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Printable PDF (344 KB) DEPARTMENT OF HEALTH AND HUMAN SERVICES Open Public Meeting Wednesday, August 2, 2000 Masur Auditorium Building 10
PARTICIPANTS Session 1 -Kathryn C. Zoon, Ph. D., Moderator
Panel Members: Session 2 -David W. Feigel, Jr., M. D., MPH, Moderator
Panel Members: Session 3 -Celia Witten, Ph. D., M. D., Moderator
Panel Members: Session 4 -Philip Noguchi, M. D., Moderator
Panel Members:
Opening Remarks SESSION I -Background Information Ruth Solomon, M. D., CBER Overview of the History of FDA Regulation of Bone As a Tissue Antonio Pereira, M. D., CBER Overview of the History of FDA Regulation of Bone As a Device Aric Kaiser, MS, CDRH Overview of Relevant Comments to the Proposed Rules Dockets Concerning Regulation of Bone Products Martha A. Wells, MPH, CBER SESSION II -Professional Associations' Overview of Bone Processing and Clinical Uses in Orthopedic Richard Russo American Association of Orthopedic Surgeons Uses of Bone in Orthopedic Surgery Dr. Laurencin Dr. Jaffe American Association of Neurological Surgeons Bone Allograft in Neurosurgical Practice Robert F. Heary, M. D. AdvaMed James Benson Questions for FDA Panel SESSION III -Public Discussion/ Comments Dr. Laurencin Dr. Jaffe American Association of Neurological Surgeons Neurosurgery's Perspective of FDA Concerns Richard Fessler, M. D., Ph. D. American Association of Tissue Banks P. Robert Rigney, Jr. Regeneration Technologies, Inc. Proposed Regulations of Bone Allograft C. Randal Mills, Ph. D. University of Florida Tissue Bank History of Minimally Manipulated Allograft Tissue Frank Glowezewskie Sulzer-Spine Tech Daniel R. Mans Hyman, Phelps & McNamara Legal Issues Posed by the Proposed Tissue Regulations and Risk-Based Criteria Jennifer B. Davis Questions from FDA Panel SESSION IV -Public Discussion/ Comments (Continued) John Block Musculoskeletal Transplant Foundation Regulation of Allograft Tissue Forms Victor Frankel, M. D., Ph. D. Orthopedic Surgical Manufacturers Association OSMA Position on Regulation of Human Bone Allograft Dr. Mark Citron Hospital for Special Surgery - Weill Medical College of Cornell University Surgical Benefits of Precision Pre-Cut Allograft Bone Harvinder Sandhu, M. D. Life Alaska Donor Allograft Usage Jens Saakvitne Spinal Patient Recipients of Allograft Tissues (Videotape played) A Donor Dad and His Story Stephen M. Oelrich Donor Parent Testimonial Donor Family Input to Proposed Adoption of Donor Christine Blackgoat Questions from FDA Panel
Closing Remarks
PROCEEDINGS DR. ZOON: Welcome to the Open Public Meeting on Human Bone Allografts. I just want to, one, thank everybody for attending this important open public meeting, especially on such short notice, as well as to also thank you for coming to Washington in the summer. That is very brave and we appreciate it. I am Kathryn Zoon. I am the Director at the Center for Biologics. This workshop is co-hosted by the Center for Biologics and the Center for Devices and Rad Health, and Dr. David Feigal, the Center Director for CDRH, is here, as well, and will be speaking in a few moments. This is an important meeting to the FDA because we are in the process of finalizing our proposed regulations on human cellular and tissue-based products, and to potentially develop guidance to assist with some of the more technical aspects in applying the definition of minimal manipulation and homologous uses as they relate to bone allografts. We certainly need the input from all of you to make sure that we do the very best job we can in providing guidance to the affected parties. We have requested information from all our stakeholders today specifically on five questions that are listed on the overhead. I will just briefly review those. The first is which processing procedures applied to human bone allograft fall within or outside of FDA's proposed definition of minimal manipulation. The second, which uses of human bone allograft fall within or outside FDA's proposed definition for homologous use. What risks to health have been identified and characterized for human bone allograft products. What control have been identified to adequately address the risks to health of use of human bone allograft products. What industry standards for bone allograft products are available, and what standards will be needed in the future. FDA is here today to listen to you in order to understand how you see bone products fitting into the regulatory approach we have proposed. We are hoping to hear specific data and information which will assist us with this task. We have not asked today for reiteration of comments that have already been sent to the docket on the two proposed regulations to date. We are currently addressing these in the final regulations for establishment, registration, and product listing and for donor suitability. Also, FDA is not here today to make decisions, draw conclusion, or answer specific questions on issues presented today. We are here today to listen and ask questions of you to help clarify where to draw the line between minimal manipulation and more than minimal manipulation and between homologous use and non-homologous use specifically for bone allografts. A summary of the meeting will be prepared and be available on our web site, along with the transcript of this meeting. Additional comments can be submitted to the docket through September 1st. We are looking forward to hearing from you and then hopefully, this information that you present today will be important in the future of our guidances and regs. Dr. Feigal is going to join us. David, we are happy that we could do this together with CDRH and we really appreciate the joint cooperation and efforts in putting this together. David. DR. FEIGAL: Good morning. We have an ambitious schedule to get through today, so I am not going to make very long remarks. When I think about this area, I often remember an anecdote, and I apologize. I have used this before, so you may have heard it. But when I was a student, the chairman of surgery was Robert Chase, who is a very noted hand surgeon. In presenting cases to him, there was a case presented from a medical school about 35 miles away where a fire-fighter had lost his thumb. The standard operation at that time would have been to swing the index finger over and put the index finger in the thumb position and then you have a three-fingered hand and a very long thumb, and it's a quite functional hand. But what they had done at the other medical school was that they had transplanted, they had moved up the toe, the great toe from the foot of this fire-fighter up and used microsurgery techniques which were just beginning to flourish at that time, the first use of microscopes for suturing of small structures, and they had actually successfully moved his toe up to this hand. So, that made a very ugly thumb. Dr. Chase was asked to comment on this, and in part because the toe actually has a lot to do with your balance, and fire-fighters need to be quite mobile, and not being a man of very many words, his comment to sum up the case before he moved down to the next one was that, well, this sounded like a triumph of technique over reason. I think as we look at some of the things that are new, some of the things that are on the forefront, one of the challenges for us is to find that boundary where we don't want to have a triumph of regulation over reason, we recognize that these areas where there are long-standing uses, long-standing practices, that we need to find a way to blend the regulatory scheme into the current practices, but also identify the new challenges that are going to come along as techniques change, as new things become possible, and we are all aware that we are seeing an increasing growth in the whole area of hybrid types of products that present multiple challenges. So, we are here to listen. We welcome very much your helping us with this area, and I look forward to your comments.
Thanks very much.
SESSION I -BACKGROUND INFORMATION Overview of the Proposed Approach to the Regulation of Human Cells and Tissues DR. SOLOMON: Good morning. I am Ruth Solomon. I am the Director of the Human Tissue Program in CBER. I want to thank all of you for coming here today to help us tackle this challenging topic. I am going to be talking about the proposed approach to the regulation of cellular and tissue-based products which FDA published on February 28th, 1997. The purpose of the proposed approach was to develop a comprehensive approach to a wide spectrum of cell and tissue products to protect the public health, but at the same time to permit innovations without unnecessary regulatory burdens. Therefore, the approach that we came up with is a tiered, risk-based approach with products having the least risk being the least regulated. This umbrella approach included cells and tissues that were already regulated by FDA, such as musculoskeletal tissue, skin, and ocular tissue, which were regulated since 1993 under 21 CFR 1270. Dr. Pereira will be telling you more about this current regulation. Also included were some products that are currently regulated as medical devices, namely, human heart valves and dura mater. In addition, under this umbrella we propose to include somatic cell and gene therapy products, manipulated bone marrow stem cells. These are currently regulated as licensed biologic products. In addition, the umbrella would include combination products which are already regulated under 21 CFR Part 3. The umbrella approach would also include some cells and tissues not currently FDA regulated, namely, hematopoietic stem cells from peripheral blood and cord blood and reproductive cells and tissue. The umbrella approach did not include vascular human organs because these are regulated by a different federal agency, namely HRSA. They did not include whole blood, blood components, and blood derivatives, because they have their own well worked-out regulatory mechanism. It would not include secreted or extracted products. It would not include minimally manipulated bone marrow, which is also regulated currently by HRSA. It would not include ancillary products used in the manufacture of cells and tissues, and cells, tissues, and organs from animals. These two last things have their own regulatory framework being developed. It would also not include in vitro diagnostic products. When we worked to develop the proposed approach, we discussed five concerns that FDA had regarding the regulation of these products. They included transmission of communicable disease, processing controls to prevent contamination and preserve product integrity and function, clinical safety and efficacy, promotional claims and labeling, and how we could best monitor and educate the industry. Taking each concern and briefly showing you how the approach is a tiered, risk-based approach, the first being transmission of communicable disease, we propose that if cells or tissues were used during a single surgical procedure, that is, they were not banked with other cells and tissues, there would be no requirement under this umbrella approach. For autologous and reproductive cells and tissues from sexually intimate partners, we would recommend certain donor testing and screening procedures, and for all others, cells and tissues from allogeneic donors, we would require donor testing and screening. The second concern was having control over processing. Again, the tiered approach proposed that for cells and tissues used in a single surgical procedure, there would be no requirement under this framework. If a product was regulated solely under Section 361 of the Public Health Service Act --and I will have more to say about that a little bit later --this is the section of the Public Health Service Act which allows us to promulgate regulations to prevent the transmission and spread of communicable diseases. If a product was regulated solely under Section 361, then, we were planning to propose good tissue practices for such products and the good tissue practices would be aimed at preventing contamination and preserving he integrity and function of the product. If the product was more highly regulated under the FD& C Act and/ or Section 351, which is the licensing procedures of the PHS Act, these products would have to follow GTP and the good manufacturing practice or quality systems currently in effect for these products. For clinical safety and efficacy, again, if a product was regulated at the lower end of the spectrum, that is under Section 361 of the Public Health Service Act, there would be no submission to FDA, that is, no premarket approval would be required. However, if the product was regulated under the FD& C Act and/ or the licensing provisions of the PHS Act, then, a submission to FDA would be required, and that could take the form of an IND or an IDE, if the studies were investigational or a BLA or PMA or 510( k). Of course, the submission would have to receive approval before the product could go on the market. Next, we were concerned about promotion and labeling of a product, so again for products used in a single surgical procedure, that is, not banked, there would be no requirement. Products regulated solely under 361, FDA would not have to review the labeling, but we would assume that the labeling was clear, accurate, balanced, and non-misleading, and this would be determined at the time of inspection. If the product were regulated under the FD& C Act and/ or the licensing provisions of the PHS Act, then, labeling would be submitted to FDA along with the application. In order to implement, the proposed approach, we envisioned setting forth three proposed rules, two of which have already published -the establishment, registration, and listing proposed rule, published on May 14th, 1998, and the second proposed rule, suitability determination for donors of human cellular and tissue-based products published on September 30th, 1999. The docket for the second proposed rule was reopened and recently closed again on July 17th. The third proposed rule, current good tissue practice, which would also include inspection and enforcement provisions, has not yet published, but we are working on it. Just briefly to review the contents of these proposed rules, the establishment, registration, and