SUMMARY OF SAFETY AND EFFECTIVENESS DATA
SUMMARY OF SAFETY AND EFFECTIVENESS DATAI.GENERAL INFORMATIONDevice Generic Name :filler, recombinant human bonemorphogenetic protein, collagen scaffoldwith metal prosthesis, osteoinductionDevice Trade Name :InFUSE Bone Graft/LT-CAGE LumbarTapered Fusion DeviceApplicant’s Name and Address:Medtronic Sofamor Danek, Inc. USA1800 Pyramid PlaceMemphis, TN 38132Premarket Approval Application(PMA) Number:P000058Date of Panel Recommendation:January 10, 2002Date of Notice of Approval of Application: July 2, 2002II.INDICATIONS FOR USEThe InFUSE Bone Graft/LT-CAGE Lumbar Tapered Fusion Device is indicated forspinal fusion procedures in skeletally mature patients with degenerative disc disease(DDD) at one level from L4 -S1 . DDD is defined as discogenic back pain withdegeneration of the disc confirmed by patient history and radiographic studies. TheseDDD patients may also have up to Grade I spondylolisthesis at the involved level.Patients receiving the InFUSE Bone Graft/ LT-CAGE Lumbar Tapered FusionDevice should have had at least six months of nonoperative treatment prior to treatmentwith the InFUSE Bone Graft/LT-CAGE device. The InFUSE Bone Graft/ LT CAGE Lumbar Tapered Fusion Device is to be implanted via an anterior open or ananterior laparoscopic approach.III.CONTRAINDICATIONS The InFUSE Bone Graft/LT-CAGE Lumbar Tapered Fusion Device iscontraindicated for patients with a known hypersensitivity to recombinant humanBone Morphogenetic Protein-2, bovine Type I collagen or to other components of theformulation. The InFUSE Bone Graft/LT-CAGE Lumbar Tapered Fusion Device should notbe used in the vicinity of a resected or extant tumor.Page 1 of 40
InFUSE Bone Graft/LT-CAGE Lumbar Tapered Fusion Device should not beused in patients who are skeletally immature ( 18 years of age or no radiographicevidence of epiphyseal closure). The InFUSE Bone Graft/LT-CAGE Lumbar Tapered Fusion Device should notbe used in pregnant women. The potential effects of rhBMP-2 on the human fetushave not been evaluated. The InFUSE Bone Gra ft/LT-CAGE Lumbar Tapered Fusion Device should notbe implanted in patients with an active infection at the operative site or with anallergy to titanium or titanium alloy.IV.WARNINGS AND PRECAUTIONSWARNINGS: Women of childbearing potential should be advised that antibody formation torhBMP-2 or its influence on fetal development have not been assessed. In the clinicaltrial supporting the safety and effectiveness of the InFUSE Bone Graft/LT CAGE Lumbar Tapered Fusion Device, 2/277 (0.7%) patients treated withInFUSE Bone Graft component and 1/127 (0.8%) patients treated with autograftbone developed antibodies to rhBMP-2. The effect of maternal antibodies to rhBMP 2, as might be present for several months following device implantation, on theunborn fetus is unknown. Additionally, it is unknown whether fetal expression ofBMP-2 could re-expose mothers who were previously antibody positive, therebyeliciting a more powerful immune response to BMP-2 with adverse consequences forthe fetus. Studies in genetically altered mice indicate that BMP-2 is critical to fetaldevelopment and that lack of BMP-2 activity, as might be induced by antibodyformation, may cause neonatal death or birth defects. The safety and effectiveness of the InFUSE Bone Graft/LT-CAGE LumbarTapered Fusion Device in nursing mothers has not been established. It is not knownif BMP-2 is excreted in human milk. Women of childbearing potential should be advised to not become pregnant for oneyear following treatment with the InFUSE Bone Graft/LT-CAGE LumbarTapered Fusion Device. The safety and effectiveness of the InFUSE Bone Graft component with other spinalimplants, implanted at locations other than the lower lumbar spine, or used in surgicaltechniques other than anterior open or anterior laparoscopic approaches have not beenestablished. When degenerative disc disease was treated by a posterior lumberinterbody fusion procedure with cylindrical threaded cages, posterior bone formationwas observed in some instances.Page 2 of 40
