Eight leading spine surgeons and industry experts discuss Medtronic's recombinant bone morphogenic-2 product Infuse and how the recent controversy over complication disclosures is impacting its use.
FDA clearance and off-label use
Since it gained FDA clearance and was released on the market in 2002, Infuse has been used in thousands of surgeries to help promote spinal fusion. The product was only cleared for the indication of use with an LT cage during single-level anterior lumbar spinal fusions for patients with degenerative disc disease from L2-S1. However, surgeons quickly began using it in a myriad of different situations. In some cases, the off-label use worked wonders where traditional fusion has a high risk of failure; in others it caused serious complications.
"I think BMP is an incredibly potent and incredibly efficacious molecule" says Hyun Bae, MD, a spine surgeon at St. John's Health Center in Santa Monica, Calif. "When we are dealing with a potent molecule, we are going to have complications and side effects. If you think about antibiotics, they are potent molecules that help with infection, but even they are associated with complications because they are so potent. To think we have a molecule that can drive osteogenesis single handedly, create bone de novo and not have any other mechanistic side effects would be naive."
Although off-label, Infuse has allowed spine surgeons to perform minimally invasive procedures with a high rate of fusion. "[Infuse] clearly has been one of the most effective bone forming proteins to enhance fusion and has had a big impact on the market because it has made minimally invasive surgery truly effective," says Neel Anand, MD, director of orthopedic spine surgery at Cedars-Sinai Spine Center in Los Angeles.
Several studies and anecdotal evidence has suggested an increased risk of complications when BMP is used in the cervical spine, and the FDA has issued a warning letter a few years ago against that application. When the letter was released, many surgeons stopped using BMP in the cervical spine. However, some surgeons such as Thomas Schuler, MD, president of the Virginia Spine Institute (VSI) and Brian Subach, MD, a spine surgeon and director of research at VSI and the Spinal Research Foundation, have been analyzing the dosage for BMP and experienced success if they use a smaller dosage in the cervical spine.
"We are achieving fusion without the risk associated with using the product in the cervical spine, such as swallowing and inflammation issues," says Dr. Schuler. "We have done an extensive number of cases without the negative side effects."
Controversial complications
In the July 2011 issue of The Spine Journal, editor-in-chief Eugene Carragee, MD (who stepped down as editor-in-chief for the issue) published results of a study he led at Stanford University in Palo Alto, Calif., showing that patients in his BMP sample group had a higher instance of retrograde ejaculation than initial studies for the product revealed. The study was accompanied by additional studies on BMP use as well as editorials and comments discussing Medtronic's initial public release of data, which may not have included all information about complication rates. However, complications from the initial studies were reported to the FDA, which still granted approval for the product in limited indications.
An additional factor in BMP studies has been compensation; some studies have been sponsored by Medtronic while others were sponsored by outside entities, and still others were conducted independently by spine surgeons. These studies from all sides of the spectrum have shown various results when comparing fusions using BMP to fusions using bone material harvested from the iliac crest. Many of these studies are not random, double-blind, controlled studies insisted upon by best evidence-based medicine practices, but healthcare providers and payors have taken notice of select results. Hospitals and payors often point to the studies showing no clinical benefits or multiple complications associated with the BMP.
"I don't think all the guidelines we follow are based on studies that include the most recent data we have," says Andrew Hecht, MD, co-director of spine surgery at Mount Sinai Medical Center in New York City. "I think everyone would agree that Infuse is a very important tool for surgeons to have in a clinical setting. We are figuring out what the right dosage is and what the carriers are in each part of the spine to prevent complications."
While it's necessary to highlight complications and publish articles about the appropriate use of spinal products, divulging all information about the studies and placing them within the context of all literature published on the topic is crucial. Otherwise, the intricacies of BMP use are lost on the lay media.
"At the Spinal Research Foundation, we believe that when this product is used properly for patients, it greatly improves their success," says Dr. Schuler. "We are very concerned about the recent articles creating a pandemonium in the press and insurance industry that is detrimental to patient access to good spine care. The centers that are publishing some of this data aren't correlating the doses; instead, they condemn BMP use across the board."