listing contained a purpose and scope, contained certain definitions, set forth which establishments would be regulated solely under Section 361. It didn't at that time, but subsequently in the donor suitability reg, we also developed criteria for regulation under the FD& C Act and/ or Section 351 of the Public Health Service Act, and also it describes establishments not required to comply with the requirements. In the Definition Section, there are three definitions that are particularly important for today's discussion. The first is the definition of the human cellular or tissue-based product, which is the product containing or consisting of human cells or tissues intended for implantation, transplantation, infusion, or transfer into a human recipient. Previously, I discussed which cells and tissues would not fit under this definition. Another important definition that is going to be helpful to us today is the definition of what we mean by homologous use. It is use for replacement or supplementation and for structural tissue-based products which are the ones we are going to be discussing today, bone allograft, homologous use occurs when the tissue is used for the same basic function that it fulfills in its native state, in a location where such structural function normally occurs. We also had a second part of the definition for cellular and non-structural tissue-based products which is not pertinent for today's products that we are discussing. The next definition that we will want to explore is the one for minimal manipulation. Again, for structural tissue which we will be discussing today, minimal manipulation means processing that does not alter the original relevant characteristics of the tissue relating to the tissue's utility for reconstruction, repair, or replacement. Again, there is a second part of the definition for cells and non-structural tissue. The establishment registration proposed rule set out the criteria for regulation solely under Section 361 of the Public Health Service Act. That is, these products would not require premarket approval or a submission to FDA, but would have to adhere to donor suitability and testing and the good tissue practices. The criteria that would allow a product to fit under this category are that the product is minimally manipulated, is not promoted or labeled for any use other than a homologous use, is not combined with, or modified by, the addition of any component that is a drug or a device, and either does not have a systemic effect or has a systemic effect and is for autologous family-related allogeneic or reproductive use. Please note that a product must meet all four criteria in order to come under this category of regulations solely under Section 361. We then described products that would be more highly regulated, that is, they would come under the regulation under the FD& C Act and/ or Section 351 of the Public Health Service Act. Such products, again to reiterate, would require a premarket review and approval by FDA for clinical safety and efficacy. In order a product to be regulated under this category, any of these criteria would apply. It is more than minimally manipulated or it is promoted or labeled for any use other than a homologous use, or it is combined with or modified by the addition of any component that is a drug or device, or it has a systemic effect and is not for autologous, family related, allogeneic or reproductive use. Then, I thought I would briefly go over the contents of the rest of the establishment registration regulation and also the donor suitability and broadly for the current good tissue practice proposed reg, which has not yet published just to complete the picture, but these points that I am making are again background, and are not really key to what we are discussing today. So, in addition to what I have already mentioned, under the establishment registration, there are procedures for when to register and list, how and where to register and list the information that you are required to submit on the form, then, a discussion of amendments to your registration, assignment of a registration number, and inspection of the registration and product list by other others. The donor suitability proposed rule, which published in September 1999, contains the following points. There is what do we mean by determination of donor suitability, what records do you have to keep about donor suitability including records that have to accompany the product, quarantine requirements until donor suitability is determined, the disposition of a product from a donor determined to be unsuitable, and there are certain situations where FDA would not prohibit the use of a product from an unsuitable donor provided that certain controls were in place. It discusses in detail donor screening for particular relevant communicable diseases, donor testing for particular relevant communicable diseases, and certain exceptions where the donor screening and testing are only recommended, but not require, but there need to be certain labeling controls in place. The current good tissue practice proposed rule, which we will publish shortly, will contain a general discussion of what do we mean by good tissue practice. There will be a section on exemptions and alternatives. The focus will be on having a quality program and control upfront. There will be discussion of organization and personnel, procedures, facilities, environmental control, equipment, supplies and reagents, process controls, changes in validation, labeling controls, storage receipt and distribution, records, tracking of the product, and complaint file. In this last proposed rule, there will also be additional requirements for reporting, labeling, and claims, and there will be regulations that cover inspections, imports, and enforcement activity, such as orders. Lastly, I would like to say a few words about the Tissue Reference Group, also known as the TRG. The TRG was established and actually had its first meeting in March of 1997. It grew out of the proposed approach where the concept of having a Tissue Reference Group was first introduced. The group consists of representatives from both centers, from CBER and CDRH, and also there is a representative from the ombudsman's office and an executive secretary. The purpose of the TRG is to provide a single reference point for product-specific questions involving jurisdiction, policy, or regulation. The TRG does not make decisions per se, but rather makes recommendations to the two centers who then consider the recommendations and decide how to proceed. The TRG can also make recommendations to the ombudsman's office. That is the Office of the Chief Mediator and Ombudsman. Some of the information that the TRG reviews consists of proprietary information that would not be available to the public. However, if the decision affects a class of products, we are committed, as explained in the proposed approach, to put forth a guidance document or a revision of existing regulations if that seems appropriate. The TRG has an SOP and annually updates the types of decisions it has made, and these are available on the CBER external web site. So, basically, I have given you an overview of how we are proposing to regulate human cellular and tissue-based products and now Dr. Antonio Pereira from the Human Tissue Program will discuss what the current regulation consists of. Return to Table of Contents
Overview of the History of FDA Regulation of Bone As a Tissue DR. PEREIRA: Good morning. I am Antonio Pereira. I am a practicing otolaryngologist, head and neck surgeon, and also a medical officer at the Human Tissue Program. I would like to give you some historical background of all the regulations that stand now and where all the regulations that were proposed come from. The first date is 1902, 100 years ago almost. The Biologics Control Act that requires the purity and safety of serums, vaccines, and similar products. Then, in 1944, the Public Health Service Act defined on Section 351 a biological product as any virus, therapeutic serum, toxin, antitoxin or an analogous product applicable to the prevention, treatment, or cure of diseases or injuries of man. On Section 361, it allows for regulations necessary to prevent introduction, transmission or spread of communicable diseases. It goes further in 1972, regulations of biologics is transferred from the NIH to the FDA, and in 1987, the Center of Biologics, Evaluation, and Research was created after a reorganization of CDER, the Center for Drug Evaluation and Research. So, CBER started to look on human tissue regulation in the 1990s. There were reports to the CDC about transmission of HIV through fresh frozen bone transplant, and in 1991, there was a Public Health Work Group recommended, federal development and publication of standards or guidance under screening and testing, and tracking procedures to prevent the transmission of infectious disease. Further on in 1993, there were reports of importation of human tissue that was not properly screened and tested for HIV and hepatitis, and there was a Senate hearing on appropriate oversight on human tissue banking. This was just a Committee on Regulation, Business Opportunities, and Technology, a Committee of Small Business. That was on October 15 of 1993. Both the workshop and the Senate gave some recommendations. First of all, persons involved in human tissue banking advocated that legislation setting forth regulatory requirements for human tissue banking be passed, and the Public Health Work Group recommended federal agencies proceed as expeditiously as possible to reduce the risks of transmission of infectious disease by human tissue transplantation. Then, on December 14, 1993, an interim rule was published and was effective immediately. This rule requires screening and testing for HIV, hepatitis B and C, of all human tissue intended for transplantation, and it was published under the authority of Section 361 for the prevention of the spread of communicable disease. This interim rule included conventional banked tissue. This is like skin and bone, things were banked on different tissue banks, excluded vascularized organs, human male reproductive tissue, and bone marrow, and excluded products regulated as drugs, biological, medical devices. It was more focused on the prevention of the transmission of disease. The language that was published in the entry rule, in the preamble, just stated that tissues that are processed or stored, only ways to prevent transmission of infectious disease and to preserve clinical usefulness will be covered by the regulation. Tissues whose structural function or functional characteristics that has not been changed through processing or other techniques will be covered by the regulation. This rule was finalized on July 29, 1997, after review of comments submitted to the docket in public meetings and workshops. The final rule defined human tissue as any tissue derived from a human body that is intended for transplantation to another human for the diagnosis, cure, mitigation, treatment, or prevention of disease, and is recovered, processed, or stored or distributed by methods that do not change tissue function or characteristics. So, as of today, the bone allograft fall within the scope of the final rule in human tissue intended for transplantation provided that they are not processed by methods that change tissue function, are not regulated as drugs, biologics, or devices, and are not combinations of bone allograft with other products regulated as drug, biologics, or devices. After 1997, 1993, all this time we have been aware that technology advances, there are new things that come in, so that, as Dr. Solomon stated, was the proposed approach that was a tiered approach based on public health risk, is a proposed approach still. The degree of manipulation and homologous use will determine the degree of regulation needed to assure safety and efficacy of human bone and allograft products. As I said, this proposal will assure our public health concern, and this meeting will give you some feedback in comments from the industry. We are looking forward to a great discussion and to hear from you. Thank you very much. Now, you will hear the history from CDRH. Return to Table of Contents
