INFUSE® Bone Graft/Interbody Fusion Devise (“INFUSE”) is used for spinal fusion procedures in skeletally mature patients with conditions such as degenerative disc disease (DDD). The FDA first approved the use of INFUSE in 2002, and it has since been approved for the following three indications: (1) fusion of the lumbar spine; (2) healing acute, open tibial shaft fractures; and (3) oral and maxillofacial uses. Medtronic generates about $900 million annually from the use of INFUSE, which is used in about 432,000 spinal fusions each year.
The INFUSE device consists of a small, hollow metal cylinder and a bone graft substitute, which is used to fill the cylinder with a solution containing recombinant human Bone Morphogenetic Protein-2 (rhBMP-2) and an absorbable collagen sponge. rhBMP-2 is a genetically engineered version of a natural protein normally found in small quantities in the body; it helps stimulate bone growth and healing. During surgery, portions of the degenerated disc and vertebral body are removed to allow the implants to be inserted between the vertebrae, stabilizing the spine while the fusion occurs. This procedure can be done laparoscopically, using a series of small holes through which the surgery is performed. It can also be done using an open anterior surgical approach, where the device is implanted through an opening in the abdomen. There are alternatives to this type of surgery, like the iliac crest autograft, which collects bone from the hip in a separate surgery to fill the fusion device placed in the spine.
The Spine Journal published an article written in 2011 by Dr. Eugene Carragee, which brought to the surface questions regarding the integrity of previous medical research on rhBMP-2. In fact, The Spine Journal devoted an entire issue to the topic. One of the articles stated that 13 studies conducted between 2000 and 2010 can be tied financially to Medtronic. “Complex financial relationships” such as the ones between Medtronic and the journal authors are a “threat to scientific integrity and public trust.” The publication claimed that original studies on rhBMP-2 underestimated the device’s risk of adverse events when used in spinal fusion; the actual rate of adverse events, including back and leg pain, cyst formation, disc space collapse, implant displacement and malignancy, infection, sterility and retrograde ejaculation, was 10-15 times higher than originally reported. Dr. Carragee told Medscape Medical News that studies linked to Medtronic “failed to report even one single adverse event of any type, and the FDA data [is] completely different. The FDA data show there was increased radiculitis, an increased number of leg pain events, increased infection rates and an increased chance of sterility.”
The Carragee review also brought to light unreported conflicts of interest in each study, study design bias against alternatives and invalid claims about the risks of the alternatives. Dr. Sohail Mirza, MD, of the Dartmouth Medical School wrote in a commentary on the review that Carragee’s “conclusion is well supported by rigorously referenced evidence.” Although disclosure documentation was limited, the authors of the 13 rhBMP-2 studies were associated financially with Medtronic, ranging from $12 - 16 million per study. The Wall Street Journal reported that Medtronic paid Dr. Thomas Zdeblick, an orthopedic surgeon, $19 million from 2003-2007. Since 2002, Zdeblick and Taz Consulting, together, have received more than $23 million in royalty payments from Medtronic. Medtronic also paid Dr. Kenneth Burkus, an orthopedist, more than $1.5 million between June 2001 and June 2006. In 2010, alone, Burkus was paid $782,000 in royalties by Medtronic. Both doctors deny these payments are related to, or had any influence on, their work on INFUSE.
In a June 2011 statement, Omar Ishrak, Medtronic’s CEO, addresses The Spine Journal articles and the disparities found in the researchers’ published studies as compared to the data Medtronic filed with the FDA. He stated:
“The articles do not raise questions about the data Medtronic submitted to the FDA in the approval process or the information available to physicians today through the instructions for use brochure attached to each product sold. Based on that data, we strongly believe that the safety profile reported to the FDA and summarized in the product label support the safe use of rhBMP-2 for the identified indications. We remain committed to ongoing study of the safety and efficacy of rhBMP-2, especially in application not covered by FDA labeling.”
Medtronic maintains they reported known adverse events to the FDA in both pre- and post-market settings and feels that the FDA had the “necessary safety information” when it approved rhBMP-2 for use. However, Medtronic did not address the issue of the financial conflicts of interest.
In July 2008, another concern was brought to the public’s attention when the FDA issued a health notification regarding the potentially life-threatening, off-label use of rhBMP-2, specifically for cervical spine fusions. The agency stressed that using rhBMP-2 in the cervical spine had not been demonstrated to be safe, nor had the FDA approved such a use. In 2008, the FDA received at least 38 reports of complications including, but not limited to, swelling of the neck and throat tissue, compression of the airway and severe dysphagia as a result of cervical fusions. Other off-label uses such as use in neck surgeries, resulted in unwanted bone growths near nerves or in areas outside the targeted fusion sites. “A Blue Cross Blue Shield Association researcher estimated that up to 73% of all procedures using BMP are for off-label uses. Other estimates place that figure closer to 85%.”
In November 2008, the U.S. Department of Justice began investigating Medtronic’s alleged promotions of off-label use of INFUSE, sending Medtronic’s chief executive, William A. Hawkins a subpoena. “Promoting the off-label use of a medical device is illegal, although doctors are allowed to use a device anyway they see fit.”
Dr. Scott Boden, who testified on behalf of Medtronic at the FDA advisory committee meeting back in 2002, refused to discuss off-label usage; at the time of his testimony, he was receiving payments of over $100,000 a year from Medtronic, continuing through at least 2006, at which time he received at least $75,000. Four other surgeons, including Dr. Regis W. Haid, Jr. and Dr. Gerald Rodts, wrote a report for the website, Spine Universe, which reported favorable results using INFUSE in the neck area and for fusing larger numbers of vertebrae. At least three of the four authors can be linked financially to Medtronic.
In June of 2011, Senator Charles Grassley also began an investigation into payments made to at least 15 doctors by Medtronic, concerned with “inordinately high consulting fees, free travel, and other perks” that could distort their decision-making abilities. The same issues arose in three whistleblower lawsuits in which former employees alleged Medtronic paid doctors to use INFUSE and other Medtronic products and/or paid doctors to promote off-label uses of the product through inflated consulting fees and fake royalty payments. Medtronic settled two of the cases for $40 million, but did not admit to any misconduct.
Plaintiffs nationwide filed suit against Medtronic, Inc. and Medtronic Sofamor Danek USA, Inc. in state and federal courts seeking damages for injuries after the defendants’ product, INFUSE, was used during their medical procedure and caused adverse side effects. Specifically, the plaintiffs in this litigation allege: 1) product defect; 2) failure to warn; 3) negligence for faulty product design and failure to fix faulty design; 4) fraudulent misrepresentation of the benefits of the device; 5) concealment of side effects; 6) medical negligence; 7) medical malpractice; and 8) breach of express and implied warranty.