enter hospice care. Cohen's only remaining option was to give him more and more morphine for his pain. "I want to find something that will extend lives by years, not days and months," he said, "to make cancer a manageable illness, like heart disease or diabetes. When there's a Jonathon Fontilla twenty years from now, I hope to have more to treat him with than I do now."

The online version of this article appears in two parts. Click here to go to part one.

Francine Russo writes frequently on behavior and social issues. Her work has appeared in The New York Times Magazine, among other publications, and she is a theater critic for The Village Voice.
Illustration by Juliette Borda

Copyright © 1999 by The Atlantic Monthly Company. All rights reserved.
The Atlantic Monthly; May 1999; The Clinical-Trials Bottleneck; Volume 283, No. 5; pages 30 - 36.

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