Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 133 of 581 1233 PageID 1 UNITED STATES OF AMERICA + + + + + FOOD AND DRUG ADMINISTRATION + + + + + ORTHOPEDICS AND REHABILITATION DEVICES ADVISORY PANEL + + + + + PUBLIC MEETING + + + + + THURSDAY, JANUARY 10, 2002 The Advisory Panel met at 9:30 a.m. in the Walker/Whetstone Room of the Gaithersburg Holiday Inn, Two Montgomery Village Avenue, Gaithersburg, MD, Dr. Maureen Finnegan, Acting Chair, presiding. PRESENT: Maureen Finnegan, M.D. Barbara D. Boyan, Ph.D. Betty Diamond, M.D. John Doull, Ph.D., M.D. Edward N. Hanley, M.D. John Kirkpatrick, M.D. John Kostuik, M.D. Kinley Larntz, Ph.D. Leon Lenchik, M.D. Stephen Li, Ph.D. Sally Maher, Esq. Richard K. Miller, Ph.D. Sanjiv H. Naidu, M.D., Ph.D. A. Hari Reddi, Ph.D. Karen Rue Gene P. Siegal, M.D., Ph.D. Rocky Tuan, Ph.D. Hany Demain, M.S. Acting Chair Executive Secretary NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 134 of 581 1234 PageID 2 TABLE OF CONTENTS PAGE Call to Order, Opening Remarks, Deputization, ...... 3 and Conflicts of Interest Statements Open Public Session Patsy Trisler ............................... 12 Dr. John McCullough ......................... 19 PMA for InFUSETM Bone Graft Cage Petitioner's Presentation Gerard Riedel ............................... 49 Scott Boden ................................. 69 Hal Mathews ................................. 84 FDA Presentation Aric Kaiser ................................ Peter Hudson ............................... Barbara Buch ............................... Telba Irony ................................ 113 116 130 145 Guest Presenters Rocky Tuan ................................. 156 Richard Miller ............................. 165 John Kostuik ............................... 178 Panel Discussion Hari Reddi ................................. 185 John Kirkpatrick ........................... 189 Kinley Larntz .............................. 196 Public Session ................................... 308 Panel Discussion and Vote ........................ 311 NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 135 of 581 1235 PageID 3 1 P-R-O-C-E-E-D-I-N-G-S 2 (9:41 a.m.) 3 MR. DEMIAN: Good morning, everyone. I 4 would first like to welcome you to this meeting. We're 5 ready to begin this meeting of the Orthopedic and 6 Rehabilitation Device Advisory Committee. 7 Hany Demian, and I'm the Executive Secretary of this 8 Committee. My name is 9 I'd first like to remind everyone that you're 10 requested to sign in on the attendance sheets which are 11 available outside the doors. 12 agenda and information about today's meeting, including 13 how to find out about future meeting dates through the 14 advisory panel phone line and how to obtain meeting minutes 15 or transcripts 16 You may also pick up an I will now read two statements that are 17 required to be read into the record. The first one is 18 the appointment to temporary voting member status and the 19 conflict of interest statement. 20 "Appointment to Temporary Voting Status; 21 pursuant to the authority granted under the Medical Device 22 Advisory Committee Charter, dated October 27th, 1990 and NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 136 of 581 1236 PageID 4 1 as amended August 18th, 1999, I appoint the following 2 individuals as voting members of the Orthopedic and 3 Rehabilitation Device Panel for this meeting on January 4 10th, 2002; Kinley Larntz, Sanjiv Naidu, Leon Lenchik, 5 Gene Siegal, John Kirkpatrick, Barbara Boyan, John Doull, 6 Betty Diamond, and Hari Reddi. 7 individuals 8 consultants to this panel or other panels under the Medical 9 Device Advisory Committee. are special For the record, these government employees and 10 They have undergone the customary conflict 11 of interest review and have reviewed the material to be 12 considered at this meeting. 13 Maureen Finnegan to serve as acting Chairperson for the 14 duration of this meeting", and this is signed by David 15 Feigal, Director of CDRH. 16 "Conflict of In addition I appoint Dr. interest statement; The 17 following announcement addresses conflict of interest 18 issues associated with this meeting and is made part of 19 the record to preclude even the appearance of any 20 impropriety. 21 agency reviewed the submitted agenda for this meeting and 22 all financial interests reported by the committee's To determine if any conflict existed the NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 137 of 581 1237 PageID 5 1 participants. The Conflict of Interest Statute prohibits 2 special 3 matters that could effect their or their employer's 4 financial interests. government employees from participating in 5 However, the agency has determined that the 6 participation of certain members and consultants, the 7 needs for whose services outweigh the potential conflict 8 of interest involved is in the best interests of the 9 government. Therefore, waivers have been granted for 10 Doctors Stephen Li, Kinley Larntz, Edward Hanley and John 11 Kirkpatrick for their interest in firms that could 12 potentially be effected by the panel's recommendations. 13 The waivers permit them to participate in 14 all matters before today's panel. Copies of these waivers 15 may be obtained from the agency's Freedom of Information 16 Office, Room 12A-15 of the Parklawn Building. 17 like to note for the record that the agency also took into 18 consideration other matters regarding Doctors Li, Larntz, 19 Maureen Finnegan, Barbara Boyan and Gene Siegal. We would 20 Each of these panelists reported current or 21 past interests in firms at issue but are not related to 22 today's agenda. The agency has determined, therefore, NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 138 of 581 1238 PageID 6 1 that they may participate fully in all deliberations. 2 Dr. Hanley has a past involvement with matters that are 3 related to today's agenda. 4 however, that he may participate in the panel discussions. 5 We would like to also note that Doctors Rocky 6 Tuan and John Kostuik are guests at this meeting and have 7 reported interests in the firms at issue. 8 that the discussions involve any other product or firms 9 not already on today's agenda, for which an FDA participant 10 has a financial interest, the participant should excuse 11 him or herself from such involvement and the exclusion 12 will be noted for the record. The agency has determined, In the event 13 With respect to all other participants, we 14 ask in the fairness -- in the interest of fairness that 15 all persons making statements and presentations disclose 16 any current or previous financial involvement with any 17 firms whose products they may wish to comment upon". 18 Before turning this meeting over to Dr. 19 Finnegan, I would like to introduce our distinguished 20 panel members for generously giving their time and effort 21 to help FDA in matters being discussed at today's meeting 22 and other FDA staff seated at this table. So we'll go NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 139 of 581 1239 PageID 7 1 around the room and give your name and affiliation and 2 your current areas of research. 3 Dr. Finnegan? CHAIRPERSON FINNEGAN: Maureen Finnegan, 4 I'm an orthopedic surgeon at Southwestern Dallas and I 5 do -- my research is mainly fracture repair. 6 DR. KIRKPATRICK: I'm John Kirkpatrick. 7 I'm an orthopedic surgeon and spine surgeon from the 8 University of Alabama at Birmingham. 9 DR. SIEGAL: I'm Gene Siegal, also from the 10 University of Alabama at Birmingham and I'm an anatomic 11 pathologist. 12 DR. HANLEY: Edward Hanley, orthopedic spine 13 surgeon, Carolinas Medical Center, Charlotte, North 14 Carolina. 15 DR. DIAMOND: 16 College 17 rheumatologist. 18 19 of Medicine. Betty Diamond, Albert Einstein I'm an immunologist and I'm on sabbatical at NIH. DR. DOULL: I'm John Doull. I'm a clinical toxicologist from the University of Kansas Medical School. 20 DR. LI: I'm Stephen Li. I'm interested in 21 biomechanics and biomaterials. I'm current president of 22 Medica Device Testing Innovations located in Florida. NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 140 of 581 1240 PageID 8 1 DR. WITTEN: Celia Witten. I'm the Division 2 Director of the Division of General Restorative and 3 Neurological Devices which is the reviewing division for 4 this product for FDA. 5 6 MS. MAHER: I'm with Smith and Nephew Endoscopy and I'm the industry representative. 7 8 Sally Maher. MS. RUE: I'm Karen Rue. I'm an R.N. I'm consumer representative. 9 DR. LARNTZ: Kinley Larntz, Professor 10 Emeritus, Statistics, University of Minnesota and I'm a 11 statistician interested in clinical trials. 12 DR. LENCHIK: Leon Lenchik, Musculoskeletal 13 Radiologist from Wake Forest University in Winston-Salem, 14 North Carolina. 15 16 DR. REDDI: I'm Hari Reddi. I'm a student of bone morphogenetic proteins. 17 DR. BOYAN: Barbara Boyan. I'm a professor 18 at the University of Texas Health Science Center at San 19 Antonio and my specialty is bone and cartilage cell 20 biology. 21 22 DR. NAIDU: Sanjiv Naidu. I'm an orthopedic surgeon at Penn State College of Medicine in Hershey and NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 141 of 581 1241 PageID 9 1 my interest is in biomechanics and orthopedic surgery. 2 3 MR. DEMIAN: In addition, I'd like to 4 introduce our three guests who are seated over here, Dr. 5 Richard Miller, Rocky Tuan and John Kostuik. 6 CHAIRPERSON FINNEGAN: Thank you, Hany. As 7 I previously stated, I'm Maureen Finnegan and I will be 8 the chair for this meeting. 9 recommendations to the Food and Drug Administration 10 regarding a pre-market approval application for a spinal 11 fusion cage with a growth factor soak in a collagen sponge 12 use to treat lumbar degenerative disc disease. Today the panel will be making 13 I need to note for the record that the voting 14 members present constitute a quorum as required by 21 CFR 15 Part 14 and we will now proceed with the open public hearing 16 session of this meeting I would like to ask at this time 17 that all persons addressing the panel come forward and 18 speak clearly into the microphone. 19 is dependent on this as a means of providing an accurate 20 record of this meeting. The transcriptionist 21 We would request that all persons making 22 statements during the open public hearing of the meeting NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 142 of 581 1242 PageID 10 1 disclose whether they have financial interests in any 2 medical device company. 3 please state your name, affiliation and the nature of your 4 financial interest if you have any. 5 someone who wishes to address the panel. 6 Before making your presentation, MS. TRISLER: There's obviously Good morning, my name is Patsy 7 Trisler and I'm a regulatory consultant at PharmaNet, 8 Incorporated, a contract research organization. 9 employee of PharmaNet, I have several clients who are 10 orthopedic product manufacturers but I have no financial 11 interest in any of them. 12 13 CHAIRPERSON FINNEGAN: As an Ms Trisler, you had made a request to make an oral presentation. 14 MS. TRISLER: Yes. 15 CHAIRPERSON FINNEGAN: What we would like 16 to do is ask those people who had not made such a request, 17 we do have two -- a request for oral presentations which 18 we have put into the program and that's the next part of 19 the program, so we would ask those people who had not made 20 such 21 presentation. a 22 submission if MS. TRISLER: they would like to make All right, I apologize. NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com a Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 143 of 581 1243 PageID 11 1 CHAIRPERSON FINNEGAN: So if you'd give us 2 one second. Is there anyone else other than the two 3 parties who had made a formal request to make an oral 4 presentation? 5 (No response) 6 CHAIRPERSON FINNEGAN: All right, if not, 7 then we have had two requests. 8 one is from Striker Biotech and we will start with Ms. 9 Trisler. 10 One is from Osteotech and Go ahead. MS. TRISLER: Thank you and I apologize for 11 jumping the gun. 12 PharmaNet, Incorporated which is a CRO. 13 thank the Chairperson and the FDA Executive Secretary for 14 providing the opportunity to speak to you today. 15 As I indicated, I'm an employee of I would like to The purpose of my brief presentation is to 16 express some concerns in the form of potentially 17 unanswered questions relating to the combination products 18 of the type under review today by this committee. 19 know, there have been several spinal fusion cages or 20 systems approved by the FDA over the last five years. 21 These products approved for treating degenerative disc 22 disease are to be used with autogenous bone grafts. As you NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 144 of 581 1244 PageID 12 1 Papers are being published reporting the 2 successes observed with the use of the cages. It is clear 3 also that there remains some problems or issues such as 4 subsidence. 5 the cages but rather on the biologic component of the 6 device, the bone morphogenetic protein or BMP. The focus of my comments, though, is not on 7 As I'm sure you are aware even though BMPs 8 have been under evaluation clinically now for about 15 9 years, only one has been allowed into the marketplace by 10 the FDA. 11 a humanitarian device exemption for treating long bone, 12 non-unions when alternative treatments have failed. 13 product is human recombinant BMP-7 and bovine bone derived 14 collagen. 15 The approval is a limited one in the form of That This PMA before you today represents an 16 important advance in medical device technology. 17 other growth factors are potent compounds that offer 18 significant promise in many therapeutic areas. 19 the potential of BMPs or other growth factors combined 20 with 21 However, before the first combined product of this type 22 achieves market approval, it's very important to be traditional medical devices is BMPs and Further, significant. NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 145 of 581 1245 PageID 13 1 certain all the appropriate questions have been addressed, 2 have been both raised and addressed and as I indicated, 3 this is the reason I'm speaking. 4 I do not know the full extent of Medtronic 5 Sofamor Danek safety and effectiveness data. 6 I do know this is a reputable company and my comments are 7 by no means meant to challenge the capabilities, integrity 8 of the data or quality of the studies performed by them. 9 While we recognize that Center for Biologic staff 10 participates in reviews of products of this type along 11 with the Devices Center, the issues posed by the biologic 12 component are quite different from the issues typically 13 presented to this committee. 14 However, The standard of proof is different for drugs 15 and biologics than for devices. 16 provided by the FDA in those areas are different. 17 issues that prompt the following questions, in fact, are 18 not covered in the devices guidance document for spinal 19 systems. 20 consider these questions in your deliberations. 21 22 The As a member of the public, I ask that you My promotion. Thus, the guidances first point is related to cancer Cancer promotion by cytokine growth factors NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 146 of 581 1246 PageID 14 1 is well known, particularly when circulating blood levels 2 are greater than normal or baseline as in the case of 3 recombinant BMP. 4 the cancer promoting capability of BMPs. 5 status if this growth factor, BMP-2 as a cancer promoting 6 compound. My question is, is enough known about I question the 7 In my review this morning of the panel 8 briefing materials, my very quick review, I was surprised 9 that FDA has agreed that certain non-clinical safety 10 studies may be conducted post-approval. If transformed 11 cells or other adverse events are seen after this implant 12 has been released to the market, what is the surgeon to 13 tell the patient? 14 I noted in the BMP-7 product that is approved, 15 that patients with a cancer history are contra-indicated 16 for the current -- for that product approval. 17 be necessary to similarly contra-indicate this BMP that 18 is before you today or is the risk to benefit fully 19 profiled? 20 Will it My second point relates to the immunology 21 area. Circulating antibodies to both Type I collagen and 22 BMPs are reported. I know the FDA has dealt with this NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 147 of 581 1247 PageID 15 1 matter in the collagen area for many years. Are enough 2 data available to demonstrate there is no correlation 3 between these antibodies and health or medical events? 4 Is the safety risk greater if a BMP is inappropriately 5 and perhaps inadvertently applied directly to the spinal 6 canal? 7 evaluated? Has the autoimmune reaction potential been fully 8 My third point relates to cardiovascular. 9 Cardiac adverse events and increased blood pressure and 10 body temperature have been reported in animal studies. 11 The effects reported are dose dependent. Is there 12 sufficient assurance that benefits of the use of the BMP 13 collagen mixture in a sensitive body area are outweighed 14 by the potential risk to the cardiovascular system? 15 other BMP approved for orthopedic use and this one are 16 provided with collagen as a carrier. The 17 While I realize this may -- this question 18 may not be particularly important, since there are 19 potentially greater risks with the use of a growth factor 20 in the spine than there are at a long bone non-union site, 21 are data available to show that collagen alone is not 22 effective in improving the rate of spinal fusion? NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 148 of 581 1248 PageID 16 1 I believe this next point deserves particular 2 attention. 3 demonstrated the ability of a bone inductive extract from 4 adult bone to induce new bone formation at ectopic sites. 5 Have the studies published since that time sufficiently 6 looked at the quality of the bone produced and at the risk 7 of uncontrolled growth of bone in the immediate and 8 surrounding region of the implant? 9 case in which bone grew into the spinal canal although 10 As is well-known, the early work of Dr. Urist I have heard of one I'm unaware of the extent of the problem. 11 Has a full enough evaluation been performed 12 to be reasonably sure that if a large amount -- if a larger 13 amount than indicated is applied in the spinal fusion area, 14 the risk of in-growth won't occur. 15 issue relating to a problem that is not limited to 16 orthopedic devices, the expanded or off-label use in the 17 medical community of a product approved for a very limited 18 indication. There is one final 19 While I believe the medical community, not 20 the government, should control the practice of medicine, 21 in this case it seems the risk is significant for off-label 22 use of the BMP component of this device system. Because NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 149 of 581 1249 PageID 17 1 of this, I feel that it is important for the panel to, 2 perhaps, give more consideration than is usually done to 3 this issue. 4 adverse events were dose dependent. As I noted earlier, many of the reported 5 Since BMPs are potent compounds that have 6 systemic effects and this particular product is the first 7 of 8 pharmacodynamics may not be fully understood. 9 product type is out in the marketplace, if it is misused 10 or misapplied, the potential for patient harm is great. a kind for this use, I am concerned that the After this 11 12 In closing, I ask the panel to give special 13 attention to the potential for off-label use. 14 I have just scratched the surface of a number of areas 15 and have not provided you with substantive information 16 or data and that others, perhaps, will raise some more 17 concerns. 18 remain issues after today's review. 19 comments. 20 I realize I am hoping, though, that none of these topics This concludes my Thank you for this opportunity. CHAIRPERSON FINNEGAN: Thank you for having 21 the interest. I did interrupt you when you were going 22 through financial your interest. Would you mind NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 150 of 581 1250 PageID 18 1 reviewing those? 2 MS. TRISLER: Yes. No, I would not mind. 3 I am employed by PharmaNet, which is a contract research 4 organization. 5 I have several clients in the orthopedic product area. 6 I have no financial interest in any of them. 7 8 CHAIRPERSON MS. TRISLER: 10 14 So you're a Yes. CHAIRPERSON FINNEGAN: Okay. And I believe our next presenter is from Striker Biotech. 12 13 FINNEGAN: consulting firm. 9 11 As such, I have clients in many areas. DR. McCULLOUGH: My name is John McCullough and I'm an orthopedic spine surgeon from Denver, Colorado. I am not from Striker Biotech. I'm here to offer an 15 opinion regarding today's discussion on the BMP-2 interfix 16 threaded fusion cage PMA and I thank the panel for granting 17 me permission to speak. 18 Striker Biotech. 19 company and I'm not a paid consultant. 20 My travel has been paid for by I have no financial interest in the I've participated in the Striker Biotech 21 pilot study 22 intertransverse using BMP-7 interval in for the which human my lumbar institution NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 151 of 581 1251 PageID 19 1 received research funds to cover the cost of the study. 2 Contrary to questions by my colleagues prior to this 3 meeting, I am here in a positive relationship with BMP, 4 not a negative relationship. 5 Studies of BMP-2 and BMP-7 have shown great 6 promise as potential osteo inductive replacements for 7 iliac crest autograft for bone healing in appendicular 8 and spinal fusion applications. 9 in the lumbar inter-transfers interval, I am impressed 10 with its effectiveness, but I'm also impressed with the 11 meticulous technique required to increase the likelihood 12 of a solid fusion. In working with BMP-7 13 It is a much less forgiving milieu for fusion 14 than the interbody interval mainly because it is a soft 15 tissue bed on which the body never intended bone to form. 16 A solid anterior lumbar interbody fusion is a relatively 17 easy outcome to achieve but it's a technically demanding 18 surgical approach fraught with serious complications. 19 The lumbar intertransverse fusion is just the reverse. 20 It's an easy, safe, posterior surgical technique but 21 obtaining a solid fusion is much more difficult. 22 As an example, allograft bone will often NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 152 of 581 1252 PageID 20 1 successfully incorporate in an interbody fusion model but 2 it is useless in the adult intertransverse interval. 3 success of fusion with BMP-2 in a collagen sponge with 4 the interfixed threaded fusion cage, the subject of 5 today's discussion, is well established by the research 6 of Boden's Zdeblick, Sandu and Hine. The 7 The researchers, the brave patients who 8 submitted themselves to this largely successful pilot 9 study and the company supporting the research are to be 10 congratulated. It is not my purpose today to call into 11 question the efficacy of BMP-2 and its use in an interbody 12 fusion with the interfixed threaded fusion cage. 13 concern, as with the last speaker's last point, is the 14 potential off-label use of BMP-2 soaked in a collagen 15 sponge. My 16 There is a potential for surgeons to take 17 an off-label approach if the panel does not carefully 18 consider 19 available with this product and provide the option that 20 will prove to be the best direction and control of the 21 product and its potential off-label use. 22 use for this BMP-2 collagen sponge model is the lumbar the labeling and packaging considerations One off-label NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 153 of 581 1253 PageID 21 1 intertransverse interval. 2 found in the research work done by Martin Boden, et al 3 in the posterior lateral intertransverse fusion non-human 4 primate model. 5 My concern for such usage is The efficacy of the BMP soaked in a collagen 6 sponge, in this particular intertransverse fusion 7 application was negatively impacted by the soft tissue 8 and muscle compressing the sponge and thereby, compressing 9 the growth factor out of the sponge. This led to an 10 unexpectedly high failed fusion rate. It is easy to 11 conclude that this scenario would conclude in humans with 12 BMP-2 and a collagen sponge carrier. 13 potential is for the muscle to compress the collagen sponge 14 and leak the BMP-2 away from where the bone is intended 15 to form. In this setting the 16 To induce new bone formation, it is not 17 currently feasible or practical to apply BMP directly into 18 a bone void for the purpose of bone growth. 19 is needed for a number of reasons. 20 is for the containment of the growth factor at a site where 21 bone growth is needed. 22 cell attachment and to provide a structural matrix for A carrier One of the main reasons A carrier is also needed for stem NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 154 of 581 1254 PageID 22 1 bone growth. 2 Well, BMP-2 and BMP-7 have been shown to be 3 two of the most effective BMPs in the bone healing cascade, 4 the carriers used by these BMPs and ultimately the 5 orthopedic application site in which they are placed can 6 effect their efficacy regardless of their potency. 7 and the studies being discussed today has been used with 8 a fibular hemostatic collagen sponge carrier placed in 9 the interfix titanium threaded interbody cage. 10 In this application, liquid BMP-2 BMP-2, a 11 combination of BMP and sterile water, is applied into the 12 collagen sponge inter-operatively and allowed to soak into 13 the sponge. 14 the cage. 15 that the BMP collagen sponge combination is protected by 16 the structure of the titanium cage. 17 The sponge is then rolled and placed into In this application it is important to note In the intertransverse interval, this same 18 BMP-2 soaked collagen sponge would enjoin no cage 19 protection. 20 compression by muscle would possibly lead to extrusion 21 and dissipation of the BMP-2 and a failed bone induction. 22 Bone morphogenic protein research represents Rather as Boden et al suggested, its NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 155 of 581 1255 PageID 23 1 an exciting and new opportunity for surgeons and patients 2 alike that over time may revolutionize the way we treat 3 our patients. 4 an exciting concept and could possibly overrun the 5 relative lack of knowledge amongst my colleagues about 6 this technology. 7 There may be a temptation to push the envelope when it 8 comes to indications and applications. 9 opportunity, also comes the responsibility and challenge 10 of not only appropriate patient selection but also 11 appropriate product labeling. Getting rid of the bond graft harvest is With this new 12 My strong assertion and belief is that we 13 need to make every effort possible to insure the health 14 and benefit of our patients through appropriate labeling 15 in regards to this PMA. 16 has been tested in an IDE study for specific spine 17 pathology with a specific type of branded cage in the 18 interbody interval. The BMP-2 collagen sponge device 19 If approved, I hope the indication for use 20 will be for this particular combination of BMP carrier 21 and cage product. 22 combination product cage with BMP, the requirement that Since this product was tested as a NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 156 of 581 1256 PageID 24 1 they be packaged together the way they are intended to 2 be used is reasonable and logical. 3 additional and important opportunity to further insure 4 that the use of the growth factor will be used in an 5 application where efficacy has been proven. 6 Off-label use in areas fusion such will as not the 7 posterolateral 8 eliminated as an option to my colleagues, but packaging 9 the BMP and cage together will limit the product's use 10 intertransverse This provides an be in an unproven and potentially flawed application. 11 In concluding, I defer to commenting on the 12 final approvability of this product. 13 supporter of the BMPs but in the event it is voted to be 14 approved, I would recommend that the combination of the 15 interfixed cage and BMP-2 be specifically required to be 16 ordered together and packaged together to insure the 17 product is used as has been tested. 18 that off-label use of BMP-2 and the collagen sponge in 19 areas 20 intertransverse interval be addressed in the product 21 labeling. outside 22 of the I am an enthusiastic I would also recommend application such as the Thank you. NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 157 of 581 1257 PageID 25 1 2 CHAIRPERSON FINNEGAN: Thank you. Dr. Witten. 3 DR. WITTEN: We also need to ask the prior 4 speaker who paid her way, whether she paid her way or 5 whether her way was paid for. 6 CHAIRPERSON FINNEGAN: Okay, I'll have her 7 come back. 8 Trisler, is she still with us? 9 are there any other persons who would wishy to make a 10 comment? MS. While she's coming up, TRISLER: I'm CHAIRPERSON FINNEGAN: MS. TRISLER: 16 CHAIRPERSON FINNEGAN: was the Who paid your way to As a consultant Osteotech has. Has paid your way to the meeting? 18 19 what the meeting? 15 17 sorry, question? 13 14 Ms. Go ahead. 11 12 Dr. McCullough, thank you very much. MS. TRISLER: Well, yeah, I live here but they paid my time. 20 CHAIRPERSON FINNEGAN: Thank you. All 21 right, if there are no other people wishing to make 22 comments, Mr. Demian has received eight letters regarding NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 158 of 581 1258 PageID 26 1 this meeting and he will now read them into the record. 2 MR. DEMIAN: I've receive eight letters and 3 seven of them are from spinal surgeons, all letters 4 regarding the use of BMP. 5 Regis Haid. The first letter is from Dr. 6 "I am currently the chief spine surgeon for 7 the Department of Neurosurgery at Emory University in 8 Atlanta, Georgia. 9 in the product being discussed before the panel. I have no vested financial interest 10 developed 11 companies, 12 Concepts. 13 an indirect conflict of interest. 14 renumerations for my interest in BMP. 15 products for including cervical Medtronic, spine Codman for and I've various Spinal These may be considered by some to constitute I've received no Our group has been involved in the use of 16 BMP. We have been given presentation on fusion techniques 17 at national and international meetings and have briefly 18 discussed the experimental use of BMP. 19 published a paper in the Neuroscience Focus on the use 20 of 21 presentations 22 surgeons, I do believe that BMP offers a significant BMP. From my I've knowledge heard of We have actually the presented by studies other and spinal NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 159 of 581 1259 PageID 27 1 advantage in the practice of spine. 2 It is very clear from my experience that the 3 literature in neurosurgery and orthopedics state that 4 autograft sites do present a well array of complications. 5 It is also commonly known that harvesting the autograft 6 iliac crest adds time to surgery and expense in the 7 operating room and pain to the patient is always part of 8 the harvesting autograft iliac crest. 9 I would ask the panel to recommend to the 10 FDA to expedite their approval of this product. This 11 would prevent further suffering of patients that occur 12 with every autograft bone harvest as well as potentially 13 decreasing the time in the operating room and, thus, 14 potentially decrease the total cost to the patient. 15 Having reviewed the data from the academic perspective, 16 it seems very clear to me its efficacy is clear-cut in 17 the use in lumbar interbody anterior devices and that the 18 product should be made available to the American public. 19 Although I'm not an expert on the FDA, it 20 is my belief that FDA required a small pilot study for 21 this device under review and this was done before a large 22 pivotal study could begin. If this is indeed the case, NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 160 of 581 1260 PageID 28 1 I believe this was unnecessary and prompted a delay of 2 the release of this product which definitely benefits 3 patients. 4 Panel recommend to FDA not to require these types of pilot 5 studies for similar issues in the future". I would suggest that the Orthopedic Advisory 6 The second letter is from David Malone. "I 7 would like to add some information to the pre-market 8 approval application for a spinal fusion cage with growth 9 factors soaked in a collagen sponge intended for treatment 10 of lumbar degenerative disease. 11 the investigators in the posterior lumbar interbody fusion 12 BMP 13 Corporation. trial 14 sponsored by I took part as one of Medtronic Sofamor Danek Dr. Frank Tomecek was the lead investigator 15 for our small group. There were a number of patients that 16 were treated with the PLIF. 17 significant posterior bony over-growth impinging on their 18 nerve roots requiring additional surgery. 19 who was my patient, required two surgeries to clear 20 excessive bone growth from his spinal canal. 21 no new bone growth over the past year. 22 to whether or not this data has been included in the Two of the patients had One patient, He has had I am unsure as NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 161 of 581 1261 PageID 29 1 application to the FDA. 2 I've been told that the posterior lumbar in 3 a body fusion cage trial was halted. 4 because of this bony overgrowth problem. 5 the patients with bony overgrowth, I personally experience 6 -- my personal experience in re-operation on both of these 7 patients, the bone quality from the BMP is robust and 8 excellent. 9 BMP is a useful adjunct to bony spinal fusion. The fusions are solid. I assume it was With regard to I do feel that the 10 However, BMP may lead to excessive bone 11 growth and may cause significant neural impingement if 12 placed in posterior lumbar interbody type of device. 13 There does need to be at this point in time some type of 14 barrier between the area where the bone can overgrow and 15 the neural elements. 16 Sofamor Danek did further experimental studies on the PLIF 17 model but I do not have the data. 18 exist and may be helpful if you are considering approval 19 of this material for a posterior lumbar interbody fusion 20 type of approach. I note that Dr. Frank Tomecek and I know the data does 21 If BMP is approved for spinal fusion, and 22 I feel that it would be useful adjunct, the caveat is that NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 162 of 581 1262 PageID 30 1 it must be placed in such a manner that bony overgrowth 2 cannot grow into the spinal canal as I think this would 3 cause significant problems for a proportion of the 4 patients whom it is used in". 5 The next letter is from Dr. Robert Banco. 6 "As chief of the spine section of the New England Baptist 7 Hospital, my colleagues and I are pleased to have 8 participated in the rhBMP-2/ACS/LT open clinical trial. 9 Serving as the principal investigator, two 10 co-investigators and myself are members of the Boston 11 Spine Group, four orthopedic surgeons and one physiatrist 12 with a practice dedicated solely to spine. 13 As a group we perform over 400 spinal fusions 14 annually many of which are accompanied by iliac crest 15 harvesting. 16 crest increases the risk of complications, including but 17 not limited to infection, nerve damage and possible damage 18 to the muscles and vessels. 19 the most common complication and patient complaint. As you know, harvesting patients with iliac Donor site pain is by far 20 BMP-2 supplants the need for harvesting the 21 iliac crest and therefore, negates the risk of these 22 complications. We at the Boston Spine Group have heard NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 163 of 581 1263 PageID 31 1 many presentations and have read the literature regarding 2 BMP-2. 3 anxious for this product to get out of the lab and into 4 the clinical practice and are looking forward to the use 5 of InFUSETM in the clinical setting". We are excited by the reported outcomes. We are 6 The next letter is from Dr. Paul McCormick. 7 "I'm a full time faculty member at Columbia University 8 of Physicians and Surgeons. My practice is exclusively 9 limited to the evaluation and surgical management of 10 patients with spinal disorders. By the way of disclosure, 11 I have no financial or other vested interest in the 12 products that are being discussed before the panel. 13 As a full time spine surgeon at a major 14 academic center, I'm well aware of active research that 15 has 16 enhancement of spinal fusion. 17 surgeons, I look forward with great anticipation when 18 effective agents will be commercially available for the 19 utilization in spinal fusion. 20 important technique for many patients who have lost their 21 mechanical integrity of their spinal elements through 22 trauma, been conducted for degenerative years changes, regarding biological Like many other spine Spinal fusion is an neoplasm, or disc NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 164 of 581 1264 PageID 32 1 herniations in prior surgery. 2 A major problem related to the spinal fusion 3 is the harvesting of the autograft which is usually 4 required for a vast majority of spinal fusions currently 5 performed. 6 autograft harvest can be considerable. 7 persists over time and may be permanent. 8 9 The pain and morbidity associated with Often this pain Further, despite significant advances in fusion techniques and spinal instrumentations, a 10 measurable number of patients continue to suffer from 11 failed fusion or pseudoarthrosis. 12 adjunct that can be utilized to facilitate and enhance 13 spinal fusion would be of tremendous benefit to patients 14 with spinal disorders requiring this type of surgery. 15 In essence, there's a tremendous need for biological 16 fusion enhancers such as BMP that diminish the reliance 17 on autograft harvesting as well as enhancing the rate and 18 the success of spinal fusion. Therefore, any useful 19 I'm also well aware of the research that is 20 currently being conducted at numerous centers regarding 21 BMP. 22 promise in enhancing spinal fusion and bone incorporation. To my critical review, BMP has shown exciting NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 165 of 581 1265 PageID 33 1 I fully appreciate the responsibilities of the FDA in 2 general and of your panel in particular in acting in the 3 public interest through oversight on the approval and 4 introduction of these devices and agents. 5 respectfully request that such evaluation be carried on 6 in an expedited fashion so that if BMP satisfies the FDA 7 requirements for approval, we can utilize this substance 8 in a timely manner. I would 9 Such an expedited approval would likely 10 reduce the pain and suffering of future patients that are 11 requiring spinal fusion". 12 The next letter is from J.J. Abitol. "I'm 13 a practicing spinal surgeon, also a current board member 14 of the North American Spine Society where I have been a 15 past scientific program chairman. 16 current official position statement from the Society, I 17 would like to express my opinion about bone morphogenetic 18 proteins or BMPs. 19 this area, I can say with certainty that BMP has been one 20 of the most heavily researched subject matters in all of 21 orthopedics. 22 Although there is no Being familiar with the research in Since the late Dr. Marshall Urist first NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 166 of 581 1266 PageID 34 1 discovered these proteins over 30 years ago, and 2 unprecedented amount of publications and research efforts 3 have been dedicated to studying these proteins. 4 practical purposes, all of these studies have demonstrated 5 to the research and medical 6 alternative to taking autograft is now at hand. For all community that safe and new 7 I strongly urge this panel to approve these 8 desperately needed proteins and make Dr. Urist's dream 9 of having bone graft in a bottle a reality. It is time 10 to take these type of proteins out of research and make 11 them available to surgeons to use in our clinical practice 12 to treat patients". 13 Our next letter is from Dr. John Peloza. 14 "I'm a nationally recognized spine expert with a tertiary 15 specialty practice in Dallas, Texas. 16 perform many spinal fusion procedures on all levels of 17 the spine from the skull to the sacrum. 18 are done from an anterior, posterior and sometimes 19 combined approach. In my practice I These fusions 20 I'm often challenged by difficult spinal 21 reconstruction problems secondary to disease processes 22 including spinal deformity, degeneration, trauma, tumor NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 167 of 581 1267 PageID 35 1 and infection. 2 involved 3 surgical implants minimally invasive and non-surgical 4 technologies as well as biological technologies for the 5 treatment of spinal disorders. in 6 My team and I have been and are presently multi-center I'm an studies authority on evaluating bone spinal morphogenetic 7 protein from my experience as a clinical investigator with 8 rhBMP-2, professional presentations, knowledge of the 9 scientific literature, national and specialty meetings 10 and think tanks. 11 impressive clinical results on my own patients utilizing 12 this protein. 13 I have direct experience with the Presently we have a number of bone graft 14 alternatives. The gold standard is the patient's own bone 15 or autograft. It is osteogenic, contains viable bone 16 cells at transplantation, osteo inductive, actively 17 promotes or enhances bone formation and osteo conductive, 18 acts as a structural framework or scaffold for bone 19 formation. 20 the patient's iliac crest. 21 22 Unfortunately, it is in limited supply, e.g. In many cases we have very little or no autograft at all. Additionally, the bone graft harvest NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 168 of 581 1268 PageID 36 1 surgery contributes significantly to post-operative pain 2 that can be permanent and can lead to other complications. 3 When autograft is not available or inadequate, surgeons 4 use allograft, bone bank or cadaver bone. 5 is mainly osteo conductive, weakly osteo inductive and 6 has no osteogenetic properties. 7 Depending on the Allograft bone surgical construct, 8 allograft fusion rates are lower than autograft and take 9 much longer to heal. Due to the massive demand for bone 10 graft worldwide, allograft bone is also in limited supply. 11 Additionally, allograft bone has a risk of disease 12 transmission. Modern bone processing is effective in 13 eradication of bacteria and viruses. 14 very difficult to detect and no processing has been 15 validated for their removal. However, prions are 16 After autograft and allograft, surgeons can 17 use bone graft extenders, demineralized bone matrix. 18 These products are mainly osteo conductive, poorly osteo 19 inductive if at all, and not osteogenic. 20 last line of bone graft material and informed surgeons 21 have little confidence in their efficacy in obtaining a 22 solid fusion. They are the NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 169 of 581 1269 PageID 37 1 Recombinant human bone morphogenetic protein 2 is an attractive infusion surgery for many reasons. The 3 fusion rates in animal models and in human trials is the 4 same or better than the gold standard autograft. 5 a production facility there would be an unlimited supply 6 of rhBMP. 7 harvesting surgery which will eliminate the associated 8 pain, potential complications and cost. With RhBMP will eliminate the need for bone graft 9 There will be no chance of disease 10 transmission. 11 the surgery fails. 12 complication such as infection but the most common reason 13 for 14 pseudoarthrosis. 15 surgeons. failed The major cost of sponsored surgery is when This can occur secondary to a major surgery is the failed fusion or This is a problem that vexes all spinal 16 A product that markedly enhances our ability 17 to heal bone with few documented side effects is an 18 extremely powerful tool in the treatment of spinal 19 disorders. 20 represents 21 technologies. 22 models and human trials. RhBMP the is best a of breakthrough our research product and that advances It has been thoroughly tested in animal It has consistently proven NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 170 of 581 1270 PageID 38 1 better and safer than our present alternatives. It is 2 time to get rhBMP into the clinical arena where it is 3 desperately needed for the optimum care of people. 4 Finally, I would like to state I have no 5 financial interest in the product rhBMP-2 nor do I have 6 a financial interest in the company that is sponsoring 7 rhBMP-2". 8 9 Second to the last letter from a trio, Stephen Papadopoulos, Curtis Dickman and Volker Sonntag. 10 practice 11 Neurological Institute in Phoenix, Arizona. 12 consists of regional and national and international 13 referrals. 14 specific product being discussed before the panel. 15 primarily spine surgery at the "We Barrow Our practice We have no vested financial interest in the We have been aware of the field of BMP 16 research for several years through peer review, 17 publications and scientific presentations. 18 believe the clinical availability of this product in the 19 United States will significantly enhance patient care. 20 Graft site complications from autograft harvest are well We strongly 21 described and documented. The availability, quality and 22 healing issues related to allograft is also well known. NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 171 of 581 1271 PageID 39 1 Fusion failure may result in chronic pain, 2 deformity and the need for additional spinal 3 reconstructive procedures. 4 of BMP will provide a significant advance in the patient 5 outcome and satisfaction". We believe that the approval 6 The last letter is from Dr. Doug Morrow. 7 "It is my understanding that you are about to discuss and 8 vote on approval or rejection of rhBMP. 9 to be one that you may not otherwise get in the sense that 10 I am both a physician and a patient waiting on the approval 11 of this enzyme to fuse my lumbar spine. 12 an unusual set of circumstances wherein I got an infected 13 disc in my lower back because of an injection called a 14 discogram. I want my voice I have rather 15 The infection all but destroyed two lumbar 16 vertebrae, leaving me in constant pain for the instability 17 associated with the deformity. 18 all the literature on the subject and especially this 19 enzyme which speeds up the natural healing process of 20 growing bone. 21 to be used in surgery on my back. 22 its use for some time delaying my surgery because of it. I've been keeping up with I'm a perfect candidate for this material I've been waiting for NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 172 of 581 1272 PageID 40 1 I have back pain every day all day. I urge 2 you prompt approval of this material so that my doctor 3 can then use it on me as soon as possible. 4 people just like me who need help. 5 beg you and thank you from the bottom of my heart". 6 That's it. 7 CHAIRPERSON There are many Please help us. FINNEGAN: Thank You may get an award for that. you, I Mr. 8 Demian. 9 proceed to the presentation of the pre-market approval 10 application P000058, Medtronic Sofamor Danek InFUSETM bone 11 graft/LT-cage lumbar tapered fusion device. 12 remind the public observers at this meeting that while 13 this portion of the meeting is open to public observation, 14 public attendees may not participate except at the 15 specific request of the panel. 16 We will now I need to We will proceed first with the sponsor's 17 presentation followed by the FDA presentation. 18 like to ask each speaker to state his or her name, their 19 affiliation and I would ask everyone to please speak into 20 the microphone so that people in the back of the room can 21 hear 22 transcriptionist can hear you. you but also most importantly I would so that The sponsors, if they NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 173 of 581 1273 PageID 41 1 would like to come up, could start. 2 DR. LIPSCOMB: Members of the Orthopedic and 3 Rehabilitation Devices Advisory Panel, my name is Bailey 4 Lipscomb and I'm the Vice President of Clinical Affairs 5 at Medtronic Sofamor Danek in Memphis, Tennessee. 6 the pleasure and the long awaited privilege to present 7 to you the results of decades of research, development, 8 and clinical studies. 9 thank literally thousands of people who have worked over We have At the outset, we would like to 10 the years to make these presentations possible. For the 11 next 90 minutes we will present for the first time to an 12 FDA advisory panel the culmination of work arising from 13 a discovery made by Dr. Marshall Urist in 1965. 14 Dr. Urist found that certain proteins which 15 he later terms as bone morphogenetic proteins, stimulate 16 the formation of bone and these proteins can literally 17 make bone where bone did not exist before. 18 1980's 19 Cambridge, Massachusetts developed a method to synthesize 20 several 21 recombinant methods. 22 researchers of these of bone Wyeth-Genetics morphogenetic In the early Institute proteins in using The BMP-2 yields from these methods are much NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 174 of 581 1274 PageID 42 1 greater in quantity and much purer in nature than can be 2 obtained from natural sources. 3 protein that will be reviewed today is recombinant human 4 bone morphogenetic protein 2 or more commonly known in 5 its abbreviated form as rhBMP-2 and this is made by 6 Wyeth-Genetics Institute. 7 The rhBMP-2 is The bone morphogenetic supplied as a sterile 8 freeze-dried powder that is reconstituted at the time of 9 surgery with sterile water to a concentration of 1.5 10 milligrams per milliliter. 11 to absorbable collagen sponge. 12 matrix to retain the rhBMP-2 in the desired location 13 sufficiently long to stimulate the formation of bone 14 cells. 15 The The solution is then applied absorbable The sponge provides the collagen sponge is a 16 commercially available product that is made by Integra 17 Life Sciences of Plainsboro, New Jersey. 18 the PMA application for the absorbable collagen sponge 19 back in 1981. 20 combination of rhBMP-2 with the absorbable collagen sponge 21 as InFUSETM bone graft. 22 covers this use with Medtronic Sofamor Danek's LT-cage FDA approved Medtronic Sofamor Danek has named the This PMA application for InFUSETM NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 175 of 581 1275 PageID 43 1 lumbar tapered fusion device, not the interfix device that 2 Dr. McCullough mentioned but the LT-cage device. 3 The LT-cage device is a hollow fenestrated 4 titanium alloy threaded interbody fusion device. FDA 5 approved the PMA application for this device over a year 6 ago. 7 an anterior surgical approach in lumbar spinal fusion 8 procedures. 9 harvested from the iliac crest, is packed into the LT-cage Typically two cages are inserted in parallel from 10 devices. 11 device. In current medical practice bone graft is This is stipulated in the labeling of the 12 Autogenous bone graft augments the fusion 13 of the treated segment and it is now considered a standard 14 of care graft material. 15 an approval recommendation from this panel to use infused 16 bone graft instead of autogenous bone graft to pack the 17 central cavities of the LT-cage devices. 18 closely on what is at issue here today. 19 Today, however, we're seeking Let's focus more It is not the LT-cage device. This product 20 is commercially available for the same medical indication, 21 that is symptomatic degenerative disc disease, and for 22 the same manner of use, anterior antibody lumbar fusion NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 176 of 581 1276 PageID 44 1 procedures. It is not the absorbable collagen sponge that 2 has been FDA approved as an implantable hemostatic agent. 