The implantation of the InFUSE Bone Graft/LT-CAGE Lumbar Tapered FusionDevice using an anterior laparoscopic surgical approach is associated with a higherincidence of retrograde ejaculation when compared to implantation using the ananterior open surgical approach.PRECAUTIONS:General The safety and effectiveness of repeat applications of the InFUSE Bone Graftcomponent has not been established. The InFUSE Bone Graft/LT-CAGE Lumbar Tapered Fusion Device should onlybe used by surgeons who are experienced in spinal fusion procedures and haveundergone adequate training with this device, for anterior laparoscopic and/or anterioropen procedures. Two LT-CAGE Lumbar Tapered Fusion Device components should be implantedside by side at the surgical level whenever possible. The LT-CAGE Lumbar Tapered Fusion Device components and instruments mustbe sterilized prior to use according to the sterilization instructions provided in thepackage insert for that component, unless supplied sterile and clearly labeled as such. The InFUSE Bone Graft/LT-CAGE Lumbar Tapered Fusion Device is intendedfor single use only. Discard unused product and use a new device for subsequentapplications. Prior to use, inspect the packaging, vials and stoppers for visible damage. If damageis visible, do not use the product. Retain the packaging and vials and contact aMedtronic Sofamor Danek representative. Do not use after the printed expiration date on the label.Hepatic and Renal Impairment The safety and effectiveness of the InFUSE Bone Graft/LT-CAGE LumbarTapered Fusion Device in patients with hepatic or renal impairment has not beenestablished. Pharmacokinetic studies of rhBMP-2 indicate that the renal and hepaticsystems are involved with its clearance.Geriatrics Clinical studies of the InFUSE Bone Graft/LT-CAGE Lumbar Tapered FusionDevice did not include sufficient numbers of patients 65 years and older to determinewhether they respond differently from younger subjects.Bone formationPage 3 of 40
The safety and effectiveness of the InFUSE Bone Graft/LT-CAGE LumbarTapered Fusion Device has not been demonstrated in patients with metabolic bonediseases. While not specifically observed in the clinical study, the potential for ectopic,heterotopic or undesirable exuberant bone formation exists.Antibody Formation/Allergic Reactions The safety and effectiveness of the InFUSE Bone Graft/LT-CAGE LumbarTapered Fusion Device has not been demonstrated in patients with autoimmunedisease. The safety and effectiveness of the InFUSE Bone Graft/LT-CAGE LumbarTapered Fusion Device has not been demonstrated in patients withimmunosuppressive disease or suppressed immune systems resulting from radiationtherapy, chemotherapy, steroid therapy or other treatments.Immunogenicity As with all therapeutic proteins, there is a potential for immune responses to begenerated to the InFUSE Bone Graft component. The immune response to theInFUSE Bone Graft components was evaluated in 349 investigational patients and183 contro l patients receiving lumbar interbody fusions. Anti-rhBMP-2 antibodies: 2/349 (0.6%) patients receiving the InFUSE Bone Graft component developed antibodies vs. 1/183 (0.5%) in the controlgroup. Anti-bovine Type I collagen antibodies: 18.1% of patients receiving theInFUSE Bone Graft component developed antibodies to bovine Type Icollagen vs. 14.2% of control patients. No patients in either group developedanti-human Type I collagen antibodies. The presence of antibodies to rhBMP-2 was not associated with immunemediated adverse events such as allergic reactions. The neutralizing capacityof antibodies to rhBMP-2 is not known.The incidence of antibody detection is highly dependent on the sensitivity andspecificity of the assay. Additionally, the incidence of antibody detection may beinfluenced by several factors including sample handling, concomitant medicationsand underlying disease. For these reasons, comparison of the incidence of antibodiesto the InFUSE Bone Graft component with the incidence of antibodies to otherproducts may be misleading.Page 4 of 40
