J Oral Maxillofac Surg 70:765-767, 2012

Adverse Events Reported After the Use of Recombinant Human Bone Morphogenetic Protein 2
Emily Jane Woo, MD, MPH*
Purpose: The US Food and Drug Administration has approved recombinant human bone morpho-

genetic protein 2 (rhBMP-2) (Infuse Bone Graft; Medtronic Sofamor Danek, Minneapolis, MN) as an alternative to autogenous bone graft for sinus augmentations and for localized alveolar ridge augmentations for defects associated with extraction sockets. The objective of this analysis was to characterize adverse events reported after the use of rhBMP-2 in oral and maxillofacial procedures. Materials and Methods: The US Food and Drug Administrations Manufacturer and User Facility Device Experience database contains reports of adverse events involving medical devices. The publicly available version of the database was searched for reports for the brand name Infuse Bone Graft. Descriptive statistics were used to summarize the procedures and adverse events. Results: As of April 30, 2011, the Manufacturer and User Facility Device Experience database contained 83 reports of adverse events after oral and maxillofacial operations involving rhBMP-2. Of these reports, 55 (66.3%) described off-label uses, such as reconstruction of the mandible after fracture or cancer or alveolar cleft repair. The most commonly reported adverse events included local reactions, graft failure, infections, and other wound complications. Of the reports, 25 (30.1%) stated that the patient required additional surgery to address the reported adverse event. Conclusions: Serious adverse events, some of which may require a second operation, can occur after the use of rhBMP-2 in oral and maxillofacial procedures. In this analysis graft, failure and pseudarthrosis were more commonly reported after off-label uses of rhBMP-2 than approved uses. This is a US government work. There are no restrictions on its use. Published by Elsevier Inc on behalf of the American Association of Oral and Maxillofacial Surgeons. J Oral Maxillofac Surg 70:765-767, 2012 On March 9, 2007, the US Food and Drug Administration (FDA) approved recombinant human bone morphogenetic protein 2 (rhBMP-2) (Infuse Bone Graft; Medtronic Sofamor Danek, Minneapolis, MN) as an alternative to autogenous bone graft for sinus augmentations and for localized alveolar ridge augmentations for defects associated with extraction sockets.1 Infuse Bone Graft is contraindicated in patients with a known hypersensitivity to rhBMP-2, bovine type I collagen, or other components of the formulation; in patients with any active malignancy or patients undergoing treatment for a malignancy; in skeletally immature patients; in pregnant women; or in patients with an active infection at the operative site.2 It should not be used in the vicinity of a resected or extant tumor.2 The manufacturers package insert also includes warnings about potential adverse effects during pregnancy and lactation; warnings about bone resorption, uid formation, and edema; precautions regarding the potential for ectopic, heterotopic, or exuberant bone formation; and a statement that the product has not been studied in extraction sites associated with molars or in the mandible.2 Postmarketing surveillance may reveal important information about adverse events that were not observed in clinical trials. The objective of this analysis was to characterize adverse events reported to the FDA after oral and maxillofacial procedures in which 765

*Medical Ofcer, US Food and Drug Administration, Rockville, MD. There was no external funding source. The author does not have any commercial association with the pharmaceutical industry. The views expressed in this article are the authors own and do not reect the ofcial policy or position of the US Food and Drug Administration. Address correspondence and reprint requests to Dr Woo: US Food and Drug Administration, HFM-222, 1401 Rockville Pike, Rockville, MD 20852; e-mail: jane.woo@fda.hhs.gov
This is a US government work. There are no restrictions on its use. Published by Elsevier Inc on behalf of the American Association of Oral and Maxillofacial Surgeons 0278-2391/12/7004-0$36.00/0 doi:10.1016/j.joms.2011.09.008

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ADVERSE EVENTS WITH RECOMBINANT HUMAN BMP-2

Table 1. OPERATIONS IN WHICH rhBMP-2 WAS USED

Results
n (%) 28 (33.7) 20 (24.1) 8 (9.6) 44 (53.0) 25 (30.1) 19 (22.9) 11 (13.3)

Operation Approved indications Sinus augmentation Alveolar ridge augmentation Off-label uses Mandibular reconstruction Alveolar cleft repair Other or unspecied oral and maxillofacial surgery

Woo. Adverse Events with Recombinant Human BMP-2. J Oral Maxillofac Surg 2012.

rhBMP-2 was used, as well as the types of operations during which the product was applied.

