Robert Califf, former head of Duke Clinical Research Institute, is new FDA Commissioner, but ties to pharma still an issue
Dr. Robert Califf
Photo courtesy of fda.gov
"Dr. Califf, it's no secret that during your time at Duke University, you received significant financial support from the pharmaceutical industry, both for you personally and for your research. And I know it's common practice for principal investigators on clinical trials, but it naturally raises questions about your relationship with the drug industry."
— Senator Elizabeth Warren at Robert Califf’s confirmation hearing for FDA commissioner
on Nov. 17, 2015
The Duke Clinical Research Institute is not shy about announcing itself. Its administrative offices sit on the eighth floor of a 15-story downtown office tower that is encased in reflective glass and in granite imported from Finland. Capped with a large sign that bears its name, the building is a defining feature of the city’s skyline.
The DCRI itself is also the defining accomplishment of Dr. Robert Califf, the Duke University cardiologist whom the Senate confirmed yesterday as the commissioner of the Food and Drug Administration.
Twenty years ago, Califf founded the institute as a place for Duke doctors and scientists to run clinical trials for hire. Under Califf’s watch, DCRI has grown to become the largest such academic research organization in the world. More than half of its research funding now comes from the drug and device companies.
These industry ties were the focus of much debate at last fall’s Senate hearings. Critics from presidential candidate Bernie Sanders to the consumer advocacy group Public Citizen challenged Califf over his long involvement with company-sponsored trials, questioning whether, if confirmed, he can do an honest job of overseeing the pharmaceutical industry.
Although, Califf has been under scrutiny for these financial ties, many experts, including fellow academic researchers and bioethicists, say these relationships are typical. Academic research institutes turn to pharmaceutical companies for money because of a lack of government and other public funding,
“Califf has more conflicts of interest than most, and on its face that’s unsuitable for the FDA,” said Dr. Howard Brody, a medical ethicist at the University of Texas Medical Branch at Galveston. But “industry money is necessary,” he added. “It appears to be the norm.”
Califf's conflict of interest forms:
What distinguishes DCRI from other academic research organizations in the country — including the Harvard Clinical Research Institute, the Stanford Center for Clinical Research, and the Cleveland Clinic Coordinating Center for Clinical Research — is its scope and its prominence.
“I would like to see the FDA be more dubious toward pharmaceutical companies.” — Dr. Howard Brody , medical ethicist
Since its inception, DCRI has completed around 1,000 human trials, enrolled more than 1.2 million patients in clinical studies, and published in excess of 9,000 papers in peer-reviewed journals. With an annual operating budget of $200 million, mostly from contracts and grants, the institute prides itself on being a one-stop shop for clinical research services.
Several factors have changed how places like DCRI operate. As government funding has become harder to come by, physician-scientists have grown increasingly dependent on industry dollars. Whereas the National Institutes of Health once funded 1 of every 3 biomedical research projects, that ratio is now down to 1 in 6.
Meanwhile, the cost of developing and testing drugs and devices has increased. Drug makers have been cutting back on in-house research operations, opting to outsource these activities, often to universities and medical schools.These two factors have encouraged industry and academic research organizations to become financially co-dependent.
Dr. Gary S. Firestein, associate vice chancellor for translational medicine at the University of California, San Diego, doesn’t see that as necessarily a bad thing. “All the good ideas don’t have to come from academia,” he said. “Together we can do what we can’t do separately.”
At most academic research organizations, roughly two-thirds of clinical trials are backed by pharmaceutical companies — and Duke is no exception, with half to 60 percent comes from the biomedical and pharmaceutical industries, says Dr. Eric Peterson, who succeeded Califf as DCRI director. One-third to 40 percent of DCRI funding comes from the National Institutes of Health and other government sources; foundations round out DCRI’s support.
However, Peterson said that doesn’t mean that academic freedoms are compromised.
“We have unfettered rights to publish information, no matter what,” he said. “We will open all data to the public and allow any investigator anywhere to examine it.”