Overview of the History of FDA Regulation of Bone As a Device MR. KAISER: Good morning. I am Aric Kaiser, the current team leader for spinal and osteosynthesis devices and a reviewer in the Orthopedic Devices Branch in CDRH, and what I would like to do is briefly go over the history of devices that we have seen in the regulation of devices that have bone as a component. Unlike what Antonio just mentioned, where the biologics regulation started almost a hundred years ago, CDRH got into the business relatively recently. Devices officially, from a regulatory standpoint, didn't exist until May 28th, 1976, with the Medical Device Amendments to the Food, Drug, and Cosmetic Act. With those amendments came along the definition of a device which didn't exist. As you can see, this is part of a big, long regulatory definition, but the important section is towards the end, where the aspect that would differentiate a device from a biologic or a drug product is that these types of products don't achieve their intended purposes through chemical action, and they are not dependent on their use as far as being metabolized. In CDRH, there are three groups that generally tend to see these products. One is the Dental Devices Branch, and the other two are the Orthopedic Devices Branch and the Restorative Devices Branch. From the dental point of view, there has been generally two types of bone products that they typically see, the freeze-dried bones in various shapes and sizes, and also freeze-dried demineralized bone. These products tend to be used for filling defects and for reconstruction. As far as what they have seen from a regulatory standpoint, certain of these products have been viewed as pre-amendments with a recommendation that they be reclassified to either Class II or Class III depending on what the actual indication for use is. An example of one of these products is the bio called TBM Sponge, which is a freeze-dried bone in a collagen sponge used to fill periodontal defects. In the orthopedic and neurosurgery realm, we see similar products to what the dental group sees with the addition of the fresh-frozen bone. Again, these products are used for filling defects and for reconstructions. What we tend to see compared to the dental group is that for the most part, the products that we would see in orthopedics and in the restorative group are post-amendments Class III devices meaning that they weren't on the market prior to May 28th, 1976. There are very new things. Examples would be the Norian SRS and the Interpore Pro Osteon 500. We also have recognized relatively recently that calcium sulphate is a pre-amendments device, the example of this being the Osteoset pellets. Some of you may remember that last summer there was a proposal and then a cancellation of a panel meeting to discuss a topic related to what we are here to talk about today, and in the information that we had released prior to the cancellation of that meeting, we were trying to get a handle on the spectrum of bone products and where things fell. On the one end we were viewing certain bone products as being nothing but tissue. On the other end of the spectrum, you could view bone products as being devices, and at somewhere in the middle, very undefined zone, were things that had to be determined whether they were devices of whether they were tissues, and this would be dependent on how they were processed potentially, how they were used. The other thing that I want to bring up here is that from the orthopedic standpoint, the way that we have seen some products recently, is that you can make a product from bone that's very similar to a product that we traditionally see made out of a metal or a ceramic or a polymer, and the fact that it is made out of bone is nothing more than a material change from the original device. An example of that is the Bonutti Research Multitak. This is a soft tissue anchor made from allograft cortical bone and except for the fact that it is made from bone, it's identical to their previous products that are made from metal or polymer, and so the decision was made that this was simply a material change and not a new entity that we needed to deal with in the realm of the things we are talking about today. Next, Martie Wells will come up and give you some background on the dockets and the comments for the proposals that have been published. Return to Table of Contents
Overview of Relevant Comments to the Proposed Rules Dockets Concerning Regulation of Bone Products MS. WELLS: Good morning. I am Martie Wells from CBER. I have been acting as Project Manager for what we call the Tissue Action Plan for the last few years, which helps coordinate all of the initiatives that we have been talking about today, as well as a couple others concerning some guidance documents that we have been working on. My job today is to give you a brief overview and some general categories of the comments that we have received to the docket of the two proposed rules which Ruth has discussed for establishment registration and donor suitability. We are addressing comments to the docket having to do with these definitions and some of the other kick-up factors and will be addressing them in response to the comments within the establishment registration rule which we are currently in the process of finalizing. Some of the general comments that we have received concerning homologous use and minimal manipulation include comments, such as the terms are vague, they are subject to broad interpretation. Other comments say they do not reflect clinical use of the products. There were questions on how the criteria for these definitions would be applied as to what would be, as we commonly say these days, "kicked-up" to 351 or remain under 361 products for tissues. Other comments were very explicit and said that these definitions should be eliminated. Others agreed that the focus that we tried to explain for homologous use is that the focus will be on promotion and labeling rather than the intent of the practitioner. We also received requests for more guidance on how the definition will be applied, and that is one of the reasons we are here today. Other comments --and again I am pulling together the comments we received to both dockets in a more general fashion, and not trying to quantify them -- we received many comments concerning bone in general, especially to the donor suitability regulation. Some of these supported and some were against regulation of allograft bone. Others were either against further regulation or additional regulation concerning these products. Many of these didn't really specify as to what they considered additional regulation as to whether they were discussing the possibilities of RGPTs or they were really referring to what was being proposed in the donor suitability regulation. Others claimed that publication and finalization of these regulations was interference with patient care. It would interfere with the doctor-patient relationship and with the practice of medicine. Many others were either in support or let's say many of them were against regulation of bone allograft as medical devices. It was very difficult. There were many comments to the docket, many repetitive comments from orthopedic surgeons, others in the clinical practice, that basically referred to what they said that the regulation was proposing that all bone products be medical devices, which was not in the regulation, so it was very difficult to understand what the actual issue of those comments were. Other supported or were against regulation bone allograft as a medical device, they said, and were specific in saying that mechanical shaping of bone is minimal manipulation. Other concerns with the regulation of bone per se stated that these regulations, when they are final, would curtail supply of bone products, they would increase the cost without increased safety. They also stated that there was satisfaction with the industry standards, the voluntary industry standards which were being followed. Others said that manipulation of bone by shaping should not determine the level of regulation. They quoted a long history of safe use. Many of these were general comments and they didn't say specifically what types of bones, whether these were the ones that we have talked about before as far as being machined and shaped for a specific purpose. There were one or two that said that FDA lacks the authority to impose premarket approval oversight on allograft bone. There were again many comments which were specific to the bone dowels that came into our donor suitability docket. This was after the issues that Aric just talked about and the proposed panel meeting that came during this period. Again, we had either support or comments against regulatory evaluation of machined or formed allografts as devices. We had support or non-support for regulation of allograft for procedures requiring stabilization, i. e., and spinal fixation. We had comments that said that the pre-machined dowels are superior to those machined in the operating room or they indicated that mechanical shaping again is not more than minimal manipulation. So, this was specific to bone dowels. Other comments specific to bone dowels, again, had a major problem with any type of regulation that would be based on kick-up factors that were based on the shape of the bone per se. Shaping of the bone by the manufacturers should be regulated the same as shaping by the surgeon. Other claimed that the bone allograft, bone dowels were superior to similar metal devices which had now been approved by FDA. Other comments said that these bone allografts should undergo the same degree of regulation as is required by these metallic implants. So, the conclusion that I was able to pull together from these is, number one, that you can't satisfy everyone, we have many conflicting views. One of the reasons we are here is to try to get more information, so that we can understand what those views are. It seemed as we read through a lot of the comments, especially to the donor suitability, that a lot of the comments there were based on misinformation which was spread by certain interested parties, certain information, as I mentioned before, that these regulations would regulate all bone allografts as devices, and there were also those that said that we were going to be interfering in what surgeons do in the surgical suite. So, the conclusion another reason that we are here, we need more information on bone allografts and their clinical uses. We would like some assistance in clarification of the definitions, and we would also like suggestions and some information that we could possibly use for technical guidance in the future to help us and help you to understand what our intent is as far as where we would kick up some of these products or whether we would or we would not. So, thank you. I would just like a quick opportunity to thank those that helped organize this meeting including Ruth Solomon and Aric Kaiser, and from our Chief Counsel Office, Areta Kupchyk, and especially to Cathy Eberhart, who has done all the administrative details in getting this meeting together in a very short period of time. So, thank you. Kathy. DR. ZOON: Thank you, Martie. Again, my thanks to all who put this meeting together and particularly for the excellent presentations that we have heard this morning, so thank you to all the speakers. We are ahead of schedule, but perhaps before we break, there might be a few minutes or an opportunity for questions to clarify any points made by the speakers. So, if there is anyone who would like to ask some of our speakers for clarification of any of the points they made, please, this is your opportunity to do so. We would love to hear from you. So, don't be shy. MR. RUSSO: I am Richard Russo speaking from AATB Governmental Affairs. This question is directed to Aric Kaiser. With regard to your deliberations about what types of bone products, bone tissue-based products might fit the category of devices, were these deliberations part of a record that we could look at to understand the type of thinking that you were considering, or is that type of thinking more or less so historical, it really doesn't have relevance to today's conversation? MR. KAISER: It is historical in the sense that it happened about a year ago, and it would certainly have some relevance because the things that were talked about internally and that we also got public comments on do relate to what we are talking about today. So, as far as getting some information, certainly there is things that were sent in as comments to us related to that canceled meeting that could be requested, but other than that, there isn't anything official. MR. RUSSO: Would it be possible to write for the informal comments or notes that you had, just so that we could be better informed? I think one of underlying difficulties in our dialogue today has been the assumption and presumption and misinterpretation of what has been proposed by the agency or thought by the agency, and it would be help for clarification, I think. MR. KAISER: I would say that most of the comments that we got in relation to the canceled meeting are the same types of comments that have already been submitted to the docket for the proposed regulation. So, if you have got those comments or want to get to those comments, it is the same type of information that we had in response to the meeting that wasn't held last summer. MR. RUSSO: Thank you. DR. ZOON: The dockets, you obviously have access to the dockets to see that. Clearly, that would be something that could be shared. DR. KITCHEL: I am Scott Kitchel. I am an orthopedic surgeon from Oregon. I am wondering if there has been a working definition established for the two terms "homologous use" and "minimal manipulation," that we are using as a starting point or if that is still just a completely open question and that is what you are here for today is to try to gain some understanding as to how you are going to pin those terms down. DR. ZOON: Right. In Dr. Solomon's presentation, she presented the definition of homologous and non-homologous. Ruth, if you would like to reiterate those or if you would like to show those again, we can do that, but again, part of the discussion here today is to even with making definitions, there is still a gray area, and I guess part of that is trying to set boundaries. So, I will ask Ruth maybe just to review that to make sure everybody is clear on that. Ruth. DR. SOLOMON: As I mentioned in my talk, the definitions that we are using were set up the establishment registration proposed rule, and those are the ones that we are still working with, and they include 1271.3( d) homologous use, which was divided into two parts, one for structural tissue, which we are talking about today, and the other for cells and non-structural tissue. So, homologous use means the use of the human cell or tissue for replacement or supplementation and for structural tissue occurs when the tissue is used for the same basic function that it fulfills in its native state. For minimal manipulation, again, it was a two-part definition, but we are particularly focused on the first of the two parts. So, minimal manipulation means for structural tissue, processing that does not alter the original relevant characteristics of the tissue relating to the tissue's utility for reconstruction, repair, or replacement. I would just like to mention that the definition of human tissue for transplantation that Dr. Pereira shared with you, that is, in the final rule, basically, it is meant to cover these same two ideas. The definition in the final rule says that human tissue, it cannot be considered a human tissue if you change --here we use the word "alter" --but if you change tissue function or characteristics, in other words, if you recover, process, store, or distribute a tissue by methods that change tissue function or characteristics, then, you are no longer considered a human tissue. So, today, we should look at how the bone allografts fit under both the definition in the final rule of the human tissue and the proposed criteria put forth in the establishment registration proposed rule for when a human cellular and tissue-based product can be regulated solely under 361 as a tissue.
