MEETING OF THE


              THURSDAY, MAY 22, 2003

      The meeting was held in the Walker/Whetstone Salons of the Holiday Inn Gaithersburg, Two Montgomery Village Avenue, Gaithersburg, Maryland, at 9:30 a.m., E. Dianne Rekow, Chairperson, presiding.



E. DIANNE REKOW, DDS, Ph.D.         Chair

MICHAEL E. ADJODHA, M.ChE.          Exec. Secretary

RICHARD G. BURTON, DDS              Panel Member

DAVID L. COCHRAN, DDS, Ph.D.        Panel Member

JULIANNE GLOWACKI, Ph.D.            Panel Member

ELIZABETH S. HOWE                   Panel Member

MARK R. PATTERS, DDS, Ph.D.         Panel Member

DANIEL R. SCHECHTER, JD             Panel Member

JON B. SUZUKI, DDS, Ph.D.           Panel Member














                    AGENDA ITEM               PAGE



      Michael Adjodha........................... 3



      Katherine McComas......................... 7



      Kevin Mulry............................... 9



      Robert Betz.............................. 13

      Vincent Morgan........................... 28

      Thomas Driskell.......................... 33

      John Long................................ 46



      Mark Reynolds............................ 58



      Gunter Uhr............................... 69



            Thomas Arrowsmith-Lowe............. 84



      Jon Suzuki.............................. 121

      Julianne Glowacki....................... 123



      Marjorie Shulman........................ 153



      Dianne Rekow............................ 207



                                         9:32 a.m.

            SECRETARY ADJODHA:  Good morning and welcome to this meeting of the Dental Products Panel of the CRH Medical Devices Advisory Committee.  My name is Michael Adjodha, executive secretary of this Panel.  This meeting is called to order.

            Allow me to introduce the members of our Panel.  Please, raise your hand as I call your name.  Because of an illness, Dr. Leslie Heffez was unable to attend this meeting.  This meeting will be chaired by Dr. Dianne Rekow.  Chairwoman Rekow is the director of Translational Research and professor in the Division of Orthodontics at the New York University College of Dentistry, New York, New York.

            Joining her as voting members are Dr. David Cochran, professor and chair of the Department of Periodontics at the University of Texas, Health Science Center, San Antonio, Texas, and Dr. Jon Suzuki, professor at the University of Pittsburgh, School of Dental Medicine, Pittsburgh, Pennsylvania.

            Joining the voting members are the following consultants, who have been deputized to vote:  Dr. Richard Burton, graduate program director of Oral and Maxillofacial Surgery at the University of Iowa at the Department of Hospital Dentistry, Iowa City, Iowa; Dr. Julianne Glowacki, senior investigator at Brigham and Women's Hospital, Department of Orthopedic Surgery, Boston, Massachusetts; and Dr. Mark Patters, chairman of the University of Tennessee, Department of Periodontology, Memphis, Tennessee.  Dr. Edmond Hewlett was invited, but was unable to attend, because of an illness.

            Also serving on this Panel as non-voting members are industry representative Mr. Daniel Schechter, general counsel for Parkell, Incorporated, Farmingdale, New York, and Ms. Elizabeth Howe, outreach coordinator for the National Foundation for Ectodermal Dysplasias, Auburn, Washington.

            Joining us at the table is Dr. Susan Runner, interim director of FDA's Division of Anesthesiology, Infection Control in General Hospital and Dental Devices.

            I will now read into the record a memorandum from our center director regarding the building status of our Panel consultants.  "Pursuant to the authority granted unto the Medical Devices Advisory Committee Charter, I appoint the following consultants as voting members for the Dental Products Panel for the meeting to be held on Thursday, May 22, 2003:  Dr. Richard Burton, Dr. Edmond Hewlett, Dr. Julianne Glowacki and Dr. Mark Patters.

            For the record, these individuals are special Government employees and are consultants to this Panel under the Medical Advisory Committee.  They have undergone customary conflict of interest review.  They have reviewed the material to be considered for this meeting.

            In addition, I appoint Dr. Dianne Rekow to act as temporary Chairperson for the duration on this meeting.  Signed, Dr. David Feigal, director of Center for Devices and Radiological Health."

            Next, I'll read into the record the Conflict of Interest statement for this meeting.  "The following announcement addresses conflict of interest issues associated with this meeting as made part of the record to preclude even the appearance of impropriety.

            The Conflict of Interest statutes prohibit special Government employees from participating in matters that could affect their or their employers' financial interests.  To determine if any conflict existed, the Agency has reviewed the submitted agenda for this meeting and all financial interests reported by the committee participants.

            The Agency has determined that no conflicts exist.  However, we would like to note for the record that the Agency took into consideration matters regarding Drs. David Cochran and Julianne Glowacki.  These panelists reported past and/or current financial interests in firms at issue, but in matters not related to today's agenda.  The Agency has determined, therefore, that they may participate fully in today's deliberations.

            In the event that the discussions involve any other products or firms not already on the agenda, for which FDA participant has a financial interest, the participant should excuse him or herself from such involvement and the exclusion will be noted for the record.

            With respect to all other participants, we ask in the interest of fairness that all persons making statements or presentations disclose any current or financial involvement with any firm whose products they wish to comment upon."

            On a related note, a Conflict of Interest Survey is available for this meeting.  This survey is the result of an FDA University of Maryland collaborative research effort.  Dr. Katherine Mccomas, assistant professor at the University of Maryland's Department of Communication, is a sponsor of the survey.  I would like to ask Dr. McComas to come to the microphone to say a few words about the survey that's been handed out at this meeting.

            DR. MCCOMAS:  Thank you and good morning.  My name is Katherine McComas, and I'm a faculty member at the University of Maryland, and I'm working with the FDA on a study of public understanding and knowledge of the Conflict of Interest Procedures that the FDA uses to monitor and manage real or potential conflicts of interest of its Advisory Committee members.  This study is being conducted at multiple Advisory Committee meetings across multiple centers at the FDA, and I would like to ask for your assistance.

            This is for non-FDA people to fill out.  I'm responsible for the questionnaires in your chairs.  It takes about 15 minutes to fill out.  If you have a chance today, there's a box at the registration desk you can drop it in.  Otherwise, there's a postage paid envelope that you can drop it in and mail it back to me.  I also have distributed a separate questionnaire for Advisory Committee members, and again I appreciate your time in filling that out and getting that back to me as soon as you can.  The higher the number of responses, the more reliable the results, and the better we are able to make recommendations to the FDA about ways that we might improve overall satisfaction with the Advisory Committee process.

            I will be here today to answer any questions that you may have, and, as is in the letter, which is included with the surveys, the results of this will be freely disseminated to anybody who is interested.  Thank you very much for your time.

            SECRETARY ADJODHA:  Thank you, Dr. McComas.  I'll now turn the meeting over to Chairwoman Rekow.

            CHAIR REKOW:  Good morning.  We have before us, of course, the issue of reclassification of the TCP for dental bone repair, and I believe that we will begin with the presentation by Dr. Mulry, please.

            DR. MULRY:  Good morning and welcome to the Dental Products Panel meeting.  Today we are asking you, the Panel, to provide a recommendation on a petition to reclassify Beta Tricalcium Phosphate from Class III to Class II.  What I will be discussing is the regulation of tricalcium phosphate beginning with the current regulation, then looking at the historical prospective and finally regulation in other parts of CDRH.

            Dr. Betz will present a review of the petition and conclude with a risk and mitigation table, which we will be requesting Panel input.  With regard to adverse events, the Agency has found one report for tricalcium phosphate, which was not associated with human use.  Dr. Betz will discuss this adverse event in his presentation.

      Today we will ask you, the Panel, to provide input on a table which lists the risks to help generally associated with the use of tricalcium phosphate and to comment on recommended measures to mitigate the identified risks.  These risks and mitigations could be included in a Guidance Document to be developed by the Dental Branch if the Panel makes a recommendation for reclassification.

            Tricalcium phosphate currently is regulated in the Dental Branch as a Class III device under 21 Code of Federal Regulations 872.3930, Tricalcium phosphate granules for dental bone repair, and is identified in the CFR as a device intended to be implanted into the upper or lower jaw to provide support for prosthetic devices.  This classification regulation for tricalcium phosphate includes all forms of tricalcium phosphate.  A reclassification of this regulation would include all forms of tricalcium phosphate.

            However, as with any new indication for use, if another form of tricalcium phosphate other than Beta Tricalcium Phosphate were submitted, appropriate data could be requested.  By policy in the Dental Branch, bone void fillers that are less than 50 percent of Beta Tricalcium Phosphate or unclassified devices, and are reviewed under the pre-market notification or 510(k) process.

            So why this tricalcium phosphate originally classified into Class III?  At the time of the enactment of the Medical Device Amendments in 1976, tricalcium phosphate for dental use was regulated as a new drug requiring a new drug application or NDA.  Under the 1976 amendments, Congress identified transitional devices, meaning those devices previously regulated as new drugs into Class III requiring a pre-market approval application or PMA.

            The transitional provisions were designed to assure that devices formally considered as new drugs continued to be subject to appropriate regulatory controls.  The final regulation for this device was published on August 12, 1987 and classified tricalcium phosphate granules for dental bone repair into Class III as a transitional device.  The Agency has approved one PMA or pre-market notification application for Beta Tricalcium Phosphate.

            So how is tricalcium phosphate regulated in other branches in the Center for Devices and Radiological Health or CDRH?  In the Orthopedic and Restorative Branches within CDRH, tricalcium phosphate is an unclassified device.  For these branches, the regulatory history is different, in that tricalcium phosphate was not identified as a new drug at the time of the enactment of the Medical Device Amendments, and thus was not automatically classified into Class III as a transitional device.  The transitional list was specific for dental bone repair.

            The Orthopedic and Rehabilitation Panel met in January 1998 and recommended that calcium sulfate bone void filler be classified into Class II, and on February 7, 2002 a proposed rule was published in the Federal Register proposing to classify the resorbable calcium salt bone void filler device into Class II.  This included Beta Tricalcium Phosphate.

            Dr. Betz, who will present next, will provide a review of the petition and present a table outlining the risks and mitigations for your consideration.  Dr. Betz?

            DR. BETZ:  Good morning.  On November 12, 2002, Dr. Vincent Morgan submitted a petition for the reclassification of Beta Tricalcium Phosphate or Beta TCP.  A revision of this petition dated April 5, 2002 was reviewed by the Dental Branch of the Office of Device Evaluation.  On 9 December 2002, the FDA received a letter from Dr. Morgan requesting that the petition be modified.  The requested modification was to change the final classification of Beta TCP in the petition from unclassified to Class II.

            The petition contains 11 sections, including appendices.  Section I is the Specifications Section.  This section describes Beta TCP, identifying physical properties, such as formula weight density and melting point, as well as identifying its Chemical Abstract Service or CAS number as 7758-87-4.

            Section II is the Statement of Action.  This is Dr. Morgan's request to reclassify the Beta TCP.  Dr. Morgan's letter of December 9, 2002 modifies this request changing the final classification to Class II with special controls.

            Section III is an FDA Supplemental Data Sheet, FDA form 3247.  Dr. Morgan identified the indication for use as that of a bone substitute.  Risks identified included infection and pyrogenic response.  The information upon which the request for reclassification is based are that Beta TCP has been successfully used in medicine and dentistry for over 20 years, and that its properties are known to be beneficial when used as a bone substitute.

            Section IV is also Appendix II.  This section is the FDA General Device Classification Questionnaire or FDA form 3429.  This questionnaire was not updated to reflect Dr. Morgan's December 9, 2002 request for a change in final classification.  Therefore, there is an inconsistency between the letter and form 3429.  This afternoon you will be asked to complete this form as part of your discussion and deliberation.

            Section V is the Basis for Disagreement with the present classification.  It includes the following:  Beta TCP has been successfully marketed for over 20 years for dental purposes; Beta TCP is presently a Class III device for dental indications requiring a pre-market approval or PMA.  However, it has been cleared for market by pre-market notification or 510(k) when used for other purposes, such as orthopedic applications; and finally, no clinical adverse events have been reported.

            Section VI contains the Reasons for Reclassification, which were a reiteration of statements made in Section V.  Appendix III includes copies of published articles the petitioner submitted to support claims of safety and effectiveness for Beta TCP.

            In Section VII, the petition states that there are no known unfavorable clinical data.

            FDA has found in its databases only one reported adverse event related to calcium phosphate compounds.  When an unspecified calcium phosphate compound was injected into the vein of a pig, blood clots formed.  This is the only adverse event within our database.  In this report, a calcium phosphate compound was injected intravascularly rather than being placed in an intraosseous location.

            The FDA believes that this report has little or no relevance to the use of tricalcium phosphate in periodontal or craniofacial applications, especially when placed in humans.  Again, there have been no adverse events reported to FDA.

            Section VIII is a Summary of New Information, which is Appendix IV.  This information is from a Medline search of data three years old or less.

            In Section IX, Dr. Morgan indicated that there were no source documents to be submitted relevant to this petition.  Appendices III and IV contain information that would normally be included in the section.

            Section X was the Financial Certification/ Disclosure Statement, which stated that Dr. Morgan has not received any compensation for any clinical studies associated with the product.  He also stated that he will not have an equity interest in the product.

            Section XI contains the appendices, which were included and reviewed as Section III, IV, VI and VIII.

            To summarize, Beta Tricalcium Phosphate is a calcium phosphate salt that has the same intended uses and is similar to legally marketed dental bone void filler and grafting materials such as:  Plaster of Paris (like Capset); Hydroxyapatite (like Hapset); Ceramics (like Bio Oss Ceramic).  Beta TCP has been successfully used in orthopedic applications without reports of adverse events.  Beta TCP is presently unclassified for orthopedic and general restorative purposes.  It has been recommended for placement into Class II by the Orthopedics Device Panel.  Publication of the Final Federal Register Notice to this effect is pending.  We hoped that would be done by the Panel today so I didn't have to say that, but that's not true.

