The Research Industrial Complex

In one tower of an nondescript, nine-story white building on Fulton Street, just across from Duke University Hospital, operates the world’s largest academic clinical research institute, generating more than $125 million in revenue per year from the research grants and contracts it receives from both government sources and from industry. Its more than 218 clients in the pharmaceutical and medical device sectors include corporate giants Johnson & Johnson, Pfizer, GlaxoSmithKline and GE Healthcare. The Duke Clinical Research Institute, composed of more than 1,000 employees supporting the worldwide clinical research projects directed by 220 Duke faculty, has evolved from a small cardiological research outfit in 1996 into an enterprise capable of conducting large-scale Phase I through Phase IV clinical trials across 20 therapeutic areas.

“There’s no other university that presents the full translational continuum in a way that blends the professionalism that you find in industry with the expertise and mission of an academic health center, in the way that Duke does,” said Dr. John March, director of neurosciences medicine at DCRI and professor of psychiatry and psychology at the School of Medicine.

In the contracts with pharmaceutical and medical device companies that provided DCRI with 67 percent of its funding in 2009, the Institute arranges to perform a range of core clinical research services—including study design, accessing patient populations and project management and execution—typically in exchange for the company providing funding or materials for the study. Of all U.S. academic institutions, Duke receives the most industry funding annually for its research and development—$152 million in 2008, according to National Science Foundation data—primarily because of DCRI’s revenue-generating power. The School of Medicine, and the University as a whole, benefit from a yearly inflow of revenue from DCRI’s funding agreements. “In a world where society is distrustful of the motives of the pharmaceutical and medical device world, it is in everybody’s best interests—society, the industry, the academic community—to have some independence over the conduct of research,” said Dr. Robert Harrington, director of DCRI, explaining his sales pitch to pharmaceutical and medical device companies.

But as a recipient of high-value funding grants from corporations, who have a significant stake in a positive outcome for trials involving their products, DCRI is particularly vulnerable to the major risks posed by financial conflicts of interest—or, formally defined, when a researcher or institution’s own economic interests contradict professional obligation. The financial ties criss-crossing the once-rigid barrier between academia and industry are many and complex, inclusive of receiving payment for consulting or research services provided to a company, and holding equity or intellectual property rights in a company—practices now ubiquitous among clinical researchers.

As collaboration between academia and industry in clinical research becomes more common and more lucrative, some warn that unaddressed financial conflicts of interest will erode the objectivity of the science and menace the welfare of clinical trial participants. Critics point to scandals like the one that erupted in 1999 over the death of 18-year-old Jesse Gelsinger, a patient enrolled in a gene therapy experiment led by a principal investigator who had founded a biotechnology company that stood to profit from the experiment’s success. They warn that a proposal offered by industry and accepted by academic clinical research—with the union sweetened with funding contracts—will undermine the credibility of academia’s findings. “Our problem, nationally, is that our research is so biased with financial interest that the scandals that plague the financial world are every bit as ubiquitous and serious in medicine,” said Jeanne Lenzer, an investigative journalist who has contributed to the British Medical Journal, Slate and The Atlantic on conflicts of interest in clinical research. “You pull back the bed covers and what we’re finding, over and over again, is not only that patients in clinical trials are not being protected, but that when bias gets into the science, it puts all of us at risk.”

Supporters of academia-industry collaborations argue that much research benefiting the public health could not take place without industry dollars, and that regulatory controls are in place to mitigate bias. A case study in commercialized academic clinical research, DCRI sits at the center of a broader debate over the propriety of using private dollars to support a discipline whose results impact public welfare at large.

Contract research organizations—or CROs, which perform clinical research services for industry or public agencies—emerged in the 1980s to capitalize on the trend toward outsourcing clinical trials once performed by pharmaceutical or medical device company staff. Targeting greater efficiency and cost reduction during the trial phases, the outsourced model has now become dominant practice in the pharmaceutical industry, with some retaining only their management teams, March said. The CRO market has grown at a break-neck speed, with annual industry revenue climbing from $7 billion in 2001 to $17.8 billion in 2007, according to a 2007 New England Journal of Medicine study. Three of the four largest CROs named in the study—Quintiles, Covance and Charles River Laboratories—are located in the Raleigh-Durham area. Media reports about mismanaged clinical trials run by CROs, such as the 2005 SFBC International trial in Florida involving Hispanic immigrants with limited knowledge of the study’s risks, have prompted questions about the organizations’ qualifications, ethics and degree of independence from corporate sponsors.

But academic research organizations (AROs) like DCRI are a different breed from companies like Quintiles, as Harrington was quick to emphasize. Typically housed within universities and run by faculty, AROs are sheltered from the allegations against professional credibility that dog CROs, yet are still not immune to the question of intellectual independence from commercial sponsors of research. Harrington spoke with gentle condescension toward CROs, which he says treat research as a commodity to be exchanged in a transaction, rather than an endeavor intended to advance a broader institutional goal. “We’re not here to do contract research,” Harrington said. “We’re here to do research that furthers our mission.”

The influence of bias in professional contexts is often subtle and nebulous and, at times, exerted without the person’s intent. But financial biases differ from personal and other biases in one important way, as Lenzer pointed out: They are always unidirectional, pointed favorably toward the source of income. Furthermore, attempts at regulating bias among researchers may come off as an affront on their integrity as scientists.