DR. ZOON: Thank you very much, Ruth. Please. DR. FRANKEL: I am Victor Frankel. I am an orthopedic surgeon in New York and a member of the board of the Musculoskeletal Transplant Foundation. Has the Orthopedic Panel had a chance to discuss these matters, and if so, what conclusions have the Orthopedic Devices Panel come to? MR. KAISER: They haven't. That was actually going to be the meeting from last summer. DR. ZOON: Please. MR. BLOCK: My name is John Block from Telos. I have a question about what is up on the overhead now with regard to minimal manipulation and processing. What is the purpose of the processing? I mean are we talking about microorganism inactivation, bacteria or viruses, or preservation, and when is that required or recommended? DR. ZOON: Ruth, do you want to comment on that, please? DR. SOLOMON: Sure. Processing is not required or recommended. It is just part of the definition of how we would view a product as a tissue versus as not a tissue. In other words, the interim rule, as Dr. Pereira explained, and the final rule, both tried to get across the idea that if you process solely to prevent infectious disease, contamination and cross-contamination, or to preserve the tissue, so that it can be utilized, it can meet its function. If you do those two things, then, we consider that minimal manipulation and you come under the definition of a human tissue under the final rule and of the 361 product under the proposed approach. In other words, you are processing so as not to change the relevant characteristics of the tissue. As I said, under the interim and final rule, this was focused on preventing contamination, preventing of disease transmission, and preserving the tissue. DR. ZOON: Yes. If you could take the mike and identify yourself, please. You can come up here if you wish too, whichever is easiest. MR. BARGANSKI: Simon Barganski [ph] at Allosource. I have a question about the word "location" in the homologous use definition. As you know, most traditional bone allograft products are used in recipients in other locations from where they are taken at the time of donation. I wonder if you could elaborate a little bit on when you say "location," whether you mean direct, one-for-one use of a donor tissue in an analogous site in a recipient. DR. ZOON: Ruth. DR. SOLOMON: Yes, that is what we had in mind in a location where such structural function normally occurs. When we are talking about the spine, our interpretation --and we are here today to hear your interpretation --our interpretation was that if you took bone, let's say from a long bone, and used it in the disc space where bone does not normally appear, the disc is quite a different material than bone, it is a soft material, and if you used the bone in the disc space for the purpose of connecting two vertebrae as in a spinal fusion, that would not be considered a location where the structural function of bone normally occurred. Now, again, we are here to discuss that, but that was the initial thinking that went into --it was discussed at the Tissue Reference Group, and those were some of our initial thoughts. Again, we are here today to hear your interpretation. MR. BARGANSKI: May I just have a follow-up on this? DR. ZOON: Is it a clarification? MR. BARGANSKI: A clarification. In using your example, then, a device, say, that might be regulated in that particular indication as a Class III device because of its use, you are making a distinction and saying in the case of this tissue, because it is being used in a different location other than what is normally present in a pathologic condition -- DR. SOLOMON: Right, in the donor. MR. BARGANSKI: So, that is the distinction you are making rather than a distinction that you would make how to classify a device, be it a Class I, II, or III device. DR. SOLOMON: Right. That is quite a different --what we are talking about today is, as Aric mentioned, along the spectrum from being solely a tissue regulated under Section 361, where a premarket application would not be required, that is one end of the spectrum, to the other end of the spectrum where you would be considered a medical device and have to submit an application. What we are trying to do is find that bright line which may not be that obvious as to where we could distinguish between those products that would fall on this side, toward the tissue side, and those that would fall toward the device side, and what can we use to draw that line in the sand, so to speak. So, that is really what this meeting is about, not so much of once you have determined that it is a device, whether it is a Class I, II or III, we will not be talking about that today. MR. KAISER: That is actually a second question, the first one being are you a device or are you a tissue, and then if you are determined to be a device, you then enter a whole other realm of questions of where do you fall in the regulation of devices, I, II, or III. QUESTION: I have a question. How do you classify, for example, umbilical vein if you don't have the possibility to transfer to the umbilical cord, you know, you are taking a vein from a tissue which appears only in the pregnancy, and then you transfer into a body, how would you match with the situation here? DR. ZOON: Can I just say that the focus of this particular workshop is on bone allografts, and we would be happy to talk about other issues, but I think for right now if we could keep the focus on the question on the topic. If one of the panel members wishes to discuss this, that is fine. Please. MR. STROBEL: Bruce Strobel of the Musculoskeletal Transplant Foundation. A follow-up to Simon Barganski's question. The most commonly used tissue in the country by far, by any tissue bank in the country, is cancellous chips, and cancellous chips are sort of the standard of all tissues. Cancellous chips come from primarily the femoral head and the condyles, and that is where tissues are recovered, tissues are processed to product cancellous chips. Cancellous chips are not used I would say probably 99.-something percent of the time, they are not used in the femoral head or in the condyles in their application. They are used many other places throughout the body. So, if you take a strict interpretation of tissues being used for the same basic function that it fulfills in its native state, in a location where structural function normally occurs, I would venture to say that 90 percent, 80 to 90 percent of tissues that are distributed by tissue banks today, and have been for years, would not qualify as a tissue under that definition. Any comments? DR. SOLOMON: You are taking the most strict interpretation. I don't think we meant to be quite that strict. In other words, when you are taking the cancellous chips, are you not putting them into a location where bone normally sits? In other words, bone to bone. It doesn't have to be the same bone, but bone from a donor going into a location in the recipient where bone normally is found is what we had in mind by that. MR. STROBEL: Right. But different types of bone for different types of function, if you look at the fusion referred to earlier, where putting bone where a disc is, that is the intended purpose. You are not trying to replace a disc, you are trying to fuse two bony segments. So, that is the intended purpose, that always has been the purpose. You are not trying to replace a disc with a bone. So, in that sense, you have a question of is that the same function, the same location. You are not again replacing a disc, you are fusing bone, and that is the purpose of the bone, and has historically been the purpose of bone. DR. ZOON: If I could just say that we are very anxious during the day to listen to a number of these discussions. The purpose of this session was really just to clarify the best we can, not to make definitions, because we are really here to listen and hear where the interpretation in some of the lines should be. So, just for the sake of moving on. One last question for clarification? MR. SANDHU: I am Harvinder Sandhu from New York at Cornell Medical Center. I wanted to follow up on that last statement. I think it is a very important point that he raises, and I am still confused with the definition. One of the common uses for cancellous bone is not for bone repair, but for fusion of wrists, ankles, knee disorders, and so on. Also, cancellous bone is often used for cortical disruption. So, I am still not sure on how we are applying that definition to these applications. DR. ZOON: Thank you for raising that. I think part of the discussion today, if people could comment and continue to give input in that consideration, it would be very valuable. What I would like to do, because of the time frame, and I know for those of you who would like to get a cup of coffee, it takes longer than 15 minutes in this places. So, I would ask that we break now and then reconvene at 10: 05 for Session II. Thank you very much and we appreciate the input. I would like to thank the speakers this morning. Thank you very much.
[Recess.]
SESSION II DR. FEIGAL: Let's start our second session. It is pretty unusual to have a meeting that is still running on time at this point in time, and not hopelessly behind. One announcement that I have been asked to make, as you may now, the Center for Devices and Radiologic Health regulate cell phones, and there has been quite a bit of controversy about that. One of the things we can't do is tell you not to use them, but actually we are going to tell you not to use them anyway in the auditorium because it is a little bit distracting.
Let's begin the second session without further
ado. Our first speaker this morning will be Richard
Russo from the American Association of Tissue Banks.