            Finally, Beta TCP has been cleared under 510(k) regulation for use in dentistry at concentrations less than 50 percent for quite some time, again without adverse events.  FDA frequently uses guidance documents to communicate to sponsors and the general public information that FDA believes is important in their review of 510(k) submissions.  The headings above, on the screen, represent section headings within guidance documents previously released by FDA.

            One of the sections of FDA's forthcoming bone void filler bone grafting material guidance document will be a table of risks encountered when bone void filling or bone grafting materials are placed in oral and craniofacial applications.  Because tricalcium phosphate bone void fillers are similar to other bone void fillers, presently cleared under 510(k) regulations, the risk table that FDA is asking you to review today may also be used within our forthcoming bone void filler or bone grafting material guidance document.

            This table of risks is proposed for you to discuss and consider in the decision making process to place Beta tricalcium phosphate into another classification.  Identifying these risks should help you determine whether general controls or special controls are needed to assure safe and effective use of tricalcium phosphates or whether they should remain in Class III.

            In your deliberation, please, feel free to add, delete and modify this risk table as you see fit.  Your recommendation, whatever it may be, should be based in part on this risk table.  The risks include, and this is a two part table:  Surgical risks; risks related to bone or soft tissue infections; adverse tissue reactions; problems associated with bone formation; failure to osseointegrate; problems associated with device migration or extrusion; and weakness in newly formed bone.

            On the right, you see the mitigations that we propose for you to consider also to mitigate these risks.  This entire table will be displayed in its entirety in one piece for your discussion.  Now, we get to the Panel questions.

            Does the petition, as filed, adequately describe the risks to health when using the device and provide appropriate controls for these risks?  If yes, you're supposed to proceed to Question 3.  If no, you proceed to Question 2.

            Question 2 is what modifications would you make to the risks to health presented by these devices?  The second part of Question 2 is what controls for these risks would you recommend to provide a reasonable assurance of safety and effectiveness?  And then you proceed onto 3.

            Question 3 is, please, complete the Classification Questionnaire and Supplemental Data Sheet for the device.  Completion of these forms will provide a formal recommendation for the reclassification of tricalcium phosphate granules for dental bone repair.  Again, 21 CFR 872.3930.  And then to Question 4.

            Question 4, given your recommended classification, what changes, if any, would you recommend be made to the labeling?  Your recommendations could include directions for use, indications for use and contraindications and anything else that you feel appropriate.  Thank you.

            CHAIR REKOW:  Does anyone have any questions for Dr. Betz before he sits down?

            DR. GLOWACKI:  I have a question for Dr. Mulry.

            CHAIR REKOW:  Or for Dr. Mulry.  Go ahead, please.

            DR. GLOWACKI:  Mr. Mulry, do I have control over turning this on?

            CHAIR REKOW:  No, I think it will take care of it.

            DR. GLOWACKI:  It will come on automatically?  Can you set the stage for the Panel's deliberation, because you've described the existing reg as including all calcium phosphates, and I heard you say for the support of dental implants and materials having the composition of 50 percent of TCP on one hand.  And then the petition on the other hand concerns Beta TCP for a specific application that is distinct from the current regs.  So can you set the stage on how we're to do the reclassification, because I thought I heard you say we're going to reclassify the whole thing for dental implants, supporting the dental implants and with the 50 percent, and that the application, the petition, is much more confined.

            DR. MULRY:  Okay.  Let me see if I can answer that.  First of all, let's look at the regulation, the current regulation 21 CFR 872.3930, which is entitled "Tricalcium Phosphate Granules for Dental Bone Repair."  It's identified and the definition is "A device intended to be implanted into the upper or lower jaw to provide support for prosthetic devices."

            This discussion today, as to whether it is reclassified from Class III to Class II, deals with the total regulation, and that regulation includes all forms of tricalcium phosphate, although, the petition is entitled "Reclassification of Beta Tricalcium Phosphate."  So what you'll need to decide is in the petition there is additional supporting information about other forms of tricalcium phosphate, besides Beta Tricalcium Phosphate.  What you need to decide today is is there sufficient information for you to make a recommendation to either have the whole regulation moved to Class II, meaning all forms of tricalcium phosphate, or whether you want to separate out Beta Tricalcium Phosphate alone to be reclassified into Class II.

            DR. GLOWACKI:  Does that also mean all physical forms like granules, blocks?

            DR. MULRY:  Yes.  It would include all forms of tricalcium phosphate.

            DR. GLOWACKI:  Okay. 

            DR. MULRY:  The other aspect of your question was about the Dental Branch's policy decision to regulate bone void fillers that are less than 50 percent Beta Tricalcium Phosphate as pre-market notification or they are unclassified and also reviewed under the 510(k) process.  And that was a policy in an administrative position that was made looking at whether combining tricalcium phosphate with other bone void fillers would present maybe different questions or would be more appropriately put in with the other bone void fillers, because this tricalcium phosphate has been separated out only because of its transitional device status.  All the other bone void fillers have been grouped together.

            So I think the policy decision related to looking at well, if it's less than 50 percent Beta Tricalcium Phosphate, then it may more appropriately have been regulated with all the rest of the bone void fillers.  And, Dr. Runner, you may have a comment on that.

            DR. RUNNER:  I don't know the history of why that happened, but it happened and we have multiple applications of products that have HA and Beta TCP in less than 50 percent concentration.

            DR. GLOWACKI:  My understanding is that those are biphasic materials not additives, not added in, manufactured in a way to render them biphasic, even a solid.

            DR. RUNNER:  I believe that's correct.

            DR. MULRY:  Yes.

            DR. GLOWACKI:  And I mean, that's very helpful.  This goes back to the slide that Dr. Betz showed about does the petition as filed describe the risks to the health?  So in one hand we're being asked questions that relate to the petition.

            DR. MULRY:  Yes.

            DR. GLOWACKI:  And yet we have to answer questions related to the reg.

            DR. MULRY:  Right.

            DR. GLOWACKI:  Am I understanding this correctly?

            DR. MULRY:  Yes, you are.  And I think in looking at reclassifying the total reg, as I said in my presentation, I think it needs to be remembered that if a form of tricalcium phosphate other than Beta Tricalcium Phosphate were to be submitted to the Agency, we would have the option of asking for data, supported data, to help us make a decision whether it is Class II or Class III.

            DR. BETZ:  I would also like to make a comment as a periodontist.  It would also include bone grafting materials, as well as bone void fillers, used in periodontal indications.

            DR. GLOWACKI:  Even though --

            DR. BETZ:  Craniofacial defects, periodontal defects and in general.

            DR. RUNNER:  Well, I think you're talking, you're discussion indications and we're talking about the regulation of the product itself.  Each individual application comes in with an indication for use, and then we are charged with looking at that indication to see if it requires additional clinical data, etcetera.  So the indications need to be --

            DR. GLOWACKI:  So just the title of the reg saying that it's for support.

            DR. RUNNER:  Right.

            DR. GLOWACKI:  Prosthetic devices.

            DR. MULRY:  Right.

            DR. GLOWACKI:  -- is not something that we take hard and fast.

            DR. RUNNER:  Right, exactly.

            DR. GLOWACKI:  We're talking about other indications?

            DR. RUNNER:  Correct.

            DR. MULRY:  It was a generic term or definition from 1976.  We're a little bit more sophisticated now, I hope.

            DR. GLOWACKI:  That's very helpful.  Thank you.

            CHAIR REKOW:  Because I was about to make the same mistake, we need to help for the people that are doing the transcription when we begin to speak, to identify who we are.  So this is Dr. Rekow.  And I have a question for Susan or either of you gentlemen.  Something that you said was the petition is the Beta TCP, we could talk about all TCPs.  Are we talking about all calcium salts of all genres?  Are we going to stick to the TCP?

            DR. MULRY:  No, specifically, TCP.

            CHAIR REKOW:  Okay.

            DR. MULRY:  This is regulation, because this was separated out as the only bone void filler in the dental arena that was regulated as a new drug prior to the 1976 amendments.

            CHAIR REKOW:  Right.

            DR. MULRY:  We need to limit this discussion today just to the regulation of tricalcium phosphate, as defined in the CFR.

            CHAIR REKOW:  Thank you.

            DR. MULRY:  You're welcome.

            CHAIR REKOW:  Are there other questions from the Panel?  Okay.  I believe we then go on to the presentation by the sponsors.  Dr. Morgan, are you taking responsibility?

            DR. MORGAN:  If you wish.

            CHAIR REKOW:  I suspect you probably are the best person to represent them.

            DR. MORGAN:  Well, I will define that.  My name is Vincent Morgan, and we brought this petition because we deemed the current classification to be an oversight of the Agency, and I believe logical scientific thought would agree with that process.  Because of the fact that it's just inconsistent to think that an orthopedic surgeon has the capability of placing tricalcium phosphate or a maxillofacial surgeon could not, to me, osteoblast and osteocyte, so the regulation is inconsistent with the reality of biology.

            So to that end, there's also evidence, historical evidence, that I shall not go into it, I spoke to Susan about, and that's my position.  Just to have you look at it as an oversight on the regulations.  Thomas Driskell is here to follow this discussion, who, in fact, is the person who developed this product in the 1970s and is the person who wrote initially a PMA and subsequently a 510(k) for the Miter Corporation, so he can speak to the history of it better than all of us.  And then Dr. John Long will be producing the product or has produced it and can address the scientific aspects of the chemistry.

            In addition to the financial statement, since you made this announcement public, I have been contacted by two parties.  One is representing a Dr. Lynch in Tennessee who wanted to be included in our presentation in support of this.  I declined.  The other I was contacted by the Curasan Corporation, a German corporation, and they wanted me to drop my petition or to consider dropping it, and if I were to drop this petition, they would offer me the sole distributorship of their product in the United States.  So I declined that, as well.  If there's any questions, I would be happy to answer.

            CHAIR REKOW:  Yes, Dr. Patters?

            DR. PATTERS:  Mark Patters.  Dr. Morgan, perhaps you could clear up a discrepancy here in my papers.  It lists you as president of Bicon, Incorporated.

            DR. MORGAN:  That's true.

            DR. PATTERS:  Somewhere else it says you have no financial interest in this product.

            DR. MORGAN:  That's true.

            DR. PATTERS:  Are both those statements correct?

            DR. MORGAN:  That's true.

            DR. PATTERS:  I think that requires some explanation.  How can you be the president of the company, but no financial interest?

            DR. MORGAN:  I think you'll find the question is do I have any equity interest in the company, and the answer is no.

            DR. PATTERS:  So you're just a paid employee of the company?

            DR. MORGAN:  True.

            DR. PATTERS:  Okay.  I would say that's a financial interest.

            DR. MORGAN:  I think the question was equity interest there.

            DR. PATTERS:  Thank you.

            DR. MORGAN:  I would be happy to tell you, I have no equity interest.  Equity is a shareholder.  You could be an employee of IBM and not own a share of it.  I do not own a share of Bicon, so to clarify that.

            DR. PATTERS:  I know.  But I'm asked as a Panel member do I have any financial interest that if your petition was granted, that I would benefit from.  That doesn't require that I be an equity holder.

            DR. MORGAN:  Well, I won't debate other than the fact that we answered the question as stated.  So if you want to know, I've so disclosed.  But I have no equity interest in Bicon.

            CHAIR REKOW:  Dr. Rekow again.  You are a paid employee and you stated that clearly.

            DR. MORGAN:  Yes, yes, I have no argument about that.

            CHAIR REKOW:  Okay.

            DR. BURTON:  Dr. Burton.  Does Bicon then intend -- because it's still sort of unclear.  I think what we're all getting at is what the benefit of doing this, but is Bicon then intending to market a product of this type?

            DR. MORGAN:  If it were, yes.

            DR. BURTON:  If it was reclassified, it would be offering a product.  And I guess the question that I would assume Dr. Patters was getting at that as president of the company, the product would have some -- whether you had an equity stake in the company or not, it would still  provide some financial incentive to you to have that approved and come to market in whatever classification.

            DR. MORGAN:  Oh, yes.  It would to Bicon.  But to me personally, I believe the question, I believe I answered it correctly, but if you want me to state that Bicon hopes to have an financial interest, absolutely, but I believe the question that was posed by the FDA is do I have an equity interest.  And I think a distinction was made on your behalf today that some of you represent other dental implant manufacturers, other dental implants, but for this particular product you don't.  So if you were to represent a competitor of Bicon in any fashion, I would also suggest to you that that's a conflict of interest.

            However, if you can distinguish between having representing or your school representing, you may not have an interest, but your school may receive a significant grant, as many do.  You don't receive it directly, but your department receives significant funding, then it may be in your best interest to vote against Bicon.  So the truth is the truth.  The question should be specific.

            DR. RUNNER:  I think that we've developed the answer to the question, so I don't think we need to continue.  You know that Dr. Morgan is financially enumerated by the company for which the product will be marketed.

            CHAIR REKOW:  Thank you.

            DR. MORGAN:  Thank you.

            CHAIR REKOW:  So, Mr. Driskell, you have a presentation, please?  And would you, please, sir, and the rest of you as you present, would you disclose whatever financial, if you have a financial, investment in the company just for clarity, please.

            MR. DRISKELL:  Okay.  I didn't want to show you any pictures particularly, so I don't need that.  My name is Tom Driskell.  I did invent this material back in the very early '70s.  Regarding my association with Bicon, I have no equity interest.  I have no salary from them.  I do receive a royalty, because they market products to which I've designed and have patents on, so I do get royalty from them, which I appreciate very much.  I'm not paid in any way for what I do.  It's just that when it goes on the market, if it makes money, maybe I make some money.  Then I appreciate that, because I'm supposed to be retired.

            I will make this very concise, but I will be happy to answer questions if you wish.  Materials oriented research ultimately leading to the development of calcium phosphate structural and void filling materials, bone implant materials I should say, began at Battelle Memorial Institute's Columbus Laboratories in 1968.  I was principal investigator of the project.  Disappointed with the results of earlier research and development of bio-inert ceramics, which the materials and coatings which began in 1967 stimulated this departure into bio-active materials development.  I think that was a new term at the time, but that's what they are is bio-active.