Materials and Methods

The FDAs Manufacturer and User Facility Device Experience (MAUDE) database contains reports of adverse events involving medical devices.3 Reports do not necessarily reect a conclusion by the party submitting the report or by the FDA that the device caused or contributed to the adverse event.3 The publicly available version of the MAUDE database was searched for reports for the brand name Infuse Bone Graft. Adverse events were reviewed and summarized. The public dataset does not include demographic information (age, gender, and so on), medical history, clinical and radiologic records related to the reported adverse event, or follow-up information regarding complications and long-term outcomes. For this analysis, the guidelines of the Helsinki Declaration do not apply, and institutional review board approval was not required. The analysis took place after surgery and exposure to rhBMP-2. Furthermore, the public dataset does not contain any patient identiers, so there is no risk to condentiality.

Through April 30, 2011, MAUDE has received 929 reports of adverse events involving rhBMP-2, of which 83 (8.9%) described oral and maxillofacial operations. Of these, 28 (33.7%) described procedures in which rhBMP-2 was used in accordance with the approved indication (Table 1). Off-label uses included reconstruction of the mandible after fracture or cancer (25 reports) and alveolar cleft repair (19 reports). Table 2 summarizes the adverse events reported after use of rhBMP-2 in oral and maxillofacial surgery. Three clinical categories together accounted for 76% of reported adverse events: local reactions, surgical site infections and other wound complications, and graft failure. Of all the reports, 25 (30.1%) stated that the patient required additional surgery to address the reported adverse event. Seven reports described the use of rhBMP-2 at the site of a resected tumor. There were no reports of rhBMP-2 use in pregnant/lactating women or in persons with known hypersensitivity to any of the device components. No deaths after oral and maxillofacial surgery involving rhBMP-2 were reported.

Discussion
Encompassing 4 years of postmarketing experience, this article summarizes all adverse reports reported to MAUDE after oral and maxillofacial procedures involving rhBMP-2. Fifty-three percent of reports explicitly described off-label uses; an additional 11 reports did not state whether the operation involved an approved use, so the percentage of offlabel uses may have been even higher. Although the manufacturers package insert states that Infuse Bone Graft has not been studied in the mandible,2 many reports described its use in operations to address mandibular reconstruction. Similarly, the prescribing information species that the use of Infuse Bone Graft

Table 2. ADVERSE EVENTS REPORTED AFTER USE OF rhBMP-2

Principal Adverse Event Local edema/erythema/pain Surgical site infections/wound complications Graft failure Pseudarthrosis Other*

Approved Use [n (%)] 15 (53.6) 8 (44.4) 3 (17.6) 0 2 (13.3)

Off-Label Use [n (%)] 13 (46.4) 6 (33.3) 12 (70.6) 5 (100%) 8 (53.3)

Type of Use Could Not Be Determined [n (%)] 0 4 (22.2) 2 (11.8) 0 5 (33.3)

Total [n (%)] 28 (100) 18 (100) 17 (100) 5 (100) 15 (100)

*Other reported events included hardware complications (3 reports), constitutional symptoms (2), no adverse event reported (2), gastrointestinal distress (1), giant cell granuloma (1), hypertrophic scar (1), lipoma (1), medication error (1), paresthesia (1), respiratory distress (1), and unintentional injury (1).
Woo. Adverse Events with Recombinant Human BMP-2. J Oral Maxillofac Surg 2012.

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767 denominator, but it would not be appropriate to combine MAUDE results and claims data to calculate incidence rates of adverse events. Conclusions about the risk of adverse events after approved and off-label uses cannot be drawn. Nevertheless, results from passive surveillance data are useful for detecting new and unexpected safety concerns. Serious adverse events, some of which may require a second operation, can occur after the use of rhBMP-2 in oral and maxillofacial procedures. In this analysis, graft failure and pseudarthrosis were more commonly reported after offlabel uses of rhBMP-2 than approved uses.

is contraindicated at the site of a resected or extant tumor,2 yet MAUDE received numerous reports stating that rhBMP-2 had been used in such a manner. The package insert further states that rhBMP-2 is indicated for skeletally mature patients,2 but some of the procedures in this analysis, such as alveolar cleft repair, are generally performed in children and adolescents. Local reactions, infections and other wound complications, and graft failure were among the most commonly reported adverse events. Because the public version of the MAUDE database does not include follow-up information, it was not possible to evaluate risk factors and alternative etiologies of the reported complications. The ndings reported in this article do not necessarily reect the true range or proportions of adverse events that can occur after oral and maxillofacial operations involving rhBMP-2. The number of patients who have been exposed to rhBMP-2 is not known. Insurance claims data could be used to estimate the

References
1. PMA P050053, original application. Available from: URL: http:// www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPMA/pma.cfm. Accessed September 1, 2011. 2. Available from: URL: https://www.infusebonegraft.com/omf_ package_insert.pdf. Accessed September 1, 2011. 3. Available from: URL: http://www.fda.gov/medicaldevices/ deviceregulationandguidance/postmarketrequirements/reporting adverseevents/ucm127891.htm. Accessed September 1, 2011.