In January 2002, a group of Food and Drug Administration advisers met on whether to approve a powerful new biological agent that promised to revolutionize back surgery.

The product was like nothing the burgeoning field of spinal fusion surgery had seen before. If used properly, it essentially turned whatever it touched into bone. This was a good thing if it could be confined to the tiny space between vertebrae, but potentially calamitous if it leaked out.

One of the FDA advisers at the meeting raised a concern about nine of the doctors whose research on the product had been submitted to the FDA: The doctorsall had a financial stake in the product, and their test results with it were nearly twice as good as the doctors who did not have a financial interest.

The concern by the FDA advisory panel member was laughed off with a joke, according to a transcript of the hearing, and the panel ultimately deferred to Medtronic, a company that stood to get billions in sales as the maker of the product known as Infuse.

What has happened since is no laughing matter.

Since recombinant bone morphogenetic protein-2, the biological agent used in Infuse, was approved by the FDA for fusion surgery, early concerns about its widespread, unapproved use and adverse reactions in patients have materialized. Studies have warned that it can cause life-threatening swelling in the neck, form bone in unwanted locations and possibly fuel the growth of cancer cells or spark adverse immune system reactions.

The approval of Infuse followed what drug industry critics say is a familiar playbook:

First, a buzz is created about a potential new therapy. Then, research - often by doctors with financial ties to the product - is presented to the FDA for a specific use in a narrow group of people. Once the product is on the market, other uses for it are promoted in articles and presentations, often by doctors with financial ties to the company.

Now, Medtronic is back before the FDA, this time seeking approval for a different BMP-2 product for use in back surgery. Once again, concerns about cancer, immune reactions and effectiveness have been raised by a different panel of FDA advisers.

The story of BMP-2 raises questions about whether doctors should be allowed to do clinical trial research involving products that might enrich them or the company they work for. It also shows weaknesses in the FDA process for approving drugs and devices.

"I find it very alarming that so many prominent surgeons have such cozy relationships," said Richard Deyo, a professor of family medicine at Oregon Health and Science University who has done research on spine surgery. "That concerns me a lot. It colors my reading of the data."

Conflicts of interest involving Thomas Zdeblick, a prominent surgeon at the University of Wisconsin-Madison, are at the heart of the BMP-2 story. He and a small group of doctors from around the country with financial ties to Medtronic have paved the way toward the product's approval and widespread use.

Zdeblick holds patent rights to a key component of the product and has received more than $22 million dollars in royalties and other payments from Medtronic since 2002. He also is co-author of research reports about the pivotal FDA clinical trial that led to the approval of Infuse.

He declined to comment for this story. Medtronic has declined to release the names of the 60 doctors who participated in the Infuse studies and whether they had financial ties to the company.

Zdeblick is one of the doctors, but participated in a different arm of the study than the nine doctors referenced at the 2002 FDA panel hearing. However, doctors in his arm of the study who had ties to Medtronic also had better success with the product, according to FDA records.

The FDA redacted sections of its 2001 file listing the financial disclosures of the Infuse investigators, and it repeatedly told the Journal Sentinel that information no longer was available.

An FDA spokesman first e-mailed this reply: "The information you are asking for was part of the sponsor's presentation and FDA did not require submission nor did the agency maintain copies."

Then Friday, a different FDA official said the agency erred and the records were available, but they would be difficult to find.

In approving the product, the FDA took into account the conflicts of interest of the investigators, said Markham Luke, chief medical officer in the FDA's device evaluation office.

Marybeth Thorsgaard, a spokeswoman for Medtronic, said the company fully disclosed the success rates of the doctors with financial ties to the company to the FDA. She noted that those doctors also had better results with the patients in the trial who did not get BMP-2.

"The panel probed the issue and made its recommendation to the FDA, which ultimately approved the product," she said in an e-mail.

She said Medtronic is strongly committed to preventing the promotion of its products for unapproved uses and has implemented corporate policies and training to prevent that.

In addition, she said the package label for BMP-2 covers all safety concerns that the FDA believes the public needs to know.

"Collaboration between physicians and industry remains absolutely vital to innovation in the medical technology industry," she added.

Controversial treatment
Spinal fusion is a controversial treatment for degenerative disc disease with a considerable amount of evidence suggesting that many patients with back pain do just as well over time without surgery.

The expected overall success for Infuse is 57.1% - virtually the same as fusion without using BMP-2 (56.7%), the FDA noted in approving the product.

In the past, spinal fusion surgery often required harvesting a small amount of bone from the hip, which can be painful and add time to the surgery. Any new therapy that could eliminate that, such as Infuse, had blockbuster potential.

That's exactly what happened. BMP jumped from being used in less than 1% of all fusions in 2002 to being used in 25% in 2006 - much of it fueled by "off-label" use.

The FDA approved the use of BMP-2 for a single-level fusion involving the lumbar spine in which the operation was done from the front.

Since then doctors have been using it off-label in surgical approaches from the back rather than the front, and on the cervical spine as well as the lumbar spine. The cervical area is at the top of the spine, near the neck, while the lumbar area is farther down the spine, at the lower back.

One recent study found a fourfold increase in the use of all BMP products in five years, from 24,000 procedures in 2003 to 103,000 in 2007. About 85% of that was off-label use, according to the study, which was presented in March at an orthopedic surgery meeting.