American Association of Tissue Banks MR. RUSSO: Thank you. I have been asked to speak about current methods of bone processing. This does not address issues specifically of homologous use or minimal manipulation, but instead was intended to set out the general practices currently in use by tissue banks in general and specifically those that are accredited by the American Association of Tissue Banks. So, the purpose of this overview is to quickly outline the general technical approaches for the processing of allogeneic bone and then to identify more concretely the specific methodologies currently in use by tissue banks accredited by the AATB. It is not intended to be an exhaustive itemization of the methods and technologies in use as that would require more time and somewhat of a different format than we have available to us. Tissue banks generally employ a method that utilizes a disinfection and cleaning process that is merged with the physical cutting and shaping, sizing, and other physical preparations of bone, so we have essentially two broad lines of activity going on at the same time. After the issue is initially cleaned and/ or debrided with operations, such as high-pressure water debridement or manual scraping and cutting, the bone tissue passes through processing steps, such as washing, soaking, sonication, rinsing, and/ or the pressurized flow of water and other agents to progressively remove and control bioburden and to remove physical components, such as residual soft tissue, cells, blood, bone marrow, and lipids. Concurrent with or after this progressive disinfection and purging, the physical alteration of the tissue to shape, size the tissue, or to modify the surface of the graft is performed. Techniques, such as cutting, sawing, grinding, milling, drilling, lathing, and other similar activities are performed to ready the graft for use as requested directly or indirectly by the surgeons. As a parenthetical note, I should add that typically, tissue banks have specifications to which they produce these grafts, and they have developed them in response to requests for surgeons. Sometimes after this primary processing has been completed, additional processing, such as complete or partial demineralization is performed to further modify and/ or refine the physical characteristics of the tissue. This type of secondary tissue processing is performed by over half of the AATB-accredited tissue banks that process bone tissue, and the specific techniques used in this type of processing, as well as the final specifications for these grafts varies somewhat among tissue banks. Inactive excipients are occasionally also added by some tissue banks to improve the handling of physical characteristics of these tissues. These tissue processing activities generally take place in a controlled environment, such as a clean room or under a laminar flow hood. Tissue banks often utilize isolation or other techniques adapted from aseptic processing approaches used in the production of other types of medical products to the extent that these techniques are feasible and useful. Tissue banks may or may not subject these grafts to terminal sterilization methods to achieve sterility. As can be seen from the above comments, it will be even more clear in the following comments, there is a spectrum of approaches and basic methods used in the processing of bone tissue. FDA should be aware that in some cases, individual tissue banks use more than one method. For example, in the issue of sterility, they can use terminal sterilization with irradiation or with ethylene oxide or don't perform terminal sterilization. These practices reflect the customer base of the individual tissue banks, such as surgeons, who may have a distinct view on the type of processing that they wish employed on the tissue grafts that they implant. Now, to talk about some specific methodologies currently in use. There are at least six basic methodologies currently used to preserve and/ or ready allogeneic bone tissues for clinical or surgical use. These are freezing, cryopreservation, lyophilization, air-drying, full demineralization, and partial or surface demineralization. There exists a variation of techniques and specifications within the tissue bank community for each one of these basic methodologies. Tissue banks use both manual and power tools and instruments to shape or size tissue grafts or to otherwise modify the surface or another physical characteristic of the bone tissue. The power tools and instruments can be hand-held or they can be table-or bench-mounted or floor-mounted. These can be drills and saws and lathes and similar equipment. Sometimes hand-held power tools, essentially those used in orthopedic surgical procedures are fixed with table or set in a fixture to allow the bone tissue to be held and manipulated by an operator and subject to an in-place tool. High-pressure water systems or wash systems rather are often used to debride tissue either as an alternative or supplement to other physical processing. Sonication and pressure-wash systems, positive and/ or negative pressure systems are used to clean or treat the internal spaces of bone tissue. Tissue banks use a variety of cleaning, wetting, and disinfecting fluids to process bone tissues. These include water, saline, surfactants, alcohols, including ethanol and grain alcohol, acetone, antibiotics, iodine preparations, hydrogen peroxide, hydrochloric acid. The water utilized can range from simple tap water to treated water including water that is labeled for, or meets the specifications for, water for injection. Excipients, such as glycerol, are sometimes used to modify the physical characteristics of the tissue. Many tissue banks utilized modified or adapted aseptic approach to processing tissue in which sterile grafts are produced without the use of terminal sterilization, and terminal sterilization is also widely used. For this purpose, tissue banks utilize gamma irradiation, electron beam, and ethylene oxide gas to perform the terminal sterilization. I should note that irradiation treatment is also sometimes used as a conditioning step prior to processing to control the bioburden of incoming bone tissue especially when no terminal sterilization process is used. Tissue processing technicians are typically isolated or gowned. This isolation or gowning technique is sometimes as complete as it is for workers in standard clean room environments. In other situations, it is more similar to what is found typically in an operating room environment. The hard surfaces on which bone tissue is placed during processing are either draped or undraped according to the cleaning validations and procedures of the individual tissue banks or to the AATB-published norms. Finally, I can mention the fact that if we view processing as a whole, tissue banks use a variety of different packaging systems, and they although directly germane, these include bottling, pouching systems, single, double and triple, wraps and tray systems. So, that provides you with an overview quickly to what is being done with bone allografts today by the tissue banks in the United States. DR. FEIGAL: Our next presentation will be by Dr. Laurencin and Dr. Jaffe from the American Association of Orthopaedic Surgeons. Return to Table of Contents
American Association of Orthopedic Surgeons DR. LAURENCIN: Good morning. This is a two-part presentation. Our first part is this morning, and we will be giving another part this afternoon. This morning, our charge has been to discuss allograft bone and orthopedic surgery, and give an overview of uses. May I have the first slide, please. This morning, we will just be talking about some of the uses in terms of allograft bone in orthopedic surgery. In the afternoon, we will get into a little bit more of the controversial areas in terms of definitions regarding minimal manipulation and homologous use. Just in the way of background, I am a practicing orthopedic surgeon mainly focusing in areas of the shoulder and knee. I am Clinical Professor of Orthopedic Surgery at MCP Hahnemann Medical School and Professor of Chemical Engineering at Drexel University. I have research interests which include bone regeneration and replacement. I have had some experience with working with the Food and Drug Administration with the Orthopedic Device Panel, and I am very privileged to be able to speak in conjunction with the American Academy of Orthopedic Surgeons. When we think of autografts in general, we think about autogenous bone mainly from iliac crest. It really is the gold standard by which we compare other materials. It has an 80 to 90 percent healing rate. It is osteo-conductive, which means that it's a scaffold for regeneration. It is osteoinductive, containing a number of growth factors including bone morphogenetic proteins. It is osteogenic, containing bone-forming cells, and osteointegrative meaning it can form a stable bond, and it is biomechanically stable as it has reinforcing properties, and again, it is the gold standard in terms of for bone repair. But, of course, these are limitations that autografts have, and these are donor site morbidity, which is pain at the donor site, and this can be actually quite significant. Infection can also be a problem in terms of these donor sites, and it is interesting, over the last 50 years, that the reported complication rate of about 15 to 20 percent really hasn't changed in terms of pain and infection at the donor site. There is also a limited supply in terms of graft. There is only a certain amount of graft that you can removed from a patient, and is especially a problem in terms of children. Also, there are issues of bone quality depending upon the patient's premorbid types of conditions. Allografts are tissues donated usually from cadavers. They are stored and processed in most cases in tissue banks and available in several forms. As a matter of history, the first successful case of allograft transplantation was in 1878 by Macewen. Numerous reports in the literature followed over the next 20 to 30 years. In 1929, a paper on spinal fusion came out by Albee, and from there a number of papers have actually focused on the use of allograft bone in spinal fusion. Shaped bone blocks for use in spinal fusion were reported by Briggs and Milligan in 1944, and there have been a number of papers that have come to the fore since then with the use of more shaped devices. When we describe allografts, we can describe them in many different ways. One way is by type. We can talk about their being massive cortical structural osteoarticular, they can be cancellous, or they can be demineralized. If we look at the uses of these allograft devices, we think about fracture care, spine, sports medicine, total joint replacement, and also tumors. My colleague, Dr. Jaffe, will be giving case presentations on these areas. In the areas of fracture care, we have 6.2 million fractures in the United States each year, and approximately 500,000 bone grafting procedures are performed annually. The majority of these are autografts, but approximately 150,000 of these are allografts, and this number is actually shifting where the numbers of allografts are actually increasing. The cost per graft is approximately 5,000, so there is a $2.5 billion health care cost that is involved. When we think about the area of the spine, traditionally, it has had a number of applications in terms of autograft. Over the years, pre-shaped bone products have come to the fore. The pre-shaped bone products allows precision in design of implants. It obviates the back table approach in terms of shaping implants in the operating room theater, which cuts down operating room time, and a number of studies have demonstrated improved patient outcome probably because of the combination of the approaches, a combination of the reasons that we have talked about above. In sports medicine, it has been traditionally used as part of reconstructive implants. The bone, tendon-bone allograft used for ACL reconstruction is a paradigm for that. There is a proven record of clinical efficacy in that area. There are new generation of implants that are coming to the fore as shaped and preprocessed for use in such areas as interfering screws and other implants, and much of these areas are what we are going to be debating today. I would like to turn the talk over to Kenneth Jaffe. DR. JAFFE: Thank you, Cato. What I would like to do today is to show you a little bit about my clinical practice. I am an orthopedic surgeon at the University of Alabama in Birmingham. My areas of interest are in orthopedic oncology and adult reconstruction. So, the use of allografts is one of my main tools in my armamentarium of devices or structures, tissue, however you would like to classify that today, and I would like to go through some of the cases that I have done. Areas that we use bone allograft is in tumor reconstruction after we remove a diseased segment of bone that may have some sort of neoplasm whether it be in failed total joints, and it is especially useful in revision of total joints after you see osteolysis in the bone and there is no bone to really hook up new devices. We use it in traumatic situations, congenital deformities, and in spine fusions. This is a defect that we see in the distal femur in which you have an osteochondral defect. One of the ways that we can rebuild that defect is with an osteochondral allograft. In this situation, what we would want to use is possibly a fresh allograft because of the preservation of the articular cartilage. This is the same defect with that osteochondral allograft, and in this situation, there is not a whole lot of good alternatives. Other areas in total joint reconstruction, if someone has a congenital abnormality and which we don't have an acetabular socket big enough to put a prosthetic device in, and in revision surgery, this is a lady who had had four total hip arthroplasties, now her acetabular component is up in her spine. She has no proximal femur. This is what I did rebuilding her bone in her acetabulum here. Here is a proximal femoral replacement. What we do is we can take bone. This is a femur right here. It is not used in its normal location, but I have bolted it to the iliac wing and then put in a acetabular component. This is her walking with a cane, and she is quite able to do her activities of her daily living. Other areas that we look at rebuilding bone is from traumatic defects, whether it be bone loss from the fracture, such as in this situation in which we do not have enough autograft to rebuild it. It involves the articular surface. Whether it be another situation in which it is a smaller injury, just involving the articular surface, or even in massive bone loss, this person was riding with his arm outside a window and hit a mailbox, this is an example of a distal humoral osteoarticular allograft, which it did include the whole joint, and the guy is playing golf again. He probably has a little higher handicap than some of us here who get to play more often. Other areas that I am more interested in is in tumor reconstruction. We can use bone allograft to pack bone defects or even to reconstruct large segments as we do in trauma situations. This is a unicameral cyst in the proximal femur. You see on the MRI the cystic changes. Here, we have a fibular cortical allograft, and this is demineralized bone matrix placed in here, as well as another fibular cortical allograft there, and this patient is functioning quite well. This is a patient who I saw in fact yesterday, who had a resection of a distal femoral osteosarcoma, and this is his osteoarticular allograft at the end of his femur, and this is him able to bend down and to stand on that leg. So, I have been able to salvage his leg instead of doing the time-honored procedure of an amputation. This is another patient with chondrosarcoma of the proximal humerus. This is the resected specimen. This is the large, massive bone allograft. This is putting it into place. This is his function post-op. In spinal surgery, and which you will hear more to day, it is used as a structural support and also to enhance fusions. This is a person with a lumbar compression fracture. You can see the bone in the canal, the massive destruction. This is a fibula strut along with a plate in there to rebuild the spine, so it enhances the fusion and it also adds structural support. So, these are some of the uses that I wanted to share with you about what we do as the end user of allografts and to give you an idea of what we are talking about from a clinical setting. Thank you. DR. FEIGAL: Thank you very much. Our next speaker will be Robert Heary from the American Association of Neurological Surgeons. Return to Table of Contents
