Becker's Spine Review

3 EXECUTIVE BRIEFING SPONSORED BY When it comes to bone graft materials, one size doesn't fit all: Best practices for evaluating bone graft materials for spinal fusion B ack and neck pain are leading causes of disability in the United States. According to the Center for Disease Control and Prevention (CDC), back pain in the United States is the leading cause of days off work, and the reason for more bed days than any other condition. In addition, back and neck pain are a costly problem; with a 2016 study estimating the annual cost of treatments for low back and neck pain cost at $134.4 billion. After adequate conservative management, spinal fusion is an accepted and reliable solution for back and neck pain. To aid with this procedure, surgeons oftentimes utilize autograft bone or bone graft substitutes to assist with bony fusion. Bone graft materials range from autograft, to other bone graft materials such as allograft, demineralized bone matrix, allogenic stem cell products, synthetics and recombinant proteins. Becker's Spine Review recently spoke with three experts about the background, efficacy, evidence, safety and cost associated with different bone graft products and how surgeons are navigating this complex landscape: • Scott Bruder, MD, PhD, founder and CEO of Bruder Consulting & Venture Group, professor of orthopedic surgery and biomedical engineering at Case Western Reserve University in Cleveland and Kuros Biosciences board member • Zorica Buser, PhD, MBA, director of research, Gerling Institute in New York City, and research assistant professor at NYU School of Medicine's Department of Orthopedic Surgery • Brandon Cook, MD, fellowship-trained orthopedic spine surgeon at Orthopedic Associates in Destin, Florida. Different bone graft materials follow different regulatory pathways to market There are four ways bone graft products receive approval for sale in the United States. Traditional allograft tissues and demineralized bone matrices (DBMs) that come from tissue banks are sold for homologous use. The FDA doesn't require an efficacy review process for these products. They simply must adhere to certain safety features associated with tissue processing to be available for commercial sale. Cellular-based allografts (CBAs) fall into the same category of regulatory approval. "The bone marrow-derived cells and the bone matrix are sold as an allograft tissue that contains living cells and allograft bone that is comprised of bone shavings or particles," Dr. Bruder said. "These products don't require efficacy reviews or human clinical evidence. You only need to demonstrate that your processing adheres to industry standards and that you aren't contaminating patients." The second pathway to market for bone graft products is FDA 510(k) premarket clearance. This category of regulatory approval requires animal data. Safety and efficacy are based on comparisons to pre-existing products that have already been cleared through the 510(k) pathway. Manufacturers must show "substantial equivalence" to a predicate product or device. Bone graft substitutes are typically regulated through the 510(k) process, and there have been over 400 product clearances completed with this approach. The 510(k) clearance process usually takes around two years, from the inception of an idea through the laboratory work and eventual 510(k) review and clearance. Although the FDA doesn't require human clinical evidence as part of 510(k) submission and review, some companies go above and beyond what the FDA requires and conduct post-market clinical studies to demonstrate product efficacy. One example of this is the eight post-market clinical trials that Kuros Biosciences is conducting for MagnetOs bone graft, which can all be found on www.clinicaltrials.gov, coupled with the recent expansion of indications for these products supported with clinical data. The third and fourth pathways to market are parallel. They are used for bone graft substitutes that are more complex in their composition, or those that seek outcome claims for the treatment of a specific condition, such as interbody spinal fusion. Examples are products that include a growth factor, genetically modified cells, or culture expanded cells. Biologic bone graft products are regulated through the Center for Devices and Radiological Health (CDRH) or the Center for Biologics Evaluation and Research (CBER), or in some cases, the Center for Drug Evaluation and Research (CDER). "Complex products that go through CDRH or CBER receive what is called a pre-market approval or a biological license application," Dr. Bruder said. "From development through human clinical trials and approval, the process could take 10 years and easily cost over $100 million." Because of these different regulatory pathways, there is a gap in the evidence when comparing bone graft substitutes When it comes to data, the challenge for CBA manufacturers is demonstrating efficacy through robust studies that can support premium pricing. "It's not a manufacturing or a regulatory challenge," Dr. Bruder said. "It's an evidence challenge."

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