Five years ago, terminal cancer patients were given hope that a longer life -- possibly even a cure for the disease -- could be within reach. Researchers at several hospitals, including the M.D. Anderson Cancer Center at the University of Texas in Houston, were conducting trials on what was being regarded as something of a cancer wonder drug -- an agent that appeared to successfully block a growth factor that turns cells malignant. Abdominal tumors nearly disappeared in a 28-year-old Miami woman taking the drug.
But this year the Miami woman died, months after the federal Food and Drug Administration rejected the application for the drug's approval, saying some clinical tests designed by the manufacturer had flaws that failed to prove the drug's effectiveness.
The drug was Erbitux, the company ImClone Systems. The FDA's rejection sent ImClone's stocks into a nosedive, and an insider-trading scandal erupted. Only then did the 195 patients who participated in clinical trials at M.D. Anderson learn that its president, John Mendelsohn, held a major stake in ImClone and sat on its board of directors at the same time his researchers were testing the company's drug.
Patients affected by the ImClone scandal have been lost in the media's rush to cover the tale of Martha Stewart and other key investors who pulled their money out of ImClone stock just before the FDA decision. Some ImClone company officials and the investors, including Stewart, they may have tipped off are facing investigation. But Mendelsohn's financial interest in Erbitux and his failure to reveal that interest to patients enrolled in clinical trials of the drug broke no federal law or regulation. In fact, Mendelsohn's stake in a drug his institution was testing is hardly uncommon in the medical community.
And that's exactly what upsets a growing cadre of healthcare advocates, lawyers and doctors, who believe the bonds between research hospitals and corporations have grown too strong -- and too acceptable. "It's as if financial conflicts of interest were a given of nature or a constitutional right -- which they're not," said Harvard professor Dr. Marcia Angell, a former editor of the New England Journal of Medicine.
The integrity of clinical trials has come under increasing scrutiny since a series of safety measure meltdowns and deaths during research trials at some of the top medical institutions in the country. Among the factors in at least some of those tragedies is the link between research and corporate funding. Though there's no indication that participants in the ImClone trials were harmed, healthcare advocates believe that corporate pressures -- and incentives -- to rush products to market that could have adversely affected Erbitux research have in other cases been responsible for cut corners and patients not being fully informed of dangers in the trials.
"Human nature is human nature, whether you have an M.D. attached to your name or not," says Vera Hassner Sharav, head of the Alliance for Human Research Protection in New York City. Financial conflicts "permeate clinical trials -- from design to selection of subjects to control of data to what's reported in medical journals."
"The cat's out of the bag," she adds. "It's not just a problem with five doctors or 25, or a single institution; it's the system. Yet patients have no way of knowing if their doctor has a vested interest in a study and if that interest may be superseding a concern about a patient's welfare."
Mendelsohn, who developed the drug that was to become Erbitux, has said he did not participate in or influence trials at M.D. Anderson. He told a congressional subcommittee recently that he's convinced Erbitux "shows great promise" for treating end-stage colorectal cancer. Mendelsohn still holds stock in ImClone, but reportedly earned $6.3 million when he sold a portion of his holdings last year to Bristol-Myers Squibb.
Since the Erbitux trials, M.D. Anderson has changed its policies regarding conflicts of interest. Primary-care physicians and principal investigators are prohibited from financial conflicts of interest. Financial conflicts of co-investigators and the cancer center's president must now be disclosed in the informed-consent document presented to each participant in a clinical trial. "We're learning," said Dr. Leonard Zwelling, vice president for research administration at M.D. Anderson. The corporate-research scene is "evolving incredibly rapidly and it's not federally regulated. What's right seems to be a moving target."
"The question is one of perception. No one has questioned people's motives, but it looks bad. We're cognizant of that and addressing it. But these issues are relatively new for us in academics."
The Institute of Medicine (IOM) of the National Academies warned in a report issued in October that fundamental change in clinical trial research -- including the management of conflicts of interest -- is critical to keep the system from imploding. "Broader federal oversight is needed to ensure that the health and well-being of people enrolled in research studies are better protected," concluded IOM committee chair Daniel Feldman of Harvard Medical School.
