AMSA's 2015 Annual Convention
Join Us Next Spring
in Washington, DC!

February 26 - March 1, 2015 

The Almighty Dollar

THE STRUGGLE OF FINANCIAL CONFLICTS OF INTEREST IN MEDICAL RESEARCH.

The New Physician December 2001
Like many physicians during the late 1980s, Dr. Robert Fiddes was frustrated. In private practice in Long Beach, California, Fiddes felt his hands were tied by managed care and that he was no longer able to do whatever was necessary to diagnose and treat his patients. So in 1987, Fiddes left his private practice to pursue a law degree. But after passing the state bar exam, he again felt the draw to medicine—but this time
in a completely different form. This time Fiddes would enter the burgeoning clinical-trials business.


In the early ’90s, the medical profession was just beginning
to open up to the concept of pharmaceutical companies using community physicians to test new drugs on patients. Seeing this as an opportunity to escape managed care, Fiddes created a “testing operation” under the names Southern California Research, the Southern California Research Institute (not to be confused with the nonprofit organization) and SCRI, among others. Soon, business was booming, testing medicines for high blood pressure, migraines, asthma, diabetes and other medical conditions. In each instance, a sponsoring company paid SCRI for every patient enrolled in a study, and Fiddes didn’t have a problem finding patients to join.


According to former employees, Fiddes would meet with new patients to explain the trial and then refer them to a study coordinator if they were interested. But as the years went on, patients frequently would be pressured into participating, even if they were hesitant to do so or not fully informed of the risks. Eventually, Fiddes advised his study coordinators to enroll patients even if they were taking drugs prohibited by the study’s protocol.


Then in 1996, a recently hired SCRI employee was conducting a study of a new asthma inhaler sponsored by British drug-maker Fison. In the course of the study, she came across a patient who had been enrolled despite the fact that she had lung disease, which was a direct violation of the protocol. When a Fison monitor asked to see the patient’s file, the new hire approached a more senior employee, who promptly removed every reference to lung disease from the patient’s chart and turned it over to the unwitting monitor.


As brash as that act may seem, SCRI’s conduct was even bolder in the following years, according to federal investigators. Under Fiddes’ direction, the firm went beyond doctoring patients’ histories. It began to rig test results, invent patients and substitute an employee’s urine when a patient’s urine did not meet a study’s requirements.


But after years of fraud, Food and Drug Administration (FDA) monitors finally caught on to Fiddes when a former employee cleared her conscience. The result was jail time for Fiddes and several of his associates, and the case was a warning for those responsible for overseeing research in an atmosphere that is often driven by money.


Of course, it would be simple—and correct—to dismiss Fiddes as a rarity, a peculiar species of physician who put his own financial interests over the health and safety of his patients. However, it is impossible to deny that money wields great power in clinical research, and more and more members of the medical community are becoming increasingly concerned about financial conflicts of interest.


RISING CONCERNS


“[Financial conflict of interest] is a huge issue,” says Virginia Sharpe, the director of the Integrity of Science project at the Center for Science in the Public Interest (CSPI). “It’s one of the biggest issues facing clinical research today. In many people’s minds, it has undermined confidence in research and is leading to increased regulation.”


Concerns for financial conflicts of interest in clinical research was practically nonexistent prior to 1980, when a regulatory firewall separated industry and academia in order to assure a basic level of independence for researchers. However, the Bayh-Dole Act of 1980 removed that firewall in an attempt to encourage “technology transfer” and private research investments. Well, it worked—and perhaps too well. With researchers and institutions free to enter into partnerships with biotechnology and pharmaceutical companies, it is estimated that of the approximately $60 billion companies spent on research last year, large companies invested approximately 20 percent of their research budgets at universities, while small companies invested almost half of their research monies. Companies are not required to divulge the specifics of their research investments; so much of their financial influence is unclear.


Regardless of the specific numbers, though, there is little doubt of the companies’ growing influence, says Vera Sharav of the Alliance for Human Research Protection (AHRP). “With the flow of corporate money came corporate influence and control,” she says. “The culture within academic institutions changed: Business ethics swept aside the moral framework within which academia had functioned.”


