DEPARTMENT OF HEALTH&. HUMAN SERVICES JUL -2 2002 Public Health Service Food and Drug Administration 9200 Corporate Boulevard Rockville MD 20850 Richard W. Treharne, Ph.D. Senior Vice President, Regulatory Affairs Medtronic Sofamor Danek 1800 Pyramid Place Memphis, Tennessee 38132 Re: P000058 InFUSE™ Bone Graft/LT-CAGET" Lumbar Tapered Fusion Device Filed: January 12, 2001 Amended: January 12, March 19, May 9, July 31, August 24, September 25, October 9, November 21, and December 6, 7 and 26,2001, January 22, February 8,March 19,April2,3, 12(2), 15, 16, 17,22,26and30,May9, 10, 14 and 28 and June 12 and 28, 2002 Procode: NEK Dear Dr. Treharne: The Center for Devices and Radiological Health (CDRH) of the Food and Drug Administration (FDA) has completed its review of your premarket approval application (PMA) for the InFUSE™ Bone Graft/LT-CAGE™ Lumbar Tapered Fusion Device. This device is indicated for spinal fusion procedures in skeletally mature patients with degenerative disc disease (DDD) at one level from L4-S 1. DDD is defined as disco genic back pain with degeneration of the disc confirmed by patient history, function deficit and/or neurological deficit and radiographic studies. These DDD patients may also have up to Grade I spondylolisthesis at the involved level. InFUSE™ Bone Graft/LT -CAGE™devices are to be implanted via an anterior open or an anterior laparoscopic approach. Patients receiving the InFUSE™ Bone Graft/ LT-CAGE™ Lumbar Tapered Fusion Device should have had at least six months of nonoperative treatment prior to treatment with the InFUSE™ Bone Graft/LT-CAGE™ device. We are pleased to inform you that the PMA is approved. You may begin commercial distribution of the device in accordance with the conditions described below and in the "Conditions of Approval" (enclosed). The sale, distribution, and use of this device are restricted to prescription use in accordance with 21 CFR 801.109 within the meaning of section 520(e) ofthe Federal Food, Drug, and Cosmetic Act (the act) under the authority of section 515( d)( 1)(B)(ii) of the act. FDA has also determined that, to ensure the safe and effective use of the device, the device is further restricted within the meaning of section 520( e) under the authority of section 515(d)( 1)(B)(ii), (I) insofar as the labeling specify the requirements that apply to the training of practitioners who may use the device as approved in this order and (2) insofar as the sale, distribution, and use must not violate sections 502(q) and (r) ofthe act. Page 2- Richard W. Treharne, Ph.D. In addition to the post-approval requirements outlined in the enclosure, you have agreed to provide the following data in a post-approval report: 1. In order to assess the long-term performance of the InFUSET" Bone Graft!L T -CAGET" Lumbar Tapered Fusion Device, please conduct a post-approval study to obtain a total of 6 years of postoperative data from a statistically-justified number of patients implanted with this device. The patients may be selected from either the IDE population, a population of post-approval implant patients or a combination of both. a. b. 2. As part of the description of the post-approval study, you should provide a justification which includes: (1) the number of patients selected from each population (IDE vs. post-approval population); (2) the method(s) used to select the patients and sites; and (3) a description of the sample size calculations, including adjustments for lost­ to-follow-up. The data from the post-approval study should be submitted to the FDA as part of your annual report and will include the following data collected biennially for each patient: (1) a description of any surgical interventions which include reoperations, removals, revisions, and supplemental fixations; (2) a radiographic assessment of fusion using the same criteria employed in the original IDE study; (3) an assessment of pain and function using the same criteria employed in the original IDE study. Because of the unknown long-term device performance, particularly the resulting bony fusion characteristics, the post-approval study should also contain retrieval analyses of any InFUSET" Bone Graft!LT -CAGET" Lumbar Tapered Fusion Device that is implanted and subsequently removed. This section of the post-approval study is not limited to the patient population described in item 1 above. Histological information (e.g., bony ingrowth quality, bone quantity, response to potential wear debris, etc.) and metallurgical information (e.g., metal wear, deformation, cracking, corrosion, etc.) should be collected and reported in the annual reports. This section of the post-approval study should continue for the duration of the study described in item 1 above. Page 3- Richard W. Treharne, Ph.D. 3. Perform post-approval studies which assess the effects ofrhBMP-2 on tumor promotion. These studies will include in vitro studies with primary tumor cell isolates. 4. Perform post-approval studies to investigate the potential for an immune response to rhBMP-2 to interfere in embryonic development in rabbits. Observations from this investigation may indicate a necessity to create a pregnancy monitoring database and/or modify your labeling. 5. Develop and validate a new antibody ELISA for antibodies to rhBMP-2 that has the potential to detect all antibody isotypes. 6. Develop and validate a neutralization assay for antibodies to rhBMP-2. Complete final reports addressing the requests identified in items 3-6 above should be submitted as the reports become available. If these reports have not been submitted by the time of submission of the first PMA annual report, you should include an approximate timeline for submission in the annual reports, as well as updates on the studies' progress. 