Community-based trials under scrutiny
Critics worry about conflicts of interest and quality of research
From the July/August 1999 ACP-ASIM Observer, copyright © 1999 by the American College of Physicians-American Society of Internal Medicine.
By Phyllis Maguire
Ask John A. Ellerton, FACP, a practicing oncologist in Las Vegas, about his experience conducting clinical research studies, and he recalls a patient whose breast cancer had metastasized to her lungs and shoulder. After the woman had undergone several types of chemotherapy, all of which failed, Dr. Ellerton enrolled her in a trial for a monoclonal antibody he was testing for Genentech Inc.
"Within a month, there was significant improvement," reported Dr. Ellerton, who is a former College Governor for Nevada. "Within three months, the cancer had disappeared. Her arm is better and her lungs are clear." The patient is still taking the drug, which was approved by the FDA in 1998, and remains cancer-free.
As the number of practicing physicians doing clinical research grows, these kinds of success stories are becoming more common. Physicians say that enrolling patients in clinical trials not only gives patients access to potentially lifesaving medications, but also keeps doctors involved in cutting-edge research, an effective scientific antidote to their crammed patient schedules.
But the fact that physicians are enrolling patients in clinical studies—and getting paid by pharmaceutical companies to do so—is drawing fire. Several news articles have detailed the unethical practices of some physicians, while one article talked about doctors cashing in on a "gold rush" of drug company payments. Critics also say that the quality of research and patients' safety are in jeopardy because the research oversight system designed to protect trial subjects is severely strained.
In light of such charges, physicians are scrutinizing their part in drug development and asking themselves some tough questions, even as they defend their role in clinical research. One of the main issues: Are physicians furthering science and enhancing patient care, or are they cutting ethical corners in their rush for drug company dollars?
Rewards and dilemmas
While physicians have always referred patients to drug trials, the number of private practitioners conducting clinical trials has almost tripled in the last 10 years. Analysts say the multibillion-dollar clinical research industry has mirrored the overall shift in health care away from academic medical centers and toward community-based physicians.
"Diseases today are being addressed in communities as opposed to in tertiary care settings," said Ken Getz, president and publisher of CenterWatch, a Boston-based information services company that focuses exclusively on the clinical trials industry. "Sponsors want to test their drugs in 'actual use settings,' or as close to actual use as possible."
The trend has benefited doctors who do clinical research in a number of ways. They have a chance to contribute to new treatments, develop an intellectual community of collaborators and discover evidence-based methodologies that they can use in clinical practice. David L. Fried, ACP-ASIM Member, a full-time internist with Coastal Medical Inc., a primary care group in Cranston, R.I., and medical director for a clinical research organization, said that research is as vital to his professional growth as continuing education. "This is absolutely something that internists should be encouraged to do, because we're testing conditions we see all the time."
Dr. Fried explained that because he is involved with research, he is more aware of products in the developmental pipeline and knows more about their potential off-label uses. In addition, he can offer effective trial medications to patients who can't afford existing treatments.
But one of the perks of conducting research—the pay—is more controversial. Drug companies typically pay physicians between $1,000 and $4,500 for each patient they enroll in a clinical trial, although some payments go much higher. Critics charge that these stipends present a significant conflict of interest for physicians, enticing them to unduly influence patients to enroll in research studies. According to recently published reports, some physicians have enrolled patients in clinical trials who have none of the conditions being studied.
Physicians involved in research counter that the depiction of per-patient stipends as pure profit—and temptation—is misleading. They say that a hefty portion of pharmaceutical payments goes to support an administrative and clinical research infrastructure, as well as for overhead and advertising costs.
Others point out that for many physicians, drug company payments help support other research efforts. Dr. Ellerton from Nevada, for instance, said he relies on stipends from community-based research to subsidize the National Cancer Institute (NCI) trials he has conducted since 1983. Likewise, many academic physicians say that industry-sponsored research is an essential financial lifeline.
And doctors claim to be bewildered by reports of colleagues making millions from patient enrollments. "I'm not raking in millions," said Northern California pulmonologist David L. P. Sachs, ACP-ASIM Member, whose non-profit research institute, the Palo Alto Center for Pulmonary Disease Prevention, is an adjunct to his private practice. "I'm not even raking in thousands. Most of the clinical trials I've done have at best broken even."
