Off-label innovation: characterization through a case study of rhBMP-2 for spinal fusion

Abstract

<jats:sec> <jats:title>OBJECTIVE</jats:title> <jats:p>Off-label therapies are widely used in clinical practice by spinal surgeons. Some patients and practitioners have advocated for increased regulation of their use, and payers have increasingly questioned reimbursment for off-label therapies. In this study, the authors applied a model that quantifies publication data to analyze the developmental process from initial on-label use to off-label innovation, using as an example recombinant human bone morphogenetic protein 2 (rhBMP-2) because of its wide off-label use.</jats:p></jats:sec> <jats:sec> <jats:title>METHODS</jats:title> <jats:p>As a case study of off-label innovation, the developmental patterns of rhBMP-2 from FDA-approved use for anterior lumbar interbody fusion to several of its off-label uses, including posterolateral lumbar fusion, anterior cervical discectomy and fusion, and posterior lumbar interbody fusion/transforaminal lumbar interbody fusion, were evaluated using the “progressive scholarly acceptance” (PSA) model. In this model, PSA is used as an end point indicating acceptance of a therapy or procedure by the relevant scientific community and is reached when the total number of peer-reviewed studies devoted to refinement or improvement of a therapy surpasses the total number assessing initial efficacy. Report characteristics, including the number of patients studied and study design, were assessed in addition to the time to and pattern of community acceptance, and results compared with previous developmental study findings. Disclosures and reported conflicts of interest for all articles were reviewed, and these data were also used in the analysis.</jats:p></jats:sec> <jats:sec> <jats:title>RESULTS</jats:title> <jats:p>Publication data indicated that the acceptance of rhBMP-2 off-label therapies occurred more rapidly and with less evidence than previously studied on-label therapies. Additionally, the community appeared to respond more robustly (by rapidly changing publication patterns) to reports of adverse events than to new questions of efficacy.</jats:p></jats:sec> <jats:sec> <jats:title>CONCLUSIONS</jats:title> <jats:p>The development of off-label therapies, including the influence of investigative methods, regulation, and changing perspectives, can be characterized on the basis of publication patterns. The approach and findings in this report could inform future off-label development of therapies and procedures as well as attempts to regulate off-label use.</jats:p></jats:sec>

The Body’s Cellular and Molecular Response to Protein-Coated Medical Device Implants: A Review Focused on Fibronectin and BMP Proteins

“…Bone morphogenetic proteins (BMPs) are involved in the initial stages of endochondral ossification. Recombinant human BMP-2 (rhBMP-2) has been applied in numerous studies for bone-healing medical devices and biomaterials [ 19 , 20 , 21 , 22 ]. Macrophages can initiate osteoinductive signals to induce BMP-2 expression that indicates their capacity in regulating osteoinduction during the bone healing process [ 23 ].…”

Evaluation of the Fusion Rate and Safety of Escherichia coli-Derived rhBMP-2 in Transforaminal Lumbar Interbody Fusion for Patients with Degenerative Lumbar Disease: A Prospective, Multicenter, Single-Arm Trial

“…Recombinant human bone morphogenetic protein-2 (rhBMP-2) has been thoroughly researched and utilized because of its powerful ability to stimulate bone formation. BMPs are a collection of growth factors that are recognized for their capacity to stimulate the differentiation of mesenchymal stem cells into osteoblasts, which are responsible for bone formation [ 8 , 9 ]. Utilizing rhBMP-2 in spinal fusion has been documented to augment fusion rates, diminish the necessity for supplementary operations, and boost clinical results.…”

rhBMP2 alone does not induce macrophage polarization towards an increased inflammatory response

“…Concerns primarily center on spatial and temporal control of combinatory therapies that often include some combination of cell, growth factor, and scaffold delivery for the treatment of disease or augmentation of surgical intervention and tissue repair. Possibly one of the biggest controversies has centered around the use of recombinant human bone morphogenic proteins (rhBMP) more specifically rhBMP2 which has been patented and marketed as Infuse by Medtronic (Cooper and Kou, 2018;Hopper and Kapadia, 2018;Schnurman et al, 2016;Vorrasi and Kolokythas, 2017). Infuse is FDA approved for several indications including closed tibial fracture, spinal fusion, alveolar ridge augmentation, and maxillary sinus lift.…”