            In fact, I even came up with a term for it, so it's not osteogenic and it is osteoconductive, but it also will allow bone to grow beyond its normal bounds if you use it as an augmentation material.  So I came up with the term osteophilic, which bone likes it and it does.  In 1971, three high purity calcium phosphate compounds were selected for in vivo evaluation in rats and rabbits.  The three compounds were monocalcium phosphate, dicalcium phosphate and Beta Tricalcium Phosphate.

            Initial in vivo studies were conducted at the U.S. Army Institute of Dental Research at Walter Reed Army Medical Center.  Beta Tricalcium Phosphate proved to be the most promising compound.  It was found to demonstrate excellent bio-compatibility reserved resorbed while being displaced by rapid bone ingrowth and as was discovered later in our research could be sintered into a relatively strong structural form.

            Our original concept was to develop a resorbable bone porous block grafting material for use as a gap filler in large bony defects and a resorbable particulate form for smaller contained defects.  We were successful in developing these concepts in 1971.  In vivo research in various laboratories continued and the results have been presented and published over the years.  Coatings of these materials were applied to dental implants and successfully implanted in Rhesus monkeys in 1972.  There is a joke that goes along with that, but I'll dispense with it for now.

            These studies and subsequent work by Hubbard, Jarcho, Kay and numerous other researchers resulted in the development of additional variations of calcium phosphate materials and coatings.  The substance of this research is the foundation upon which the field of calcium phosphate materials technology and hydroxyapatite coatings has developed.  Thank you.  Any questions?

            CHAIR REKOW:  I suspect there will be some questions.

            MR. DRISKELL:  All right.

            CHAIR REKOW:  Do you want to stay for just a minute, please?

            DR. GLOWACKI:  I'm not a chemist, so forgive me if I don't ask the question, this is Dr. Glowacki, if I don't pose the question in the precise terms that you are used to.  We know that the Beta Tricalcium Phosphate, at least what we read in the books, is resorbable material and that the hydroxyapatites are dense ceramics with the different type of crystallinity and are far less resorbable.

            My question is whether there is control over the degree of resorption in the class that we're calling the Beta Tricalcium Phosphates?  What I understand is that after preparing the material that there's an amount of compression and sintering in order to make it into the granular form, small granules, large granules or blocks.  Do those processes give you a consistent rate of resorption an how dependent is the rate of resorption on compression and temperature of sintering?

            MR. DRISKELL:  Okay.  Well, I think it probably does have quite an effect.  The denser it is, the more material that's there.  It obviously is going to take longer to resorb.  The largest factor is quite possibly the particular proclivities of the patient.  For example, if you have a person that is not particularly hale or hearty, I hate to say it but post-menopausal women, people who have some sort of an ongoing illness or something that affects their health, the resorption would probably be slower.  That is one of the inconsistencies of it as you really are not sure how long it will take.

            But I can tell you that in a healthy patient, it heals pretty quickly, anywhere from within six months to a year.  And as the material does resorb, it is immediately replaced by bone in those areas, because actually osteocytic -- well, the osteocytes seem to osteoblast, I'm sorry.  Osteoclastic activity seems to be the major cause of resorption of the material.  And it is resorbed and broken down into calcium phosphorous, which is already in the body, which I think accounts for the lack of side effects.  It's a material that is basically already there.

            DR. GLOWACKI:  So there is patient to patient variability.  But let's talk about animal studies where there may be more consistency with respect to the recipient.

            MR. DRISKELL:  Yes.

            DR. GLOWACKI:  If you put material that came from one batch of preparation of a Beta Tricalcium Phosphate compared to another batch in similar types of animals, is there a wide range of resorbability on the basis of the manufacturing process?

            MR. DRISKELL:  Well, presuming that you have adequate controls over the manufacturer, there shouldn't be any appreciable differences.  Again, with the exception of the relative hale and heartiness of the critter that you're putting it in.  But really, you have to have a good manufacturing process.  It is not a simple material to make, and we have been very careful over the years in making it and being consistent in the process, because things like that can affect the resorption.  No doubt about it.

            DR. GLOWACKI:  And -- I'm sorry.

            MR. DRISKELL:  Well, as I say, it can vary from patient to patient.  But the thing to keep in mind is that the structural integrity is still there to a fair degree, because the bone actually does bond to the material.  It is not just a resorption as the material disappears the bone just fills in.  The bone has already bonded to it.  I have scanning electron microscopy that shows that very nicely.

            DR. GLOWACKI:  So with respect to the careful manufacturing steps then, are there tests that are done at the end of the manufacturing to say, you know, this is a batch that's going to have the same physical properties as the previous batch?

            MR. DRISKELL:  Well, actually, the way it is made pretty well controls what it is going to be.  And if you follow the parameters of how it should be made, of course the chemistry of it you can do with x-ray faction patterns and that sort of thing, but frankly over the years of personally making it, I never really found any discrepancy, because of the way that we ran the materials.  We sieve them.  And we have the same particulate size that's used all throughout the whole process.  So the variations in the manufacturing process are very, very slight, because we just are very careful with what we do.

            CHAIR REKOW:  Can I perhaps ask the question with a slightly different spin?

            MR. DRISKELL:  Okay. 

            CHAIR REKOW:  For a fixed manufacturing and sintering regime, can you give us some sense of the range and variation you would expect in the important parameters?

            MR. DRISKELL:  I think I'll let our chemist answer that.

            CHAIR REKOW:  Okay. 

            MR. DRISKELL:  I think that might be the person.

            CHAIR REKOW:  We'll put that question on hold.

            MR. DRISKELL:  If you don't mind?

            CHAIR REKOW:  No.

            DR. GLOWACKI:  That's fine.  I just wanted to give you, you know, coming from the questions, I can't quite picture in the manufacturing how you get granules of different sizes.

            MR. DRISKELL:  Oh.

            DR. GLOWACKI:  You applied just now that you just sort of pressed them and crushed them and sinter them, and then you sieve them to separate them.

            MR. DRISKELL:  Well, we do do that, and we sieve them so that we have a certain particle size, both plus and minus, so that we have a certain particulate that we use, and that is pretty consistent.

            DR. GLOWACKI:  Thank you.

            MR. DRISKELL:  So we don't have a problem with that.

            CHAIR REKOW:  Jon, did you have a question?  Jon first and then you David, please.

            DR. COCHRAN:  Okay. 

            DR. SUZUKI:  Okay.  Jon Suzuki, FDA Panel member.  You used the word osteophilic to describe and relate to your product.

            MR. DRISKELL:  Yes.

            DR. SUZUKI:  And could you just differentiate osteophilic versus osteoconductive and make that definition?

            MR. DRISKELL:  Well, the osteophilic materials are always osteoconductive, but osteoconductive is more of a passive term.  Osteophilic means that it seems to have -- by the way, we don't claim that.  But we have noticed and I'll give you an example.  In some of our orthopedic studies in earlier years, we put some block form material, this was porus block form, in the femurs of dogs and these were fairly large.  I can't remember the exact size, but they were probably 25 millimeters or 30 millimeters in length, maybe even longer than that come to think of it.

            But they stuck above the bone by 10 millimeters, and so only the lower part of that implant was actually implanted in a cut, a defect that was created in the bone, and we got bone all the way to the top.  So that's 10 millimeters beyond the normal bounds of a long bone.  So I think there is something in there, but it does not -- we do not claim anything as far as being osteogenic or anything.  I don't think it is.  But osteophilic it does seem to be from the standpoint that it will cause bone to grow into an area that it wouldn't normally be expected to grow into.  Now, whether that bone would stay over a long period of time, I doubt it, because there's no reason for it being there.  But it does grow in there.

            DR. SUZUKI:  Jon Suzuki again.  Just one follow-up question.  Then osteophilic to me, at least, implies there is no adverse reactions like immune rejection or anything like that, but you're not making that claim?

            MR. DRISKELL:  Well, actually, I have never seen any immune rejection.  Honestly, I have never known anything like that.  The only thing that we have ever seen was an occasional infection, and those are going to happen I don't care what you use, but that's all I can say.  That this never has any sort of an immune response or anything like that.

            CHAIR REKOW:  Dr. Cochran?

            DR. COCHRAN:  David Cochran.  My question centers around the indications for this material.  As you have alluded to, when you put in a bony site you see osteoclastic resorption, macrophage resorbate, but in many of the indications in the oral cavity that we use today, and especially the particulate material, sometime it gets fibrous and capsulated.  There's fibrous tissue that will encapsulate the particles.  Can you tell us how that might be resorbed and is that a slower process or how is that turned over?

            MR. DRISKELL:  It would be, but I would like to know precisely what you're talking about, because I know, for example, the hydroxyapatite that's not uncommon.  But if it is actually in contact with fresh bleeding bone, and you know, to a reasonable degree, I mean, I'm not sure I want to give you the total definition of that, but if it's just sitting on top of some abraded bone, it might or might not fill.  I do have histology, though, on say a ridge augmentation which has, as you know, become a very equivocal thing as to whether you really ought to do that.  But I can show you absolutely gorgeous bone in a year, and there's very little of the tricalcium phosphate left.  It's just solid bone.  So again, it has to be in contact with fresh bleeding bone to make it work.

            CHAIR REKOW:  Are there any other questions?  Thank you, sir.

            MR. DRISKELL:  You're welcome.

            CHAIR REKOW:  Dr. Long, would you, please, again identify yourself and your potential conflict of interest?

            DR. LONG:  My name is John Long.  I'm the director of technology at GFS Chemicals in Columbus, Ohio.  I have no equity, financial or other personal interest, other than as a supplier, of tricalcium phosphate to Bicon.  We are a private company.  We have been in the same location in Columbus since 1928.  We're in the third generation of family management.  The letters in the company name GFS come from the professor of analytical chemistry, who founded the company.  He was at the University of Illinois.  And over the years he developed many analytical reasons that his colleagues were interested in and eventually formed the company with his brothers, because he and his graduate students could not keep up with the bucks.

            We had specialized in high purity and materials for analytical markets over the years, branched off into some other things as well.  In the 1960s when the Apollo Program was in full force and NASA was looking for high purity acids to use in the analysis of lunar samples, our company was contacted to produce high purity perchloric acid for the digestion of those samples.  So we have a long history of working with very high purity materials.

            The Beta Tricalcium Phosphate is made in a dedicated room in our facility.  We've got about 15 buildings on our plant site in Columbus, Ohio.  Within one of those buildings there is a room dedicated to its production as well as dedicated equipment, ovens, various other parts of the operation are confined to that one room.  We are ISO-9000 certified, which means we have the traceability and accountability with our computer system to govern the batches of the material that are produced and to provide whatever information might be needed to look at vendor data, vendor lot information, our lot information, finished goods information, analytical information that are connected to a given batch.

            The material is qualified by a number of things.  It requires a very particular calcium phosphorous ratio that is governed in the manufacturing steps.  It also can be confirmed by analytical methods after it is made.  The primary analytical method is x-ray diffraction.  It allows you to determine that the proper phase, the Beta phase of tricalcium phosphate is present, usually to the exclusion of all other phases.  We have made this material a couple of times.

            We have been visited by a Cincinnati representative of the FDA, who came and discussed with us what our process was.  He looked at our facility.  He looked at our equipment.  And as we get into the further production of this material, he will be available to oversee its operation, so we have been in contact with a gentleman named Jeffrey Sincek at the Cincinnati Office of the EPA.  So we are in the position to produce this material in significant quantities and are pleased to be able to support Bicon in this petition.  I'll be happy to answer any questions that you might have.

            DR. GLOWACKI:  I'll ask you a question then.  This is Dr. Glowacki.  Good morning, Dr. Long.  Can you paint a picture then of the differences in the actual crystal structure as one varies the formulations?  I'm talking about making granules versus, can I use the word, casting a larger block with a particular shape?

            DR. LONG:  Sure.

            DR. GLOWACKI:  Does the casting or does the, I'm calling it compression, you'll give me the correct technical words, compression and sintering to make different forms of it give you materials with 100 percent similar x-ray diffractions or is there some modification due to the preparation of different forms?

            DR. LONG:  The x-ray part of diffraction defines the microscopic property of the material.  It's based upon the repeating array of unit cells in the solid.  This could occur with particles of various sizes.  It's not a function of particle size, but you do have to grind the material to get a powder to be able to do the x-ray effectively.  So if you have carried out your synthetic process properly, regardless of the number of times or the nature of the compression of the material, when you grind it to get the x-ray powder pattern, it will tell you whether you have the Beta phase or if you have mixed phases.

            It requires a very particular temperature in order to achieve the Beta phase.  If you miss that temperature, the x-ray will show you that you have impurities present and the product is not properly qualified.  This is done after all the processing, after the compression, after the grinding, so in that sense the x-ray testing is independent of all of that until you get it ground and you can put it on the machine and look at it.

            DR. GLOWACKI:  Thank you.  Now, with respect to the point about the rate of resorption, because people are always asking in journal articles and reviewing articles in presentations, you know, what about the rate of resorption?  In your view, does the rate of resorption in an animal model where there is consistency in the recipient tissue, are there differences in the rates that are due to casting the blocks or making or getting granules that have been ground up to greater or lesser degrees that can influence the rate of resorption because of something that can be measured, because of some physical property?

            DR. LONG:  My opinion, which is not necessarily an expert opinion in your area, but my opinion is that you're talking about a microscopic property, especially the ability of blood to flow through the microcrystalline structure of the material.  And do me, that is independent of most aspects of the processing that we do.  Once the material is cast and there is pressure applied, you produce a bulk material and you grind that material into the final form.

            Once you produce that material, you have created a microcrystalline property that is identifiable by x-ray in the Beta form, which according to what Mr. Driskell says in all the studies that have been done, allow this porosity, blood flow, this clinical action that enables it to perform as it does.  I don't see that variations leading up to the final step would significantly change the property of the material, as long as you fire it to the right temperature and get the Beta phase, that's the key aspect.  If you have different phases in there, the microcrystalline property is changed and it will effect the blood flow in the resorbability of the material.

            DR. GLOWACKI:  Thank you.

            CHAIR REKOW:  Okay. 

            DR. BURTON:  You spoke of your plant in Columbus.  Do you currently manufacture this product for other companies, other than Bicon?  You know, you said you had a dedicated facility for this.  I mean, it must be going somewhere.