3 It has a long history of safe and effective use dating 4 back over 20 years. The real issue today is the safety 5 and effectiveness of rhBMP-2 when used with the two 6 previously approved products and whether it is a suitable 7 replacement for autogenous bone graft, the gold standard, 8 in antibody fusion procedures. 9 We believe the years of basic research and 10 development of this product have yielded considerable 11 evidence to support the safety and effectiveness of the 12 product. 13 is supported by clinical data arising from a large 14 multi-centered prospective randomized clinical trial, a 15 desirable scientifically valid study design, but one that 16 is rarely used for orthopedic implants in the United States 17 due to its difficulty in execution. 18 Further, the infused bone graft LT-cage device This study embodies an idyllic scientific 19 research. Eliminate as much of the variation as possible 20 except for the variable being studied. 21 that's exactly what occurred. 22 entrance criteria and received the same interbody fusion In this study Patients met the same study NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 177 of 581 1277 PageID 45 1 cage. The only variable was the 50/50 chance that a 2 patient would receive either infused bond graft or would 3 receive autogenous bone graft in their surgery. 4 It is our opinion that this study presented 5 today overcomes virtually all of the objections to study 6 trial designs that have been voiced over the years by this 7 orthopedic advisory panel. 8 as 9 information, and labeling were submitted to FDA as a 10 modular PMA application with the first module being 11 submitted in April of 2000. 12 under review by FDA since then and presenting this 13 information to this advisory panel is part of the review 14 process. the pre-clinical These clinical data as well test results, manufacturing The PMA application has been 15 As typical for these meetings, we plan to 16 present overviews of the relevant information contained 17 in the PMA application. 18 project director of the rhBMP-2 program at Wyeth-Genetics 19 Institute, will make the first presentation and he will 20 cover 21 pre-clinical safety studies. 22 by Dr. Scott Boden, an orthopedic surgeon from Emory the origin and Dr. Gerard Riedel, the senior biology of rhBMP-2 and the Dr. Riedel will be followed NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 178 of 581 1278 PageID 46 1 University. Dr. Boden will discuss the results of 2 pre-clinical testing of infused bone graft in animal 3 studies as well as the results of the pilot trial involving 4 infused bone graft with the LT-cage device and that study 5 supported the initiation of the larger pivotal trials. 6 Dr. Hallett Matthews, an orthopedic spine 7 surgeon from Richmond, Virginia, will review the results 8 of the large scale pivotal IDE trial of the infused bone 9 graft with the LT-cage device. Dr. Matthews was an 10 investigator in the open surgical approach study. I will 11 then return to the podium for concluding remarks. 12 In addition to these speakers, we have 13 assembled here today a group of physicians and scientists 14 who should be able to answer the questions you may have 15 about the product under review. 16 several clinical investigators, the inventor of the cage, 17 radiologists and immunologists, an OB/gyn physician, a 18 histologist, a statistician, basic scientist and the 19 discoverer of the rhBMP-2 that has been used in the study. 20 So without further ado, I will now turn the 21 These experts include podium over to Dr. Riedel. 22 DR. RIEDEL: Thank you, Bailey. Good NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 179 of 581 1279 PageID 47 1 morning. 2 Wyeth-Genetics Institute, a pharmaceutical company, that 3 collaborates 4 development of BMPs in spine surgery. 5 I will briefly describe the origin and the biology of 6 recombinant human bone morphogenetic protein 2. 7 also summarize the pre-clinical studies we have conducted 8 that compliment the pre-clinical studies conducted by 9 Medtronic Sofamor Danek. 10 My name is Gerard Riedel. with Medtronic I'm employed by Sofamor Danek in the In my presentation I will As a reminder, the letters rhBMP-2 represent 11 recombinant 12 Scientists at Genetics Institute use molecular biology 13 techniques to isolate the human gene in coding BMP-2. 14 This gene was inserted into a chromosome of an industry 15 standard mammalian cell line and this cell line was 16 subsequently engineered to enable it to produce high 17 levels of rhBMP-2 protein. 18 large vessels and synthesize the protein as it does so. 19 RhBMP-2 is purified from the media, filled into sterile 20 human bone morphogenetic protein 2. This cell line can grow in vials and subsequently freeze-dried. 21 RhBMP-2 is a member of a large protein family 22 whose members all have activities associated with the NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 180 of 581 1280 PageID 48 1 growth and differentiation of tissues. Endogenous 2 rhBMP-2 plays a key role in bone repair and embryonic 3 development. 4 glycosylayted 5 approximately 30,000 Daltons. 6 conserved and active across species. 7 allows the use of recombinant human BMP-2 in all of the 8 animal studies I will present rather than having to prepare 9 specie specific versions of this protein. Recombinant human BMP-2 is a homodimeric molecule with a molecular weight of The protein is highly This conservation 10 Finally, the biological activity of rhBMP-2, 11 that is the basis for its therapeutic development, is its 12 ability to induce bone in both animals and humans. 13 This slide demonstrates that bone induction 14 activity of rhBMP-2 in the classic in vivo assay known 15 as the rat ectopic implant assay. 16 originally developed in Dr. Reddi's laboratory. 17 assay, rhBMP-2 is implanted at a non-bony site. 18 bone is induced at this site within seven to 14 days 19 following implantation. 20 the gross appearance of an ossicle of bone induced by 21 rhBMP-2 in the subcutaneous space of a rat's thorax. 22 Histological analysis of this new bony tissue reveals This assay was In this Typically The photograph on the left shows NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 181 of 581 1281 PageID 49 1 extensive formation of trabecular bone corresponding to 2 the dark pink regions in the photo micrograph on the right, 3 a complete compliment of bone associated cells such as 4 osteoblasts, osteoclasts and stromal cells and a highly 5 vascularized structure with all bone marrow elements 6 corresponding to the light pink regions in the photograph 7 on the right. 8 9 This activity in this rat model has been labeled osteo induction. inducing BMP Only rhBMP-2 and several other 10 bone proteins exhibit this biological 11 activity. 12 activity in this model. 13 comprising 14 Following the implantation of recombinant human BMP-2 15 cells initially migrate to the site and undergo several 16 rounds of cell replication. No other protein or drug has demonstrated this 17 bone Some of the biological events induction Subsequently, have been identified. fibroblasts appearing 18 mesenchymal cells differentiate into osteoblasts. 19 is 20 subsequently 21 osteoclasts and osteoblasts into lamellar bone. formed, 22 initially remodeled The newly as woven by the induced trabecular combined tissue Bone bone and action of is highly NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 182 of 581 1282 PageID 50 1 vascularized as demonstrated by the numerous blood vessels 2 in the photo micrograph on the left. 3 of events induced by rhBMP-2 recapitulates the physiologic 4 process of bone formation. 5 Considerable about the The entire sequence information mechanism of has also rhBMP-2 been 6 published action. 7 Responsive cell types and major cell surface receptors 8 have been identified. 9 signal transduction pathway have been identified by which Additionally, elements of the 10 rhBMP-2 exercises its effects on cells. 11 importantly, it has been shown that it is necessary to 12 apply rhBMP-2 locally in order to obtain bone induction 13 in vivo. 14 To facilitate the local Finally, and very application of 15 rhBMP-2, the protein is combined with a biomaterial that 16 is generally called a matrix. 17 rhBMP-2 enables its surgical placement at the treatment 18 site, facilitates retention of rhBMP-2 at that site and 19 ideally provides an environment that is compatible with 20 bone induction. The use of a matrix with 21 The matrix selected for clinical development 22 in this specific program is an absorbable collagen sponge, NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 183 of 581 1283 PageID 51 1 abbreviated as ACS. This sponge was selected after 2 screening dozens of matrix candidates. 3 commercially available product marketed in the United 4 States since 1981 as a surgically implanted hemostatic 5 agent and has an extensive commercial experience of safe 6 use. 7 type 1 collagen. 8 regulatory requirements. The sponge is a The sponge is composed of bovine tendon- derived Its manufacturer meets or exceeds all 9 This next slide shows an example of the dry 10 absorbable collagen sponge in its original packaging prior 11 to the addition of rhBMP-2. 12 preparation of rhBMP-2 ACS. 13 freeze-dried powder of rhBMP-2 is reconstituted with an 14 appropriate volume of sterile water, abbreviated WFI in 15 the diagram. 16 is 17 generating a cohesive pliable implant that can be readily 18 manipulated in the operating room as depicted in this slide 19 which shows that the wetted sponge can be rolled and 20 subsequently inserted into an LT-cage. 22 The vial containing the The resulting sterile solution of rhBMP-2 subsequently 21 This diagram describes the I applied mentioned uniformly before to that the one dry ACS, desirable attribute of a matrix is its facilitation of rhBMP-2 NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 184 of 581 1284 PageID 52 1 retention at the site of implantation. 2 describes one experimental system we used to assess this 3 attribute. 4 which we implanted rhBMP-2 ACS contained radioactively 5 labeled rhBMP-2. 6 amount of rhBMP-2 retained at the implantation site over 7 time 8 scintigraphy. 9 remaining at the site over time and this method has been 10 validated by several supplementary analyses including 11 direct 12 characterization of the radio labeled BMP-2 derived from 13 the explants. by 14 This slide We generated rabbit ulnar osteotomies onto a Following implantation, we measured the non-invasive technique of gamma camera Basically, we measured the radioactivity explant measurement and biochemical This slide shows the retention of rhBMP-2 15 in 16 represents the percent of the rhBMP-2 initial dose 17 remaining at the implantation site and the X axis 18 represents time in days. 19 of ACS as a matrix facilitates the local retention of 20 rhBMP-2 at the site, in contrast to the application of 21 rhBMP-2 in buffer depicted by the line with black squares. 22 the rabbit Significantly ulnar more osteotomy model. The Y axis The graph shows that the use rhBMP-2 is retained at the NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 185 of 581 1285 PageID 53 1 implantation site when it is applied in combination with 2 ACS 3 Radio-labeled rhBMP-2 can be detected at the implantation 4 site for as long as 14 days in this model. depicted by the line with yellow diamonds. 5 With this background information in mind, 6 I will now discuss the non-clinical safety studies that 7 have been conducted. 8 combined with ACS has been assessed in a variety of 9 studies. The safety of rhBMP-2 alone or Implantation of rhBMP-2 ACS to assess its 10 implant safety has been conducted. 11 distribution, 12 abbreviated ADME, has been assessed. 13 of 14 assessments. rhBMP-2 metabolism alone has and been The absorption, excretion of rhBMP-2, Finally, the safety studied in a panel of 15 The safety of rhBMP-2 ACS implantation has 16 been evaluated in three anatomic sites, including a spine 17 safety study conducted in Dr. Hanley's laboratory. 18 results of this spine study have already been published. 19 The two other implant safety studies used rat and canine 20 models with follow-up extending through six or 12 months. 21 In these two studies we used rhBMP-2 dosing that greatly 22 exceeded the specie specific therapeutic range and I The NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 186 of 581 1286 PageID 54 1 should explain this. 2 I have previously mentioned that recombinant 3 human BMP-2 is biologically active in all mammalian 4 species. 5 concentrations of rhBMP-2 within ACS for optimal bone 6 formation 7 concentration of rhBMP-2 is lowest in rodents, higher in 8 canine and even higher in non-human primates and patients. 9 We took advantage of this phenomenon to However, different species require different and specifically exceed the the optimal species therapeutic 10 deliberate specific optimal 11 concentrations of rhBMP-2 within ACS in order to assess 12 any toxic effects. 13 studies were uniform. 14 observed, no gross pathology or histopathology findings, 15 no effects on blood chemistry, hematology or urinalysis 16 and no incidents of bone formation distant from the site 17 of implantation. The safety results of all these There were no systemic effects 18 Furthermore, the local effects observed in 19 these studies were consistent with the bone inducing 20 biological activity of rhBMP-2. 21 biodistribution of rhBMP-2 following its implantation. 22 We also looked at the We used two implantation models in two species. The NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 187 of 581 1287 PageID 55 1 results are similar. 2 implantation site with a maximum of 0.1 percent of the 3 implanted 4 circulation. rhBMP-2 RhBMP-2 is slowly released from the dose detected in the systemic 5 This slide shows the retention of rhBMP-2 6 at the site of implantation but this time in a rat femur 7 onlay model. 8 site for as long as 14 days following surgical implantation 9 in this model. RhBMP-2 can be detected at the implantation In this same study we measured rhBMP-2 10 levels in the blood and showed that the maximum amount 11 detected was 0.1 percent of the total rhBMP-2 implanted. 12 I've not graphed those levels on this slide because they 13 would all cluster at zero on this scale. 14 Nevertheless, because some small amount of 15 rhBMP-2 was detected in the systemic circulation following 16 the product's implantation, we studied the fate of rhBMP-2 17 following systemic administration. 18 animal models of pharmacokinetics and biodistribution in 19 rats and non-human primates and applied rhBMP-2 protein 20 dissolved in buffer via intravenous administration. 21 these models we observed that rhBMP-2 is rapidly cleared 22 from the systemic circulation with a terminal half-life We used standard In NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 188 of 581 1288 PageID 56 1 of 16 minutes in rats to seven minutes in monkeys. 2 The liver is the principal organ of 3 clearance. Subsequently, the protein is rapidly degraded 4 and excreted into -- completely degraded and then the 5 remnants are excreted into the urine. 6 the clearance of rhBMP-2 from the systemic circulation 7 following intravenous administration of the protein in 8 rats. 9 initial dose remaining in the blood and the X axis 10 represents time but now in minutes rather than in days 11 as used in the previous graphs. This graph shows The Y axis represents the percent of the rhBMP-2 12 This slide shows that rhBMP-2 is rapidly 13 cleared from the circulation and contrasts dramatically 14 with its relatively slow clearance from the site of 15 implantation. 16 the local and systemic clearance of rhBMP-2. 17 release from the site of implantation combined with rapid 18 systemic clearance, results in very low systemic exposure. 19 This low systemic exposure has implications for the 20 This slide summarizes the net effect of Slow rhBMP-2 safety results described in the following slides. 21 I switch now to a description of various 22 safety assessments of rhBMP-2 alone beginning with studies NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 189 of 581 1289 PageID 57 1 relevant to tumor formation or proliferation. Published 2 studies have screened many different tumors and identified 3 several tumor types that express either BMP-2 or BMP 4 receptors. 5 of BMP-2 in the initiation or the promotion of tumor 6 formation. These published data do not indicate any role 7 We have also assessed rhBMP-2 in standard 8 assays and determined that 9 cytotoxic nor mutagenic. histological the protein is neither Additionally, we performed a 10 thorough assessment of the local 11 implantation site in the implant toxicity studies I 12 previously mentioned. 13 features at the site of implantation in any study at any 14 time point. 15 implanted concentrations of rhBMP-2 on ACS that were 40 16 times higher than the optimal therapeutic concentration 17 for this species. We detected no abnormal cellular For example, in our rat implant study, we 18 The histopathology assessment of the implant 19 site revealed no abnormal cellular features at any time 20 point through the one-year follow-up period. 21 combined data suggest that rhBMP-2 has no role in the 22 initiation or the promotion of tumor formation. These To NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 190 of 581 1290 PageID 58 1 investigate the effect of rhBMP-2 on tumor cells that 2 already exist, we have conducted in vitro studies. 3 focused our efforts on in vitro assessments because it 4 is possible to achieve relatively high exposure levels 5 to rhBMP-2 in contrast to the very low systemic exposure 6 levels that can be achieved in vivo. 7 summarized on the following slide. We These studies are 8 We have provided FDA with the results of 9 series of studies including our own that investigated the 10 effect of rhBMP-2 on the growth of human tumor cells in 11 vitro. 12 aggregate, these studies have assessed 51 human tumor cell 13 lines to date. 14 promotion in the presence of rhBMP-2 as compared with 15 growth in the absence of the protein. 16 lines first. 17 Most of these studies have been published. In Three lines have shown some growth Two of these lines I will discuss these were derived from 18 pancreatic tumors. When these lines were cultured in the 19 absence if serum, rhBMP-2 stimulated cell growth by 12 20 or 25 percent above that of the controls. 21 carried a mutation and a key component of the intracellular 22 BMP signal transduction pathway. Both lines Other pancreatic tumor NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 191 of 581 1291 PageID 59 1 cell lines were evaluated and showed either no effect or 2 growth inhibition. 3 The third tumor cell line demonstrating 4 increased growth was derived from a prostate carcinoma. 5 This cell line only showed growth promotion in the absence 6 of serum or the absence of androgen. When either of these 7 components was added back to the medium, rhBMP-2 actually 8 inhibited the growth of this cell line. 9 48 cell lines, the addition of rhBMP-2 had either no effect 10 or resulting in the inhibition of tumor cell growth in 11 approximately 50 percent of the cell lines tested. 12 lines included many different tumor cell types including 13 seven osteosarcoma lines as well as the three additional 14 pancreatic tumor lines and four additional prostate tumor 15 cell lines. In the remaining These 16 Besides testing rhBMP-2 on established tumor 17 cell lines, the protein has also been tested on primary 18 tumor isolates generally obtained following surgical 19 debulking procedures. 20 isolates have been tested to date and all show either no 21 effect or inhibition this time in approximately 25 percent 22 of the isolates tested. Seventy-one independent tumor NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 192 of 581 1292 PageID 60 1 Finally although inhibition of tumor growth 2 has been observed most dramatically in the cell lines and 3 primary isolates of multiple myeloma cells, the degree 4 of inhibition is not extensive enough to consider rhBMP-2 5 for therapeutic applications in patients with these 6 tumors. 7 Over the course of the review of this PMA 8 submission, we met with FDA on several occasions to discuss 9 additional tumor biology studies that could be conducted. 10 We mutually agreed to perform that additional studies 11 outlined in this slide as a post-approval commitment. 12 These studies are intended to compliment the scientific 13 literature and to more systematically assess rhBMP-2 14 effects on tumor cells that express the known BMP 15 receptors. 16 The first study is designed to screen tumor 17 cell lines for the levels of messenger RNA in coding each 18 known component of the BMP receptor complex. 19 performing the screening activity by using a sensitive 20 polymerase chain reaction assay for each known receptor 21 component 22 messenger RNA levels in tumor cells with messenger RNA and comparing the individual We are component NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 193 of 581 1293 PageID 61 1 levels in other cell types known to respond to rhBMP-2. 2 We used this comparison to operationally classify tumor 3 cell lines as positive or negative for BMP receptor RNA. 4 5 The second cell line evaluates 6 representative tumor cell lines from the first experiment. 7 If possible, cell lines will be selected that represent 8 a variety of tumor types and different messenger RNA levels 9 of BMP receptor components. The growth of these cell 10 lines will be assessed in vitro in the presence and the 11 absence of rhBMP-2. 12 In the third study, representative tumor cell 13 lines from the second experiment will be assessed if 14 relevant as xenografts in an appropriate mouse model 15 system in the presence and absence of implanted rhBMP-2. 16 As I stated earlier, these additional studies constitute 17 a post-approval commitment in agreement with FDA. 18 I will now discuss additional safety 19 assessments of rhBMP-2 alone that have been performed. 20 We have also conducted formal studies of rhBMP-2 safety 21 in well-characterized animal toxicological models. We 22 studied the systemic safety of rhBMP-2 in two species using NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 194 of 581 1294 PageID 62 1 intravenous administration to apply a single dose or doses 2 repeated daily for 28 days at systemic exposure levels 3 that greatly exceeded anticipated human exposure. 4 Similarly, during because indigenous embryogenesis, active 6 reproductive safety of rhBMP-2 using repeated intravenous 7 administration in standard rat and rabbit models that 8 assess 9 systemic exposure levels that greatly exceed anticipated or teratological have studied is 5 fertility we BMP-2 effects again the at 10 human exposure. 11 assessed rhBMP-2 effects on clinical signs, ophthalmic 12 evaluations, electrocardiograms and blood pressure, bone 13 marrow 14 urinalysis, growths pathology and histopathology of all 15 major organs. and In these formal toxicity studies, we hematology parameters, blood chemistry, 16 In the reproductive toxicity studies, we 17 additionally assessed rhBMP-2 effects on maternal and 18 paternal mating performance and reproductive parameters, 19 maternal toxicity, embryo lethality, litter size and 20 viability and fetal abnormality. 21 these studies were similar. 22 observed. The results of all of There were no effects NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 195 of 581 1295 PageID 63 1 Studies were also conducted according to the 2 tripartite 3 devices and a series of general safety pharmacology 4 studies were conducted using systemically administered 5 rhBMP-2. 6 biocompatibility guidelines for medical The results of these studies were also similar. There were no effects observed. 7 In the course of the review of this PMA 8 submission, we have recently met with FDA to discuss issues 9 related to an immune response to rhBMP-2. Following 10 consultation with FDA, we have mutually agreed to perform 11 the additional studies outlined in this slide as a 12 post-approval commitment. 13 more thoroughly assess the overall immune response to 14 rhBMP-2. These studies are intended to 15 Our first commitment in this area is to 16 develop a broader clinical antibody assay to detect human 17 antibody isotopes in addition to the major IgG isotopes 18 that we currently detect. 19 develop a valid assay to assess the ability of antisera 20 to block or neutralize the biological activity of rhBMP-2. Our second commitment is to 21 22 Finally, we have also recently begun a NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 196 of 581 1296 PageID 64 1 discussion with FDA concerning experimental approaches 2 to 3 anti-rhBMP-2 antibodies to have adverse effects on fetal 4 development during pregnancy. 5 rhBMP-2 ACS has been comprehensively evaluated in a series 6 of non-clinical safety studies that used either local 7 implantation or systemic administration. 8 pre-clinical profile that we have observed in these 9 studies can be characterized as follows. appropriately assess the potential of maternal In summary, the safety of The overall 10 There was no observed systemic adverse effect 11 of rhBMP-2 whether it was administered as an intravenous 12 solution or implanted in association with the absorbably 13 collagen sponge. 14 effects to low systemic exposure caused by the gradual 15 release of rhBMP-2 from its implantation site combined 16 with a very rapid clearance of rhBMP-2 from the systemic 17 circulation. 18 with the bone inducing activity of rhBMP-2. 19 observed no dose limiting toxicity related to rhBMP-2 in 20 our 21 anticipated human exposure. 22 In We attribute this lack of adverse Local effects were observed with consistent studies at amounts conclusion, substantially our We have exceeding pre-clinical safety NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 197 of 581 1297 PageID 65 1 assessment supports the use of infused bone graft in 2 patients. 3 this presentation over to Dr. Scott Boden, who will review 4 the data from several pre-clinical spine fusion studies 5 and the results of the infused bone graft pilot clinical 6 study. 7 Thank you for your attention. DR. BODEN: I'll now turn Thank you, Dr. Riedel. My name 8 is Scott Boden and I'm a Board certified, practicing 9 orthopedic spine surgeon in Atlanta, Georgia. 10 11 I'm also a professor of orthopedic surgery at Emory University. I've written extensively proteins on and I the am subject familiar of bone with the 12 morphogenetic 13 literature in this area. 14 interest in the product being discussed today before this 15 distinguished panel but I am a paid consultant for 16 Medtronic Sofamor Danek. I have no direct financial 17 I also participated in the pilot study for 18 the device being presented today which began five years 19 ago when recombinant human BMP-2 was first used inside 20 the LT-fusion cage device in humans. 21 22 I'd like to focus my remarks on the pre-clinical studies that led to the design and rationale NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 198 of 581 1298 PageID 66 1 and evaluation tools for the pivotal clinical trial which 2 you'll hear about shortly. 3 of the key pre-clinical studies looking at the recombinant 4 BMP-2 protein in an interbody spine fusion environment. 5 Before I go into them individually, I want 6 to point out the theme for these studies is that it was 7 done in an animal model where the gold standard of the 8 control had a less than 50 percent success rate in three 9 of those four studies. This slide summarizes four And the empty cage or without 10 protein had a zero percent success rate in the a fourth 11 of 12 recombinant BMP-2 had a 95 or 100 percent success for 13 inducing bridging bone in each of these challenging animal 14 models. those 15 studies. The Similarly first study or looks in at contrast, single the level 16 interbody fusion with a titanium cage in a sheep model. 17 In this study the cage was either filled with autogenous 18 bone graft or the recombinant BMP-2 absorbable collagen 19 sponge device. 20 challenges in non-invasively evaluating the presence or 21 absence of bone formation in the interbody fusion area. 22 In the autograft controls, plain radiographs This slide highlights some of the NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 199 of 581 1299 PageID 67 1 measuring lucencies of the primary determinant of presence 2 or absence of fusion suggested that there might be 100 3 percent successful fusion rate. 4 analysis which directly visualizes bridging trabecular 5 bone which is the criteria for a solid fusion, show that 6 only 37 percent of those animals actually had bridging 7 trabecular bone. 8 x-ray showed a very -- or indicated a very high success 9 rate just using the lucency criteria but the difference 10 here was that the histologic analysis showed bridging 11 trabecular bone in each and every animal receiving BMP-2. 12 However, histologic In the case of BMP-2, again, the plain These pictures illustrate that point. Here 13 is a micro-radiograph of an autograft control where there 14 is clearly bone inside the cage but there are some areas 15 that are not filled with bone and histology demonstrates 16 that this is fibrous tissue shown in the pink color as 17 compared to bone shown in the blue. 18 with both a radiograph and histology from one of the other 19 animals in that study that had BMP-2 absorbable collagen 20 sponge inside the cage rather than autogenous bone graft. 21 One of the other relevant questions that has 22 already been raised this morning is what is the mechanical This can be contrasted NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 200 of 581 1300 PageID 68 1 quality of bone that is induced using BMP-2 as compared 2 to bone that would be initially formed and remodeled using 3 autogenous iliac crest bone graft? 4 that using a variety of mechanical testing modes that the 5 mechanical properties of the bone induced by BMP-2 were 6 comparable comparing the red bar and the green bar to those 7 seen with bone formed by autogenous bone graft from the 8 iliac crest. And this study shows 9 The second study looks at single level 10 interbody fusion with titanium cage this time in a goat 11 model. 12 groups were again the same. 13 autogenous 14 absorbable collagen sponge. 15 challenges of using just plain radiographs to assess the 16 presence of bone inside a fusion cage. 17 the autograft group clearly less than 100 percent but more 18 than the just under 50 percent that had an actual fusion 19 based on histology, were assessed to be fused again using 20 lucency as the primary criteria. The end point was again six months and the two bone or Cage was either filled with recombinant human BMP-2 on the Once again, we see the In this case in 21 In contrast in the case of the BMP animals, 22 although 100 percent lacked lucency on the plain x-ray NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 201 of 581 1301 PageID 69 1 criteria, only 95 percent, which means all but one animal 2 had continuous bridging bone as measured by histology, 3 the ultimate assessment of bone formation inside the cage. 4 5 Once again, biomechanical testing show that 6 there was no statistical difference in the stiffness 7 between the fusions that were formed with the autograft 8 or fusions that were induced by the recombinant BMP-2. 9 So, again, bone induced by BMP-2 absorbable collagen 10 sponge functionally, inside the cage functioned similar 11 to that of autograft bone. 12 presence of the metal cage might interfere with the ability 13 to truly assess the quality of the bone and for that reason 14 I'll just briefly show some mechanical assessment of bone 15 with recombinant BMP-2 on the same carrier matrix, that's 16 the absorbable collagen sponge but from a posterolateral 17 fusion model where there's no metal. 18 The Now, one could argue that the advantage of this model, which 19 incidentally the autograft once again fused less than 50 20 percent of the animals and BMP-2 absorbable collagen 21 sponge fused 100 percent of the animals but we can do 22 testing that looks at just the strength and quality of NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 202 of 581 1302 PageID 70 1 the bone formed in the fusion without any confounding 2 information from metal fixation. 3 case, the mechanical properties of the bone formed with 4 BMP-2 shown in the green bars were essentially comparable 5 to those in terms of relative strength and relative 6 stiffness seen with autogenous bone. Once again, in this 7 Now moving onto the non-human primate studies 8 which are extremely relevant as was mentioned earlier by 9 Dr. Riedel, because of the close parallel of the required 10 concentration of BMP-2 to get efficacy of bone formation 11 in non-human primates and how that translates to human 12 clinical trials. 13 or bone cage was filled with either BMP-2 and absorbable 14 collagen sponge or with autogenous bone graft and inserted 15 in a rhesus monkey single level, interbody fusions. In this case an allografted bone dowel 16 These two x-rays show an example from a 17 control and you can see that the intervertebral disc space, 18 that black line, is still present and there was no bridging 19 bone or fusion across the segment when the allograft bone 20 dowel was filled with BMP-2. 21 you can see that bone has bridged the two vertebral 22 segments completely obliterating the disc space with the In contrast, in this case NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 203 of 581 1303 PageID 71 1 allograft dowel was filled with BMP-2 and in addition, 2 the allograft dowel has been remodeled. 3 These microradiographs again highlight this 4 point. Two controls shown on the to, in this case, the 5 remnant of the allograft dowel can be seen but bone is 6 growing into and through it. 7 fallen out of the histologic section but you can see that 8 bone has not grown completely through the specimen. 9 contrast, these are two examples from animals that had 10 BMP-2 with absorbable collagen sponge inside that cage 11 and you can see that there's bridging trabecular bone 12 across the interspace and remodeling of the allograft bone 13 cage. In this case the dowel has In 14 The last pre-clinical study is the one that 15 most closely simulates what was to take place in human 16 -- in the fact that this time BMP-2 with absorbable 17 collagen sponge was placed into a scaled down titanium 18 fusion cage. 19 lumbosacral junction with a six-month end point and the 20 cage was either filled with the absorbable collagen sponge 21 with buffer only, in other words, no BMP-2 or one of two 22 doses, .75 This was inserted into rhesus monkey at the or 1.50 milligrams per milliliter of NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 204 of 581 1304 PageID 72 1 recombinant human BMP-2. 2 What we found was that the sponge alone did 3 not result in any spontaneous bone formation through the 4 cage in either of those control animals. 5 of the animals that received either dose of recombinant 6 BMP-2 on the collagen sponge had histologic bone formation 7 through the cage as can be seen on these two examples. However, all 8 This slide is important because it leads to 9 the reliance and the importance of using CT scans to assess 10 the presence of bone inside an interbody fusion cage. 11 Here you can see that histologically in this case there 12 was no bone forming inside the cage and on the CAT scan 13 you can see that this dark area rather than a bright white 14 area suggests that there is not a density consistent with 15 bone inside the metal fusion cage. 16 animals where bone grew through the cage, a CT scan 17 revealed homogeneous bridging trabecular bone through the 18 center of the cage on the CAT scan. In contrast, in 19 The quality of the bone and the normalcy in 20 the non-human primates was as described earlier by Dr. 21 Riedel in rodents and other animal models being entirely 22 normal bone with osteoblast-line trabeculae remodeling NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 205 of 581 1305 PageID 73 1 and bone marrow elements. 2 Now I'd like to briefly describe the pilot 3 clinical study that was undertaken following that rhesus 4 monkey pre-clinical study as an introduction to validating 5 the evaluation tools. 6 four investigational sites, the LT-threaded tapered 7 fusion cage was filled with either autogenous bone graft 8 in a small number of patients or with infused bone graft, 9 that is recombinant human BMP-2 in absorbable collagen 10 In this study which was done at sponge. 11 First I'd like to briefly review the surgical 12 anatomy for those who may be less familiar with the spine. 13 The normal spine would have two vertebra adjacent 14 connected by the intervertebral disc cartilage and in the 15 approach that's being put before the panel today which 16 is an anterior surgical approach, two cages are inserted 17 from the front of the spine. 18 there is residual disc or annulus material that serves 19 as 20 compartmentalization that Dr. McCullough was asking for 21 earlier preventing gross leakage of BMP-2 and carrier 22 matrix into the area where the neuro elements would be. a microscopic It's important to note that barrier creating that NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 206 of 581 1306 PageID 74 1 2 Looking at this in cross section, we can see 3 here the normal or pre-operative and then post-surgical 4 schematic of two cages inserted side by side again with 5 residual annular tissue serving as a macroscopic barrier. 6 I should point out that while this is a macroscopic 7 barrier and there can be fissures, in none of the animal 8 studies nor in the human studies have we seen formation 9 of bone posterior to the cage outside the confines of the 10 disc space when the anterior surgical approach has been 11 used which is under consideration today. 12 So the device before it goes in, has the 13 wetted collagen sponge inside the taped fusion cage and 14 in this clinical pilot study, 11 out of 11 patients were 15 deemed by independent review of plain x-rays and CT scans 16 to have achieved bridging trabecular bone through and/or 17 around the fusion cages. 18 were shown to have successful bridging bone. 19 Two of three of the autograft Another issue is the impact on clinical 20 outcome. In the Oswestry Disability Index is a disease 21 specific patient derived outcomes measure, which is 22 commonly used in patients with low back problems. In this NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 207 of 581 1307 PageID 75 1 case having a lower score is desirable or indicative of 2 less symptoms or less disability. 3 from pre-op to 24 months, gradually decreased on both 4 groups, in this case it seemed a little bit quicker in 5 the infused group and it nearly reached statistical 6 significance but in the end the clinical outcome was at 7 least as good in patients that used infused and did not 8 have to have a second site harvest with autogenous bone 9 graft. In the Oswestry scores 10 Lastly, I think showing some representative 11 pictures are really important to bring home the fact that 12 bone is forming in an area where there otherwise wasn't 13 bone. 14 at a slice through the right-hand cage, the left-hand cage 15 and a coronal view of both cages or frontal view using 16 reconstructed thin sliced CT scans. 17 represent different points in time; six months, 12 months 18 and 24 months. 19 started with autograft bone, that in fact, there was 20 incorporation of the autograft in this case and there is 21 bridging trabecular bone through the cages both on the 22 lateral and on the frontal view. The format of the next several slides will look And the three columns And you can see from this patient that NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 208 of 581 1308 PageID 76 1 Here's an example of another autograft 2 patient where you can see that there's less density inside 3 the cage perhaps with resorption of the autograft bone 4 and over time there were lucencies that formed around the 5 cage and absence of ridging bone suggesting a failure of 6 bone formation and fusion. 7 of some of the infused patients keeping in mind that the 8 cage starts out without any bone in it and so when we see 9 white bone growing through the cage, we know that it was 10 Contrast that with an example induced as a result of infuser BMP-2. 11 You can see here in both cages there's bone 12 growing through the cages and as time progresses you can 13 see secondary ossification which is a normal adjunctive 14 finding in any solid fusion around the cages through the 15 disc space. 16 showing an increase in bone density in the cage over time 17 and also the secondary healing around the cage normal for 18 a solid interbody fusion. Another example of an infused patient, again 19 Another question is what happens to the bone 20 inside these cages over a longer period of time and 21 although this was a pilot study, these patients have 22 continued to be followed and this is an example of one NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 209 of 581 1309 PageID 77 1 of the autograft patients at 48 months showing that when 2 autogenous bone was put inside the cage, then in fact, 3 it remains bridging through the cage and remodels similar 4 to the density of bone in the adjacent vertebral bodies. 5 Looking at a patient that received infused 6 we saw this same trend of preservation of bone in the cage, 7 not disappearing of bone, and continuing to mature the 8 adjunctive fusion throughout the interspace. 9 that's induced with BMP behaves ostensibly the same as 10 bone that was put by autograft bone in the case of inside 11 the fusion cage. So the bone 12 And just one other example of a patient with 13 BMP, again with longer term follow-up showing that the 14 fusion is maintained even at four years with bone both 15 through the cage and around the side of the cage. 16 think it's important to summarize the goals of the 17 recombinant BMP-2 absorbable collagen device. 18 heard much about systemic safety and toxicity in the first 19 talk and I think at this point it suffice it to say very 20 simply that we did not see any bone formation at a distance 21 from the cages or in any place outside the caged in matrix 22 in any of the animals or any of the pilot patients that So I You've NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 210 of 581 1310 PageID 78 1 have been discussed so far. 2 Equally important to safety is 3 effectiveness. 4 should be considered the ability to eliminate bone 5 grafting morbidity which is substantial in these patients 6 and to obtain equal or better healing success rate defined 7 as bridging trabecular bone across the interspace and 8 through the cage. 9 goal of recombinant BMP-2 absorbable collagen sponge 10 And effectiveness for this device really In other words, stated more simply the device is to make bridging bone. 11 So in conclusion, based on a series of 12 detailed pre-clinical and a clinical pilot trial, I 13 believe that recombinant BMP-2 absorbable collagen sponge 14 has shown success in 95 percent or better in four animal 15 studies, substantially better than autograft controls in 16 those 17 biomechanically equal to that formed with autogenous bone 18 graft. 19 histology of bone and therefore, is an important indicator 20 of the presence of new bone formation by BMP-2 inside 21 fusion cages. models. 22 The bone formed is normal and CT scan analysis correlates the best with the And finally, the concentration of BMP-2 that NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 211 of 581 1311 PageID 79 1 was successful in the rhesus monkey pre-clinical study 2 was also successful in the clinical pilot study with 100 3 percent success in humans at the same doses that were 4 predicted by the rhesus monkeys. 5 to turn the podium over to Dr. Hal Mathews, who will 6 describe the results of the pivotal clinical trial in 7 greater detail. At this point, I'd like 8 DR. MATHEWS: Distinguished panel members, 9 ladies and gentlemen, good morning. My name is Hal 10 Mathews. I'm a practicing spine surgeon from Richmond, 11 Virginia. 12 an 13 neurosurgery at the Medical College of Virginia in 14 Richmond. 15 product under review here today and I'm not being paid 16 for my participation in this meeting. 17 the open surgical approach study of this device as an 18 investigator. My entire clinical focus is spine associate clinical professor of care. I'm orthopedics and I have no direct financial interest in this I participated in 19 I'm here today to present the results of the 20 InFUSETM Bone Graft/LT Cage Lumbar Tapered Fusion Cage 21 Device clinical trial. 22 want to report to this advisory panel and to the audience Before I discuss the details, I NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 212 of 581 1312 PageID 80 1 the top line findings from this open surgical approach 2 study. 3 clinical trial as stated in the protocol was met, thus 4 establishing the safety and effectiveness of the InFUSETM 5 bone graft in the treatment of degenerative disc disease. 6 Secondly, the InFUSETM bone graft stimulates 7 the formation of bone which results in very high fusion 8 rates. 9 experience shorter operative times and less blood loss First and foremost the primary objective of the Thirdly, the InFUSETM bone graft patients 10 than the control patients. And finally, patients who 11 receive the InFUSETM bone graft avoided the complications 12 and significant post-operative pain associated with bone 13 graft harvesting in the control group. 14 Let me offer a few additional observations 15 that I believe will bring into sharper focus the clinical 16 trial results. 17 physicians to help our patients in the least invasive and 18 least painful ways. 19 graft was taken from their iliac crest, at the time of 20 discharge, 80 percent of patients registered a score of 21 at least 10 out of 20 and nearly 15 percent of these 22 patients had a score of at least five at 24 months. At the end of the day it is our job as For the patients from whom a bone In NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 213 of 581 1313 PageID 81 1 addition, six percent of these patients experienced graft 2 site complications, including bone fractures, nerve 3 injuries, infections and hematomas. 4 Given its equivalent performance in 5 achieving fusion, the infused bone graft is clearly the 6 most humane way to treat this painful condition. 7 now elaborate on the clinical trial and the results and 8 I will conclude with a brief review of the laparoscopic 9 clinical trial that was also conducted showing equivalent 10 rates of fusion as well as some other potential patient 11 benefits. 12 I will Let us now discuss the open surgical approach 13 for device implantation. 14 randomized 15 treatment patients received the LT cage device filled with 16 the InFUSETM bone graft. 17 patients as the InFUSETM group. 18 treated in a 19 with autogenous harvested bone from the iliac crest. 20 These patients will be designated the autograft group. control This study had a prospective design. The investigational Henceforth, I will refer to these The control patients were similar manner with the LT cage device filled 21 The primary objective for the clinical trial 22 was to determine if the overall success rate for the NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 214 of 581 1314 PageID 82 1 InFUSETM is at least as high statistically as the rate for 2 the autograft group. 3 variable encompassing primary safety and effectiveness 4 considerations. 5 equivalency and superiority of specific end points were 6 also developed. 7 Overall success is a derived Secondary objectives focusing on Bayesian methods were used for statistical 8 comparison of study outcomes. 9 study had a single level symptomatic degenerative disc 10 disease as noted by back pain of discogenic origin with 11 or without leg pain with degeneration of the disc confirmed 12 by patient history and radiographic studies. 13 a number of additional inclusion and exclusion criteria 14 such as age, weight, mental competency, medical history, 15 and existing medical condition. 16 Patients admitted to the There are Patients involved in the clinical trial were 17 evaluated pre-operatively, at surgery and 18 post-operatively at six weeks, three, six, 12 and 24 19 months. A total of 143 patients received the InFUSETM bone 20 graft. There were 136 patients who were treated with 21 autogenous bone graft. 22 all post-operative periods exceeded 90 percent. Patient follow-up compliance at Sixteen NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 215 of 581 1315 PageID 83 1 investigational centers contributed to these patients. 2 3 Patients in both treatment groups had very 4 similar demographic characteristics and pre-operative 5 medical conditions. 6 interpret 7 confounding factors did not impact with the results. 8 terms of surgery results, the mean operative time for the 9 InFUSETM group was approximately one-half hour less than 10 that for the autograft group and this finding was 11 statistically different. the This enhances one's ability to treatment effects since potentially In 12 The blood loss for the InFUSETM group was also 13 statistically lower than that for the autograft group. 14 The mean hospital stays of patients in both treatment 15 groups were slightly more than three days and did not have 16 statistical difference. 17 variables such as treated level, operative approach and 18 type of orthosis were similar for both groups. 19 outpatient and inpatient classification and return to work 20 times were also comparable. 21 For 22 clinical The results of other surgical outcomes I would like The to emphasize that 24-month data are being used a primary NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 216 of 581 1316 PageID 84 1 supporting evidence of the safety and effectiveness of 2 treatments. 3 spinal implant studies, a composite variable termed 4 overall success was created and this variable is the 5 primary end point of the entire study for PMA approval 6 purposes. 7 In order to satisfy the FDA's guidance for Overall success is comprised of the 8 effectiveness parameters of fusion, Oswestry success, 9 neurologic success. It is also influenced by two 10 important safety considerations, the occurrence of any 11 serious adverse events possibly associated with the device 12 and 13 classified as a failure. 14 is very demanding. the occurrence of a second surgical procedure The overall success criteria 15 The primary objective of this study was to 16 determine if the overall success rate for the InFUSETM group 17 was at least as high statistically as for the autograft 18 group. 19 rates for the two treatment groups at 12 and 24 months 20 following surgery are very similar and stable over time. 21 These rates were statistically equivalent at 24 months. 22 Therefore, the primary clinical trial objective was met, As evidenced from this slide, the overall success NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 217 of 581 1317 PageID 85 1 thus supporting approval of this product. 2 I will now discuss in detail the safety and 3 the effectiveness parameters that were used in this 4 clinical trial. 5 nature and the frequency of adverse events and second 6 surgery procedures and the formation of antibodies to 7 rhBMP-2 and collagen. 8 infused group was found to be as safe as the autograft 9 group. 10 Safety was assessed as a function of the Based on these assessments, the Now for more details. Reported adverse 11 events in each group were classified by their nature, their 12 severity according to the World Health Organization 13 criteria, and their duration. 14 Danek instructed investigators to report all adverse 15 events that occurred whether or not the event was related 16 to the treatment or the device. 17 approach led to the reporting of many unrelated events 18 that were included in the analysis. 19 only 17 patients or 11.9 percent had an event that was 20 possibly related to the device and only 11 of these 21 patients or 7.7 percent were the events considered 22 serious. Also Medtronic Sofamor This conservative For the InFUSETM group NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 218 of 581 1318 PageID 86 1 Overall, a total of 113 InFUSETM patients had 2 at least one adverse event with a substantial majority 3 not being related to the device. 