With the changing research culture, there has been growing public concern that this new business atmosphere has come at the cost of unbiased work. And a litany of government and nongovernment reports released over the past few years has shown that the concern is justified. In November 2001, the General Accounting Office, the investigative arm of Congress, reported there was a significant amount of confusion within research institutions on when it was necessary to report conflicts of interest. The report recommended that the Department of Health and Human Services (HHS) better communicate methods to identify and manage conflicts of interest held by individual researchers. It also suggested the HHS develop guidelines or regulations addressing potential conflicts of interest held by the academic and research institutions, which can have financial stakes in the successes of drugs being studied.


The Institute of Medicine (IOM) released a report in October stating that medical research institutions need to make fundamental changes. It also recommended that federal oversight of human research projects be expanded to include privately funded studies. The IOM report said the Institutional Review Boards (IRBs), which are responsible for overseeing clinical trials, have become unable to manage the studies’ necessary protocols. Furthermore, it suggested IRBs develop a mechanism to review and manage potential conflicts of interest. “Confidence about the current system of participant protection is undermined by the perception that harm to research participants may result from conflicts of interest involving the researchers, the research organization and/or the research sponsor. This concern is particularly acute regarding financial conflicts of interest,” the IOM report stated. “Therefore, mechanisms for identifying, disclosing and resolving conflicts of interest should be strengthened.”


In January, the Association of American Medical Colleges’ (AAMC) Task Force on Financial Conflicts of Interest in Clinical Research issued a report warning that “the steadily deepening engagement of clinical research with the world of commerce is seen by many influential observers as threatening both research integrity and the welfare of research participants.” The task force followed up in October by recommending that institutions adopt high standards for the reporting, review and disclosure of researchers’ interests in both federally funded and privately funded human-subjects research.


Dr. David Korn, senior vice president of the AAMC Division of Biomedical Health Sciences Research, says the task force’s recommendations attempt to restore public confidence while respecting the autonomy of research institutions. “We do not wish to stifle the entrepreneurial spirit that spurs medical innovation; rather, we are attempting to create research relationships that are principled and will withstand public scrutiny,” he says.


However, legislation addressing financial conflicts of interest recently introduced by Sen. Edward Kennedy (D-Mass.) may breach some of that autonomy and give the government a greater role in assuring the integrity of all clinical research. While it is clear that the legislation, the Research Revitalization Act of 2002, will not move forward by the end of this year, a Kennedy spokesman says the issue will certainly be addressed again next session. “[Kennedy] was hoping to develop a bipartisan bill working with Sen. [Bill] Frist (R-Tenn.), but that didn’t work out, so he went ahead to propose the legislation,” spokesman Jim Manley says. “It is something he will revisit next year.”


ABANDONING ACADEMIA


The calls for oversight beyond federally funded clinical trials appear to be getting louder with the rapidly increasing use of a new research model comprised of commercially oriented networks of contract-research organizations (CROs). CROs are for-profit enterprises that develop and manage clinical trials on behalf of pharmaceutical and biotechnology companies. The organizations employ their own physician-researchers, pharmacists, statisticians and managers, and then affiliate themselves with individual physicians or networks of physicians, who are paid for each patient that is included in a clinical trial. By becoming one-stop testing service centers for drug and biotech manufacturers, CROs have been raking in billions of dollars each year.


And with CROs available to do research, pharmaceutical companies no longer need academia to provide patient subjects and expertise on clinical trials’ designs and analyses, and they don’t need academics to lend prestige to studies. And with companies growing frustrated with the slow process associated with academic institutions—which can cost millions of dollars for each day a drug’s FDA approval is delayed—many were eager to make the jump to a new model.


According to Centerwatch, a clinical trial industry newsletter, 80 percent of the money for clinical trials went to academic medical centers in 1991. But by 1998, the figure dropped to 40 percent, and the trend appears to be continuing. “Academic medical centers have a bad reputation in the industry because they are over-promising and under-delivering,” says Gregg Frommell of Covance, a leading CRO, in an article in the May 18, 2000, New England Journal of Medicine (NEJM).