American Association of Neurological Surgeons Bone Allograft in Neurosurgical Practice DR. HEARY: Good morning. I would like to thank the American Association of Neurological Surgeons for the opportunity to come here and speak to this group today. What they have asked me to speak about would be the uses of allograft bone in neurosurgical practice, and what this basically comes down to is where we use it in spine surgery. A point that I would like to clarify from listening earlier today is uniformly in spine surgery, every time we use allografts as a neurosurgeon, we are connecting two pieces of bone, one above to one below, spanning a place where at least a single intervertebral disc was located. As such, there would never be a point that we would put bone in a place of bone in an isolated fashion. It will always be spanning a motion segment with the goal of that to be trying to obtain a fusion. I would like to touch on some of the uses and importance of allograft bone, as well as the safety and some conclusions that can be drawn. It is estimated that there are currently over a quarter of a million spinal surgical procedures performed yearly in the United States where allograft bone is utilized. In addition, there are greater than 200 peer-reviewed articles specifically describing the use of allograft bone in spine surgery over the past three decades. We use allograft bone as a general rule to provide structural support. In addition, this can be augmenting or replacing autograft bone. Autograft bone has previously been mentioned. It typically is bone taken from the iliac crest although it can be taken from the lower portion of the leg in the fibula as well, but oftentimes there is a limitation in the amount of autograft bone that you can take from the patient themself, as well as whenever you take autograft bone it requires a separate incision being made in the patient with the attendant morbidity that can occur as a result of a second operation on the same patient. The different types of bone we use are either cortical bone or cancellous bone. The cortical bone advantages are that it is rigid and provides immediate structural support when placed into the spine. In addition, cancellous bone can be utilized, which allows for a trellis or lattice-like network that will be allowing bone to grow through this area, and that may be used either anteriorly or, more often, posteriorly. Allograft bone incorporates by a total of five stages. These are the same five stages that autograft bone needs to go through when a fusion is to occur. Typically, inflammation will occur within the first 14 days after the fusion procedure has been performed, which is followed by a vascularization stage somewhere around 14 to 21 days this occurs. Osteoinduction and osteoconduction occur, and these are at variable rates. Autograft bone tends to go through those stages a little more rapidly than allograft bone, however, the same identical stages are necessary to occur in order for a fusion to occur, and finally remodeling occurs. The point of this is basically, although the two types of bone come from different sources, the identical process is necessary in order for a long-term bony fusion to be able to occur. Surgery can be done either from the front or from the back, and for the purposes of this study, the majority of allograft procedures are done anteriorly. The purposes of using the allograft bone when anterior surgery is one is typically to maintain height after removal of either disc material, possibly tumor tissue or infectious tissue, some tissue is removed from the front of the vertebral column, and there is a need to restore and preserve height, and that is accomplished with the allograft bone. In addition to this immediate restoration of height and maintaining of anterior support, there is a need for a ventral incorporation or fusion to occur. Posteriorly, there is occasional uses for a structural support although that is less common than the use of it anteriorly, as well as to augment fusion processes using it posteriorly. When we need structural support in spine surgery, typically, it is with anterior processes needing one of the vertebra needs to be replaced or a disc between vertebra needs to be replaced. The choices we have of what we can put in the space to maintain the structural support would either be autograft bone coming from either the patient's iliac crest or their own fibula, uncommonly done in the fibula, commonly done in the iliac crest, allograft bone available from the tissue bank, or metal instrumentation, which may be made of either steel or titanium. An important concept to remember with spinal fusion surgery done in the neurosurgical and orthopedic practices involving allograft is that the long-term result requires that a stable bony arthrodesis or fusion occur. Instrumentation, any of the metal products, be it cages, be it screws, hooks, rods, or any of those things, will eventually weaken with time. A bony fusion will strengthen with time, and that poses a very marked disparity between those two that devices, such as metal rods, eventually loosen up with time. It is a bony fusion that solidifies and takes the pressure away from the metal implants. No instrumentation is able to take the place of a solid bony fusion or to obtain a successful result. When the purpose of doing a spinal fusion of spinal surgery is to obtain a solid fusion, what we are interested in getting happened would be the bone, the allograft bone that we placed to fuse with the adjacent bone above and below it. This will allow for long-term spinal stability to occur, it will allow for decreasing of the amount of pain, as well as a decreasing the amount of deformity or the potential for deformity if a stable fusion can be achieved, and it also can prevent potential catastrophic neurologic demise. I think some of the tissue bank data has already been expressed but needless to say, there is a very exhaustive amount of work done prior to any allograft tissue being available to the neurosurgeon for implantation in the spine. Fresh frozen or freeze-dried bone grafts are utilized in spinal surgery among neurosurgical practice. Tomford in 1995 wrote an article in the Journal of Bone and Joint Surgery showing that basically unprocessed bone has a very, very minimal risk of disease transmission, and basically processed bone, which is typically utilized in a neurosurgical practice, has essentially no risk of disease transmission with the current strict guidelines for harvesting of bone. I am going to present a couple quick studies that were mentioned showing the safety and/ or efficacy of allograft bone. Grogen, in 1999, showed the use of allograft bone in scoliosis surgery and demonstrated this bone among 87 adolescent patients to be safe, reliable, an effective option, and found comparable results and clinical outcomes when compared to autograft bone. Young and Rosenwasser utilized fibula allograft bone and found that there was less postoperative pain than what is utilized when autograft bone is employed. Molinari, in 1999, and his group analyzed the use of autograft bone in anterior thoracolumbar spine surgeries. They had 67 patients and got a 98.5 percent incorporation or fusion rate. There were no episodes of graft collapse, and what they found was that there was no loss of structural integrity when they compared the immediate postoperative x-rays to x-rays that occurred at two and five years afterwards, thereby showing the utility of allograft bone for this purpose. I think this is the most important point right here with respect to allograft bone. In addition to decreasing operative time, you eliminate the donor site morbidity. I myself have personally presented information both at the Joint Spine Section in Neurosurgery, as well as at the American Association of Neurological Surgeons, where a large study was performed of over 200 patients where what we did was analyze pain postoperatively and we spoke to the patients. I spoke to them for a period of four years asking them about the pain they had from autograft bone and recorded their answers and found that 92 percent of people said they had no pain. When people distinct and separate from my practice called the patients seven months apart from the average time when I had called them, my time was a mean of 12 months, the study time was a mean of 19 months, three separate people calling my patients blinded to me found that 66 percent of people said they had no pain and 34 percent of people had pain. This was a high statistically significant difference and what it showed is that many, many patients are having pain, about a third of all people, autograft bone is taken. Oftentimes they may not relay that information to their surgeon for a variety of different reasons, however, I think when we are analyzing how much pain people are having, we have to look at blinded outcome studies. This information has been submitted to the Journal of Neurosurgery, and I am sure it will be published at some point in the near future. The bottom line of what it let us know is that more people are having pain than are letting us be aware, and as such, my practice has changed as a result of that study to incorporate additional, more widespread use of allograft bone which does not cause the patients to have the degree of postoperative pain. In addition, infection is possible, cosmetic deformity, blood loss and structural weakness are all possible things that can occur whether the bone is taken from the more common site in the iliac crest or the less common site in the fibula, down at the lower portion of the leg. In addition, when you put in allograft bone, you are better able to evaluate a fusion compared to when you use metal implants, which make evaluation of fusion status somewhat difficult. As a summary of the use of allograft bone in a neurosurgical spine practice, this has become the standard of care in the community. There is a long history of successful surgeries, and the practice has been shown to be safe and efficacious for over 50 years, and my belief is that the use of allograft bone should fall under the category of medical judgment. Thank you.
DR. FEIGAL: Next, Dr. Scott Kitchel from the
Orthopedic Healthcare Northwest will make some comments.
Orthopedic Healthcare Northwest Human Bone Allograft in Lumbar Spine Surgery DR. KITCHEL: Good morning. Indeed, I am Scott Kitchel. I am an orthopedic spine surgeon from the University of Oregon. I am here at my own expense to try to represent my thoughts about this, and hopefully, also my patients and some of my colleagues. I am going to try to center on human bone allograft in lumbar spine surgery, however, I must say that I am concerned by the topic of the entire meeting that the spine is somehow being differentiated, and if you look at the official posting of the name of this, it seems to call into question particularly the use of these products in the spine, and I think really we need to look at a more general topic of the use of bone allograft in all orthopedic applications. The points that I would like to try to make in the next few moments are that spinal bone is really no different from bone anywhere else. In shorthand, bone is bone, if you will, what my perceptions are of what minimal manipulation should be considered going by the definitions that I have seen this morning, what I would consider homologous use, and a reiteration that bone is really used for grafting or to make bone grow to other bone. Bone isn't used as a disc replacement or bone isn't used as a joint replacement, bone is really put where you want bone to grow, so it is bone being put in a position for bone. I think we might all benefit if we go back and think a little bit about bone in the practical terms of how we are using it for bone grafting. With apologies to the bone physiologists, really bone for bone grafting has two purposes, and one of these is structure, which comes from dense cortical bone or the outer lining of all bone. This happens to show the femur. The other is cancellous bone or the lining bone inside of that cortical bone, which really acts, as has been mentioned, as a scaffold for bone to grow. Those are the only two real kinds of bone there are, and if doesn't matter whether that comes from the femur or the tibia or the spine or the skull or any other bone in the body. Again, I think it is important to remember bone is bone, and it is either cortical or it's cancellous. We routinely take iliac crest bone autograft and put that into the spine, and I guess I am confused by this most strictest definition of homologous use. To me, that would go outside of what is homologous use, and I think that is a mistake. We are taking bone we want to have new bone grow through. We are putting into a structural position. It is structural bone, and it is allowing bone to grow. So, to me that should be homologous. It is every bit the same as when we use allograft femur to replace a tumor in the lumbar spine. This time we were taking the part of the bone that indeed represents the structure. We are putting it where we need structure to get bone to grow from bone to bone. Even though it's a femur, it is still bone and you are getting one bone to grow to another. So, to me, that represents homologous use. The definition that I was shown this morning when I asked that question is that it has to provide the same basic function. Indeed, in all instances, the same basic function is the support, so that bone can grow solidly together. This is a picture of a piece of allograft bone from a femur, again with my apologies to the bone physiologists, this is what bone looks like when it is dead, and even autograft bone, once it has been harvested, is essentially dead, the osteocytes die, but it's a stroma of connective tissue with cells in it that are originally the osteocytes and osteoblasts. The reason that I put this