V.DEVICE DESCRIPTIONThe InFUSE Bone Graft/LT-CAGE Lumbar Tapered Fusion Device consists of twocomponents containing three parts– a tapered metallic spinal fusion cage, a recombinanthuman bone morphogenetic protein and a carrier/scaffold for the bone morphogeneticprotein and resulting bone. The InFUSE Bone Graft component is inserted into theLT-CAGE Lumbar Tapered Fusion Device component to form the completeInFUSE Bone Graft/LT-CAGE Lumbar Tapered Fusion Device. Thesecomponents must be used as a system. The InFUSE Bone Graft component mustnot be used without the LT-CAGE Lumbar Tapered Fusion Device component.LT-CAGE Lumbar Tapered Fusion Device componentThe LT-CAGE device consists of a hollow, perforated, machined cylinder withopposing flat sides. The cage has a tapered design with an angle of 8.80 and is availablein diameters ranging from 14mm to 18mm at the narrow end of the taper, 17mm to 22mm at the wide end of the taper and in lengths ranging from 20mm to 26mm. There aretwo holes on each of the two flat sides. On each of the two rounded aspects, there is asingle rounded slot. The implants have a helical screw thread on the outer surface. Oneend of the device is closed. The other end is open to be filled with the InFUSE BoneGraft component.The LT-CAGE implants are made from implant grade titanium alloy (Ti-6Al-4V)described by such standards as ASTM F136 or its ISO equivalent.The LT-CAGE Lumbar Tapered Fusion Device component is sold separately from theInFUSE Bone Graft component, however, these two components must be usedtogether. The package la beling for the LT-CAGE Lumbar Tapered Fusion Devicecontains complete product information for this component.InFUSE Bone Graft componentInFUSE Bone Graft consists of recombinant human Bone Morphogenetic Protein-2(rhBMP-2, known as dibotermin alfa) p laced on an absorbable collagen sponge (ACS).The InFUSE Bone Graft component induces new bone tissue at the site ofimplantation. Based on data from non-clinical studies, the bone formation processdevelops from the outside of the implant towards the center until the entire InFUSE Bone Graft component is replaced by trabecular bone.rhBMP-2 is the active agent in the InFUSE Bone Graft component. rhBMP-2 is adisulfide- linked dimeric protein molecule with two major subunit species of 114 and 131amino acids. Each subunit is glycosylated at one site with high- mannose-type glycans.rhBMP-2 is produced by a genetically engineered Chinese hamster ovary cell line.rhBMP-2 and excipients are lyophilized. Upon reconstitution, each milliliter of rhBMP-2solution contains: 1.5 mg of rhBMP-2; 5.0 mg sucrose, NF; 25 mg glycine, USP; 3.7 mgL-glutamic acid, FCC; 0.1 mg sodium chloride, USP; 0.1 mg polysorbate 80, NF; and 1.0mL of sterile water. The reconstituted rhBMP-2 solution has a pH of 4.5, and is clear,colorless and essentially free from plainly visible particulate matter.Page 5 of 40
The ACS is a soft, white, pliable, absorbent implantable matrix for rhBMP-2. ACS ismade from bovine Type I collagen obtained from deep flexor (Achilles) tendon. TheACS acts as a carrier for the rhBMP-2 and acts as a scaffold for new bone formation.Three sizes of the InFUSE Bone Graft component are available based on the internalvolume of the LT-CAGE Lumbar Tapered Fusion Device component that is selected.The table below lists the appropriate InFUSE Bone Graft kit for the corresponding LT CAGE Lumbar Tapered Fusion Device component size:InFUSE Bone Graft/LT -CAGE Lumbar Tapered Fusion Device CombinationsLT-CAGE Lumbar TaperedFusion DeviceAppropriate InFUSE Bone Graft KitPart #Size(lead diameter, mmx length, mm)Part #Kit name (size in cc)Reconstituted rhBMP-2/ACSgraft volume894142014x207510200Small (2.8)2.8ml894142314x237510200Small (2.8)2.8ml894162016x207510200Small (2.8)2.8ml894162316x237510400Medium (5.6)5.6ml894162616x267510400Medium (5.6)5.6ml894182318x237510400Medium (5.6)5.6ml894182618x267510600Large Pre-Cut (8.0)8.0ml894182618x267510800Large II ( 8.0)8.0mlEach kit contains all the components necessary to prepare the InFUSE Bone Graftcomponent: the rhBMP-2 which must be reconstituted, sterile water, absorbable collagensponges, syringes with needles, this package insert and instructions for preparation. Thenumber of each item may va ry depending on the size of the kit.The rhBMP-2 is provided as a lyophilized powder in vials delivering either 4.2 mg or 12mg of protein. After appropriate reconstitution, both configurations result in the sameformulation and concentration (1.5 mg/mL) of rhBMP-2. The solution is then applied tothe provided absorbable collagen sponge(s). The InFUSE Bone Graft component isprepared at the time of