However, not everyone is applauding the new research model, warning that these for-profit organizations are beholden to drug companies and only concerned with the approval and marketing of new drugs. “The rise of separate for-profit human experimentation corporations—a more accurate name for the more benign-sounding name currently in use, contract research organizations—has introduced new techniques for rapidly recruiting patients,” says Dr. Sidney Wolfe, director of Public Citizens’ Health Research Group. “When combined with the appallingly inadequate federal regulation of human experimentation in general, and recruitment practices in particular, and the failure as usual of the medical profession to police itself, the risk of abuse of patients increases dramatically.”


Furthermore, the May 2000 NEJM article warns that physician-researchers are concerned with the amount of control sponsoring companies have over the data that comes from clinical trials. Dr. Thierry LeJemtel of Albert Einstein College of Medicine’s division of cardiology says that when industry does disseminate data, it will “provide the spin on the data that favors them.” The result is the publishing of analyses based on inaccurate or incomplete data that’s still accepted as fact by physicians, who in turn may base patient treatment on misleading information.


WHO'S IN CONTROL?


This quiet battle between researchers and their sponsors came to the attention of national media in November 2000, when a team of researchers, led by Dr. James Kahn of the University of California, San Francisco, (UCSF) School of Medicine, published a study in the Journal of the American Medical Association (JAMA) over the objections of its sponsor, the Immune Response Corporation (IRC). The researchers concluded that an experimental treatment in development by IRC failed to improve the health of AIDS patients. More specifically, the study revealed that the health of AIDS patients worsened at the same rate, regardless of whether they took IRC’s therapeutic vaccine or a placebo.


IRC officials accepted the study’s conclusion but were upset that Kahn and his colleagues decided not to include an analysis of a sub-study of 250 of the 2,527 patients in the trial. This smaller group of patients, who had stronger immune systems, showed steeper drops in their viral loads if they were taking IRC’s vaccine.


“We thought it was scientific misconduct not to include the data,” IRC president Dennis Carlo told the Washington Post. However, Kahn and his researchers disagreed, arguing that including the sub-study would be the equivalent of “data dredging,” a pejorative term for hunting for any positive result in a larger body of work. Furthermore, Kahn says the statistical test used by IRC researchers to discover the sub-study results was an inappropriate and manipulative analysis that was not included in the protocol provided at the initiation of the experiment. “What they are doing is dredging the data for any possible positive outcome, and it’s unfair and shameful that they would disrespect the [study’s] patients, who are the real heroes in all of this,” Kahn told Reuters.


Not surprisingly, this dispute led to a legal battle with IRC seeking $10 million in damages from researchers and UCSF, and asking an arbitrator to insert an injunction preventing further publication of the study. UCSF then filed a counterclaim asserting IRC wrongfully withheld data regarding the subjects’ final clinical visits, and the university accused IRC of refusing to provide the information unless the sub-study was published. “The protocol [signed by both parties] is quite clear that the company does not get editorial control or veto power over publication,” a UCSF attorney told Reuters. “The company has misinterpreted a provision in the agreement that applies to who owns patients’ charts to try and suggest that the study team can’t publish, but that’s not the intent or the language of the agreement.” The arbitrator agreed and dismissed IRC’s claim. Researchers also received all of the study’s data.


THE FACTS OF CLINICAL TRIALS


Kahn and his colleagues were able to prevent what they considered misleading data from appearing in their study, but what happens if you’re a researcher who is unaware that the data you are analyzing is misleading? That was the case for Dr. Michael Wolfe, a gastroenterologist at Boston University. In the Sept. 13, 2000, issue of JAMA, Wolfe wrote an editorial cautiously endorsing a study revealing that Celebrex—under its pharmacological name celecoxib—was safer than other pain relievers because of its lower rates of stomach and intestinal ulcers. Wolfe based his editorial on six months of study data provided by the journal’s editorial staff.


The following February, Wolfe discovered the data he was provided was incomplete. A member of the FDA’s arthritis advisory committee showed him the complete data from the study, which had lasted a full year, not just six months. In analysis of the full study—which had been completed when he wrote the editorial—Wolfe discovered that most of the ulcer complications in the second six months were experienced by Celebrex users. Wolfe then concluded there was only a minimal advantage in taking Celebrex. “I am furious…. I wrote the editorial. I looked like a fool,” Wolfe told the Washington Post. “But…all I had available was the data presented in the article.” The journal’s editors had only been aware of the six months of study data, too. And soon after Wolfe’s discovery, JAMA editors learned that all 16 of the study’s authors were either employees or paid consultants of Pharmacia, the manufacturer of Celebrex.


