Autologous bone graft remains the gold standard by which bone graft substitutes are compared in spine fusion surgery. The utilization of bone graft substitutes, either as (1) an extender for spinal fusion constructs or (2) an alternative to minimize morbidity while maximizing outcomes, is changing. Moreover, current procedures technology (CPT) code 20939 became effective in 2018 defining bone marrow aspirate for bone grafting, spine surgery only. Changes in the complex landscape of grafting materials have prompted ISASS to provide category guidance for bone graft substitutes by comparing and contrasting US regulatory pathways, mechanisms of action, and supportive clinical evidence for these bone grafting materials.
Over the past 3 decades, there has been an increased interest in bone grafting materials as these materials have become a vital part of most spinal procedures. Unlike other areas of orthopedics, spinal surgery often requires grafting procedures to induce de novo bone in an area stabilized by metal devices. When considering potential graft materials, assuming an adequate blood supply, it is important to note that a successful graft needs to have at least 2 of the following: cells, signal, and/or matrix. Cells refers to the process of osteogenesis that is defined as cellular formation of new bone. These are dedicated cells in the area of the graft, such as osteoblasts or stem cells, that enter the osteoblastic lineage and ultimately form new bone. The signal, or osteoinduction, is orchestrated by bioactive molecules, primarily low-molecular-weight members of the transforming-growth-factor–β family that actively recruit mesenchymal cells, and stimulate them to differentiate into bone-forming cells for osseous repair. The matrix is the scaffolding that permits cell infiltration and in-growth of new host bone that is referred to as osteoconduction. The combination of these properties can either come from materials introduced to the site or those recruited from the host.
When evaluating the complex landscape of grafting materials, it is difficult to compare the options as the regulatory pathways, mechanisms of action, and supportive clinical evidence of the materials vary widely. In the 1990s, demineralized bone matrix (DBM) and synthetic bone grafts became widely available. Whereas DBMs were initially classified as tissue product and not a medical device, synthetics were classified as medical devices subject to the 510(k) pathway. In 2006, the regulatory pathway significantly changed in the United States regarding DBMs, with the Food and Drug Administration (FDA) reclassifying versions of DBMs with a nontissue carrier to require 510(k) clearance, while leaving pure DBM versions exempt as human tissue products. Further, in 2001, the first Class III medical device grafting material was approved by the FDA, bone morphogenetic protein (BMP)-2. In the mid-2000s, annual sales of BMP-2 rose to approach $900 million per year, but, in response to new data and the medico-legal concerns, revenues declined to less than $450 million annually in 2017. Lastly, an area almost nonexistent a decade ago has now gained almost 10% of the market: cell-based matrices. These matrices are a broad category of materials marketed as human cell or tissue products (HCT/Ps) claimed to contain stem cells and related factors. (Note: HCT/P status requires that the market product’s mechanism of action not “be dependent on the metabolic activity of living cells.”)
US Regulatory Pathways for Bone Graft Products
The required regulatory pathways by which bone graft products get to market, and the required data to support those pathways are varied.
Human Cell or Tissue Products
The US Code of Federal Regulations Title 21, part 1271 (Human Cells, Tissues, and Cellular and Tissue-Based Products), contains all of the regulations related to materials covered by these regulations. Section 361 describes products that are minimally manipulated, are for homologous use only, do not have a systemic effect, and are not dependent on the metabolic activity of living cells for their primary function, in addition to other qualifications. Once a manufacturer determines a product meets all of these requirements and follows the appropriate regulations, the manufacturer can place the product on the market by simply notifying the FDA of the intent to do so. There is no premarket review by the FDA for safety or efficacy of such products and, therefore, there are no requirements for preclinical or clinical data.
Section 510(k)
Section 510(k) of the Federal Food, Drug, and Cosmetic Act describes a regulatory process for the clearance of products meeting certain requirements that have been demonstrated to the FDA’s satisfaction to be “substantially equivalent” in safety and effectiveness to another lawfully marketed device when used for the same purpose. In the case of bone graft materials, there are currently 2 options for 510(k) clearance for materials used in the extremities and pelvis or for the spine. For the extremities label, the FDA requires a drill-hole defect model in animals comparing the new device to the predicate. For the spine label, the FDA requires a rabbit posterolateral fusion model. With a 510(k) for the spine, the product is cleared for use as an autograft extender in posterolateral fusion. The manufacturer can choose to conduct postmarket clinical studies but is under no obligation to do so. There are currently 398 510(k) clearances for bone graft products.
Premarket Approval
The premarket approval (PMA) pathway is the most stringent and is required for Class III medical devices. In bone grafting, the drug-device combination products have been required to utilize this pathway to market. The PMA pathway is based on demonstration of safety and effectiveness through “adequate and well-controlled” clinical trials. The required trials are done under FDA supervision in the form of an investigational device exemption (IDE) in which the study design, outcome measures, etc., are approved by the FDA prior to initiation of the study. As these are level 1 clinical studies, the data from them can be relied upon in making clinical use decisions.
READ THE COMPLETE ARTICLE: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6314336/
SOURCE:https://www.ncbi.nlm.nih.gov/