An FDA Regulatory Perspective on Bone Grafts

After trauma, lost or damaged bone tissue can naturally remodel and repair fractures and small noncritical size bone defects. But, large bone defects (critical size) created by severe trauma or tissue resection due to cancer or infection cannot heal on their own without help from therapeutic aids or materials designed to encourage bone regeneration. A bone graft acts as a filler or scaffold for new bone growth, and bone grafting is a surgical procedure that uses bone graft to repair and rebuild diseased or damaged bones. Approximately 500,000, and more than 2 million bone graft procedures are performed annually in the U.S. and worldwide respectively.^1,2 Market research³ estimates the global bone graft and substitutes sector to have been worth $2.68 billion in 2019 and will grow 5.1 percent annually through 2027.

There are various bone grafts with different composition, source, mechanical strength, and functional biological mechanisms. Each type of bone graft has its own unique advantages and disadvantages regarding biological properties and bone healing, which make them suitable for numerous orthopedic, craniomaxillofacial, and dental indications. Some of a bone graft’s biological properties are summarized below.²

• Osteoconduction: The ability to promote migration, attachment, and growth of osteoblastic cells onto the bone graft.
• Osteoinduction: The ability to recruit and stimulate differentiation of immature (osteoprogenitor) cells toward an osteoblast lineage.
• Bioactive: The ability to induce the formation of a direct chemical bond with surrounding tissue by eliciting a biological response at the interface.
• Osteointegration: A direct structural and functional connection between ordered living bone and a load-carrying implant surface.

Types of Bone Grafts^2,4,5
Autografts: Considered the “gold standard” in bone substitution, autogenous bones are those that are harvested from bones of the same individual (the iliac crest, fibula, ribs, mandible, chin, or skull).

Autogenous cancellous bone also can be obtained from the intramedullary canal. Autogenous bones are osteoconductive, osteoinductive, and contain growth factors and osteogenic cells with no associated immune or infective-related risks. However, they have limited availability and procurement morbidity, and they require a second surgery, which can result in donor site pain, infection, fracture, and other complications such as neurovascular injury and cosmetic deformity.

Allografts: These bone substitutes are derived from another living human or cadaver and must be processed within a bone tissue bank. Allografts are osteoconductive but since they undergo tissue processing (e.g., endotoxin [pyrogenic]/viral inactivation), freeze drying, and sterilization, they lack important growth factors and proteins found in a healthy bone, and therefore have little or no osteoinductive property. They are available in large quantities and are less invasive than autografts with less surgery time and minimum recovery and complications. Nevertheless, allografts have lower mechanical strength than natural bone, are more slowly incorporated, and can precipitate immunogenic reaction, as well as transfer disease. Demineralized bone matrix (DBM) can be obtained from allograft bones by removing the mineralized component using acid extraction. The resulting matrix is predominantly type I collagen in addition to several growth factors including bone morphogenetic proteins (BMPs) and can be used as osteoconductive and osteoinductive bone graft extenders.

Xenografts: These bone substitutes are taken from a non-human donor such as bovine or porcine. Xenografts must be anorganic (as a calcified matrix), meaning all remnants of the donor animal must be removed to minimize antigenic responses. Therefore, they undergo copious washing, endotoxin (pyrogenic)/viral inactivation, and heat treatment processes to remove, grease, lipids, proteins, and collagens. Xenografts are osteoconductive, easily available, economical, and have good mechanical properties. However, they are not osteoinductive, and have limited validation in clinical orthopedic practice.

Synthetic bone grafts: These grafts are produced from different biomaterials such as calcium phosphates including hydroxyapatite or tricalcium phosphate (TCP), bioactive glasses, composites of bioinorganics such as magnesium, silicon, and strontium ions into TCP, and composite of polymers such as collagen, PLA, PGA, PLGA, and PCL with ceramics. They are available in many forms (blocks, granules, cements, and injectable kits). They are associated with less pain, operating time, blood loss, and complications compared with autografts. Synthetic bone grafts are usually osteoconductive but have the lowest osteoinductivity of any other grafts. They are not as widely accepted as other types of bone grafts and still lack significant market penetration due to the lack of clinical evidence regarding their efficacy.

Cellular-based grafts: Cellular bone matrices (CBMs) are allogenic or synthetic bone grafts containing live mesenchymal stem cells (MSCs). In addition to their osteoconductive property, these grafts promote osteogenesis, as isolated MSCs are the osteogenic cells that can differentiate into the osteoblasts required for bone repair, remodeling, and maturation. CBMs are estimated to comprise more than 17 percent of all bone grafts. However, further in vivo and clinical investigation of their potential is required; based on literature, for example, their efficacy in spinal fusion surgery remains highly inconclusive.

Regulatory Considerations
FDA classifies a product as a drug, device, biological product, or combination product.⁶ A combination product is composed of any combination of a drug and device; a biological product and device; a drug and biological product; or a drug, device, and biological product.⁷

FDA has published two special controls guidance documents related to bone grafts,^8,9 which comply with the special controls proposed in 21 CRF §888.3045, and 21 CFR §872.3930.^10,11 According to these special controls, bone grafts intended to fill bony voids or gaps caused by trauma or surgery that are not intrinsic to the bony structure’s stability, or those aiming to fill, augment, or reconstruct periodontal or bony defects of the oral and maxillofacial region are considered “Class II devices.” They therefore are subject to premarket notification procedures and special controls, and when combined with general controls, are sufficient to provide reasonable assurance of the bone graft’s safety and effectiveness.