7. Provide the results of three additional assays, i.e., silver stained SDS-PAGE, Edmans test and glycoform analysis, on the release specifications for the drug substance. These should be submitted as PMA reports. Expiration dating for this device has been established and approved at three years for the Small and Medium InFUSET"' Bone Graft components, two years for the Large and Large II InFUSE™ Bone Graft components and five years for the LT -CAGE™ Lumbar Tapered Fusion Device component. CDRH does not evaluate information related to contract liability warranties, however you should be aware that any such warranty statements must be truthful, accurate, and not misleading, and must be consistent with applicable Federal and State laws. CDRH will notify the public of its decision to approve your PMA by making available a summary of the safety and effectiveness data upon which the approval is based. The information can be found on the FDA CDRH Internet HomePage located at http://www.fda.gov/cdrh/pmapage.html. Written requests for this information can also be made to the Dockets Management Branch, (HF A-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852. The written request should include the PMA number or docket number. Within 30 days from the date that this information is placed on the Internet, any interested person may seek review of this decision by requesting an opportunity for administrative review, either through a hearing or review by an independent advisory committee, under section 515(g) of the Federal Food, Drug, and Cosmetic Act (the act). Page 4- Richard W. Treharne, Ph.D. Failure to comply with the conditions of approval invalidates this approval order. Commercial distribution of a device that is not in compliance with these conditions is a violation of the act. You are reminded that, as soon as possible and before commercial distribution of your device, you must submit an amendment to this PMA submission with copies of all approved labeling in final printed form. The labeling will not routinely be reviewed by FDA staff when PMA applicants include with their submission of the final printed labeling a cover letter stating that the final printed labeling is identical to the labeling approved in draft form. If the final printed labeling is not identical, any changes from the final draft labeling should be highlighted and explained in the amendment. All required documents should be submitted in triplicate, unless otherwise specified, to the address below and should reference the above PMA number to facilitate processing. PMA Document Mail Center (HFZ-40 1) Center for Devices and Radiological Health Food and Drug Administration 9200 Corporate Boulevard Rockville, Maryland 20850 If you have any questions concerning this approval order, please contact Mr. Aric D. Kaiser at (301) 594-2036. sm;re~~./ Daniel Schultz, M.D. Deputy Director for Clinical and Review Policy Office of Device Evaluation Center for Devices and Radiological Health Enclosure Last Modified: 1-31-02 CONDITIONS OF APPROVAL PREMARKET APPROVAL APPLICATION (PMA) SUPPLEMENT. Before making any change affecting the safety or effectiveness of the device, submit a PMA supplement for review and approval by FDA unless the change is ot' a type for which a "Special PMA Supplement-Changes Being Effected" is permitted under 21 CFR 814.39( d) or an alternate submission is permitted in accordance with 21 CFR 814.39(e) or (f). A PMA supplement or alternate submission shall comply with applicable requirements under 21 CFR 814.39 of the final rule for Premarket Approval of Medical Devices. All situations that require a PMA supplement cannot be briefly summarized; therefore, please consult the PMA regulation for further guidance. The guidance provided below is only for several key instances. A PMA supplement must be submitted when unanticipated adverse effects, increases in the incidence of anticipated adverse effects, or device failures necessitate a labeling, manufacturing, or device modification. A PMA supplement must be submitted if the device is to be modified and the modified device should be subjected to animal or laboratory or clinical testing designed to determine if the modified device remains safe and effective. A "Special PMA Supplement - Changes Being Effected" is limited to the labeling, quality control and manufacturing process changes specified under 21 CFR 814.39(d)(2). It allows for the addition of, but not the replacement of previously approved, quality control specifications and test methods. These changes may be implemented before FDA approval upon acknowledgment by FDA that the submission is being processed as a "Special PMA Supplement- Changes Being Effected." This procedure is not applicable to changes in device design, composition, specifications, circuitry, software or energy source. Alternate submissions permitted under 21 CFR 814.39(e) apply to changes that otherwise require approval of a PMA supplement before implementation of the change and include the use of a 30-day PMA supplement or annual postapproval report (see below). FDA must have previously indicated in an advisory opinion to the affected industry or in correspondence with the applicant that the alternate submission is permitted for the change. Before such can occur, FDA and the PMA applicant(s) involved must agree upon any needed testing protocol, test results, reporting format, information to be reported, and the alternate submission to be used. Alternate submissions permitted under 21 CFR 814.39(f) for manufacturing process changes include the use of a 30-day Notice. The manufacturer may distribute the device 30 days after the date on which the FDA receives the 30-day Notice, unless the FDA notifies the applicant within 30 days from receipt of the notice that the notice is not adequate. page 1 POSTAPPROVAL REPORTS. Continued approval ofthis PMA is contingent upon the submission ofpostapproval reports required under 21 CFR 814.84 at intervals of 1 year from the date of approval of the original PMA. Postapproval reports for supplements approved under the original PMA, if applicable, are to be included in the next and subsequent annual reports for the original PMA unless specified otherwise in the approval order for the PMA supplement. Two copies identified as "Annual Report" and bearing the applicable PMA reference number are to be submitted to the PMA Document Mail Center (HFZ-40 1), Center for Devices and Radiological Health, Food and Drug Administration, 9200 Corporate Blvd., Rockville, Maryland 20850. The postapproval report shall indicate the beginning and ending date of the period covered by the report and shall include the following information required by 21 CFR 814.84: 1. Identification of changes described in 21 CFR 8i4.39(a) and changes required to be reported to FDA under 21 CFR 814.39(b). 