surgery and allowed a prescribed amount of time (no less than 15minutes) before placement inside of the LT-CAGE Lumbar Tapered Fusion Devicecomponents. The Instructions for Preparation contain complete details on preparation ofthe InFUSE Bone Graft/LT-CAGE Lumbar Tapered Fusion Device.No other warranties, express or implied, are made. Implied warranties of merchantabilityand fitness for a particular purpose or use are specifically excluded.VI.ALTERNATIVE PRACTICES AND PROCEDURESNon-surgical alternatives to performing interbody fusion with the InFUSE BoneGraft/LT-CAGE Lumbar Tapered Fusion Device include, but are not limited to,Page 6 of 40
watchful waiting with no intervention, physical therapy, medica tions, external bracing,chiropractic care, spinal injections, bed rest and exercising.Surgical alternatives include posterior lumbar interbody fusion (PLIF) procedures with orwithout instrumentation, anterior lumbar interbody fusion (ALIF) procedures with orwithout instrumentation, combined anterior and posterolateral (360 ) fusion procedures,fusions using anterior/anterolateral spinal systems (e.g., plate and screw systems) orfusions using posterior spinal systems (e.g., pedicle screw/rod and hook/rod systems). Ineach case the fusions would involve the use of autograft and/or allograft bone.VII. MARKETING HISTORYThe InFUSE Bone Graft components, manufactured by Genetics Institute, Inc., hasonly been used in IDE studies in the United States.The LT-CAGE Lumbar Tapered Fusion Device component, manufactured byMedtronic Sofamor Danek, has been distributed in the United States since September,1999 and it has not been withdrawn from marketing for any reason. Since 1995, thisdevice component ha s been distributed outside of the United States and it has not beenwithdrawn from marketing for any reason.The InFUSE Bone Graft/LT-CAGE Lumbar Tapered Fusion Device has not beenmarketed for the combined use described in the PMA in the United States or any foreigncountry.VIII. POTENTIAL ADVERSE EFFECTS OF THE DEVICE ON HEALTHThe InFUSE Bone Graft/LT-CAGE Lumbar Tapered Fusion Device was implantedin 288 investigational patients and compared to 139 control patients who received an LT CAGE Lumbar Tapered Fusion Device filled with iliac crest autograft. Theinvestigational patients were implanted with the device via either an open anteriorsurgical approach or a laparoscopic anterior surgical approach. The control patients wereimplanted only via the open anterior surgical approach.Adverse event rates presented are based on the number of patients having at least oneoccurrence for a particular adverse event divided by the total number of patients in thattreatment group.Page 7 of 40
ADVERSE EVENTS(InFUSE Bone Graft/LT -Cage Device data combined from all experience with the device)SurgeryPostoperative6 Weeks(1 day - 4 Weeks) ‡ 4 Wks - 9 Weeks)Inves. Control Inves.ComplicationControlInves.3 Months(‡ 9 Wks - 5Months)Control Inves.6 Months(‡ 5 Mos- 9Months)12 Months(‡ 9 Mos- 19Months)24 Months(‡ 19 Mos - 30Months)Control Inves. Control Inves. Control 00000000Back and/or Leg ascular20456213213201Death00000000010000Dural 45Graft Site Related00000800000000Implant 8441513002Malpositioned n -Union00000010132011Other66171172348414898Other ade Ejaculation00415010002000Spinal 04453116145279117Urogenital102052022612142Vascular Intra-Op155000000000000Vertebral Fracture00100000000000Any Adverse Event# of Patients Reporting &Total adverse eventsInvestigational# (% of 288)total eventsControl#(% of 139)total events10 (3.5)1065 (22.6)721 (0.3)115 (5.2)180 (0.0)00 (0.0)053 (18.4)670 (0.0)05 (1.7)535 (12.2)395 (1.7)536 (12.5)395 (1.7)550 (17.4)6421 (7.3)255 (1.7)511 (7.9)11224 (8.3)277 (2.4 )760 (20.8)7233 (11.5)3714 (4.9)151 (0.3)13 (2.2)330 (21.6)331 (0.7)112 (8.6)141 (0.7)11 (0.7)127 (19.4)328 (5.8)81 (0.7)116 (11.5)170 (0 .0)021 (15.1)224 (2.9)437 (26.6)4312 (8.6)134 (2.9)41 (1.4)2116 (11.5)172 (1.4)229 (20.9)3410 (7.2)115 (3.6)50 (0.0)0213 (74.0)112 (80.6)The reported rates of several adverse events were high, but similar, in both theinvestigational and control groups. These events included back and leg pain,neurological events, gastrointestinal events, spinal events, cardiovascular events andinfection.The rate of graft site related events was 8% in the control group and not applicable in theinvestigational groups.12Percent of 140 males.Percent of 70 males.Page 8 of 40