4 slide, these rates are very similar to those rates for 5 the 6 categorized according to their nature and comparisons were 7 made between the two treatment groups. 8 statistical differences for all reported categories of 9 adverse events except for two. autograft group. Adverse were also There were no These categories in which differences were 11 urogenital. Nearly six percent of the autograft patients 12 had 13 included bone fracture, nerve injuries, infection and 14 hematoma. 15 site were events 10 graft noted As you can see from this graft complications. site These events and complications Obviously, there were not graft site adverse 16 events for the InFUSETM group. 17 the use of InFUSETM bone graft since it eliminates the need 18 to harvest bone graft. 19 favor the autograft group. 20 mainly due to urinary retention following surgery and 21 these events resolved in all patients prior to discharge 22 from the hospital. This fact clearly supports Urogenital complication rates The difference in rates was NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 219 of 581 1319 PageID 87 1 Overall the occurrence of adverse events in 2 the clinical trial were considered typical for a patient 3 population having an anterior lumbar interbody fusion 4 procedure and were not unanticipated. 5 of safety assessment is the number and nature of additional 6 surgical procedures performed after the initial study 7 surgery. 8 additional surgical interventions. 9 According This and slide lists to the the classifications protocol, revisions, removals 11 significant procedures at the treated spinal level that 12 effect 13 Therefore, a patient having one of these procedures is 14 considered a treatment failure for study purposes. 15 the 16 procedures that are believed to have no effect on the 17 treated level are therefore, not considered failures. 18 The second surgery rates for both groups were comparable 19 and there were no statistical differences for any of the 20 additional surgery category comparisons. other assessments hand, of fixations of 10 the supplemental Another component the re-operations are considered treatment and other outcome. On surgical 21 Because of the proteinaceous nature of both 22 rhBMP-2 and the absorbable collagen sponge the development NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 220 of 581 1320 PageID 88 1 of antibodies was assessed as part of the IDE clinical 2 trial. 3 pre-operatively to establish their baseline condition and 4 at three months following surgery. 5 analyzed for the presence of antibodies specific to 6 rhBMP-2 and to bovine type I collagen. 7 a positive response to bovine type I collagen, the serum 8 was also tested for antibodies to human type I collagen. 9 Serum samples were taken from each patient Antibody levels were checked in These samples were If a patient had both InFUSETM and 10 autograft patients, even though the latter group was not 11 exposed to the InFUSETM product. 12 The rates of antibody formation were not 13 different for the two treatment groups. 14 InFUSETM 15 authentic positive responses to rhBMP-2. 16 rates were very low, at less than one percent. 17 no adverse events that appeared to be related to these 18 findings. patient and one autograft There was one patient who had The incidents There were 19 Approximately 13 percent of patients in both 20 treatment groups had authentic positive responses to 21 bovine type I collagen. 22 appear to result in any clinical manifestation nor impact These antibody responses did not NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 221 of 581 1321 PageID 89 1 the overall success rates of the study. 2 patients who tested positive for bovine type I collagen 3 had a positive result for human type I collagen. These 4 antibody other 5 Medtronic Sofamor Danek clinical trials involving the 6 InFUSETM bone graft. findings are similar to those None of the from 7 Since I've presented a lot of information, 8 I want to briefly review the impressive safety profile 9 of the use of the InFUSETM bone graft with the LT-cage device 10 before moving onto the effectiveness results. 11 events and second surgery procedures for the InFUSETM 12 treatment were very similar to the autograft treatment. 13 The rates of antibody formation were not different for 14 the two treatment groups. 15 antibody 16 manifestation. response appeared Adverse In addition, any positive to be without clinical The use of the InFUSETM bone graft eliminated 17 18 graft harvesting 19 approximately six percent of the autograft patients and 20 significant graft site pain in approximately 80 percent 21 of 22 significant since it supports a major reason for using patients adverse events peri-operatively. that This occurred finding in is NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 222 of 581 1322 PageID 90 1 the InFUSETM bone graft. 2 There were also no cardiovascular adverse 3 events associated with the use of the InFUSETM bone graft. 4 Therefore, based on the data, the InFUSETM bone graft 5 LT-cage device is safe for its intended use in the anterior 6 lumbar interbody fusion procedures to treat degenerative 7 disc disease. 8 Now, we'll focus on device effectiveness. 9 Briefly in summary, these patients received the InFUSETM 10 bone graft experienced exceptionally high fusion rates, 11 pain relief, maintenance or improvement in neurologic 12 status. 13 more detail. 14 point since the intended use of the infused bone graft 15 is to induce bone formation in spinal fusion procedures. Let's review specific effectiveness results in We consider fusion to be the primary end 16 17 For this clinical trial, CT scans and 18 radiographs were used to assess fusion. 19 evaluated at the University of California San Francisco 20 under the direction of Dr. Harry Genant, a board certified 21 radiologist. There were two teams of reviewers who were 22 masked to patient treatment. These films were Each team worked NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 223 of 581 1323 PageID 91 1 independently of each other. 2 conclusions differed, a third reviewer would adjudicate 3 the findings. 4 the percent agreement between the two primary review teams 5 exceeded 98 percent at all time points. 6 If their overall fusion However, this occurred in frequently since Fusion was based on evidence of bone, 7 spanning the two vertebral bodies of the treated segments, 8 using CT scans and radiographs. 9 stability and lucent line criteria also had to be met to In addition, segmental 10 be considered fused. 11 procedures 12 pseudoarthrosis or non-union were also considered as 13 fusion failures regardless of independent radiographic 14 findings. reported 15 Patents having second surgical by the investigator as due to This later condition dramatically impacts 16 fusion rates for both treatments. 17 months post-operatively, all non-unions in the InFUSETM 18 group were due to second surgery criteria and not the 19 radiographic 20 treatment groups were high at 12 and 24 months following 21 22 surgery. criteria. The For example, at 24 fusion rates for both At 24 months following surgery the InFUSETM fusion rate was 94.5 percent and was statistically NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 224 of 581 1324 PageID 92 1 equivalent to the autograft rate of 88.7 percent. 2 Frankly, for the study the most important 3 aspect of the fusion criteria is whether bone, spanning 4 the two vertebral bodies at the treated level could be 5 detected by the independent radiologist. 6 indicative of whether the InFUSETM bone graft was effective 7 in stimulating de novo bone formation. 8 that in all patients in both treatment groups with CT scans 9 available, such spanning bone was detected at 12 and 24 scans were It is noteworthy 10 months. 11 detecting the bone. 12 prime importance since fusion cannot exist unless bone 13 is connecting the treated segment. 14 CT This would be particularly important in These findings are considered of In addition, these findings agree with the 15 data previously presented by Dr. Scott Boden. The 16 Oswestry Low Back Pain Disability Questionnaire was used 17 to measure the effects of back pain on a patient's ability 18 to manage everyday life. 19 10 questions and is self-administered. 20 are expressed as a scale ranging from zero to 100 points 21 with a lower score indicating less pain and disability. 22 As seen with this slide, the mean Oswestry The Oswestry Questionnaire has Oswestry scores NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 225 of 581 1325 PageID 93 1 scores for the two treatment groups were very similar at 2 all time periods. 3 mean improvements in Oswestry scores from pre-operatively 4 were approximately 29 points for both treatment groups. 5 These findings are quite gratifying and represent an 6 At 24 months following surgery, the approximate 55 percent improvement. 7 This slide illustrates the distribution of 8 patients demonstrating pre-operative to post-operative 9 improvements in Oswestry scores of at least 15 points, 10 which is a very rigorous condition mandated by the FDA. 11 This is termed Oswestry success. Like mean Oswestry 12 scores, the Oswestry success rates were similar for both 13 treatment groups. 14 Oswestry success rates were found to be statistically 15 equivalent with rates of 73 percent in both groups. At 24 months following surgery the 16 The neurologic status of patients was also 17 assessed pre-operatively and post-operatively and at 18 every follow-up visit and is considered an indicator of 19 safety and effectiveness. 20 consisted of measurements of motor function, sensory, 21 reflex, and degree of straight leg raise producing pain. 22 A successful outcome for each parameter was based on the The neurologic evaluations NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 226 of 581 1326 PageID 94 1 post-operative condition 2 pre-operative condition. being no worse than the 3 Overall neurologic success for a patient in 4 any given post-operative time period was based on having 5 successful outcomes for all four neurologic parameters. 6 This slide shows the overall neurologic success at 12 7 and 24 months following surgery for the two treatment 8 groups. 9 treatment. The rates are very similar across time and The 24-month neurologic success rates for the 10 InFUSETM and autograft groups were determined to be 11 statistically equivalent. 12 In addition to overall to these other points that 13 contribute 14 measurements were made during the course of this study. 15 These measurements included back pain, leg pain, disc 16 height maintenance and general health status via the SF-36 17 survey. 18 comparable for the two treatment groups and statistically 19 equivalent between treatments was demonstrated for all 20 but two comparisons. 21 component summary or MCS of the SF-36. 22 success, end effectiveness The 24-month results for these parameters were They were back pain and mental I will not focus on the MCS finding since NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 227 of 581 1327 PageID 95 1 the difference between the two treatment groups was less 2 than four percentage points and this is not considered 3 clinically significant. 4 favored the autograft group and it is believed to be due 5 to arbitrary cut-off assumptions of the analysis, since 6 a mean improvement of back pain scores for the InFUSETM 7 group was actually higher, showing more improvement than 8 that for the autograft group. 9 Another For back pain the success rate very important effectiveness 10 parameter that was assessed was graft site harvest pain. 11 This was measured in autograft patients using two 12 numerical rating scales, one for pain intensity and the 13 other for duration. 14 zero to 20 with a lower number signifying a better outcome. 15 This slide shows a mean graft site pain for autograft 16 patients from time of hospital discharge to 24 months 17 post-operatively. 18 was 12.7 and approximately 80 percent of patients had 19 scores of at least 10. 20 improved over time. The composite pain score ranged from At hospital discharge the mean score As expected, the harvest site pain 21 However, nearly 15 percent of patients had 22 a score of at least five at 24 months post-operatively. NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 228 of 581 1328 PageID 96 1 Aside from the pain approximately 16 percent of patients 2 indicated they were still bothered by the appearance of 3 the graft site at one and two years following surgery. 4 When these rates are coupled with the adverse events 5 associated with harvesting the bone, a very compelling 6 case can be made for using infused bone graft in spinal 7 fusion procedures since it eliminates the negatives of 8 graft site appearance, pain and morbidity. 9 There is additional good news about the 10 InFUSETM bone graft. Another clinical trial was performed 11 examining the laparoscopic implantation of the device and 12 the results are just as compelling as for the open study. 13 The data from the laparoscopic study augments the safety 14 profile of the device and support approval of that surgical 15 method of cage implantation. 16 one treatment group, those patients treated with the 17 InFUSETM bone graft and the LT-cage device. 18 this, the protocol was identical to that of the open study. The laparoscopic study had Other than 19 20 A total of 134 laparoscopic patients 21 investigational 22 centers contributed the patients. received treatment. the Fourteen There was no overlap NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 229 of 581 1329 PageID 97 1 in surgeons between the open and laparoscopic studies. 2 On average the hospital stay for laparoscopic patients 3 was approximately two days shorter and statistically 4 different than for patients of either treatment group of 5 the open study. 6 Further, nearly 45 percent of laparoscopic 7 patients were treated on an outpatient basis as compared 8 to virtually none in the open study. 9 patients also returned to work some 20 days sooner than The laparoscopic 10 for the open study patients. 11 and return to work findings for the laparoscopic patients 12 may suggest that there is a synergistic effect of the use 13 of the InFUSETM bone graft and the laparoscopic insertion 14 of the LT-cage device. 15 The overall These surgery, hospital stay success rate at 24 months 16 following surgery for laparoscopic patients was more than 17 68 percent and nearly 12 percentage points higher than 18 for the autograft rate of 56 percent. 19 only statistically equivalent to the autograft, but 20 statistically superior, a finding that more than satisfies 21 a primary objective of the laparoscopic study. 22 This rate was not The safety profile of the laparoscopic use NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 230 of 581 1330 PageID 98 1 of the device was also comparable to the open surgical 2 treatment groups. 3 rate was higher than with the open surgical treatment due 4 to 5 patients. 6 noted in other large studies using the laparoscopic 7 implantation of the LT-cage device. the As expected retrograde ejaculation transperitoneal approach for laparoscopic However, the rate was lower than previously 8 The effectiveness investigational results patients for were the 9 laparoscopic also 10 impressive. 11 be claimed for all comparisons to the autograft group from 12 the open study. 13 identical to that for the open InFUSETM bone graft treatment 14 at approximately 94 percent, these compared to an 88.7 15 percent value for the autograft group. 16 bone was noted in all evaluated patients at 12 and 24 months 17 radiographically. This slide shows statistical equivalence can At 24 months the fusion rate was virtually Again, bridging 18 Since seeing is believing, I want to spend 19 the next few minutes showing a few slides of some study 20 patients using CT. 21 these 22 treatment for at least six months prior to being included patients According to the protocol criteria, had not responded to non-operative NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 231 of 581 1331 PageID 99 1 in this study and had significant amounts of pain. 2 first case is an example of a successful radiographic 3 fusion in an autograft patient. 4 The The patient is a 37-year old female that had 5 an L5/S1 fusion procedure. Since cortico cancellous 6 autogenous bone chips are placed in this autograft 7 patient's cages, it appears radio-opaque immediately 8 after surgery. 9 and consolidate to form bridging bone through the cages. 10 The second patient was a 38-year old female who had an Over time the bone chips begin to bridge 11 L5/S1 fusion procedure. This particular patient's cage 12 were filled with autograft. 13 successful fusion. The patient was not a 14 As a result of the failed fusion and lack 15 of stabilization across the disc space, the surrounding 16 bone undergoes some absorption that becomes evidenced by 17 radiolucencies and black lines around the cages. 18 third patient is a 42-year old female who had an L4/5 fusion 19 procedure with the InFUSETM bone graft placed inside the 20 cage. In contrast to the autograft filled cages, when 21 InFUSETM bone graft is placed into the cage, it is not 22 initially radio-opaque. The The InFUSETM bone graft starts NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 232 of 581 1332 PageID 100 1 out as a dark appearance within the cage, so as to increase 2 whiteness, this is due to new bone formation. 3 The CT scan clearly shows evidence of new 4 bone 5 radio-opacity. 6 formation at six months, evidenced by the And over time this bone becomes denser. In addition, anterior bridging bone can be seen in front 7 of the cage and around the sides of the cage. This is 8 further evidence of mechanical stabilization across the 9 disc space. 10 One question you may be considering is do 11 these impressive CT scans infusion results hold up over 12 time and the answer is yes, and this is based on four-year 13 post-operative CT scans from the same InFUSETM treatment 14 that Dr. Boden previously presented. 15 as demonstrated in both animal and human studies CT scans 16 are the most practical and definitive method of detecting 17 new bone formation within cages and determining fusion 18 status. So to summarize, 19 The scientific data I have presented has been 20 impressive and we believe the results certainly support 21 approval of the product. 22 to be satisfied with their results. Science aside, patients need So study patients NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 233 of 581 1333 PageID 101 1 were asked at their post-operative visits to respond to 2 three questions related to satisfaction. 3 vouches for the high levels of satisfaction at 24 months 4 following surgery for both InFUSETM bone graft LT-cage 5 device treatments and for the autograft group. This slide 6 Generally 75 to 82 percent of the patients 7 offered positive responses which are very gratifying 8 findings considering the complex nature of low back pain 9 and degenerative disc disease. In conclusion, the 10 primary objective of the prospective randomized study of 11 the open surgical implantation of the InFUSETM device was 12 met. 13 LT-cage device was found to be statistically equivalent 14 to the autograft treatment. The overall success rate of the InFUSETM bone graft 15 The InFUSETM treatment was associated with 16 shorter operative times, less blood loss than their 17 autograft control patients. 18 of InFUSETM bone graft are that it induces bone formation 19 and that it eliminates the need to harvest autogenous bone 20 graft in spinal fusion procedures. 21 results attest to the need for InFUSETM bone graft treatment 22 since 80 percent of the Two of the primary benefits The autograft group patients had significant NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 234 of 581 1334 PageID 102 1 perioperative graft site pain and nearly six percent of 2 these patients had an adverse event associated with graft 3 harvesting. 4 Further, the laparoscopic implantation of 5 the infused device produced very positive clinical results 6 as well. 7 higher than the autograft group. 8 patients had hospital stays that were two days shorter 9 than the autograft group and they returned to work some The overall success rate was statistically In addition, the 10 20 days sooner. Therefore, the results of this study of 11 the open and laparoscopic implantation of the InFUSETM bone 12 graft with the LT-cage lumbar taper fusion device showed 13 the device to be safe and effective in the treatment of 14 degenerative disc disease. 15 Thank you very much. 16 DR. LIPSCOMB: as clearly Members of the panel, in 17 conclusion demonstrated in these 18 presentations, and in the information that was submitted 19 in the PMA application, more than a reasonable assurance 20 of the safety and effectiveness of InFUSETM bone graft with 21 the LT-cage device has been presented. 22 following our presentations the FDA will pose several We understand that NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 235 of 581 1335 PageID 103 1 questions to this panel. We believe that our 2 presentations have provided much information to address 3 FDA's questions. 4 For the sake of clarity, let me summarize 5 what you have just heard as it relates to some of these 6 questions. 7 of rhBMP-2 stimulating cell proliferation from existing 8 tumor. 9 a preponderance of evidence that rhBMP-2 has either no One question pertains to a theoretical issue A comprehensive review of the literature provides 10 effect or an 11 proliferation. inhibitory effect on tumor cell 12 We believe that ongoing laboratory testing 13 at Wyeth-Genetic Institute as well as precautionary 14 labeling 15 theoretical concerns. 16 pertains solely to the effects of rhBMP-2 on an existing 17 tumor and there is no scientific evidence to suggest that 18 rhBMP-2 transforms a normal cell into a tumor cell. statements will address any remaining Again, to emphasize, this issue 19 Another FDA question to the panel involves 20 an immunology issue, specifically, what effects, if any, 21 do antibodies to rhBMP-2 have on a developing fetus and 22 the mother. Again, this is a theoretical issue that has NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 236 of 581 1336 PageID 104 1 not been manifested in either animal studies or in our 2 human clinical trials. 3 antibody response was less than one percent and was similar 4 to that in the control group in our InFUSETM clinical trials 5 that you heard about this morning. 6 We do The rate of authentic rhBMP-2 believe via this issue precautionary can be 7 adequately 8 statements and instructions to females of child bearing 9 age. 10 addressed that labeling Also we intend to discuss further with FDA the necessity for a pregnancy register. 11 Another line of questioning to the panel 12 pertains to radiological issues. One aspect, is there 13 functioning bone inside the cage? 14 Histological results from animal studies have verified 15 that InFUSETM bone graph causes normal bone to form and 16 that accompanying CT scans show that the appearance of 17 the bone radiologically. 18 similarly reveal the presence of bone where none existed 19 before in the InFUSETM bone graft patients. 20 remains intact and dense over time as evidenced from the 21 CT scans that have been presented to you some of which 22 are out as far as four years following surgery. The answer is yes. Our clinical study CT scans This bone also NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 237 of 581 1337 PageID 105 1 Finally, the major panel consideration, is 2 the use of InFUSETM bone graft with the LT-cage safe and 3 effective in the treatment of symptomatic degenerative 4 disc disease? 5 here 6 response to that question. 7 in vivo and in vitro studies attest to the safety of InFUSETM 8 bone graft. 9 data from a pilot study as well as two large scale pivotal 10 studies demonstrate InFUSETM bone graft safely stimulates 11 the formation of bone. today 12 The valid scientific evidence presented unquestionably provides an affirmative A multitude of pre-clinical Functional animal model testing and clinical The data from nine animal species and from 13 humans are consistent. They are compelling and they are 14 convincing. 15 bone where none existed before and is an effective 16 substitute for autograft bone. 17 than a reasonable assurance that the device is safe and 18 effective for its intended use and this is the criterion 19 for PMA approval. 20 the importance and the validity of this information and 21 make this breakthrough technology available to surgeons 22 and their patients by recommending approval of this PMA InFUSETM bone graft can safely form normal These data provide more We believe that you will acknowledge NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 238 of 581 1338 PageID 106 1 application. 2 This concludes Medtronic Sofamor Danek's 3 presentations. 4 questions. 5 6 7 We are available to respond to any of your Thank you. CHAIRPERSON FINNEGAN: Thank you. Actually, I think we'll do the questions later on today. We are going to take a 10-minute break. We will return 8 at 12:00 o'clock for the FDA's presentation and then we 9 will break for lunch. 10 (A brief recess was taken.) 11 CHAIRPERSON FINNEGAN: We are going to have 12 the FDA presentation and this is in two parts. 13 part is the FDA panel. 14 staff who will give their presentations and the second 15 portion will be three guest reviewers that the FDA has 16 asked to look at particular portions of this PMA. 17 the FDA presentation will be started by Dr. Aric Kaiser. 18 DR. KAISER: The first Those are the members of the FDA Good morning. And I'm Aric Kaiser, 19 an expert reviewer in orthopedics and the lead reviewer 20 for the PMA. 21 members of the primary review team for this PMA who will 22 be making the FDA presentations this morning. I would like to first introduce the other Peter NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 239 of 581 1339 PageID 107 1 Hudson was the lead pre-clinical reviewer, Barbara Buch, 2 the clinical reviewer and Telba Irony, the statistical 3 reviewer. 4 efforts of a number of other people involved in this 5 project both from the Center for Devices as well as 6 valuable input from the Center for Biologics. I'd also like to acknowledge the expertise and 7 The sponsor has gone into detail describing 8 the product, their pre-clinical data and the clinical 9 results. And I'd like to remind the panel that the device 10 that we're seeking your recommendations on today is the 11 InFUSETM bone graft LT-cage lumbar tapered fusion device 12 which is a three-component spinal fusion device that 13 consists of a spinal implant, a growth factor and a 14 carrier. 15 The first component, the cage component, is 16 a titanium alloy tapered spinal fusion cage and as the 17 sponsor has already mentioned, it has received PMA 18 approval for use in the treatment of degenerative disc 19 disease when filled with autograft. 20 components, the InFUSETM bone graft consists of rhBMP-2, 21 the growth factor which is soaked into the ACS collagen 22 sponge carrier. The other two NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 240 of 581 1340 PageID 108 1 From a pre-clinical standpoint, there were 2 two areas that we looked at, those having to do with the 3 cage itself and those having to do with the BMP and carrier. 4 Since the fusion cage has already received PMA approval 5 and has not been changed since that approval, there was 6 no additional review necessary and we will not be 7 presenting any information that the sponsor has not 8 already presented. 9 The BMP and carrier will be the focus of the 10 FDA presentations and our presentation will focus 11 primarily on the issues having to do specifically with 12 our questions and not repeat the full review that the 13 sponsor has already given. 14 our analysis of the clinical and statistical data. 15 sponsor has given a detailed presentation and we'll focus 16 our comments on those issues having to do with the 17 questions. The same thing will occur for The 18 After the last FDA presentation, I'll get 19 up and go through an overview of what our questions are, 20 but beforehand, I'd like to just give you an idea of the 21 general areas of concern so that when you're listening 22 to our presentations, you have some idea of where to focus. NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 241 of 581 1341 PageID 109 1 We will be asking you for your input on issues having 2 to do with reproduction and teratogenicity with 3 tumorigenicity, radiographic effectiveness, end point 4 interpretation, issues having to do with instructions for 5 use and we'll also be looking for some input on potential 6 post-market studies. 7 And with that, I'd like to introduce Peter 8 Hudson, who will be giving the pre-clinical presentation. 9 10 DR. HUDSON: Hello, I'm Peter Hudson and I'm 11 the lead pre-clinical reviewer for FDA regarding this 12 product. 13 effort of colleagues in the Center for Drugs, Biologics 14 and Devices for review of this application. 15 provided 16 pre-clinical 17 important to note that review of the manufacturing 18 information of this application has met the full standards 19 of review that the Center for Biologics uses for review 20 of recombinant reproduced growth factors. 21 briefly go over the pre-clinical evaluations and identify 22 the issues that FDA believes need further evaluation. I'd like to acknowledge the collaborative critical and input into manufacturing the They have review information. of the It's I'm going to NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 242 of 581 1342 PageID 110 1 The sponsor has been informed of FDA's 2 concerns and in part has either begun to address some of 3 these concerns or is committed to addressing some of the 4 concerns as post-market commitments. 5 would greatly appreciate your input and guidance regarding 6 the issues that remain as concerns. As you know, we 7 I'll first go over the extensive toxicology 8 and biocompatibility testing conducted on the produce 9 although not as detailed as Dr. Riedel has done. Then 10 I will discuss the experiments used to demonstrate bone 11 inductive ability of the product. 12 questions that have arisen in the course of review of the 13 pre-clinical test information. 14 that these questions did not arise specifically due to 15 the 16 pre-clinical or clinical studies. 17 questions 18 literature. experimental in Finally, I will present I would like to stress observations consideration of from the sponsor's We have posed the relevant research 19 As has already been described, part of the 20 device consists of recombinant human bone morphogenic 21 protein 2 in an absorbable collagen sponge or matrix. 22 The rhBMP-2 ACS is placed within the lumbar tapered cage NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 243 of 581 1343 PageID 111 1 or fusion device. 2 single and multiple dose general toxicology experiments. 3 The results of those studies indicated that the cytokine 4 did not cause toxicity except for the occurrence of 5 injection-site related tissue thickening. 6 To in RhBMP-2 alone was evaluated in acute assess sponge, the a chronic six-month toxicity canine of the 7 cytokine mandibular 8 maxiofacial defect study and a one-year rat femur onlay 9 study were conducted. No toxic effects were observed. 10 The cytokine sponge combination as well as the fusion 11 cage itself was tested in accordance with internationally 12 recognized standards of biocompatibility testing. 13 cytokine sponge product passed all the tests shown here. The 14 15 Studies of the ability of rhBMP-2 on a 16 collagen carrier to induce bone included critical size 17 defect repair models and fracture repair models on various 18 entopic 19 Histologic analysis of a monkey ulnar defect model and 20 other studies suggest that bone formation in response to 21 rhBMP-2 ACS occurs through a process of spindle or 22 mesenchymal cell infiltration, vascular invasion and a sites in rabbits, rats, dogs and monkeys. NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 244 of 581 1344 PageID 112 1 combination of endochondral and direct bone formation. 2 3 Histologic analysis indicated that the bone 4 formation process temporally extended from the outside 5 of the implant towards the center until the implant was 6 replaced by trabecular bone. 7 induction studies included dose ranging studies and from 8 these 9 identified. results a broad Many of the animal bone therapeutic dose range was The effective dose range is bordered on one 10 side by inadequate bone formation and on the other by 11 excessive bone formation. 12 The therapeutic rhBMP-2 concentration range 13 shifts with the animal species tested. Higher 14 concentrations are required in canines than in rats and 15 higher concentrations are required in non-human primates. 16 The ability of rhBMP-2 ACS contained within the fusion 17 cage to cause interbody fusion was evaluated in non-human 18 primates, sheep and goat studies. 19 and fusion cage combination device cause more fusion in 20 comparison to autograft control and the fuse bone was not 21 significantly different mechanically than autograft fused 22 bone. The cytokine collagen These results indicate that the bone induced by NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 245 of 581 1345 PageID 113 1 rhBMP-2 in combination with ACS and/or the fusion cage 2 is comparable to autograft induced bone and mechanically 3 is not significantly different. 4 As a I have number summarized of studies the to sponsor has establish the 5 conducted 6 biocompatibility and safety of the product and has used 7 various animal, non-human models to demonstrate bond 8 inducing capability of the product. 9 two questions related to the safety. However, the FDA has Again, these 10 questions don't arise due to pre-clinical and clinical 11 observations of adverse effects due to the product but 12 due to consideration of the potential for adverse effects 13 that might occur. 14 The potential cells bearing for 16 receptors to proliferate and the potential for an immune 17 response to rhBMP-2 to cause adverse effects in developing 18 fetuses in pregnant women. 19 question for the potential for rhBMP-2 to stimulate 20 transferring cells in a patient's body. Bone transformed the rhBMP-2 22 stimulate regard 15 21 to questions BMP I'll first go over the morphogenetic proteins form a sub-family within a transforming growth factor a super NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 246 of 581 1346 PageID 114 1 family of cytokines. 2 and BMP specifically have been shown to play crucial roles 3 in embryogenesis. 4 sub-family 5 differentiation and apoptosis of various cell types 6 including osteoblasts, condroblasts, neuro cells and 7 epithelial cells. 8 receptors in order to induce cellular signal transduction. 9 Like other members of the TGF beta family, 10 BMPs may elicit various types of responses in cells due 11 to the cell type and/or receptor type expression. 12 reasonable to attempt to investigate the potential for 13 BMP-2 to stimulate transformed cells. 14 testing was conducted to address this issue previously 15 by the sponsor. 16 contained 17 relevant to the topic. 18 studies or actually, I'll kind of briefly go over that 19 since Dr. Riedel has pretty adequately discussed that 20 already, the studies that were recommended by us. have within 21 22 Cytokines within the TGF beta family In addition members of the BMP been shown to influence growth, BMP is type 1 and type 2, serum kinase It is Some pre-clinical Now I will review the information the sponsor's application that is Then I'll go over the additional First of all, I'll go over the pharmakinetic information pretty quickly. The experimental NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 247 of 581 1347 PageID 115 1 observations indicated that the systemic availability of 2 rhBMP-2 is low. 3 evaluations and assuming a one milligram per kilogram dose 4 suggested systemic exposure to rhBMP-2 would be in the 5 low nanogram per NL range. 6 the clearance of rhBMP-2 from the systemic circulation 7 is rapid and that the residents time and tissues involved 8 and clearance is brief. 9 with the device will likely have some low exposure to 10 The prediction is based upon pre-clinical The experiments indicate that However, individuals implanted rhBMP-2 outside the implant site. 11 To address -- to more directly address 12 concerns regarding carcinogenicity or for lack of a better 13 term, tumorigenicity or promotion or stimulation of 14 transformed 15 mutagenicity assay in which they found that the results 16 with that were negative. 17 product in a one-year chronic toxicity study in the rat 18 and they have evaluated the product's ability to influence 19 the 20 cell lines and primary tumor cell isolates. the sponsor conducted the Ames In addition, they evaluated the proliferation or growth of a limited number of tumor 21 22 cells, No carcinogenic effects were observed in the one-year rat femoral onlay study. In in vitro tumor cell NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 248 of 581 1348 PageID 116 1 growth experiments, BMP-2 was observed to inhibit two 2 prostate carcinoma tumor cell lines, one breast tumor cell 3 line, one tongue cell line and one lung tumor cell line 4 and not to effect the growth of four osteocarcinoma lines. 5 In assessing BMPs activity against primary tumor cell 6 isolates, Soda, et al, found that of 65 available 7 specimens, 16 were inhibited. 8 to be stimulated. 9 investigators 10 No tumors were observed In neither in vitro cell study did the evaluate the cells for BMP receptor these studies expression. 11 We cannot state that 12 demonstrate a lack of stimulatory effects of BMP-2 on tumor 13 cells or tumor cell lines expressing BMP-2 receptors. 14 Traditionally, the two-year rats carcinogenicity study 15 isn't recommended for evaluation of implanted devices. 16 We don't believe this assay would adequately assess for 17 the potential of rhBMP-2 to stimulate transformed cells. 18 In consultation with the sponsor we devised a series of 19 experiments that Dr. Riedel has already gone over. 20 FDA believes that the studies can be done 21 as a post-market commitment. You will be asked to comment 22 on the concern of the ability of rhBMP-2 to stimulate NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 249 of 581 1349 PageID 117 1 transformed cells and whether you believe additional 2 studies are necessary. 3 Now I'll go over FDA's question regarding 4 the potential for an immune response to rhBMP-2 to cause 5 adverse effects. 6 contained in the application regarding anti-rhBMP-2 7 immune response findings and then I'll present research 8 literature regarding BMP-2 knockout mice. I'll briefly discuss the information 9 I'll mention what post-market commitments 10 the sponsor and FDA have discussed with respect to 11 revisions of the Elisa used to detect anti-rhBMP-2 12 antibodies. 13 to think about in preparation for our questions at the 14 end. Finally, I'll tell you what we'd like you 15 Enzyme link immune absorbants and assays were 16 established to measure anti-rhBMP-2 anti-collagen type 17 1 antibodies in animals and patients implanted with the 18 device. 19 screened on rats, dogs and rhesus monkeys pre-clinically. 20 In the femur onlay rat models, serum samples were obtained 21 pre-operatively at four weeks, 26 weeks and 52 weeks. 22 No rats Anti-rhBMP-2 and collagen type I antibodies were demonstrated a positive anti-rhBMP-2 or NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 250 of 581 1350 PageID 118 1 anti-collagen type I response. 2 In at 28-day daily IV injection beagle dogs' 3 toxicity study, three of eight animals receiving a high 4 does of rhBMP-2 were determined to have a positive immune 5 response. No animals exhibited an anti-collagen immune 6 response. In non-human primate studies the antibody 7 responses to rhBMP-2 were evaluated pre-operatively at 8 four, 9 Antibodies to rhBMP-2 were detected in 35 percent, 7 of eight, 12 and 16 weeks post-operatively. 10 20 of the animals treated with the device. 11 responses were transient of a low titer. 12 The antibody No control animals exhibited an anti-BMP-2 13 response. 14 anti-bovine collagen type I response. 15 suggest that immune responses to implanted rhBMP-2 can 16 be expected. 17 determined in these studies. 18 if the antibodies cross react with endogenous BMP. 19 20 21 22 Eight percent of the animals exhibited an These studies The type of responding antibody was not In addition, In addition, we don't know the antibody response was undefined as to whether it was of a neutralizing character. For clarification, effectively prevent a the neutralizing BMP-2 from antibody inducing would signal NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 251 of 581 1351 PageID 119 1 transduction in responding cells. 2 revise the Elisa to better characterize the immune 3 response 4 post-market commitment. elicited 5 In by the The sponsor plans to implantation clinical of study rhBMP-2 the as a immunologic 6 findings of which Dr. Buch will further discuss, two of 7 277 patients implanted with the cage contained rhBMP-2 8 exhibited a positive immune response. 9 patient exhibited a positive immune response to rhBMP-2. 10 The incidents of antibody formation observed in this 11 limited clinical study was very low and did not correlate 12 with adverse clinical findings. 13 applications of 14 evaluations done 15 incidents of the immune response to rhBMP-2 was higher. 16 FDA's concern about immune responses to 17 rhBMP-2 regard to two issues; throatigenecity (ph) and 18 restimulation of -- and the potential for restimulation 19 of an immune response in the women during pregnancy. 20 This 21 observations obtained from research literature regarding 22 BMP-2 deficient mice. concern is rhBMP-2 in and non-human driven One control In other clinical in the primate chiefly by pre-clinical models, the experimental Again, I want to stress that these NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 252 of 581 1352 PageID 120 1 concerns were not raised by observations of adverse 2 effects in the pre-clinical or clinical evaluations done 3 by the sponsor. 4 Also it should be stated that pre-clinical 5 evaluations were not specifically designed to evaluate 6 these issues. 7 fertility pre-clinical evaluations of rhBMP-2 but these 8 studies were designed to assess if exogenously added 9 rhBMP-2 itself would have deleterious effects on the 10 development of fetuses or if it adversely effected 11 performance parameters of reproduction. The sponsor conducted teratology (ph) and 12 These studies did not investigate whether 13 the deletion of rhBMP-2 due to antigen-specific antibodies 14 would cause embryonic morbidity. 15 were not done to investigation a fetal expression of BMP-2 16 in pregnant females immune responsive to rhBMP-2 could 17 cause toxicity in the mother. 18 cognizant of research and literature regarding the role 19 of that cytokine plays in normal bone physiology as well 20 as in embryogenesis in order to anticipate potential 21 safety issues. 22 In addition experiments It is important to be The reason why we pose these questions is NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 253 of 581 1353 PageID 121 1 based upon experiments conducted in mice deficient for 2 BMP-2 or BMP-2 knockout mice. 3 noted that a deficiency of BMP-2 was embryonically lethal. 4 The embryos were noted to have failed to close the 5 pro-amniotic canal which cause the malformation of the 6 amniotic cavity and chorionic tissue. 7 embryos also exhibited a defect in cardiac development 8 manifested by the abnormal development of the heart and 9 the exocelimic (ph) cavity. In these mice investigators BMP-2 deficient Homozygous deletion of BMP 10 family members has resulted in other embryonic lethal 11 events as well. 12 and BMP-2 deficient mouse embryos, BMP-7 deficient mice 13 had defects in the development of eyes and kidneys. 14 For example, as shown in this slide, BMP-7 BMPs obviously, play significant critical 15 roles during embryonic development. If 16 rhBMP-2 to the barrier, they 17 theoretically could adverse effect embryogenesis. This 18 diagram captures the essence of the issue. 19 child bearing potential is treated with 20 vertebrae. 21 immune response. 22 of BMP-2 restimulates the anti-rhBMP-2 immune response were cross placental antibodies A woman of rhBMP-2 to fuse The implantation of the cytokine elicits an During a pregnancy, fetal expression NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 254 of 581 1354 PageID 122 1 would have potentially adverse effects for the embryo as 2 well as the mother. 3 We would like you to discuss this issue and 4 look forward to your recommendations. 5 type of animal models do you believe would sufficiently 6 address the question of whether maternal antibodies to 7 rhBMP-2 8 deleterious effects on the developing fetus, also what 9 type of animal models would you recommend to answer the 10 question regarding fetal expression of BMP-2 and its 11 potential for adversely effecting maternal or embryonic 12 development in women who have anti-rhBMP-2 antibodies. can cross the placental Specifically, what barrier and cause 13 14 We would like you also to consider the use 15 of a registry for women of child bearing potential in order 16 to monitor for these potential effects. 17 DR. BUCH: Good afternoon. Thank you. My name is 18 Barbara Buch and I'm the FDA's clinical reviewer for this 19 PMA. 20 with this review, especially Dr. Martin Yahiro. 21 sponsor has already presented a detailed account of the 22 results regarding safety and effectiveness of the clinical I'd like to thank my colleagues for their assistance As the NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 255 of 581 1355 PageID 123 1 trial, I will not repeat that but I would like to start 2 by highlighting some of the key points relating to the 3 effectiveness and the safety of this device based on the 4 data that was presented by the sponsor in PMA. 5 will briefly review some additional considerations in this 6 and 7 interpretation of radiographic data specifically. supporting 8 9 studies in the PMA Then I regarding the Given all this information, I will then as you, as the panel, to issues focus which on will the lead radiographic 10 interpretation you into 11 discussion of the radiographic panel question. 12 this clinical trial was well conducted. 13 out that Bayesian statistical analysis were used and there 14 was a high patient follow-up and data accountability. 15 In addition, there was meticulous adverse event reporting. 16 As previously been discussed many times, there were two 17 arms of the randomized portion and one non-randomized 18 laparoscopic clinical trial. 19 that the follow-up rates, again, are very high and that 20 in the laparoscopic group the follow-up rate does not take 21 into account those patients who are not yet evaluated for 22 that 24-month evaluation. Overall, I'd like to point I'd like to also point out NEAL R. GROSS (202) 234-4433 a COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 256 of 581 1356 PageID 124 1 Dr. Mathews has already explained in detail 2 these clinical end points that were evaluated to determine 3 overall patient success for the determination of safety 4 and effectiveness of this combination device. 5 randomized 6 accountability of patients and the data at 24 months was 7 greater than 85 -- greater than 87 percent. 8 the antibody testing for anti-rhBMP antibodies and for 9 anti-bovine collagen antibodies. 10 clinical trial, as I've For the said, the This included In the randomized group there was very little 11 difference 12 pre-operatively. 13 the 14 evaluation scores. 15 of the clinical results. 16 the trial, the investigational group had less blood loss 17 and less overall operative time than the control group. 18 This is in part attributable to the lack of bone graft 19 in the co-variates between groups This included a strong correlation of pre-operative SF-36 obtained in the Oswestry I'd like to briefly highlight some In the randomized portion of harvest as has been mentioned. 20 The laparoscopic group, as expected, had a 21 shorter hospital stay when compared to the randomized 22 treatment groups and also had a shorter operative time. NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 257 of 581 1357 PageID 125 1 I'm sorry, the operative time was equivalent. Regarding 2 antibody testing, as been explained previously, the 3 patients were tested for the presence of antibodies to 4 rhBMP bovine type I collagen and then to human type I 5 collagen. 6 including the laparoscopic, there was only one patient 7 that 8 antibodies for a total of three in the entire clinical 9 trial. had In each of the three treatment groups, an authentic positive response to rhBMP 10 The overall study outcome was a success for 11 the control patient that was positive and failures for 12 the patients in the investigational and laparoscopic 13 treatment groups. 14 occurrence, the significance of this finding cannot be 15 determined. 16 authentic positive elevated antibody responses to bovine 17 collagen in each of the three treatment groups. 18 greater than 60 percent of the patients in the randomized 19 groups were overall success. 20 treatment groups has a positive response to type I human 21 collagen. 22 However, because of the low rate of There is also a relative low rate of Of these No patient in any of the What's important to know is that analysis NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 258 of 581 1358 PageID 126 1 was completed comparing clinical outcomes with antibody 2 responses. 3 and bovine antibody results with the overall outcome 4 individual end point success or failure or the occurrence 5 of adverse events. 6 is that in the randomized treatment groups both sets of 7 patients returned to work in an average of approximately 8 64 days following surgery and not unexpectedly the 9 patients in the laparoscopic arm returned to work faster 10 There were no correlations of any of the rhBMP One other interesting final result than those in the open procedure groups. 11 This clinical trial has demonstrated that 12 the outcomes for patients treated with the investigational 13 device were as effective as those in the control treatment 14 group. 15 effectiveness end points, the investigational treatment 16 group were equivalent to the control. 17 said about the majority of the secondary end points. 18 As this table shows, for the results of the primary When looking at the The same can be adverse events in 19 general, the incident of any adverse event in either of 20 the randomized treatment arms was high. 21 due to the detailed reporting of the adverse events and 22 the nature of the surgical procedures. This is, in part, Specifically, NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 259 of 581 1359 PageID 127 1 there was one death in a patient in the control group who 2 had a history of cardiac disease. 3 finding was the incidence of graft site related adverse 4 events aside from pain that occurred only in the control 5 treatment group and were absent in the investigational 6 treatment group. 7 The most significant These included fractures, nerve injuries, 8 infection and hematoma. 9 immediately Donor site pain was high post-operatively but as we've seen 10 significantly resolved by six months to a year. Finally, 11 important to note is that there were six pregnancies in 12 women in this clinical trial. 