The Clinical-Trials Bottleneck

Randomized clinical trials are the most conclusive way to test new treatments for cancer, but these trials are often resisted by patients, by doctors, and by insurers reluctant to pay for unproven therapies

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JONATHON Fontilla, a thirty-five-year-old engineer, had run out of treatments for his kidney cancer. A tall, thin fellow with a pale wisp of a beard and a rural twang, Fontilla described to me how, the year before, he had decided to take part in "A Multicenter Randomized Trial of Interferon Alfa-2a (Roferon) With or Without 13-Cis-Retinoic Acid (Accutane)." Beside him in an examining room at the University of Virginia Cancer Center, Fontilla's wife, Sandra, also thirty-five, who is a nurse, explained that the standard treatment, Interleuken II, which her husband tried after participating in the Interferon study, had had little effect on him beyond leaving him exhausted, feverish, and in pain. And they both wanted to keep life as normal as possible for their three children. They had the clear impression that the trial had bought him nine months of relatively normal living. "I made the right decision," Fontilla said.

Fontilla had been among the fewer than three percent of adult cancer patients in the United States who are treated as part of a clinical trial. We spoke in January of last year, just days after President Bill Clinton announced his intention to devote unprecedented funding to promising new cancer research.

Media coverage of breakthroughs in the laboratory has obscured for many the grim reality that even now more patients die of cancer than are cured. Though three years ago the government announced the first-ever drop in cancer deaths, the statistics, when age-adjusted to the population, in fact represent little real change and are attributable primarily to a decrease in smoking among men. Few people understand that before new treatments can reach the more than a million people who will be found to have cancer this year, the treatments will have to trickle through a narrow bottleneck -- called clinical trials -- that will prolong their testing and delay their use for years. At the centers where this country's cancer patients are treated and trials are conducted, this fact, along with resistance on all sides -- from patients, doctors, and health insurers -- amounts to an immense problem. "As a country, we have to find a way to widen the bottleneck," Harmon Eyre, the executive vice-president for research and medical affairs at the American Cancer Society, says. "Without randomized clinical trials we might as well stop research."

The University of Virginia Cancer Center wrestles with resistance to trials as much as any cancer center in America. Located in a conservative region, it enrolled very few patients before 1994. That year Charles Myers, a prominent researcher known for developing new treatments, came to head the cancer center, and Roger Cohen, formerly a deputy division director for the Food and Drug Administration, came to direct the clinical-trials program. Myers and Cohen put together a staff of physician investigators who could design clinical experiments to follow through on the discoveries and hypotheses of University of Virginia laboratory scientists and others, and helped the center to qualify in 1995 as an officially designated, federally funded NCI cancer center. Fifty-eight such centers now exist.

At eight o'clock on the January morning when I visited, Roger Cohen began his clinical rounds. Forty-five years old and slight, with salt-and-pepper hair and beard and wearing wire-rimmed glasses, Cohen has the ascetic look of someone who often forgets to eat. Meticulously organized, he maintained a gentle if tense manner as he saw patient after patient, some of them participating in trials, most not.

A fifty-seven-year-old prostate-cancer patient was doing fairly well on the standard chemotherapy. He had been treated in two clinical trials that had done him very little good, but he hoped that his participation might someday help his grandsons.

A fifty-year-old forklift driver in a lung-cancer trial who had driven three hours to get to the clinic learned that his cancer had recurred. "If I took trials and they didn't work," he said with a sheepish smile, "what the hell. I'm gonna die anyway." He lifted up his plaid cap, pointed, and laughed. "I already lost all my hair."

In another examining room a fifty-three-year-old nurse, a glamorous blonde wearing suede high-button boots, reeled off in a honeyed accent the treatments that have kept her breast cancer at bay since 1989: lumpectomy, mastectomy, thirteen Taxol treatments, three adriamycin treatments, the smart bomb (a targeted radiation treatment), methotrexate and gemcitabine. Several of these had been in trials. She was worn out and close to saying "No more." But, she added, "I would do it all again." With rare times out, she had been able to babysit for her grandchild and shop and keep house for herself. She laughed. "And I aerobicize with that good-looking fella on TV at noon."

Like oncologists all over the country, Roger Cohen is frustrated. "For most of the patients, many of the treatments are wrong. Many of them are not life-extending, don't work, or have significant side effects. The treatments that do work seem to benefit about a third of our patients. For the other two thirds the treatments are a waste of time. We just don't know which two thirds won't benefit, and we don't know what else to do. This can be solved only through cancer prevention -- which is like the Holy Grail -- or better therapy. We figured out how to cure the few cancers we can cure by the systematic and relentless application of clinical trials."