            DR. LONG:  We have only manufactured this up to this time for Bicon.  We have had discussions with a couple of other companies about calcium phosphates of various types.  We are interested in the Beta phase and we have had contact with other companies about the Alpha phase and about hydroxyapatite.  To this point, we have not made any of those phases.  We have made no commitment with any other companies about any of those materials.  We have only made the Beta phase for Bicon.

            DR. BURTON:  Okay.  So we've mentioned the fact that there are dental products that contain less than 50 percent, and those are manufactured by some other companies then?

            DR. LONG:  To my knowledge, yes.  The material that we have produced has shown well over 95 percent Beta phase.  In fact, the x-ray that we have seen has shown no contamination.  It would lead me to believe it's 98 to 99 percent.  The more pure it is, the more efficient it is going to be in its function.

            DR. BURTON:  Yes.

            DR. LONG:  I think it would still function below 95 percent, but the specification will be a very, very clean x-ray.

            DR. BURTON:  Okay.

            CHAIR REKOW:  Jon?

            DR. SUZUKI:  Jon Suzuki, Panel member.  Just for my own edification, I'm not a chemist.  Can you just highlight the differences between Beta and the other forms of TCP?

            DR. LONG:  Okay.  Hydroxyapatite is not a strictly a calcium phosphate.  You're looking at a formula of CA3 PO4 taken twice for tricalcium phosphate.  The hydroxyapatite has hydroxyl groups on it, as the name applies, and it is not a pure phase, single phase TCP.  The Alpha and the Beta forms are distinguished simply by the difference in temperature to which they are taken in their final step.

            A few dozen degrees too high or too low in this step, you will not have pure Beta phase.  You will either have a mixture of Alpha and Beta or you could revert to Alpha, and that simply represents the three dimensional array in which all the phosphates and all the calciums align themselves.  They can be aligned in more than one way.  And the temperature allows you to fix the way in which all the elements that are present are aligned.  So that's the primary difference between the two is the temperature to which it is taken and its final sintering step.

            DR. SUZUKI:  Thank you.

            CHAIR REKOW:  Can I ask one more?  Dianne Rekow, I'm sorry.  Can I ask one more question?  You have some quality assurance specifications.  Can you give us some sense of the percentage of tolerance control you are able to get?  I don't think you need to disclose what you are measuring, but are you holding things to 1 percent, 20 percent, you know, 200 percent?  I'm being facetious clearly.

            DR. LONG:  We would be very comfortable talking about a percent purity in the high 90s.  Now, you're talking -- there's various ways of defining chemical purity.

            CHAIR REKOW:  Let me interrupt.

            DR. LONG:  Yes.

            CHAIR REKOW:  I'm asking more about any physical properties you might measure, rather than the purities.

            DR. LONG:  There are density specifications.  There is a particle science specification.  There is a calcium phosphorous ratio, which can be a specification, and that can be managed by careful blending of the starting materials.  Then there is the x-ray, which is the primary specification.  We use an independent laboratory to provide that information.

            CHAIR REKOW:  Okay. 

            DR. LONG:  The other testing we can do on site.  We do not have x-ray diffraction on our site, so we usually use the Ohio State facility in Columbus.  So there is a distinct set of parameters that are set up in our computer for qualifying the material.

            CHAIR REKOW:  Okay. 

            DR. LONG:  And we also qualify starting materials, as well.

            CHAIR REKOW:  Okay.  Susan?

            DR. RUNNER:  Just a comment that when we do get applications on these types of materials that is the sort of information that we request.

            CHAIR REKOW:  Okay.  Thanks.

            DR. GLOWACKI:  I have one question, too.

            CHAIR REKOW:  Yes?

            DR. GLOWACKI:  This is Dr. Glowacki.  Do you provide sterile product to Bicon?

            DR. LONG:  Which product, ma'am?

            DR. GLOWACKI:  Sterile.

            DR. LONG:  Sterile products, no.  At this point, the product that we provide was not sterile.  We can develop those capabilities if that turns out to be part of what Bicon would desire.  To this point, we have not.

            DR. GLOWACKI:  Thank you.

            CHAIR REKOW:  Thank you.

            DR. LONG:  Yes.

            CHAIR REKOW:  Are there other questions for any of the three company representatives?  I'm told that Dr. Morgan has to leave by noon, so perhaps we can continue if there's no more questions right this minute, but keep in mind that we have a time issue that we'll need to make sure that we pick his brain sufficiently before he disappears.

            Shall we take a five minute break, maybe six minutes?

            (Whereupon, at 10:38 a.m. off the record until 10:50 a.m.)

            CHAIR REKOW:  If we could, please, reconvene?  I understand that Dr. Boyan is unable to attend today.  She was going to make a presentation on behalf of the American Academy of Dental Research.  The next speaker who has agreed to provide some information is Dr. Mark Reynolds, who is speaking on behalf of the American Academy of Periodontology and I will let him introduce his academic credentials and his potential conflicts of interest.  Please, Mark, good morning.

            DR. REYNOLDS:  Good morning.  Thank you very much for this opportunity to address the Panel.  I am an associate professor and director of the Post-Doctoral Residency and Periodontist at the University of Maryland.  To my knowledge, I have no conflicts of interest or vested interest in Bicon or any other manufacturers related to this issue.

            On behalf of the American Academy of Periodontology, I would like to make several statements regarding the position of the academy with respect to this issue of reclassification.  Following this presentation, at the request of the Panel, the AAP will be delighted to provide additional and specific scientific documentation to support any of the points that I raise this morning.

            We speak in support of the reclassification of Beta Tricalcium Phosphate as a Class II device based on both scientific and clinical considerations.  Clearly there are numerous publications that document both the clinical effectiveness and safety of Beta TCP granules that we use as a bone substitute in periodontal applications.

            Moreover, there is emerging literature from outside the United States that continues to provide additional information on the safety and clinical efficacy in use of Beta Tricalcium Phosphate and other applications including sinus augmentation.  These observations and documentation coupled with similarities and clinical and safety profiles that have already been established for other legally marketed ceramic bone grafting materials argue strongly for reconsideration of the current classification of tricalcium phosphate.

            We feel that the reclassification of TCP should result in greater public access to this bone replacement material.  Although there are other materials such as allogeneic bone replacement grafts, there are considerations that limit their use and acceptance by the public.  Furthermore, the clinical characteristics of other alloplastic and grafting  materials also place limitations on the clinical indication and use within the community.

            Although Beta Tricalcium Phosphate shares similar physical and chemical characteristics and properties with other marketed dental grafting materials, we feel that the inherent properties, both handling and otherwise, may afford clinicians with a broader range of bone replacement materials for use in clinical practice.  It appears that in the axis of a 510(k) mechanism, cost-benefit considerations will continue to deter manufacturers from bringing this device to market, ultimately impairing practitioner and patient accessibility to this technology.

            Finally, there is increasing recognition that future advances and repair to medicine including periodontal and alveolar regeneration will require the adjunctive use of biologic mediators.  Beta Tricalcium Phosphate offers great potential as a graft material for the delivery of such adjunctive mediators.  These include platelet-rich plasma.  The adjunctive biologic mediator such as platelet-rich plasma are already cleared for market via 510(k), and as such the reclassification of TCP will recognize the current clinical practice and bring about a consistency in this regulation.  Thank you.

            CHAIR REKOW:  Does the Panel have any questions for Dr. Reynolds?  Yes, Elizabeth?

            MS. HOWE:  Elizabeth Howe, consumer representative.  I have a question about the comparison of using this product in orthopedic versus oral implication, and I'm wondering about the reference that it's soluble in mineral acids and how that would differ in using this product for oral implications?

            DR. REYNOLDS:  If I may ask, please, a question?

            MS. HOWE:  In using this product for oral use, the fact that it is soluble in mineral acids, would that be different because of infection in the mouth that might be present?  Is there some indication that we need to be aware of?

            DR. REYNOLDS:  If I understand your question correctly, would there be clinical characteristics of the wound orally that would make the material behave differently?  For example, the presence of acid secondary bacterial colonization?

            MS. HOWE:  Right.

            DR. REYNOLDS:  I would argue that there probably are instances in which oral wounds do differ from orthopedic applications.  However, all of these environments become contaminated in the surgical process.  What makes some applications, particularly periodontal applications, different is that we have a delay in closure of the wound.  However, there is a long history of use of bone replacement materials in that environment and almost, you know, uniformally meet with varying degrees of success.  So I don't know if that answers your question directly.

            MS. HOWE:  Would there be a concern then in closing the wound directives that would be given on problems for follow-up that they need to be aware of?

            DR. REYNOLDS:  I would anticipate that there would be no difference in clinical practice from use of any other bone replacement material, and those would include appropriate patient management and post-operative follow-up.  One should not, based on material, anticipate any difference in clinical behavior.  In fact, if anything, there is properties that might suggest that it may behave more favorably.

            MS. HOWE:  Thank you.

            DR. GLOWACKI:  This is Dr. Glowacki.  One of the comments in the orthopedic directives mentioned a voidance of its use, Beta TCP, in patients who have problems with calcium homeostasis.  Are you aware of any experience in the periodontal field using this material inside patients?  For example, what type of calcium malignancy or patients with renal diseases?

            DR. REYNOLDS:  No, I'm not.  If I might add, though, when we look at periodontal applications versus orthopedic indications, there are a considerable difference in the volumes of material that are used generally, and I would suspect that that would also be a consideration and concerns regarding that.  There may be potential issues in the patient populations.

            DR. GLOWACKI:  And you talked about your constituency use in periodontal and alveolar reconstruction, and it's my understanding that in the orthopedic applications use is restricted to metaphyseal defects.  In other words, not in cortical bone or bone that is really supporting structure.  But with respect to the alveolar ideas and possibly an association with dental implants, do you have an opinion about whether there is sufficient experience in the use of Beta TCP and periodontal disorders for construction of -- for replacement of cortical bone?  Let me put it that way.

            DR. REYNOLDS:  Excellent question, and I can only offer my opinion, and that is to say that I believe it will depend in large measure on the form of the TCP on its placement and whether other mechanisms are provided to stabilize and support the graft material.  Particular material tends to move and that's a dilemma that we're confronted with with, essentially, all the material, particularly bone replacement materials that we use in those types of applications.  But we don't have any in general indications that would require structural support.  More often than not it's all tissue support to the wound healing process.

            DR. GLOWACKI:  Thank you.

            CHAIR REKOW:  Mark?

            DR. PATTERS:  Mark Patters.  Dr. Reynolds, in your opinion, given the existing data, what indications do you think that this product should be labeled for in treatment of periodontal defects?

            DR. REYNOLDS:  Well, at this time, recognizing that there is variability in clinical outcome in this material, but others of similar characteristics, currently intrabonal defects, furcation defects, both associated with dentition and for bonal defects associated with implants and very likely there will be other augmentation as well as sinus augmentation.  There's very scant literature though currently on the latter applications, and so there's no reason that I would expect that the clinical outcome or histologic outcome would differ appreciably from the use of other ceramics.

            DR. PATTERS:  Do you believe that there is existing data to support the use of furcation defects?

            DR. REYNOLDS:  Point well taken.  I would argue that currently the literature suggests that there is no single modality that is appropriate for this successful management and predictable management furcations if we taken a spaced approach.  In fact, we probably should revisit a number of materials and approach it that way.

            DR. PATTERS:  Thank you.

            DR. BURTON:  Richard Burton.  Two questions.  You had said that, you know, reclassifying this product would expand.  My understanding was that there are some products of lower percentage on the market.  Is there not one that is currently a 3, but that are not marketed now?  Is that correct or not?  I mean, what's available right now in the periodontal area in terms of existing products?

            DR. REYNOLDS:  Well, in terms of alveolar?

            DR. BURTON:  No, of this particular material, the other one.

            DR. REYNOLDS:  To my knowledge right now, there is no currently marketed TCP.

            DR. BURTON:  Okay.

            DR. REYNOLDS:  A centigraph was available.  I believe that is no longer available in the United States.  Please, correct me if I'm wrong.

            DR. BURTON:  No, you alluded earlier that there was some things on the horizon as well.  I would assume you are planning that this would have the potential then to act as some kind of a scaffold.  You mentioned PRP as one alternative, but also obviously plans looking at potentially BMP as a delivery system for that as well.

            DR. REYNOLDS:  I would say yes.  I did not mention I served frequently as a reviewer on OPM II and on Reparative Study Section, an area of keen interest.  Clearly, the use of biologic mediators will be in our future and are here now to one extent.  Scaffolding remains the one frontier, too, that we need to address.  So opportunities to identify material that might need specific clinical indications are extremely important.

            DR. BURTON:  Yes, thank you.

            CHAIR REKOW:  This is Dianne Rekow again.  I'm assuming you people of the FDA, please, confirm or correct me, that we're talking about this in its pure form not in its mixture with all the primordial soup options, right?  We're not talking about the BMPs and the gross factors and the various other stuff that could be added?

            DR. RUNNER:  That's correct.  Any addition of those types of factors would push that into a PMA Class III type of device.

            CHAIR REKOW:  I share your enthusiasm for that, but I just want to be clear that what we're addressing here is simply the material as a material.

            DR. REYNOLDS:  Yes.

            DR. RUNNER:  And I also wanted to make the comment that there were a lot of specific questions from the Panel about the manufacturing of this particular company of the product.  You should be thinking of it as a broad reclassification not of the specific company.

            CHAIR REKOW:  Thank you.  Are there any other questions for Dr. Reynolds?

            DR. REYNOLDS:  Thank you very much.

            CHAIR REKOW:  Thank you.  Both Dr. Gunter Uhr and Dr. Thomas Arrowsmith-Lowe from Curasan, if that's not the proper pronunciation, I'm sorry, are here.  How would you gentlemen like to proceed, and would you, please, identify yourselves and your interests?

            DR. UHR:  Thank you.  Thank you very much.

            CHAIR REKOW:  Can you use the microphone, please, because it needs to be public information?

            DR. UHR:  Okay.  Thank you.