13 the two investigational device treatment groups, that is 14 the laparoscopic and the open investigational group, there 15 were two early trimester miscarriages, both in the 16 laparoscopic group and three healthy births. Of the five pregnancy in 17 In the overall analysis of adverse events 18 in randomized treatment groups, there were 12 categories 19 which -- in which both groups had a greater than five 20 percent occurrence rate. 21 treatment group had a slightly numerically higher rate 22 of non-device related events including back and leg pain, Of those the investigational NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 260 of 581 1360 PageID 128 1 GI symptoms, retrograde ejaculation, spinal events, 2 incidents of trauma, one vertebral fracture and urogenital 3 events. 4 Of these only the urogenital event rate was 5 statistically significant as a difference compared to the 6 control. 7 involved post-operative urinary retention. 8 an unexpected event following spinal surgery. 9 events resolved prior to discharge from the hospital. Approximately half of those urogenital events 10 This is not All these Other events in this category included kidney 11 stones, bladder and rectal symptoms and erectile 12 dysfunction. 13 post-operatively, 14 procedure. 15 investigational 16 difference was not considered statistically significant. 17 And as would be expected and has been mentioned many 18 times, the incidents of graft related adverse events were 19 statistically and numerically worse in the control group. These events occurred at least six weeks a period unrelated to surgical Retrograde ejaculation was documented in five and one control patient but this 20 21 In reviewing all of three treatment groups, 22 retrograde ejaculation was higher in both investigational NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 261 of 581 1361 PageID 129 1 groups but 2 laparoscopic treatment group. 3 to the surgical approach. 4 immune related adverse events. 5 or potential events that may be considered immune related 6 and 7 responses to either anti-rhBMP antibodies or anti-bovine 8 collagen type I antibodies. none 9 only of statistically these different in the This is, again, attributed There were no directly linked There were five possible patients had authentic positive There were two cases of cancer diagnosed 10 during the clinical trial. 11 was 12 treatment group and a case of breast cancer was found in 13 a 14 osteogenic cancers reported. 15 device related events, as we have seen, was similar between 16 the investigational control and laparoscopic groups. 17 What 18 malpositioning of the device, migration, loosening and 19 subsidence in addition to non-unions. 20 are removed from this scenario the incidents is low, falls 21 to less than one percent which is expected for the caged 22 devices. diagnosed control I'd in group like a One case of pancreatic cancer patient patient. to point in There out the investigational were no cases of The overall occurrence of is that this includes When non-unions NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 262 of 581 1362 PageID 130 1 When compared to the control group, the 2 laparoscopic group had a higher occurrence rate of 3 migration, 4 difficulties as well as has been discussed retrograde 5 ejaculation. 6 the procedural approach and are consistent with other 7 spinal literature. 8 is similar in both randomized groups. Although the rate 9 of removals was higher in the investigational group, the 10 rate of supplemental fixations was slightly higher in the 11 control groups. 12 however, are very similar with eight percent in the 13 investigational group, 10 percent in the control group, 14 and seven and a half percent in the laparoscopic group. malpositioning and related anatomic These occurrence rates probably relate to The occurrence of second surgeries The relative rates of occurrence, 15 16 Based on the clinical data provided in this 17 trial, patients receiving the investigational device 18 achieved equivalent fusion and clinical scores compared 19 to 20 eliminating the possibility and necessity of bone graft 21 donor site and its attendant morbidity. 22 mostly equivalent adverse event profiles and occurrences. the patients receiving autograft control while Again, they were NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 263 of 581 1363 PageID 131 1 2 Now, I'd like to turn your attention to the 3 question of radiographic interpretation. This question 4 arises because this clinical trial was the first to use 5 both x-rays and thin sliced CT scans with reconstructions 6 to determine fusion which is an important primary end 7 point. 8 versus CT validation study as part of the IDE and Dr. Irony 9 will The sponsor has provided the results of an x-ray discuss this in her presentation. All the 10 radiographic results of this clinical trial, both plain 11 radiographs and CT scans were presented in order to assess 12 fusion. 13 One other of our concerns is whether or not 14 we can interpret the radiographs of patients treated with 15 this combination device in the same way as we do the 16 radiographs of those treated with autograft given that 17 the fusion sites may calcify at different rates and the 18 progressive rate diffusion may be different. 19 I will review the current definition of fusion in this 20 trial, show you some examples of radiographs from this 21 trial and discuss some issues and interpretation within 22 this trial and other studies presented in the PMA. To this end, NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 264 of 581 1364 PageID 132 1 Plain films were reviewed for the presence 2 or absence of translational motion and angulation. 3 were 4 trabecular bone. 5 and no motion on fluction extension films, the patient 6 was considered to be fused. 7 apparent on the plain films, the CT scans were assessed 8 for bridging bone. 9 motion on plain films, no lucencies, the patient was then reviewed for the presences of They bridging If there was trabecular bone present If there was no bridging bone If there was bridging bone on CT, no 10 determined to be fused. The sponsor utilized both plain 11 radiographs and CT scans to determine the presence of 12 bridging trabecular bone in the assessment of fusion. 13 There were no instances where there was 14 bridging bone on plain films that was not seen on CT scan. 15 However, there were many instances of false negative 16 plain films, that is cases where the CT scan showed no 17 bridging bone when the plain film did not. 18 there were no cases -- there were many instances of false 19 negative plain films, that is cases where the CT scan 20 showed bridging bone and the plain radiograph did not. 21 22 I'm sorry, This phenomena could potentially inflate the success rate in the open investigational group. As seen NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 265 of 581 1365 PageID 133 1 on this slide, the table compares the determination of 2 bridging bone by x-ray and CT scan at various time points. 3 At six and 12 months, the proportion of disagreement 4 between the x-rays and the CT scans was high. This problem 5 was minimized at 24 months which was the end point of the 6 clinical trial. 7 progressed from six months to 24 in all three groups, 8 there's an actual decrease in the number and rate of 9 patients with bridging bone detected. You will also notice that as the study 10 At 24 months, however, only 8.3 percent of 11 the patients who were considered failures by plain x-ray 12 became 13 approximately five percent of the patients who were 14 failure by plain radiographs, became successes by CT. 15 I'd like to direct your attention now to the next series 16 of CT scans which are examples of patients in the clinical 17 trial. successes by CT. In the control group, 18 The slices are taken through the center of 19 the fusion cage and while I realize the determination of 20 bridging bone and fusion are naturally determined by 21 multiple serial axial to sagittal and reconstruction 22 views, these views are an attempt to provide you with some NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 266 of 581 1366 PageID 134 1 representative examples of the patients in the trial which 2 can supplement those presented by the sponsor. 3 reviewing 4 progression of fusion and differing densities of the 5 material within and around the cages at different time 6 points. these 7 scans, consider, if When possible, the The first series are patients considered 8 successful fusions in the trial. The second set represent 9 patients who were considered failures. I'm going to ask 10 you if you were able to determine which side represented 11 the investigational device and which represented the 12 control. 13 patients who were in the investigational group and on the 14 right represent the control. On the left side of the slide the cuts represent 15 Now let's look at what information we've 16 learned from prior animal studies and human studies that 17 looked at radiographic results compared to surgical 18 findings. 19 subjects implanted with spinal devices using autografts 20 -- autograft only and then were taken back to surgery. 21 22 Fusion These studies that looked at animal and human was determined at the time of surgery by manipulation and histologic analysis and then compared NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 267 of 581 1367 PageID 135 1 to pre-operative x-ray and CT fusion status analysis. 2 A summary of these studies showed the CT scan 3 correlated in most cases to the findings at surgery and 4 that the CT scans specifically had higher sensitivity and 5 specificity for determining fusion status compared to the 6 plain radiographs. 7 surgical fusion in animal subjects, a similar analysis 8 was done at second look surgery to determine fusion and 9 then compared to pre-operative x-ray and CT radiographic 10 In the case where BMP was used in fusion analysis. 11 In summary the CT scans again highly 12 correlated with the surgical findings and histological 13 analysis. 14 rate of progression of repair or remodeling differed 15 somewhat in comparison to what's known about autograft 16 and allograft. 17 extremely high fusion rate in all treatment groups when 18 using both x-ray and CT to make the determination of 19 fusion. In addition, it appeared that the density and In this clinical trial there was an 20 When considering the data from other studies 21 regarding the radiographic interpretation of fusion, you 22 should bear in mind a few key points. First, in the x-ray NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 268 of 581 1368 PageID 136 1 and CT validation study that was done by the sponsor, 2 autograft was the basis for the conclusion used to consider 3 this method for determining fusion in this PMA. 4 Second, we may not be able to extrapolate 5 the information from animal trials to potential human 6 responses. 7 potentially the rate and extent of radiographic changes 8 between autograft and rhBMP may differ. 9 in mind, you'll be asked to comment on the interpretation And finally, we need to recognize that With all of this 10 of radiographic data in this clinical trial. Please keep 11 in mind the following additional issues when commenting 12 on the determination of successful fusions in patients 13 implanted with this combination device. 14 This includes the presence and absorption 15 rate of the collagen sponge, the identification of 16 progression of bone repair processes in the presence of 17 rhBMP and the ability of bone formed at various time points 18 to accommodate applied loads. 19 to consider the implications of all of these factors on 20 the interpretation of radiographic fusion and physician 21 training in the future. 22 DR. IRONY: And finally, I'd like you Thank you for your attention. My name is Telba Irony and I'm NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 269 of 581 1369 PageID 137 1 going to comment on the statistical issues relevant to 2 your consideration for the questions presented by the FDA. 3 I have discussed two statistical issues. I will briefly 4 report about the analysis of safety and effectiveness in 5 this submission and these analysis were made through 6 Bayesian methods. 7 statistical comparison of the use of x-rays and CT scans 8 in assessing spinal fusions. And second, I will talk about the 9 First, with respect to the Bayesian methods 10 that were used here, as was said before, we have two main 11 studies. 12 was a multi-center study prospective and randomized. 13 There were like 143 investigational devices and 136 14 control devices. 15 study which was non-randomized and in this statistical 16 comparison we made a comparison with the same control as 17 we did in the open surgery study. One was an open study -- open surgery study which The second study was a laparoscopic 18 Well, Bayesian methods were used and I will 19 very briefly explain the methodology that was used in this 20 submission. 21 were used and I'm just stressing that because usually when 22 Bayesian methods are used, in many cases they use prior First, non-informative prior distributions NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 270 of 581 1370 PageID 138 1 information meaning information from other studies. 2 was 3 probabilities instead of p-values and predictions of 4 results for 24 months were made from some cases in which 5 the patients had only some data; in the cases of the 6 patients for which the 24 month values of some end points 7 were missing or some patients that were lost to follow-up 8 and patients that were not yet due for their 24-month 9 visit. not the case here. We computed That posterior 10 Such conditions improved the accountability 11 at 24 months was already high especially for the open study 12 and as a consequence it enhanced the accountability and 13 improved the precision of the estimates at 24 months. 14 Just to give you a brief idea of what was done here, let's 15 think that for each endpoint, P0 will be the chance of 16 success for that point, endpoint in the control group and 17 P1 will be the chance of success for the endpoint in the 18 treatment group. 19 between zero minus P1, you will conclude that if P0 minus 20 P1 is large, that will mean that the control is better 21 than the treatment and if P0 minus P1 is negative, meaning 22 small, the control will be considered worse than the So if you think about the difference NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 271 of 581 1371 PageID 139 1 treatment. 2 So we are going to look for a large 3 probability that the difference is small enough and that 4 will provide us evidence that the treatment was not 5 inferior 6 equivalent. 7 probabilities. 8 9 For than each the So control we are and then going to will look declare at this Small enough will depend on the endpoint. endpoint, we had a minimal clinically significant difference and high probability or large 10 probability was in this case 95 percent. 11 results for effectiveness endpoints for the open surgery 12 control group -- open surgery compared to the control 13 group. 14 That's the table. So here are the For instance, for fusion, 15 the chance of success in the treatment group and that 16 chance is already corrected for the loss to follow up and 17 for patients that for instance didn't come at 24 months 18 was 92.8 percent and for the control group was 88.1 19 percent. 20 the probability that this difference was small enough was 21 basically 100 percent. 22 effected endpoints, the probability of equivalence was The probability of equivalence, in other words, And you can see for all of the NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 272 of 581 1372 PageID 140 1 considerably high. 2 There were two endpoints which was back pain 3 and the MCS. I put a little red star there to say that 4 that probability was high but was not 95 percent. Now, 5 for the laparoscopic group we have a similar table. The 6 values are different and basically for all endpoints the 7 probability of equivalence was larger than 95 percent. 8 And for this group there was a higher -- the group started 9 late, so there were more patients that had not yet reached 10 24 months by the end of the study, so predictions was -- 11 were made for more or less 25 percent of the patients. 12 13 Now the second issue I'm going to assess which 14 is the statistical comparison for the use of x-ray and 15 CT scans in determining fusion. 16 about a validation study that was done independently on 17 the submission and second, I'm going to talk about the 18 scenario in the current submission and how it compares 19 to the validation study. First I'm going to talk 20 Our problem was the false positive rates. 21 We don't want to have false positive rates because that 22 will inflate the results on fusion and consequently on NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 273 of 581 1373 PageID 141 1 overall success which was the primary endpoint of this 2 submission. 3 will stress, independently on the study in this PMA. 4 There was a surgical exploration of 53 spinal fusion 5 methods in humans in order to assess sensitivity and 6 specificity of both x-rays and CT scans for determining 7 fusion. So in the validation study, it was done, I 8 So before the surgical exploration, which 9 was the gold standard; they opened the patient, they could 10 see if the patient was effectively fused or not, the fusion 11 status was determined by both x-rays and CT scans and the 12 relevant parameters evaluated in the study with respect 13 to this PMA are the sensitivity which is the probability 14 of testing positive, in other words, determining fusion 15 when in fact there was fusion, the specificity which was 16 the probability of testing negative, determine there was 17 no fusion when there was no fusion and a false positive 18 rate, the probability of saying that there was fusion when 19 in fact, there was no fusion. 20 These are the results of the study. These 21 are point estimates. And for instance, for x-rays, the 22 sensitivity was 79, about 79 percent, specificity 86 NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 274 of 581 1374 PageID 142 1 percent, so the false positive rate was about 14 percent. 2 For the CT scans both sensitivity and specificity were 3 higher resulting in the lower false positive rates. In 4 that study there was a third method to determine fusion, 5 which was a combination of x-ray and CT scan and in that 6 case, the patient was determined fusion -- fused only if 7 both x-ray and CT scan determined fusion. 8 conservative method. That's a very 9 The conclusion for this validation study is 10 that sensitivity and specificity is higher for CT scans 11 and for x-rays. 12 and the smallest false positive rate is from the combined 13 x-ray/CT scan method. 14 not used in this submission. False positive rate is lower for CT scans That's very conservative and was 15 Now, the validation study characteristics 16 were different than the ones in the current PMA and that's 17 an important point for consideration for the people that 18 are trying to answer the questions that FDA has posed. 19 First, the patients in this study did not have cages, 20 they did not have spinal fusion cages. The inclusion 21 criteria in this study was different. 22 this study were patients with continued or worsening pain The patients in NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 275 of 581 1375 PageID 143 1 following instrumented lumbar fusion for instability or 2 degenerative disc disease requiring surgery. 3 Given that, we will expect that we'll have 4 a higher prevalence of known fusions in this study but 5 however, the distribution was even, where 24 patients that 6 were fused and 29 patients that were not fused. 7 the time period of the exams were approximately a year 8 after 9 extension. surgery. The x-rays examined were Second, flexion There was no presence of BMP is the study and 10 the method of performing CT scans was different than the 11 one in the present PMA. 12 13 Now, what happened in the current submission? I will briefly explain how fusion was determined. It 14 was actually based in several evaluations. First, it was 15 based on evidence of bridging bone and the determination 16 was first made by x-ray. 17 detected, then CT scan was used and if bridging bone was 18 detected by at least one method, either x-ray or CT scan, 19 then the evidence of bridging bone was considered present. 20 After evaluating bridging bone, these other evaluations 21 were made based on x-ray; segmental stability, and lucent 22 line criteria and in addition if there was a second surgery If bridging bone was not NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 276 of 581 1376 PageID 144 1 due to pseudoarthrosis, that will be a failure and the 2 patient was not considered fused. 3 Now, as a consequence, the actual comparison 4 that we are making is in the methods of detecting bridging 5 bone. 6 evaluation. 7 is not conservative because it's sufficient to have 8 evidence of bridging bone with one of the methods. 9 finally, in the submission there was no case in which the 10 presence of bridging bone was detected by x-ray and was 11 not detected by a CT scan. The other factors are the same in both methods of The adopted way of detecting bridging bone And 12 So I'm going to present a table in which I 13 will show the disagreement between the x-rays and CT scans 14 in the examination of bridging bone. 15 I will note some important considerations. First, again, 16 in all disagreement cases the CT scans indicate that fusion 17 and x-rays did not agree. 18 at 24 months than at 12 months and the relevant point for 19 this submission is actually 24 months. 20 table that shows the disagreement. 21 months there was disagreement in 52 patients out of 130. 22 In other words, 40 percent of the patients there was But before I do that, There is much less disagreement So this is the For instance, at 12 NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 277 of 581 1377 PageID 145 1 disagreement between the determination through CT scans 2 and x-ray. 3 In the control group, that disagreement was 4 also high and the same with the laparoscopic group. When 5 we go down to 24 months, the disagreement is much smaller. 6 It's about seven percent for the open group, five percent 7 for the control group and there was no disagreement for 8 the laparoscopic group. 9 disagreement in the success rates of fusion? Now, what is the effect of this At 12 10 months, for instance, an open group that will be determined 11 by x-ray to have only 57.3 percent of success whereas if 12 it was determined by CT scans the success rate will 13 increase to 96.9 percent. 14 The same behavior was seen in the control 15 group; by x-ray the success rate will be about 30 percent 16 and by CT scan will be about 92 percent and the same with 17 the laparoscopic group. 18 again, I will insist is our final and primary endpoint, 19 this disagreement is much smaller. 20 in red just to say that in a few cases actually the success 21 rates decreased but they decreases slightly. 22 However, at 24 months which, You cannot -- I put Now, what's the impact of that in the overall NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 278 of 581 1378 PageID 146 1 2 success. Of course, there will be a large impact as well. The impact will be more pronounced at 12 months with 3 x-rays. For instance in the open group, the success rate 4 will be about 32 percent and with CT scans will raise to 5 59.7 percent. 6 difference basically disappears, it was just reduced to 7 a much smaller difference. 8 As Again, at 24 months, primary endpoint this a conclusion, the determination of 9 bridging bone has impact on the determination of overall 10 success and the impact is much more pronounced at 12 months 11 than at 24 months. 12 in patients at approximately 12 months after surgery and 13 in the study both the sensitivity and specificity of CT 14 scans 15 characteristics of the study were different than the ones 16 in the PMA and should be taken into account by the panel 17 members. were 18 higher The validation study was performed than for the x-rays, but the And that concludes my presentation. CHAIRPERSON FINNEGAN: Thank you. Aric, 19 we're going to actually ask you to do yours after lunch 20 so that we can have the panel looking at questions right 21 away. 22 presentations from our three guest presenters and the We're going to have three short, five to 10 minute NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 279 of 581 1379 PageID 147 1 first one is going to be Dr. Rocky Tuan who is a -- who 2 has expertise in the BMPs and their biological effect. 3 DR. TUAN: So the purpose of my presentation 4 is to give you an overview of the biology both in vitro 5 and in vivo, of BMP as a group of molecules. 6 be divided into four topics. 7 the protein itself. 8 molecular mechanism action. 9 its biological activity both developmental and also in 10 post-natal pharmacological applications and then finally 11 some discussion on issues related to potential biological 12 complications related to the usage of BMP. My talk will The first one has to do with The second part has to do with its The third part has to do with 13 As already has been described and detailed 14 by previous speakers, the BMP or bone morphogenic protein 15 of bone morphogenic activity was actually first discovered 16 quite awhile ago. 17 work of Nicholas Sen at Rush Medical College who used bone 18 grafts to treat osteomyelitis was in fact, the first 19 indication ever of bone inductive activity coming out from 20 bone itself. 21 of course, was instrumental in identifying, discovering 22 activity from the demineralized bone matrix. In fact, more than 100 years ago the The pioneering study of Dr. Marshall Urist, Later on NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 280 of 581 1380 PageID 148 1 the work of Hari Reddi and Dr. Huggins in the early '70's 2 with the subcutaneous implantation of demineralized bone 3 matrix substantiated all of these earlier findings. 4 Later on, Urist, Sampath, Reddi and several 5 other groups isolated in at least a certain degree of 6 purity, 7 sequences were obtained and then these were then used to 8 generate 9 subsequently these BMPs were cloned. these bone nucleotide morphogenic probes to molecules. screen Partial libraries and And at this point 10 there are at least 20 BMPs and they belong to the larger 11 family of transforming growth factor beta super family 12 which was originally isolated from tumor cell extracts 13 and called transforming growth factor beta for that 14 reason. 15 The only exception is BMP-1 which is actually 16 an enzyme. It's a procollagen C peptidase actually, so 17 it doesn't belong in the same group although it's called 18 BMP-1. There are at least four sub-families of the BMPs. 19 There's a BMP-2,4, BMP-3, the OP1 BMP-7 and then finally 20 the cartilage derived morphogenic protein which are also 21 called growth and differentiation factors. 22 and there are others that have not been neatly fallen into These are -- NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 281 of 581 1381 PageID 149 1 specific sub-categories. 2 The structure of BMP as already has been 3 described by other speakers. 4 homodimer, sometimes heterodimer. 5 originally as larger precursor forms which are then 6 photolytically processed into carboxyl and into yield a 7 mature 8 residues, one of which is involved in a very critical 9 disulfide knot (ph) structure important for its activity. 10 Okay, the second part now, the molecular 11 mechanism action; BMPs because they are in the family of 12 TGF beta super-family, they are actually signalling 13 molecules, that's the best way to describe them. 14 interact with cell surface receptors. 15 two receptors, each of which, of course, also has cousins 16 and relatives. 17 receptor 2, both of which are also enzymes. 18 kineses. product. 19 It It's a dimer, some time contains They are synthesized canonical 7 cysteine They There are at least These are the BMP receptor 1 and BMP They are Upon binding of BMP to the BMP receptor 2, 20 BMP receptor 1 is then phosphorylated. 21 activates a whole series of signaling events. 22 receptor complexed and interacts with This then a This family of NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 282 of 581 1382 PageID 150 1 molecules known as SMAD or S-M-A-D. 2 Mothers Against Decapentoplegic, which is actually a fly 3 protein and which is also a member of the BMP super-family. 4 Again, I just want to also reiterate that the BMPs have 5 MAD stands for been found across all species so far. 6 So at any rate, the SMAD, these are the 7 signaling partners, SMADs 1, 5 and 8 interact in a 8 sequential manner. 9 common partner called SMAD 4, which then removes the entire 10 complex into the nucleus of the cell to activate specific 11 genes, so that's basically how this whole thing works. 12 Later on they then interact with a There are also anti-SMADs. They're also called SMADs. 13 They's called SMAD 6 and 7. So these are the inhibitory 14 SMADs. 15 description of the molecular mechanism of action is that 16 this signaling pathway does not work in isolation. Now, I want to emphasize one point in this 17 Nature being the way it is, there is 18 tremendous cross-talk between one signaling pathway and 19 other 20 laboratories have shown that this particular -- from the 21 outside of the cells to the surface receptor and then to 22 the signaling nucleus, pathways. this Recent particular data pathway, from this many access, NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 283 of 581 1383 PageID 151 1 actually 2 extracellular matrix and receptor complex signaling 3 mechanism via intergrins and fibronectin and collagen, 4 et cetera, as well as most recently the wind-signaling 5 pathway. 6 fly protein. 7 cell 8 morphogenesis, et cetera. 9 as a family of signaling molecule, we have to consider 10 interacts with other axes, such as the Again, that's another distant relative of some Again, the function there is to stimulate growth, proliferation, differentiation, So when we consider BMP family what they also do with other signaling pathways. 11 All right, the third topic is activity, 12 developmental as well as post-natal. One thing I want 13 to emphasize again is that BMP action is highly cell 14 specific. 15 there is one cell that is -- all cells react to BMP the 16 same way. 17 BMP can do different things to different cells depending 18 on its own repertoire of receptors and also all the 19 signaling molecules inside the cell. There we should get it out of our mind that That is absolutely not true. BMP -- the same 20 Now, during development as Dr. Hudson already 21 pointed out earlier, BMP is absolutely crucial for 22 survival and development of the fetus. The evidence is NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 284 of 581 1384 PageID 152 1 ample at this point. 2 of BMP genes, you will get embryo lethality. 3 are 4 receptors for BMP, you also get embryo lethality. 5 remember these things happen way before there is any bone 6 or cartilage or anything like that. missing, 7 again If you have a knockout, i.e. deletion by transgenic If you also methodology, the So now, So where BMP works is actually depending on 8 the developmental stage of the animal. For example, 9 during very early development, during gastrulation, BMP 10 works be defining the polarity of the animal, particularly 11 the dorsal-ventral polarity, who's on top, who's on the 12 bottom, and again, nothing to do with bone or cartilage 13 at that point. 14 And a very crucial example would be the 15 specification of the formation -- of the development, the 16 differentiations of the paraxial mesoderm. 17 those are the cells that ultimately give rise to the spine. 18 So before you even have a spine, the cells that are 19 precursors to the spine already are responsive to BMP. 20 Whether it's in the same manner or not, we do not know In fact, 21 at this point. Nevertheless, if there is a perturbation 22 in the distribution of BMP, the dorsal aspect and the NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 285 of 581 1385 PageID 153 1 ventral aspect would get all mixed up. 2 In the development of a limb, which of course 3 has bones and cartilage, et cetera, again BMP is very, 4 very 5 differentiation event of forming cartilage as well as the 6 death of cells in the interdigital area. 7 a positive factor in the sense that it makes cells, becomes 8 something else or it can make cells undergo apoptosis and 9 die so that there will be a space between the fingers. crucial. It is important for the initial So it can be 10 11 And also member of the BMP family, TGF-5, 12 is absolutely crucial for joint development. 13 that, there would be a decrease in the number of joints. 14 There would be a fusion of joints, mainly the joint never 15 will actually form in the first place. 16 developmental. Without So that's 17 In terms of post-natal, we have already seen 18 many pieces of data on the results of pharamocological 19 application or therapeutic application of BMP to a 20 post-natal 21 osteochondroinductive activity, of course, is obvious. 22 Fracture repair, critical size defect, feeling, spine animal, the historical findings of NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 286 of 581 1386 PageID 154 1 fusion, we saw many pieces of data and also recently in 2 terms of osteointegration and that is how bone cells 3 interact with an implant bio-material. 4 may be relevant to the topic at hand, namely that there 5 is a piece of alloy that is part of this device. In this case it 6 Now, how the presence of BMP may influence 7 the interaction between the neighboring cells and the 8 metal alloy is something for us to think about. 9 Finally, potential biological 10 complications; one thing that needs to be considered is 11 the distribution of the BMP that has been placed into a 12 particular site and also retention of this material once 13 it has distributed to other places. 14 systemic level. 15 ends up is something that perhaps to think about. 16 We notice the low However, exactly where the BMP finally Tumor induction in terms of either inhibitory 17 or stimulatory 18 transformed or not yet transformed cells, hematological 19 perturbation has been shown for the grandfather of the 20 TFG beta super-family, TGF beta-1. 21 beta-1 can cause hematological perturbations. 22 in terms of cell proliferation for The presence of TGF Teralogical effects, which will be discussed NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 287 of 581 1387 PageID 155 1 later, for example, whether the BMP can cross the placenta, 2 the window of time in terms of its action, whether the 3 effect can be transgenerational is also something worthy 4 of consideration and finally immunoreaction which has also 5 been discussed, so I think I'll stop here. 6 CHAIRPERSON FINNEGAN: Thank you very much, 7 Dr. Tuan. Now, Dr. Miller is going to talk to us 8 generically about animal models and the use of registries 9 for teratogenicity. While he's setting up, the really 10 bad news is we do not need to have a closed session, so 11 we will go to lunch once Dr. Kostuik has finished his 12 presentation. 13 2:00 o'clock, so I would ask you to make it a short lunch. 14 Consider it a way to get over your Christmas indulgences. 15 We do need to start back immediately at DR. MILLER: Good afternoon. I'll try to 16 make it brief. You have a handout so some of the slides 17 have been eliminated in the interim to shorten it a bit. 18 I've been asked to look at some principles and concepts. 19 The developmental toxicology animal testing is how it 20 is done. The evaluation of biotech products which really 21 introduces a whole new question into the reproductive and 22 developmental area and then post-marketing pregnancy NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 288 of 581 1388 PageID 156 1 registries and I'll try to do that all within 10 minutes. 2 I am offering a course at the FDA next month 3 that takes four hours to do this, so I'm putting it in 4 perspective. 5 different spectrum of malformations depending upon the 6 mechanisms of action as one sees here with Accutane, with 7 valporic acid in terms of spina bifida and methyl mercury 8 down below. 9 pharmacologic orphan. Different molecules will produce a We know that the pregnant female is a We don't study products in them 10 by choice necessarily and that we really are treating two 11 different organisms and that's actually one of our 12 questions. 13 Dose is the problem, threshold concept is 14 critical to the area of developmental toxicology and 15 usually we say where is that threshold there is a toxic 16 effect? 17 it there are doses that won't produce that toxicity and 18 maybe that's what we should be looking at as well. 19 those lines, dose, length of exposure and time during 20 gestation are our critical areas of evaluation and this 21 will certainly become more important when one is talking 22 about different surgeries and what time they may be Well, in many instances when we're looking at Along NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 289 of 581 1389 PageID 157 1 occurring in a woman if she is pregnant. 2 There are certainly sensitive windows along 3 these lines and I've borrowed this from Keith Moore, where 4 you see in red here many different organ systems that are 5 sensitive from the brain down to limbs and other organs. 6 If we move just a little earlier, the whole 7 pre-implantation, implantation area is one also of equal 8 concern. 9 removed it. I added this just at the last moment. I had However, when we are thinking of mechanisms 10 of action, the National Academy of Sciences just completed 11 their work in the past year and published a volume called 12 Risk Assessment of Developmental Toxicology, which I 13 recommend to you and have been using the 17 different 14 signal transduction pathways to look across species to 15 see the commonality for agents and I do have an asterisk 16 up there; one for transforming growth factor, because 17 obviously, that is the family cluster in which BMPs are 18 found. 19 So if these are some of our concepts, what 20 are the animal testing that we must undertake and follow 21 guidelines on? 22 fertility and And there are three areas, one being early embryonic development, usually NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 290 of 581 1390 PageID 158 1 performed in the rodent, the rat; embryonic and fetal 2 development, sort of the teratogenic period, that is done 3 in two species; one the rat, the other the rabbit or some 4 other species that is a non-rodent. 5 And then some pre/post-natal developmental 6 studies to look at behavioral and functional changes. 7 Along those lines, studies are conducted according to 8 these guidelines and these are sort of the minimum 9 requirements that we really need to think about. 10 Treatment via the likely human route with obviously some 11 exceptions but we would like to perhaps more closely mimic 12 that. 13 Results should permit identification of a 14 NOAEL and a LOAEL and also look at a maternally toxic dose. 15 Maybe the compound one is looking at doesn't get to a 16 toxic dose that one can demonstrate in the mother but at 17 least you've tried to go there. 18 most sensitive species unless there is evidence that the 19 species is inappropriate might, in fact, be reason to look 20 at another species based upon drug metabolism, formation 21 of reactive metabolites, and then obviously, we need to 22 have clarity of a thought Extrapolation from the about detection versus NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 291 of 581 1391 PageID 159 1 characterization. 2 If these are our primary roles, then we're 3 looking at the identification of hazard and we're looking 4 at the identification of risk. 5 hazard really is an animal studies agenda, especially with 6 a new agent because we don't have human case reports to 7 rely upon in many instances and if we generated that, the 8 dose response model from animal studies is what we would 9 need to utilize in trying to identify risk. And along these lines, And probably 10 the most important phenomena we need to consider here is 11 biological plausibility. 12 And biological plausibility really 13 encompasses all of what we know about pharmacology and 14 about actions in pregnancy and is that, in fact, reasonable 15 what you are seeing. 16 assessment 17 toxicodynamics and outcome and the toxicokinetics becomes 18 an 19 extrapolate among species. model extremely So here in terms of the risk we're important talking component toxicokinetics, here to try to 20 Range finding studies are important as well 21 as doing the definitive study as listed below here and 22 in that one would certainly stop at delivery, actually NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 292 of 581 1392 PageID 160 1 before around 21 days to do a Caesarean section to evaluate 2 the animals and in other studies doing the follow-up 3 post-natally to see survival and what may, in fact, be 4 happening in terms of behavior. 5 usually starts with the non-pregnant dose ranging study 6 and then does a pregnant one to see if there is enhances 7 sensitivity 8 developmental studies, exposures between seven and 25 days 9 to look for those types of problems that may be associated 10 and then going on In the rabbit, one to embryo fetal with the agent under study. 11 So selective reproductive toxicity can be 12 detected in range finding studies and if there aren't any, 13 usually one would perform according to the ICH guidelines 14 and do sort of the minimum requirements. 15 have 16 characterize 17 relationships looking at the critical periods and looking 18 at the adverse effects in terms of both structural and 19 functional 20 toxicokinetics in terms of the critical periods and 21 determining whether the agents are formed and delivered 22 in fact, to the conceptus. found toxicity, it but better you by also However, if you would certainly want doing the response emphasizing dose again, to this NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 293 of 581 1393 PageID 161 1 In vitro models can be used to better 2 understand the toxicity itself. So in an identification 3 of risk, we have a decision tree and these you need to 4 keep in mind. 5 assessment? 6 dynamics among species especially trying to extrapolate 7 to human risk? 8 physiology or timing of development which should be taken 9 into account? Is the species appropriate for risk Are there differences in pharmokinetics and Are there differences in reproductive What is the likelihood humans will be 10 exposed and treated under the conditions one has used in 11 these 12 characteristics of the patient population? animal studies for critical periods and 13 And finally, conclusions about the potential 14 of the agent to produce reproductive toxicity, is that 15 similar to other agents and in this case you sort of have 16 a unique agent and you may not be able to look across 17 therapeutic classes. 18 though early in pregnancy and I show here a Doppler where 19 you can see the heart in red here in the early embryo and 20 you can also see the blood flow in the mother. 21 22 One of the main questions here is Along these lines, this is the time we really want to know what is going on inside. Are we, in fact, NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 294 of 581 1394 PageID 162 1 having our compound arrive at the site? 2 a more schematic diagram we are looking at the early embryo 3 and we can see the exocoelomic cavity and the amniotic 4 fluid cavity. 5 early on and Eric Jauniaux over in London has done such. 6 And I want to share just a bit of data with you to help 7 Well, here in Now, these, in fact, can be sampled very put some of your deliberations in perspective. 8 Now, neither you nor I can read this from 9 this distance but what it indicates is that mother villous 10 tissue, decidua and embryo all are producing different 11 products. 12 some of those products there? 13 nice job of looking at this and I have circled two in 14 particular, IgG and IgA. 15 serum, you will find that there is substantial IgG there 16 and also certainly substantial IgA. And, in fact, if we sample them, can we find And Eric has done a very And if you look at the maternal 17 If we though, look at the celomic fluid, we 18 find very little IgA and non-detectible in amniotic fluid 19 but still the IgG tends to get across. 20 reasons for this is, in fact, that the placenta does have 21 receptors that will allow for that to occur. 22 particular study you can see also that HCG is produced And one of the In this NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 295 of 581 1395 PageID 163 1 and tremendous amounts are ending up in the conceptus. 2 So one can say do IgGs get to the early embryo 3 and the answer is, yes. In terms of our evaluation of 4 biotech products, we're really on the horizon here of 5 unique agents to try to evaluate and how do we try to assess 6 that? 7 are not new but Fab fragments which are used clinically 8 such as RheoPro have, in fact, been unique agents. 9 they cross into the conceptus, anti-sense (ph) compounds? 10 The issue here is the difficulty in testing 11 in rodents and lagamorphs because if it's a human protein 12 you 13 extrapolations from human are often difficult to do and 14 the biological plausibility issue comes forward with SARs 15 and pharmacokinetics and pharmacologic action. 16 what can we do to look at this and I'd like to leave two 17 thoughts with you along those lines. 18 returning to the non-human primate model, and in the 19 non-human primate model there are some studies that have 20 been undertaken with recombinant cytokines, G-CSF and stem 21 cell factor and they have looked at these in terms of 22 whether they transit the placenta and enter into the fetus. Well, we have many new proteins. might get a heterologous Now cytokines response. Do Also Well, One is again, NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 296 of 581 1396 PageID 164 1 And to abbreviate which was a very extensive 2 study, is that when they administered it to the mother 3 and 4 insignificant 5 concentrations of materials in the maternal circulation. 6 these were recombinant transfer even cytokines, though they they They also did not find any fetal effect. found had huge However, when 7 they directly administered it to the fetus, they found 8 rapid rises in fetal neutrophil counts. 9 that in terms of some agents, they may or may not be 10 So you can see transiting and having fetal impact. 11 So the non-human primate model may be a good 12 one to explore in the reproductive area as well. Another 13 possibility is looking at human placental profusions where 14 you isolate a lobule and you have a maternal circulation 15 and a fetal circulation and the maternal circulation you 16 can add your agents to and see if they cross into the fetal 17 side. If they do, you can quantitate how much one has 18 seen. I just give you a list of examples here of a few 19 that might be of interest to you and here is G-CSF again 20 and you find very little really transferring across in 21 four or five hours in the Gregor study published a couple 22 of years ago. NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 297 of 581 1397 PageID 165 1 Interleukin-8 was not detected when it was 2 given to the maternal side. 3 a very, very small amount of the maternal dose appear in 4 the fetal side, as also with recombinant erythropoietin 5 where they really did not find any significant levels on 6 the fetal side. And the same with the RheoPro which is 7 an FAB fragment. So there are examples. 8 explain this particular issue and one is the placenta is 9 a wonderful machine for breaking down proteins and if you 10 aren't bound to a receptor mediated process, such as IgG 11 being bound, the rest of them may, in fact, be catabolized 12 and reutilized as basic amino acids to support the placenta 13 as well as the embryo fetus. 14 Epidermal growth factor had Now, how do you So many of these are being broken down and 15 recycles. So if these are going on, then if we make a 16 decision 17 pre-clinical 18 post-marketing evaluations. 19 reasonably undertaken in about the last 10 years mainly 20 because of Accutane. 21 registry by the Boston group headed by Alan Mitchell but 22 along those lines, these are some of the issues that one that a compound analysis, has what do survived we do all in of the terms of And in fact, this has been And that has been the most rigorous NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 298 of 581 1398 PageID 166 1 needs to think of whether you're doing an in-house one 2 using the university center or using the Organization of 3 Teratology Information Services. 4 But along these lines, pregnancy registries 5 are epidemiologic studies and therefore, you have to think 6 about what is an appropriate control group when you are 7 initiating those? 8 pregnancies based upon voluntary contact from patients 9 or health care providers, i.e., the referral bias that 10 can often come in; follow-up of exposed pregnancies to 11 obtain 12 unfortunately, at the FDA as well as at many pharmaceutical 13 companies, that information is not completely collected. complete 14 When Prospective identification of exposed information should because pregnancy often times, registries be 15 conducted? And perhaps the best time is when a new 16 molecule entity is being introduced such as live virus 17 vaccines or an entity like this one, BMP, expectations 18 of high use in pregnant women or of women of child bearing 19 age, agents necessary for conditions associated with high 20 morbidity or mortality that cannot be discontinued as a 21 recognition of pregnancy and an agent's suspected adverse 22 effects during pregnancy based on SAR, pharmacology and NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 299 of 581 1399 PageID 167 1 laboratory findings and agents known to be harmful during 2 pregnancy which obviously was an issue with Accutane when 3 it was first marketed. 4 So what design of the pregnancy registries; 5 one, you need a preparation of written protocol, you need 6 to explore consent issues, you need to have incentives 7 to promote voluntary reporting and have a preparation of 8 information documents which is a means to communicate with 9 the public and also have a major advertising campaign. 10 And with these, the initiation at the time of marketing 11 for new products is probably the optimal time. 12 Window of opportunity for collecting reports 13 is really within the first five years; quickly identifying 14 any potential risks and not likely to be used for agents 15 on the market for an extended period of time due to 16 diminution of voluntary reporting. 17 background, the next part that obviously needs to be done 18 is to provide annual reports, publish occasions of interim 19 results and really get the care providers involved. 20 21 So with that sort of So I hope we've reviewed that in as quick an amount of time as I can possibly do. 22 CHAIRPERSON FINNEGAN: We thank you both for NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 300 of 581 1400 PageID 168 1 the quality of information and the time. 2 Kostuik? 3 different ways to image the spine. 4 Thank you. Dr. Dr. Kostuik is going to give us generics on DR. KOSTUIK: Thank you, Dr. Finnegan. My 5 name is John Kostuik. I'm the director of spinal surgery 6 at Johns Hopkins and as I was preparing this talk in the 7 last few hours, since I was only notified that I would 8 be asked to do this yesterday, I realize that I have been 9 a spinal surgeon for 35 years. That, in itself, is 10 frightening since it constitutes approximately 40 percent 11 of the time since spinal fusion was first introduced to 12 mankind so I am getting old. 13 14 What is the problem in assessing a fusion? It's a difficult proposition. It is far more difficult 15 today than it was when I was an embryonic spinal surgeon 16 because of the advent of rigid internal fixation. 17 is particularly true in posterior approaches to the spine. 18 There is no doubt today that the implants used are much This 19 better than they were even seven to 10 years ago. It has 20 been relatively easy to assess fusion from an anterior 21 interbody approach up until the development of metallic 22 interbody cages. NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 301 of 581 1401 PageID 169 1 It has been stated that expiration of the 2 fusion mass is the gold standard. 