Bone grafts containing drugs are considered a therapeutic biologic and are regulated as Class III devices, requiring a PMA. According to the FDA, human demineralized bone matrix (DBM), when combined with other components (sodium hyaluronate, glycerol, or calcium phosphate) for easier handling and thus becoming a putty or paste, are regulated under the device provisions.¹² Any other novel materials, new indications for use, or manufacturing process that is not addressed in any FDA recognized conformance standard or FDA guidance document may raise different types of safety and effectiveness questions. In that case companies should consider submitting a pre-submission (Q-submission) for feedback on the type of information needed.¹³

FDA guidance¹⁴ states that cultured cells combined with other materials (i.e., bone grafts) are considered combination products and may be regulated as devices or biological products. If the classification of a product as a drug, device, biological product, or combination product is unclear or in dispute, a Requests for Designation (RFD) may be requested to obtain a formal determination of a combination product’s primary mode of action as well as assignment of the lead agency center for the product’s premarket review and regulation within 60 days.6 If it is determined the cells contribute a primary mode of action for the combination product, the Center for Biologics Evaluation and Research (CBER), Office of Cellular, Tissue and Gene Therapies provides the administrative and review leads. In this case, the CDRH/OPEQ/OHT6 provides consult reviews for CBER.

Bone grafts reviewed under 510(k) should demonstrate sufficient performance data to support their indications for use and labeling including bench testing and animal (in vivo) study.8,9 Performance data should be conducted on the final, sterilized bone grafts, with a legally marketed predicate device to demonstrate substantial equivalence. Bench testing should cover the physical properties, chemical composition, and mechanical characteristics of bone grafts. FDA guidance indicates that bone grafts containing animal-derived materials such as collagen should provide sufficient information about the animal material and viral inactivation validation.^15,16 Also, any claim regarding superiority, or biological properties including osteoinduction, or bioactivity should be supported by performance data. In addition to bench testing and in-vitro testing, the agency usually requests a controlled in vivo study to demonstrate the substantial equivalence of bone grafts compared to similar safety and effectiveness predicates. There are special considerations for bone grafts containing nanomaterials.^17,18

All types of bone grafts should demonstrate biocompatibility in accordance with ISO 10993-1. According to attachment A of FDA’s guidance on ISO-10993-1,¹⁹ bone grafting materials are implant devices in contact with tissue/bone/dentin for a permanent contact duration. Therefore, the following biocompatibility endpoints should be addressed for bone grafts in compliance with Good Laboratory Practice:

• Cytotoxicity (per ISO 10993-5)
• Sensitization (per ISO 10993-10)
• Irritation or intracutaneous reactivity (per ISO 10993-10)
• Acute systemic toxicity (per ISO 10993-11)
• Pyrogenicity
• Lot-release Limulus Amoebocyte Lysate (LAL) Test;²⁰ and
• Rabbit Pyrogen Test (per ISO 10993-11)
• Subacute/Subchronic Toxicity (per ISO 10993-11)
• Genotoxicity (per ISO 10993-5)
• Implantation (with histology of the surrounding tissue per ISO 10993-6)
• Chronic toxicity (per ISO 10993-11)
• Carcinogenicity (per ISO 10993-5)

According to FDA guidance, sponsors may leverage information from existing marketing applications to support a rationale that bone graft biocompatibility has been established. If the sponsor can prove the raw materials, manufacturing process, sterilization, and packaging of the bone graft is identical to another cleared predicate in the U.S. market, no additional biocompatibility testing is necessary.

Moreover, the agency accepts the use of chemical characterization/risk assessment approach (per ISO 10993-18) in lieu of biological testing to evaluate the systemic as well as genotoxicity and carcinogenicity risks.

While the agency does not usually request for clinical studies for 510(k) bone grafts, clinical trials/evidence may be requested when the bone graft has different technology, indications for use, or formulation compared to predicates, or when performance testing raises concerns that warrant clinical evaluation. Amongst different types of bone grafts, those that contain drugs are regulated as Class III devices, requiring a PMA and a clinical trial. Moreover, resorbable bone void fillers containing human DBM are generally considered significant risk devices, and require a conduct of clinical study.²¹ 

References

1. www.ncbi.nlm.nih.gov/pmc/articles/PMC6417250/
2. pubmed.ncbi.nlm.nih.gov/24865980/
3. bit.ly/2NvitHh
4. pubmed.ncbi.nlm.nih.gov/30623986/
5. pubmed.ncbi.nlm.nih.gov/22500826/
6. bit.ly/2Mh1sjc
7. bit.ly/3685kue
8. www.fda.gov/media/71406/download
9. bit.ly/2Y8mQtI
10. FDA, Device Classification Panels, (2018)
11. FDA, Product Classification Database
12. bit.ly/2LVFanu
13. bit.ly/3peaE6S
14. bit.ly/3sROwRJ
15. bit.ly/2KKQzGg
16. bit.ly/3od0q58
17. bit.ly/2Mkw3wE
18. bit.ly/3cgyds7
19. bit.ly/3sRD3l6
20. bit.ly/3sQY9An
21. bit.ly/39QNJIc

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Prior to joining MCRA, Mehdi worked in the FDA’s Center for Devices and Radiological Health as a pre-market and post-market lead reviewer of orthopedic and dental devices. He is a biomedical engineer with five years of FDA experience in medical device regulation, and is a consultant for biocompatibility, animal study, and antimicrobial-associated devices. At MCRA, Mehdi provides guidance on regulatory strategies and submissions development across various therapies, including orthopedic, general hospital, cardiovascular, neurologic, and as well as antimicrobial devices, drugs, and combination products. Mehdi received his Ph.D. in biomedical engineering from the University of British Columbia, Vancouver. He also received his MS and BS in biomedical engineering from Iran.