Clinical trials are essential to medicine. Only when treatments and drugs can be compared among different groups of patients participating in a clinical trial can researchers discover what works and what doesn't -- or what's safe and what isn't. Major breakthroughs in medicine -- from new surgical techniques to vaccines to potent drugs to combat AIDS -- are now standard care because research volunteers took the risk to try them. In turn, research institutions are expected to fully inform patients of the risks and to protect them from foreseeable harm.
"No research effort is without at least some risk," said Feldman when the IOM report was released. "But research should be done only with appropriate safeguards for participants, whose presence is indispensable to the progress that beckons all of us."
The report was commissioned by HHS following the 1999 death of 18-year-old Jesse Gelsinger. The teen suffered from a relatively mild form of a genetic liver disease, which he controlled through diet. He volunteered to participate in a gene therapy trial at the University of Pennsylvania's Institute for Human Gene Therapy in Philadelphia, solely to help find a cure for other children.
Despite several negative results using the same gene therapy on monkeys, researchers injected Jesse with massive doses of a genetically engineered virus. His vital organs failed within hours and he was dead four days later. When the National Institutes of Health reminded hospitals after Gelsinger's death to advise the agency of problems with gene therapy, researchers reported nearly 700 adverse effects and seven deaths in similar trials.
The public and press would never look at clinical trials in quite the same way. "The Jesse Gelsinger case changed the universe," says Alan Milstein, a New Jersey attorney who has filed lawsuits in several clinical-trial cases and won an undisclosed sum from the University of Pennsylvania for Gelsinger's parents.
Conflict of interest was a major issue in the Gelsinger case, which illustrated that money isn't always at the root of potential conflict in scientific research. Investigators can also be motivated by career advancement, fame or the drive to break new ground.
"Money wasn't God" for James Wilson, the lead researcher in the Gelsinger case, says Milstein. "He was in it for the scientific discovery." But the financial conflict wasn't insignificant. Wilson, along with the University of Pennsylvania, held substantial stock in Genovo, a company Wilson founded to market the gene technique used in the Gelsinger clinical trial. When Genovo was purchased by Targeted Genetics Corp. a year after Gelsinger's death, Wilson received $13.5 million in stock, and Penn got $1.4 million.
U.S. researchers currently conduct an estimated 80,000 clinical trials with 20 million participants annually. Precise participation numbers don't exist. There's no tally of people in research and no one tracks the totals of how many people are harmed -- or helped -- in studies each year.
People volunteer for clinical trials for a variety of reasons. Terminal patients grasp for anything that might prolong their lives. Some who enroll believe their participation will win special attention from their doctors.
Motivated patients can seek clinical trials online and track down hospitals and doctors that offer opportunities for participation in such trials.
More likely, patients are invited to participate in a trial when they arrive at their doctor's office or hospital for treatment. The number of trials has soared in the last five years and competition for warm bodies is intense. Some doctors collect fees as high as $10,000 for each patient they enroll and retain in a clinical study.
"These fees are becoming an important, if not a main, segment of income for doctors, who are dealing with cost reductions by HMOs," said Virginia Sharpe, a project director at the Center for Science in the Public Interest in Washington. "Companies who want their drugs tested welcome these physicians with open arms."
Before the money incentives even kick in, researchers who also treat clinical subjects as patients face an inherent conflict of interest: They must weigh patient risk against the potential for a medical breakthrough. Should an individual's health be sacrificed to new information if it means that thousands may be saved in the future? "Clinical trials aren't intended to help patients," says Sharpe. "They're supposed to further scientific knowledge."
Patients often don't have a clue that these kind of conflicts exist. They tend to believe their doctor has only their best interest at heart, and informed-consent documents are often not worded clearly enough to overcome that preconception, say healthcare advocates.
"There's a myth among patients that clinical trials are intended to help them," says Milstein. "Patients always tend to see doctors as their doctor, while doctors may view them primarily as research subjects."