Dr. Anand has authored three papers on his experience with BMP, which weren't referenced in The Spine Journal's recent articles analyzing the product. He used Infuse for patients with spinal disorders, including deformities, and outlined the dosage for each patient in his report. The papers all reflected good results he achieved using the product.
"The articles showing good results aren't often referenced; they only focus on the bad complications," says Dr. Anand. "You have to talk about all the facts that exist. It would be a sad day if this product was taken off of the shelf because of a focus on the negative articles. We would be put back to prehistoric times because BMP has made minimally invasive surgery a reality."
In August, Medtronic announced it would grant $2.5 million to Yale University researchers to independently review the safety and efficacy of Infuse. The company will release the original data from its trials in an effort to prove the product's integrity, although the studies include very little controlled data. The researchers could also request the original data from independent studies for the overall analysis.
Costs gone wild
Even as scientists and researchers are making advances in the most effective way to use BMP, many hospitals and payors are discouraging the use of Infuse because of its price. Infuse is the only FDA approved BMP product available, and the price for Infuse is very high compared to what it costs for surgeons to harvest bone from the iliac crest.
Hospitals are increasingly asking spine surgeons to justify their Infuse use more than they have in the past. Some hospitals have even created committees to monitor the cost of spine care, says Robert S. Bray, MD, founder of DISC Sports & Spine Center in Marina del Rey, Calif. "There has been a massive cost increase for hospitals because BMP alone can cost $3,000-$7,000 per case, and more when surgeons use it with scoliosis cases," he says. "This is a direct increase in the cost of healthcare and you can't increase the cost of healthcare that much without someone to off-set it, especially without the literature showing it does something dramatically better than the current standard of care."
Results of studies on the efficacy of BMP — and even spinal fusions — vary, which leaves a lot of room for providers, payors and surgeons to cite studies supporting their particular views. Now, with the trend toward lowering hospital costs, the days of widespread Infuse use could be limited.
"If orthopedic surgeons, spine surgeons and neurosurgeons don't support the applicable use of BMP and its benefits for our patients, we may actually lose the privilege of using it," says Dr. Bae.
Spine surgeons around the country may also be weary of using Infuse for medicolegal reasons, especially in off-label situations. Patients could sue their surgeons if a complication arises and all studies are fair game when building a legal case.
"The critical papers are creating an environment which prevents patients' access to these biologic tools even when it is the best treatment possible," says Dr. Schuler. "It's already happening because people are afraid of medical liability down the road because of the negative papers."
Solution: find the correct dosage
While the research and approval for BMP use is limited, many surgeons agree on one of the most important aspects of BMP use: having the correct dosage is critical. Complications are more likely to arise when patients receive too much BMP, and there are several factors that play into how much is the appropriate dosage for each individual. Surgeons are using smaller doses in the cervical spine than in the lumbar spine, and in multi-level procedures the appropriate dosage varies depending on the level of fusion.
"If you can decrease the dose but still obtain the desired goal of fusion in the cervical spine, you can get the good effects of BMP without the complications," Dr. Schuler says. "Just because there are dose complications in some situations doesn't mean that those complications apply across the board to all patients and doses."
Top surgeons and investigators around the country are already working on studying the correct dosage and patient selection, and the recent focus on BMP has served to increase interest in looking at these factors.
Greg Yoshida, MD, medical director of spinal deformity/scoliosis at Tri-City Regional Medical Center in Hawaiian Gardens, Calif., also reports having good results with cervical spine surgery, although he no longer performs cervical spine fusions using Infuse to avoid controversy.
"I used to use [Infuse] sometimes in the neck instead of a resorbable cage or allograft and it worked wonderful there," he says. "I never had any patients with adverse reactions, but I know there have been adverse reactions to that application. When complications occur, surgeons were using a ton of BMP in the neck and laying it against the front of the spine, which is right next to the esophagus. Even though I've avoided these things and had a good result with BMP in the cervical spine, I wanted to avoid controversy so I don't use it there anymore. When something becomes controversial, I become stricter with it."