            CHAIR REKOW:  We need as a society to come up with some comfortable segway from getting computers up and running.  You know, there's got to be something we have to learn to do to take care of that pause.

            DR. UHR:  Okay.  Thank you for the possibility that I'm here, and that I have you to give me the chance to make a small presentation.  My person, I'm Gunter Uhr from the Curasan.  I'm the head of the Clinic of Research, and the Curasan also purchased the PMA from Miter and intended to bring the product here in America on the market.

            My intention is to show you that we not agree with reclassification from III to Class II.  Why?  You see on the left side is the skeleton.  You'll see the skull, and what I intend to show is that we have two bones.  Bone is not bone.  And bone and wound healing of the skull differ from those in the skeletal system.  This concerns the histogenesis.  This concerns the function and the healing process.  And the etiology of maxillofacial defects is also different.

            And to take an inference on the wound healing, for example, and therefore we need material which has a special feature.  We need a material that's as pure, that means more than 99 percent, and you must have a special shape of the material, the granule form, the size and the porosity, because all these four features will affect safety and the effectiveness.

            Now, I structured this presentation in two parts.  One part is a biological one and the second is material.  Now, at first to the histogenesis.  The skull we have an intramembranous bone formation.  What does it mean?  We have small cells, that's this one, this aggregate, the mesenchymal stem cells, you know, and they differ into osteoblast and they form at different location simultaneously bone.  That's typical for the skull, especially, you see here the child at nine weeks, and you see the maxillar mandibula and the frontal bone is formed at nine weeks.

            The blue color it's cartilage.  This is typical for the skull.  The next bone is enchondral bone formation, and this is a typical bone formation for the skeleton.  And what is the difference?  Here the green color it's cartilage, and cartilage is replaced to bone, and this is here shown.  And what is the function?  Both bone types have different function.  Here the skeleton has to carry the load, has to bear the weight, and the function probably here of the mandible or the maxilla is to carry this, and the load is periodically, not continuously.  And also, the bone quality is different.  The modeling, for example, you have a higher remodeling rate in this skeleton system than here in the skull.

            Now, we come to the etiology of the bone defects, and most of the bone defects in the skeleton have a systemic origin.  There are no contaminations with microorganisms, bacteria, viruses, and each orthopedic surgeon fears the bacteria invasion.  Then you got problems in bone.  If you have a bacteria invasion, you know, the osteomyelitis.  This occurs in long bones.  What is the situation, the region of the mouth?

            Now, we are speaking about, you know, the periodontosis.  The periodontosis is a chronicle infection with bacteria.  It's a completely different situation.  And, for example, the apicoectomy, you get an invasion of bacterial through the root canal in the apex.  Here we have an invasion with bacteria.  The next point, filling of tooth sockets.  You extract the tooth not just for fun.  And it burns when you have an invasion there of bacteria, and also if you make a sinus for elevation or augmentation, lateral or horizontal augmentation, you are working in the field of contamination with bacteria and microorganisms.  And also, in large defects, for example, in tumors.  If you have contact with vestibulum, you have the problem of the infection.

            And now, we look at the time frame.  This infection also has an effect on the time of healing.  Here we have typical defects, for example, in long bone.  We take this from the hand, because here we have comparable volumes to defects in the mouth region.  Here we have a broken finger.  You see the surgery.  You see the osteosynthesis, microplate to stabilize the bone, and you see here the Beta Tricalcium Phosphate.  It's completely resolved at six months.  It's a marvelous result.

            Here below, that's the young girl.  Of course, we have influences on bone regeneration.  You know the age is important, also if their system make diseases.  But here, we see it was a horse bite.  The joint was destroyed.  And the surgeon made a chiroplasty and filled it with Cerasorb.  You see at two and a half months you take a biopsy to look what has happened in the defect.  And this is a biopsy, and we can enlarge it, and what you see is that the Cerasorb, the granules were totally disappeared.  They are dissolved.  And we have a very smooth, smooth transition from the cartilage here, the joint to the bone.  If you use a higher magnification, you will see some rests here of Cerasorb, but only some rests.  Cerasorb is the better TCP.

            Now, what will happen in our maxillofacial region and the dental region?  Here we have the Beta TCP in the sinus for elevation situation.  And what you see is, at first, we have separated the regeneration phase into -- we have separated the regeneration into four phases.  The first phase is the stability of the bone regeneration material during the acute inflammatory reaction.  That's the first phase in wound healing, and it's very important.  Just a minute ago here there was a question about the acidity, the pH and I will speak a little bit later and come to this point.  It's very important for the material.

            The next point is, at first, we have the fibrin network, coming from blood, and this fibrin network is replaced by the collagenous fibers network and then at about three months, here at this side, the woven bone formation begins into the inter-granular spaces, and at about six or eight months here, we have the transition of the maturation into lamellar bone at eight months.  And finally, we need 12 to 24 months for the remodeling, the remodeling starts and the total appears in the material.  This is longer than in long bones.

            Now, we go into detail.  What happened?  What has occurred in the wound?  Probably have a broken bone here.  What you see is that's the bone line, the osteoblast.  We have at the broken side, we have to relieve the growth factors, BMPs, for example.  We have the clotted blood vessels here in the bone marrow.  Now, the space here is filled with blood and you put in some granules, Beta TCP granules.  The activation of platelets occurs immediately.  They release growth factors, and then we see here the fibrin network and the cell tied, but first which come in from the clotted blood vessel, this is the granule side.  Here clears the region, but at 12 to 48 hours, they will disappear.  They will disappear, but will be phagocytized.  They make their drop and then they disappear.

            And now the next cell come on the plan and this is a macrophage.  And a macrophage is as a central role in this period.  It organizes the whole wound healing process.  The macrophage and we have seen, here on the top, we had a pH of 4 to 6 until the fibroblast formed the collagenous fibrin network.  They replace the fibrin network, and then the blood vessels move in.  And this is a point that the pH now goes to a normal physiological level of 7.4.

            But here we have two important functions concentrated in the macrophage, and the macrophage will attack, at first, now that's a biological principle, you know.  At first the antigen, the bacteria, they will clean the region.  Also they phagocytize the microorganisms, and they do it together with the T lymphocytes.  And when this process comes to an end, then the regeneration begins.

            So if there is a stimulation for the macrophages, the phase of defense will extend, and they phagocytize not only the bacteria, but they phagocytize everything which is smaller than 10 H to 10 microns.  So if you have a material here, the Beta TCP granules, which are not stable and they disintegrate, you know, we have an acid situation.  And if this acid situation links to disintegration of a particle, then this particle below 10 microns will phagocytize by the macrophages.  And it comes to a shrinkage of the defect, of the filling of the defect.

            CHAIR REKOW:  Can I interrupt for just one second, please?

            DR. UHR:  Yes.

            CHAIR REKOW:  These are fascinating slides.  There's no question about it, but I need to remind you that almost everyone in this Panel is a clinician and trained in dentistry and bone regeneration, so maybe we could have a slightly shorter version of some of the basic concepts.

            DR. UHR:  Okay. 

            CHAIR REKOW:  I don't want you to miss your main points, by any stretch of the imagination.

            DR. UHR:  Okay. 

            CHAIR REKOW:  Thank you.

            DR. UHR:  Now, to the material, and the material, here we have four features, which are necessary, which are very important.  It's purity, the shape, the size and the porosity.  This effects the safety and effectiveness.  Now, a very important point is that the Beta Tricalcium Phosphate in Europe was on the market since 1970, and we see here some publications, also here from the U.S.  And this material disappeared in 1980, roundabout in the '80s, from the market, because no one wants to use any more the Beta TCP.

            Why?  They got here from Holland published that Beta TCP disintegrates very rapidly into particles that can be found in the neighboring lymph nodes.  And that means the end for this product.  And then this guy here, this Dr. Heide, he was convinced that Beta TCP is a good material.  But he says it is good if it is pure and is pure higher than 99 percent.  And here we have a lot of publications which show that this material works.

            Now, I will show you what happens in the body if you have an impure material.  It's a competitive material in Germany.  It comes on the market and it disappears very rapidly, because you see here it corrects, it's covered by am impure phase and it is very instable material.  And if you test or will test -- if a material is, I'm looking for it, suitable for the defect to use it, you can move it between your fingers.  And if you use this granule and move between your fingers, and you put it back, and you blow, you have no abrasion, and also you can also eat them, because there is just like to drink a glass of milk.

            But we go back to impure material and I can show you what will happen.  These are all immunohistological figures and this is a result.  And what you see is after 11 months, you'll see the persistence of lymphoid cells together with macrophages.  And you will see like stars in the night sky, you'll see the small particles of this Beta TCP distributed in the tissue.  And up to now, there is no regeneration of material of bone.

            So to sum up, impurities impair the results and process.  Impurities less resorbable than Beta TCP.  These particles migrate to lymph nodes, De Groot.  Especially, we have talked also about the Alpha TCP, and it is know that Alpha TCP converts into hydroxyapatite in the biological system.  And the impurity is more soluble than Beta TCP.  You have retarded bone formation.

            Now, important for the material is the size, the size and the micro-porosity.  Here we see the movie and the spherical shape is important, because you need the intragranular spaces.  We have spoken about osteoconductivity.  You need the intragranular spaces for the invasion of blood vessels.  And additionally, the spherical size is necessary.  Most of these indications where you can use this material in dental field is to fill the sinus.  You have to push the Schneider's membrane.  Then you have to put these granules below.  If you have a material which is broken and has edges, there is a danger to hurt this membrane.  Especially, if you use the Summers method.

            The next point, you need a well-defined micro-porous structure, because we don't -- we also need the movement of blood vessels and fibrins.  It's a street for the cells.  The first streets and highways for the cells into the granule.  And so we have a porosity of 1 to 20 microns, and it's a lower limit for small blood vessels are, you know, 5 microns.

            The next point is you need a product which is very strong sintered.  With this table, you'll see here the cubic sugar.  This will happen with a material, which is not stable.  And you will get particles which will be phagocytized.  What you need is a solvent from the surface, a continuous solvent from the surface, and this prevents the particle decomposition and genus solubility, we call it halisteresis.  And there is no degradation by osteoblast that came there, and the question is the degradation by the osteoblast plausible?

            We know that for the degradation of osteoblast you need two informations.  We need the bio-contact with osteoblast and we need the membrane of the osteoblast, we need bio-receptors information from the bone matrix proteins.  So in a acidic material we never have this information.

            And finally, this granule is built up of particles, of primary particles, and these have a size of 50 percent larger than 10 microns, that's another point.  So I want to summary it.  Bone and wound healing, I think, I have shown it in a very short time, so it differs.  We have a different histogenesis.  We have a different function.  We have a different healing process.  And the etiology of the maxillofacial defects differs from the skeletal defects.

            Therefore, you need a material which -- and this is a point, the human body sets the limits not the material, and therefore we need a purity, a shape, a size and a special porosity.  Thank you.  That's the end.

            CHAIR REKOW:  Thank you.  Are there questions for Dr. Uhr?  Yes, Mark?

            DR. PATTERS:  Mark Patters.  Dr. Uhr, it's a very pretty presentation, but what I didn't get from it was why you oppose the petition?  The petition says nothing about purity, only reclassification of not just their product, but all tricalcium phosphates that are intended for use in oral cavity, so why do you oppose that?

            DR. UHR:  As a purity.

            DR. PATTERS:  The petition, as I read it, does not address purity.

            DR. UHR:  Yes, but may I explain why it is important that you have such a high purity?  For example, these granules consist of primary particles, batch primary particles and during a sintering process, these particles are recrystallized, and you get -- between these particles you get sintering next that means from both primary particles the crystals move to each other, they bridge, and the impureness, for example, hydroxyapatite, for example, calcium phosphate, other phosphates move in front.

            Now, this material gets contact.  At this bridge you have the impureness, and if it is more soluble, the material breaks down.  Especially in the acid condition, in the acute inflammatory reaction.  And then there's a possibility that these particles below 10 are phagocytized by the macrophage.  Then you will stimulate the new reaction.

            DR. PATTERS:  Now, I understand that, but the purity issue can be covered in the guidance document with special controls if this is reclassified.  Are you saying that highly purified Beta TCPs should be reclassified, but impure ones should not be?

            DR. UHR:  Yes, I think it's -- so I'm a scientist.  I would say the purer the material is, if you have a high pure material, it is -- whether it is to control, you want to control the purity.  Of course you can make batch controls.  You can make batch controls with diffracture meters, yes?

            DR. PATTERS:  Maybe the FDA process is not completely clear to you.  I've been on the panel for more than 10 years and it's not completely clear to me.  But my understanding, however, is that the guidance documents and the special controls can deal with issues of purity.  What we're looking at, the Panel is being asked to look at a much more generic issue.

            CHAIR REKOW:  Thank you.  Dr. Arrowsmith?

            DR. ARROWSMITH-LOWE:  Yes, I think I'll be addressing more of the regulatory aspect of this.

            DR. UHR:  Yes, okay.

            CHAIR REKOW:  Could you introduce yourself, please?

            DR. ARROWSMITH-LOWE:  Yes, I'm Tom Arrowsmith-Lowe.  I'm a regulatory consultant, Curasan AG is one of my clients.  I am compensated by Curasan AG for consulting services that I provide to them, including my presentation.  I am a retired FDAer.  I'm a retired public health service captain and served in the FDA until my retirement.  I was a deputy office director in the Center for Devices and was director of the Human Tissue Program in the Center for Biologics prior to my retirement from the Agency, and hopefully I can work this.

            CHAIR REKOW:  Just for the record, Dr. Uhr, I'm sure, will have some more questions for you, but perhaps we can finish the other presentations and then combine them.

            DR. ARROWSMITH-LOWE:  As has previously been stated Curasan AG is speaking in opposition to the proposal to reclassify Beta TCP from Class III to Class II.  As we reviewed the reclassification petition it distilled down essentially in making two points.  One that there was no difference between skeletal and maxillofacial bone, essentially saying that the use is the same whether it is used maxillofacially a Beta TCP for an implant or whether it is used in skeletal bone, and the second point being that there were no reported problems.