Peterson also emphasized Duke’s commitment to transparency regarding conflicts of interest. According to disclosure reports, Califf received money from at least two-dozen companies — including AstraZeneca, Bayer, Janssen Pharmaceuticals, and Bristol-Myers Squibb — which paid for salary support for clinical trials and for expert advice through Faculty Connection, a consulting group made up of Duke faculty members.
Califf also held an equity stake in N30, now Nivalis Therapeutics, which develops drugs for cystic fibrosis, and Portola Pharmaceuticals, which focuses on blood diseases. He divested his interests when he joining the FDA last year as deputy commissioner for medical products and tobacco.
That may appear troublesome to people outside of clinical research. But go to many academic meetings nowadays and you’ll find a PowerPoint slide filled with company disclosures at the beginning or end of the talks.
That doesn’t sit well with Josephine Johnston, director of research at the Hastings Center, a bioethics think tank in Garrison, N.Y., who would like to see a change. “It doesn’t look good,” she said. “You need more diverse funders.”
The years 1998 to 2003 were the years of milk and honey for academic researchers. NIH support doubled. Then in 2003, congressional appropriations for the agency decreased; the amount has dropped after adjusting for inflation in every year since then but one.
“If you look at [Califf’s] support I see why some might be concerned, but you have to look at his performance. He can’t be fooled.” — Dr. Daniel Ford, vice dean for clinical investigations at Johns Hopkins School of Medicine
Even within NIH, funding for basic research has historically taken precedent over translational medicine, the application of that knowledge in medical settings. Clinical drug trials compose a large part of the research that DCRI, Johns Hopkins and many other institutions conduct. The FDA reviews these trials, and flagged at least one conducted by DCRI.
DCRI conducted a clinical trial of Xarelto, an anticoagulant manufactured by Bayer and marketed by a Johnson & Johnson subsidiary, Janssen Pharmaceuticals. Califf co-chaired the executive steering committee and was the primary author on its publication. He presented findings and drugs on Xeralto in front of the FDA advisory committee.
The committee eventually voted 9–2 to approve Xarelto, but with reservations. Members noted several troubling aspects of the trial, including missing data and dosing amounts that skewed results against Warfarin, the drug’s competitor, and in favor of Xeralto. Primary clinical reviewers noted that 30 days after the study ended, Xarelto subjects had 22 strokes—nearly four times more—than the six strokes experienced by those taking Warfarin. And trial subjects who were weaned off Xarelto did not receive another similar medication to reduce the risk of stroke.
Dr. Eric Peterson of DCRI defends the Xarelto trial. “I was in the room many times, and we developed the design and that drug with a lot of scientific input,” Peterson says. “It was done in a rigorous fashion.”
DCRI has strict disclosure requirements, Peterson said, that provide transparency on investigators’ relationships with pharmaceutical companies. “We don’t think the process is bad. We work to get science going and disseminate that knowledge.”
Barring a windfall of federal funding, which isn’t likely, university and pharmaceutical companies will continue to work closely together. And that, said Dr. Daniel Ford, vice dean for clinical investigations at the Johns Hopkins School of Medicine, means accepting an FDA commissioner who, despite links to industry, has proven himself in clinical research.
“If you look at [Califf’s] support I see why some might be concerned, but you have to look at his performance,” Ford said. “He can’t be fooled.”
With political will, money could come from state governments and other non-commercial sources, said Dr. Arthur Levine, senior vice chancellor for the Health Sciences and dean of the School of Medicine at the University of Pittsburgh. However, few private grants are awarded without restrictions. “Philanthropy is also a complicated affair because strings are attached,” he says. “And a biotech company is not going to give $100 million without strings attached. But the number one goal is to improve the lives of human beings.”
A conflict of interest is an ethical warning sign, said Dr. Brody of the University of Texas Medical Branch at Galveston, but not necessarily an ethical violation.
Brody says he wants to see a more circumspect FDA. “I would like to see the FDA be more dubious toward pharmaceutical companies,” he said. “And we need a major change in the way research is funded.”