In order to avoid financial conflicts, some critics suggest shifting studies out of doctors' offices and into full-time research institutes. Yet physicians who do research insist that their participation has distinct advantages for patients. Donna E. Sweet, FACP, Chair-Elect of the College's Board of Governors, cares for HIV/AIDS patients at the University of Kansas Medical School in Wichita. As clinical director of research there, she also enrolls them in industry-sponsored studies.
"My personal bias is that patients are better served if the same provider is doing all of their global care," Dr. Sweet said. "You know those patients, you know what else is going on in their lives, you know whether they can fulfill the criteria and the rigors of follow-up. I personally do not view the primary provider-as-researcher as anything but a very positive thing."
Countering charges that they're pressuring patients to enroll, physicians claim that many patients are eager to participate in clinical research. A CenterWatch Web site (www.centerwatch.com) that lists 7,500 clinical trials receives 160,000 to 175,000 visits every month, according to Mr. Getz. More than 85% of patients surveyed by CenterWatch rated the care they received while they were trial subjects very favorably.
And keeping research in communities furthers patient participation. In the early 1980s, for example, the NCI realized that the number of patients entering its research studies had begun to decline, in part because patients didn't want to go to cancer centers and universities. In response, it created the Community Clinical Oncology Program: Today about 40% of all NCI patient trials are conducted by community organizations.
While the money physicians receive to perform clinical research has generated the most controversy, it is only one issue in the growing field of community-based research. Physicians and critics alike are also worried about how the quality of clinical research is being affected by drug companies' aggressive push to enroll physician investigators in studies.
Some are wary of the intensifying competition for patients. "I get faxes and flyers every single day," said Dr. Ellerton of Nevada. "In the last year or two, it's really escalated."
Increasingly, drug company representatives are being enlisted in the effort to sign up physicians. "Five years ago, pharmaceuticals were not that aggressive in promoting their studies," Dr. Ellerton continued. "Now the detail guys are really out there pushing them."
"It's the entrepreneurial bent that we have in the business of medicine that is driving us in that direction, not necessarily our desire to have good research data," said David A. Fleming, FACP, a member of the College's Ethics and Human Rights Committee and a practicing internist in Moberly, Mo. "It becomes a commercial venture, similar to selling products or services out of the office."
Even supporters of community-based research worry that for some physicians, the pressure from drug companies may be too hard to resist. According to published reports, some physicians are straying dangerously far from their field of expertise. A recent New York Times article, for instance, cited a psychiatrist who was offered studies on hormone replacement and diabetes.
"The real problem is when you get doctors who have no experience with the disease they're studying," said Jack Geller, MACP, an endocrinologist and clinical professor at the University of California, San Diego, School of Medicine. "If you're not familiar with that area of medicine in detail, it's much harder to make useful decisions and have discriminating ideas about what's going on with a new drug."
Another trend that physicians find disturbing is drug companies' use of high premiums to encourage them to enroll large numbers of patients quickly. Dr. Sachs in Palo Alto, for example, refused to participate in a trial organized through "competitive enrollment." The drug company contracted with several sites, giving them each two months to enroll a set number of subjects. The catch: If one site could recruit the total number of subjects in one month, the other sites would be dropped from the study.
Dr. Sachs also turned down a study that featured a severe financial disincentive: The drug company refused to make its first payment until he had enrolled 20 patients. Dr. Sachs likened the offer to loaning a highly profitable pharmaceutical company between $100,000 and $150,000.
Physicians like Dr. Sachs are worried that such recruiting techniques—which tend to alienate highly trained, meticulous investigators—will affect the quality of the investigators who are recruited and the research they conduct. "At first, I was concerned that we'd have dangerous drugs coming on the market," Dr. Sachs said. "But what is a more likely consequence ... is that drugs that could be useful additions may simply never get there because the data are so poorly collected and the studies so poorly executed that they won't show a difference between active and placebo."
Typically, a number of oversight mechanisms have caught these types of problems in both the academic and community settings before they became major issues. Gradually, however, the system of oversight used to control such problems is eroding, leading to concerns about the integrity of data produced by clinical trials.
Since the 1970s, drug companies have increasingly shifted study implementation and monitoring to contract research organizations (CROs). While some researchers describe individual CROs as excellent oversight entities, other physicians are troubled by this new player in the drug development process.