“We often meet with people when there’s a significant conflict, and they say, ‘How can you say that some amount of money can influence me more than providing care for patients? You are demeaning me by accusing me of being influenced by these external relationships,’” McKinney said. “When you look at their data, their opinions are bullshit. It doesn’t hold water. In fact, we are influenced.”

Institutional policy and practice lay down rules governing some types of financial conflicts of interest among researchers, which shape the degree to which such biases can enter into research. “Conflicts of interest must be defined, disclosed and eliminated when they are avoidable or particularly threatening, and managed if there is no other option,” said Marilyn Field, a National Academy of Sciences researcher who authored a book on conflicts of interest in medicine. Several recent reviews of U.S. academic medical centers, however, have found substantial variations in conflict of interest policy, and judged most to be insufficient.

Benchmarked against its peers, McKinney said, Duke’s policy requires more vigorous reporting of financial interests than those of other institutions, protecting from the influence of bias and damage to the University’s good name. The School of Medicine’s 2008 conflict of interest policy mandates reporting to the Conflict of Interest Office financial interests in excess of $600, and it requires a management plan for interests between $10,000 and $25,000. Researchers with financial relationships exceeding $25,000 are banned from participation as a lead principal investigator in a study related to that company or its products. Those researchers would still be eligible to participate in the study in a different capacity.

In addition, DCRI enables its researchers to voluntarily disclose potential conflicts of interest—a measure Harrington, whose own disclosure form inventories financial relationships with 15 corporations, says is relatively unique among clinical research organizations. About half of the 95 faculty financially supported by DCRI have opted to publicly disclose, said Kristen O’Berry, director of faculty finance and administration at DCRI. Although O’Berry said she was unsure why some faculty did not opt to disclose their financial relationships, Weinfurt said researchers may be loath to fill out additional forms or have privacy concerns regarding how the public would interpret the information. Although it is useful to set certain dollar-based thresholds for disclosure of researchers’ financial relationships, research suggests that bias can influence decisions even when the economic stakes are small, Field said. “We don’t know a lot about the way in which that kind of bias might occur,” she said. “For example if you had a nice visit with a drug company representative, perhaps there’s a greater potential for that physician to use the drug represented by that company.”

Another vital component to the protection of scientific integrity in industry-funded clinical research concerns which intellectual property rights the research organization guards. DCRI fiercely protects its rights to access data and to publish the results of research in contractual language, Harrington said, indicating its intent to carefully manage the data and show confidence in association with its results.

When March looks toward the future of biotechnological research, he sees the dominant model as a public-private collaboration, where clinical research institutes like DCRI carry out studies with funding from both governmental agencies and corporations to explore shared areas of interest. “We have to find a way of making this work, and we have to do it in a transparent and ethical way,” he said. “Otherwise we’ll be doomed to the ethical lapses of the past, and that will encourage people to divorce research completely from industry funding.”

Harrington noted an example of a typical DCRI study that fits the public-private vision March had elaborated. DCRI performed a large randomized trial whose operations were funded by the National Heart, Lung and Blood Institute to determine whether implanting a defibrillator would reduce risk of death in patients with heart damage. The defibrillator devices, which cost around $75,000 each, were provided by Medtronic, a medical device company that manufactures several types of implantable defibrillators.

 “If, in fact, the defibrillator was shown to be superior to no defibrillator, that obviously has potential marketing implications for the company,” Harrington said. “They now have something that’s been done independently of them, so it raises the credibility of the research that then might benefit them.” The trial, whose results were published in 2005 in the New England Journal of Medicine, found that single-chamber implantable cardioverter defibrillators reduced the rate of sudden death within five years by 23 percent, as compared with a placebo or a drug that corrects abnormal heart rhythms.

Both Harrington and March view these public-private partnerships, which tend to grow organically through researchers’ contacts in the industry, as mutually beneficial arrangements. The public gains academically-verified knowledge about the efficacy of certain drugs or devices, and the private company gains an evaluation that—if positive—can be used to market their products. Although supportive of the consortia model, McKinney emphasized that strict ground rules need to be set to prevent private funding sources from overriding the public interest—which, as a tax-exempt institution, Duke is obliged to represent.

But Lenzer, terming the intermingling of public and private funding for clinical research a contamination of the science, noted that in some jointly-funded studies, the resulting data is owned by the participating university, unavailable even through a Freedom of Information Act request. “We have to increase public funding that is not combined with private funding, and there should be comparative effectiveness studies,” Lenzer said. “Without that, we’re really lost.”

One provision of the health care reform bill will shed more light on the degree of financial involvement between academia and industry by requiring American drug, device, biologics and medical supplies manufacturers to disclose payments made to physicians and teaching hospitals. Public disclosure of these records, which will start in 2013, McKinney said, may make industry “cagey” about its routine payments, though Lenzer doubted that the public would know what to make of the data.

Most sources, however, said governmental agencies would never be able to fill the funding void that would open up if industry and academia divorced—particularly in clinical research, where an estimated 70 to 80 percent is funded by industry. To remove or greatly reduce the amount of industry money flowing through clinical research would cripple the funding system and make it difficult for companies to harvest the expertise of clinical researchers. “To remove industry sponsorship of individual studies would obviously create a pretty huge hole in clinical research right now,” Weinfurt said. “This is just how research is getting done. You can try to change the system, but that is going to take an awful lot of time.”