            We would like to respond to those two statements.  Dr. Uhr has fairly clearly shown that there are some differences between the two bones, that bone is not just bone, that there is a difference between skeletal bone and maxillofacial bone.  He has pointed out that the origin of the bones, the histogenesis of the two types of bones is different.  He has also shown a difference in function with the maxillofacial bone existing for support of the dentition for use in mastication and other uses speaking as well, and has also shown in that that the pressures that are generated in the function of the two different types of bone are different as well.  That there's a different function, one being for skeletal musculoskeletal support and the other for support of dentition.

            And has then also shown that there is a difference between the stresses that are applied to the two bones with periodic stresses being the case for the bone that is supported of dentition with much more constant stresses being applied to the musculoskeletal system bone.  In addition, he pointed out that there is a difference in the healing process between the two bones when Beta TCP is used for treatment of a defect, that the post-operative healing process is a longer process in the maxillofacial bone than the process that occurs in long bone.

            As well, he has also pointed out a difference in the etiology of the bony defects in the two types of bones, pointing out that principally the main etiology for defects that develop in musculoskeletal bone tend to be defects that are systemic defects.  Whereas, the main etiology for defects that occur in the bone supporting the dentition is primarily of an infectious origin.

            And so we do support the idea that there really are differences between the two bones.  There are differences not only in how those bones function, but also differences in their origin and differences in the etiology of the defects that occur in those bones.  So I think the point can be made that we really can't say that bone is bone in this case.  That there are differences that are easily demonstrated here.

            In addition to that, the second point that was made in the petition is a point about, essentially, there have been no problems reported.  One of the points that Dr. Uhr mentioned having to do with the growth article that was published in the 1980s was that there actually was a product removal that occurred and Beta TCP was unavailable for a period of approximately 10 years for dental use in Europe, and that really primarily related to the fact that the TCP that was being marketed initially in the 1970s had problems of purity that very definitely effected the safety and effectiveness of that product.  And so the clinical community stopped purchasing the product, and the product, essentially, was removed from the market by the manufacturer of that product.  Dr. --

            CHAIR REKOW:  Could I --

            DR. ARROWSMITH-LOWE:  Yes.

            CHAIR REKOW:  Oh, I'm sorry.  Actually, I'll wait.

            DR. ARROWSMITH-LOWE:  Okay. 

            CHAIR REKOW:  Sorry.

            DR. ARROWSMITH-LOWE:  Dr. Uhr also talked about other issues that we feel are fairly essential parts of making a determination of safety and effectiveness.  That variations in the purity of the product, variations in porosity and particle shape and in particle size can very definitely have an effect on the product itself and make that product less safe and less effective.  This is an issue that is of concern to us, and we feel it should be a concern to the Panel and to the clinical community as well.

            Because it is our feeling that the most appropriate way to try to make an assessment that a product truly is safe and effective and to include in that determination of safety and effectiveness is looking at how purity, porosity, particle shape and particle size actually affect the performance of that product in a clinical setting.  So actual review of data as opposed to just making a comparison between two products, looking at physical properties, such as purity, porosity, particle shape and particle size.

            And so our recommendation is against reclassification as I have already said, and for reasons that we feel that the petition has not adequately established those two primary points about the similarity of bone being bone, and the point that the product actually has had no problems associated with it throughout its period of use.  And so as I said, we're recommending against reclassification.  If, however, reclassification were to occur, we would like to make two recommendations to the Panel and to the Agency about how they would make a determination of substantial equivalence using a 510(k) process.

            One, we feel that a predicate product, to which substantial equivalence would need to be established, has to be a current generation Beta TCP.  A purer product than the sort of product that was initially manufactured back at the point when the first PMA was cleared for Beta TCP.  As was mentioned, Curasan AG now is the owner of the original PMA and, as the Panel may be aware, there is a submission that has come in from Curasan AG, a supplement, to that original PMA to, essentially, change the product into a form that is a purer product form that addresses issues having to do with the size of the particles and also with porosity and with particle shape as well.

            And so we feel that to have an adequate determination of substantial equivalence if the 510(k) process is used, that there really must be a comparison made and a determination that the product that has submitted to pre-market notification does favorably compare with the current generation of Beta TCP when looking at a product or particle size, particle porosity, looking at particle shape and looking at the overall purity of the product.  And we feel that if the 510(k) process were applied, that it would need to include a determination of substantial equivalence looking at these factors.  Thank you.

            CHAIR REKOW:  Thank you.  Dr. Patters, does that answer your question or would you like to restate it?

            DR. PATTERS:  Well, Mark Patters.  My understanding is then that you feel that this product should come to market through the PMA route, and you already have a PMA, which I was unaware.  I think the Panel is not aware.

            DR. ARROWSMITH-LOWE:  Okay. 

            DR. PATTERS:  As you thought they were.  We're not.

            DR. ARROWSMITH-LOWE:  Oh, okay.  I thought the Panel was aware.  Yes, we feel that --

            DR. PATTERS:  PMAs are a closely guarded secret, I believe, by FDA and they do not share that.

            DR. ARROWSMITH-LOWE:  Well, we feel that the PMA process provides a better opportunity for making a determination of the safety and effectiveness of the product, rather than just making a comparison with a predicate product.  One of the things that we want to make certain of is that given the advancement of this product over the last several decades, and given the improvement in clinical utility and the decrease in incidences with the purer product and with a product that addresses some of the other issues as well, that we do have a level of safety now and a level of product effectiveness.

            That is really a standard with the newer Beta TCP.  And it would be a concern that we would have that using a comparison method in establishing substantial equivalent might not necessarily provide sufficient information to really make a determination that this implantable product really is safe and effective.

            DR. PATTERS:  So if I could summarize then what I understand you to be saying is you do not believe that, at the present time, there is adequate data in the literature to support reclassification?  And you believe that new clinical trials and new -- not just clinical trials, but new data need to be presented?

            DR. ARROWSMITH-LOWE:  Well, I believe that the presentation of new data would go toward establishing safety and effectiveness of any new product that would come on the market, as opposed to just merely doing a comparison to a predicate product, yes.

            DR. PATTERS:  Thank you.

            CHAIR REKOW:  Dr. Cochran?

            DR. COCHRAN:  David Cochran.  You mentioned four different aspects:  The purity,  porosity, shape and size, and you are implying that one would receive one set of outcomes in testing if you reach some point.  Say purity was 99 percent, I think you mentioned, but maybe at 96 percent it would not.  In other words, for each of these issues, these four issues, that you've mentioned here, you are implying that there is data to say that there is going to be a difference in performance at some cutoff value.  Can you provide any data that would suggest that that's true?

            DR. ARROWSMITH-LOWE:  Well, part of the reason some of the data, the basic science data, that was presented already goes to establishing the significance of determining each of those.

            DR. COCHRAN:  Well, that was one study or publication.

            DR. ARROWSMITH-LOWE:  Well, no.  Actually, the De Groot study basically was looking at what was wrong, why the product was, essentially, not being an effective product, and the dental community turned against the use of the product.  And principally, that was really looking at only one of these issues, looking at the purity issue.  Because what was determined was that when you had purities that were, say only at a 95 or 96 percent range, that you were going to get a change in the healing process.

            What we've further found beyond that was some of the work that Dr. Uhr was talking about is the presence of impurities also can effect particle size, because the success of the sintering, which brings the impurities to the surface when two of the primary particles join in the sintering process, because the impurities are brought to the surface through the heating process, the point of juncture actually is the point of impurity between those two primary particles, and that increases the likelihood of that particle, primary particles, that have been sintered and joined of those breaking apart.

            Then what is more likely to happen when you have those smaller particles is that you are going to get a greater likelihood of having a response on the part of the body that the macrophages will come in and will consume the smaller particles and you are actually going to have a slowing of the overall healing process, because you are having particle disintegration occurring more rapidly.

            DR. COCHRAN:  Yes, but what I'm asking for is do you have data that says that 96 is not good, but 98 is good or you think 99 is good?  I mean, if you're going to make this recommendation, it would be nice to see data that suggests that there is a cutoff area.

            DR. ARROWSMITH-LOWE:  Yes.

            DR. COCHRAN:  Or that one is better or not.  Otherwise, we're doing the same thing, because the Panel has got to make decisions as to what it would recommend.

            DR. ARROWSMITH-LOWE:  Right.

            DR. COCHRAN:  Without the data to support it, it's tough for us to do that.

            DR. UHR:  Sorry, I can answer.  We, in our company, tested -- our company tested not for its own, but we test the material.  We give it to a nurturer institute, another university, sorry, and there we tested the material.  And so you can see in a different meter whether there is impure or not impureness.

            CHAIR REKOW:  Has that been published yet?

            DR. UHR:  It will be published, yes, but not by us, of course.

            CHAIR REKOW:  Yes.

            DR. UHR:  It's not in press, but it will come soon.  Another point is we have publications, especially also of Alpha TCP, that's a material which converts probably into hydroxyapatite and you can see it in the animal model.  You can see in the lymph nodes the particles, the hydroxyapatite.  And I think it is not the target to use a material which normally it has to be solved and it should be replaced totally by bone.  So we will not find any particles anywhere.  This should be the target.

            CHAIR REKOW:  Yes, Dr. Burton?

            DR. BURTON:  Richard Burton.  Does your company represent currently market a competing product or is this product that you have now currently marketed?

            DR. ARROWSMITH-LOWE:  Curasan AG markets Beta TCP in Europe and markets Beta TCP in the United States for orthopedic, for non-dental use in the United States.  As I also mentioned, they are the holder of what was originally Miter's PMA and have intentions if the --

            DR. BURTON:  And I assume then it's under that PMA without a reclassification they could market it?

            DR. ARROWSMITH-LOWE:  They could basically market under that PMA the product that was described in the original PMA.

            DR. BURTON:  Which was inferior product.

            DR. ARROWSMITH-LOWE:  Which is a product that does not meet Miter standards of production, yes.

            DR. BURTON:  Okay.

            CHAIR REKOW:  Jon?

            DR. SUZUKI:  Jon Suzuki, Panel member.  Just this is a question to Dr. Gunter Uhr.

            DR. UHR:  Yes.

            DR. SUZUKI:  It's a point and then a question.  First, you mentioned that neutrophilic PMM leukocytes both disappear from the scene and that's not exactly true.  They are always indeciduous and connected, even in the subsequent stages of wound healing, so just for the point.

            DR. UHR:  I'm sorry.  I didn't understand you.  Speak a little louder.

            DR. SUZUKI:  The PMM neutrophilic leukocytes --

            DR. UHR:  Okay, yes, yes.  Okay. 

            DR. SUZUKI:  -- appear and that's not exactly correct, to my knowledge, but that's a minor point.  The question really deals with macrophage and your indication that they begin to engulf particles of 10 microns or less.  Are you indicating that this is harmful because of a potential foreign body reaction or are you saying that the macrophage is interfered with in terms of their molecular quarterbacking?

            DR. UHR:  I think you have to look what they are phagocytized, of course.  But the phagocytosis process is a stimulation of the activity of the macrophage.  And we know that the activated macrophage released growth factors or signals proteins to attract more and more macrophages into the region.  They leave the peripheral blood vessels, yes.  So you get a higher concentration of macrophages.  You ultimately activate more and more the acute inflammation reaction.

            But of course, if they phagocytize the material, which is resorbable in the user zones, it will disappear.  But if it is an impure material, hydroxyapatite, it will not be resorbable.  So on the market now it's the tendency, you know, no particles for a bone regeneration material, and these particles, of course, are phagocytized by the macrophages, but there is no chance, because these particles is hydroxyapatite.

            DR. SUZUKI:  Jon Suzuki again.  Just a follow-up question.  Sir, the macrophage is then when they begin the phagocytosis of the particles that are 10 microns or less.  They are impeded in their "regulation."  Is that what you are implying?

            DR. UHR:  Yes.

            DR. SUZUKI:  Or if you're not familiar with the macrophage, they are sometimes considered the field generals or the sponsor or the host.

            DR. UHR:  Yes, yes.

            DR. SUZUKI:  And sometimes referred to as the quarterback.

            DR. UHR:  Yes.

            DR. SUZUKI:  And where they came from.

            DR. UHR:  Okay, right.

            DR. SUZUKI:  So this is impeding?

            DR. UHR:  Yes.

            DR. ARROWSMITH-LOWE:  And in addition to that, you are having a loss of material as well, and so instead of the material being able to do its initial function, if the particle size is too small, then it is not able to do its intended use, because the particles are phagocytized by the macrophages and you are actually losing some of the material that would have been maintained as a part of the graft for the reparative process.  And so there's the downside of it not being able to actually meet its intended use, because the particle size being somewhat say below 8 microns actually.

            DR. UHR:  And the other point is you extend the phase of low pH.

            DR. ARROWSMITH-LOWE:  Right.

            DR. UHR:  And we know Beta Tricalcium Phosphate dissolved very quickly in a low pH in an acid environment.

            DR. SUZUKI:  Jon Suzuki.  And you also indicated that some of these particles are seen histopathologically in sites in the lymphoid tissue of lymph glands.

            DR. UHR:  Yes.

            DR. SUZUKI:  It's not the macrophages that have carried this product, but it is rather the lymphoid cells.  Is that my understanding?

            DR. UHR:  No, no, the macrophages runs part of it.

            DR. SUZUKI:  And what are the lymphoid cells doing there?

            DR. UHR:  The T lymphocytes, for example, they stimulate the fever of the fiber, and the fever is the temperature, yes, and they release interleukines, for example, you know, to attract the interleukines.  Probably they are transported to the liver, yes.  You know, they induce release of factors.  You know it, certainly, there is an interconnection between the T lymphocytes and the macrophage.

            DR. SUZUKI:  One last question, Madam Chair.  The T lymphocytes that you just mentioned are frequently associated with a delayed hypersensitivity or allergic type or rejection reactions.  Are you suggesting that that might be a parameter, too, that we need to consider?

            DR. UHR:  I think so, so that's in the histological figure.  At 11 weeks, we see a reaction to this small particles distributed in still connective tissue.  It's not a bone formation there, yes, and at this time, the women have a bone regeneration.  That's the point.

            CHAIR REKOW:  Daniel?

