The US Food and Drug Administration (FDA) has approved a new prospective, randomised clinical trial evaluating the use of recombinant human bone morphogenetic protein-2 (rhBMP-2, Infuse, Medtronic) during transforaminal lumbar interbody fusion (TLIF) procedures. The study is part of Medtronic’s long-term global clinical trial programme (BONE) evaluating the safety and efficacy of the product in both TLIF and posterolateral fusion (PLF) surgeries. However, previous industry-sponsored studies of Infuse were heavily criticised for, allegedly, under reporting adverse events and for being biased.
A Medtronic press release reports that rhBMP-2, the key ingredient of Infuse, is “a manufactured version of a protein already present in the body that promotes new bone growth”. It adds that the product is applied to an absorbable collagen sponge that is used as a carrier to deliver the rhBMP-2 to the implant site and “acts a scaffold for the formation of new bone and, it will resorb, or disappear over time”. FDA approved since 2002, Infuse can be used with certain interbody fusion devices for the management of single-level degenerative disc disease. It is designed to eliminate the need for an iliac crest bone graft (ICBG).
Speaking about the recent FDA approval for the TLIF trial, the principal investigator Joseph D Smucker (Indiana Spine Group, Carmel, USA) comments: “The potential to expand the indications for use of Infuse in posterior spine procedures may give a broader group of patients access to this novel biologic technology. When considering this patient, site, and procedures, Infuse can be a powerful option in a spine surgeon’s armamentarium. This study has the potential to add to the broader clinical and scientific evidence regarding the use of Infuse, and may allow surgeons to better understand its safe and effective use in TLIF procedures.”
After Infuse received FDA approval, concerns about adverse events (specifically, a possible increased risk of cancer) with the product started to emerge. In 2011, The Spine Journal (the official journal of the North American Spine Society; NASS) dedicated an entire issue to a heavily critical review of the product. In one article, Eugene Carragee (Department of Orthopedic Surgery, Stanford Medicine Outpatient Center, Stanford University School of Medicine, Stanford, USA) and colleagues claimed that the industry-sponsored studies had underestimated adverse events with Infuse. More importantly, they observed that the authors of the industry-sponsored studies had financial interests with Medtronic and these interests may have led to bias.
The criticisms prompted Medtronic to ask the Yale University Open Data (YODA) access project to conduct an independent review of the patient-level data of Infuse. Speaking at a NASS symposium on biologics—held the day before Medtronic issued a press release about the FDA approval for the TLIF trial—Peter G Whang (Department of Orthopaedics and Rehabilitation, Yale University School of Medicine, New Haven, USA) reported that the YODA review indicated that “there was no evidence of a clinically significant difference between rhBMP-2 and ICBG for inducing spinal fusion”. He added that these findings also showed that the rate of complications with Infuse was similar to ICBG for anterior lumbar interbody fusion (ALIF) and PLF but were increased with anterior cervical fusion. Whang, who did not participate in the YODA reviews, said his interpretation of the data was that while Infuse should not be routinely used for anterior cervical fusion ACF), using it as an alternative to ICBG for ALIF or PLF “may be reasonable”. Regarding the concerns about a possible link to cancer with Infuse, he commented that YODA showed that the “absolute risk is small and no longer apparent at four years”.
Current views on Infuse
At the NASS symposium, Gregory D Schroeder (Rothman Institute at Thomas Jefferson University Hospital, Philadelphia, USA) looked at data for Infuse post YODA—noting that more than 650 studies have been published in the six years since the review (with 80 this year alone). According to Schroeder, a plus and a minus of these studies were that they were predominantly independent. Therefore, he said, the “literature is less tainted by industry but there are lower quality studies”. “I think rhBMP-2 does get the bones to heal. It is probably not needed in routine cases but should be considered for deformity cases. Post YODA, the data show no real evidence for an increased risk of cancer,” he concluded.
Wellington Hsu (Department of Orthopaedic Surgery, Northwestern University Feinberg School of Medicine, Chicago, USA) also spoke at the symposium, reviewing the use of Infuse in clinical practice today. He said: “Our current level of information [for rhBMP-2] is as good as it gets. We are not going to have an increase in data that will dramatically help our understanding of what is going on [in terms of overall safety and efficacy rather than the applications of the product].” According Hsu, in future, both zealously and fear should be avoided when looking at new spinal technologies. According to the Medtronic press release, the TLIF trial could potentially enrol up to 50 sites with more than 1,000 patients. The trial is part of a long-term clinical trial programme (announced in 2017) that is designed to expand the clinical understanding of Infuse and to evaluate the safety and health-economic outcomes for use in PLF and TLIF. The PLF study received FDA approval two years ago. Jacob Paul, senior vice president and president of Medtronic’s Spine division, comments: “With 17 years of clinical use, Infuse bone graft has become the most extensively-researched biologic technologies available today. Medtronic continues to invest in scientific evidence on Infuse to continue adding to the growing body of clinical data, and we believe these trials will generate additional data to expand indications, increase access to surgeons and alleviate pain and restore health for patients around the world.”
N.B. The NASS symposium was held during the 2019 NASS annual meeting (25–28 September, Chicago, USA).
This article is part of a series of BIBA Briefings columns published in Spinal News International. For previous columns, see click here.