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NASS Panel Revisits Medtronic Infuse Bone Graft Controversy Medtronic plc

NASS Panel Revisits Medtronic Infuse Bone Graft Controversy

Panelists concluded that the Infuse bone graft has an important role in spinal surgery when used in appropriate patients and for approved indications.

A panel at the North American Spine Society (NASS) meeting in Chicago, IL, revisited a controversy that dates back nearly 15 years surrounding Medtronic’s Infuse bone graft, which contains a recombinant version of bone morphogenetic protein-2 (rhBMP-2).

The timing of Wednesday’s panel session, “The Biologic Hasn’t Changed but the Evidence Has,” was interesting given Medtronic was already gearing up to announce on Thursday that FDA has signed off on a new Infuse trial that could lead to the product being cleared for a new indication.

“It was interesting to see the progression of thinking over time laid out as more and more data comes to bear on the question and it was done in a very academic way, but it was good to see it,” Brett Knappe, VP and general manager of Medtronic’s biologics business, told MD+DI in an interview at NASS soon after the panel session. “I felt like most of the panelists were truly making an effort to be unbiased and data-oriented and that plays to our strength, so I was happy to see that.”

Knappe also talked about his key takeaways from the panel discussion, which we’ll share further down in this story, under the subhead “Key Takeaways from the BMP Panel.”

Medtronic also issued a public statement about the Infuse panel Wednesday that largely echoes what Knappe said.

“We appreciate NASS’ efforts in organizing the Infuse panel and furthering evidence transparency. The panel presented a historical, balanced review of the evolution of the clinical evidence supporting BMP to date,” the company said. “Since the Yale University Open Data Access (YODA) review, there have been over 650 investigator-initiated studies about Infuse. The panelists concluded that Infuse has an important role in spinal surgery when used in appropriate patients and approved indications.”

Furthermore, Medtronic stood by the safety and effectiveness of Infuse for approved indications and said the company is committed to advancing the evidence of Infuse and to offering a broad range of bone graft technologies to help doctors address patient needs.

How the Infuse Controversy Began

FDA approved Infuse in 2002 for use with certain Medtronic interbody fusion devices in single-level spine surgeries. Infuse eliminated the need to harvest bone from the patient’s body in a secondary surgical procedure and the Biologic product was expected to revolutionize spine surgery.

“Not a single BMP-related complication was noted in any of the publications. Conflicts of interest were misrepresented or were poorly documented and the device quickly became adopted,” said Eugene Carragee, MD, a professor of orthopedic surgery at the Stanford University Medical Center. Carragee was the editor-in-chief of the Spine Journal at the height of the Infuse controversy.

After being on the market for a couple years, reports began to emerge suggesting that rhBMP-2 may cause unwanted side effects including male sterility and increased cancer risk. In 2008, FDA issued a public health notification warning of “life-threatening complications associated with recombinant human bone morphogenetic protein in cervical spine fusion.”

The integrity of some peer-reviewed journals was called into question and Medtronic faced hundreds of lawsuits alleging off-label marketing of Infuse.

“In 2011 I was editor-in-chief of the Spine Journal and in that year, we had 39 papers all on BMP complications that were not reported in the original [industry-sponsored] studies,” Carragee said.

What Did YODA Teach Us?

As part of the panel discussion at NASS, Peter Whang, MD, a spine surgeon in New Haven, CT was tasked with reviewing the findings of the Yale University Open Data Access (YODA) Project, which led to independent, systematic reviews of the entire body of scientific evidence regarding the safety and effectiveness of Medtronic’s rhBMP-2 product (Infuse).

The reviews were conducted independently by two academic teams with full access to the company’s clinical trial, post-marketing, and safety data on the product. In June 2013 the YODA Project found Infuse procedures to be as good as but not better than traditional iliac crest bone graft procedures. The report also found cancer rates to be higher among Infuse patients; however, the studies that were commissioned by Medtronic said the data regarding cancer risk was limited.

Whang also shared his personal takeaway from the YODA Project.

“My thinking is that it may potentially be reasonable to use Infuse for an ALIF (anterior lumbar interbody fusion) or PLF (posterior lumbar fusion as an alternative to iliac crest bone graft …” Whang said. “While the risk of cancer may be slightly increased in patients receiving Infuse, the absolute risk is small and not necessarily apparent at four years and the clinical relevance is somewhat questionable.”

Whang also noted that the Infuse controversy sent a strong message to spine surgeons regarding the importance of the informed consent process. “The relative risks and benefits of using Infuse has to be explicitly discussed with the patient who needs to be an active participant in this decision-making process,” he said.

Infuse in the Post-YODA Era

Today Medtronic’s Infuse bone graft is approved for two indications: ALIF and oblique lateral interbody fusion (OLIF) when used with certain PEEK or Titanium cages. The company currently has two trials to evaluate Infuse in additional indications – posterior lumbar fusion (PLF) and transforaminal (TLIF) lumbar interbody fusion spine procedures.

Gregory Schroeder, MD, a fellowship-trained spine surgeon and an assistant professor of orthopedic surgery at Thomas Jefferson University, provided his perspective on the use of Infuse and the evidence that has emerged since the YODA Project. Schroeder disclosed that he is a paid consultant for Medtronic but he said his work with the company has nothing to do with Infuse or any other biologics.

Schroeder said that of the 650 studies published on BMP since the YODA Project, more than 80 studies have been published this year alone. “So, it is still a very hotly researched topic,” he pointed out.

Most of the data since YODA is not industry sponsored, which is both good and bad, Schroeder noted.