What we've learned
The back-and-forth conversation between spine surgeons who use Infuse in a variety of applications has served as a springboard into a new era of spine research and innovation. While discussion has created controversy among spine surgeons and confusion in the media, there are good things that have emerged from the storm.
"In the future, we will start using it in situations that are more appropriate and stick to on-label applications," says Dr. Bae. "What's really going to be fleshed out from all this is understanding of the different demands of various fusion environments. I think most of us can agree that BMP is an incredibly useful product and it will be used more for cases were the demand for fusion is the greatest."
The controversy also raised questions about the conflict of interest for spine surgeons when they receive compensation, in any form, from device companies. The relationship between device companies and surgeons is necessary for product development, research and education, but balancing the appropriate level of compensation with unbiased medical care and research can be tricky. One solution could be the formation of non-biased academic-based technology committees that can produce position statements and share them at professional society meetings.
Spine surgeons are quick to disclose conflicts of interest these days and even quicker to mention financial ties. The Spine Journal recently took steps to make disclosures a more apparent part of the article instead of a footnote, and other journals may soon follow suit.
"This controversy has brought out the need for a little higher scrutiny of studies coming out regarding new technology, especially focused on the editorial conflicts in journals," says Robert Eastlack, MD, a spine surgeon at Scripps Clinic in San Diego. "At the end of the day, I think it's going to be a useful tool. We'll have a better understanding of how to harness the dose so we can eliminate the side effects and utilize the product for more patients. The effective use of current BMP products will allow new product development so one company will not have a hold on the market."
Will surgeons still use BMP in the future?
While there could be a decrease in off-label use in some applications of BMP as a result of recently reported complications, spine surgeons and industry experts are predicting that the fusion-promoting device will remain a tool for spine surgeons. According to a study published in a Sept. 2010 issue of Spine, off-label use accounted for 85 percent of BMP procedures between the 2002 and 2007 and was predominantly used in primary posterior lumbar interbody fusion or transforaminal interbody fusion.
An additional report from Global Pipeline Analysis released in July 2011 showed that in 2010, Medtronic held 44 percent of the bone graft substitute market and more than 90 percent of the global BMP market, valued at $868 million. The company's success was largely driven by Infuse, although the report suggested that other medical device companies such as Synthes, Wright Medical, Orthovita and Stryker could increase their presence in the bone graft substitute market as it becomes more lucrative.
"The field will likely continue to progress as the industry learns more about these technologies, understands their strengths and weaknesses, and then applies them to benefit patients," says Aartie Shetty, a medical device industry analyst with Frost & Sullivan. "Off-label use of Infuse gave rise to controversy about its use and efficacy, which Medtronic is still battling. But, that said, all the positive aspects of BMPs that attracted surgeons in the first place still remain. As and when new products are introduced and companies are able to support their claims of efficacy of the device in spine surgery with hard clinical data, surgeon confidence will take shape for these products."
Surgeons who have used and trusted Infuse for several years without noticing many complications in their practice will most likely continue to use the substance, if given the opportunity. The second battle being waged on clinical use of Infuse is the cost factor; if the price for the product does not come down, surgeons may be forced to forego its use by cost-conscious hospitals and insurance companies, especially if literature doesn't completely support the notion of superior outcomes when using Infuse.
In the near future, there will most likely be an influx in new studies about BMP to support or oppose the most recent complication data. These new studies will need to report how the product was used and the specific dosage to be considered viable. The authors of the studies will also need to contend with their biases and conflicts of interest.
"It's impossible not to have a conflict; even when surgeons tell their patients they need surgery that they are paid for, it's a conflict," says Dr. Bae. "However, when studies are multi-center and randomized, some of the conflict is eliminated. It's incredibly difficult to affect that type of study and gain from research in these trials. When surgeons demonstrate efficacy in a multi-center, randomized trial, the results are close to accurate."