THE first randomized clinical trial in medicine occurred in 1946, when the British tested streptomycin as a cure for tuberculosis. The first trials in cancer began in the United States in 1958, with the National Surgical Adjuvant Breast and Bowel Project, which first tested chemotherapy -- unsuccessfully -- for breast cancer. In the 1970s trials became more numerous. Notable were two large NSABP studies, conducted from 1971 to 1985, that showed that the less disfiguring "total mastectomy" and lumpectomy were as likely to help breast-cancer patients as the Halsted radical mastectomy, which had been the accepted treatment since 1890. The National Cancer Institute now lists 1,500 active cancer trials, some sponsored by the NCI, some by drug companies alone or in partnership with the NCI, and many by the Coalition of National Cancer Cooperative Groups, whose 12,000 cancer researchers across the country are supported by both the NIH and private industry.

Many people imagine that a new drug is developed in the lab, tested in human beings, and approved -- boom: a new treatment. Few realize how excruciatingly slowly cancer research moves. A drug ready to be tested in human beings is first used in a Phase I trial, in which perhaps two dozen people, in groups of three, take varying doses to establish a maximum safe dose. Then another small group receives it in a Phase II trial to test the drug's effectiveness. If at this stage it looks promising (and often it does not), the drug will enter a randomized Phase III trial, involving hundreds, perhaps thousands, of patients at several hospitals, typically over three to five years. A Phase III is considered a success (and few are) if the new drug extends median survival by 25 percent, which might be as little as three months.

Even after a drug is approved, further randomized studies may be needed to answer such questions as Will this drug work against other cancers? Does it work against early as well as advanced disease? Is it more effective given over time or all at once? Alone or with other drugs, and in what combinations? The announcement in February that chemotherapy added to radiation could reduce rates of death from cervical cancer by 30 to 50 percent emerged from five separate studies. Every other recent major advance in cancer also emerged from clinical trials, including the discoveries that Tamoxifen could help prevent breast cancer in high-risk women, that Taxol could benefit women with early as well as advanced breast cancer, and that Herceptin could shrink tumors in certain women with advanced breast cancer. Each of these discoveries will require further trials to refine these treatments. Angiostatin and Endostatin, which created excitement in the media when shown to eradicate tumors in mice, have yet to be tested in any clinical trials on people.

For a variety of reasons, few patients are given the opportunity to participate in trials, and this has a range of unfortunate consequences. Some trials have had to be abandoned for lack of patients. Others, such as those for relatively rare kinds of cancer, can never be done at all. Getting answers to important questions can take years. Moreover, the elderly, a burgeoning group among those who will require treatment, are seriously underrepresented in clinical trials, as are minorities and, in some areas, women. The picture is very different for cancers in children. Ninety-five percent of children with cancer in the United States were enrolled in studies in the 1970s and 1980s. Seventy-five percent of cancers in children are now curable. No one can predict this outcome for the myriad of very different adult cancers, but vastly increased participation in adult-cancer studies would surely bring cures faster. Already trials have led to major advances in the treatment of melanoma and cancers of the breast, the cervix, the uterus, the prostate, and the bladder.

IN the public imagination the ghosts of the Tuskegee Syphilis Study still haunt clinical research. Recent events, such as the controversies over AZT-and-placebo trials for AIDS in Africa and over some psychiatric experiments, have revived the negative associations with experimentation on human beings. But placebos are almost never used in cancer research except to test ancillary treatments, such as anti-nausea drugs, or in prevention studies with healthy patients. A typical trial today will place patients in groups that receive only slightly different treatments -- the "standard treatment" versus some new wrinkle on it.

Clinical trial

Still, researchers constantly wrestle with ethical questions. For example, should desperate patients be asked to participate in Phase I studies, the only purpose of which is to measure toxicity, when experts estimate that only four to six percent of patients who do take part in them derive any benefit? Unsurprisingly, surveys show that patients participate because they hope they will benefit. Some physicians worry about giving dying patients false hope, while others argue that access to new drugs gives the patients in trials a psychological advantage. Ethicists also struggle with the question of what constitutes truly free and informed consent, since surveys have shown that many patients do not understand the consent forms they signed upon entering a trial. Is total disclosure best? Some surveys indicate that too much information makes patients anxious.

Randomizing probably gives rise to the most concern. In the past the randomized-trials requirement was criticized for slowing down the delivery of experimental drugs to patients who would certainly die without them. But the FDA's fast-tracking policy, initiated in 1992, has blunted criticism. Now, in the rare cases when Phase I and II studies suggest that a new treatment can benefit patients suffering from a disease for which few if any standard treatments exist, such as advanced breast cancer or AIDS, the FDA will approve the treatment without a Phase III.