Pharmacia officials and study authors defended the decision to send only data from the first six months, arguing that an unusually large number of dropouts from the comparison groups during the final six months had biased all of the findings during that period. Stephen Geis, a vice president for clinical research at Pharmacia, added that the final decision to provide only six months of data was made by a three-member executive committee composed of authors who were not company employees. “The intention really was not to be deceptive in any way,” Geis told the Washington Post. “People thought that six months was the appropriate analysis.” Geis also argued that, even taking into consideration the final six months, Celebrex exhibited superior safety levels, just by a more narrow margin.


However, the FDA arthritis advisory committee concluded that the margin was not wide enough to be noteworthy. As a result, the FDA turned down Pharmacia’s request to change Celebrex’s label to state that it is safer, and it has requested more conclusive data supporting the claim.


In the meantime, an editorial in the British Medical Journal lambasted the study and claimed that Pharmacia’s explanation was inadequate. “The flawed findings in the original article appear to be widely distributed and believed,” wrote Dr. Peter Juni, a senior researcher at the University of Berne in Switzerland. He pointed to the 30,000 reprints of the article purchased by Pharmacia and the 169 times the study was cited in other articles. He said Pharmacia should be required to inform physicians that the conclusion that Celebrex is safer than drugs like ibuprofen and aspirin has been contradicted.


In response, the editors of JAMA and 11 other international medical journals, including the NEJM, the Lancet, the Annals of Internal Medicine, the Canadian Medical Association Journal and MEDLINE, wrote a joint editorial warning of the growing influence of pharmaceutical companies on clinical research and the publication of results. “As editors, we strongly oppose contractual agreements that deny investigators the right to examine the data independently or to submit a manuscript for publication without first obtaining the consent of the sponsor. Such arrangements not only erode the fabric of intellectual inquiry that has fostered so much high-quality clinical research, but also makes medical journals party to potential misrepresentation, since the published manuscripts may not reveal the extent to which the authors were powerless to control the conduct of the study,” the editorial stated.


Therefore, the journals instituted a new policy for company-sponsored research: An author not employed by the sponsoring company is required to take responsibility for the integrity of the data and the accuracy of the analyses. Furthermore, an author may be required to disclose greater details of his role in the study as well as the role of the sponsor. “By enforcing adherence to these revised requirements, we can, as editors, assure our readers that the authors of an article have had a meaningful and truly independent role in the study that bears their names. The authors can then stand behind the published results, and so can we,” the editors stated.


The changes were also adopted in a revision of the “Uniform Requirements for Manuscripts Submitted to Biomedical Journals: Writing and Editing for Biomedical Publication,” a set of guidelines developed by the International Committee of Medical Journal Editors (ICMJE) and widely used by medical journals for editorial policies.


The editors said the move was an attempt to give researchers more clout when negotiating protocol agreements with sponsoring companies. NEJM’s editor in chief, Dr. Jeffrey Drazen, acknowledges that, with most research contracts already in place, it could be three years or more until they see the effectiveness of their policy change, but something had to be done to address the conflicts of interest.


“In the worst cases, the drug firms design the trial, explain to physicians how to carry it out, analyze the study, do not let researchers see all of the data, and then control the publication,” Dr. Harold Sox, editor of the Annals of Internal Medicine, told U.S. News and World Report. “Physicians aren’t happy with the arrangement.”


However, a study in the Oct. 24 NEJM warns that medical schools are ignoring the new ICMJE guidelines, limiting the participation and access researchers have in a clinical trial. The study found that: only 1 percent of researchers working with multiple sites were guaranteed access to data from all of the sites; only 2 percent of trials included an independent executive oversight committee; and just 5 percent of research agreements require the results to be published, regardless of the findings.


Unfortunately for clinical researchers, there are only a few funding options available. Often, they need sponsorship from a pharmaceutical company. In the last decade, the flow of money from pharmaceuticals has grown exponentially, overshadowing federal sources of funding. “The relative rate of expansion in industry money vs. government money is three times more for industry,” CSPI’s Sharpe says. “There is more money coming from pharmaceuticals than ever before.”