Federal regulation requires the disclosure of financial conflicts of interest in federally funded research. But an estimated 80 percent of medical research is now privately financed and is not affected by the law. Universities and hospitals are free to design their own regulations concerning financial conflicts. A study in the Journal of the American Medical Association (JAMA) by Mildred Cho, the acting director of bioethics at Stanford University Medical Center, found that hospitals and universities have a "wide variation" on how they manage conflicts of interest and that many rules "lack specificity." Few hospitals require conflict disclosures to patients.
Cho believes financial conflicts of interest should not be allowed unless a researcher can make a case for it. But she admits there's little support in the medical community for such a view.
"Journalists and lawyers are trained to be aware of potential conflicts. Doctors are trained to believe they're only concerned with the greater good," says Cho. "As a profession, doctors and biomedical researchers don't see themselves as anything other than advocates for patients. They bristle when you suggest another possibility."
A revolutionary change in the relationship between academia and private enterprise occurred in 1980 when the Bayh-Dole act became law, allowing universities to patent government-funded research and to license their inventions to corporations. The result was an explosion of start-up companies by professors and marriages between major pharmaceutical corporations and university hospitals.
"It's unclear if nonprofit institutions ever really benefited from the kind of income the bill intended," Sharpe says. "What is certain is that it broke down the barriers between academic institutions and private enterprise by introducing many more financial arrangements between the two groups. Research is now predominantly market driven, making academic institutions essentially outposts of private corporations."
Angell believes the law has turned academic medical centers into "little more than hired hands supplying human subjects and collecting the data."
Health advocates are concerned about the effects of such relationships on study results. A 1998 report in the New England Journal of Medicine found that 96 percent of medical journal authors whose research was favorable to certain heart drugs had financial ties to the drug companies. Only 37 percent of the authors of studies critical of those drugs had financial ties. Another study found that nonprofit studies of cancer drugs were eight times more likely to reach unfavorable conclusions than industry-sponsored studies.
The IOM report blames the rash of problems in part on overworked independent research boards (IRBs), internal oversight panels established by hospitals and universities. A report by the Inspector General's office in HHS concluded last year that IRBs are "inundated with protocols and adverse-event reports," and that many IRBs are "hard-pressed to give each review sufficient attention."
The report proposes a number of changes in the system of clinical trials, including increasing the scrutiny by IRBs within federal oversight and improving the ethical training of researchers. It also recommends that participants be continually updated about the risks they face and that anyone harmed in clinical trials be financially compensated without being forced to resort to lawsuits. It urges that each study be examined by IRBs for scientific integrity as well by research ethics review panels (including community and participant representatives) for financial conflicts of interest.
Milstein praised the report. "It identifies the fact that this is a sick system. Sometimes that's 90 percent of a solution," he says.
But health watchdogs say the report sidesteps the elephant in the living room: what to do about financial conflicts of interest. "Managing financial conflicts of interest should lie with the research organization," the report recommends. But Sharav of the Alliance for Human Research Protection insists: "You can't manage conflict of interest. It has to be eliminated."
Angell, who characterizes the IOM report as "pretty timid," agrees. She believes all research on human subjects should be subjected to ethics supervision by bodies independent of the institutions conducting the research. "Current IRBs are creatures of the institutions they supervise, which have an interest in the research," she says. She also wants an outright ban on financial conflicts. She believes that investigators who receive grant support from industry should have no other financial ties to those companies and that institutions should not be allowed to accept grants with strings attached. That means investigators should design their own studies, analyze the results, and write their own papers -- without corporate manipulation or pressure.
A report also issued in October by the Association of American Medical Colleges takes a harder stance than IOM on financial conflicts. "The growing perception that research institutions may have financial conflicts of interest ... threatens to weaken public support for research," the report warns. It calls for a ban on most financial conflicts unless a compelling case can be made for an exception.
The current situation will change only if the public "becomes outraged," says Angell. Academic institutions "are tax exempt because they're supposed to be independent organizations, but they're deep into financial deals with corporations. They can't have it both ways. That's creating widespread cynicism about the integrity of research and the outcomes. The public is going to begin to wonder what function these institutions are serving if they're increasingly set up to make money."
"These institutions talk about public trust the way a beer company talks about public trust," she says. "You've got to be trustworthy to earn public trust. They want to get the trust without the trustworthy part."
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