While the study included a product made by a different company as well as BMP-2, the vast majority was BMP-2, said lead author Kevin Ong, managing engineer at the consulting firm Exponent Inc. of Menlo Park, Calif.

Ong said he was surprised to see that off-label use of BMP-2 continued despite warnings about safety concerns.

Billions at stake
Billions of dollars were at stake eight years ago when the FDA advisory panel met to consider the fate of BMP-2.

At the time, panel member Stephen Li asked about the financially connected doctors getting better results than doctors who did not have financial ties to Medtronic.

"I don't really raise this at all to impugn anybody's integrity..." Li said, according to a transcript of the hearing.

Li's comment was laughed off at the hearing after he quipped about giving all doctors a financial stake in the product to improve their skill, since the ones with ties got better results.

Likewise, the panel also discounted fears that BMP-2 would be used off-label, though that concern was brought up several times at the hearing.

It is not illegal for doctors, including those with financial ties to such companies, to tout off-label use of products, although it is illegal for companies to do so. Once a drug or medical device gets FDA approval, doctors can use such products as they see fit, thereby opening up a product's potential market.

The skyrocketing off-label popularity of BMP in risky and expensive fusion surgery suggests vigorous promotion by industry-sponsored surgeons, said Eugene Carragee, a professor of orthopedic surgery at Stanford University School of Medicine.

"I don't think that any of this wasn't foreseeable from the get-go," he said.

When Infuse was approved in 2002, there was little way for the medical community and public to know if physician investigators had financial conflicts of interest, let alone how much money they got from the device companies.

Amid heightened concerns about transparency and conflicts of interest in medical research, Medtronic in May joined several drug companies in publicly listing payments to doctors - in advance of federal legislation that mandates such reporting beginning in 2013.

During the first three months of the year, about 230 physicians nationwide received payments from Medtronic of more than $5,000 for consulting, royalties and other reasons, the company reported.

Several of the doctors on that list are the same ones who wrote articles about the original Infuse clinical trial or who wrote about off-label uses for BMP-2.

And as with Infuse, Medtronic has gone to its stable of financially connected doctors to try to sway the FDA to approve its new BMP-2 product, known as Amplify.

That research for Amplify, which targets a different slice of the lucrative spinal fusion market, was considered by the FDA last month. The Amplify clinical trial, which involved 463 patients, was completed in 2009.

Twenty-seven of 63 surgeons - who operated on more than half of the patients in the clinical trial - had a financial interest in Medtronic at the time of the research, according to FDA records reviewed by the newspaper. Medtronic maintains that because the financially connected surgeons had results that were similar to those who did not have such conflicts, their financial interest in Amplify's success did not affect the results of the trial.

Infuse treatment
The Infuse treatment consists of a tapered, metallic fusion cage that looks like a thimble and the BMP-2 bone graft substitute. The substitute, which is placed inside the LT-Cage, includes the genetically engineered human protein (BMP-2) that is placed on an absorbable sponge.

The LT-Cage maintains spacing between the vertebrae while the BMP-2 generates the formation of new bone in order to permanently stabilize that section of the spine.

UW surgeon Zdeblick is the inventor of the LT-Cage. In 2007 alone, the LT-Cage brought him $1.4 million in royalty payments.

Zdeblick and three other doctors co-authored a 2002 paper touting the benefits of Infuse. The paper was published in the journal that Zdeblick has been the editor of since 2002.

All four of the surgeons listed as authors show up as receiving six-figure royalty payments from Medtronic for various products during the first quarter of 2010. Zdeblick got the most among the four - $473,000 for the three-month period.

Off-label concerns
The BMP-2 story highlights a problem with the way medical research is done in the United States, said Sohail Mirza, a professor of orthopedics at Dartmouth Medical School.

"The information that comes from the manufacturers and people who are very vested in the product succeeding often dominates the literature," he said. "That does taint the information. There is a conflict there."

Compelling research on the product, especially when it is used off-label, is thin, he said.

He said it is worrisome that patients may not always know that BMP-2 is being used in an unapproved approach.
"I am not sure patients always know it is off-label and I think they should," he said.

As far back as 2002, when the FDA was deciding whether to approve Infuse, experts were expressing concern that once the product was approved for one use, doctors would start using it for off-label purposes.

"After this product type is out in the marketplace if it is misused or misapplied, the potential for harm is great," Patsy Trisler, a consultant with the firm Pharmanet Inc., told the FDA advisory panel at the 2002 hearing.

One panel member, physician John Kirkpatrick, said he wanted to prevent off-label use of the product and proposed requiring that it be packaged in a way that would make that difficult. However, Medtronic officials at the hearing successfully argued against the idea.

For Medtronic, off-label use meant a potential windfall of increased sales.

Sales of BMP-2/Infuse have grown to about $800 million a year, said Rick Wise, an analyst with the firm Leerink Swann.

He declined to estimate how much of that is from off-label use, noting that companies are not allowed to promote off-label use of their products.

"It's clear off-label use is substantial," he said.

John Fauber reported this story in a joint project of the Journal Sentinel and MedPage Today. MedPage Today provides a clinical perspective for physicians on breaking medical news at www.medpagetoday.com.

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