Ethically, a patient may be randomly assigned to one of several treatments only when the physician -- or the larger medical community, as its opinions are reflected in a review board for the study -- is uncertain which treatment is better for the patient. But Emil Freireich, of the M. D. Anderson Cancer Center, in Houston, a pioneer in conquering leukemia, says what few doctors will admit they think: "The new treatment is always preferred, because it must have shown evidence of potential superiority over conventional therapy to justify the additional risk." In fact no one knows how often the new treatment is better. Few centralized records are kept, and because negative studies are usually not published as prominently as positive ones, the impression persists that the new treatment wins out a majority of the time.

Perhaps, suggests Richard Simon, who heads the group that reviews statistical and other results of all NCI trials, doctors' views are distorted by the attention given promising Phase II trials, many of which do not pan out in Phase III. Simon estimates that no more than 20 percent of experimental treatments are successful, that the vast majority of the remainder are equivalent to the standard treatment, and that a few are actually worse. "If it were true," he asserts, "that the new treatment was usually better, cancer would be cured by now." At least negative studies help to limit the large-scale use of toxic or ineffective treatments. However, recent advances in tumor biology have opened up promising new avenues of treatment. Researchers believe that the proportion of successful trials will increase as patients with molecularly homogeneous cancers are grouped together and treated with agents that target only the cells that cause cancer.

In every trial the physician investigators must consider how funding and the prospect of career advancement might influence their behavior. Patients should ask, as candid clinicians put it, What's in this for you, doctor? Money, advancement, your name on a paper? The NCI's patient booklet suggests asking "Who has reviewed and approved the study? How are the study data and patient safety being checked?"

Ethical problems -- in one case, even fraud -- have arisen. However, trials conducted by the National Institutes of Health at least are backed by a consensus of acknowledged experts that the potential for benefit outweighs the potential for harm to study subjects.

Since the explosion of trials in the 1970s, and the passage of legislation requiring that trials take place before the FDA approves a new treatment, patient protection has increased. Every hospital must have an institutional review board (IRB), composed of independent doctors, patients, and community members, to scrutinize studies for undue risk and possible bias -- for example, in favor of a trial that might make money for the hospital from insurance or drug companies. Though the Inspector General's Office of the U.S. Department of Health and Human Services last June issued a report criticizing IRBs for all areas of medical research as being too overworked and underinformed to protect patients in trials adequately, Mark Yessian, a regional inspector general, says, "In NCI-sponsored trials there is a degree of oversight that doesn't exist in other research."

The greatest protection for patients is their freedom to leave a trial at any time, for any reason, without penalty. If they are not doing well, their doctors will remove them: patients are not left to languish for years on treatments that don't help them. The sort of controversy that erupted recently over Schering-Plough's refusal to release viral-load information to hepatitis-C patients in a study it sponsored is unknown in cancer trials, in which the benchmark is most often tumor growth or recurrence. Moreover, if within a short time -- even months -- a cancer study shows that one treatment is better than another, the trial is closed and everyone gets the better treatment, if possible.

"Being a guinea pig is often the best thing that can happen to a patient," Roger Cohen insists. No body of hard data is available to support this assertion, but a few studies do show higher survival rates for those participating in trials. And the quality of care and level of follow-up in cancer trials is almost universally considered to be the very highest.

Why do so few patients enter trials when virtually every patient-advocacy group supports them? "We encourage people to go on peer-reviewed trials such as those conducted by the NCI," says Susan Scherr, of the National Coalition for Cancer Survivorship, "but a lot of patients still think of rats in a cage or experiments where one person gets a sugar pill. And they arrive thinking existing cancer treatment is more effective than it is." Media hype has created a "credibility gap," Richard Simon says, because "the public is repeatedly bombarded by reports of promising high-tech magic bullets" even as death rates from most cancers remain fairly steady.

Many patients don't actually know what trials are. Recent NCI surveys found that the majority of Americans were unfamiliar with the term "clinical trial," and fewer than five percent could name the National Cancer Institute as the federal agency that funds most cancer research. When randomized trials are explained to them, patients are often puzzled by the doctor's statement "We just don't know which treatment is better -- that's why we're doing this study." Many will look for a doctor who claims to know. One survey found that 70 percent of a patient group believed that their doctors actually knew which treatment in a study was better.

When patients strongly prefer one treatment to another, they will refuse to be randomized. For example, some are sure -- despite inconclusive data -- that autologous bone-marrow transplant, a treatment that involves a virulently toxic form of chemotherapy, is the most effective breast-cancer treatment. But even as their efforts led several states to mandate insurance coverage for it, a current NCI study to compare it with standard chemotherapy was prolonged by more than five years because too few patients enrolled. Preliminary reports released in March indicate that this treatment may be of questionable benefit.

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

Illustration by Juliette Borda

The Atlantic Monthly; May 1999; The Clinical-Trials Bottleneck; Volume 283, No. 5; pages 30 - 36.