Approval at any cost creates ethical minefield
Approval at any cost creates ethical minefield
Enrollment incentives raise compelling issues
As pharmaceutical and clinical trial companies take more aggressive measures to get their products to the market, ethics committees and institutional review boards must intensely scrutinize the study protocols and informed consent requirements of proposed drug trials to ensure any conflicts of interest are brought to light and patient interests are adequately protected.
A 10-month investigation by journalists at the New York Times recently revealed a wide spread pattern of financial bonuses and multi-tiered incentives paid by pharmaceutical companies and their intermediaries to physicians who enrolled their patients as subjects in the company-sponsored drug trials.1
According to a New York Times article published May 16, 1999, the newspaper obtained contracts, protocols, and related financial records for more than 300 recent drug trials that show the companies routinely paid physicians thousands of dollars for each patient they were able to enroll as study subjects.
Some even offered financial bonuses if the subjects were enrolled within a certain time frame. Medical staff working as study coordinators also were offered bonuses for enrolling a certain number of test subjects quickly. In some cases, physicians not actually involved in collecting data were offered "finder’s fees" for referring patients to doctors who were participating in the studies.
Mergers make it murkier
In addition to criticism about physician incentives, a recent announcement regarding the merger of two clinical trial companies created a furor among patient advocacy groups. Princeton, NJ-based Covance announced it was acquiring Waltham, MA-based Parexel International in late April. That propelled both companies, formerly second and third largest in the industry, to the top spot.
Critics argue that the merger will give the company a competitive edge by allowing each subsidiary to conduct clinical trials worldwide. That would eliminate the time involved in drug companies seeking approval in individual countries.
The public advocacy group Public Citizen in Washington, DC, is just one organization that opposes the merger. "There’s a huge amount of money to be made by rapidly enrolling and finishing studies," says spokesman Sidney Wolfe. Mergers such as this create a process subject to conflicts of interest, he adds.
Validity and safety are concerns
The involvement of physicians in enrolling patients raise serious ethical issues both in terms of the validity of data obtained and the safety of patients enrolled in this manner, says Sarlin Soukiasian, MD, a physician and chairman of the institutional review board at the Lahey Clinic, a nonprofit multi-specialty group practice with 500 physicians and 3,000 support staff in Burlington, MA.
"I think that there is an inherent conflict of interest for a physician to receive compensation for each patient that is enrolled," he states, adding that Lahey does not permit any of its physicians to receive individual compensation for enrolling patients in clinical trials.
The Times article cited one instance in which a patient who should have failed the study’s exclusion criteria was enrolled in the trial by his physician. The man later dropped out after experiencing additional health problems.
A growing concern, Soukiasian says, is that the sites of research are more likely to be private physician offices instead of academic research centers or institutions. Unfortunately, private offices may have less of an oversight system in place to guard against potential abuses.
"Now days, it is common practice to have physicians in private offices participating in clinical drug studies, and I think the main concern is, What is the ethical rationale for doing the studies? Is it to gain scientific information to benefit a large number of patients and mankind in general, which is what research is intended for? Or is it more of a marketing ploy to get physicians and patients used to a particular drug?’" he asks.
Not a new problem
The problem is not news to many people involved in clinical research. "It’s been an underrecognized problem for quite a while now," says Diane Petitti, MD, director of research for Kaiser Permanente’s South California region.
Petitti says Kaiser also has policies in place that prohibit any physician from receiving compensation for enrolling patients in clinical trials on a per patient basis. "We try to build that cost into the total contract with the company for whom the research is being performed," she says. "But in no circumstances do we allow physicians to accept anything — not a computer in the office, nothing — on a per patient enrollment basis."
Kaiser also does not permit additional compensation to study coordinators or other staff, she says.
As a group-model HMO, Kaiser contracts for medical services with separate physician groups. But those physician groups work only for Kaiser and do not have patients outside the HMO, Petitti says. Those physician groups must abide by Kaiser’s policies for research participation.
In fairness to physicians, notes Soukiasian, enrolling patients in research protocols does take a significant amount of work and time and can be expensive. Lahey negotiates a set amount in a clinical trial contract to cover the overall costs of enrolling patients in the study. The funds then are divided among participating physicians.
"There are costs involved in doing the study. At the Lahey Clinic, we often have contracts regarding what payments [from the sponsoring organization or company] would be in terms of overhead costs, time, medications — if those need to be covered, but no individual per se gets financially rewarded for enrolling patients," he explains.
Paying physicians a set amount per patient not only gives them the incentive to enroll patients, it also gives them an incentive to limit the costs related to the drug study.
Petitti, however, has noticed another potential ethical problem creep up in proposed drug studies. "In a lot of cases, you have physicians who are part owner in a pharmaceutical development company, and then they come to you proposing to do research on one of the products," she says. "Within this group, the research division, we have the internal review board [IRB], and we have to go over these studies and say, No, that is a clear conflict of interest there.’"
First, however, the IRB must be aware of the conflict, she adds. "We actually have a space on the application form that asks, Do you have any significant financial interest in the product studied?"
Full disclosure is definitely a requirement in any clinical trial to ensure patients are at least made aware of whether physicians have any sort of financial or compensatory interest in the research being performed, Soukiasian says. And, he adds, money is not the only potential conflict facing clinical researchers.
"There is inherent potential for conflict for anyone who participates in clinical studies," he says, noting that it often means the physician has dual obligations to the research and the best interests of individual patients. "Research that physicians do, even if they don’t receive financial rewards from it, . . . can have other implications in terms of their academic careers."
To protect patients, bodies in charge of overseeing research — IRBs for example — first must carefully consider the history the institution has with the sponsoring organization and the individual investigators, Soukiasian says.
"If they have protocols that are not to our liking, which seem kind of sloppy, or they have not put a lot of thought into it or don’t have the patient’s safety in mind, we tend to be more critical," he explains. "This would be particularly true with companies that have a history of poor compliance or a physician who has a history of not being totally compliant."
The IRB also should scrutinize the scientific justification for the study itself. "You want to make sure they are gathering valid data and not just saying, Try it in 20 patients and see what they think.’ That is pretty dubious."
Finally, the Lahey board makes sure the studies it approves have specific inclusion and exclusion criteria and informed consent protocols. "Informed consent is not only a signed piece of paper, but a whole educational process that makes sure that the patient has full understanding of the implications of being involved in a clinical trial," he adds.
"If it is a very complex research protocol with risk to the patients, obviously you would want them to explain to the patient why it was being done, all of the potential complications and alternatives, and that the patient has the option and all participation is voluntary."
The problem, Petitti and others contend, is that there are no strict laws, regulations, or oversight governing conflict-of-interest issues for private physicians who are not subject to an institutional review. Government protections are not easily enforced at that level. She compares it to the dilemma in the 1980s involving physicians who referred patients to outpatient treatment and testing centers in which they had a financial interest. "It was an ethical issue, but the government finally had to step in with legal restrictions because this was a widespread practice," she says. This situation is the same in that physicians receive significant compensation for behavior that has signifi- cant impact on patients’ care but may not be in the patients’ best interests, she says.
Reference
1. Eichenwald K, Kolata G. Drug trials hide conflicts for doctors. NY Times. May 16, 1999.
sourceS
• Diane Petitti, MD, Kaiser Permanente, South California, Regional Administrative Office, 393 E. Walnut St., Pasadena, CA 91188.
• Sarlin Soukiasian, MD, Lahey Clinic, 41 Mall Road, Burlington, MA 01805.
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