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 Administration’s 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, 2012On March 9, 2007, the US Food and Drug Administra- tions for defects associated with extraction sockets.1tion (FDA) approved recombinant human bone mor- Infuse Bone Graft is contraindicated in patients with aphogenetic protein 2 (rhBMP-2) (Infuse Bone Graft; known hypersensitivity to rhBMP-2, bovine type IMedtronic Sofamor Danek, Minneapolis, MN) as an collagen, or other components of the formulation; inalternative to autogenous bone graft for sinus aug- patients with any active malignancy or patients un-mentations and for localized alveolar ridge augmenta- dergoing treatment for a malignancy; in skeletally immature patients; in pregnant women; or in patients with an active infection at the operative site.2 It *Medical Ofﬁcer, US Food and Drug Administration, Rockvi- should not be used in the vicinity of a resected orlle, MD. extant tumor.2 The manufacturer’s package insert There was no external funding source. The author does not haveany commercial association with the pharmaceutical industry. The also includes warnings about potential adverse effectsviews expressed in this article are the author’s own and do not during pregnancy and lactation; warnings about bonereﬂect the ofﬁcial policy or position of the US Food and Drug resorption, ﬂuid formation, and edema; precautionsAdministration. regarding the potential for ectopic, heterotopic, or Address correspondence and reprint requests to Dr Woo: US exuberant bone formation; and a statement that theFood and Drug Administration, HFM-222, 1401 Rockville Pike, product has not been studied in extraction sites asso-Rockville, MD 20852; e-mail: email@example.com ciated with molars or in the mandible.2This is a US government work. There are no restrictions on its use. Postmarketing surveillance may reveal importantPublished by Elsevier Inc on behalf of the American Association of Oral and information about adverse events that were not ob-Maxillofacial Surgeons served in clinical trials. The objective of this analysis0278-2391/12/7004-0$36.00/0 was to characterize adverse events reported to thedoi:10.1016/j.joms.2011.09.008 FDA after oral and maxillofacial procedures in which 765
766 ADVERSE EVENTS WITH RECOMBINANT HUMAN BMP-2 Table 1. OPERATIONS IN WHICH rhBMP-2 Results WAS USED Through April 30, 2011, MAUDE has received 929 Operation n (%) reports of adverse events involving rhBMP-2, of which 83 (8.9%) described oral and maxillofacial operations.Approved indications 28 (33.7) Of these, 28 (33.7%) described procedures in which Sinus augmentation 20 (24.1) Alveolar ridge augmentation 8 (9.6) rhBMP-2 was used in accordance with the approvedOff-label uses 44 (53.0) indication (Table 1). Off-label uses included recon- Mandibular reconstruction 25 (30.1) struction of the mandible after fracture or cancer (25 Alveolar cleft repair 19 (22.9) reports) and alveolar cleft repair (19 reports). Table 2Other or unspeciﬁed oral and maxillofacial summarizes the adverse events reported after use of surgery 11 (13.3) rhBMP-2 in oral and maxillofacial surgery. Three clin-Woo. Adverse Events with Recombinant Human BMP-2. J Oral ical categories together accounted for 76% of re-Maxillofac Surg 2012. ported adverse events: local reactions, surgical site infections and other wound complications, and graft failure. Of all the reports, 25 (30.1%) stated that therhBMP-2 was used, as well as the types of operations patient required additional surgery to address the re-during which the product was applied. ported adverse event. Seven reports described the use of rhBMP-2 at the site of a resected tumor. There wereMaterials and Methods no reports of rhBMP-2 use in pregnant/lactating women or in persons with known hypersensitivity to The FDA’s Manufacturer and User Facility Device any of the device components. No deaths after oralExperience (MAUDE) database contains reports of and maxillofacial surgery involving rhBMP-2 wereadverse events involving medical devices.3 Reports do reported.not necessarily reﬂect a conclusion by the party sub-mitting the report or by the FDA that the devicecaused or contributed to the adverse event.3 The Discussionpublicly available version of the MAUDE database wassearched for reports for the brand name Infuse Bone Encompassing 4 years of postmarketing experi-Graft. Adverse events were reviewed and summa- ence, this article summarizes all adverse reports re-rized. The public dataset does not include demo- ported to MAUDE after oral and maxillofacial proce-graphic information (age, gender, and so on), medical dures involving rhBMP-2. Fifty-three percent ofhistory, clinical and radiologic records related to the reports explicitly described off-label uses; an addi-reported adverse event, or follow-up information re- tional 11 reports did not state whether the operationgarding complications and long-term outcomes. involved an approved use, so the percentage of off- For this analysis, the guidelines of the Helsinki label uses may have been even higher. Although theDeclaration do not apply, and institutional review manufacturer’s package insert states that Infuse Boneboard approval was not required. The analysis took Graft has not been studied in the mandible,2 manyplace after surgery and exposure to rhBMP-2. Further- reports described its use in operations to addressmore, the public dataset does not contain any patient mandibular reconstruction. Similarly, the prescribingidentiﬁers, so there is no risk to conﬁdentiality. information speciﬁes that the use of Infuse Bone Graft Table 2. ADVERSE EVENTS REPORTED AFTER USE OF rhBMP-2 Approved Off-Label Type of Use Could Total Principal Adverse Event Use [n (%)] Use [n (%)] Not Be Determined [n (%)] [n (%)]Local edema/erythema/pain 15 (53.6) 13 (46.4) 0 28 (100)Surgical site infections/wound complications 8 (44.4) 6 (33.3) 4 (22.2) 18 (100)Graft failure 3 (17.6) 12 (70.6) 2 (11.8) 17 (100)Pseudarthrosis 0 5 (100%) 0 5 (100)Other* 2 (13.3) 8 (53.3) 5 (33.3) 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.
WOO 767is contraindicated at the site of a resected or extant denominator, but it would not be appropriate to com-tumor,2 yet MAUDE received numerous reports stat- bine MAUDE results and claims data to calculate inci-ing that rhBMP-2 had been used in such a manner. dence rates of adverse events. Conclusions about theThe package insert further states that rhBMP-2 is in- risk of adverse events after approved and off-labeldicated for skeletally mature patients,2 but some of uses cannot be drawn. Nevertheless, results from pas-the procedures in this analysis, such as alveolar cleft sive surveillance data are useful for detecting new andrepair, are generally performed in children and ado- unexpected safety concerns. Serious adverse events,lescents. Local reactions, infections and other wound some of which may require a second operation, cancomplications, and graft failure were among the most occur after the use of rhBMP-2 in oral and maxillofa-commonly reported adverse events. Because the pub- cial procedures. In this analysis, graft failure and pseu-lic version of the MAUDE database does not include darthrosis were more commonly reported after off-follow-up information, it was not possible to evaluate label uses of rhBMP-2 than approved uses.risk factors and alternative etiologies of the reportedcomplications. References The ﬁndings reported in this article do not neces- 1. PMA P050053, original application. Available from: URL: http:// www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPMA/pma.cfm.sarily reﬂect the true range or proportions of adverse Accessed September 1, 2011.events that can occur after oral and maxillofacial op- 2. Available from: URL: https://www.infusebonegraft.com/omf_erations involving rhBMP-2. The number of patients package_insert.pdf. Accessed September 1, 2011. 3. Available from: URL: http://www.fda.gov/medicaldevices/who have been exposed to rhBMP-2 is not known. deviceregulationandguidance/postmarketrequirements/reportingInsurance claims data could be used to estimate the adverseevents/ucm127891.htm. Accessed September 1, 2011.