Related Articles on Spine Surgery:
How Are Spine Surgeons Using BMP Today? 10 Surgeon Responses
Dr. Robert Watkins: 4 Points on Biologic Solutions for Spine Surgery
What Happened With Infuse: 6 Points From Dr. Eugene Carragee
Since it gained FDA clearance and was released on the market in 2002, Infuse has been used in thousands of surgeries to help promote spinal fusion. The product was only cleared for the indication of use with an LT cage during single-level anterior lumbar spinal fusions for patients with degenerative disc disease from L2-S1. However, surgeons quickly began using it in a myriad of different situations. In some cases, the off-label use worked wonders where traditional fusion has a high risk of failure; in others it caused serious complications.
"I think BMP is an incredibly potent and incredibly efficacious molecule" says Hyun Bae, MD, a spine surgeon at St. John's Health Center in Santa Monica, Calif. "When we are dealing with a potent molecule, we are going to have complications and side effects. If you think about antibiotics, they are potent molecules that help with infection, but even they are associated with complications because they are so potent. To think we have a molecule that can drive osteogenesis single handedly, create bone de novo and not have any other mechanistic side effects would be naive."
Although off-label, Infuse has allowed spine surgeons to perform minimally invasive procedures with a high rate of fusion. "[Infuse] clearly has been one of the most effective bone forming proteins to enhance fusion and has had a big impact on the market because it has made minimally invasive surgery truly effective," says Neel Anand, MD, director of orthopedic spine surgery at Cedars-Sinai Spine Center in Los Angeles.
Several studies and anecdotal evidence has suggested an increased risk of complications when BMP is used in the cervical spine, and the FDA has issued a warning letter a few years ago against that application. When the letter was released, many surgeons stopped using BMP in the cervical spine. However, some surgeons such as Thomas Schuler, MD, president of the Virginia Spine Institute (VSI) and Brian Subach, MD, a spine surgeon and director of research at VSI and the Spinal Research Foundation, have been analyzing the dosage for BMP and experienced success if they use a smaller dosage in the cervical spine.
"We are achieving fusion without the risk associated with using the product in the cervical spine, such as swallowing and inflammation issues," says Dr. Schuler. "We have done an extensive number of cases without the negative side effects."
Controversial complications
In the July 2011 issue of The Spine Journal, editor-in-chief Eugene Carragee, MD (who stepped down as editor-in-chief for the issue) published results of a study he led at Stanford University in Palo Alto, Calif., showing that patients in his BMP sample group had a higher instance of retrograde ejaculation than initial studies for the product revealed. The study was accompanied by additional studies on BMP use as well as editorials and comments discussing Medtronic's initial public release of data, which may not have included all information about complication rates. However, complications from the initial studies were reported to the FDA, which still granted approval for the product in limited indications.
An additional factor in BMP studies has been compensation; some studies have been sponsored by Medtronic while others were sponsored by outside entities, and still others were conducted independently by spine surgeons. These studies from all sides of the spectrum have shown various results when comparing fusions using BMP to fusions using bone material harvested from the iliac crest. Many of these studies are not random, double-blind, controlled studies insisted upon by best evidence-based medicine practices, but healthcare providers and payors have taken notice of select results. Hospitals and payors often point to the studies showing no clinical benefits or multiple complications associated with the BMP.
"I don't think all the guidelines we follow are based on studies that include the most recent data we have," says Andrew Hecht, MD, co-director of spine surgery at Mount Sinai Medical Center in New York City. "I think everyone would agree that Infuse is a very important tool for surgeons to have in a clinical setting. We are figuring out what the right dosage is and what the carriers are in each part of the spine to prevent complications."
While it's necessary to highlight complications and publish articles about the appropriate use of spinal products, divulging all information about the studies and placing them within the context of all literature published on the topic is crucial. Otherwise, the intricacies of BMP use are lost on the lay media.
"At the Spinal Research Foundation, we believe that when this product is used properly for patients, it greatly improves their success," says Dr. Schuler. "We are very concerned about the recent articles creating a pandemonium in the press and insurance industry that is detrimental to patient access to good spine care. The centers that are publishing some of this data aren't correlating the doses; instead, they condemn BMP use across the board."