2. Bibliography and summary of the following information not previously submitted as part of the PMA and that is known to or reasonably should be known to the applicant: a. unpublished reports of data from any clinical investigations or nonclinical laboratory studies involving the device or related devices ("related" devices include devices which are the same or substantially similar to the applicant's device); and b. reports in the scientific literature concerning the device. If, after reviewing the bibliography and summary, FDA concludes that agency review of one or more of the above reports is required, the applicant shall submit two copies of each identified report when so notified by FDA. ADVERSE REACTION AND DEVICE DEFECT REPORTING. As provided by 21 CFR 814.82(a)(9), FDA has determined that in order to provide continued reasonable assurance of the safety and effectiveness of the device, the applicant shall submit 3 copies of a written report identified, as applicable, as an "Adverse Reaction Report" or "Device Defect Report" to the PMA Document Mail Center (HFZ-401), Center for Devices and Radiological Health, Food and Drug Administration, 9200 Corporate Blvd., Rockville, Maryland 20850 within 10 days after the applicant receives or has knowledge of information concerning: 1. A mix-up of the device or its labeling with another article. 2. Any adverse reaction, side effect, injury, toxicity, or sensitivity reaction that is attributable to the device and: a. has not been addressed by the device's labeling; or b. has been addressed by the device's labeling but is occurring with unexpected severity or frequency. page 2 3. Any significant chemical, physical or other change or deterioration in the device, or any failure of the device to meet the specifications established in the approved PMA that could not cause or contribute to death or serious injury but are not correctable by adjustments or other maintenance procedures described in the approved labeling. The report shall include a discussion of the applicant's assessment of the change, deterioration or failure and any proposed or implemented corrective action by the applicant. When such events are correctable by adjustments or other maintenance procedures described in the approved labeling, all such events known to the applicant shall be included in the Annual Report described under "Postapproval Reports" above unless specified otherwise in the conditions of approval to this PMA. This postapproval report shall appropriately categorize these events and include the number of reported and otherwise known instances of each category during the reporting period. Additional information regarding the events discussed above shall be submitted by the applicant when determined by FDA to be necessary to provide continued reasonable assurance of the safety and effectiveness of the device for its intended use. REPORTING UNDER THE MEDICAL DEVICE REPORTING (MDR) REGULATION. The Medical Device Reporting (MDR) Regulation became effective on December 13, 1984. This regulation was replaced by the reporting requirements of the Safe Medical Devices Act of 1990 which became effective July 31, 1996 and requires that all manufacturers and importers of medical devices, including in vitro diagnostic devices, report to the FDA whenever they receive or otherwise become aware of information, from any source, that reasonably suggests that a device marketed by the manufacturer or importer: 1. May have caused or contributed to a death or serious injury; or 2. Has malfunctioned and such device or similar device marketed by the manufacturer or importer would be likely to cause or contribute to a death or serious injury if the malfunction were to recur. The same events subject to reporting under the MDR Regulation may also be subject to the above "Adverse Reaction and Device Defect Reporting" requirements in the "Conditions of Approval" for this PMA. FDA has determined that such duplicative reporting is unnecessary. Whenever an event involving a device is subject to reporting under both the MDR Regulation and the "Conditions of Approval" for a PMA, the manufacturer shall submit the appropriate reports required by the MDR Regulation within the time frames as identified in 21 CFR 803.10(c) using FDA Form 3500A, i.e., 30 days after becoming aware of a reportable death, serious injury, or malfunction as described in 21 CFR 803.50 and 21 CFR 803.52 and 5 days after becoming aware that a reportable MDR event requires remedial action to prevent an unreasonable risk of substantial harm to the public health. The manufacturer is responsible for submitting a baseline report on FDA Form 3417 for a device when the device model is first reported under 21 CFR 803.50. This baseline report is to include the PMA reference number. Any written report and its envelope is to be specifically identified, e.g., "Manufacturer Report," "5-Day Report," "Baseline Report," etc. page 3 Any written report is to be submitted to: Food and Drug Administration Center for Devices and Radiological Health Medical Device Reporting PO Box 3002 Rockville, Maryland 20847-3002 Copies ofthe MDR Regulation (FOD # 336&1336)and FDA publications entitled "An Overview of the Medical Device Reporting Regulation" (FOD # 509) and "Medical Device Reporting for Manufacturers" (FOD #987) are available on the CDRH WWW Home Page. They are also available through CDRH's Fact-On-Demand (F-0-D) at 800-899-0381. Written requests for information can be made by sending a facsimile to CDRH's Division of Small Manufacturers International and Consumer Assistance (DSMICA) at 301-443-8818. page4