up is that again this is a piece of allograft. This is a piece of harvested autograft, and I would defy anyone in the audience to be able to tell me, if I hadn't told you, which one is allograft and which one is autograft. Autograft is just as dead as allograft by the time we put it into the body. So, to begin to try to differentiate between allograft and autograft, as it is used particularly in the lumbar spine for either structural support or a lattice for bone to grow through, I think is an artificial definition, and the one that we probably need to try to get away from a little bit. Switching topics a big to minimal manipulation, this is a drawing from a surgeon by the name of Vich in 1985, and this was where threaded cortical bone dowels came from. This is a drawing of a bone dowel that he harvested off the iliac crest. He then, with his own tap and dies set, cut these threads manually in the operating room, estimated that it took him about 30 to 45 minutes, and through that felt that he was gaining much better pullout strength and better mechanical properties of the bone by how he was manipulating it in the operating room. Well, that 30 minutes cost us increased time, the wound is open, so there is an increased risk of infection, and certainly this technique is less precise than were available for today, but even considering all of those things, and again going back to the definition of minimal manipulation, or of manipulation, I don't think it alters the original relevant characteristics of that bone, and that was that definition that we were shown. Can we do better than that? Sure, we do better than that all the time now. This is clean room processing of allograft bone. The bone is processed in a hypersterile condition. The most modern possible sets are used with taps and dies to cut it very precisely. You wind up with this, which is a threaded femoral cortical bone dowel, certainly a more precise and a little bit more elegant implant than what Dr. Vich was cutting on his own, but I would say that it's not significantly different. Again, I don't think even when this is done commercially that this in any way alters the original relevant characteristics of the tissue. Still, it is there to provide structural support. Bone is bone. This happens to be a femur going into the spine, but as a spine surgeon, that to me meets the definition of homologous use. I am putting a piece of structural bone where I need structure to occur. This is just another look at the spine. If we look at the spine, the bone that we used is almost always to try to make these vertebral bodies grow together, and I won't belabor that because several other people have said that this morning, but we tend to use structural pieces in these interbody positions, between the vertebral bodies. We tend to use cancellous pieces more posterolaterally with an attempt to try to get bone to grow through that lattice. But again, whether we are using allograft or autograft, and whether it's iliac crest or fibula or femur, whether it has been machined or not machine, to me, those are all homologous uses because they all have the same basic function, and that is to fulfill the goal of getting bone to grow solidly to bone. In some area, structure is also needed, hence, the use of cortical pieces. In other areas, all you need is that lattice for bone to grow, and that is when cancellous is used. Fusion can certainly occur in human beings without putting any bone into that area. We see spontaneous fusions in various degenerative conditions at all times, so it isn't even necessary sometimes to add bone or it may occur naturally without any grafting at all. This is the insertion of one of the bone dowels that was earlier portrayed. Clearly, this cut piece and machine piece of femur providing structural support has been one of the index pieces allograft that has led to the interest on the FDA's part and whether or not this should be regulated. But again, I would say that this is a piece of bone that is providing the structure. Often, this inner table will be packed with cancellous bone to provide that lattice, but in my definition, this is clearly homologous use because I am putting human bone into a human. I am putting structural bone into a spot where I want structure, and I am putting cancellous bone into the spot where I want it to grow, and at least by my definition, I have not functionally altered or clinically altered the significance of that bone by placing threads on it. I have merely improved the chances that it won't displace and have a complication. This is what the bone dowels indeed look like radiographically when they are in place, and as the fusion begin to occur. This is a schematic picture, again, that bone dowel in place in that interbody position. Again, I would like to stress not replacing the disc. Bone is not a disc replacement. Bone is there to provide structural support and a lattice to allow bone to grow solidly to other bone and create a solid piece of bone. This is just an example again to show that bone can bridge without any implant. That is radiographic contrast agent in the disc space, but what is being outlined there is a bridging osteophyte, and that is a natural process and part of the degenerative cascade, and not reliant upon us putting bone into that inner space at all times. So, the points again that I would like to leave you with is that spinal bone is not any different than any other bone. There really are only two types of bone -cortical and cancellous. Those occur in the spine, those occur in the femur, those occur in the skull, those occur in the radius and the ulna. To me, minimal manipulation allows that I change that bone, whether I do that freehand in the operating room or it is given to me in a more precise manner, but again, going back to that original definition that I have shown, I don't think that that manipulation alters the original relevant characteristics of that bone, which to me are structural support and allowing bone to grow through it. Homologous use, again, there is only two basic uses of bone in the spine. It is either structure or allow bone to grow through it. So, to me, any human bone being put into a position in the spine is by definition homologous use, because I am using either structural cortical bone or I am using cancellous bone to provide that lattice, and those will all grow together and allow a solid arthrodesis. Just as a last point, again, bone is used for grafting and to make bone grow. It is not used as a disc replacement. In conclusion, I would just urge that, as much as possible, the FDA consider this in the care of our patients. I know this is a very difficult and controversial topic, but I am concerned that there is going to be increased regulation which is going to lead to more difficulty in obtaining these and ultimately not be in the best interests of my patients, both by decreasing the availability of these products and by increasing their cost. Thank you. DR. FEIGAL: The final speaker is this session is Jim Benson from AdvaMed. For those of you that haven't paid attention, formerly known as HIMA, and Jim once upon a time was one of my predecessors, so brings a long view to some of these issues. Jim. Return to Table of Contents
AdvaMed MR. BENSON: Thank you. As Dr. Feigal said, I am Jim Benson. I am Executive Vice President for AdvaMed. I have trouble saying that, I haven't gotten used to it yet. We were formerly known as HIMA, and are the largest medical technology association in the world. I am here today because a number of AdvaMed members process human bone allograft and provide it to the clinical community. For many years, human bone allograft has provided significant clinical benefit to thousands of patients for a variety of disease states. The of allograft bone in clinical practice is well established and has evolved over time through surgeon use, and to many, innovative and useful forms. AdvaMed advocates innovation for patient care through development of new medical technologies and products, however, we recognize that the regulation of these products is a challenging matter for the agency. This morning I will present one possible mechanism for regulating these products. FDA has established regulations to address tissue products including human allograft bone under the authority of Section 361 of the Public Health Service Act and under applicable sections of the FD& C Act, as amended. AdvaMed supports the regulation of human bone allograft as either transplanted human tissue or medical devices. Plainly, it is in the interests of FDA, industry, the health care delivery system, and most importantly, patients, for these regulations to be administered in a fair manner to achieve safe and effective products. We believe that FDA must take great care when more than one center is involved with regulating human tissues or materials derived from such tissues to ensure that designated means of regulatory control for each product is, in fact, enforce. Only by doing so can the public health be protected and a level playing field among companies be created. Our members report to us that despite efforts by the agency and the combination product law and regulation --which I think I actually signed, didn't I, I don't know whether that was a good thing or not -- jurisdictional questions still abound regarding which FDA component has the lead for regulating human tissue and its derivative products. We commend the agency's efforts to address this problem through the creation of cross-functional groups, such as the Tissue Reference Group, however, we have a few suggestions for strengthening the effectiveness of that group. Specifically, we suggest improvements in the operation of the TRG. We encourage a more transparent and open process in its activities, including use of notice and comment rulemaking. Also, there is a need to ensure that product-specific agency decision-making is more open to public participation when it involves creating precedent for a product type. This is particular important with the TRG because the group makes recommendations on individual products that may be binding for an entire product class. Public meetings should be held prior to making binding decisions that affect a class of products. Additionally, the good tissue practices regulation needs to be implemented as soon as possible. The proposed regulation is encouraging and will be helpful to the tissue banking and processing industry. When finalized, the proposed regulation will help to reduce confusion over the regulatory requirements necessary for companies working in this industry. AdvaMed is appreciative of the effort that must take place to establish this regulation, but it is urgently needed now. We believe that finalizing this reg is critical before FDA proposes additional tissue-related regulations because of the agency's tendency to revisit each outstanding proposed regulation in light of the newest proposal. In other words, proposed regulations become a moving target that are unlike to be resolved as final until the target stands relatively still. Moreover, standards, such as the tissue engineering medical product, or TEMP, standards developed by ASTM will be helpful in providing continuing guidance for the industry. Generally it appears that a regulatory framework for consistent, appropriate, and equitable regulations of human bone allograft either exists or is in preparation, but there is an urgent need for these regulatory elements to be completed and appropriately applied. There is a need for a better and more encompassing definition of human bone allograft products to ensure that the TRG and regulated companies can more efficiently and predictably proceed in the future. We recommend that homologous use and minimally manipulated criteria for determining whether a human cellular and tissue-based product is subject to regulation as a medical device or as a tissue be eliminated. These agency proposed definitions fail to reflect the current FDA approach to regulating most tissue-based products as tissue. For example, the definition of homologous tissue states that such tissue fulfills in its native state, in a location where such structural function normally occurs. This language is confusing. It appears to state that in order for a product to be regulated as tissue, it must be used in the same location from which it was removed and for the same purpose the tissue originally fulfilled. The definition of minimal manipulation is imprecise, making it very difficult to draw a meaningful distinction between tissue-based products that are minimally manipulated and those that are more manipulated or more minimally manipulated. Moreover, the result of manipulation should be more important than the fact of manipulation. Specifically, the shaping of bone, for example, into screws, wedges, pins, or dowels has not changed the character or identify of the bone, and should be seen as manipulation of tissue that remains tissue, and should be regarded as such. In other words, tissue-based products labeled "promoted for tissue replacement, construction, restoration of function" should be regulated under 21 CFR 1270 as human tissues. However, if false or misleading claims are made by the processor regarding the performance of tissue, then, the agency should enforce the Act against such persons or product. In contrast, AdvaMed believes that tissue loses its identity when it is combined with a non-tissue component, such as combination products. For example, when bone is demineralized and combined with a device, collagen, for example, or a drug, then, it should fall outside of the tissue regulatory category. From this, AdvaMed contends that FDA should consider deleting the homologous use and minimally manipulated concepts from the tissue definition and replacing them with a definition that reflects the current tissue versus device definitions. By so doing, the agency will provide enough breadth to fairly capture the products of the future and ensure the safety and effectiveness of current products and those still developing in innovators' minds. If FDA is wedded to its proposed definition of tissue-based products, we strongly urge that the agency fully explore the meaning of its approach and include in the definition a range of examples that will clarify the scope of the term. This is important to ensure certainty and not create regulatory delays and deny physicians excellent and needed products and ultimately hurt patients. AdvaMed requests the agency to return to the primary goal as stated in the proposed registration rule -improve protection of the public health without the imposition of unnecessary restrictions on research, development, or the availability of new products. AdvaMed recognizes that the regulation of tissue products is a complex issue. Although I have recommended one possible approach, AdvaMed would be happy to explore alternative approaches with the agency in a cooperative manner. I appreciate the opportunity to present our views to this forum. Thank you. DR. FEIGAL: I wonder if the panel could join us. The structure of the remainder of the session, and the only thing standing between you and lunch, is opportunity to have a little questions and answers from the panel, and if time permits, we will take some from the audience, as well.
