By John Fauber, Milwaukee Journal Sentinel
MILWAUKEE — Even before it went on the market in 2002, doctors were talking about how the back surgery product known as bone morphogenetic protein-2 would revolutionize medicine.
It did — but in ways no one imagined.
Instead of offering 100 percent success in fusing ailing spines with virtually no complications, BMP-2 became a biotech breakthrough associated with skepticism and scandal, epitomizing questions over whether corporate-funded research carried out by financially conflicted doctors can be trusted.
The saga of BMP-2 is prompting bedrock reforms in the policies of medical journals as well as changes in public attitudes about medical research. Experts say the controversy offers some promise that the business of developing new medicine and treatments will become more transparent and credible.
Until just a few years ago, some medical journals and the doctors who wrote papers often failed to disclose financial conflicts or spell out how conclusions about how a product’s safety and effectiveness were reached.
Now, journals — especially those in the orthopedic field — are demanding more, insisting on detailed disclosures of financial data and study methods.
“I don’t think it is solved, but … the ship has turned,” said Dan Spengler, a professor of orthopedic surgery at Vanderbilt University and former medical journal editor. “I don’t think anybody is going to go back.”
At the heart of the controversy has been a small circle of prominent surgeons, including Thomas Zdeblick at the University of Wisconsin-Madison, whose research papers failed to link BMP-2 to serious complications, including cancer, infections, the painful growth of unwanted bone and sterility in men.
A Milwaukee Journal Sentinel/MedPage Today investigation found that as a group those doctors have received tens of millions of dollars in other royalties from Medtronic, the company that markets BMP-2. Seldom were those payments disclosed in the papers. In some instances the articles made no mention of the financial conflicts. In others, the disclosures were so cryptic as to be meaningless.
The stakes are high.
Crucial and sometimes daunting treatment decisions made by doctors and patients every day often are based on what appears in the medical literature.
For instance, over the years spine surgeons have become increasingly aggressive in their treatment of common back problems without adequate evidence that it actually benefits patients, said Bradley Weiner, chief of spine surgery at Methodist Hospital in Houston and a deputy editor of the Spine Journal.
Part of the reason is philosophical. Weiner said for some spine surgeons fusing the spine is the goal, rather than how much the patient improves. To get a high fusion rate, they may use the most aggressive techniques and newest technologies.
But there’s also a profit motive.
“Big operations make more money for surgeons, companies, and hospitals,” he said, “and that can be a real motivator.”
Also at fault are the published papers written by authors who fail to accurately report complications or who overstate the benefits of a treatment.
“Bottom line, reforms are needed on every front; corporate, physician-consultant, hospital, FDA, etc.,” he said in an email.
In December, Vernon Tolo, editor-in-chief of the Journal of Bone and Joint Surgery, wrote an editorial saying that concern among doctors and the public about conflicts of interest “continues unabated.” Some of the questionable BMP-2 research appeared in that journal, including a 2009 paper that failed to link the product to an increased cancer risk.
Citing the BMP-2 controversy, Tolo noted that in February the editors of 17 other orthopedic journals agreed to adopt a standard conflict of interest disclosure form for authors.
Another of the questionable BMP-2 articles was published in the Spine Journal.
In June, that publication shocked the medical community by publishing an unprecedented rebuke of BMP-2 research. An entire edition of the journal was devoted to a scientific and financial expose of the product and the financially conflicted doctors who tested and promoted it.
In 2010, a different analysis found that the financial relationships of nearly half of all surgeons who received at least $1 million in payments from orthopedic device companies were not disclosed in their scientific papers.
For years, drug companies were the focus of conflict-of-interest scandals, said David Rothman, senior author of the study and president of the Institute on Medicine as a Profession, part of Columbia University College of Physicians & Surgeons.
The BMP-2 controversy changed that.
“Medtronic took the device industry from below the radar and into the spotlight,” said Rothman, a consultant to the North American Spine Society, which publishes the Spine Journal.
Until recently, readers of the Spine Journal would have to search around if they wanted to find out about an author’s financial conflicts. But the journal is changing its policy so that study funding and the financial relationships of authors will be spelled out in ranges within the body of the article in the methods section.
For instance if an author who receives seven-figure royalty payments, it will be identified as getting either $1 million to $2.5 million or more than $2.5 million. The article will also include information on who paid for the study.
The penalty for deliberately not disclosing that kind of information could be substantial, including the retraction of the paper and possible barring of future submission.
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The new disclosure policies are part of a sea change in attitude about known sources of potential research bias, said Eugene Carragee, editor-in-chief of the Spine Journal and an orthopedic surgeon at Stanford University.
Just two years ago, he said, some in the device industry claimed there was little if any systematic bias and argued that industry-sponsored trials could stand up to any scrutiny.
Now, he said, for at least some investors and promoters in the spinal device field, the posture has become: “We really resent this kind of close examination of methods, data and disclosures. This high level of scrutiny is going to be bad for our business and possibly bad for innovation.”
Amid the cries for reform are calls for the U.S. Food and Drug Administration to do more.
Spengler, the Vanderbilt surgeon, said someone at the FDA must have been aware that BMP-2 data it held didn’t always match up with what was being put in the medical journal articles.
But the agency “didn’t throw a flag,” he said. “They have to be more aggressive.”
FDA spokeswoman Karen Riley said many of the complications associated with BMP-2 occur mainly in off-label uses, those for which it was not initially approved. And some of those complications are listed on the product label.
“The FDA does not regulate the practice of medicine,” she said.
Monitoring what is being said in the medical literature would mean the FDA would have to play “journal cop,” she said.
“That’s the job of the peer-review process, not the FDA,” said Riley. “Shouldn’t the journals be checking the label and asking the hard questions?”
One reform that could emerge from the BMP-2 controversy is a concept of ensuring more independent review of clinical trial research.
Often when drug and device companies fund new research, the companies collect the data, analyze it and may even have a hand in deciding how it is disseminated in the medical literature.
Critics say that can create a one-sided, commercially influenced picture of new therapies.
In some cases, that means sitting on negative research results.
In 2008, the Journal Sentinel reported that Schering-Plough may have delayed the release of a study showing that its popular cholesterol drug Vytorin provided no benefit in reducing the build-up of plaque in arteries.
In other instances, drug companies wield so much control over research that the conclusions of studies written by doctors they hire are called into question.
A Journal Sentinel/MedPage Today investigation in 2010 found glaring problems with a New England Journal of Medicine paper about the heart drug Multaq, made by Sanofi-Aventis. The newspaper found that all six co-authors of a large study that led to the drug’s approval by the FDA had financial ties to company.
Co-author Richard Page, chairman of the department of medicine at the University of Wisconsin School of Medicine and Public Health, put his name on the influential paper. In doing so he vouched for the accuracy and completeness of the study despite not seeing the raw data.
The company, which paid for the study, collected that information and performed the analysis without an external audit for accuracy or completeness.
The New England Journal of Medicine paper that Page and the others prepared also was criticized because it cited a 29 percent reduction in cardiovascular deaths with the drug, a finding that was disallowed by an FDA panel.
Since then the drug has been linked to a growing number of deaths and other adverse events, including stroke, heart failure and impaired kidney function.