3 be very reluctant to explore a fusion mass on the anterior 4 side of the spine because of scarring and potential risk 5 to vascular structures could result in serious problems. 6 But even on the posterior side of the spine, it is not 7 a very valid technique because a bone graft regardless 8 of how it may be stimulated, may fuse to itself but not 9 fuse to the underlying host and therefore, you have a 10 pseudoarthrosis which is very, very difficult to ascertain 11 in any form of radiological investigation, including three 12 dimensional CT scanning. 13 One, of course, would When should one do plain x-rays following 14 a spinal fusion? 15 course, immediately post-operatively, probably at about 16 10 days after that. 17 and not pertinent, I think to this group; then I think 18 probably at about eight weeks, four months, six months, 19 nine months, one year, 18 months, two years, after that 20 depending upon the problem, for instance deformity cases, 21 on should follow those for life. 22 I think that they should be done, of Those are for medical-legal reasons Now, it has been stated also that flexion/ NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 302 of 581 1402 PageID 170 1 extension x-rays are valid. They are not valid since the 2 introduction of rigid forms or internal fixation. 3 have gross motion on flexion/extension, that is fine but 4 generally that is not seen particularly with modern 5 implants. If you Therefore, I rarely ever recommend their use. 6 I do recommend, however, at least four views, including 7 oblique views, which are frequently not done but which 8 can be of great value in looking at the spine from other 9 angles. 10 There are many, many false positives with 11 flexion/extension x-rays which brings us next to the 12 question of CT scanning. 13 well. 14 as presented here today are of more value with the 15 sponsor's product than it would be with autograft since 16 there is no intercage density at the beginning. 17 it isn't the beginning that we are interested in. 18 the end point that we are interested in and we do not know 19 or at least I don't think there is sufficient data to tell 20 us when we see significant enough ossication or it has 21 been called bridging within the cage. 22 bridging we see is within the cage only. This has been controversial as There is no doubt that I think that the CT scans However, It is Moreover, the NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 303 of 581 1403 PageID 171 1 There has been studies done, including some 2 of our own work, to show that if you take a cage and fill 3 it 4 post-operative, it looks like it's fused. 5 scanning has a lot of potential error and although I do 6 admit that it may be more valuable with this product. with 7 bone and take a CT scan, the first day So I think CT What about the type of CT scans? There's 8 no doubt that the modern new thin scans are much better. 9 There are -- there is software available that allows you 10 to subtract the metal artifact. 11 inaccurate and recently has been thrown out in a court 12 of law where it was presented as a means of assessment 13 in a particular patient where a legal suit arose. Probably 14 one of the most difficult radiologically to tell whether 15 or not you have a fusion is the question of radiolucency 16 or loosening. 17 However, it is still Particularly loosening I think is obvious. Radiolucency around a device screw cage can be a bit more 18 subtle. 19 if there is still the presence of pain which may be 20 different than the original pain the patient presented 21 with. 22 It is my opinion that any lucency means non-union If there is a lucency and pain then I think NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 304 of 581 1404 PageID 172 1 investigation probably should lean towards injections of 2 dye to see if it flows freely or semi-freely and, perhaps, 3 the addition of local anesthetic for pain relief. 4 scans are very little value, radioactive bone scans are 5 very little value in assessing fusion mass since most 6 fusions 7 approximately two years from the time of fusion. 8 after that probably indicates a pseudoarthrosis at least 9 unless proven otherwise. will remain warm or hot until two Bone years Hot 10 The real way, I think with anterior to body 11 fusions with metallic devices to tell whether you have 12 a solid fusion is the presence of an anterior sentinel 13 graft, that is anterior to the cage. 14 comes up is how thick should that anterior bridge be and 15 that is not known scientifically. 16 the personal experience on many occasions to remove a few 17 millimeters of solid looking anterior bone definitely 18 fused to the vertebral bodies to find a significant 19 underlying pseudoarthrosis. 20 Now, the big question I have certainly had So I think we do need to know the answer to 21 how thick should an anterior bridge be? Should it be eight 22 millimeters, five millimeters, 10 centimeters -- 10 NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 305 of 581 1405 PageID 173 1 millimeters rather. 2 has not been announced and I'm perhaps unclear here is, 3 what about more than one level of fusion, if the devices 4 are to be placed at more than one level because it is far 5 more common to do a two-level fusion than it is to do a 6 one level fusion and then when do you decide when you have 7 a pseudoarthrosis. 8 9 I don't know. A question also which That is about all I have to say. very much. 10 CHAIRPERSON FINNEGAN: 11 All right, we will reconvene at 2:00 o'clock. 12 13 Thank you Thank you so much. (Whereupon, at 1:38 p.m., a luncheon recess was taken.) 14 15 16 17 18 19 20 21 22 NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 306 of 581 1406 PageID 174 1 A-F-T-E-R-N-O-O-N S-E-S-S-I-O-N 2 (2:13 p.m.) 3 CHAIRPERSON FINNEGAN: Ladies and 4 gentlemen, I do think we are ready to begin if you would 5 take your seats. 6 We are now going to have the panel reviewers give their 7 presentations. 8 Reddi is going to give his review of the pre-clinical. 9 Dr. Kirkpatrick is going to give his review of the 10 clinical and Dr. Larntz is going to give his review of 11 the statistics. 12 13 14 Dr. Reddi, we'd be waiting for you. The panel reviewers are three. DR. REDDI: Dr. Hari Madam Chairman, I would like to do you a favor and finish my comments in five minutes. I'll give you an extra five minutes. 15 CHAIRPERSON FINNEGAN: Well, your comments 16 are very valuable, so you actually get as much time as 17 you'd like. 18 DR. REDDI: I just want to help out the 19 Chairperson. First, as far as the biological problem is 20 concerned, we are going into a stage where how can we 21 improve on nature, that is bone itself. 22 has three main ingredients; the cells, the matrix, and So the autograph NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 307 of 581 1407 PageID 175 1 the signals. It turns out these are the same three 2 ingredients which are needed in manmade approaches for 3 tissue replacement, what is generally referred to as 4 tissue engineering. 5 Now, I want to make some comments concerning 6 this isolation of BMPs and some of the questions which 7 were posed by FDA and what comments I can make in relation 8 in general, not specifically. 9 evolution they have been found not just in mammals but 10 11 in other organisms. First, the BMPs during Let me tell you what I mean by that. First, there are several ways to get out the signals 12 during development. One can isolate it from a tissue like 13 bone. 14 they are found in other tissues. One can look at other organisms and find out if 15 In the case of BMPs, it happens to be a rather 16 unconventional method in which signals were isolated from 17 bone which is really one of the ingredients in the graft 18 itself, 19 substance. 20 years Nicholas Sen. 21 the idea that normal substances present in human body could 22 be used as therapeutic agents was first propounded by none so bone morphogenic proteins are natural Dr. Tuan mentioned the history for about 100 I want to take it back further that NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 308 of 581 1408 PageID 176 1 other than our old friend Hippocrates. 2 centuries ago the best therapeutics are therapeutics mined 3 from the human body. 4 Next. He said 23 These signals, although isolated from 5 bone, it turns out in this case was later described in 6 other organisms. 7 immunity. 8 but I want to make a point that because it has been 9 conserved in evolution, the insect BMPs could be equally This addresses the issue of possible Of course, I can see one should keep in mind 10 effective and safe in humans. The other point which I 11 want to make upon which considerable effort has been 12 directed mainly because of some misunderstanding about 13 the transforming growth factor, it terrifies people 14 because it is something called transforming growth factor 15 and if one reads the literature, it's only the name and 16 the name is a misnomer. 17 Although it's considered as involved in 18 cancer research, it is really due to an in vitro artifact 19 that this particular factor was called transforming growth 20 factor. 21 to normal physiology. 22 is, one needs to be careful but not to worry too much about In effect, all these proteins are very important So the point which I want to make NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 309 of 581 1409 PageID 177 1 the teratogenicity which, of course, will come up. 2 making general comments, not specifically for a particular 3 BMP. 4 normal constituents to the human body and the word here 5 is moderation. I'm talking about signaling molecules. I'm These are 6 And the point which I want to make in response 7 to certain tests is again, one needs to really look at 8 the physiology. 9 one other point. This is normally present. I want to add BMPs are not just in bone. It turns 10 out this particular family of molecules are involved long 11 before bone formed during the pattern formation. 12 is, for example, your right hand and left hand are the 13 same, yet the DNA is the same but the right hand is a mirror 14 image of the left hand which is involved in a subject called 15 pattern formation. 16 That Simply put for a lay person, if you want to 17 build a building, you need to have architecture. This 18 is usually referred to in the parlance of developmental 19 biology as pattern formation. 20 make is long before bone and cartilage appeared, BMPs have 21 arose in defining where particular tissue forms including 22 that your heart is placed on the left side so that is very The point which I want to NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 310 of 581 1410 PageID 178 1 important, the pattern formation having that it is 2 involved in the initial differentiation of tissues such 3 as cartilage in the lumbar. 4 spine it is involved in the early stages. 5 For example in the developing So in effect, what we are looking at in terms 6 of repairing is really a recapitulation. 7 same 8 maintenance of tissues and finally in the regeneration 9 and repair. molecules play a very important Finally, these role in the So in summary then, in conclusion, I want 10 to point out that BMPs are normal natural substances, 11 normally found in the human body and it is not surprising 12 they may have therapeutic implications. 13 14 CHAIRPERSON FINNEGAN: Thank you very much. Dr. Kirkpatrick. 15 DR. KIRKPATRICK: Thank you. I was 16 beginning to fear that not only did I need to have prompting 17 for what I was going to say but I was going to prove the 18 orthopedic surgeon still is not technology proficient but 19 fortunately with the aid of our gentleman there. 20 I'm going to provide an overview from a 21 clinician's standpoint of the clinical results that we 22 heard about today. The device basically we know pretty NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 311 of 581 1411 PageID 179 1 well by this time. 2 titanium fusion cage, recombinant human BMP-2 and an 3 absorbable collagen sponge. 4 standpoint, appear to be reasonably similar. 5 an open arm with a surgical placement of the device for 6 the control, fairly evenly divided and randomized. 7 The It's a combination product with a The study groups, from my laparoscopic arm was There was basically a 8 non-randomized group but compared again to the controls 9 that were done. There was -- it was multi-center, which 10 is one of the things that we always like to hear and there 11 were roughly 135 patients in each group meaning the numbers 12 were reasonable from my standpoint but, of course, the 13 statistician 14 possible, 15 implications. 16 will add obviously, The to that because indications for and of blinding the the wasn't graft surgeries site were 17 degenerative disc disease at L4 to S1, single level 18 disease, 19 Spondylolisthesis had to be grade 1 or less. 20 of you that don't recall, that means just a little bit 21 of subluxation but not more than 25 percent of the size 22 of the vertebral body and then failure of non-operative Oswestry scores of greater than 135. For those NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 312 of 581 1412 PageID 180 1 treatment for four months, although I heard it was six 2 months. 3 -- just confirm whether the paperwork is right or what 4 you said was right would be appreciated. So maybe they could make sure that the paperwork 5 I do want to remind the panel that many of 6 us have been away from spine surgery for a little while 7 and maybe don't do spine surgery. 8 disease 9 controversial subject. as an indication in Degenerative disc itself, is a fairly Degenerative disc disease is 10 thought to be a source of low back pain. 11 we cannot attribute it specifically as the source of low 12 back pain. 13 here, 70 percent range, we wonder if that means that 14 they're really doing better for back pain. 15 consideration issue I think we need to have the clinical 16 understanding 17 degenerative disc disease and are having fusions for 18 degenerative disc disease, it is for back pain and not 19 for the disease that they're getting fused. 20 Unfortunately And so when we look at clinical results in that most of the So from a panel patients that have Many people have degenerative disc disease 21 without having evidence of discomfort 22 limitations or functional limitations. or clinical And in fact, one NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 313 of 581 1413 PageID 181 1 of our panel -- I mean, not our panel experts but one of 2 the applicant's experts, in fact, has published well on 3 asymptomatic degenerative disc disease. 4 equate fusing degenerative disc disease with eliminating 5 pain which may be a consideration that we have to raise 6 later with our discussions. So we can't 7 At any rate, the other indications are all 8 appropriate and for their device it may have been the only 9 reasonable one that they could get us a defined population 10 for. Sorry, I went the wrong way. They excluded 11 appropriate things, prior fusion at the level, significant 12 co-morbidities, inorganic behavior, that's people that 13 are trying to fake out the doctor about their pain, for 14 those of you that aren't familiar with what inorganic 15 behavior would be, substance abuse and then a few others 16 that made a lot of sense as well. 17 The patient populations were very similar 18 in the three groups and so beyond just stating that once 19 again, I don't think we need to belabor that point. 20 primary 21 pointed out exactly why I put it in quotes. 22 we need to go on with that. outcomes, radiographic fusion, Dr. The Kostuik I don't think The Oswestry scales, the NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 314 of 581 1414 PageID 182 1 neurologic function and the overall success were the 2 primary outcomes. 3 the back pain, leg pain, the PCS and MCS of the SF-36 and 4 then they also had another issue of this type early on 5 to see about subsidence, I believe was the main target 6 of that. 7 Secondary outcomes, of course, were Basically, they found either equivalent or 8 superior results. I would attribute the Oswestry 9 superior rating there as being simply because they didn't 10 have to take the bone graft is in my mind one of the bigger 11 things as well as the limitation of the surgical exposure. 12 Surgical exposures do lead to some patient symptoms and 13 some problems down the road and I think that's the main 14 reason that we're seeing a difference there. 15 think it's attributable to the device itself. I don't 16 As far as the secondary outcomes that they 17 were looking at, again, we didn't find a great deal of 18 benefit there or difference there between all the groups, 19 but you do notice that there was really in the open 20 procedure for back pain we're getting back into that 21 clinical problem, I think, where even the morbidity of 22 the exposure may be enough of a problem to give them a NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 315 of 581 1415 PageID 183 1 bad result from a back pain standpoint. 2 And then, of course, as you see the PCS on 3 the SF-36 was superior. 4 anything in the data to attribute a problem with the 5 antibodies either from the BMP or the bovine collagen 6 antibodies. 7 wouldn't mind taking the question now and writing it down 8 so that I can have an answer later. 9 to why -- how would you explain the fact that you would 10 get bovine collagen antibodies in the control group when 11 they did not apparently get exposed to the bovine collagen? 12 13 Antibodies, I really didn't find I will be asking the applicants if they I'm just curious as And I'm sure you have an answer prepared for that. I'd just like to hear your explanation. 14 Let's see, so in summary, the device in my 15 review of the data appears as safe as a cage with autograft 16 for a single level fusion in degenerative disc disease. 17 It appears to be as efficacious as well again with the 18 quantification of the fusion data and I really have to 19 reserve the comment on some of the embryological effects 20 and that sort of thing for our other experts on the panel. 21 22 Discussion issues again, will be a radiographic evaluation of the cage fusion from my NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 316 of 581 1416 PageID 184 1 standpoint, the immune response, the tumorigenicity and 2 the time course of the BMP-2 presence and just to reiterate 3 again, the quality of the films that we were provided on 4 our CD roms, failure or success, I have no idea how to 5 tell this as a clinician, which one is the failure and 6 which one is the success. 7 I'd be interested to know if the audience 8 could pick those out. 9 not convinced that they could tell me which of these were 10 study or control and so from a radiographic standpoint, 11 we have those questions and I thank you for your time. 12 13 CHAIRPERSON FINNEGAN: 16 Thank you very much. Dr. Larntz. 14 15 Similarly with the CT scans, I'm DR. LARNTZ: all right. many. I'll just sit here if that's I've got a few comments, actually not very First, let me say I don't know if anyone said it 17 but compliments to the company and the FDA for their 18 presentations. 19 presentations and very clear and well, I'll just say that, 20 that's true. 21 22 I thought Compliments randomized open study. to they the were company very for good their The device clearly meets the NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 317 of 581 1417 PageID 185 1 criteria set up in the protocol. 2 should just stop there and maybe you should say please 3 do. 4 you call it, the device clearly establishes that with 5 respect to the primary endpoints and actually comes close 6 to this from the secondary endpoints. 7 pretty good. 8 where that's not always true. 9 case that as far as the protocol criteria is concerned, 10 As a statistician I Not only in inferiority or equivalence or whatever I mean, that's Some of us have been involved in studies So I think it's a very clear the device meets the specifications. 11 Again, compliments. The documentation, has 12 anyone seen what we have up here? 13 actually quite extensive, but it actually gives me good 14 confidence in what was done and even down to providing 15 some interesting programs which gave me great confidence 16 in how the calculations were carried out. 17 that. 18 Okay, enough of that. The documentation is I appreciate Now, one issue that 19 seems to be coming up are CT scans and x-ray. I'm a 20 statistician. 21 I don't know anything about lots of things but I do know 22 it's important to take measurements in a blinded fashion I don't know anything about those things. NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 318 of 581 1418 PageID 186 1 and to have adjudication and remeasurement and a process 2 that allows multiple looks at these x-rays or CT scans. 3 It appears to me that the company did that. It appears 4 to me that with respect to some issues, with respect to 5 that, it doesn't matter much in the sense that the -- all 6 of the conclusions wouldn't change whether you use the 7 x-rays or the CT scans. 8 So I feel very comfortable that with respect 9 to the clinical aspect, we can talk about what fusion is 10 or is not, I'm not going to deal with that. 11 a statistical issue but I don't think there's an issue 12 with respect to the data or the conclusions with respect 13 to that issue. 14 conclusions don't depend on that issue. 15 don't depend on whether CT scans or plain films are used. 16 A terribly small point and this is only 17 because the documentation, there are some missing data. 18 That's not So I would like to say that the study It's not all perfect. How is that, The world sometimes doesn't 19 collect all the data and there are some methods given in 20 the documentation which no one talked about today which 21 is fine, called intent to treat and I'm just going to say 22 for the record, that particular method of dealing with NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 319 of 581 1419 PageID 187 1 missing data is not appropriate. 2 of sensitivity analysis, that is some kind of analysis 3 that says, if the control group did better than the 4 treatment group by a certain amount, would it change our 5 conclusions. 6 it's a question, if any sensitivity analysis of that sort 7 was done, I didn't see that and I think we saw a lot of 8 what was done. 9 We need to do some kind There wasn't, as far as I could tell, and But I don't think it would change the 10 conclusions much in this case because again, I think, as 11 I said, the criteria set up and protocol, were met and 12 met fairly convincingly. 13 don't know how much analysis was done of covariates to 14 find out if there are sub-groups of the patients that do 15 better on one -- on the device, not comparatively but are 16 there sub-groups of patients for whom this procedure is 17 better indicated, "the overall success rate", quote, 18 unquote, I realize it's a very stringent criteria, but 19 they're not very high, so are there ways to pick out 20 sub-groups that have higher overall success rates for 21 instance, and I don't know the answer to that. 22 Another question which is I Again, a small minor point, this is not NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 320 of 581 1420 PageID 188 1 necessarily for the company, maybe for the FDA, a number 2 of these measures are scales. 3 you say it, is a scale, back pain are scales and they're 4 analyzed as success/failures because of some arbitrary 5 criteria and actually the company mentioned -- I was 6 actually pleased. 7 have some slight difference on back pain because they 8 actually 9 proportion was lower. have The Oswestry, is that how The company mentioned that they might a higher average but their success 10 And I think that when we have scales like 11 that we lose information when we go to arbitrary cut 12 points. 13 before and it probably -- if you're on this panel again 14 with another study, it will be a comment I'll make again 15 because it seems there seems to be this drive to call it 16 success or failure rather than trying to measure the size 17 of the effect and the amount of change, and I'd prefer 18 to see the continuous variables analyzed as continuous 19 variables and there was, of course, some of that analysis 20 done in the reports. 21 study. 22 That's a comment, it's actually a comment I made Now, Okay. the So that's the open randomized laparoscopic study is not NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com a Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 321 of 581 1421 PageID 189 1 randomized study. 2 as an extra arm and when you have -- but the comparison 3 was done to the control group in the open study. 4 you do that, you've got to be very careful. 5 think we haven't been so careful because I do think there 6 are differences between the patients. 7 I think, at various points, but there are differences if 8 I read it right and, of course, again, I'm just a 9 statistician so I might not have read it right. 10 It's an extra arm, right? It was done When And here I It was minimized, But if I understand right, the laparoscopic 11 patients had less previous back surgery. 12 mean to me? 13 much. 14 stage because they're on more non-narcotic as opposed to 15 strong narcotic medications. 16 pre-op neurological scores, better SF-36 MCS scores, 17 better 18 population, just from my perspective as an unbiased -- 19 well, I think I'm unbiased, as a statistician looking at 20 it, how is that? Well, they haven't been in to the doctor so I mean, that's good. leg What does that -- they look They're maybe at an earlier Okay. like They have better they're a healthier I'll say that. 21 Now, if you have differences in a group and 22 you want to make a comparison to control and you have NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 322 of 581 1422 PageID 190 1 differences of some sort, you really should think about 2 making some adjustment for that and I didn't see any 3 adjustment. 4 look very good. 5 superior but I don't think any of those analysis I know 6 of made adjustments for perhaps that the laparoscopic 7 patients were better to begin with. 8 happened. So that's a question I have. The results In fact, in some cases, they're called I don't think that 9 So with respect to laparoscopic, I think 10 we're in a situation where there is a possibility that 11 an adjusted analysis would change the conclusions somewhat 12 but I don't feel, given they had reasonably good results, 13 I don't feel it would change it so much that we should 14 discard the good results we have. 15 I 16 laparoscopic patients that were better turned out to do 17 better, that's at least comforting. 18 adjusted analysis might give us a slightly different story 19 there. would say advantage there because at least the But I do think an And so on that note, I think I'll stop. 20 Thank you. 21 CHAIRPERSON FINNEGAN: 22 You do have some what was, as usual, very enlightening. Thank you. That What we're going to NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 323 of 581 1423 PageID 191 1 do now is I'm going to ask Aric to put up the questions 2 and then we're going to go around the panel and I'm going 3 to ask each panel member with their expertise and their 4 comfort level, to discuss their concerns, questions and 5 perhaps, some thoughts they have on what's been presented 6 so far, and just to warn you, Stephen, we're going to start 7 with you. 8 DR. KAISER: Okay, as I mentioned earlier, 9 we've got some general topic areas where the questions 10 are coming from and as we move into the first area, 11 reproduction, teratogenicity, we have several questions 12 that we would like you to discuss in this area and would 13 you like me to go through all the questions in the topic 14 and then come back to the beginning? Okay. 15 In this area, the first thing we'd like you 16 to do is discuss the potential for an immune response in 17 the mother to effectively block BMP-2 expression in the 18 developing fetus. 19 potential that the fetal expression of BMP-2 could 20 restimulate a maternal immune response and cause adverse 21 effects in the mother. 22 We'd also like you to discuss the I'll go back to the first question. NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 324 of 581 1424 PageID 192 1 2 CHAIRPERSON FINNEGAN: Actually, I'm going to have you run through them all, all the questions. 3 DR. KAISER: Okay, all right, the next 4 category, tumorigenicity, we'd like you to discuss the 5 potential for rhBMP-2 to stimulate growth of transformed 6 cells. 7 previously that this category and the previous category 8 are based on potential issues, hypothetical issues. 9 These were not things that were seen in the clinical data 10 set presented by the sponsor but these are things based 11 on information from the literature that could happen in 12 the presence of the growth factors. Now, I want to mention and it's been mentioned 13 Okay, next radiographic effectiveness and 14 this is a question that comes actually from the data 15 presented by the sponsor. 16 the sponsor data and from our presentation, we'd like you 17 to comment on interpretation of the radiographic findings 18 at various time points in view of the following factors; 19 the presence and resorption rate of the collagen sponge, 20 the carrier for the BMP, the progression of bone repair 21 in 22 investigational patients and the absence of rhBMP-2 in the presence of Given what you've seen from rhBMP-2 in the case of the NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 325 of 581 1425 PageID 193 1 the control patients and the relative ability of bone 2 formed at various time points to withstand the applied 3 loads. 4 Now, we move onto some things that based on 5 the data we'd like to get some input on some of the labeling 6 issues with this product. 7 to instructions for use, we'd like you to provide some 8 suggestions for adequate instructions with respect to the 9 radiographic interpretates, so based on the previous 10 question if there's anything that we should be putting 11 in the labeling. The first thing, with respect 12 In addition, we'd like you to discuss any 13 other specific training that should be implemented with 14 respect to this product. 15 that are related to post-market studies. 16 to do with reproduction in teratogenicity. 17 that additional animal studies may be useful for assessing 18 an immune response effect on fetal growth and development 19 and so we'd like you to comment on the need for these 20 studies. 21 the types of studies that should be performed as well as 22 appropriate animal models. We have a number of questions The first has FDA believes If you decide that these studies are necessary, NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 326 of 581 1426 PageID 194 1 In the area of tumorigenicity, we've 2 described and the sponsor has described that there's been 3 an agreement to conduct some additional studies -- 4 additional non-clinical studies to evaluate potential for 5 rhBMP-2 to stimulate transformed cells. 6 like you to do is comment on whether there are any 7 additional studies beyond those ones that we've already 8 agreed to, to address this issue and if you believe that 9 there are, we'd like some comment on the type of studies 10 to be performed as well as the appropriate animal models. 11 And then finally we'd like to have your 12 comments on the use of ongoing post-market registry data 13 bases 14 abnormalities. 15 if you believe that registries are recommended, we'd like 16 to have some input on the types of data to be captured. to 17 further assess And what we would potential for congenital And as with the previous two questions, CHAIRPERSON FINNEGAN: Okay, thank you. 18 Just to clarify for the panel, I would like you to give 19 your opinions. 20 you might give them a heads up but we're going to go around 21 a second time with specific questions for the sponsor, 22 so this is mainly a generic discussion of your concerns If you have questions for the sponsor, NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 327 of 581 1427 PageID 195 1 and any thoughts you have on the questions. 2 DR. KAISER: Dr. Li. I'll leave this first question 3 up and then let me know when you want me to pop to the 4 next one. 5 6 CHAIRPERSON FINNEGAN: I think we've got a copy. 7 DR. LI: Yeah, my materials and engineering 8 background doesn't exactly equip me to answer this 9 question directly. A heads up maybe to the FDA or experts 10 or the sponsor, I guess my question would be, are there 11 any examples of any agent, pharmaceutical or otherwise, 12 that actually passed all the in vitro tests that you've 13 done on tumorigenicity or teratogenicity or the other 14 things that you've tested that actually in vitro did not 15 cause any ill effects but actually turned out to actually 16 have a clinical effect? 17 then I'm really stuck with this question. Because if the answer is yes, 18 CHAIRPERSON FINNEGAN: 19 DR. DOULL: Dr. Doull. Yeah, my question is peripheral 20 also, and it's a heads up. When Dr. Hudson was talking 21 about BMPs he mentioned the fact that there's a lot of 22 variability in specie sensitivity to these agents. That NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 328 of 581 1428 PageID 196 1 also was brought up a couple other times and it's in our 2 book and my concern is usually when you have intraspecies 3 variability like that, you also -- or interspecies 4 variability, you 5 variability. Yet, as I understand it, you're talking 6 about taking a vial of this material, a standard dose, 7 diluting it up, putting that on the sponge and putting 8 it in the cage and it's the same dose for everybody; old, 9 young, male, female, whether they are immuno compromised. 10 And if that's true, it makes it a little hard 11 to look at the worst case kind of assumption that one would 12 like to make to evaluate systemic toxicity as opposed to 13 local toxicity. usually also 14 CHAIRPERSON FINNEGAN: 15 DR. DIAMOND: have intraspecies Dr. Diamond? I guess my concerns have to 16 do with the antibody assays because I'm concerned that 17 they represent arbitrary numbers with a definition of 18 authentic response but no definition of a biologically 19 significant response and I think that, you know, one 20 doesn't know what a neutralizing antibody titer is and 21 -- unless there are studies that haven't been done and 22 we certainly do know that antibodies, maternal antibodies NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 329 of 581 1429 PageID 197 1 can cause problems in a developing fetus and the IgA 2 antibodies may not get across the placenta but they 3 certainly get into milk and get into neonate. 4 So it's about the antibody assay. 5 CHAIRPERSON FINNEGAN: 6 DR. HANLEY: Dr. Hanley, sir. Yes, I'd like to preface my 7 comments by saying that I've been to many of these meetings 8 before and served as the chair of many of these. 9 non-voting member at this meeting because of my previous 10 involvement in studies on the spine and particularly in 11 some of the initial studies with BMP use on the spine prior 12 to what is going on here, some with Genetics Institute 13 but not with the current sponsor Medtronic Sofamor Danek. I'm a 14 15 Several years ago we had a meeting of the 16 Food and 17 Rehabilitation Advisory Panel with regard to spinal 18 conditions in an attempt to set some criteria such that 19 sponsors would have a good idea of what was needed for 20 us 21 Heretofore, I have personally not seen studies put 22 together in a fashion that we could do it well. to pass Drug Administration scientific judgment Orthopedic on what they and did. NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 330 of 581 1430 PageID 198 1 I would compliment the sponsors on meeting 2 all the criteria which were set down several years ago 3 and I don't know if anyone's here who participated in that 4 but what they have done is exactly what we've asked people 5 to do so that we could make our job easier and not spend 6 all afternoon saying, "What did you mean by that", or 7 trying to make up for things that weren't there. 8 So I applaud them on their issues. I'm a 9 spine surgeon, a clinician and I view myself as reasonably 10 knowledgeable with regard to the issues; spine surgery, 11 the 12 procedures and the use of the implants and materials under 13 discussion here. selection of patients, the performance of the 14 We will not and cannot solve the enigma of 15 back pain in the selection of patients for surgery for 16 it here. 17 believe that radiographic issues brought up have great 18 pertinence to this presentation. 19 and our opinions on what's better if any of CT, regular 20 radiograph, bears not on -- in my opinion, on decisions 21 that should be made here. 22 practice. It is not part of this discussion. I do not They are what they are Those are part of the clinical NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 331 of 581 1431 PageID 199 1 It's nice to see that they included CT. It 2 just means they're trying to give us everything that could 3 be meaningful but I don't think it matters in the long 4 run if the device is deemed to be approved and is approved, 5 that the criteria be set up for what a practicing clinician 6 should do. 7 That's a study issue. I'm sure plain 8 radiographs are just as satisfactory and the patients, 9 ultimately if this were approved, operated on with a device 10 that should not be -- need not be subjected to CT unless 11 for specific instances such as a clinical failure. 12 Some of the other things that might not be 13 apparent to non-clinicians are issues like blood loss and 14 blood loss is so small in all the groups that it makes 15 no difference. 16 import and this is one time where not taking a bone graft 17 probably does dramatically improve the length of stay 18 issue, particularly in that other arm that we criticized 19 a little bit, laparoscopic arm. 20 The length of stay, however, has some I'm not an expert on teratogenicity and 21 tumorigenicity and that sort of thing. I think we'll let 22 others who have more expertise work that out. I think NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 332 of 581 1432 PageID 200 1 the issue here at the table today is mainly one of labeling, 2 indications 3 perspective for -- if approved for people utilizing a 4 device, how best it can be controlled and doing some 5 appropriate follow-ups on it. 6 experience, one of the easier ones I've seen. for use, trying to CHAIRPERSON FINNEGAN: 8 DR. SIEGAL: the proper Thank you. Gene. Well, if there's a good cop, I guess there has to be a bad cop, too. 10 11 in This is -- it's been a good 7 9 put CHAIRPERSON FINNEGAN: You said that with a smile. 12 DR. SIEGAL: I have a number of issues. I 13 do think that the sponsor did everything that reasonably 14 could be done as far as the radiology, especially by 15 acquiring the expertise of Dr. Genant and his associates, 16 who is a world renowned authority and I feel very confident 17 that everything that could be done radiologically has been 18 done. 19 multiple times, both in the pre-clinical and the clinical. However, histology/pathology has been eluded to 20 21 22 And it was used as the gold standard, if you will, to validate the radiology. I have a multi-part NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 333 of 581 1433 PageID 201 1 question depending on the answer and the question goes 2 something like this. 3 pathologists that did those studies, neither or both? 4 Did they work for the company or was there an independent 5 vetting of the pathology results? 6 recognized as experts in bone diseases? 7 Changing Were those veterinary or human subjects, Were the pathologists as I understand the 8 carcinogenicity issues, two pancreatic cell lines showed 9 increased proliferation in the presence of BMP-2 and one 10 patient developed pancreatic carcinoma while receiving 11 the therapy. 12 a potential problem. 13 perhaps, that at the time of surgery, the rhBMP-2 must 14 be rehydrated, if I could use that term, with sterile water 15 and then must be, quote, "applied evenly" end quote to 16 the ACS which is loaded into the cage. 17 discussed pre-loading the BMP-2 sponge to maximize even 18 distribution, either requiring hydration by perhaps 19 emersion in water or pre-hydrating it and packaging it 20 to keep it intact? I would like to hear that coincidence or I wonder too, way off the topic Why was it not 21 And to come full circle back to the pathology 22 question, I wonder would it not be of value to do a NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 334 of 581 1434 PageID 202 1 carefully controlled radiology histopathology study with 2 pathologists to see, in fact, if there is a gold standard 3 one against the other? 4 DR. KIRKPATRICK: other panel comments, I'd like to echo some of 5 the that that was quite a 6 well-prepared presentation and a substantial data set to 7 review. 8 are, you mentioned that you have data beyond 24 months. 9 How complete is it and did you see deterioration in the 10 clinical results which is something that we often see with 11 other fusion techniques? A few questions that I'd like to see addressed 12 I would like to see if you could provide me 13 with some general insight with the expression of BMP-2 14 normally in the time course of the fusion. 15 do we have any information on when BMP is normally produced 16 in the fusion healing process and whether the application 17 of the BMP-2 at the onset is coincident with what it would 18 be in the autograft group, for example? 19 already have that data. In other words, I imagine you 20 You mentioned that the metabolic pathway of 21 BMP was through the liver but I did not hear a specific 22 of what that pathway was in the liver and the package NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 335 of 581 1435 PageID 203 1 insert, as I recall, indicates that no liver studies were 2 done. 3 the toxicity was the fact that it was rapidly metabolized, 4 what liver impairments would prevent it from being rapidly 5 metabolized and as such, what liver enzymes should be 6 checked prior to giving the device or using the device. 7 And the next question is perhaps one, if we 8 find it approvable, in light of the history of the pedicle 9 screw off label use, how would you recommend guarding 10 against off-label use of this product, especially the 11 rhBMP-2? I'm wondering since one of your explanations about 12 Thank you. CHAIRPERSON FINNEGAN: I basically have two 13 areas that I would sort of like to see discussed. One 14 is there were some very nice elution studies of the BMP 15 but you didn't look at elution or I didn't see any data 16 for elution from -- of the BMP inside the cage and I would 17 suggest that that's probably a different pattern than just 18 BMP in a sponge. 19 And the other thing that fascinated me that 20 I couldn't find anywhere is why did the cases that failed 21 fail. 22 spine problems and I was wondering if you have any feeling You picked pretty straightforward pretty simple NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 336 of 581 1436 PageID 204 1 for why the ones that failed failed. 2 DR. NAIDU: 3 congratulate 4 outstanding study. 5 the I'd sponsors like for to doing comment an -- excellent I thought it was very well presented. The data showed that the device is effective and with 6 regards to safety, I will hold on. I'm an orthopedic 7 surgeon with a biomechanics background. 8 question to the biologists on the panel, but in general, 9 from what I've heard at least, the antibody response was 10 detected in only three of the patients and from Dr. 11 Miller's comments, it appeared as if hardly any cross the 12 placenta barrier nor the amniotic cavity and our respected 13 panel member, Dr. Reddi, goes on to comment that this is 14 a normal substance. 15 it. 16 the rest of the biologists on the panel. I will defer that We should not be too concerned about And so I will defer that thought to Dr. Reddi and 17 But as far as the radiographic findings, I 18 think that it appears as if at least from the CD Roms, 19 the CDs that I got, the disks, the fusion mass started 20 to show up at six months as the sponsor stated, and the 21 thing is I don't have any time zero CT scans to judge as 22 to what it would look like. I can only imagine the NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 337 of 581 1437 PageID 205 1 2 collagen sponge would be hollow and it would be black. It would only be logical to assume that. So I think that 3 there is bone forming, but I don't know the mechanical 4 integrity of this bone. 5 And Dr. Kostuik stated that at least eight 6 millimeters of bone must be needed to -- a thick -- eight 7 millimeter thickness of bone must be needed to stabilize 8 an intersegmental fusion. 9 of Dr. Kostuik's comments where he stated that it is hard 10 to judge on flexion/extension views mainly because of the 11 superior instrumentation that we have developed today, 12 such as segmental spinal fusion devices such as pedicle 13 screws, it's hard to depend on flexion/extension views. 14 And the other thing is in light Those are the words that I recall from Dr. Kostuik. 15 These are not -- you don't have pedicle screws 16 here. You just have two cages. And so I would assume 17 that the flexion/extension criteria that you guys used 18 would be credible at least. That's what common sense 19 would dictate to me at least. But I think that's all to 20 an issue to discuss further is just the stability of these 21 devices. 22 constructs that flexion/extension views and angular Are they similar to these pedicle screw NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 338 of 581 1438 PageID 206 1 distortion is not considered credible as a radiographic 2 criteria. 3 I think that you guys have shown a pretty 4 reasonable product here that seems to be safe and 5 efficacious but obviously, there are some issues as far 6 as packaging and I'm also assuming that -- this is actually 7 a question to the sponsor, that you are seeking approval 8 for this for degenerative disc disease with less than grade 9 one spinal disc thesis (ph) for single level fusion. 10 That's what I'm assuming that this device is up for. 11 I'm wrong as far as that goes, I would appreciate 12 clarification but thank you very much. 13 CHAIRPERSON FINNEGAN: 14 DR. BOYAN: If Dr. Boyan. I have just two issues that have 15 come up in my reading of the documentation and the 16 discussion today and overall I, too, want to compliment 17 the applicant. 18 but the two comments I want to make have to do -- one with 19 mineralization and the other one has to do with antibodies. It truly was a beautiful package to read, 20 21 22 And the mineralization has to do with how the use of CT and x-ray. I would like to echo the comments NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 339 of 581 1439 PageID 207 1 from down at the end of the table that it's very difficult 2 at least early on to determine whether or not something 3 is bone or if it's just remineralized collagen and given 4 that you're using a collagen sponge, even x-ray or CT isn't 5 able to discern whether or not that's bone, bone or if 6 it's 7 remineralized. a graft that was fortuitously structurally 8 And I say that only as informational because 9 the only way you could ferret that out is with histology 10 and you're not likely to take a nicely fused human and 11 do histology but to bear that in mind in interpreting the 12 data. 13 while I may not be as concerned as some people are about 14 this future consequence to a pregnant person and her fetus, 15 I am somewhat concerned about elderly individuals and 16 people who are likely to have more than one experience 17 with this device in their lifetime. The other comment has to do with antibodies and 18 And if there has been any consideration given 19 to people that might have multiple surgeries at different 20 times and whether or not we're sensitizing them to be BMPs 21 and sensitizing them to type 1 collagen. 22 CHAIRPERSON FINNEGAN: Thank you. Dr. NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 340 of 581 1440 PageID 208 1 Reddi. 2 DR. REDDI: Yes, thank you for giving me this 3 opportunity, Madam Chairman. First, I'd like to also 4 compliment the sponsors for giving us a good package but 5 however, I have some questions which I was not sure whether 6 I should outlay while I made a brief presentation or not 7 because I'm a novice at this but I will very soon learn. 8 But I would like to ask as far as the 9 tumorigenicity is concerned, whether the sponsor or some 10 of their contractors have done studies because we are 11 really interested in induction of tumors as opposed to 12 stimulating growth of transformed cells. I found copious 13 amounts of data on about 60 cell lines. A lot of cancer 14 research today in the United States has shied away from 15 cancer research because it doesn't mean anything for the 16 human patient, because you can get whatever you want in 17 a cell line, it might please some FDA regulators, but we 18 are really -- it's a very important issue from the point 19 of your patient. 20 If you really want to study tumorigenicity, 21 it needs to be done in a living animal and I wanted to 22 find out if such attempts are being made or being thought NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 341 of 581 1441 PageID 209 1 about by the sponsor, so I'd like to find out whenever 2 the time is opportune for that. 3 The other question concerning the 4 antibodies, I wanted to find out if the sponsor in their 5 volumes of study have developed antibodies to the native 6 BMP-2 as opposed to anti-peptide antibodies or monoclonal 7 antibodies because you might make an antibody to a peptide 8 by one of the scientists in Wyeth-Genetics Institute but 9 I would like to see if there is such data and if such data 10 is available, I would like to strongly recommend that the 11 transplacental passage of these antibodies to native 12 recombinant BMP-2, does it cross and does it have any 13 adverse effects on the fetus. 14 That's a very important thing because we have 15 been dancing around this issue. 16 definite studies in order for both the -- to allay the 17 fears of both the patients as well as the surgeon. 18 I think we need to do CHAIRPERSON FINNEGAN: Thank you. Now 19 we're going to get a definitive answer about x-rays and 20 CT scans, right? 21 22 DR. LENCHIK: about teratogenicity. I thought we were still talking I don't have much to say about that NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 342 of 581 1442 PageID 210 1 but to your preview, the sponsor, I have a couple of 2 questions relating to CT. 3 the quality of the CT really varied widely from having 4 real quality CTs with beautiful coronal and sagittal recon 5 to other CT scans that were virtually uninterpretable. The CDs that we were given, 6 7 So my question to Harry Genant in particular 8 is what was your experience in the study in terms of CTs 9 that were potential equivocal because you couldn't -- 10 because of metal artifact perhaps or due to reconstruction 11 artifacts. 12 what do you think the explanation is why there were fewer 13 patients fused by CT at 24 months compared to 12 months? And the second question, again to the sponsor, 14 CHAIRPERSON FINNEGAN: 15 DR. LARNTZ: 16 Dr. Larntz? I don't have any more to add than I already did. 17 CHAIRPERSON FINNEGAN: 18 MS. RUE: I have Ms. Rue? a couple questions. 19 They're points of discussion I guess. One was there was 20 an agreement made with the women in the group for them 21 not to get pregnant and they talked that there were six 22 pregnancies anyway, not to get pregnant for 16 weeks and NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 343 of 581 1443 PageID 211 1 it doesn't say at what time these women got pregnant. 2 So I'm wondering what effect that agreement held. 3 And also, if there's going to be a pregnancy 4 registry board, that it include miscarriages of the fetus 5 or embryo at any stage and also some pathology on that 6 to see if there's any effects on the fetus. And also, the 7 fact that the majority of pregnancies are not planned and 8 most women don't know that they are pregnant for the first 9 at least five to six weeks, a lot longer than that, what 10 is going to be done as far as that goes prior to surgery. 