Some of the reported adverse events required surgical intervent ions subsequent to theinitial surgery. The number of subjects requiring a second surgical intervention was10.4% (30/288) in the investigational groups and 13.7% (19/139) in the control group.The majority of supplemental fixations were due to painful no nunion.Urogenital events occurred with greater frequency in the investigational groups (11.5%)compared to the control group (7%). Retrograde ejaculation rates were greater in theinvestigational groups (11 subjects) compared to the control group (1 sub ject) with themajority of events occurring in the early postoperative period.The incidence of adverse events that were considered device related, including implantdisplacement/loosening, implant malposition and subsidence were all greater in theinvest igational groups compared to the control group. The rates of these events werelow, however, and may be partially attributed to a learning curve associated with thelaparoscopic surgical approach. The rate of nonunion requiring secondary surgery in theinvestigational groups was comparable to that of the control group. One death wasreported - a control group subject with cardiovascular disease.Potential Adverse Events:The following is a list of potential adverse events which may occur with spinalfusion surgery with the InFUSE Bone Graft/LT-CAGE Lumbar TaperedFusion Device. Some of these adverse events may have been previously reportedin the adverse events table. Bone fracture. Bowel or bladder problems. Cessation of any potential growth of the operated portion of the spine. Lossof spinal mobility or function. Change in mental status. Damage to blood vessels and cardiovascular system compromise. Damage to internal organs and connective tissue. Death. Development of respiratory problems. Disassembly, bending, breakage, loosening, and/or migration of components. Dural tears. Ectopic and/or exuberant bone formation.Page 9 of 40
Fetal development complications. Foreign body (allergic) reaction. Gastrointestinal complications. Incisional complications. Infectio n. Insufflation complications. Neurological system compromise. Nonunion (or pseudarthrosis), delayed union, mal- union. Postoperative change in spinal curvature, loss of correction, height, and/orredu
July 2, 2002 . II. INDICATIONS FOR USE The InFUSE Bone Graft/LT-CAGE Lumbar Tapered Fusion Device is indicated for spinal fusion procedures in skeletally mature patients with degenerative disc disease (DDD) at one level from L 4-S 1. DDD is defined as discogenic back pain with
LINK ), and are intended to improve coronary luminal diameter. Long term outcome (beyond six months) for this permanent implant is unknown at present. Summary of Safety and Effectiveness -P970020/S40 Page 1 of 13. For more information on the data that supported the original indication, the summary of safety and .
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2013 Waters Corporation 5 Summary Reports Summary By All A single-summary report for all of the selected data items (every channel, injection, and vial). Summary By Vial A summary report for each vial in the selected data items (including multiple injections and channels). Summary By Injection A summary report for each injection ID.
Special 5 10(k) SONOACE R7 LDiagnostic Ultrasound System 510(K) SUMMARY OF SAFETY AND EFFECTIVENESS . Submitter's Information: 21 CFR 807.92(a)(1) SAMSUNG MEDISON CO., LTD. 1003, Onechi-dlong, Gangiiam-gu, Seoul 135-280, Korea Contact Person: Kyeong-Mi, Park Regulatory Affairs Manager Telephone: 82.2.2194.1381 Facsimile: 82.2.556.9209 Data .
PMA P050053: FDA Summary of Safety and Effectiveness Data page 3 I0. VII. MARKETING HISTORY The INFUSE Bone Graft has not been marketed in the United States or any foreign country for the indications described in Section II above. INFUSE Bone Graft is marketed in the United Stat
About this summary: This summary is based on the report The Effectiveness of Occupational Health and Safety Management Systems: A Systematic Review Authors: Lynda Robson1, Judy Clarke1, Kimberley Cullen1, Amber Bielecky1, Colette Severin1, Philip Bi