"I prefer to deal directly with the [pharmaceutical] medical directors of each of the projects," said Leonard Keilson, FACP, medical director of the clinical trials unit at the Maine Medical Center in Portland and Governor of the Maine Chapter. "CROs can be so far away from the research that they don't understand it. They don't have the same quality invested and they are not accountable."
There are also signs that academic institutional review boards (IRBs), which are charged with ensuring patient safety, are overtaxed. At Duke University Medical Center, for instance, 2,000 trials were briefly suspended this spring after a number of alleged institutional review board violations were uncovered. Several other institutions are being investigated for similar problems.
Critics say that local review boards, which are typically organized through hospitals to review community-based research, are also stretched too thin. Drug companies and individual investigators have responded by using for-profit review boards. But because these review boards are hired by pharmaceuticals for multi-site studies, critics say that conflicts of interest may be inevitable.
"Private IRBs have all the problems of university IRBs, plus the additional concern that they exist to enable for-profit research," said radiation oncologist David S. Shimm, FACP, a member of the ethics committee at Porter Adventist Hospital in Denver who has written about the conflicts doctors face doing clinical research. "I think it would be very difficult for a member of a private IRB to look critically at a study and say, 'This isn't right.'" In a report issued this spring, the president's National Bioethics Advisory Commission recommended "significant revision" in the IRB oversight of industry-sponsored research.
Concerns over research oversight have caught the attention of the FDA and its Center for Drug Evaluation and Research. David A. Lepay, MD, PhD, supervisory medical officer of the center's scientific investigations division, pointed out that drug companies must now tell the FDA whether investigators—both academic and community-based—are patent holders. Drug companies must also report if investigators have received more than $25,000 in payments or own more than $50,000 in sponsor equity. The goal of these reports is to target investigators with potential biases. To help ensure that CROs adequately monitor clinical studies, Dr. Lepay said, the center is also looking into ways to integrate more patient protection features into studies.
Strengthening the safety net
As concern mounts, a number of physicians are calling for more safeguards in clinical research. Dr. Shimm from Denver, for example, believes that physicians should make full financial disclosure to patients they are trying to enroll in studies. He also recommends that IRBs track how many patients participate in studies from each physician investigator in order to catch physicians who may be pressuring patients to enroll.
In the Fourth Edition of its "Ethics Manual," the College recognized the conflicts of interest and potential for patient exploitation that can arise in community-based research, and the Ethics and Human Rights Committee is now drafting a case study to examine those conflicts more closely. In the meantime, many physicians already act on their own to contain conflicts of interest.
Dr. Fried from Rhode Island, for example, removes himself from the enrollment process. He tells patients when his affiliated research institute is conducting a trial that he feels might benefit them, but then he steps back. "I present it as an option and if they're interested, I have them contact the institute," Dr. Fried said. "I'm not the one calling them. I believe there's a role for clinical studies in medicine, but I draw that line."
At Fenway Community Health Center in Boston, which has a research division, physicians do not receive compensation for enrolling patients. Instead, explained Thomas A. La Salvia, Fenway's director of research and evaluation, all per-patient stipends go to support the center's research and medical departments.
In addition, both Fenway's informed-consent process and study implementation are handled by a research nurse or project manager, a system "that reduces any influence a doctor might have over a patient," Mr. La Salvia explained. To ensure that all research is above board, Fenway also maintains its own internal review board.
Even physicians who argue that clinical research is in their patients' best interests admit that when they serve as investigators, they walk a very fine line. Charles L. Schulman, ACP-ASIM Member, is a cardiologist based in Brookline, Mass., who enrolls his own patients in clinical studies. He points out that physicians must approach the ethical issues raised by clinical research with the same critical faculties they use to weigh fee-for-service incentives—which can reward physicians for inappropriate procedures—or managed care capitation, which can tempt doctors to cut back on patient care.
For Ramona L. Doyle, ACP-ASIM Member, a pulmonologist at Stanford University School of Medicine, research is just one more component of a complicated physician-patient relationship.
"I think about this every day, not just in the context of clinical trials, but even when I obtain an informed consent for a procedure that a patient needs," she said. "I am always aware of that ethical obligation, and the stakes are even higher when you're involved with a trial."
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