11 12 CHAIRPERSON FINNEGAN: Thank you. Ms. Maher? 13 MS. MAHER: I don't have much to add above 14 and beyond what everybody else has said and I thought what 15 I heard was very well put together. 16 to be cautious about trying to mandate the practice of 17 medicine as you're going forward and talking about 18 labeling that would determine when fusion has occurred. 19 I think most surgeons know when fusion has occurred and 20 will be making that determination on their own no matter 21 what's in the labeling. 22 I would ask the panel So I would ask us to all be cautious and think NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 344 of 581 1444 PageID 212 1 about that. 2 about off-label use. 3 labeling but there's -- mandating packaging or something 4 like that will increase the cost of the product to the 5 consumer without probably stopping much of what you're 6 probably trying to stop. 7 I would go the same way towards the concerns I think labeling can go into the Thank you. CHAIRPERSON FINNEGAN: All right, we'll now 8 start back around the table and you can ask your questions 9 and we'll get them to answer them one at a time. 10 DR. LI: 11 CHAIRPERSON 12 Dr. Li. Do I ask the same question? FINNEGAN: Yeah, the same question or a new one if you have another one. 13 DR. LI: Yeah, I guess my original question 14 was, if you've done a variety of in vitro tests to test 15 tumorigenicity, teratogenicity 16 complications. My question actually was either the 17 sponsor or the FDA or panel members, are there examples 18 of any agent that actually would pass all these tests, 19 yet turn out to be clinically something you'd want to 20 avoid? and other possible 21 In other words, how -- the fact that you 22 passed all these tests, is that actual assurance that these NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 345 of 581 1445 PageID 213 1 things will not happen clinically? 2 CHAIRPERSON FINNEGAN: I don't know who the 3 most appropriate -- probably, Dr. Riedel, did you want 4 to answer that or did you -- 5 DR. RIEDEL: To the best of my knowledge and 6 the knowledge of my colleagues who are professional 7 toxicologists, there is no example of such an agent. 8 would be just hypothesize. 9 DR. LI: It Okay, my question did ask earlier 10 because I was limiting myself to teratogenicity, was on 11 the x-rays versus CT. 12 was the determination of whether or not there was a bone 13 bridge, is that just a yes or no determination? 14 it was just a yes or no determination, there's like one 15 spicule or one trabecula that goes from side to side, does 16 that count as a bone bridge or was there some threshold 17 amount of bone that had to be in there to be qualified 18 as a bone bridge. I guess my question on that is, And if 19 And a follow-up question to that is, no matter 20 how you determined whether or not it was fused or not fused 21 by radiographic approaches, how predictive of clinical 22 failure were those radiographic approaches? For NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 346 of 581 1446 PageID 214 1 instance, were there cases where there was a radiographic 2 failure but the patient was perfectly happy with it and 3 conversely, 4 radiographically looked great? 5 were there clinical CHAIRPERSON FINNEGAN: failures that I think, Dr. Miller, 6 did you want to address the question about whether there's 7 been an example of -- in something not showing any signs 8 in vitro but turning out to have some effects in vivo? 9 DR. MILLER: Thank you. Some of the estrogens 10 might fall into that category, being diethyl stebesteral 11 (ph) originally and probably that might be out closest 12 that we might look at along those lines both being 13 tumorigenitic birth defects and for quite awhile one 14 didn't have that understanding because the right tests 15 weren't done but -- 16 CHAIRPERSON FINNEGAN: 17 one example. 18 your question? All right, Dr. Doull, did you want to ask 19 DR. GENANT: 20 CHAIRPERSON FINNEGAN: 21 So there is at least Can we answer? Oh, yes. Well, actually, I think that was -- oh, radiographic, I'm sorry. 22 DR. GENANT: I'm Harry Genant from the NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 347 of 581 1447 PageID 215 1 University of California, San Francisco. I have no vested 2 interest in the product and I'm a paid consultant. 3 also been a consultant with Ostech in the past. I've 4 Now, with regard to the predictability of 5 the radiographic features, that is either plain films or 6 the CT in relationship to success, we have to keep in mind 7 here that at 24 months we did have a very high success 8 rate. 9 of And so we're talking about relatively small numbers cases. The majority of those cases that were 10 re-operated were not re-operated specifically with the 11 suspicion that they were, in fact, unstable, but rather 12 related to other symptoms and findings that were being 13 addressed. 14 So I would say that there was not a strong 15 or tight correlation in those small cases between the 16 radiographic 17 presence, for example, of a need for re-operation. 18 and/or DR. LI: CT features Were there of fusion cases and where the there 19 appeared to be radiographic failures either by x-ray or 20 by CT but were clinically -- had no complications? 21 22 DR. GENANT: There were cases in which lucencies had been observed in which there were no clinical NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 348 of 581 1448 PageID 216 1 manifestations. 2 Thank you. DR. LI: Thank you. Oh, yeah, the issue 3 about how you determine whether or not there was bone 4 bridging. 5 DR. GENANT: Yes, the question with regard 6 to the amount of bone that might be relevant for bridging 7 and in particular based upon the CT observations, I would 8 point out that by 12 and particularly by 24 months, one 9 observed not only the bony bridging within the cage, but 10 in the majority of cases one observed also substantial 11 bridging of bone either in front, behind or on the sides 12 adjacent to the cage. 13 I'm not certain that we made a determination 14 of what the minimum amount for thickness of the bridging 15 would be necessary in order to consider this to be 16 clinically 17 assessment of whether we could judge there to be solid 18 bony union across either within or outside of the cage. 19 relevant, but DR. BODEN: we essentially made the I just want to expand one point 20 about the dissociation between radiographic outcome and 21 clinical outcome which I believe was the subject of your 22 question. It is not at all uncommon in treating patients NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 349 of 581 1449 PageID 217 1 with spinal disorders, particularly patients that have 2 so-called degenerative disc disorders, which is the 3 subject of these patients, to have solid fusions yet 4 persistent symptoms or cases where symptoms improve and 5 it doesn't correlate with the radiographic outcome. 6 So that's inherent with the disease, the 7 disorder and even accomplishing a fusion by any means 8 independent of whether it uses bone graft or infuse. 9 That's particularly why it's important to focus on the 10 more direct or primary outcome and goal of something like 11 infused, which is to generate bridge in bone. 12 start to add the overall success factors, there's a lot 13 of other things multi-factorially that go into that that 14 go well beyond the device in question. 15 DR. LI: When you So you're saying that the -- if I 16 understand what you told me, that the presence of bridging 17 bone is not just a biomechanical benefit, but it's actually 18 a reflection of other things that are going on with the 19 device? 20 21 DR. BODEN: No, I don't think that I was trying to say that at all. 22 DR. LI: Okay, sorry. So let me follow, just NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 350 of 581 1450 PageID 218 1 maybe to pinpoint this again; do you have any correlation 2 from animal data or any other data that correlates the 3 amount of bridging bone in any biomechanical measurement; 4 torsion, strength, failure? 5 -- 6 DR. BODEN: Is there any number that you Well, we showed -- we showed in 7 the cases of the animals that the biomechanical properties 8 of those fused segments were equal to or greater than those 9 with autogenous bone graft at the same point in time and 10 so, if anything, there's a trend to possibly achieving 11 bony union a little bit faster and more consistently with 12 infused compared to with autograft. 13 there's -- the fusion can occur through the center of the 14 cage, which is typically the way it occurs with autograft 15 and is considered clinically to be mechanically solid and 16 solvent. 17 Unfortunately, There's no clinical definition in humans of 18 how much bone is enough bone. It's empiric. However, 19 I will say that it tends to be a more than all or none 20 response and I think that kind of case that Dr. Kostuik 21 highlighted where there was some bone but it turned out 22 to be not good bone, is more the exception than the rule NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 351 of 581 1451 PageID 219 1 and we tend to clinically think of fusion as a binary event, 2 either solid bridging bone and then it remodels because 3 of continued mechanical stress whether that bone was put 4 there by autogenous bone graft or InFUSE actually wouldn't 5 effect the ultimate remodeling. 6 And so on the other hand, the clinical problem 7 is you never get that union of bone. 8 and then it never remodels. 9 DR. LI: Does that help clarify? Yes, thank you. 10 CHAIRPERSON FINNEGAN: 11 DR. GENANT: 12 CHAIRPERSON Yes, I wanted to address the FINNEGAN: Well, we'll get around to him in a second. 15 16 Go ahead. question that Dr. Lenchik had. 13 14 It never sees load DR. GENANT: Oh, okay, it was relevant to this topic with regard to the -- 17 CHAIRPERSON FINNEGAN: 18 DR. GENANT: All right, go ahead. And that was with regard to the 19 CT and the quality of the images that were reviewed, and 20 I sympathize with you to some extent with regard to the 21 review of the CDs. 22 representative of the studies that we looked at with the I think that in most cases they were NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 352 of 581 1452 PageID 220 1 direct hard copy images but on the other hand, in some 2 reproductions they did not capture the original image 3 quality. 4 I would say that overall the CT quality of 5 the images that we viewed were reasonable. 6 range in that quality but I think by and large, were 7 acceptable for most -- the vast majority of cases and of 8 course, 9 imaging. 10 11 we had, in general, excellent CHAIRPERSON FINNEGAN: There was some radiographic Thank you. Dr. Doull. 12 DR. DOULL: Well, as you know, in order to 13 answer the question about safety, you need to ask whether 14 the quantity and the quality of the tox studies were 15 sufficient to provide one the ability to be reassured about 16 safety and as I indicated, we have two kinds of safety 17 questions here. 18 local toxicity. 19 There's the systemic toxicity and the I think in terms of these studies, they were 20 well-described and well-done. The doses looked fine and 21 they are standard studies, so that I find those reassuring 22 in regard to the systemic safety. I'm not exactly sure NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 353 of 581 1453 PageID 221 1 what additional studies you're talking about that you 2 might do to focus on the question of local toxicity 3 transformation and so on. 4 DR. RIEDEL: If I can respond to that 5 question, Dr. Doull. 6 You had raised earlier the question of intra-species 7 variability 8 inter-species 9 intra-species variability and if I might, I'd like to 10 This is Gerard Riedel speaking. raising the issue variability of raising -the I'm sorry, issue of address that question first -- 11 DR. DOULL: 12 DR. RIEDEL: Fine. -- because I think it is 13 relevant to this question. What we have observed is that 14 it is the local concentration of BMP-2 applied on the 15 absorbable collagen sponge which correlates with efficacy 16 within a species and that that efficacy which is defined 17 by that local concentration is consistent across all the 18 anatomic sites where we've tested it in that species, and 19 is independent of the total volume of the material that's 20 implanted or in other words, independent of the total 21 volume -- of the total dose of BMP that's implanted at 22 that site. NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 354 of 581 1454 PageID 222 1 A more specific application -- example is 2 the following. If we implant rhBMP-2 in critical size 3 defects in long bones or in periodontal defect pockets 4 in a canine what we have found is that the optimal 5 therapeutic concentration of BMP-2 on the sponge is 6 identical in those two anatomic sites, but of course, the 7 volume that's implanted in those two bony defects is very 8 different. So that's the empirical observation. 9 Then to address the question about how does 10 one appropriate dose in order to assess local toxicity, 11 what we took was the strategy that we -- we tried to use 12 as high a concentration as was feasible in terms of 13 manufacture. 14 study that I described to the panel earlier this morning, 15 we applied a concentration of BMP-2 to the absorbable 16 collagen sponge that was four milligrams per mil. 17 the highest we can manufacture and put on the sponge. And in the case of the rat implant toxicity That's 18 Now, that's in excess of the concentration 19 that's used in the human clinical setting which is one 20 and a half milligrams per milliliter. 21 somewhere between 40 and 80 times in excess of the optimal 22 therapeutic concentration in rats, which is somewhere in However, it is NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 355 of 581 1455 PageID 223 1 the range of 50 to 100 micrograms per milliliter. We took 2 this approach in order to drive the concentration in order 3 to look for some effect of cellular abnormality or toxicity 4 at the local site. 5 So we didn't take a total mass of protein 6 to total body weight approach, but rather this local 7 concentration approach and that's the approach that we 8 took. 9 DR. DOULL: You're on the low end below the 10 threshold for a lot -- in the net conclusion of all your 11 tox studies was no effect and that conclusion of many of 12 your pharmacology studies were no effect, which, I guess 13 it's a little hard to talk about therapeutic index for 14 those kind of things, but that's, I guess the way the ball 15 park is. 16 DR. RIEDEL: Your observations are correct. 17 We tried very hard to find dose-limiting toxicity doses. 18 We were unable in any of our studies no matter how high 19 we drove the dose to identify a dose limiting toxicity. 20 21 DR. BODEN: Can I add a word about the intra-species variability or inter-species variability? 22 CHAIRPERSON FINNEGAN: Certainly. NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 356 of 581 1456 PageID 224 1 DR. BODEN: Stated another way, the 2 definition of the minimally effective dose for any given 3 species 4 intra-species variability. 5 defined as the dose that would yield 100 percent consistent 6 response in that species. 7 wide range of therapeutic excess, in a sense, if you lower 8 the 9 minimally effective concentration for a given species, 10 you will see animal to animal variability but the way those 11 are defined for each species is to take that out of play. the concentration 12 13 was dose below DR. DOULL: They're all which telling took out of play and In other words, it was And because there is a pretty what we've defined as the I was struck by our BMP experts. us about the variability and 14 sensitivity of different organs, of different cells, for 15 example, and it just seems that that kind of variability 16 between species, between cells, between -- that surely 17 there must be a little difference between an immunal 18 compromised patient for example, what she really needs. 19 What you did in the rat was figured out how 20 much you need in order to get that bone response and what 21 is the maximum that increasing the dose no longer increases 22 that response, which gives you that nice therapeutic range NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 357 of 581 1457 PageID 225 1 in your animal studies. 2 to humans, it leaves me -- I don't know, interesting 3 question. 4 Whether one can extrapolate that CHAIRPERSON FINNEGAN: 5 want to add anything? 6 DR. TUAN: Dr. Tuan, did you Sure, just around that one point. 7 Just along that same direction, a question that I think 8 ought to be addressed is also that different cells respond 9 to BMPs in the cell types and therefore, the different 10 tissues respond to BMP with a different type of dose 11 response, generally, in a nanogram for mil range or lower 12 even. 13 milligrams at the site and then about one percent out there 14 in the circulations. 15 but maybe it will be useful to give the panel some 16 information as to, if you have the data that is, what is 17 the local concentration of BMP at various tissue sites 18 as a function of time, what the concentration may be and 19 perhaps that may address some of the concerns of the panel. 20 So I'm just thinking with -- about a couple I can't do the math that quickly DR. RIEDEL: 21 again. 22 summary this morning. This is Gerard Riedel speaking This is a topic which I started to address in my Dr. Tuan is correct in terms of NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 358 of 581 1458 PageID 226 1 the exposure that comes from the -- to the body from BMP 2 implantation. 3 animal models that approximately one-tenth of one percent 4 of the BMP that's implanted at a local site becomes 5 systemically available and is detected in the circulation. And that is that we've observed in several 6 7 This predicts a very low systemic exposure. 8 But to address the issue that Dr. Tuan raised, that is 9 that BMP has effects on different cell types, we 10 administered BMP-2 protein in buffer by an intravenous 11 administration to these animals and we did so with doses 12 of BMP that were thousands of time higher on a per kilogram 13 body weight basis than what was anticipated to be the human 14 exposure as a result of implantation of BMP-2 and the 15 results that we found were uniform and they were striking 16 in their uniformity. 17 We saw no effects. Now we know that there 18 are cells that could respond, but we saw no effects and 19 when 20 pharmokinetics and the bio-distribution of BMP-2 in these 21 animal models, we found that BMP-2 was very rapidly cleared 22 from the circulation, principally by the liver and that we explored that further by looking at the NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 359 of 581 1459 PageID 227 1 it was rapidly degraded by the liver and cleared through 2 the kidney and excreted in the urine within 24 hours and 3 that's the explanation we think will -- 4 DR. DOULL: Yeah, I think that's an important 5 point. In order to define exposure, you need to talk about 6 not only the dose but also the time and your kinetic studies 7 have clearly shown that in 16 minutes it's gone in a rat 8 and it's even less in a monkey. 9 even less than that. So in a human it's probably So if you're defining exposure 10 correctly in terms of both dose and time, then you're 11 exposure is indeed, trivial. 12 13 CHAIRPERSON FINNEGAN: ahead. 14 If I could -- go Microphone, microphone. DR. TUAN: This might also address some 15 concerns of another panelist and that is have you looked 16 at the same thing in a pregnant animal and how much of 17 the BMP that's administered to the pregnant mother is found 18 in the fetus as a function of time, the pregnancy period? 19 DR. RIEDEL: I think it's very important for 20 the panel, we'll keep the issue of the protein versus an 21 antibody to the protein. 22 issues. We try and keep those as separate We have only administered unlabeled BMP-2 NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 360 of 581 1460 PageID 228 1 protein in our reproductive toxicity studies but we did 2 administer that protein over the duration that was 3 described by Dr. Miller in his slides per the ICH 4 guidelines for performing reproductive toxicity studies 5 both before and during the early portions of gestation. 6 7 And in those cases, at exposure levels, 8 again, that were calculated to be many times greater, more 9 than a thousand fold greater than the anticipated exposure 10 in humans. 11 that were evaluated. 12 13 We saw no observations on any of the parameters CHAIRPERSON FINNEGAN: Dr. Diamond, the floor is yours. 14 DR. DIAMOND: I have a few questions but can 15 you just clarify for me something that I think I just heard 16 but I'm not certain. 17 at a concentration of one and a half milligrams per mil; 18 is that correct, into the sponge? You put in a total of five milligrams 19 DR. RIEDEL: 20 DR. DIAMOND: But it's not -- 21 DR. RIEDEL: It's not quite correct, Dr. 22 I'll be happy to clarify. Diamond. NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 361 of 581 1461 PageID 229 1 DR. DIAMOND: Okay. 2 DR. RIEDEL: Depending upon the volume of 3 the sponge, we soak the sponge with a solution of BMP that 4 contains one and a half milligrams of BMP-2 per milliliter 5 of that solution. 6 straightforward answer is that the total volume of 7 solution that we use depends upon the size of the sponge. The reason why I can't give you a 8 9 DR. DIAMOND: But are you suggesting that 10 if you use it at 1.5 milligrams per mil it doesn't matter 11 if the total amount of protein you give is 10 milligrams 12 or five milligrams in that reasonably little space? 13 DR. RIEDEL: What we have advised surgeons 14 and in all of our animal models was to fill the space with 15 the volume of the wetted absorbable collagen sponge and 16 not to over-pack it. 17 required small volumes of the wetted absorbable collagen 18 sponge, the concentration of the applied BMP was the same 19 but the total dose was different. 20 they got a smaller total dose. 21 studies got a larger total dose and what we found 22 correlated with optimal therapeutic efficacy was the And so, yes, in small defects that So for small defects, Large defects in our animal NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 362 of 581 1462 PageID 230 1 concentration of BMP that was applied to the sponge. 2 That's the empirical observation. 3 DR. DIAMOND: I guess that's a little 4 surprising, I think, but so I guess I had a question that 5 was raised previously about are there studies with liver 6 dysfunction? 7 this? 8 Is there limitations on who can receive DR. RIEDEL: From a pre-clinical perspective 9 we have not looked at the pharmacokinetics nor the 10 bio-distribution of BMP-2 in a liver impairment model and 11 any animal model. 12 DR. DIAMOND: And do you know if the 13 pancreatic tumor was receptor positive, the one that 14 developed in the individual who got the -- 15 DR. LIPSCOMB: 16 DR. DIAMOND: 17 DR. LIPSCOMB: 18 And can I ask -- the patient. Wait a minute, wait. You're talking about whether they were positive antibodies? 19 DR. DIAMOND: 20 DR. LIPSCOMB: 21 DR. RIEDEL: 22 They were negative. No. Okay, I'm sorry. Just to clarify the question, I think you were asking whether or not the patient in the NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 363 of 581 1463 PageID 231 1 clinical study who had a pancreatic tumor was positive 2 for receptors for BMP-2. 3 DR. DIAMOND: 4 DR. RIEDEL: Right. Well, the patient is still alive 5 about 13 months after diagnosis. 6 materials to assess. 7 8 DR. DIAMOND: We don't have any I see, okay. That's a fair answer, a good answer even. 9 Can I ask some questions about the antibody 10 studies? 11 animals with the serum diluted one to 50 when I don't know, 12 30 percent of the dogs or whatever got -- or monkeys got 13 antibody or was there different dilutions in the animals 14 where there seemed to be more antibody? 15 16 DR. RIEDEL: DR. Institute. 19 20 RUP: Bonnie Rup, Wyeth-Genetics So the question is -DR. DIAMOND: Were the dilutions of serum the same in the humans and in the animal studies? 21 22 I think it's appropriate to call one of my colleagues to the podium to address this answer. 17 18 I guess it begins with were the studies in DR. RUP: They're basically the same starting dilutions -NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 364 of 581 1464 PageID 232 1 DR. DIAMOND: 2 DR. RUP: 3 -- and we diluted out in order to get to a titer. 4 5 So what -- DR. DIAMOND: 50 dilution? 6 Why did you start at a one to I mean -DR. RUP: Yeah, it's our experience that 7 generally below that concentration one often sees very 8 high background readings that gives you something that 9 could be more variability in the background of your 10 baseline which could be attributable to antibodies, 11 perhaps. 12 to antibodies but it's more likely to be due to just 13 background high reactivity and especially in dogs. 14 had a lot of problems with high background. It could be interpreted as being attributable 15 DR. DIAMOND: We So did you do any assays either 16 in the animals or in human serum to look for neutralizing 17 activity? 18 to BMP-2 is. 19 sensitive assay to look for neutralizing antibodies, but 20 I assume that there are others here and elsewhere who know 21 that. I don't know what the most sensitive cell line So I don't know which would be the most Did you look for -- 22 DR. RUP: We have been talking to the FDA NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 365 of 581 1465 PageID 233 1 about developing a neutralizing antibody assay and we've 2 made some attempts to start trying to look at a cell line, 3 the same cell line that's used as the bio-assay to 4 determine potency of BMP-2, which obviously, is a logical 5 choice. 6 But there is -- that assay is in development. There has been some difficulty in trying to use serum 7 on it, as you can expect. 8 alkaline phosphatase in response to BMP-2 stimulation and 9 obviously, we'd be looking at a reduction in alkaline 10 It's a cell line that produces phosphatase production. 11 The serum itself also inhibits the cell 12 line's alkaline phosphatase production. 13 work on ways of reducing that as an issue. 14 15 DR. DIAMOND: So we need to Using your control, is your control, positive control, is it monoclonal? 16 DR. RUP: We have looked at -- we have a few 17 antibodies that were generated as reagent antibodies, both 18 monoclonal 19 obviously, we can test in a purified fashion, and we 20 haven't seen any evidence that those are neutralizing. 21 22 and polyclonal DR. DIAMOND: antibodies and those, But do you have -- can you calculate based on those how many micrograms per mil of NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 366 of 581 1466 PageID 234 1 antibody you have in the serum? 2 DR. RUP: Well, we've avoided trying to do 3 anything like that because, as you know, antibody potency 4 is really a function of both concentration and affinity. 5 And there -- yeah, and so on, so we feel like reporting 6 out nanograms 7 obviously, if you test it against a high affinity antibody, 8 you get low numbers and if you test it against a low 9 affinity antibody, you get high numbers and we just feel 10 like that would be misleading and, you know, obviously, 11 it's just relative to what you use to begin with, so we've 12 never tried to do that. 13 per mil DR. DIAMOND: would be misleading because I guess my concern is with the 14 antibody testing that as you know, an ELISA depends how 15 much antigen you put on the plate, what your starting 16 dilution is, if you don't reduce the IgM antibodies and 17 there are lots of IgM antibodies, you may not see the IgG 18 antibodies that are present in the serum. 19 a very artificial assay until it is validated with a gold 20 standard of a biologic assay because do you know what kind 21 of titer you would call at this point a clinically 22 significant titer? And it's I guess NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 367 of 581 1467 PageID 235 1 DR. RUP: Well, that's always a difficult 2 thing to do because the intention of the assay was just 3 to set up something that was very sensitive and would be 4 able to give us a very reproducible assay during the 5 duration of a long study. 6 the intention of just developing a sensitive assay and 7 you really don't know whether your assay is sensitive 8 enough to pick up clinically relevant antibodies until 9 you get clinically relevant responses. 10 And so one always goes in with DR. DIAMOND: 11 gestating 12 immunized? animals or Have antibodies been given to have 13 DR. RUP: 14 DR. DIAMOND: gestating animals been No. And I guess I have another 15 question that will reveal what I don't know. This 16 pregnancy registry certainly sounds like an appealing idea 17 but how many pregnancies would you have to see to have 18 a degree of fetal loss or teratogenicity that is important 19 and how many child bearing -- women of child bearing age 20 a year come to this kind of procedure. So over the five 21 years we were told is realistic, are numbers, the kinds 22 of numbers that will give meaningful information going NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 368 of 581 1468 PageID 236 1 to be available? 2 3 And the answer may be clearly yes or I just don't know this. 4 DR. LIPSCOMB: Well, on that particular 5 question I did try to run the numbers to see, you know, 6 what you could come up with just based on the demographics 7 of patients that were in our clinical trials and then 8 taking some information that's available in the literature 9 about how often do women get pregnant during the course 10 of a year and I came up with this calculation. 11 DR. DIAMOND: 12 DR. 13 Once. LIPSCOMB: As a whole. Not in Tennessee. 14 (Laughter) 15 DR. LIPSCOMB: But anyway, if you look at 16 the slide here that's on the screen, for every 10,000 17 patients a year that would receive treatment, and I'm 18 talking about all patients, not just women, based on our 19 demographics from our clinical trials, about 5,000 of them 20 will be women. 21 distributions that are in our study, then about half of 22 those or about 2500 of them would be women of child bearing And then if you look at the age NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 369 of 581 1469 PageID 237 1 age. 2 And then this where the statistic comes in, 3 I think we received out of a document that came from the 4 FDA, in which this 11 percent of women of child bearing 5 age in the general population would maybe become pregnant 6 during the course of a year. 7 times 2500 and you get down to a factor of about 275 women 8 a year -- 275 women during the course of a year out of 9 10,000 people treated, would get pregnant in our patient 10 So you multiply 11 percent population. 11 Then if you look at our antibody rate that 12 we had in our clinical trial and you multiply that, you 13 know, roughly -- surely less than five but the numbers 14 calculate out to about two per year out of 10,000 people 15 treated may be positive for antibodies they get pregnant. 16 So you can see the number is pretty small, and even if 17 you put safety factors, let's say -- well, not a factor 18 of five. 19 Let's get you up to 10. And at the bottom of that slide, the 20 population rate, this would be -- what would be the adverse 21 event that you would expect in the general population, 22 whatever, the birth defect or whatever you would be looking NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 370 of 581 1470 PageID 238 1 for, if it occurs at one percent or three percent or 10 2 percent, and if you look at a relative risk of two, which 3 would be the doubling of the rate versus the control, then 4 you'd need those numbers that are underneath that patient. 5 6 So if it's one percent, you'd need 2,000 7 patients or 700 patients for three percent. 8 see by the numbers generated in the population and then 9 what it would take in a registry, then to do anything 10 statistically meaningful, it's kind of a hard thing for 11 me to come to, you know, grips with when you start talking 12 about a registry. 13 a situation where you're just taking -- assuming that women 14 are going to get pregnant. 15 that, you know, women that have had back surgery which 16 will probably lower that number some and it's also probably 17 -- you know, you might tell them not to get pregnant, you 18 know, for some period of time, so that will reduce it even 19 more. 20 So you can And this also, too, takes into account That doesn't take into account In our clinical trial, only about 1.5 percent 21 of the people got pregnant. I know there was a question, 22 you said, you know, when did these people get pregnant NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 371 of 581 1471 PageID 239 1 and everybody got pregnant in the study after 16 weeks 2 except one. 3 and that pregnancy went to a normal delivery. 4 thing, too, that was mentioned, I think, in Dr. Miller's 5 talk this morning when he was going through the registry 6 concept, tell me when to be quiet, but he gave several 7 reasons why you might want to do a registry, I think at 8 the end of this talk and it seems like to me some of those 9 points that you made wouldn't fit our particular situation 10 which was, say maybe a registry wasn't appropriate here. There was one, I think, at about eight weeks So the other 11 12 13 So that's -- I hope that answers your question. 14 DR. DIAMOND: I guess it seems to me though 15 that the numbers of patients who are going to accrue over 16 five years and the number of anticipated pregnancies is 17 probably at the low end of where you're going to be able 18 to detect teratogenicity for sure and even fetal loss and 19 so I think that makes it all the more important to look 20 in animal models to see whether these antibodies have a 21 potential negative effect on pregnancy outcomes. 22 DR. RIEDEL: I just wanted to add one piece NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 372 of 581 1472 PageID 240 1 of information. We have looked very hard in making 2 monoclonal antibodies to recombinant human BMP-2 to make 3 an antibody that would neutralize the activity of the 4 protein and we've tried for now eight, nine years and we 5 have yet to make a neutralizing monoclonal antibody 6 against this protein. 7 that we have to address as we work with FDA on this matter. So we do have some technical issues 8 9 CHAIRPERSON FINNEGAN: Are you comfortable 10 -- you're comfortable with the answers? 11 questions? 12 DR. HANLEY: Dr. Hanley, We have one question and that 13 relates to one of those letters that was read earlier about 14 putting the BMP adjacent to the nerve for a posterior 15 approach. 16 sought for here but any comments from people on that? 17 It doesn't relate to the indication being DR. BODEN: Obviously, the risks and 18 complications of the device are that of the surgery, the 19 insertion of the cage and what's inside the cage, and this 20 specific application before the panel today is through 21 an anterior approach, either an open or a laparoscopic 22 and to talk about safety issues that are related to a NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 373 of 581 1473 PageID 241 1 different surgical approach seems to me to be outside the 2 scope of what we ought to be focusing on today. 3 CHAIRPERSON FINNEGAN: Actually, I'll take 4 a little bit of exception to that because you know that 5 in the skilled hands of the people who did your trial, 6 that was placed where it was supposed to be placed, but 7 if it goes out into the free market it's going to be 8 probably placed close to nerve roots and I think that's 9 a really valid question. 10 DR. BODEN: Okay. We can go into it in a 11 little bit more detail then. Why don't we go to slide 12 36? 13 study where the cage was inserted through the posterior 14 aspect of the spine. 15 actually? The issue with the study that's been raised was a Why don't we go forward one slide 16 And so there was no longer a barrier, in fact, 17 between the cage and the InFUSETM bone graft and the neuro 18 elements. 19 insert cages from behind is, in fact, that you have 20 roughened surfaces of bone. 21 sometimes hemostatic agents are put in place. 22 from the anterior insertion of the cage, it is in fact, One of the other things that happens when you You can have hematoma, As we see NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 374 of 581 1474 PageID 242 1 not uncommon to see bone formation in front of the cage 2 from the direction of the surgical approach. 3 Somebody referred to it earlier as a sentinel 4 sign. I think it might have been Dr. Kostuik and in fact, 5 that's a very positive thing. 6 another slide? 7 forming in front of the cage, and this is, of course, a 8 patient from the application we're discussing today which 9 is from the front of the spine, the notion that you would 10 have a bump or bone in front of the spine, otherwise known 11 as the sentinel sign is, in fact, a normal and a desirable 12 finding. Why don't we move forward So the notion that there would be bone 13 However -- why don't you back up one for a 14 second -- if that sentinel sign occur -- if the insertion 15 of the cage is through the canal and that sentinel sign, 16 if you will, is a reverse sentinel sign, and occurs 17 posteriorly, then that can potentially encroach into an 18 area where there are nerves. 19 Forward. So I would say that it's not at all an 20 unexpected finding. It's something that, in fact, with 21 posterior lumbar interbody fusion with the same cage 22 filled with autogenous bone graft we see variable amounts NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 375 of 581 1475 PageID 243 1 of bone formation and the patients in that study were 2 analyzed in great detail looking at how often that occurred 3 and it was with an intermediate degree of frequency and 4 to differing degrees or the size of the bump, just like 5 we would expect from that anterior approach, but I think 6 the most important thing in that trial was that the 7 presence or absence of that little bony bulge did not 8 correspond with any clinically measurable differences 9 between the groups. 10 So it was a radiographic observation that 11 I would say is not at all unexpected based on our experience 12 from putting them in from the front of the cage and it 13 is something that, you know, when you look at the groups 14 as a whole, groups of patients that had, you know, a little 15 bit of bone versus no bone, there was really not a 16 clinically detectable difference in their outcome. 17 that -- 18 DR. LARNTZ: 19 statement? 20 of that? Does Could I follow up just from that Did you actually do a statistical analysis 21 DR. BODEN: 22 DR. LARNTZ: No. Okay, that's all I wanted to NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 376 of 581 1476 PageID 244 1 say. 2 3 DR. BODEN: Does that answer the question, Dr. Hanley? 4 CHAIRPERSON FINNEGAN: Just one addendum to 5 that; was the PLIF -- I don't think you were part of it. 6 Was the Sofamor Danek PLIF study with the cage not stopped 7 because there were some problems? 8 DR. BODEN: Yeah, the trial was put on hold 9 and that was actually a somewhat controversial decision 10 which I can take some personal responsibility for because 11 I was not one of the participating surgeons in that trial 12 and the surgeon group met and analyzed this when it first 13 became apparent that people were observing it and actually 14 felt very strongly about continuing the trial. 15 I, as a consultant, wanted to actually watch 16 these patients longer and make absolutely certain that 17 this was not going to be of clinical consequence and made 18 the recommendation to Medtronic Sofamor Danek that they 19 consider holding the study until there could be more 20 follow-up and a better determination of the extent of what 21 this observation meant. 22 And it was after that deliberation that the NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 377 of 581 1477 PageID 245 1 study was put on hold merely to follow these patients. 2 3 4 DR. DIAMOND: Can I ask something following up on this? 5 CHAIRPERSON FINNEGAN: 6 DR. DIAMOND: Yes. Didn't we hear in a letter that 7 there was one patient who had bony ingrowth into the spinal 8 canal? 9 10 CHAIRPERSON FINNEGAN: I think Dr. -- is Dr. McCullough still here? 11 A VOICE: No. 12 CHAIRPERSON FINNEGAN: He left but I think 13 Dr. McCullough's presentation had from using the material 14 posterially with a -- 15 DR. DIAMOND: That was post -- 16 CHAIRPERSON FINNEGAN: 17 DR. DIAMOND: 18 CHAIRPERSON FINNEGAN: 19 DR. WITTEN: It was in a letter. Right. Yes. Yeah, I just want to mention 20 that to the extent that these things -- you know, these 21 other 22 indication, then I think asking questions is appropriate studies relate to the effectiveness of this NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 378 of 581 1478 PageID 246 1 but to the extent that they're just about some other use, 2 we really want to focus the discussion here on the 3 particular indications sought by the sponsor. 4 CHAIRPERSON FINNEGAN: Understood, 5 understood, but I think there is some relative safety as 6 far as leaving some space. 7 to add to that? 8 glasses. 9 DR. Yes, Dr. Kostuik, did you want Yes, Dr. Miller. MILLER: While He's cleaning his he's cleaning his 10 glasses, perhaps Dr. Diamond and the group here could 11 address an issue I've been fumbling with. 12 patients 13 experimental, one in the control and another experimental 14 that was, in fact, positive before they -- in the pre-op 15 stage. 16 of the population that is carrying these antibodies not 17 associated at all with your giving BMP-2. who are positive on We have three antibodies; one an Now, does this mean really we have a small segment 18 If you took 500 women, pregnant women and 19 screened them, how many of them would have that antibody? 20 CHAIRPERSON FINNEGAN: Well, I think that 21 relates to Dr. -- to Barbara's question, too, so hang on 22 a second and we'll get around there. Gene. NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 379 of 581 1479 PageID 247 1 DR. SIEGAL: I'd like to go back to the 2 pancreas because I did not understand the answer. 3 said the patient was still alive. 4 was made by either open biopsy, by fine needle aspiration 5 or perhaps by radiologically guided brushing. 6 of those should give you enough cells to seek the answer 7 that was requested. 8 9 DR. LIPSCOMB: You Certainly the diagnosis Any one They performed surgery on this gentleman. 10 DR. SIEGAL: So you do have tissue. 11 DR. LIPSCOMB: Yes. 12 receptor has been looked at though. 13 DR. SIEGAL: Okay. I don't think the So let me then go back 14 and ask that question I asked before which is two cell 15 lines appeared to show increased mitogenesis and one 16 patient developed pancreatic cancer, the first two were 17 pancreatic cell lines. 18 of data? 19 DR. BODEN: How do you interpret that cohort When we looked at the expected 20 frequency of tumors in the population of this size and 21 age and demographics, it turns out that the number of 22 tumors is actually less than what you would expect in the NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 380 of 581 1480 PageID 248 1 population. The issue that the -- you know, that one of 2 the tumors happened to be pancreas, I think at this point 3 it would be hard to make any statistical case that would 4 be more than just coincidence. 5 The other thing is -- 6 DR. SIEGAL: 7 There was two, were there not, two cell lines, one? 8 DR. BODEN: 9 DR. SIEGAL: 10 DR. BODEN: No, no, in the cell lines. Two cell lines, one patient. There were two cell lines. 11 There were also pancreatic cell lines that did not have 12 that response and also when you look at tissues from tumors 13 which Dr. Riedel presented earlier in none of the 14 transformed tumor cell lines, so none of the live tissue 15 that came out of patients with tumors was it ever observed 16 that there was that increase in division. 17 DR. SIEGAL: Okay, thank you. Now, I want 18 to go back to my question about whether or not there were 19 pathologists involved in any of these studies. 20 21 DR. RIEDEL: Can I just ask one clarification? 22 DR. SIEGAL: Yes, please. NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 381 of 581 1481 PageID 249 1 DR. RIEDEL: Are you referring to the animal 2 studies that looked at spine fusion or the animal studies 3 that looked at the safety of the implanted product? 4 DR. SIEGAL: I guess I would ask in any 5 studies were there board certified veterinary or human 6 pathologists involved? 7 DR. RIEDEL: For the animal safety studies 8 the implant safety toxicology studies were conducted at 9 a contractor, Clinical Trials Bioresearch in Centerville 10 -- in Canada. 11 and veterinary surgeons. 12 I can't remember at this moment and will have to get back 13 to you on whether the histologist was a board certified 14 veterinary histologist but I believe he was. 15 16 On staff were board certified pathologists DR. SIEGAL: To the best of my recollection, And so you don't know either whether they have any expertise in bone pathology. 17 DR. RIEDEL: Oh, no, I'm sorry, I should 18 follow up with that point. 19 people with specific expertise in bone biology to assess 20 the histological samples from these studies. 21 22 DR. LIPSCOMB: We did specifically ask for We also have here Dr. Jeffrey Toth, who has done histological reports as well on samples. NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 382 of 581 1482 PageID 250 1 DR. TOTH: Yes, I'm Jeffrey Toth. I'm an 2 associate professor of orthopedic surgery at the Medical 3 College 4 laboratory for orthopedic surgery. 5 interest in the company or product being reviewed here 6 today nor any other company or product. 7 of Wisconsin, also direct the biomaterials I have no financial I am not a pathologist. I have done work 8 over the last 10 years that has involved bone histology 9 as a method of analysis for biomaterials and bone implants. 10 I have about 25 publications and peer review publications 11 and book chapters in that area especially dealing with 12 spinal implants. 13 There were four pre-clinical studies that 14 Dr. Boden talked about his morning. 15 actually did histology on two of those, so I don't know 16 exactly which ones you're referring to. 17 slide 18 produced the histology for the -- number 19 13, please. DR. SIEGAL: Our Our laboratory If I could have laboratory actually I don't wish to in any way impugn 20 your reputation but I just want to make sure you said you're 21 not a pathologist. 22 DR. TOTH: I am not a pathologist. NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 383 of 581 1483 PageID 251 1 DR. SIEGAL: Thank you. 2 DR. RIEDEL: Dr. Siegal, my colleague just 3 corrected me and I should correct for the record, the folks 4 that did the work for us at Clinical Trial were not boarded 5 histologists. 6 pathologists. 7 8 DR. SIEGAL: were boarded veterinary In the human studies, were there any human pathologists involved? 9 10 They DR. RIEDEL: Well, Dr. Toth did the analysis in the human explants. 11 DR. SIEGAL: Okay, thank you. Then the next 12 question, I guess, out of order if you will was, would 13 there then not be value in performing a study comparing 14 the radiology to the pathology in animals with appropriate 15 expertise in pathology and radiology? 16 DR. ZDEBLICK: Good afternoon, my name is 17 Tom Zdeblick. I'm an orthopedic surgeon at the University 18 of Wisconsin. I do have a financial interest. 19 inventor of the LT-cage and I have patents on the LT-cage 20 and one of the four studies that were quoted this morning 21 was the original one that I did with goats using a different 22 cage, titanium cage, using BMP-2 and that was performed I'm the NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 384 of 581 1484 PageID 252 1 at our School of Veterinary Medicine at the University 2 of Wisconsin. 3 the pathology read by a certified veterinary pathologist, 4 two of the mechanical results that we found in that study. 5 And there was very good correlation between 6 what we saw in histology, the radiograph and the mechanical 7 performance. 8 And that correlated the radiographs and DR. SIEGAL: Thank you. The last question 9 I have had to do with whether you consider preloading the 10 cage with already hydrated BMP-2 in the sponge, to minimize 11 the amount of handling required at the time of surgery. 12 DR. RIEDEL: Yes, Dr. Siegal, we did consider 13 that but there are significant technical obstacles to 14 generating, to manufacturing such a preloaded material. 15 We have chosen to go with aseptic manufacture of the 16 protein in order to preserve the integrity of the protein 17 and avoid any problems associated with damage to the 18 protein due to terminal sterilization of the product. 19 The collagen sponge is terminally sterilized 20 with ethylene oxide treatment. We wanted to avoid the 21 potential damage to the protein associated with that 22 terminal sterilization. Consequently, we have performed NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 385 of 581 1485 PageID 253 1 validation studies using radiolabeled BMP-2 to validate 2 that the method that we use for instructing the surgeons 3 to apply the protein results in a uniform application of 4 protein across the entire volume of the wetted sponge and 5 that information has been provided to the agency in the 6 application. 7 DR. SIEGAL: Thank you very much. 8 CHAIRPERSON FINNEGAN: 9 DR. KIRKPATRICK: Dr. Kirkpatrick. I think a couple of my 10 questions can be dispensed with fairly quickly but first 11 with a yes or no question with regard to my question raised 12 during 13 specific reason that the patients in the control group 14 developed an antibody to the bovine collagen? 15 because the surgeon used a hemostatic agent during the 16 surgery? 17 the presentation. DR. BODEN: Have you identified the Was it There's no way to know that for 18 sure, but certainly people are exposed to bovine products 19 in many aspects of life in addition during surgery, and 20 so any gelatin-based product of some kind, you know, 21 sutures and things. 22 DR. KIRKPATRICK: So as a yes or no question, NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 386 of 581 1486 PageID 254 1 it's no, you don't know? 2 3 DR. BODEN: that. 4 5 We have no way of confirming DR. KIRKPATRICK: Right, that's all I wanted to make sure. 6 DR. BODEN: No. 7 DR. KIRKPATRICK: Thanks. Sorry, Scott, 8 but there's a lot of people trying to catch planes tonight. 9 With regard to the radiographic data beyond 24 months 10 and the clinical data beyond 24 months, can you just give 11 me again as short an answer as possible, did you see the 12 deterioration continue that you demonstrated between 12 13 and 24? 14 DR. BODEN: No. 15 DR. KIRKPATRICK: In other words, we can 16 assume that even though there would be a smaller number 17 of patients beyond 24 months, that we would find percentage 18 of fusions approximating the ones that you saw at 24, no 19 more than a five or 10 percent -- 20 DR. BODEN: Understand that the 48-month 21 follow-up is really limited to the pilot study which had 22 11 investigational patients and three autogenous bone. NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 387 of 581 1487 PageID 255 1 2 DR. KIRKPATRICK: Would you not also have a number at 36 however? 3 DR. BODEN: 4 DR. KIRKPATRICK: 5 up those patients are no longer studied? 6 7 It wasn't part of that study. DR. BODEN: So once the 24 months was Are you talking in the pivot trial or the clinical? 8 DR. LIPSCOMB: I'm talking about the 9 clinical trial between the open -- the two open groups. 10 You didn't do them all in the first month of the trial. 