Actually, I thought for a moment there Jim was
going to propose that if you could say more than
minimally manipulated for homologous use 10 times real
fast, that you could have your product approved or
exempted, but we will work on she sells seashells by the
seashore next.
Questions from the FDA Panel Let me start with a question while people are getting settled, and let me direct this at Richard Russo for starters, but anyone can tackle this. Much of the focus of some of the comments have related to the possibility of transmitting infectious risk, and indeed that is an important part of the approach to tissue-based products, but another important part of FDA's role in consumer protection is to assure that products are manufactured with integrity and consistency. So, if there is a product that is going to be used in a setting, and you want to know something about its tensile strength or time-to-failure, many of those types of things, most of which for devices is determined at the bench, it is not determined in clinical uses, there is a lot of attention to how do manufacturing methods affect product performance, and how do the tissue banks meet the challenge of knowing when they --you know, you mentioned that there is many washes, debridements, different kinds of things that are done as you work with tissues --how do you know, for example, if you choose to freeze something as opposed to another method of storage, how you have affected the performance of that product, the kinds of things that we would typically expect to see in an application for a product which says this is going to go, you know, your examples this morning have been largely in the spine to provide structural integrity for the spine, how do all of the tissue banks know what best practices are and if they have changed a practice, that it won't somehow affect the strength of the product or some other product characteristic? MR. RUSSO: Thank you. I think that there are a couple of points to be made. First of all, the tissue banks that are accredited are to be validating the procedures. Now, that does not get submitted to AATB in the sense of an application similar to what would be submitted to the agency, but during the accreditation procedures, during the accreditation visits, the investigators review the validations that these people are performing, and they don't do it from the perspective of again looking at a label claim per se, but they look at the process. So, validation is one of the basic methods. I think that another issue that you raised, though, that is implicit, needs to be made here. The agency is proposing today something about some definitions. It becomes much more difficult to look at those definitions without the concept of label controls for Section 361 tissues because the only label controls that you really have at the moment are for "Section 351" tissues. That is what the whole debate is about. So, we need to set into place the concepts that we would have for label controls for Section 361 tissues to make sure that they are adequate, because we have an unusual situation with allograft bone tissue, if I could just finish the comment here. Synthetic devices were developed because of the shortage of allograft bone tissue. Bone tissue that was available was suspected to be unsafe for disease transmission primarily, and also was not viewed to perform effectively and may not be available. So, many people spent a lot of time and effort to develop synthetic devices to approximate bone tissue. As bone tissue processing has improved and allograft tissue banking has become much more successful, and tissues much more widely available, we are taking the same concepts to look at tissue that we were looking at the devices that were intended to replace tissue, and we are saying, well, let's look at them all the same way, and it is kind of a circular argument. If you start looking at a natural tissue transplant, and do not have enough of it, and you try to approximate it with a synthetic device, one understands the regulation of that. What happens when you now have a tissue available, do you regulate it like you did the device? It is not really the same issue, but some of the same issues are involved. DR. FEIGAL: Thanks for the comment. Are there some questions? Kathy. DR. ZOON: I have a comment and then a question. One, I want to thank the presenters this morning. Your presentations certainly were very helpful in understanding how the community, one, uses these products, and then some of the impact by the tissue banks and their control procedures, and Jim representing a number of the constituents who are manufacturing these. Ultimately, the goal of this regulation in terms of FDA's controls here was to provide a risk-based strategy for a variety of different tissues going from very simple to very complex. One of the issues, and clearly getting right down to the nitty-gritty, is the issue with bone dowels, because there you are right at the cusp of two technologies merging, and as I view many of the presentations this morning, as physicians and surgeons, you want reliable material. Your underlying assumption is the material that you are using is reliable. I think that is important because if you have defective material or material that didn't meet a certain set of standards, it would present problems for you and your patients as you were to use these materials. The question is what are the appropriate standards, then, and expectations for those materials. Clearly, the impact of those I think, and what are those standards, are really the focus of this discussion. I would actually be interested in the views of the panelists. If there weren't devices, if there weren't tissues, and we were just focusing on bone dowels, just focus, what are the important parameters, the important points that you would see in your community that would be important to you to ensure maximum success for your particular outcome, which would be patient health and safety. DR. KITCHEL: I think to limit the discussion to bone dowels, the things that I would be interested in would, of course, be disease transmission, which you didn't really specifically mention, but I would want to know both the estimated and the actual risk of any sort of bloodborne infection or other disease transmission. The second thing I would want to know would be something about the biomechanical characteristics of that bone dowel itself, and I believe you are aware, but the bone dowels that we are putting in the spine are tested to the same ASTM standards as the metallic implants that we put into the spine, and actually, their characteristics are known, their fatigue strength, their ultimate load to failure, and a good deal about their ability to stabilize the spine as compared to other implants. So, that information is out there and has been done independent of the companies that are providing them to us. It has been done in research labs that are recognized. I would also like to know something about the immunology of that bone as it is put into place, whether I should be expecting that there is going to be some sort of large immunologic or graft versus host response, and if so, then, what I might do or how I might better match that to the patient, so that I could have a better selection. DR. HEARY: I think another point that might be worth making in addition to what Scott has said is that on our patients, what we are trying to do is prevent a difficult bad situation where something needs to be done, and I think we need to look at what the relative alternatives are. I think that although it is important to specifically evaluate the allograft for itself, it is also important to recognize that the alternatives typically today include either metal, which will weaken with time, or autograft, which has some real morbidity to obtaining it, and with that thought in mind, I think it is more helpful to evaluate some of the regulations or lack of regulations with respect to allograft bone. MR. RUSSO: From the tissue banking or AATB's perspective, I must say that when threaded bone dowels first became available, there was some concern I think among surgeons that possibly these cortical pieces of bone in the normal remodeling process might collapse and that there would be a loss of height, and that that would be a danger to the patient. What has transpired or what we have kind of thought about this, but haven't done anything about this, is that we now have tens of thousands of cases, and no real reports of this. To my knowledge, none of the tissue banks that are participating in this have had complaints about the collapse of the bone dowel and the loss of height, and I believe that the surgeons have said that that is an important criteria for evaluating an implant. So, in this particular case, we arrive at a situation in practice where the theoretical concerns haven't been borne out. So, just possibly, maybe now is the time to take a careful look at what we are about to do because we are not pressed on a clinical basis. DR. FEIGAL: Dr. Witten. DR. WITTEN: First, I just want to make a minor comments because there has been such a question about spine in the title of the meeting, and that's just that we recognize that it is not just orthopedic surgeons that do spine reconstruction and repair. So, we thought we would make sure it clearly included neurosurgeons. I thought it may be helpful just to provide that clarification. My question is no one has commented on the use of demineralized bone matrix in their practice, and I would be interested in hearing from the clinicians about that, how they use it, for what, what they mix it with, if they mix it with any autologous material from the patient, for example, and then a follow-on question, similar to Dr. Zoon's question, which is what type of product characterization do they think would be important for demineralized bone matrix. DR. JAFFE: I use a significant amount of demineralized bone matrix in my practice in two areas. One is to pack defects, and I use it also in conjunction with allograft bone or with autograft bone as sort of a hamburger helper sometimes to expand the area. The interesting aspects of demineralized bone matrix is its osteoinductive properties, and there are some commercial entities that are now commenting on their product has more of an osteoinductive characteristics than another commercially available product, and these sorts of questions and how they are making these comments, I do believe need to be addressed. Because demineralized bone matrix is osteo-inductive to other areas that we are using it in is to enhance fracture fixation or osteosynthesis in using it in the same way that we may use autograft bone, as well, and we are doing that for the same reasons that the spine people said with the pain, et cetera, from taking autogenous grafts. So, it is a big portion of my practice of using that type of bone. DR. FEIGAL: Would anyone else like to comment? DR. LAURENCIN: I will be giving these comments this afternoon in my talk, but I think that just to sort of pre-reiterate what will be saying, there is a problem I think in terms of demineralized bone and other allograft bone materials in the measurement of biological potency, not only from the standpoint that different companies make different claims about the biological potency, but there are no standardizations in even some instances in terms of how biological potency is actually measured. One of my slides from this afternoon says that if you are going to buy a tanning lotion that will havean SPF rating on it, but you can buy allograft bone and not really be sure what the potency of that material is, and when you look at what is up for grabs in each situation, you wonder why that doesn't exist. MS. WELLS: We have some of the representatives of some of the associations here, and I don't know whether it will be part of the comments this afternoon, but I was wondering if we could focus a little bit on one of the questions that we asked for this meeting. Again if it is part of the presentations for this afternoon, then, fine. We asked about industry standards, and it relates to another question that was just raised, just to get your opinion on what you think is the adequacy of what is available for bone allograft, and if you have any reflections on what you think could or should be developed in the future. DR. LAURENCIN: I think, number one, I think that one issue is I guess there are no industrywide standards right now. There are standards that the American Association of Tissue Banks has, and many entities follow that, but in terms of standardized industrywide standards, they are not there. I think that is a major issue. I think it is also going to be a major issue, and I think it is good that the FDA is looking at this situation right now, because I think over the next four to five years, as we see more processing methods come to the fore, more for-profit companies come to the fore in terms of tissue banks, there will be a number of different proprietary methods that will be coming to the fore for processing tissue that may not be available widely for other banks to use even.
So, I think there may be some difficulties in
terms of that. So, I think there is a real gap in terms
of development of industrywide standards that all banks
will use. That is one of the questions of an end user that I would like addressed from the industry that is processing these.
MR. BENSON: I think the ASTM standard I guess
is in practice, and I don't know the extent to which that
answers some of the questions. Well, you raised an
excellent one, I think, in terms of bio --I forget the
term you used, not compatibility. In my opinion, the use of standards in the future is going to become much more important in this country. There are several legislative and regulatory reasons for that, which I won't go into. So, I think that that can happen in a much more efficient and effective way of we kind of bring people together to address it. I think I can speak for our industry at least in saying that we would be delighted to participate in such a process. MR. RUSSO: From an AATB perspective, I think it is important to remember where we are coming from. Maybe five to 10 years ago, specifically, the big concern, and up until very recently, the big concern has been disease transmission. So, the standards that have been developed widely throughout the tissue banking community have been aimed at safety, and safety specifically in light of disease transmission. They did not incorporate the concepts that might be used in medical devices, such as a failure of an implant, that might be considered a safety issue. So, from that perspective, we have minimum standards. From the perspective of performance --and I hesitate to use the word "efficacy" because that is a 35 |