            MR. SCHECHTER:  Dan Schechter.  Taking for argument's sake that all of the biological information you have given is true and that these various factors are important to the product and to the safety and effectiveness of the product, these parameters could be spelled out in special controls in a Class II product, and my question is are you saying that the parameters are not known in the literature, and the only way that an application could be properly reviewed would be with data, since there is nothing to compare it to, as I suppose your company has done, or is it that it just needs to be spelled out, because it's known?  The purity is known.  The particle size that is needed is known in the literature that we, as a Panel, could recommend it be put into special controls, because then you are not just comparing to another product, you're comparing to a standard, but that can be done with a reclassification?

            DR. ARROWSMITH-LOWE:  No, that's exactly right.  It could be done with a reclassification, and so what -- that's why the final slide was there, that if the reclassification occurs, you know, we feel that it's absolutely essential that those parameters be assessed as a part of a determination of substantial equivalents.  There is a good bit that is known, at least a good bit based on work that has been done either in Curasan AG or by independent researches that Curasan AG has been collaborating with to make a determination about what is an acceptable level of purity.

            And, you know, I have to say that the acceptable level of purity that Curasan supports is a higher acceptable level of purity than the ASTM standard, for instance, on this, and that really is based upon the clinical performance of the product, the fact that you can actually see histologically that you have a better healing process when you have far fewer impurities, and the same holds true for the other aspects that we're talking about, as well.  For particle shape, that you can see actual clinical negative occurrences that can happen from particle shape.

            In addition, particle shape may prevent having intragranular spaces that really are sufficient for blood vessel introduction, you know, from a standpoint of porosity, that the healing process is going to proceed more appropriately, because the porosity provides the opportunity for adequate fiber and attachment, and then that's a pathway that is subsequently used through the healing process and, ultimately, to the point of creation of new bone there.

            And so each of these actually does have what we feel is some fairly high significance and yes, one of the ways of approaching that would be to use a special control to develop a mandatory standard and just say that, you know, adherence to this mandatory standard is going to be something that would be required of any product that is regulated, the Beta TCP product, if it were regulated as a Class II.

            CHAIR REKOW:  Just as a point of clarification, Dianne Rekow again, I would like a simple yes or no if it's possible.  Is --

            DR. ARROWSMITH-LOWE:  I worked at FDA too long.

            CHAIR REKOW:  Yes.

            DR. ARROWSMITH-LOWE:  So there is never a simple yes or no.

            CHAIR REKOW:  Is it your belief that there is scientific data to support upper and lower thresholds for each of those four parameters that you specified, the purity, the particle size, the particle shape and --

            DR. ARROWSMITH-LOWE:  Yes, particle shape and porosity.

            CHAIR REKOW:  Porosity, yes, I'm sorry.

            DR. ARROWSMITH-LOWE:  Yes.

            CHAIR REKOW:  Okay.  Thank you.

            DR. ARROWSMITH-LOWE:  That was an easy one.

            CHAIR REKOW:  Susan, did you have --

            DR. PATTERS:  But is that data available?

            CHAIR REKOW:  Yes, is that in the open literature?  Is that within the company study?

            DR. ARROWSMITH-LOWE:  Well, some of it is within the company.  Some of it is published European literature.  All of that we would be able to make available.

            CHAIR REKOW:  Okay.  Susan?

            DR. RUNNER:  But my question for that is is that, those limits, the standard of care, is that accepted in the clinical community or is that something that is proprietary to Curasan and you would be making the standard yourself, as opposed to out in the broad literature?  Is it something that FDA or the Panel could recommend or is this just your opinion based on your product and the clinical data you have?

            DR. ARROWSMITH-LOWE:  It's the latter.

            CHAIR REKOW:  I have one other question, if I may, David, before -- I have heard each of you refer to the fact that historical material was withdrawn from the marketplace.  I don't need to know all the details.  I am just curious if it was removed because of market pressures or if it was removed from requirements from any of the regulatory agencies.

            DR. ARROWSMITH-LOWE:  It was based on market pressures.  It essentially was a response to the fact that the product was not performing effectively.  Clinically, it was not performing.

            CHAIR REKOW:  Clinicians were not happy, so the market --

            DR. ARROWSMITH-LOWE:  The clinicians were not happy and so it ceased to be purchased, and was ultimately removed from the market.

            CHAIR REKOW:  Okay.  That's an important point, I think.  Dr. Cochran?

            DR. COCHRAN:  David Cochran.  I guess my question is a little bit of follow-up the same way.  I mean, with any parameters for a product, there is going to be a range, and clearly it's in the interest of any company to produce the best product they can, and I think, you know, the Panel needs to consider that as a Panel making a recommendation when we think of controls, certainly we're going to probably make recommendations or when we do, that it's some sort of range, but we don't think ever an intention is that a company is going to come out with a product that's not something that's going to be effective.  Otherwise, it's a little silly.

            CHAIR REKOW:  Dr. Burton?

            DR. BURTON:  Richard Burton.  Just to carry on to that, was the product that was removed from the market the license that you now own?

            DR. ARROWSMITH-LOWE:  No.

            DR. BURTON:  So it was a different product than the one that you have purchased the license to?

            DR. ARROWSMITH-LOWE:  Yes, that's correct.

            DR. UHR:  We have, may I say, some additional information to that.  Curasan was the first on the market in Europe with a pure Beta Tricalcium Phosphate, and then other companies recognized this as a very successful material, so they tried to imitate it, and they go with the material on the market as a CE certificated product, and then it disappears and you can wait two, three or probably yes, one year, and they have the result.  And, you know, one dentist to try a material and he has a bad result, he will not use this material anymore, and so we have no negative publication or a publication about negative results.  It's a problem.  That material comes on the market.  It is tested and the human being is the model, and then it disappears.  This is the way.

            CHAIR REKOW:  Yes.

            DR. ARROWSMITH-LOWE:  And I think a part of what we're saying, if I may follow-up on that, is that in the European situation, the competing company is able to introduce a less pure product given the regulatory situation that exists there in Europe, and what then subsequently happens is the performance --

            CHAIR REKOW:  Right.

            DR. ARROWSMITH-LOWE:  The effectiveness of that product is not up to the standard that has been set by Curasan's product, and so the product ceases to be purchased and to be implanted and to be used, and it eventually leaves the market.

            CHAIR REKOW:  Good five-year market share.  That way, they will gain.  I'm teasing.

            DR. GLOWACKI:  This is Julie Glowacki.  I want to ask the question, Dr. Arrowsmith, in just a slightly different way, but I think it will be a yes or no answer.  To any degree, has your opinion been informed by an analysis of the guidance document that was generated out of the orthopedic proposal to reclassify it to Class II?

            DR. ARROWSMITH-LOWE:  Yes.  Actually, I have read the document.  I have had discussions with people in that branch and they let me know when the document was forthcoming, because again, Curasan has a product that was cleared from market through the 510(k) process for orthopedic use, so we have been interacting also with the Orthopedic Branch, and so we were made aware of this previously, yes.

            DR. GLOWACKI:  So you're saying that these four terms should really just be highlighted in that, being to a greater degree than it is?  I haven't reread it since your presentation.

            DR. ARROWSMITH-LOWE:  Yes.

            DR. GLOWACKI:  But to be sure that those four parameters as far as --

            DR. ARROWSMITH-LOWE:  Exactly, and we really do support the idea of the central nature of assessing those four parameters and, you know, as Mr. Schechter pointed out, that can be done in several ways.  We think probably the most appropriate way is through establishing the safety and effectiveness, but if there were a reclassification, then the use of a special control and mandatory standard would be another way of trying to achieve that, as well.

            DR. GLOWACKI:  Thank you very much.

            CHAIR REKOW:  Dr. Cochran?

            DR. COCHRAN:  I'm a little naive about the European products over there, but I understand that Ceros is another product.  Is that a product that you would say is the current type TCP standard or the old type standard?

            DR. UHR:  No, sorry.  I know the Ceros.  We also studied this product, and this material has no inter-connective porosity.

            DR. COCHRAN:  Which means what?

            DR. UHR:  Which means you put this material into the defect, and there is only from the surface the solvent, but there is no ingrowth into a granule.  It's not possible.  It just bubbles, yes, which make the porosity, but it's not inter-connective, but we need an inter-connective porosity that is lodged, invades into the granule, and afterwards --

            DR. COCHRAN:  What is the purity of that?

            DR. UHR:  It's not larger than 99.  It's smaller, and there is an impure phase in it.

            DR. ARROWSMITH-LOWE:  If I may just follow-up on that.  The role of the micro-porosity is really for fibrin attachment, and it forms a pathway that ultimately, fibroblast can follow the pathway and there can be an establishment of connective tissue, and it helps maintain the integrity of the implant itself.  Whereas, if you have something without adequate micro-porosity, you're going to have a decreased opportunity for fibrin attachment.

            DR. COCHRAN:  The reason I raise that question is that we were provided documentation from a published manuscript that indicated that that product was used, and there didn't seem to be any outstanding problems with that material.

            DR. ARROWSMITH-LOWE:  Well, some of that may have to do with the method of assessment of how they made a determination of problems or effectiveness.  I think we would think it appropriate to be looking at healing time, to be looking at any possible other negative things that might occur from differences in the product.  And, again, to me that sort of argues for the whole option of doing some clinical evaluation, rather than just strictly making a determination on what are more physical factors.

            CHAIR REKOW:  We have a published schedule for the open hearing, and we're getting close to the end of that time.  Perhaps I could ask if there are any other groups in the audience that would like to make a public presentation.

            DR. UHR:  Thank you.

            CHAIR REKOW:  And then I would like to have options for questions to be asked to any of the people.  Are there any other groups that would like to say anything?  Okay.  Failing to hear that, does the Panel have any questions for any of the people that have presented or any of the experts that you know are in the audience?  Mark?

            DR. PATTERS:  Mark Patters.  I would like to give the petitioners just a couple of minutes to respond to Curasan's presentation, if that's appropriate, Madam Chair.

            CHAIR REKOW:  I think it is.  Thank you.

            DR. MORGAN:  Having heard their presentation, the logic escapes me.  The history is the following.  Thomas Driskell is the person who developed the product under a U.S. Department of Defense grant, and was the owner of the Miter that initially sold this product.  May I discuss the issue, the PMA?  May I?

            CHAIR REKOW:  Go ahead.

            DR. MORGAN:  The PMA that they so state that they have, and that the FDA recognizes that they have, is not, in fact, reality.  The history, and Thomas Driskell could give it to us, is the following, that he initiated a PMA.

            CHAIR REKOW:  Can I interrupt for one second?  It will be fascinating, I'm sure, to hear that, but unless it addresses some important scientific issues --

            DR. MORGAN:  Okay.

            CHAIR REKOW:  I think that unless the FDA is anxious to have it in the public record, I'm not sure that it helps us with our decision.

            DR. MORGAN:  Okay.  Then I can bypass that.

            CHAIR REKOW:  Thank you.

            DR. MORGAN:  Then if what they are saying, they purchased the Miter PMA, that it was marketed in the United States for over 20 years without a single dental device report, which is true, so this product has been continuously marketed until they purchased it, I believe, last year.  Why would they purchase it?  It is already on the market in the United States.  Now, they are bringing it back to Germany and claiming that that product, which they claim the FDA recognizes as a PMA, is going to be modified to their standards.  No American company has the opportunity of conforming to their standards without a PMA.  Am I making sense?

            CHAIR REKOW:  So the point that you're making is that, from a scientific perspective, if I may, and, please, correct me if I'm wrong, is that a less than a 100 percent pure Beta TCP has been successfully used in dental products in the United States for over 20 years?

            DR. MORGAN:  Over 20 years.

            CHAIR REKOW:  Without an adverse --

            DR. MORGAN:  Without a single adverse report.

            CHAIR REKOW:  Without a single adverse report.

            DR. MORGAN:  And personally, I have used it.

            CHAIR REKOW:  Right.  And so yours becomes a counter argument to the need for higher purity.  Is that --

            DR. MORGAN:  Well, I'm not adverse to higher purity.

            CHAIR REKOW:  No.

            DR. MORGAN:  And I don't --

            CHAIR REKOW:  But you're arguing that the lower purity has been able to perform successfully in the market?

            DR. MORGAN:  No, because I don't think you or I know --

            CHAIR REKOW:  Okay. 

            DR. MORGAN:  -- the exact purity of Miter or their claim.

            CHAIR REKOW:  Fair point.

            DR. MORGAN:  So we don't know what the purity is.  I could state Miter is 100 percent pure.

            CHAIR REKOW:  Yes.

            DR. MORGAN:  I could state the product is going to -- you know, we don't know.

            CHAIR REKOW:  Okay.

            DR. MORGAN:  So I think there was a lot of smoke and mirrors, but logic escapes me.

            CHAIR REKOW:  Well, I think that there is a lot of business issues that are critical for each of your companies to succeed, but I don't think that this is the forum to have this discussion.

            DR. MORGAN:  I agree, I agree.

            CHAIR REKOW:  Okay.  Thank you.

            DR. MORGAN:  But if the argument is that the bone of the skull is different elsewhere, and if you accept that argument, then I would suggest the FDA as a unit should go back to their medical counterparts, their orthopedic counterparts, and restrict the use of that product by any plastic surgeon or orthopedic surgeon.  That's the argument.  I don't accept the argument that the bone of the skull is different than the bone elsewhere.  I'm sorry.  I just don't accept it, and if you do accept it, then the Orthopedic Branch should restrict the use of all their approved products to only non-skulls.

            CHAIR REKOW:  Clearly, the progenitors are different.

            DR. MORGAN:  Oh, yes.

            CHAIR REKOW:  The issue is whether or not the mature bone is different from immature bone.

            DR. MORGAN:  Which is true, yes.

            CHAIR REKOW:  Okay.

            DR. MORGAN:  I agree with that.  So without any questions or --

            CHAIR REKOW:  So are there questions for any of the Panel, any of the presenters, any of the groups?  Would anyone else from the audience like to make any comments or statements?  I appreciate all of what you have done.  I applaud Dr. Uhr for the most remarkable slides we have seen for awhile, and surely a lot of useful and valuable information has been conveyed this morning.  I thank you for your time and the considerable energy that went into all of these presentations and the thoughtfulness, and your helpfulness in providing questions to us.  I guess now, we break for lunch and the Panel discussions will resume around 1:15.  Thank you again.