11 DR. BODEN: No, I mean, there -- 12 DR. KIRKPATRICK: So I know you've got 13 patients beyond 24 months that might be at 36. I'm 14 wondering 15 deteriorated I think it was like four percent between 12 16 and 24, did you continue to see that between 24 and 36 17 even though you're probably down to what, 50, 75 patients 18 at that time? 19 since you showed DR. BODEN: in your data that you The best long term follow-up 20 going out to four years is in eight of the 14 patients 21 from the pilot trial which is essentially the same 22 protocol. And in there, there was five investigational NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 388 of 581 1488 PageID 256 1 and three control and at the 48-month follow-up five out 2 of five in the investigational were still deemed as fused 3 radiographically and the same two out of the three of the 4 control were rated fused. So there was no change in the 5 primary outcome variable which was radiographic fusion 6 at 48 months. 7 What happens to change in the overall success 8 rate that you're observing is not a change in the 9 radiographic or CT determined fusion success. It's 10 patients that over time may, with their surgeons, decide 11 to have another operation or may require another operation 12 for an adjacent problem. 13 was very strict in that if anything occurred. So the definition of success 14 And so what you're seeing with that quote, 15 unquote "deterioration", is not really a change in the 16 hard core result of bridging bone but rather that those 17 other criteria that go into the more clinical fusion rate. 18 19 DR. KIRKPATRICK: What I saw in at least one 20 of your case reports of a failure was that between 12 months 21 they were deemed a fusion and at 24 they were a failure 22 because of a pseudoarthrosis, okay, specifically in your NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 389 of 581 1489 PageID 257 1 case example. 2 24 months. 3 4 5 So what I'm asking is, did that happen after DR. BODEN: That was because of a second surgery, not because of a radiographic change in reading. That patient was -- 6 DR. KIRKPATRICK: The clinical report that 7 I saw said he had a pseudoarthrosis, period, okay. 8 pseudoarthrosis is a failure even if it took an operation 9 to discover it. 10 DR. LIPSCOMB: A That was the reason for the 11 second surgery that was filled out on the adverse event 12 form. 13 was a diagnostic reason for why a second surgery. 14 a conservative approach there. 15 radiograph show on the fusion criteria, if a patient is 16 still having pain or whatever and the physician says that 17 I had a suspected pseudoarthrosis here, then they -- and 18 if they do a second surgery, they may put pedicle screws 19 on the other side, we count that as a fusion failure, just 20 because the surgeon called it a suspected or a possible 21 pseudoarthrosis, even though it may not jive at all with 22 the radiographs. That's why the second surgery was performed. It We take Regardless of what the NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 390 of 581 1490 PageID 258 1 DR. KIRKPATRICK: I'm sorry, I didn't 2 memorize the number of the patient so we could discuss 3 it specifically. 4 possible pseudoarthrosis. 5 because it was a pseudoarthrosis. 6 correct, I'd like to know. 7 if you followed the patients that are now beyond 24 months 8 and found if you have any more. 9 However, the report I read did not say DR. LIPSCOMB: It says he was reoperated on If that data is not If it was, I'd like to know The protocol for the pivotal 10 trials specify that patients are seen after 24 months and 11 then bi-annually which means every other year, thereafter 12 until every person in the study has gotten two years. 13 That's the criteria, so there is no 36-month visit for 14 patients to come back in according to the schedule. 15 Forty-eight would be the next one provided that everybody 16 didn't get to 24 in the meantime. 17 18 I am aware, I think there's been a couple of second surgeries after 24 months, though. 19 DR. KIRKPATRICK: If you had said that in 20 the beginning, my question would have stopped. If I knew 21 you weren't looking at anybody from 24 until 48, that was 22 -- you can't answer my question. I think you've already NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 391 of 581 1491 PageID 259 1 answered my question on the liver. 2 correct? 3 DR. LIPSCOMB: 4 DR. KIRKPATRICK: You don't know, That's right. I think in the interest 5 of time, the expression of the BMP in a normal is probably 6 not worth discussing. 7 your specific recommendations as far as my other question 8 on the off-label use, which is, in light of the history 9 of the pedicle screw issue and the off-label use there 10 and resulting litigation, how would you guard against 11 off-label use of this product especially with rhBMP-2? 12 I would like, however, to know DR. LIPSCOMB: Well, you mentioned the 13 pedicle screw situation. 14 concept because when we, as a company, were dealing with 15 that issue, and in discussing labeling throughout the 16 years with FDA, when we started talking about a warning 17 or a precaution or some statement like that about, "Don't 18 use a screw in the pedicle", it came back that if you tell 19 somebody not to use a screw in the pedicle, that's in 20 essence an indication. 21 22 That is -- that's an interesting So a contra-indication or a warning would be an indication. So we couldn't basically do that. NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com I Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 392 of 581 1492 PageID 260 1 think we could propose labeling or would propose labeling. 2 We'll discuss it more with FDA when we're discussing the 3 final labeling, but statements could be made or -- along 4 the fact that safety and effectiveness of InFUSETM bone 5 graft 6 established. and other spinal applications 7 DR. KIRKPATRICK: 8 CHAIRPERSON 9 Kirkpatrick. has not been you, Dr. Thank you. FINNEGAN: Thank All right, just a couple of short questions. 10 The question of elution within the titanium cage, has 11 that been looked at and a second part of that question 12 is, do you know if there's any affinity for titanium ions 13 and the BMP? 14 DR. RIEDEL: Neither Medtronic Sofamor Danek 15 nor we have looked at the bio -- the clearance of BMP 16 implanted in a titanium cage. 17 at 18 geometries of the implanted rhBMP-2 ACS and in general 19 the clearance from the implantation site follows the same 20 time course and the same general pharmokinetics from the 21 site. several 22 animal models We have, however, looked that have used different With respect to your second question about NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 393 of 581 1493 PageID 261 1 interaction with titanium ions, we have done no studies 2 to look at interactions with any metal ions and the BMP-2. 3 CHAIRPERSON FINNEGAN: The next question is, 4 any idea why the ones that failed, failed? 5 a pretty simple standard -- 6 DR. LIPSCOMB: It depends on what you mean 7 by fail. 8 failure, why that rate is what it is? 9 I mean, it's If you're talking about overall success, CHAIRPERSON FINNEGAN: Actually, did not 10 fuse. The other back pain patient population problem 11 we're not that interested in but didn't fuse. 12 DR. BODEN: Actually, there's very few, if 13 any, that did not fuse based on using the CT criteria, 14 bridging trabecular bone. 15 is a bit of a confusion because of the way the protocol 16 is defined and the way it's presented, a radiographic 17 failure technically could be somebody who is fused but 18 had another operation because they had persistent pain 19 or had adjacent segment degeneration. 20 The ones that are -- and this And that would be shown as a radiographic 21 failure. If you separate out the radiographic -- the 22 definition of radiographic success as bridging trabecular NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 394 of 581 1494 PageID 262 1 bone, I think Dr. Genant will say that every patient met 2 that criteria. 3 CHAIRPERSON FINNEGAN: No, but at least I 4 know there are two women over 50 who had migration of their 5 cage and one of them very definitely. 6 CT scan I could see -- 7 DR. BODEN: 8 a completely different situation. 9 failures because of technical problems with the cage 10 insertion irrespective of whether the cage is filled with 11 autogenous bone graft or infused bone graft. 12 cage technique insertion problem that surgeon technical 13 irregularity. 14 Those x-rays and Yeah, that's -- I'm sorry, that's CHAIRPERSON FINNEGAN: Those were early That's a Because one of them 15 was not approached surgically again, but still did not 16 fuse, so I would assume that the material is still there 17 and the BMP is still in the cage. 18 DR. BODEN: The BMP is going to be gone from 19 the cage presumably within in 14 days. And there are a 20 number of different animal studies and a variety of 21 different venues to support that, as well as somebody asked 22 earlier about the -- or it's one of the questions about NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 395 of 581 1495 PageID 263 1 the collagen sponge. That's going to be resorbed in four 2 to six weeks most likely, depending on the animal model. 3 4 So I think if a cage was sticking out front 5 what you have is a situation where you don't have the 6 adjacent bone in order to develop blood supply and have 7 a continuous or connecting bone. 8 in a sense would be an isolation, but if there's a case 9 where -- 10 11 So that particular cage CHAIRPERSON FINNEGAN: You have soft tissue there. 12 DR. BODEN: Huh? 13 CHAIRPERSON FINNEGAN: You have soft tissue 14 around it. Anyway, never mind. You obviously haven't 15 looked at it. 16 president is, when I looked at the materials that you sent 17 it looked like these were all packaged together, that is 18 the cage, the BMP hydrated and there was one picture that 19 had sort of what this was supposed to look like. 20 guess my question is, if you have different sized cages, 21 do you have different sizes of the sponge but the same 22 -- this is like somebody else's question -- but the same My last question, I think, for your vice And I NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 396 of 581 1496 PageID 264 1 amount of BMP? 2 DR. LIPSCOMB: Yes. The key point as Dr. 3 Riedel said is the concentration of 1.5 milligrams per 4 milliliter and depending on the size of the cage, it would 5 take different sizes of vials of BMP. 6 7 CHAIRPERSON FINNEGAN: size and the vial size differ. 8 9 So both the sponge DR. LIPSCOMB: the inner lumen. Right, because it would be It would be the inner lumen of the cage 10 that would dictate what size sponge to put in. 11 CHAIRPERSON FINNEGAN: So that goes back to 12 my question about packaging. 13 are you going to have an associated size vial of the BMP 14 and associated size of the sponge? 15 DR. LIPSCOMB: So then for each size cage Well, the BMP kits will be 16 sold with a certain size vial with the sponge inside the 17 kit. 18 know, not packaged with that. The cage will be sold separately or will be, you 19 DR. RIEDEL: There is a volume to volume. 20 CHAIRPERSON FINNEGAN: Right, but if your 21 cage volume is different then you have to match the cage 22 volume to the sponge size and to the volume of your -NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 397 of 581 1497 PageID 265 1 okay, and the consumer is going to know this by -- so I 2 guess two questions then. 3 as a separate unit. The InFUSETM is going to be sold It's not sold with the cage. 4 DR. LIPSCOMB: That is the plan, yes. 5 CHAIRPERSON FINNEGAN: Okay, and so then how 6 is the consumer to know which size of InFUSETM goes with 7 which size of cage and how do you control that? 8 DR. LIPSCOMB: It would be in the labeling. 9 CHAIRPERSON FINNEGAN: All right, but then 10 the surgeon could, in fact, use more or less at his or 11 her discretion because they could just buy a different 12 size package. 13 DR. LIPSCOMB: Well, the inside of the cage 14 would dictate what size kit would be required to fill the 15 cage. I guess I'm not understanding the question but -- 16 CHAIRPERSON FINNEGAN: Actually, I think 17 you're not understanding the creativity of orthopedic 18 surgeons, that's my concern. 19 (Laughter) 20 CHAIRPERSON FINNEGAN: 21 question. 22 You answered the Dr. Naidu? DR. NAIDU: Yes, I have a couple of short NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 398 of 581 1498 PageID 266 1 questions. 2 guys talk about surgical technique. 3 in detail but just looking at your manual, nowhere do you 4 describe the preservation of the posterior annulus, just 5 be careful about not -- you know, you talk about not 6 perforating through, but is that going to be addressed 7 in a manual in more detail as to how not to place it too 8 close to the nerve roots or -- I mean, as far as the 9 technique, the surgical technique? 10 The question about excess bone formation, you DR. ZDEBLICK: Dr. Boden goes into The surgeon technique manual 11 is pretty specific about templating for size and the 12 templating takes into account the area of the disc space 13 and how far away from the posterior longitude and the 14 ligament you need to stay and then second, when you're 15 preparing the channels for the cages with the reamer, 16 they're depth specific and depth stop will keep you in 17 that range so that you inadvertently don't go too far 18 posterior. 19 20 So at several steps in the technique manual it addresses that concern. 21 22 DR. NAIDU: Okay, thank you. And the second question is, the size ranges of your cages, what were the NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 399 of 581 1499 PageID 267 1 size ranges, small to the largest, the diameter of the 2 cages? 3 DR. MATHEWS: Yeah, the cages range from 14, 4 they go to 16, 18 and 20 millimeters. 5 DR. NAIDU: 6 DR. MATHEWS: 7 So 14 is your smallest diameter? Yes, and they have different lengths from 20 to 26 millimeters in length. 8 DR. NAIDU: Okay, now, so when you're seeing 9 these -- this bone formation at 12 months on CT scans, 10 what we get are a couple of reconstructions at 12 months 11 and 24 months and you're saying that the dowel of bone 12 that forms between the two segments is, at best 14 13 millimeters thick -- I mean, I'm sorry, at best 22 14 millimeters thick and if you use the smallest cage it's 15 about 16 radiographic data mean? 14 millimeters thick. 17 DR. BODEN: 18 CHAIRPERSON FINNEGAN: Is that what those Yeah. Scott, you need to 19 state your name for the record, so the transcript shows 20 it. 21 22 DR. BODEN: I'm sorry, Scott Boden. -- the early fusion tends to be through the cage. What That's NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 400 of 581 1500 PageID 268 1 the way the device works whether you're using autogenous 2 bone graft or InFUSETM. 3 is, in a sense, independent of what is causing bone to 4 form. 5 around the cages or what is secondary bridging across the 6 interspace. 7 sign, that we discussed earlier. 8 it going around the sides of the cages. So this is a question that really However, what you see over time is bone forming It can be in front of the cage or the sentinel We showed examples of 9 We see a clear trend that in the case of 10 InFUSETM, which seems to have more reliable bone form 11 earlier based on measuring units on CT scans, that we tend 12 to see more reliably this bone around the cage. 13 anything, I would say that you get additional bone sooner 14 and more reliably in the InFUSETM cases but that's not a 15 statistical 16 endpoint. 17 gets to the same endpoint in appearance if you had used 18 autogenous bone graft, but it appears to get there quicker 19 with some of those additional areas and zones of bone 20 formation. 21 22 observation. It was not an So, if official It's a empiric observation, but it ultimately DR. NAIDU: Okay, thank you. And the next question that I have is more directed towards our experts, NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 401 of 581 1501 PageID 269 1 Dr. Kostuik 2 flexion/extension views not being too reliable with the 3 advent of this posterior instrumentation world that we're 4 in today. 5 criteria that the sponsor has established such as less 6 than three millimeters of translation and less than five 7 degrees of angulation, with the use of these cages is a 8 valid radiographic criteria since -- if you could expound 9 on that. 10 mainly. Dr. Kostuik, you talk about Would you say that the flexion/extension DR. KOSTUIK: I would say that they are not 11 valid. 12 positioned, how the x-ray is taken, slight location of 13 patient during taking the lateral view, but the most 14 particular reason for my saying that is that these implants 15 provide very significant rigidity at least within the 16 first few months, and it's certainly been, I think, 17 well-shown and a long-term practice with other forms of 18 anterior cages that flexion/extension x-rays are not 19 statistically valid in assessing motion. 20 21 There's too much variation in how the patient is DR. NAIDU: Thank you. Those are all the questions I have. 22 CHAIRPERSON FINNEGAN: Thank you. Dr. NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 402 of 581 1502 PageID 270 1 Boyan? 2 DR. BOYAN: Well, I don't really have a 3 question. 4 question is really for Integra. 5 sponge, you clearly have had 20 years experience with that 6 clinically, have you found that patients have become 7 sensitized to the type I collagen in the sponge or that 8 particular type of type I collagen where if they've had 9 repeated procedures, that they don't develop an immune 10 I just wanted to state again -- maybe my On the -- in the HelistatTM response? 11 DR. O'GRADY: Regulatory Good afternoon. Affairs, Integra Life I'm Judy 12 O'Grady, Sciences 13 Corporation. 14 collagen sponge which is also known as HelistatTM, also 15 known by other names. We're the manufacturer of the absorbable 16 Let me start off by saying that there is a 17 21-year history, as you mentioned, of this -- of approvals 18 through FDA and marketing of the absorbable collagen 19 sponge. 20 an implantable medical device, and also in numerous 21 clinical trials and the clinical trials involve often 22 repeated application and multiple applications of the In our experience in marketing this product as NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 403 of 581 1503 PageID 271 1 collagen product, not necessarily the HelistatTM but we 2 -- all our products are manufactured from the same source 3 of collagen and also undergo the same purification 4 process. 5 To this date, in 21 years, both in marketing 6 the product and in clinical trials, we have never seen 7 any immunogenic response or allergic reaction to the 8 product. 9 DR. BOYAN: Okay, thank you. And then not 10 to cause a problem but, Dr. Riedel, I'm going to turn it 11 over to you on the BMP side of things and the only reason 12 why I do this is just to clear the air but BMP, you know, 13 it revs a lot of things up and it does, in fact, rev up 14 some times immune cells. 15 -- I mean, it's -- they're not unhappy but they're 16 energized. 17 18 They're there and it isn't a And so have you done -- in any of your animal studies have you looked at this specifically? 19 DR. RIEDEL: Other than performing a 20 histological assessment at the site of implantation, we 21 have not looked at specific immunological markers in any 22 of our studies. NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 404 of 581 1504 PageID 272 1 DR. BOYAN: 2 CHAIRPERSON FINNEGAN: 3 Okay, thanks. Thank you. Dr. Reddi. 4 DR. REDDI: Yes, my questions and issues are 5 for the folks from Medtronic Sofamor Danek and their 6 collaborators and Wyeth-Genetics Institute. 7 the tumorigenicity in which the FDA has specifically 8 charged the panel to provide guidance to the FDA, I'd like 9 to follow up with one of the experts from the sponsors. 10 In addition to studying the effects of recombinant human 11 BMP-2 on transformed cell lines from one of your grantees 12 in Texas, has there been any direct long-term effects on 13 either mice or rats to see whether there might be any in 14 vivo tumorigenic actions, positive or negative? 15 DR. RIEDEL: As far as I'll start just by summarizing 16 the results that I presented this morning and that is that 17 we conducted in canines and in rats a chronic toxicity 18 study with endpoints at various time points to either six 19 or 12 months of follow-up and did extensive histological 20 assessment of the implantation site in those animal 21 models. 22 Using local concentrations of BMP-2, they've NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 405 of 581 1505 PageID 273 1 greatly exceeded the therapeutic optimal concentration, 2 local concentration, for those specific species and in 3 both of those animal models, we saw no evidence of any 4 abnormal cellular events that would be suggestive of 5 tumorigenicity in those models. 6 7 DR. REDDI: mostly confined locally to an osseous environment. 8 9 10 All right, I take it, it was DR. RIEDEL: correct, Dr. Reddi. In both instances, you are The implant resulted in a formation of an osseous environment at the site of implantation. 11 DR. REDDI: Yes. I was most impressed by 12 your presentation and description of the effects or 13 recombinant human BMP-2 on the femoral onlay model. 14 in your extensive pre-clinical studies at Medtronic, 15 either Scott Boden or some of the other three centers, 16 has there been an attempt to do the same experiment of 17 placing such a device, InFUSETM in the environment of the 18 disc? 19 DR. RIEDEL: I'll start the Now, answer by 20 referencing a safety study that was done in a canine model 21 in which the safety of BMP-2 on the absorbable collagen 22 sponge was assessed when it was applied directly to the NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 406 of 581 1506 PageID 274 1 dura of 2 procedure. 3 an academic laboratory and it was actually Dr. Hanley's 4 lab that performed this study 5 study have been published and there were no significant 6 findings in that study. 7 the spinal cord following an laminectomy This study was conducted as a GLP study in DR. REDDI: and the results of that There is a lot of panel members 8 at various times have asked already questions about the 9 antibody and the transplacental passage and I had given 10 you a heads up to tell me whether you have antibodies to 11 the native recombinant BMP-2 and what happens if such 12 antibodies are administered to rats or mice. 13 14 DR. RIEDEL: I'm going to defer to my colleague to address this question. 15 DR. RUP: I'm Bonnie Rup, Genetics 16 Institute, Wyeth. 17 were 18 antibodies that we were able to make by immunizing were 19 actually against Ecoli-derived, onimeric (ph) BMP-2, or 20 against peptides conjugated to immunogen proteins. made 21 22 as You're referring to antibodies that reagent DR. REDDI: antibodies? Yeah, the only And when you administered -- did you administer to pregnant mice or rats and what effects NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 407 of 581 1507 PageID 275 1 did it have on the embryos? 2 DR. RUP: We never tried to administer them 3 to animals. 4 to 5 cell-based bioassay and they don't seem to neutralize. see I can't tell you that we've tried to look whether 6 they have DR. REDDI: neutralizing effects in Yes, and it is also well-known, 7 even the best antibodies made by Wyeth-Genetics Institute 8 the recombinant BMP-2 cross-reacts with BMP-4. 9 there be a concern that these antibodies in these patients 10 might effect functions which are directed in the embryo 11 or elsewhere by BMP-4 or do you think it would be a concern 12 that we should address? 13 DR. RUP: Would I think that the antibodies that 14 -- you know, the few antibodies that can be generated in 15 humans, they might cross-react with BMP-4 since they're 16 very homogenous. 17 18 DR. BOYAN: May I make a comment, Madam Chairman? 19 CHAIRPERSON FINNEGAN: 20 DR. BOYAN: You may. I think that we're all dancing 21 around about the antibodies and I'm going to take the risky 22 thing of saying something out loud scientifically and hope NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 408 of 581 1508 PageID 276 1 that I'm right but it isn't easy to make an antibody to 2 native recombinant BMP-2 and I think everybody needs to 3 know it's not easy to make one and it isn't easy for humans 4 to make one. 5 that we have in our bodies all the time. This is a highly conserved common protein 6 Generating an antibody to it is not a small 7 feat and that's why they've had to go through such 8 extensive things to generate them to peptides and hook 9 them onto stuff to get the antibodies made. 10 DR. RUP: 11 DR. DIAMOND: 12 And we definitely concur with that. Can I just say one thing, though? 13 CHAIRPERSON FINNEGAN: 14 DR. DIAMOND: Yeah. I think that the experience 15 with recombinant human proteins in people is that when 16 you give it to enough people, you get antibodies. 17 DR. BOYAN: 18 DR. DIAMOND: with I agree. And that we know this with 19 thrombopoietin, 20 recombinant 21 immunogenic and I think it really depends on having an 22 assay that can look for an interference with biologic human erythropoietin, proteins. They these are shouldn't be NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 409 of 581 1509 PageID 277 1 function and that's very important because, you know, very 2 immunogenic, not very immunogenic, eventually it will be 3 immunogenic. 4 5 DR. BOYAN: impossible. I agree. I didn't say it was I said it isn't easy. 6 CHAIRPERSON FINNEGAN: 7 DR. REDDI: Dr. Lenchik (sic). The last question I have for 8 perhaps Dr. Boden or somebody else from Medtronic Sofamor 9 is that since when you first put the cage with the InFUSETM 10 device, the cells which are going to see it are either 11 the nucleus palposa (ph) cells and/or the annular cells, 12 has there been some basic studies to find out the 13 responsiveness of these cells at what you might call a 14 therapeutic index concentrations? How do they respond? 15 16 17 CHAIRPERSON FINNEGAN: Don't all jump at once there? 18 DR. BODEN: Scott Boden. We have 19 histologically not observed any changes in the surrounding 20 cartilage. 21 cartilage is removed in order to create the crevice or 22 the tunnel that the cage goes into. As part of the procedure, obviously the And the cells that NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 410 of 581 1510 PageID 278 1 really grow into the sponge, which is where the BMP is 2 and if the BMP elutes into the adjacent bone because of 3 circulation, tends to be more of an exchange with bone 4 cells and marrow cells than the relatively acellular and 5 quiescent intervertebral disc cells. 6 In most cases these discs are very 7 degenerative and so the cellular activity is somewhat low. 8 There are a number of in vitro studies looking at BMP-2 9 and others effects on disc chondrocytes and again, those 10 are in vitro studies. 11 effects that I know of. 12 to be beneficial and whether or not that would be possible 13 with a single dose application, as in this case to make 14 any difference I suspect probably not. 15 Most There have not been any deleterious of In fact, many of them are thought those beneficial attempts at 16 intervertebral disc cartilage therapeutics are more with 17 longer term exposures or gene therapy approaches. 18 DR. REDDI: Thank you. 19 CHAIRPERSON FINNEGAN: 20 DR. LENCHIK: Dr. Lenchik? I have a couple of questions, 21 hopefully it will be brief. To get back to that question 22 of posterior anatomical barrier that exists behind the NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 411 of 581 1511 PageID 279 1 cage, what do you do about patients that have annual tears 2 or worse disc herniations? 3 such that this device is contra-indicated in those 4 patients or how do you keep them from ossifying the spinal 5 canal? 6 DR. BODEN: Is the labeling going to be Scott Boden. I think that's a 7 very appropriate question and, in fact, as you know and 8 others know, the normal population has a very high 9 frequency of annular tears. Some of them are microscopic, 10 many of them are macroscopic. Patients can have defects 11 in the annulus because they've had previous disectomy or 12 current herniated discs. 13 We believe that all of that existed because 14 this is a normal disc population and remember that in order 15 to form bone at a distant site away from the implantation 16 site, it requires not only the elution of recombinant BMP-2 17 protein but it requires a matrix or a substrate in order 18 which to form the new bone on. 19 of patients which inevitably, based on pathologic studies 20 we know from the prevalence of annular fissures and tears 21 was that an issue in the pilot clinical or in the pivotal 22 clinical trials. So in none of these hundreds NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 412 of 581 1512 PageID 280 1 2 DR. LENCHIK: So there was not a single patient that formed bone posterior to the cage? 3 DR. BODEN: There was not a single patient 4 -- Scott Boden again. 5 formed bone posterior to the cage outside the confines 6 of the disc case. 7 disc case, anterior, posterior, laterally to the cage is 8 a normal finding that we see even with successful autograft 9 fusions over time. 10 There was not a single patient that Remember bone in the confines of the DR. LENCHIK: A second question, a repeat 11 to what I asked earlier, what do you think the explanation 12 is for why the number of patients fused by CT criteria 13 were less at 24 months compared to 12 months? 14 initial false positives at 12 months and did you look at 15 that group specifically to see if there was any correlation 16 with clinical symptoms in that small group? 17 DR. BODEN: Were these Scott Boden again. That drop 18 in the apparent fusion rate was all due to the second 19 surgery criteria. 20 operations, for reasons as I stated earlier, that may have 21 either been persistent pain, new pain, adjacent segment 22 degeneration. So it was not a change in the radiographic (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 Those were all people that had NEAL R. GROSS www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 413 of 581 1513 PageID 281 1 reading or appearance or the grading of the CT scan. 2 So in a sense, in terms of positivity, false 3 or otherwise, the numbers and the statistics that you're 4 probably thinking of were radiographic fusion rate, 5 include in it the requirement that there not have been 6 a second surgery in order to be considered a fusion success 7 as the study is currently defined. 8 in that percentage is because of some patients that are 9 getting second surgeries. 10 DR. LENCHIK: So the apparent drop I guess you confused me by 11 that. So what you're saying is that actually the number 12 of CTs that were fused was not less at 24 compared to 12? 13 DR. BODEN: That's correct. 14 DR. LENCHIK: The other question is also 15 somewhat a repeat of what was asked earlier but I'm not 16 sure I heard an adequate response. 17 assessment of fusion either by CT or plain films, was there 18 any quantitation of that? 19 document I read that it was graded one through four and 20 A through D, and if so, how much of it did you need before 21 you called it fused, either on plain film or CT? 22 Was one Was the radiographic I thought somewhere in the trabecular bridging across NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 414 of 581 1514 PageID 282 1 sufficient or how much of it was required? 2 DR. BODEN: This is Scott Boden again. The 3 grading system you're referring to was created in the pilot 4 study as a means of assessing whether or not that type 5 of quantitative analysis would be helpful or not since 6 this was broaching somewhat new ground. 7 that effectively the criteria as outlined in the pivotal 8 protocol that that quantitation of that sort was not useful 9 in coming up with an all or none binary answer that was 10 It was determined meaningful. 11 So there wasn't, as Dr. Genant mentioned 12 earlier, 13 independent readers and I think that if there had been 14 one little spicule, that they would not grade that as 15 bridging trabecular bone. 16 but if you want further clarification, then we can get 17 Dr. Genant back. 18 formal quantitation DR. LENCHIK: but there were two It would have to be meaningful That's all right. The last 19 question is perhaps the easiest to answer. I have read 20 several times in the documentation that patients -- plain 21 films were evaluated first and if they were fused by plain 22 films then they were basically considered fused. If not, NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 415 of 581 1515 PageID 283 1 they had CT scan. 2 not evaluated in the patients who were fused by plain films 3 or were CT scans actually read in every single patient 4 from whom they were obtained? 5 Does that mean that the CT scans were DR. BODEN: CT scans were -- this is Scott 6 Boden. 7 was only the decision algorithm as to whether or not they 8 were classified as fused. 9 CT scans were read in every single patient. DR. GENANT: That This is Harry Genant again. 10 Yes, Leon, that is correct, that basically we did an 11 evaluation of the CT in all of the patients in whom CTs 12 were available and that was a vast majority. 13 DR. LENCHIK: Since you're up there, Harry, 14 what about the issue of artifact coming off the metallic 15 cage on CT, were there any patients in whom you thought 16 you simply couldn't tell whether there was bridging across 17 or this is a hypothetical that just exists in my head and 18 not in real life? 19 DR. GENANT: Well, indeed, that is an issue. 20 Although that we recognize that in this case we're dealing 21 with titanium cages and clearly if we had other metal 22 alloys that would be -- would almost preclude the NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 416 of 581 1516 PageID 284 1 evaluation. 2 combination of the axial images with the coronal and with 3 the sagittal reformations, that we were able to make an 4 estimate of the intracage ossification in virtually all 5 the cases. 6 7 CHAIRPERSON FINNEGAN: Okay, thank you. Dr. Larntz? 8 9 But nevertheless, we found that with the DR. LARNTZ: question is, was any Just one question. analysis done to The one adjust the 10 laparoscopic results for the difference in baseline 11 variables? 12 DR. LIPSCOMB: The answer is yes. In 13 anticipation of your question, Dr. Larntz, we did do a 14 co-variant 15 investigation of lap group to the control group. 16 slide, 17 preoperative conditions and also some of the surgical 18 variables 19 co-variants and from a logistic regression, we identified 20 eight that seemed to be -- that had the most significant 21 effect. 22 adjustment please. to We get analysis looked out base at of Next slide, please. 25 what comparing demographic other the Next and possible And those are the eight NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 417 of 581 1517 PageID 285 1 that came up from the logistic regression. Some of them 2 obviously, make a lot of sense when you start thinking 3 about what maybe would effect the outcome. Next slide. 4 And then when you do the Bayesian analysis, comparing 5 the lap to the control with the adjustments, you see that 6 an equivalence is established in all the major categories; 7 fusion, Oswestry, neuro and overall success and in fact, 8 superiority could be claimed in three of them, Oswestry, 9 neuro and overall, so yes, we did. 10 DR. LENCHIK: Thank you. 11 CHAIRPERSON FINNEGAN: 12 MS. RUE: Ms. Rue. I think my other questions and 13 comments were pretty much discussed but I do have one. 14 You had a very nominal amount of patients that had 15 hepatitis. 16 about their outcomes? 17 Was there anything specifically different DR. LIPSCOMB: I'd have to look to see if 18 there's anything. 19 patients that had that and if you can give us a second, 20 we can -- 21 22 I think there's only just one or two MS. RUE: I think there was like three in one and two in the other. It was just nominal. NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 418 of 581 1518 PageID 286 1 2 DR. LIPSCOMB: Yeah, if you can give us a second we can check. 3 CHAIRPERSON FINNEGAN: 4 MS. MAHER: 5 CHAIRPERSON FINNEGAN: 6 7 Ms. Maher? I have nothing further to add. All right, if you will all -- while he's looking that up -- hang on a second. Yes. 8 DR. KOSTUIK: 9 CHAIRPERSON FINNEGAN: 10 DR. KOSTUIK: May I ask a question? Microphone. It's John Kostuik. It's my 11 understanding that there was statistically significant 12 difference in urological or urogentic problems between 13 the InFUSETM 14 mainly retention and that they all resolved, but I do have 15 some concerns. 16 that there may be some influence BMPs in the prostate. 17 I would like to know the breakdown between sexes and ages 18 as to who had the significant problems with urinary 19 retention because this could lead in the older population 20 to some difficulties. 21 22 group and the controls and that these were It's my understanding, probably wrong, DR. MATHEWS: Kostuik. Hal Mathews. Thank you, Dr. We did not urogenital issues in the patients NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 419 of 581 1519 PageID 287 1 in the investigational group. 2 specific mechanisms for that and we didn't really come 3 up with anything specific to that but Dr. Kostuik's point 4 is 5 distribution of age and sex. well-taken. We're We tried to look at currently searching for the 6 We discussed this clinically amongst the 7 investigators and we thought that there were two issues 8 which were really pretty obvious in treating these 9 patients. Number one was the fact that the patient that 10 received the investigational control device did not have 11 a bone graft harvest; and hence, when the surgery was over, 12 if they were treated laparoscopically, they were going 13 home in 45 percent of those patients. 14 If they were treated as an open surgical 15 patient, they wanted to get up because they didn't have 16 much pain. They didn't have the iliac crest harvestation. 17 And hence if one is up and mobile, one will typically 18 ask the nurse, "May I have my catheter removed", because 19 as you know, the catheter insertion and Foley catheter 20 drainage during and alift procedure (ph) is paramount to 21 that procedure. You want to have the bladder deflated. 22 NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 420 of 581 1520 PageID 288 1 And hence, if you didn't have an iliac crest 2 harvestation, you had your catheter taken out very early 3 and you were up and mobile. 4 that that's an anterior procedure and that anterior 5 approach still has the risk of having ileus and also 6 urogenital complications just from being there and hence 7 those patients may have had reinsertion of a Foley catheter 8 later because of this. However, we still always know 9 However, it is important to note that all 10 of these retention issues did resolve before they went 11 home and no patients needed additional catherizations. 12 13 14 CHAIRPERSON FINNEGAN: All right, thank you. We're going to have to proceed to questions, to the FDA questions but I think Dr. Li had one question. 15 DR. LI: I just have one question I failed 16 to ask earlier. In one of the summaries, it compares the 17 results of nine of the investigators who had a financial 18 interest in the product versus the investigators that did 19 not have a financial interest. 20 fact that the surgeons that had the financial interest 21 had a better overall success rate in both your control 22 and your test group, almost by a factor of two in the test And I was taken by the NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 421 of 581 1521 PageID 289 1 group, versus those physicians that did not have a 2 financial interest. 3 So I don't really raise this at all to impugn 4 anybody's integrity but my question is, is there something 5 that we can learn about that? 6 your nine investigators that had a financial interest, 7 did they have a higher experience level, did they have 8 a better technique? 9 away from that that you could put into the labeling or 10 instruction or manuals than that would basically make 11 everybody's -- or you could give everybody a financial 12 -- Was there something that Is there something that we can take 13 (Laughter) 14 DR. LIPSCOMB: Well, what a question. The 15 only thing I can say about that is we did the analysis, 16 as you had in your packet, and it just speaks to the beauty 17 of having a prospective randomized control trial because 18 if you look at the results that were presented, yes, those 19 with the financial interest did better than those that 20 didn't on the numerical -- different numerical parameters, 21 but they also did equally well in the control group as 22 well. So when you start making those comparisons, that's NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 422 of 581 1522 PageID 290 1 where those kind of wash out. 2 DR. LI: Yeah, I guess my question is, did 3 you investigate why that was? 4 that we could take from that to teach everybody across 5 the board to have the same -- 6 7 DR. LIPSCOMB: I mean, was there something We didn't specifically look past that point, no. 8 CHAIRPERSON FINNEGAN: Time out. If you 9 will bear with me, we need to actually officially have 10 a second open public session, so I would like to proceed 11 with that at this time. 12 addressing the panel come forward and speak clearly into 13 the microphone so that the transcriptionist can have a 14 valid means of providing an accurate record of this 15 meeting. I would ask that all persons 16 And we request that all persons making 17 statements during the open public session of the meeting 18 disclose which company they represent and whether they 19 have financial interests in any medical device company. 20 Before making your presentation to the panel, in addition 21 to stating your name and affiliation, please state the 22 nature of your financial interest, if any. Is there NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 423 of 581 1523 PageID 291 1 anyone wishing to address the panel? 2 DR. PATEL: Please. I'm Tushar Patel. I'm a service 3 consultant to Depuy Acromed as well as Striker Biotech. 4 And I'm here with my travel expenses paid for by Depuy 5 Acromed. I'm a clinical assistant professor at Yale 6 University and a private practice spine surgeon, limited 7 to spine surgery, orthopedics. 8 This is a two-part question, a follow-up of 9 that to Dr. Finnegan, who commented upon the endless 10 resourcefulness of orthopedic surgeons. I plead guilty. 11 How does one insure, given Dr. McCullough's comments 12 earlier about off-label application, different carriers, 13 et cetera, and this is a particularly important question. 14 I would be delighted to see BMPs approved in the sense 15 that I think that's a tremendous advance in treating spinal 16 disorders, but I think it is important to address the 17 off-label issue. 18 The second is for the people from Integra 19 Life Sciences, in which the question was asked, have any 20 antibodies been seen. 21 29 years ago, were any tests done to look for the 22 antibodies? Knowing that it's been approved I understand that nobody's ever reported any NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 424 of 581 1524 PageID 292 1 immune response but did anybody ever look for an immune 2 response and specifically the antibodies? 3 4 CHAIRPERSON FINNEGAN: Thank you. Would you guys like to answer the first question? 5 MR. DEMIAN: He's just giving a comment. 6 You don't have to specifically answer the questions. 7 is open public session where he's providing his comments 8 to the panel, so that's it. 9 CHAIRPERSON FINNEGAN: This All right, at this 10 time I would like to ask the sponsors, Medtronic Sofamor 11 Danek if they have any final comments before we proceed 12 with reviewing the questions. 13 14 MS. RUE: answer the question about -- 15 16 Dr. Finnegan, I'd like them to CHAIRPERSON FINNEGAN: Oh, certainly, hepatitis. 17 DR. LIPSCOMB: We did a quick analysis of 18 the patients that had hepatitis and if you'll just look 19 at the overall success, bear with us, the data that we 20 could garner quickly, three out of five of the open 21 investigation patients were successes at their last visit, 22 overall successes. Sixty-six percent or virtually 60 NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 425 of 581 1525 PageID 293 1 versus 66 percent in the control were successes and then 2 100 percent in the lap group were successes. 3 MS. RUE: 4 CHAIRPERSON FINNEGAN: 5 Thank you. Would you like to make any final comments? 6 DR. LIPSCOMB: 7 CHAIRPERSON No. FINNEGAN: Oh, thank you. 8 Aric, if you would go ahead and put up the questions, 9 please. 10 MR. KAISER: Okay, the first question has 11 to do with reproduction and teratogenicity and we would 12 like the panel to discuss the potential for an immune 13 response in the mother to effectively block BMP-2 in the 14 developing fetus. 15 16 CHAIRPERSON FINNEGAN: Comments from the panel. 17 DR. DIAMOND: I think we have to say it's 18 a potential hazard and that this study so far doesn't prove 19 the null hypothesis, so it's a potential concern. 20 CHAIRPERSON FINNEGAN: 21 DR. LENCHIK: 22 CHAIRPERSON FINNEGAN: Any other comments? I've got one. Yes. NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 426 of 581 1526 PageID 294 1 DR. LENCHIK: registry. We're Why not talking pregnancy 3 contra-indication in women who are pregnant, no one has 4 brought that up as an option. CHAIRPERSON FINNEGAN: 6 DR. WITTEN: Can make the 2 5 just about it a All right. I provide some 7 clarification to that question, just in response to that, 8 which 9 presentation, it's not the -- what we're concerned about 10 potentially is a potential concern, it's not something 11 demonstrated in the study. 12 itself 13 developing fetus but that the problem -- that the product 14 may cause an immune response in another that could at some 15 time, not necessarily related to you know, the time point 16 at which it was implanted, cause a problem. is as when 17 Peter Hudson administered explained during his It's not that the product is causing a problem in So then, you know, the question would be if 18 a woman had it which would be suggesting 19 contra-indicating event. 20 keep in mind, you then contra indicate it or -- you know, 21 there's a sort of -- it's not clear what the time limit 22 would be of that contra-indication. So that's just something to NEAL R. GROSS (202) 234-4433 a COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 427 of 581 1527 PageID 295 1 DR. BOYAN: Madam Chairman? 2 CHAIRPERSON FINNEGAN: 3 DR. BOYAN: Yes, Dr. Boyan. The -- I guess I would argue 4 against that contra-indication because I don't think we 5 have enough information one way or the other except to 6 say that the incidents of an immune response in the mother 7 was exceedingly low in the clinical trial and based on 8 the information that was given to us would be very low 9 in the general population, but I don't think we should 10 ignore it. 11 I think that we need to make it clear in the 12 labeling somewhere that it's a potential issue and that 13 I guess I might even go as far as to say that there may 14 be some wording to suggest that the patient be made aware 15 of that not just in some vague discussion but should they 16 then get a second or a third treatment using BMP-2 in some 17 sort of device, that they maybe want to pre-test to see 18 if they have antibody titer at that time. 19 20 DR. KIRKPATRICK: Dr. Finnegan, may I comment? 21 CHAIRPERSON FINNEGAN: 22 DR. KIRKPATRICK: Go ahead. John Kirkpatrick. NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com I Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 428 of 581 1528 PageID 296 1 would just suggest that as a surgeon, and I hope my 2 colleagues would agree but I can't read their minds, that 3 I would not plan to do an elective surgery on a pregnant 4 woman anyway. 5 kind of not relevant to medical practice. 6 So putting it as a contra-indication is DR. DIAMOND: I think the concern, the 7 caution would be for women who want to get pregnant, who 8 plan to get pregnant and I think that maybe there should 9 be 10 some post-marketing continued studies of these antibodies in gestating animals. 11 CHAIRPERSON FINNEGAN: And actually I 12 strongly support that as well. One of my questions, Dr. 13 Witten, is that one of the studies that is proposed or 14 no, because I don't see that as a -- 15 DR. WITTEN: That's actually one of the 16 studies that we're asking you to make a recommendation 17 on. 18 that and what it would look like. If you do propose such a study, we'd like to know 19 20 CHAIRPERSON FINNEGAN: You can go ahead. 21 22 Okay. MR. KAISER: same topic, discuss All right, the next question, the potential that the fetal NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 429 of 581 1529 PageID 297 1 expression of BMP-2 could restimulate a maternal immune 2 response and cause adverse effects in the mother, which 3 was the question that Dr. Witten had brought up. 4 CHAIRPERSON FINNEGAN: All right. Dr. 5 Diamond, do you have any comment on this being as you are 6 our resident immunologist? 7 DR. DIAMOND: You know, I think that I don't 8 know if that transplacental model that we heard about goes 9 in both directions and whether you can actually see whether 10 fetal protein goes into the -- I mean, I think it's an 11 interesting question. 12 13 I'm more concerned the other way. CHAIRPERSON FINNEGAN: Okay. Dr. Miller. You need a microphone. 14 DR. MILLER: There certainly are data that 15 suggests in mouse models that the decidua is they're 16 producing tremendous amounts of RNA about day seven and 17 perhaps, influencing where implantation will be occurring 18 in that process, Dr. Day out at the University of Kansas 19 in a group. 20 maternal reaction to generating a large amount. 21 not be transplacental. 22 DR. BOYAN: So it may not just be fetal. It may be It may I guess I would be worried about NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 430 of 581 1530 PageID 298 1 it going the other way. I mean, I also would be in favor 2 of worrying about unborn fetuses but there's lots of us 3 that are like already born and there is a certain amount 4 of use of BMPs in normal fracture healing even in 5 micro-fractures. 6 and since the company is more than willing to investigate 7 that and FDA is willing to let it be investigated after 8 a post-approval moment, I think we should encourage them 9 to do so and suggest that study -- I have to admit this 10 is not my field, so I don't know how to suggest a study, 11 but I'm willing to put my thoughts to it. I think it is important to know that 12 CHAIRPERSON FINNEGAN: 13 MR. KAISER: Thank you. Okay. With respect to tumorigenicity, 14 we would like you to discuss the potential for rhBMP-2 15 to stimulate growth of transformed cells. 16 DR. DIAMOND: You already recommended the 17 study of primary isolates that are receptor positive and 18 receptor negative, correct? 19 CHAIRPERSON FINNEGAN: So the question is 20 do we agree with the proposed study? 21 DR. DIAMOND: 22 CHAIRPERSON FINNEGAN: I think that's a good study. Dr. Reddi, did you NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 431 of 581 1531 PageID 299 1 have any comment on that? 2 DR. REDDI: No, I think I'm very -- I'm not 3 enthusiastic on wasting time on looking at transformed 4 cells. 5 the contractors who do research for Genetics Institute 6 and it doesn't give any useful information. 7 to see in vivo data. Although Dr. Riedel has mentioned 8 that he has done some dog studies, I still would like him 9 to keep his eyes open, ears open and senses open to see 10 if anybody's talking about it and it should be brought 11 t the attention of FDA and it's the duty of every one of 12 us in this room, like Dr. Miller here, he has Dr. Day's 13 studies in Kansas City. 14 attention, especially our hard working colleagues in FDA. Cell lines are a dime a dozen. I would like It should be brought to the 15 CHAIRPERSON FINNEGAN: 16 MR. KAISER: we'd It only enriches Okay. With respect to radiographic 17 effectiveness, like your comment on the 18 interpretation of the radiographic findings at various 19 time points in view of the following; the presence and 20 absorption rate of the ACS, the progression of bone repair 21 and the presence or absence of rhBMP-2 and the relative 22 ability of bone formed at various time points to withstand NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 432 of 581 1532 PageID 300 1 the applied loads. 