“One of the big things that I took out of the BMP issue is that there’s a problem with industry-sponsored data, even if we think that it’s done right … these are supposed to be the best studies but there clearly is – even though I know a lot of the people who have done these studies, they’re nice people – but there is something that is inherent about the industry-sponsored data that makes it a problem,” he said.

That said, Schroeder also noted that the industry-sponsored studies tend to have better follow up data compared to non-industry studies. “We can’t get 50% of the follow up at a year but industry can get 80% of follow up data at seven years,” he said.

One of the best Post-YODA studies on BMP in Schroeder’s opinion is a prospective Canadian study that enrolled 197 patients at eight centers and found an increased rate of fusion in patients when rhBMP-2 was used compared to patients who received a iliac crest bone graft (94% versus 69%) at 48 months. On the other hand, he also pointed out that there was no difference in health-related quality of life outcomes at two years between the two patient groups in that study.

As for the Post-YODA cancer discussion, Schroeder said most studies conducted after the YODA Project have found no significant difference in the cancer rate when BMP is used but the quality of some such studies should be taken with a grain of salt. For example, he pointed to one study that found BMP actually decreases the risk of cancer, which should raise a red flag because that finding, while positive, doesn’t make a whole lot of sense.

“Post-YODA, what can we say? I think the literature is less tainted by industry studies but there’s lower quality studies. I think that BMP does help the bones to heal, it’s probably not needed in routine cases, and I would say at this point the Post-YODA data suggests that there’s no real evidence for BMP and cancer.”

The Hype Cycle of BMP

Wellington Hsu, MD, a spine surgeon and a faculty member at Northwestern University in Chicago, IL, used his own background and experience with Infuse to illustrate the hype cycle of BMP. Hsu disclosed that he is a paid consultant of Medtronic and a member of the company’s advisory board but he says his affiliation with Medtronic is not related to BMP.

Hsu said he started his practice in 2008 and had heard the hype about Infuse and how the BMP product was expected to revolutionize spine care. At that time, he began using BMP for anterior lumbar interbody fusion (ALIF) procedures (on label) and posterior lumbar fusion (PLF) procedures (off label). Remember that physicians are allowed to use medical devices off label at their discretion, but it is illegal for medical device companies to market devices for such off-label uses. Hsu said if you had asked him at that time about complications associated with BMP he would not have been able to name a single one.

Fast forward five years to 2013 (the year of the YODA Project), and it was an entirely different story. Hsu was only using BMP in ALIF procedures under heavily scrutinized cases with informed consent, he was getting calls from lawyers about BMP on a routine basis, and he considered the long-term success of the product at that point to be unclear.

Fast forward again to 2019 and Hsu’s experience with BMP has shifted dramatically once again. Today he is using BMP a lot more including some off-label use (TLIF and PLF), “informed consent is really an afterthought, I don’t really hear from lawyers at all, and I do think recent studies have shown long-term success with BMP usage,” Hsu said.

So why this dramatic shift from a high level of BMP use in 2008, to a significantly decreased use in 2013, and an increased use now? Hsu said the reason has to do with the hype cycle of the product. In the beginning, he explained, the industry and surgeons alike were very zealous about BMP. That was followed by a trough of disillusionment during which surgeons were afraid to use the product because of the potential for BMP to cause cancer, and now there seems to be a slope of enlightenment supported by recent evidence.

“Most spine surgeons will tell you that at some point in their career their mentors have told them ‘you are never the first and you should never be the last to use a new technology. It should really be somewhere in the middle.’ It’s easier said than done though,” Hsu said.

He added that the evidence from the past six years have shown that perhaps the complications that were seen after Infuse hit the market were a product of being over-zealous in how it was used.

The lesson, Hsu said, is that the adoption of new technology should not be the same for surgeons as it is for investors and consumers. He also said it’s best to avoid both zealousness and fear when it comes to new technology in spine surgery.

“But make no bones about it,” Hsu said. “Our current level of information is as good as it’s going to get. You’re not going to see a dramatic increase in publications with BMP that will dramatically help our understanding of what’s going on.”

Another surgeon who participated in the panel, Christopher Chaput, MD, noted one difference between the typical hype cycle and BMP. To explain his point, Chaput used the example of pedicle screws, which the ABC news program 20/20 did an exposé on after the devices first came out in the 1980s. There was a trough of disillusionment over the following years but then there was a slope of enlightenment, he said, that included the release of second- and third-generation products entering the market.

“This has not happened with rhBMP-2,” Chaput said. “We do not have other biologically recombinant products coming to market so we do not have a typical hype-versus-hope curve when it comes to biologics.”

Key Takeaways from the BMP Panel

In an interview with MD+DI after the panel on Wednesday, Medtronic’s Knappe shared three main takeaways from the discussion.

“My first takeaway is that the evidence shows over time more and more strongly that there is no association between cancer risk and clinical use of BMP,” Knappe said. “In a business sense that’s important because once there is a negative halo over something it takes a long time for that to relax, so the more data and open discussion there is about this, the less fear we’ll have. And to be honest we’ve had a pretty good run with BMP recently.”

He noted one of Medtronic’s big success stories with Infuse is that a group of Australian surgeons who had previously stopped using the product recent came back to it because they have become comfortable with it again.

Knappe said another big takeaway from the panel discussion at NASS was the acknowledgment that perhaps there was a bit too much enthusiasm and over-zealousness with BMP and the amount of it used in the beginning. But, he said, as surgeons have come through that fear trough to realize that BMP is “extremely effective” and that, when used as indicated and for appropriately-selected patients, it has a role in the surgeon’s armamentarium.

“We want it used safely and effectively, and it’s important that the industry understands that we are continuing to invest [in Infuse] and we do stand behind the product.”

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