Dr. Anand has authored three papers on his experience with BMP, which weren't referenced in The Spine Journal's recent articles analyzing the product. He used Infuse for patients with spinal disorders, including deformities, and outlined the dosage for each patient in his report. The papers all reflected good results he achieved using the product.
"The articles showing good results aren't often referenced; they only focus on the bad complications," says Dr. Anand. "You have to talk about all the facts that exist. It would be a sad day if this product was taken off of the shelf because of a focus on the negative articles. We would be put back to prehistoric times because BMP has made minimally invasive surgery a reality."
In August, Medtronic announced it would grant $2.5 million to Yale University researchers to independently review the safety and efficacy of Infuse. The company will release the original data from its trials in an effort to prove the product's integrity, although the studies include very little controlled data. The researchers could also request the original data from independent studies for the overall analysis.
Costs gone wild
Even as scientists and researchers are making advances in the most effective way to use BMP, many hospitals and payors are discouraging the use of Infuse because of its price. Infuse is the only FDA approved BMP product available, and the price for Infuse is very high compared to what it costs for surgeons to harvest bone from the iliac crest.
Hospitals are increasingly asking spine surgeons to justify their Infuse use more than they have in the past. Some hospitals have even created committees to monitor the cost of spine care, says Robert S. Bray, MD, founder of DISC Sports & Spine Center in Marina del Rey, Calif. "There has been a massive cost increase for hospitals because BMP alone can cost $3,000-$7,000 per case, and more when surgeons use it with scoliosis cases," he says. "This is a direct increase in the cost of healthcare and you can't increase the cost of healthcare that much without someone to off-set it, especially without the literature showing it does something dramatically better than the current standard of care."
Results of studies on the efficacy of BMP — and even spinal fusions — vary, which leaves a lot of room for providers, payors and surgeons to cite studies supporting their particular views. Now, with the trend toward lowering hospital costs, the days of widespread Infuse use could be limited.
"If orthopedic surgeons, spine surgeons and neurosurgeons don't support the applicable use of BMP and its benefits for our patients, we may actually lose the privilege of using it," says Dr. Bae.
Spine surgeons around the country may also be weary of using Infuse for medicolegal reasons, especially in off-label situations. Patients could sue their surgeons if a complication arises and all studies are fair game when building a legal case.
"The critical papers are creating an environment which prevents patients' access to these biologic tools even when it is the best treatment possible," says Dr. Schuler. "It's already happening because people are afraid of medical liability down the road because of the negative papers."
Solution: find the correct dosage
While the research and approval for BMP use is limited, many surgeons agree on one of the most important aspects of BMP use: having the correct dosage is critical. Complications are more likely to arise when patients receive too much BMP, and there are several factors that play into how much is the appropriate dosage for each individual. Surgeons are using smaller doses in the cervical spine than in the lumbar spine, and in multi-level procedures the appropriate dosage varies depending on the level of fusion.
"If you can decrease the dose but still obtain the desired goal of fusion in the cervical spine, you can get the good effects of BMP without the complications," Dr. Schuler says. "Just because there are dose complications in some situations doesn't mean that those complications apply across the board to all patients and doses."
Top surgeons and investigators around the country are already working on studying the correct dosage and patient selection, and the recent focus on BMP has served to increase interest in looking at these factors.
Greg Yoshida, MD, medical director of spinal deformity/scoliosis at Tri-City Regional Medical Center in Hawaiian Gardens, Calif., also reports having good results with cervical spine surgery, although he no longer performs cervical spine fusions using Infuse to avoid controversy.
"I used to use [Infuse] sometimes in the neck instead of a resorbable cage or allograft and it worked wonderful there," he says. "I never had any patients with adverse reactions, but I know there have been adverse reactions to that application. When complications occur, surgeons were using a ton of BMP in the neck and laying it against the front of the spine, which is right next to the esophagus. Even though I've avoided these things and had a good result with BMP in the cervical spine, I wanted to avoid controversy so I don't use it there anymore. When something becomes controversial, I become stricter with it."