2 CHAIRPERSON FINNEGAN: Well, actually, I 3 think I'm going to take this and I think that Dr. Kostuik 4 and Dr. Hanley and Dr. Lenchik probably all together have 5 told us that none of them work and it's probably not worth 6 fussing about. 7 DR. KIRKPATRICK: If I could add, John 8 Kirkpatrick, with regard to the last point that you had 9 about to withstand applied loads, I believe that the loads 10 will be shared between the graft and the titanium cage. 11 The titanium cage is more than adequate to withstand the 12 loads even after the graft is formed. 13 DR. LENCHIK: Can I just make a comment? 14 I think the way you have the questions broken down don't 15 make a lot of sense to me because we've heard from the 16 sponsor that the ACS is gone by six weeks or two months 17 and the first set of radiographic studies were at six 18 months. 19 part. So I'm not really sure how we can answer the first 20 The second part, I think, we can answer. 21 I think you can see bone ingrowth at the rate that you 22 would expect to see it. I think that has been shown with NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 433 of 581 1533 PageID 301 1 both plain films and with CT. 2 the CT in the study or not I think the efficacy of the 3 system would have still been proven. 4 included CT is interesting. 5 difference from the standpoint of patient evaluation and 6 some people will still use CT. 7 use plain films. 8 9 I wouldn't So whether they included The fact that they I don't think it makes any Other people will still regulate how you evaluate radiographic fusion in the labeling of the device. So 10 I agree with everything that's been said previously. I 11 think the third question you simply can't answer from any 12 of the data that's been provided because nobody's really 13 told us what kind of loads were applied at what time points, 14 so 15 sub-question. I'm not 16 17 exactly sure how to answer CHAIRPERSON FINNEGAN: that third That's a no, Dr. Witten. 18 DR. WITTEN: 19 MR. KAISER: Okay, thank you. Okay, instructions for use. 20 We would like you to provide suggestions for adequate 21 instructions 22 interpretation and also to discuss any other specific for use with respect to radiographic NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 434 of 581 1534 PageID 302 1 training that should be implemented with the product. 2 CHAIRPERSON FINNEGAN: 3 DR. HANLEY: Go ahead, Dr. Hanley. These questions are part of the 4 normal clinical practice of medicine and are not specific 5 to any particular device. 6 this particular issue personally. 7 CHAIRPERSON I don't see the relevance for FINNEGAN: Can we address 8 packaging or not? I have some serious concerns about 9 packaging but you haven't actually asked about that and 10 I was going to try and cheat and put it under instructions 11 for use but I don't know if that will work. 12 The question has been brought up by our 13 toxicologist about the volume inside the cage, basically 14 what he's saying is the amount of medication or drug that's 15 available. 16 different 17 concentrations of BMP and they're all going to be packaged 18 separately and somebody gets to figure out how much of 19 what they put in where and I have serious concerns about 20 that. You have different sizes of cages, you have sizes of sponges, 21 DR. WITTEN: 22 CHAIRPERSON FINNEGAN: you have different And the concern is -The concern is that NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 435 of 581 1535 PageID 303 1 the amount of BMP that gets to a specific disc space may 2 be inadequate, may be over adequate or may be appropriate 3 and there's no guidance to the user. 4 me to make much more sense to package a size of cage with 5 an associated size of sponge with an associated size of 6 BMP as one package that came together because then you 7 know you've got a controlled amount of everything. 8 9 10 MS. MAHER: a response to that? It would seem to Dr. Finnegan, can I actually give I'd also like the sponsor to help out. 11 CHAIRPERSON FINNEGAN: 12 MS. MAHER: Sure. I think by having them packaged 13 together, you would be adding a tremendous extra expense 14 to the consumers because of the sterilization methods of 15 the different products, because of the different sizes 16 and how they're going to be used, but I think Medtronic 17 Sofamor Danek can better answer the question as to how 18 it will be controlled. 19 DR. BODEN: This is Scott Boden. From the 20 standpoint of an operating surgeon and in the interest 21 of patient care, the reality of it is that you need the 22 ability to mix and match cage sizes and sometimes you NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 436 of 581 1536 PageID 304 1 change something. You think you're going to use a certain 2 size and while we template these patients, it's hard to 3 predict in advance what we're going to actually need and 4 sometimes you need a different cage size on one side than 5 on the other depending on the shape of the spine. 6 So the practicality of having that together 7 would be difficult in terms of feasibility, in terms of 8 what goes on in the operating room. 9 once you've figured it out, then the 15-minute wait for I should mention that 10 reconstitution. The reality of it is there's only 11 actually one concentration of recombinant BMP-2 and that's 12 1.5 milligrams per milliliter and the instructions to 13 rehydrate the lyophilized powder (ph) are effectively the 14 same. 15 The only variable is what size the sponge 16 is and that's based on the size of the cage and the little, 17 you know, template that says how to cut it, and then 18 therefore, the volume that appropriately fills up the size 19 of the sponge, based on the sponge. 20 not impossible, to -- the sponge can only hold so much 21 volume. 22 full, too much on, it's technically not really possible. It is difficult, if So in terms of putting, you know, large excess, NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 437 of 581 1537 PageID 305 1 2 I mean, this thing ends up like a wet little, 3 sort of mushy thing, cigar, and even if you went and doubled 4 the volume you put in, it wouldn't hold it. 5 that it's designed for is a wetting volume that's 6 appropriate for the sponge so that when you handle it, 7 it doesn't go squeezing out all over the place and all 8 those have been worked out. 9 CHAIRPERSON FINNEGAN: The volume But then what would 10 stop someone from taking, once you've squeezed it up to 11 put two of those sponges in? 12 really compress down and so the cage could take two of 13 them. 14 dose exposure. I mean, the cage, it does I mean, I really don't see that you're controlling 15 DR. BODEN: I guess it's based on 16 concentration and so if you take 1.5 milligrams per 17 milliliter and put it in half the size of the cage, it 18 will make bone in that half of the cage. 19 another sponge and put it in the other half of the cage, 20 then it would still make the bone. 21 why a surgeon would try and use twice as much of something 22 that's been shown to work using the instructions. And if you take I guess I'm not sure I mean, NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 438 of 581 1538 PageID 306 1 I don't understand how this is different than -- 2 CHAIRPERSON FINNEGAN: 3 DR. BODEN: You've never -- -- any other drug, you know, 4 where you have instructions, and you know, if you use twice 5 as much of an anti-inflammatory you might get an ulcer 6 risk. 7 effectively a 100 percent bone induction, why even would 8 in the mind of a creative orthopedic surgeon, which I'll 9 subscribe also to that group of people, it just wouldn't 10 go through my mind to think to use more of something that's 11 not inexpensive. I don't know why -- if you're getting, you know, 12 13 CHAIRPERSON FINNEGAN: Any other comments? Okay, next. 14 MR. KAISER: In the area of post-market 15 studies, the first question has to do with reproduction 16 and teratogenicity. 17 models may be useful for assessing an immune response 18 effect on fetal growth and development. 19 your comment on the need for these studies and if you 20 believe they're necessary, the type of studies to be 21 performed and the type of animal models. 22 FDA believes that additional animal CHAIRPERSON FINNEGAN: And we'd like So comments. NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 439 of 581 1539 PageID 307 1 MR. REDDI: I'm Hari Reddi. I just want to 2 echo the comments made by Dr. Betty Diamond from Albert 3 Einstein College of Medicine. 4 sort of combined views, but if you have good antibodies 5 for recombinant BMP-2 that it be used to study in a mouse 6 model 7 administering it, prior to implantation, which is four 8 to five days, after implantation between nine days and 9 10 days when the first skeletal elements begin to form 10 and then again after implantation and after limb bud 11 formation, and during the joint formation such as -- and 12 also spine formation in the embryo, say 16 days or 17 days 13 to see what it does. to see, number does it effect after Can you agree, Dr. Diamond? 14 DR. DIAMOND: 15 CHAIRPERSON 16 one, I hope I'm sort of giving Yes. FINNEGAN: All right, that sounds like that's -- 17 MR. KAISER: Okay. In the area of 18 tumorigenicity, FDA and the sponsor have agreed to conduct 19 additional non-clinical studies to evaluate the potential 20 for rhBMP-2 to stimulate transformed cells. 21 your comment on the need for any other non-clinical studies 22 and if you believe they're necessary, the types of studies We'd like NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 440 of 581 1540 PageID 308 1 and the appropriate models. 2 CHAIRPERSON FINNEGAN: Dr. Reddi, if I 3 understand you correctly, you feel that there are some 4 clinical studies that should be done. 5 DR. REDDI: 6 MR. KAISER: 7 DR. REDDI: Non-clinical studies. Non-clinical. Yes, I would like to -- I didn't 8 want to speak up first. 9 panel to -- I have very strong views, I think people already 10 know, at the risk of repeating, adding these substances 11 to 60 other transformed cell lines is worthless. 12 should not be done. 13 sponsors a very careful study be done using again simple 14 animal like mouse and administer -- the studies about 15 tumorigenicity is not that you give one big bolus and go 16 off to Miami for vacation. 17 I wanted somebody else in the It But instead I recommend to these You've got to take these mice and you have 18 to see these mice every day. You've got to have such good 19 technicians and they should be administered the dose 20 equally distributed over about three to six months. 21 the mouse has a longevity of two years, I don't buy the 22 study in which they say we give 1000 times the dose and If NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 441 of 581 1541 PageID 309 1 the mouse was fine at six months. 2 study in cancer research. 3 That's not a useful Cancer research is the dose distributed over 4 a period of time and see what happens. 5 done and I strongly recommend such a non-clinical study 6 be implemented. 7 DR. DIAMOND: This should be But I think the study that you 8 suggested -- they're really are two questions. 9 promoting tumor growth and one is inducing tumors and the 10 One is question Dr. Reddi is addressing is inducing tumors. 11 Promoting tumor growth would also be an 12 unfortunate outcome. 13 lines are not the way to go. 14 to have them identified as receptor positive so because 15 it may be that of the 71 primary isolates looked at or 16 whatever, only three were receptor positive. 17 So I think, I agree that tumor cell DR. BOYAN: Primary isolates are and I would agree with both of you 18 except that I'm not sure I would limit it to receptor 19 positive primary isolates because BMP induces its own 20 receptors. So it can be that you just take your best and 21 -- 22 DR. DIAMOND: But identified -- NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 442 of 581 1542 PageID 310 1 2 DR. BOYAN: The you know one way or another if it was or not. 3 DR. DIAMOND: 4 DR. BOYAN: Yes, yes. And I must stress again no more 5 cell lines because we could take -- just the people sitting 6 at this table could pick one cell line each and we could 7 get the cells to proliferate or not proliferate or inhibit 8 or whatever we wanted them to get depending on how 9 confluent they were in the culture, how we set up the 10 experiment. 11 acceptable way to go. 12 I think MS. MAHER: an animal study is the only Can I just ask Genetics Institute 13 to give on one-sentence response to Dr. Reddi's comments 14 on the cell -- 15 CHAIRPERSON FINNEGAN: Well, I think this 16 is basically for the panel to make its decision, so you 17 can go onto the next. 18 MR. KAISER: Okay. We'd like you to comment 19 in the use of ongoing post-market registry data bases to 20 further assess the potential for congenital abnormalities 21 and if you agree that registries are recommended, discuss 22 the types of data to be captured. NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 443 of 581 1543 PageID 311 1 CHAIRPERSON FINNEGAN: 2 DR. LARNTZ: 3 Any comments on this? Registries are just hard to do. They're hard to follow. Hard for people to -- it's a 4 serious undertaking and you have to be very specific about 5 what you want to find out. 6 particular issue it's going to be difficult to get enough 7 patients to make it worthwhile. 8 9 DR. DIAMOND: DR. LARNTZ: You But it's hard to do anyway and if you're not going to get enough people, why bother? 12 13 I think that's the point. won't get enough numbers to get statistical significance. 10 11 It would seem like for this CHAIRPERSON FINNEGAN: Any other comments around the table? 14 All right, I need the panel to listen very 15 carefully because this gets really complicated. 16 to ask her if we've adequately answered the questions? 17 I don't think she wants to hear us any more. 18 DR. WITTEN: 19 CHAIRPERSON FINNEGAN: 20 Do I want Yes. Dr. Witten, have we adequately answered the questions? 21 DR. WITTEN: Yes, thank you. 22 CHAIRPERSON FINNEGAN: All right, we are now NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 444 of 581 1544 PageID 312 1 going to move to a vote. For the panel, your instructions; 2 the options are that we do not approve the PMA. 3 option is that we approve with conditions and the third 4 option is that we approve with no conditions. 5 and the third are obvious. 6 condition, we have to vote, so this is -- it's actually 7 -- if you've been here before, this is a very good way 8 to deal with this -- if this is the way we go, a good way 9 to deal with the conditions, but you have to be patient 10 and you have to understand that for each new condition, 11 we have to have another vote. Second The first The second one for each 12 So I would ask Dr. Kirkpatrick, who is the 13 panel's clinical reviewer for this, if he would like to 14 make a motion. 15 16 DR. KIRKPATRICK: I'd like to move that it's approvable with conditions. 17 CHAIRPERSON FINNEGAN: All right, we will 18 go around the table and see if that is comfortable with 19 people and if it is, that's fine. 20 give your reasons. 21 22 If not, if you could Dr. Li. DR. LARNTZ: He needs a second for that before we -NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 445 of 581 1545 PageID 313 1 2 CHAIRPERSON FINNEGAN: all right. 3 DR. LARNTZ: 4 CHAIRPERSON FINNEGAN: 5 DR. LI: 6 CHAIRPERSON FINNEGAN: 7 DR. DOULL: 8 CHAIRPERSON FINNEGAN: 9 DR. DIAMOND: I second it. DR. HANLEY: 12 CHAIRPERSON FINNEGAN: 15 CHAIRPERSON FINNEGAN: Oh, he's -- you're I concur. I concur -- I don't Dr. Naidu? 17 DR. NAIDU: 18 CHAIRPERSON FINNEGAN: 19 DR. BOYAN: I concur. Dr. Boyan? And are we actually voting here because I would have wanted to vote for no conditions. 21 22 Dr. Hanley? Dr. Siegal? DR. SIEGAL: 20 Dr. Diamond? Non-voting. 14 vote. Dr. Doull? Also. 11 16 Dr. Li? I concur. CHAIRPERSON FINNEGAN: not voting. All right. I concur. 10 13 He needs a second, CHAIRPERSON FINNEGAN: You're allowed to say that you would like to vote against this and vote for no NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 446 of 581 1546 PageID 314 1 conditions. 2 3 DR. BOYAN: for approval. 4 5 Let me just give this a thought a second. CHAIRPERSON FINNEGAN: around you and come back. 6 7 Well, I don't want to not vote DR. REDDI: Dr. Reddi? Yeah, I would like to proceed with the rest of the group. 8 CHAIRPERSON FINNEGAN: 10 DR. LENCHIK: Concur. 11 CHAIRPERSON FINNEGAN: 12 DR. LARNTZ: 13 CHAIRPERSON FINNEGAN: 14 DR. BOYAN: 9 15 All right, let me go All right, Dr. Lenchik? Dr. Larntz. I concur. Dr. Boyan? Oh, yeah, the crowd is for this. I'm going with approvable with conditions. 16 CHAIRPERSON FINNEGAN: right, 18 Kirkpatrick, would you like to add conditions or would 19 you like others to add conditions? 21 have approvable DR. KIRKPATRICK: with conditions. All 17 20 we Thank you. Dr. Can I defer and then come back? 22 CHAIRPERSON FINNEGAN: You can defer. Dr. NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 447 of 581 1547 PageID 315 1 Diamond, would you like to add a condition? 2 DR. DIAMOND: I would like to add the 3 condition that there be some testing of the effect of 4 anti-BMP-2 antibodies on all stages from implantation to 5 birth in a rodent model for fetal development. 6 CHAIRPERSON FINNEGAN: All right, so your 7 condition is that there be further studies on the 8 reproduction teratogenicity and you're comfortable with 9 the studies that were proposed? 10 DR. KIRKPATRICK: 11 CHAIRPERSON FINNEGAN: 12 DR. KIRKPATRICK: 13 Dr. Finnegan, if I may. You may. We've already passed notes on exactly how to word the condition. 14 CHAIRPERSON FINNEGAN: 15 DR. KIRKPATRICK: Go for it. Assess the potential for 16 BMP-2 to promote growth of primary tumor isolates which 17 have been analyzed for BMP-2 reception expression. 18 CHAIRPERSON FINNEGAN: 19 DR. DIAMOND: 20 DR. 21 different one. 22 Okay. That's a different one. KIRKPATRICK: Sorry, that was I missed the first one. CHAIRPERSON FINNEGAN: All right, would you NEAL R. GROSS (202) 234-4433 a COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 448 of 581 1548 PageID 316 1 like to reword the first one? 2 DR. DIAMOND: Okay, to assess the potential 3 for anti-BMP-2 antibodies to cause reproductive problems 4 with -- problems with implantation or fetal development. 5 CHAIRPERSON FINNEGAN: 6 DR. KIRKPATRICK: 7 line. All right. I'm sorry, I read the wrong Can I make sure we've got it the way we want it? 8 CHAIRPERSON FINNEGAN: 9 DR. KIRKPATRICK: Okay. Study anti-rhBMP-2 in 10 systemic administration mouse model for antibodies at 11 conception, implantation and limb bud formation time 12 points. 13 DR. DIAMOND: That's fine. 14 CHAIRPERSON FINNEGAN: 15 have a second for that condition? 16 A VOICE: 17 CHAIRPERSON FINNEGAN: 18 DR. LI: 19 CHAIRPERSON FINNEGAN: 20 DR. DOULL: 21 CHAIRPERSON FINNEGAN: 22 better like it. All right. Do we I second it. All right, Dr. Li? Concur. Dr. Doull? Yeah, I like that. Dr. Diamond, you'd Dr. Siegal? NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 449 of 581 1549 PageID 317 1 DR. SIEGAL: I concur. 2 CHAIRPERSON FINNEGAN: 3 DR. KIRKPATRICK: 4 CHAIRPERSON FINNEGAN: 5 DR. NAIDU: 6 CHAIRPERSON FINNEGAN: 7 DR. BOYAN: 8 CHAIRPERSON FINNEGAN: 9 DR. REDDI: I agree. Dr. Naidu? Concur. Dr. Boyan? I concur. Dr. Reddi? I concur. 10 CHAIRPERSON FINNEGAN: 11 DR. LENCHIK: 12 CHAIRPERSON FINNEGAN: 13 DR. LARNTZ: 14 CHAIRPERSON FINNEGAN: 15 Dr. Kirkpatrick? Dr. Lenchik? Concur. Dr. Larntz? Concur. All right. Next condition, Dr. Kirkpatrick. 16 DR. KIRKPATRICK: I believe it was Dr. 17 Reddi's condition. Study the mouse model with equal 18 dosing and multiple dosing over long periods of time to 19 compliment the large dose at a single time data. 20 correct, Dr Reddi? 21 DR. REDDI: 22 CHAIRPERSON FINNEGAN: Is that Yes. Do I have a seconder NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 450 of 581 1550 PageID 318 1 for that, Dr. Reddi? 2 DR. REDDI: I would second it. 3 CHAIRPERSON FINNEGAN: 4 DR. KIRKPATRICK: 5 the same thing so I'll second it for him. He can't move and second 6 CHAIRPERSON FINNEGAN: 7 DR. LI: 8 CHAIRPERSON FINNEGAN: 9 DR. DOULL: 10 All right. All right. Dr. Li? Concur. Dr. Doull? Could you read it again? I want to hear that again. 11 DR. KIRKPATRICK: Study the mouse model with 12 equal dosing of the rhBMP-2 and multiple dosing over a 13 long period of time to compliment the data we've already 14 heard which was single large dose at a single time. 15 DR. DOULL: 16 CHAIRPERSON FINNEGAN: 17 DR. DIAMOND: 18 CHAIRPERSON FINNEGAN: 19 DR. SIEGAL: 20 CHAIRPERSON FINNEGAN: 21 already seconded it. 22 Yeah, I agree. Dr. Diamond? Yes. Dr. Siegal? Yes. Dr. Kirkpatrick, you Dr. Naidu? DR. NAIDU: I concur. NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 451 of 581 1551 PageID 319 1 CHAIRPERSON FINNEGAN: 2 DR. BOYAN: 3 CHAIRPERSON FINNEGAN: 4 DR. LENCHIK: 5 CHAIRPERSON FINNEGAN: 6 DR. LARNTZ: 7 CHAIRPERSON FINNEGAN: 8 Dr. Boyan? I concur. Dr. Lenchik? Concur. Dr. Larntz? Concur. All right. Dr. Doull, did you want to make a condition on toxicity? 9 DR. DOULL: No, I think that issue has been 10 covered by that condition. 11 previous chronic studies they've done were adequate to 12 indicate reasonable assurance of safety and I think this 13 study clearly would strengthen that position a lot. 14 15 The question is whether the CHAIRPERSON FINNEGAN: And Dr. Siegal, do you have any conditions on pathology? 16 DR. SIEGAL: I do not except to say as a 17 friendly suggestion that those studies be done with the 18 use of a pathologist who has expertise in those areas, 19 especially 20 embryo/fetal studies. 21 22 a perinatal DR. LIPSCOMB: pathologist with those Dr. Finnegan, can I just ask one point of clarification? Are these post-approval NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 452 of 581 1552 PageID 320 1 recommendations or are these -- I mean, what's the -- 2 CHAIRPERSON 3 conditions attached to the approval. 4 5 DR. 10 I know, CHAIRPERSON FINNEGAN: but are are the they I think we give the FDA the freedom -- they're post-approval, right. 8 9 LIPSCOMB: These post-approval conditions, post-PMA approval conditions? 6 7 FINNEGAN: DR. WITTEN: I'm assuming you're recommending them from the way they've been worded as post-approval. 11 DR. KIRKPATRICK: It was my understanding 12 that these would be -- you would have the approval and 13 then these studies would be required of you after the 14 approval. 15 DR. LIPSCOMB: 16 CHAIRPERSON FINNEGAN: 17 I just wanted clarification. All right, Dr. Naidu, did you have any conditions that you were concerned about? 18 DR. NAIDU: No, I just have a quick question. 19 This is strictly for single level fusion, am I correct? 20 I just want to clarify that. 21 22 CHAIRPERSON FINNEGAN: That's being done. Dr. Boyan? NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 453 of 581 1553 PageID 321 1 DR. BOYAN: 2 CHAIRPERSON FINNEGAN: 3 I have nothing further. Dr. Lenchik, any -- Dr. Larntz? 4 DR. LARNTZ: I have nothing further. 5 CHAIRPERSON FINNEGAN: 6 All right, Dr. Kirkpatrick, your next one? 7 DR. KIRKPATRICK: Yeah, I'd like to propose 8 two conditions that would be regarding -- one is regarding 9 the labeling and one is regarding the packaging. One is 10 that the labeling be specific for the anterior approach 11 and I guess it's in there already as I understand it and 12 a single level is in there, as I recall. 13 I would like to restrict it to only tapered 14 cages and I believe that that will prevent a majority of 15 surgeons from applying this from a posterior lumbar 16 interbody fusion perspective and therefore getting in the 17 canal bone formation. 18 in a tapered cage from the back and give induced lordosis, 19 so I would trust that judgment of surgeons would prevent 20 that because that is a concern that I have. 21 if we restrict it to the tapered cage, we'll solve that, 22 so we'll leave it at that specific thing and then I have Not many of us would try and put And I think NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 454 of 581 1554 PageID 322 1 another one after that. 2 DR. WITTEN: Can I just point out the device 3 is a three-component device that includes a lumbar tapered 4 cage. 5 6 CHAIRPERSON FINNEGAN: cage that is his concern. 7 8 DR. KIRKPATRICK: DR. WITTEN: CHAIRPERSON FINNEGAN: DR. WITTEN: 14 is 15 consideration. the 16 description of Well, it's officially -- that the product CHAIRPERSON FINNEGAN: that's under Will it upset anybody if -- 18 DR. WITTEN: 19 CHAIRPERSON FINNEGAN: 20 So that's officially in the title and does not need to be a condition? 13 17 That's a component of the product. 11 12 I'm making sure it's a tapered cage. 9 10 But it's the tapered No, you can put it in. All right, okay. Do I have a seconder for that? 21 DR. SIEGAL: I'll second it. 22 CHAIRPERSON FINNEGAN: Thank you. Dr. Li? NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 455 of 581 1555 PageID 323 1 DR. LI: I'll just raise this issue even 2 though I know the rest of the panel members may disagree, 3 but with all due respect to Dr. Larntz, the idea of not 4 doing a registry because it's difficult in this case is 5 a little peculiar to me. 6 of that but the alternative right now is to do a mouse 7 study, which I agree with, but at the end of that mouse 8 study, even if it turns out to be an immune response it's 9 going to be, well, that was a mouse, will it happen in 10 I understand the difficulties a human. 11 So I think if you don't do some kind of 12 registry, if you don't look for sure you're not going to 13 find anything. 14 you make an honest attempt to look for a certain set of 15 conditions and the immunologist and biologist could 16 probably set the type of things to look for, I don't really 17 understand how you could not do it in this case where you 18 have a small potential for not a very good effect. 19 And if you have some sort of registry where CHAIRPERSON FINNEGAN: Why don't -- I'm 20 going to ask you to make that as a condition but we'll 21 vote on this condition about the tapered cage first. 22 DR. LI: Sorry. NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 456 of 581 1556 PageID 324 1 2 CHAIRPERSON FINNEGAN: DR. LI: So do you want me to make that a condition? 5 6 I'm glad you brought that up. 3 4 No, perfect. CHAIRPERSON FINNEGAN: Isolated to the tapered cage. 7 DR. LI: Well, for the device that's 8 described in the application, I would like a post-market 9 surveillance registry of -- I guess you want a definition 10 of what the registries would include; is that correct, 11 or what you should look for? 12 13 CHAIRPERSON FINNEGAN: back to you on that. 14 15 I'm going to come DR. WITTEN: Right now, Dr. Finnegan is asking for -- 16 CHAIRPERSON FINNEGAN: 18 DR. WITTEN: -- a vote on the condition -- 19 CHAIRPERSON FINNEGAN: 17 20 A vote on the condition. -- of only using the tapered cage. 21 DR. LI: Oh, well, fine. 22 CHAIRPERSON FINNEGAN: I need a yes, is what NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 457 of 581 1557 PageID 325 1 I need. 2 DR. LI: 3 CHAIRPERSON FINNEGAN: 4 DR. LI: 5 CHAIRPERSON FINNEGAN: Dr. Doull? 6 DR. does 7 Thank you. Yes, sorry, I got all excited. DOULL: Yeah, that include information on the dose? 8 9 Yes. CHAIRPERSON FINNEGAN: No, no. That's just trying to keep it out of there. 10 DR. DOULL: I agree. 11 CHAIRPERSON FINNEGAN: 12 DR. DIAMOND: 13 CHAIRPERSON FINNEGAN: 14 DR. SIEGAL: 15 DR. DOULL: Dr. Naidu? 16 DR. NAIDU: Yes, I concur. 17 CHAIRPERSON FINNEGAN: 18 DR. BOYAN: 19 CHAIRPERSON FINNEGAN: 20 DR. REDDI: 21 CHAIRPERSON FINNEGAN: 22 DR. LENCHIK: Dr. Diamond? That's fine. Dr. Siegal? Yes. Dr. Boyan? Yes. Dr. Reddi? I concur. Dr. Lenchik? Yes. NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 458 of 581 1558 PageID 326 1 CHAIRPERSON FINNEGAN: 2 DR. LARNTZ: 3 CHAIRPERSON FINNEGAN: 4 Dr. Larntz? Yes. Okay. Now, Dr. Li, your condition? 5 DR. LI: My suggested condition is that the 6 sponsor does conduct a post-market surveillance by way 7 of a registry and I'll let, perhaps, some biological 8 colleagues determine what they should look for in that 9 registry. 10 CHAIRPERSON FINNEGAN: 11 DR. SIEGAL: 12 All right. Can I ask just a point of information? 13 CHAIRPERSON FINNEGAN: 14 DR. SIEGAL: Yes. Isn't there going to be a 15 required adverse reporting to the FDA anyway? 16 CHAIRPERSON FINNEGAN: 17 that with a 10-foot pole, Dr. Witten or -- 18 19 DR. WITTEN: Sorry, I missed the context but the question was is adverse event required? 20 CHAIRPERSON FINNEGAN: 21 DR. WITTEN: 22 Do you want to touch Reporting to the FDA. Adverse event reporting for -- is required and it will happen for things that are NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 459 of 581 1559 PageID 327 1 recognized to be related to the product. 2 3 CHAIRPERSON FINNEGAN: Problem but not -- yeah, but not -- yes, Dr. Li. 4 DR. LI: Yeah, can I comment on that? I 5 guess in total hips and total knees which is subject to 6 the same adverse reporting schedule, it's estimated that 7 somewhere only about one or two percent of actual adverse 8 events actually get reported in that system. So my own 9 experience is in the absence of a separate pre-determined 10 mandated sort of post-market surveillance, it isn't going 11 to happen. 12 DR. LARNTZ: 13 CHAIRPERSON FINNEGAN: 14 Can I ask a question? Do I have a -- go ahead. 15 DR. LARNTZ: No, the question is you're 16 talking about a registry of all patients? 17 on that before. 18 I wasn't clear Is it an all patient registry? DR. LI: That's a good question. I guess 19 in the context of our discussion today, it would obviously 20 be a registry that would at least be of -- minimally would 21 be of women of child bearing ages. 22 CHAIRPERSON FINNEGAN: Do I have -- go ahead. NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 460 of 581 1560 PageID 328 1 DR. KIRKPATRICK: I have just a question 2 about kind of thing we're asking them to do. 3 basically asking them as the sponsor to maintain sales 4 records on who gets the implant because they are not going 5 to be responsible for following up those patients once 6 they've had the implant. 7 DR. WITTEN: Are we Well, they're not responsible, 8 no, for following up patients who've got an implant that's 9 commercially distributed, no. To do a registry you'd -- 10 it's similar to doing a study. They'd have to design it 11 and describe how they would be recruiting patients and 12 what kind of data they would be collecting. 13 the kind of thing we'd want recommendations from you all 14 on. 15 16 CHAIRPERSON FINNEGAN: I mean, that's How long would you like them to do this registry? 17 DR. LI: I guess the biologist and 18 radiologist would have to tell me what a reasonable time 19 course would be. 20 MS. MAHER: Can I make a comment? I think 21 that we need to be careful and I know you haven't gotten 22 a second yet, so I'm going to throw my two cents in a little NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 461 of 581 1561 PageID 329 1 early. 2 they threw up there. 3 capture any information but it would be very expensive 4 for the company to maintain and I think as a panel we need 5 to be very careful not to throw cost, which ultimately 6 goes down to the consumer, there's no way around it, the 7 consumers bear the cost in the long run, that aren't going 8 to provide any relevant information at all. 9 would like you all to think about that as you're deciding 10 But if you're going to -- I mean, I saw the numbers I'm not sure that a registry would So I just whether to second it. 11 CHAIRPERSON FINNEGAN: But with information 12 systems on the internet that's available now, the registry 13 may not be as difficult as it was say five or 10 years 14 ago. 15 DR. LARNTZ: I would disagree totally. It's 16 very difficult to do a registry, do it right. So many 17 registries are so sloppily done and then you get our 18 garbage at the end and someone says, "Nothing happened" 19 but there wasn't good enough -- it's very difficult to 20 do. 21 a registry is a study. 22 right, it's a study, so we're requiring another study to It's important to do it right and I just have to say Dr. Witten said that and she's NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 462 of 581 1562 PageID 330 1 be done. 2 work. It's a serious effort. It requires serious 3 I don't -- I like registries if they can be 4 done well, but I see too many that are done so poorly and 5 then the information misused out of them, that that's my 6 concern. 7 DR. BOYAN: I actually -- I mean, we haven't 8 had too much discussion after any of these conditions and 9 it hasn't been good. 10 This is good that we're having this. I would like to go ahead and second it so we can vote 11 it down or just -- or agree not to do it. And I really 12 would -- while I appreciate your reasons for doing it, 13 Steve, I have to say that I think it's something that is 14 -- we're going to get the answer we want from the mouse 15 study. 16 If something comes out of the mouse study 17 -- this company has distinguished itself by being willing 18 to get a tremendous amount of science done before they've 19 come forward with the product. 20 run in -- I don't foresee a problem developing. 21 data should come out from the mice in an unfortunate way, 22 I think that the rest will follow naturally. I don't think that we would If the NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 463 of 581 1563 PageID 331 1 DR. LI: Are you comfortable then that just 2 as a follow-up question, if you do the mouse study, and 3 it turns out there's no negative effects of the BMP-2, 4 then you would be comfortable that we will never see an 5 effect in humans? 6 DR. DIAMOND: I think the issue is that it 7 will take more than five years, more than 10 years with 8 the kinds of numbers of patients to be able to see what 9 are generally small -- I mean, they can be two-fold 10 increments, but you still need to look at thousands and 11 thousands to see. 12 very costly and very difficult to keep the effort going 13 over that time frame and the chance of actually reaching 14 numbers where you can say with confidence it's not 15 teratogenic is vanishingly small. 16 issue. 17 And so I think the problem is that it's DR. LI: I think that's the Well, and again, I just throw this 18 out, number one, so we could have the conversation and 19 if you want to vote it down -- 20 CHAIRPERSON FINNEGAN: 21 DR. LI: 22 It's on the record. Okay, and that's fine. I guess my only negative on this product is this potential problem NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 464 of 581 1564 PageID 332 1 for which we actually have no evidence for. Right? 2 I'm just not completely comfortable that the only way we're 3 going to answer that is with a bunch of mice. 4 5 CHAIRPERSON FINNEGAN: All right, And Dr. Kirkpatrick, your next condition. 6 DR. KIRKPATRICK: Actually, it's not my next 7 condition. I just want to amend a condition that we've 8 already talked about because Dr. Reddi provided me with 9 specifics on the studying of the mouse model with equal 10 dosing and multiple over a long period of time. 11 suggests monthly over a one-year period and since we're 12 going to add that, I need to make sure that everybody agrees 13 with that. 14 15 CHAIRPERSON FINNEGAN: 18 DR. KIRKPATRICK: I'm just he Or we can delete it, yeah. provided me with this extra Okay. CHAIRPERSON FINNEGAN: I don't think we want to tell them how to do their study. 21 22 saying information. 19 20 Well, we don't want to tell them how to do their study, do we? 16 17 He DR. LI: Madam Chairman, I think Dr. Boyan actually seconded my condition. If nobody else wants to NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 465 of 581 1565 PageID 333 1 vote on it, that's okay, but -- 2 DR. BOYAN: I only seconded it in the event 3 that we were going vote for it and then I was going to 4 suggest in my seconding that we vote negatively, but -- 5 DR. LI: 6 DR. BOYAN: 7 don't have to vote. 8 DR. LI: 9 me away on this one. That's okay, that's okay. But if there's no second, we That's okay, I just want you to put That's okay. 10 DR. BOYAN: 11 CHAIRPERSON FINNEGAN: 12 DR. BOYAN: DR. DIAMOND: Can I ask, did we actually vote on assessing the potential for promoting tumor growth? 17 18 No, no, if there's no other second, then we don't have to worry about it. 15 16 Are you formally seconding -- 13 14 Great. CHAIRPERSON FINNEGAN: We did, yes. All right, Dr. Kirkpatrick, your next one. 19 DR. KIRKPATRICK: Okay, I do have another 20 condition which in all due deference to inventory issues 21 and the difficulty that will require my implant supplier 22 to come into the operating room with an entire tote full NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 466 of 581 1566 PageID 334 1 of product, I would like to propose the condition that 2 the cage and the infused must be packaged together. 3 4 CHAIRPERSON FINNEGAN: for that? Am I allowed to second? 5 A VOICE: 6 CHAIRPERSON FINNEGAN: 7 DR. DIAMOND: Okay, do I have a Well, I'll second so there can be discussion but I don't -- 10 11 No. seconder for that? 8 9 Do I have a seconder CHAIRPERSON FINNEGAN: All right. Comments? 12 DR. KIRKPATRICK: Would you like me to -- 13 CHAIRPERSON FINNEGAN: 14 DR. KIRKPATRICK: In Go ahead. order to give a 15 rationale to this, we've already heard several instances 16 that surgeons will vary from the indications on the package 17 insert. 18 of the company indicate not directly but between the lines 19 that while he would not encourage off-label use of the 20 InFUSETM by itself, it sounds like he would welcome its 21 use because it would be an issue where people would be 22 able to use the InFUSETM without the cage. In addition, we have heard the vice president I'm not sure NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 467 of 581 1567 PageID 335 1 that they would be adequately policing that. 2 MS. MAHER: I never heard them say that, sir. 3 DR. KIRKPATRICK: Between the lines he 4 mentioned that they would be packaged separately as 5 separate components and we'd have to match them in the 6 operating room. 7 appropriate dose. 8 they know the dose for each cage that's right, they can 9 package the two together and that way we don't have the 10 burden in the operating room of saying, "I need a 14 11 millimeter by 20 cage, what dose do I need to apply to 12 it". 13 If We'd have to match our cage with the What I am suggesting is, is that if it's already pre-determined and 14 pre-packaged that way, we don't have that problem. 15 also will stop the problem of a surgeon taking just the 16 InFUSETM without the cage and applying it in an off-label 17 use if that is a concern at this time. 18 DR. BOYAN: 19 CHAIRPERSON FINNEGAN: 20 DR. BOYAN: You May I comment on that? Uh-huh. I would like to see us not do 21 that for another reason and that's because things happen 22 and as a consumer myself, I'm thinking right now but things NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 468 of 581 1568 PageID 336 1 do happen in the operating room and there is a change in 2 the cage size, a dropping on the floor of the sponge. 3 I 4 opportunity to buy the sponge with the BMP as a separate 5 entity just because of the sheer -- the complexities of 6 this, the end stage sterilizing. think it's important that the surgeon have the 7 I was very much taken with the fact that they 8 explained how they decided to prepare the BMP under sterile 9 conditions rather than ethylene oxide. That's very 10 important to me as a biologist and it means that they're 11 able to use a lower dose of BMP than they would have had 12 to have done if they sterilized it another way and these 13 are large doses but they're not as large as they could 14 be if they had to start off with the ethylene oxide 15 sterilizing. 16 So there are some really compelling reasons 17 for me that they be able to package them separately and 18 -- 19 20 CHAIRPERSON FINNEGAN: sterilize them differently and package them together. 21 22 But they can actually DR. BOYAN: Well, okay, I'll just go on record as saying that it would be my intent to vote against NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 469 of 581 1569 PageID 337 1 that. 2 3 CHAIRPERSON FINNEGAN: How do you address the volume concern, then? 4 DR. BOYAN: 5 CHAIRPERSON FINNEGAN: 6 DR. BOYAN: 7 CHAIRPERSON FINNEGAN: you address How do I address it? Yeah, I mean -- Well, I -- 8 would the fact 9 concentration you're getting to -- 10 DR. BOYAN: -- as a scientist how you don't Well, you would. know what I mean, I just 11 can't believe that the surgeons are not -- and their staff 12 are not intelligent enough to say, "I have a cage from 13 column A and I'm going to match it with a package from 14 column B that is BA. 15 think there is times when they have to make decisions and 16 sometimes those -- they need the flexibility of that 17 decision. I think they can do that, but I also 18 Now, I agree with you, there is a potential 19 for off-label use and I've already been sitting over here 20 thinking of the 15 ways I would do it if I had the 21 opportunity, you know, once that went into my brain, but 22 I also think that there's consequences for making those NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 470 of 581 1570 PageID 338 1 decisions and they know what they are. 2 trust that they would use their brain activity. 3 MS. MAHER: And we have to You also have to consider that 4 if you package them together if something falls on the 5 floor and it becomes contaminated, you're going to open 6 up a whole new package which is -- from an industry 7 standpoint, that's another sale, but I don't think that 8 the hospitals are going to be particularly happy with that. 9 Or if you open them up and say, "Oh, damn, I need another 10 size", it's going to mean that you go back and you have 11 to open everything up again as opposed to one at a time. 12 So I think that's another problem. 13 DR. KIRKPATRICK: With regard to the second 14 issue about sizing, do we not use a size before we open 15 the implant? 16 tapered reaming and a specific tapping for this implant? 17 I haven't reviewed the specifics of the implantation 18 protocol, but I believe that you do size it before you 19 open the implant. 20 In other words, are we not doing a specific DR. MATHEWS: Hal Mathews. In general, 21 you're correct. However, there are times when the 22 position of the cage for some reason isn't optimal, the NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 471 of 581 1571 PageID 339 1 anatomy of the approach isn't optimal and for some reason 2 the cage will tend to migrate towards one side of the 3 intervertebral space. 4 to up-size the cage after you've already opened the cage. 5 And that up-sizing would then generate a whole another 6 second BMP being brought onto the table that wouldn't have 7 had to happen if you could do it individually with cage 8 sizing and then once you determine the appropriate cage 9 size, then actually getting the BMP and putting it in 10 That migration may cause the need secondarily. 11 DR. KIRKPATRICK: Can you provide me with 12 an incidence of when that happens or how often that would 13 happen because I can provide you with the relative 14 incidence of dropping things in our ORs being very low 15 fortunately. 16 DR. MATHEWS: Well, I would love to know that 17 incidence historically in the study. I can tell you that 18 it happened to me. 19 cage insertion device which for the panel members is a 20 device that actually lets you come down on the spine and 21 actually have the channels for the reaming already 22 established. I was not able to use a double-barrel We had to use what's called a free-hand NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 472 of 581 1572 PageID 340 1 technique 2 experienced than others, it did not allow for that cage 3 size to go in and I had to up-size the cage on the table. 4 Now, I've never dropped one on the floor, 5 10 my hands, DR. KIRKPATRICK: DR. MATHEWS: And you had that cage open adjustment during surgery. 12 the cases were in your hands? 13 DR. MATHEWS: And roughly how many of There were 13 of the investigational patients in my hands. 15 DR. KIRKPATRICK: So we're talking less than 10 percent at least. 17 DR. MATHEWS: 18 DR. KIRKPATRICK: 19 more migration in the insertional process and had to make an DR. KIRKPATRICK: 16 somewhat I had that cage open, saw the 11 14 being before you recognized that? 8 9 in I can give you that, but I've had to up-size a cage. 6 7 which, That happened in my hands. Yeah, but less than 10 percent. 20 DR. MATHEWS: That is the math, correct. 21 DR. KIRKPATRICK: 22 DR. NAIDU: Okay. Can I just make a comment? You NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 473 of 581 1573 PageID 341 1 know, I don't think that packaging together is going to 2 discourage off-label use because, you know, if the guy 3 wants to use the BMP off-label, he's going to use it anyway. 4 For example, in fact, it could turn out to be a more 5 expensive proposition because if you look at the small 6 finger joints that we use nowadays, they package it with 7 titanium grommets which they double the price of the 8 implants. 9 and we throw them out. And a lot of us don't even use the grommets 10 We just put in the implants for finger joints. 11 I mean, you know, the lower end on the totem pole, but 12 still the suggestion that the guy's not going to use that 13 BMP off-label by packaging them together is probably not 14 a good, you know, issue to package them together. 15 16 CHAIRPERSON FINNEGAN: a second for this before we go any farther. 17 DR. DIAMOND: 18 CHAIRPERSON FINNEGAN: 19 Actually do we have okay. Yes, I believe I seconded it. Oh, you seconded it, Yes, Dr. Witten? 20 DR. WITTEN: Yeah, I just want to make one 21 comment because people keep mentioning off-label use which 22 is we're really asking you to focus your discussion on NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 474 of 581 1574 PageID 342 1 this product and its safety and effectiveness as the label 2 indication -- 3 CHAIRPERSON FINNEGAN: 4 DR. WITTEN: Okay. -- and not, you know, speculate 5 on what other uses might not be safe of, you know, a portion 6 of the product or some other product. 7 8 CHAIRPERSON FINNEGAN: do a vote on the packaging. 9 DR. TREHARNE: All right, we will Dr. Li? Sir. May I make one point? 10 CHAIRPERSON FINNEGAN: 11 DR. TREHARNE: I guess, yeah. My name is Rick Treharne. 12 I'm with the sponsor and I just want to remind the panel 13 that this cage is already commercially available. 14 already in hundreds of hospitals around the country and 15 if this is packaged together then people who have those 16 cages would not be able to use those. 17 them away and buy a new one, so it's just not practical. 18 There's a lot of other -- a number of other reasons why It's They'd have to throw 19 this can't be done, different shelf lifes. 20 different methods of sterilization and it's just not a 21 practical thing to do. 22 They have I just wanted to add that. CHAIRPERSON FINNEGAN: Okay. Dr. Li? NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 475 of 581 1575 PageID 343 1 DR. LI: No. 2 CHAIRPERSON FINNEGAN: 3 DR. DOULL: Dr. Doull? I guess I could support the idea 4 of a recommendation but conditions are mandates and I don't 5 -- would not approve of a mandate. 6 CHAIRPERSON FINNEGAN: 7 DR. SIEGAL: 8 CHAIRPERSON FINNEGAN: 9 DR. NAIDU: Dr. Siegal? No. Dr. Naidu? I disagree. 10 CHAIRPERSON FINNEGAN: 11 DR. BOYAN: 12 CHAIRPERSON FINNEGAN: 13 DR. REDDI: 14 CHAIRPERSON FINNEGAN: 15 DR. REDDI: 16 CHAIRPERSON FINNEGAN: 17 DR. REDDI: 18 CHAIRPERSON 19 Okay. Dr. Boyan? No. Dr. Reddi? This is to package -Package, yes. -- in one single package? Yes. I disagree with that. FINNEGAN: All right, Dr. Lenchik? 20 DR. LENCHIK: No. 21 CHAIRPERSON FINNEGAN: 22 DR. LARNTZ: Dr. Larntz? No. NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 476 of 581 1576 PageID 344 1 CHAIRPERSON FINNEGAN: All right, so are 2 there any other conditions to attach that the panel wishes 3 to attach to this? 4 will be approvable with the listed conditions and I'll 5 ask Dr. Kirkpatrick to list the conditions. 6 If not, we'll do our final vote which DR. KIRKPATRICK: Summarizing the approved 7 conditions, number one was study anti-rhBMP-2 in systemic 8 administration mouse model for antibodies at conception, 9 implantation and limb bud formation time points. This 10 was approved as a post-approval study. The next was study 11 mouse model with equal dosing and multiple dosing of 12 rhBMP-2 over long time to compliment the large dose at 13 a single time, also approved as a post-approval study. 14 Assess the potential of BMP-2 to promote 15 growth of primary tumor isolates which have been analyzed 16 for BMP-2 receptor expression, also a post-approval study. 17 And tapered cages only was the other condition. 18 other two that were brought up were not approved. 19 CHAIRPERSON FINNEGAN: The All right, so Dr. Li, 20 we are voting on whether we approve with conditions and 21 with all of the conditions that were just listed. 22 DR. LI: I vote to approve the device with NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 477 of 581 1577 PageID 345 1 all the conditions just listed. 2 CHAIRPERSON FINNEGAN: 3 DR. DOULL: 4 CHAIRPERSON FINNEGAN: 5 That's three conditions. Three conditions. Four. 6 7 Dr. Doull? DR. KIRKPATRICK: Three studies and one tapered. 8 CHAIRPERSON FINNEGAN: 9 DR. DOULL: You're still a yes? Yes. 10 CHAIRPERSON FINNEGAN: 11 DR. DIAMOND: 12 CHAIRPERSON FINNEGAN: 13 DR. SIEGAL: 14 CHAIRPERSON FINNEGAN: 15 DR. KIRKPATRICK: 16 CHAIRPERSON FINNEGAN: 17 DR. NAIDU: 18 CHAIRPERSON FINNEGAN: 19 DR. BOYAN: 20 CHAIRPERSON FINNEGAN: 21 DR. REDDI: 22 CHAIRPERSON FINNEGAN: Dr. Diamond? Yes. Dr. Siegal? Yes. Dr. Kirkpatrick? Yes. Dr. Naidu? Yes. Dr. Boyan? Yes. Dr. Reddi? Yes. Dr. Lenchik? NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 478 of 581 1578 PageID 346 1 DR. LENCHIK: 2 CHAIRPERSON FINNEGAN: 3 DR. LARNTZ: 4 CHAIRPERSON FINNEGAN: 5 Yes. Dr. Larntz? Yes. Dr. Witten, are you happy? 6 DR. WITTEN: I'm happy. I think, does the 7 panel need to go around and state their reasons? Yes, 8 I'm happy except you still have that one last step to do. 9 10 11 CHAIRPERSON FINNEGAN: -- 12 13 State our reasons for DR. WITTEN: vote. State your reasons for your Is that right? 14 CHAIRPERSON FINNEGAN: We haven't spent like 15 the last eight hours talking about the reasons for our 16 vote? 17 DR. WITTEN: You -- well, yes, you have and 18 if someone summarizes them, other people can -- you know, 19 don't have to repeat the same reasons. 20 -- 21 DR. LI: 22 CHAIRPERSON FINNEGAN: I mean, you can I'll start if you want. Okay, go ahead. NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 479 of 581 1579 PageID 347 1 DR. LI: I voted for approval because a 2 method criteria for safety and effectiveness for this 3 device. 4 CHAIRPERSON FINNEGAN: 5 DR. LI: 6 And the conditions are appropriate to make the device safe and effective. 7 8 And the conditions? CHAIRPERSON FINNEGAN: All right. Dr. Lenchik, if you agree, we can just agree. 9 DR. LENCHIK: Agreed. 10 CHAIRPERSON FINNEGAN: 11 DR. REDDI: 12 CHAIRPERSON FINNEGAN: 13 DR. BOYAN: 14 CHAIRPERSON FINNEGAN: 15 DR. NAIDU: 16 CHAIRPERSON FINNEGAN: 17 DR. KIRKPATRICK: 18 CHAIRPERSON FINNEGAN: 19 DR. SIEGAL: 20 CHAIRPERSON FINNEGAN: 21 DR. DIAMOND: 22 CHAIRPERSON FINNEGAN: Dr. Reddi? I agree. Dr. Boyan? I agree. Dr. Naidu? I agree. Dr. Kirkpatrick? I agree. Dr. Siegal? I agree. Dr. Diamond? I agree. Dr. Doull? NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com Case 2:13-cv-02985-JTF-cgc Document 37-3 Filed 04/28/14 Page 480 of 581 1580 PageID 348 1 DR. DOULL: I agree. 2 CHAIRPERSON FINNEGAN: 3 DR. LI: 4 CHAIRPERSON FINNEGAN: 5 DR. WITTEN: Dr. Li. I agree. Dr. Witten? And I thank you. I thank all 6 the panel members here, the guests of the panel, the 7 sponsors and particularly the FDA staff and also the 8 chairperson. 9 10 (Whereupon, at 5:30 p.m. the above-entitled matter was concluded.) 11 12 13 14 15 16 17 18 19 20 21 NEAL R. GROSS (202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com