Back 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.”
Dr. Buser agreed. “The FDA considers every osteobiologic to be a medical device. Class III is the most stringent and the most regulated, but only a handful of osteobiologics used in spinal fusion are Class III. Less evidence is needed for Class II which is 510(k) approval. Animal models are required, but post-market clinical studies are optional. The least stringent category, where CBAs are classified, is HCT/Ps. These products don’t require any clinical evidence and the sterility requirements aren’t as stringent as the other two classes.”
In recent years, sales of CBA products have decreased. “Physicians and value committees at hospitals and ambulatory surgery centers require more data and evidence to justify the use of higher-cost bone graft products,” Dr. Bruder noted. “In terms of cost, you have first- and second-generation synthetics and then you have CBAs which are a big step up in expense, just below growth factor technologies. Many hospitals and doctors prefer to use a $3,000 synthetic treatment that’s been cleared through a 510(k) with excellent animal data, rather than choosing a $4,000 CBA treatment that doesn’t have good data to support the sale.”
Bone graft companies should have transparency in reporting safety data
Safety issues are another contributor to decreased demand for CBAs. “I recently had a patient with a cell-based allograft that was contaminated with tuberculosis and it spread to their spine,” Dr. Cook said. “With synthetics, the side effect profile is very small and there is pretty much zero infection risk. I now use synthetics for 99 percent of my cases. I tend to use MagnetOs since I’ve gotten better results than with other products and I find the handling properties easier to use.”
One “ideal” bone graft material doesn’t exist — surgeons must educate themselves on the options and consider the characteristics of each case
The pathology of a patient’s condition is highly variable, as are patient risk factors. “No two patients are the same,” Dr. Buser said. “Certain osteobiologics might be better or worse in a challenging environment. In addition, surgeons must look at the complexity of the surgery, a single-level procedure versus multi-level.”
The handling characteristics of different bone graft materials are also an important consideration. “The graft could be anything from a block of material to a wet piece of tissue paper, a moldable putty or granules that can be poured but don’t hold their shape,” Dr. Bruder said. “This is a serious challenge for surgeons. To make a meaningful decision, they must spend extra time educating themselves… not only on the different categories of grafts, but the specific products within each category.”
This means understanding the science that underpins the different graft categories and the specific products, as well as their associated economics. Surgeons must challenge the status quo, read the literature, challenge what sales reps say and ask for evidence and data.
“It is confusing and tough for surgeons when someone asks them what level of evidence is needed to make a decision about a bone graft material,” Dr. Buser said. “I think more clinical evidence on products is necessary, but not every single randomized controlled trial is generalizable. People should first read what FDA class the device is — that will help them understand whether the product has any clinical evidence, then they can dive deeper.”
Dr. Cook agreed that surgeons must do considerable research when selecting a bone graft material and not all of the information he would like is always available. “I always look at the research papers and clinical trials first,” he said. “Personally, I like randomized controlled trials, but they aren’t commonly done because they take time and are expensive. I also want to see the histology, including the actual histo slides and studies that have been performed.”
To help surgeons select the most appropriate bone graft material for each case, new tools have emerged like the AO Spine Knowledge Forum’s BOnE (Bone Osteobiologics and Evidence) Classification and the AAOS Biologics Dashboard. The BOnE Classification categorizes every existing osteobiologic on the market, based on the level of evidence. “Our goal is to bring everyone to the table, remove the bias and find a way to help patients,” Dr. Buser said.
The AAOS Biologics Dashboard from the American Association of Orthopedic Surgeons is also designed to help surgeons better understand the products currently on the market, by aggregating existing evidence and making it easily accessible in a neutral fashion with agreed-upon guidelines from the stakeholders.
The intersection of immunology, biology and bone is moving the needle in spinal fusion.
Osteoimmunology is an emerging field of science based on the relationship of the immune system and the skeletal system to stimulate bony healing. “The goal is to see how modifications of the inflammatory environment and ecosystem can drive and support bone formation, using only synthetic bone graft products like MagnetOs,” Dr. Bruder said. “We also now have the ability to create sub-micron surface technology and changes in architecture.”
These developments arm the scientific and clinical communities with a new set of tools to drive bone formation, as well as possibly other tissue types for use in tissue repair, regeneration, and healing. “I think we’re at a very exciting time in the evolution of biology,” Dr. Bruder said, “and I’m thrilled to be a part of it.”