The relationship between researchers and sponsoring pharmaceuticals is further blurred by a common goal: to be published in an internationally recognized medical journal. Researchers seek the prestige accompanying being published, while pharmaceuticals hope to further legitimize the drug, therefore increasing sales.


As a result, the NEJM editors—while maintaining their new policy on company-sponsored research—felt it was necessary to relax their strict guidelines for authors of reviews and editorials, which before could not have any financial ties to products in the article. “We have concluded that our ability to provide comprehensive, up-to-date information, especially on recent advances in therapeutics, has been constrained,” Drazen and NEJM’s executive editor, Dr. Gregory Curfman, wrote in an editorial. They pointed to the journal’s ability to publish only one editorial on drug therapy during the previous year.


“Certainly, if we publish nothing on a given subject, we run no risk of promulgating a biased opinion, but our silence does not serve our readers. Without authoritative review articles written for scholarly journals by the best possible authors, physicians may find that pharmaceutical companies become their chief source of information about new therapies. This situation is not in the best interest of either physicians or patients,” they wrote.


In its new policy, the NEJM prohibits review and editorial authors who receive $10,000 or more a year from a product discussed in a review or editorial. Also forbidden are authors holding stock options or patent interests in related companies. Meanwhile, original studies published in the journal continue to include the identity of any sponsors and must divulge any financial interests the authors may have in the study.


In the end, editors say, it becomes almost impossible to completely remove the influence of sponsoring pharmaceuticals, but medical journals still need to meet their deadlines and provide a continuous stream of research that is presumed to be unbiased. Medical journal editors hope their policies will provide some level of independence for investigators, while maintaining public trust in the research being published.


THE RESPONSIBLE PHYSICIAN


So through this shift of money and structure, physicians are left to ponder where they fit. When reading a study in a journal, it still comes down to a matter of trust. An individual physician must primarily rely on a journal’s editorial integrity, but he can also take into consideration an author’s conflicts noted in the article.


For community physicians conducting clinical trials, there may be little more they can do than be vigilant in ensuring that patients participating in studies meet the necessary criteria and fully understand any risks involved. “Clinical trials are a very high-risk endeavor and [the patients] don’t understand that,” AHRP’s Sharav says.


Meanwhile, the task is much greater for physician-researchers who are often left on their own to ensure their independence from financial influence. “I think that physicians who enter into these agreements don’t understand that they could be compromising—compromising their patients and compromising the research,” Sharpe says. “Clinicians don’t understand that.” She compares physicians’ perceptions of financial conflicts of interest to recent studies revealing that physicians, despite believing otherwise, are influenced by pharmaceutical giveaways. She says they always believe it’s the other guy who is influenced by conflicts of interest but refuse to acknowledge their own altered behavior. “They still think they have a de facto loyalty to their patients and don’t think they will be swayed,” she says.


For its part, medical education is attempting to get into the act by offering ethics courses to students. And progress is being made, says Francis Macrina, Ph.D., the director of the Phillips Institute of Oral and Craniofacial Molecular Biology at Virginia Commonwealth University and author of Scientific Integrity: An Introductory Text with Cases. He says that a decade ago, many medical students dismissed the importance of conflicts of interest, believing there was no need to even divulge it because it wouldn’t influence their work. “Whether it was a graduate student, a resident student, a medical student or a premedical student, several years ago the biggest problem was convincing people that the perception of conflicts of interest is just as important as real conflicts of interest. Students are starting to get that now,” he says. “Now the next step is convincing people that disclosure isn’t enough. You have to do something about it.”


However, all of this education may be futile if a physician chooses to ignore the laws and guidelines for clinical research. Macrina says educators attempt to show future physicians how to behave responsibly and explain the reasoning of the guidelines and the consequences for violating them. However, he acknowledges that education isn’t enough and that some physicians ignore ethics guidelines and the law to serve their own interests. “We just hope they are weeded out. We hope [our students go on to] practice science in a responsible way and then, more importantly, they pass along that behavior to people working in their labs and in their studies,” he says.
Scott T. Shepherd is an associate editor with The New Physician.