What we've learned
The back-and-forth conversation between spine surgeons who use Infuse in a variety of applications has served as a springboard into a new era of spine research and innovation. While discussion has created controversy among spine surgeons and confusion in the media, there are good things that have emerged from the storm.
"In the future, we will start using it in situations that are more appropriate and stick to on-label applications," says Dr. Bae. "What's really going to be fleshed out from all this is understanding of the different demands of various fusion environments. I think most of us can agree that BMP is an incredibly useful product and it will be used more for cases were the demand for fusion is the greatest."
The controversy also raised questions about the conflict of interest for spine surgeons when they receive compensation, in any form, from device companies. The relationship between device companies and surgeons is necessary for product development, research and education, but balancing the appropriate level of compensation with unbiased medical care and research can be tricky. One solution could be the formation of non-biased academic-based technology committees that can produce position statements and share them at professional society meetings.
Spine surgeons are quick to disclose conflicts of interest these days and even quicker to mention financial ties. The Spine Journal recently took steps to make disclosures a more apparent part of the article instead of a footnote, and other journals may soon follow suit.
"This controversy has brought out the need for a little higher scrutiny of studies coming out regarding new technology, especially focused on the editorial conflicts in journals," says Robert Eastlack, MD, a spine surgeon at Scripps Clinic in San Diego. "At the end of the day, I think it's going to be a useful tool. We'll have a better understanding of how to harness the dose so we can eliminate the side effects and utilize the product for more patients. The effective use of current BMP products will allow new product development so one company will not have a hold on the market."
Will surgeons still use BMP in the future?
While there could be a decrease in off-label use in some applications of BMP as a result of recently reported complications, spine surgeons and industry experts are predicting that the fusion-promoting device will remain a tool for spine surgeons. According to a study published in a Sept. 2010 issue of Spine, off-label use accounted for 85 percent of BMP procedures between the 2002 and 2007 and was predominantly used in primary posterior lumbar interbody fusion or transforaminal interbody fusion.
An additional report from Global Pipeline Analysis released in July 2011 showed that in 2010, Medtronic held 44 percent of the bone graft substitute market and more than 90 percent of the global BMP market, valued at $868 million. The company's success was largely driven by Infuse, although the report suggested that other medical device companies such as Synthes, Wright Medical, Orthovita and Stryker could increase their presence in the bone graft substitute market as it becomes more lucrative.
"The field will likely continue to progress as the industry learns more about these technologies, understands their strengths and weaknesses, and then applies them to benefit patients," says Aartie Shetty, a medical device industry analyst with Frost & Sullivan. "Off-label use of Infuse gave rise to controversy about its use and efficacy, which Medtronic is still battling. But, that said, all the positive aspects of BMPs that attracted surgeons in the first place still remain. As and when new products are introduced and companies are able to support their claims of efficacy of the device in spine surgery with hard clinical data, surgeon confidence will take shape for these products."
Surgeons who have used and trusted Infuse for several years without noticing many complications in their practice will most likely continue to use the substance, if given the opportunity. The second battle being waged on clinical use of Infuse is the cost factor; if the price for the product does not come down, surgeons may be forced to forego its use by cost-conscious hospitals and insurance companies, especially if literature doesn't completely support the notion of superior outcomes when using Infuse.
In the near future, there will most likely be an influx in new studies about BMP to support or oppose the most recent complication data. These new studies will need to report how the product was used and the specific dosage to be considered viable. The authors of the studies will also need to contend with their biases and conflicts of interest.
"It's impossible not to have a conflict; even when surgeons tell their patients they need surgery that they are paid for, it's a conflict," says Dr. Bae. "However, when studies are multi-center and randomized, some of the conflict is eliminated. It's incredibly difficult to affect that type of study and gain from research in these trials. When surgeons demonstrate efficacy in a multi-center, randomized trial, the results are close to accurate."
Related Articles on Spine Surgery:
How Are Spine Surgeons Using BMP Today? 10 Surgeon Responses
Dr. Robert Watkins: 4 Points on Biologic Solutions for Spine Surgery
What Happened With Infuse: 6 Points From Dr. Eugene Carragee