            (Whereupon, the hearing was recessed at 12:09 p.m. to reconvene at 1:25 p.m. this same day.)




          A-F-T-E-R-N-O-O-N S-E-S-S-I-O-N

                                         1:25 p.m.

            CHAIR REKOW:  We will begin with Jon Suzuki.  First, Dr. Suzuki, are you going to do it from here or there?

            DR. SUZUKI:  It doesn't matter.

            CHAIR REKOW:  Wherever you would like, sir, it's yours.

            DR. SUZUKI:  Jon Suzuki.  I will try to address the Panel's questions succinctly, and then we can have a discussion later on if necessary.  The Panel questions are not on the board anymore.  They are not on the board anymore.  Does the petition, as found, adequately describe the risk to the health of the device, and provide appropriate controls to these risks?  I believe the answer to this question is no, and other guidelines that may need to be spelled out, especially indications, including matters to OP and including the possible degradation of the product.  And with respect to appropriate controls for these risks, perhaps the indications and the reeducation of the clinician needs to be at least identified more specifically.

            And on Question 2, what modifications would you make to the risk to the health presented by the device with respective modifications and controls perhaps identifying that the risk of infection needs to be identified, and especially the sterility of the product and its use in infected sites needs to be further elaborated, especially in periodontal sites where the infection would be different than that of skeletal bone sites.

            With respect to the controls, we're looking at the form, the shape, the size and other parameters I think need to be further identified and defined, and that probably is going to be left up to other FDA Panel members and other FDA investigations to determine what that threshold is, a maximum and a minimum control for the regulation of these particular products.

            We will skip the part of classification questionnaire, but we'll spend more time on that later, Madam Chairman, I'm assuming, so I'll go onto Question 4.  With respect to recommended classification and changes and, especially recommend to the labeling of these devices once again to reiterate the importance of considering infections and the possible acidity of the site, as a role in the degradation and/or signed-ability of the product, and also the potential risk of infections if it's not already included on the existing labels needs to be identified.  And that concludes my initial rhetoric, and Dr. Glowacki has some follow-up comments, too.

            DR. GLOWACKI:  Yes.  This is Julie Glowacki, and my comments come from the point of view of not being a clinician, so I'm actually going to be asking the other Panels for some clinical input down the line.  But with respect to whether the petition, Question 1, adequately describes the risk to health of the device and appropriate controls for this, I view it as the petition was filed to do one thing.  However, we are here as a Panel that is voting on a reclassification of the current rule, which includes other materials, other indications.

            So the petition does not address the issues of the classification, but I think gives me a way of looking at how much information is available for us to feel that there are some materials within the current rule that do not pose a Class III, a continuation of a Class III.

            And so with respect to the description of the device being one of the major issues here, that I think I will be feeling comfortable on the basis of the information that we're given and, moreover, solely on the petition that Beta TCP is really what we ought to be reclassifying, and to that end, a more precise description of the device needs to be provided, and that concerns a composition, the form, is it granular, is it in blocks, is it a single phase?

            I think we have not been given enough information to say that biphasic materials perform with the same degree of fidelity with respect to efficacy as does pure Beta TCP.  I think we can talk about some of the standards that are out there with respect to elemental analysis, x-ray diffraction, provide the information about the nature of the material.

            I think we needed more clarity than what was in the petition for the intended use or indications, and I would feel more comfortable talking about intraosseous applications of this material.  I think the orthopedic literature, as well as what the experience has been in oro-periodontal maxillofacial uses of these types of materials is that it cannot be implied that the material is providing the physical properties of cortical bone, so that stability needs to be an issue.  And I think one doesn't want to give the clinicians the impression that you can use this in discontinuity defects.

            So I am just talking about some of the applications that everybody is comfortable with, and I think it's primarily intraosseous.  We were provided some information about untoward results if the material is inserted into an endosseous defect simultaneously with an endosseous implant, and that that seems to be something to be avoided, that there is literature recommending that Beta TCP be used first to promote bone formation and subsequent insertion of a dental device.

            I think all of these things with respect to intended use, indications and precautions against potentially very damaging misuse need to be put into guidance documents.  I would hope that there would be a precaution against the use in infected sites, that there would be a precaution against overfilling or use in discontinuity defects and information provided to the clinician about how to remove excess.

            One can imagine a situation where the cortical bone structure might be very, very weak and if someone were very, very aggressive in implanting this material, there could be potential fractures to thin walls of bone.

            With respect to whether the material we're considering is in granular or block form, again, looking at the orthopedic guidance document as a guide here, there ought to be information provided to the clinician on whether the block can be cut or trimmed or reshaped or made smaller to fit into a disk, into a particular defect.

            Some of the other materials that are out there are very, very brittle, provide lots of debris that is very difficult to get rid of, and I think that information ought to be in the clinician's insert.   Precaution against concurrent use with implants, information about the suitability to mix this material with other materials, I think, ought to be provided.  This material's potency as an osteoconductive material is in large measure due to its rate of resorption, and if it's mixed with other materials that interfere with that, I would think that that would be a potential problem.  So adding mixtures I would worry about.

            Some people, I understand, are using Beta TCP or have used it as kind of hamburger helper, mixed with autogenous bone graft inadequate to fill in the material, so we think we need to see some information about whether that would be an indication.

            Let's see.  Oh, I think also because of some of the adverse information that we saw on what happens when this material gets into the bloodstream, one would want to be sure that there were precautions to avoid soft tissue nerves, pulp and, again, this idea of overfilling the material with the potential of it getting into the bloodstream.  I think those are things that are different in the oral dental application than in orthopedic.

            I think that it should be possible, just sort of jumping ahead, that talking about the risks, which were not really that adequately dealt with, I think, in the petition, the risk of causing an infection or using the material in an infected or previously infected site has to be addressed.

            In general, I feel that we may, by the end of the day, consider that Beta TCP is -- there is enough information about its use and the properties that contribute to its successful use and to its safety, so that it could be reclassified in Class II with some special controls.

            And one other thing, back to the question about the clinical input.  I would really like to hear the clinicians' views about who should be able to put this material into people.  Is this something that a dental degree would give enough still to be able to follow those instructions and to use it safely?  Does advanced training come into the use of this at all?

            CHAIR REKOW:  Is that all?

            DR. GLOWACKI:  That's all.

            CHAIR REKOW:  Well, let's have some conversation and discussion.  It seems to me, if I can put this into some categories, the questions that are the most compelling and may form the basis for the conversation is do we look at the form that the material is presented?  Is it block?  Is it granules?  Is it both?  Are we looking at all the TCPs?  Are we looking at only the Beta TCP?  What is a list of precautions and indications, and then what is the level of training to be able to utilize it.

            Is that a fair basis to form the conversation around?  Before I start driving any conversation thought, are there questions and issues that you would like to address?  Would some of the clinicians like to address some of the questions that Julie addressed?

            DR. PATTERS:  Mark Patters.  Let me say that I don't recall ever being at another Panel meeting that had such a dearth of scientific data to try to make a decision with.  As far as I'm concerned, most of the papers that were provided in the petition are case reports and uncontrolled studies.  So there is really not a lot of scientific data to even say that this material is safe and effective.

            However, I would say that clinicians generally regard it as safe, but I don't know that it has been definitively proven as safe through carefully controlled clinical trials, so I regard it as safe.  There have not been, as we have heard before, adverse reactions reported from the use of this material.  On the other hand, I don't believe the material is widely used enough to be able to gauge what adverse reactions might occur.  So I don't see that we have a lot of data here to help us.  It's just that, as a clinician, it seems that this material is regarded as safe, but I have not seen any data demonstrating it.

            DR. GLOWACKI:  I, too, was disappointed by it.  Ms. Glowacki again.  I was disappointed by the papers that were provided in the petition, but I did take an opportunity to go onto PubMed and look up my own references on this, and found that sure, you know, there are a couple of small studies there that could give this material versus other materials or that use this material for other studies, adding in platelet-rich plasma or as a carrier for Beta TCP.

            And with respect to the evidence-based practice of medicine, I think Dr. Patters makes a very important point.  Yet, the general level of experience, and I think I am understanding him correctly, is that safety and efficacy can be defined.  Do you disagree with that?

            DR. PATTERS:  In general or for this product?

            DR. GLOWACKI:  For Beta TCP.

            DR. PATTERS:  That can be defined, yes, I agree, but the question is have they been?

            DR. GLOWACKI:  Yes.

            CHAIR REKOW:  David?

            DR. COCHRAN:  I have used this product myself clinically or not this particular, but a TCP product.  We have used it in different clinical applications.  We have used a lot of other different kinds of bone graft fillers, if you will, or bone replacement grafts, BRGs is what we tend to call them, and I feel like, Mark, that probably there is a lot of experience over many years with this material and similar type materials that I don't think we need to worry so much about the safety of this material in humans for human use, and so I would agree that, from a clinical point of view, it can be a useful material.

            We have used it not only intraosseously, but as on-lay type materials with flat coverage with periosteum and flat mucoperiosteal flaps over it, and there certainly does not seem to be any adverse reactions.  Histologically, we really don't see that either.  Clinically, we don't see that as a problem.  We have gone back and placed endosseous implants in this type of material, and have really not had any problems with the osseointegration around the implants.  So I see it from a safe point of view as not a problem.

            CHAIR REKOW:  This is Dianne Rekow.  You're talking about the granular form, right, not the block form or are you?

            DR. COCHRAN:  As regards to the TCP, it's granular form that we have had experience with.

            CHAIR REKOW:  Okay.  David?  Richard?  Sorry.

            DR. BURTON:  I would agree.  I think that the safety issue is sort of one side of it, but I am not sure that when I look at this, and certainly in the case study format that we have here though, that some of the efficacy has been really established.  I mean, I think we have sort of lumped them together, but in reality, they need to be separated, as well.  I think everybody says well, gee, this is really, you know, it's a good product.  It's not going to hurt anybody.  It doesn't seem to do anything terrible.  It doesn't fall out.  It doesn't have marked adverse reactions.

            The real question is also that there is some question of efficacy in terms of being a reasonable product for that, and then I think it goes back, what was mentioned earlier also, is going to be the clinical indications for this, because my experience has been that once you get a material out there, people end up sticking it just about anyplace you can think of to put it, and then again whether or not we know now that this particular material needs a certain amount of either bony contact, you mentioned continuity defects.

            Sinus lift situations, we all know, have very poor vascular supplies to those, and does it have a sufficient vascular supply to such that it's also conductive prostheses and actually functions?  So, I mean, I think that yes, I would certainly agree that the safety probably has been established.  I just have some questions regarding what its efficacy is and then how that translates into what clinical applications it's appropriate for, given the information we have, at this point in time.

            It might be, that later on, that those clinical indications might be expanded once there was further usage and research with it once it was in clinical applications, but I'm not sure that that's been really defined in anything that I see that has been presented thus far.

            CHAIR REKOW:  Jon, do you want to -- Elizabeth?

            MS. HOWE:  Elizabeth Howe.  I would just like to make an appeal on behalf of consumer issues, and make one statement that it is certainly exciting to have products that are more accessible, certainly a lot cheaper, which would encourage patients to seek treatment, less invasive, a lot less risk, a lot less recovery time.

            But given all of that excitement for such a product, some of the concerns would be having a standard of quality that patients can be assured that they are getting a quality product, certification for the person that is providing that treatment to know that it's being handled properly and finally, any contraindications for patients who have special needs because of a disease process, if it could be, I think somebody mentioned, somebody who is post-menopausal, if there are any studies on at what point this product is not appropriate for certain patients.

            CHAIR REKOW:  Do you have anything you would like to add, Dan?

            MR. SCHECHTER:  I guess from an industry standpoint where, as a whole, we're always interested in the least amount of obstacles and burdens to bring a product to market, so generally we would always be in favor of a lower classification, going from III to II.  And I guess from a practical standpoint, this is almost a question for FDA, Susan, perhaps.

            Given that the general feeling is that there is kind of a dearth of scientific evidence here that we can base maybe specific recommendations on, would it be appropriate for the Panel to, in general, reclassify, recommend that special controls for certain parameters exist and then leave it up to FDA to state those more specifically?  I'm just asking the question.  If we can kind of defer some of the specific issues or is that issue for a further Panel meeting, which I wouldn't advocate as an industry rep?

            DR. RUNNER:  You could certainly.  We take all of your comments during the Panel process into consideration when we're developing the guidance documents, any labeling recommendations, any contraindications and warnings.  So you wouldn't necessarily have to vote on each and every contraindication and warning, but give us a general feeling as to what you feel would be appropriate areas for us to address and any guidance or labeling for this product.  Does that answer your question?

            MR. SCHECHTER:  Yes, definitely.  That is what I was hoping the answer was, because it doesn't seem like we're going to get to the point where, you know, we can say here that it's got to be 97 percent or you can't have more than .5 percent Alpha, etcetera.  So, you know, I would encourage the Panel to go as far as we can with whatever the Panel is comfortable with.

            CHAIR REKOW:  I want to remind everyone, too, that we can engage the people from the audience that have presented, so if questions come up that can be clarified by them, we have the opportunity of calling on them.  Yes, Susan?

            DR. RUNNER:  The other comment I wanted to make about indications, you are voting on the indications as stated in the present regulation and that would be included from the original Miter PMA.  Any additional indications that might come to FDA would, of course, have to be supported with appropriate data.  For example, I think, sinus lift you mentioned, I don't believe that is in any of the-- it's not in the original classification, per se, and is also not in the original Miter PMA and, therefore, theoretically, we could request clinical data to support those types of indications.

            DR. BURTON:  Dianne?  Richard Burton.  I don't think we have the original PMA to know what their indications were.

            CHAIR REKOW:  Well, I can read what this--

            DR. BURTON:  Oh, okay.  You have it?

            CHAIR REKOW:  Michael has got it.  He is way ahead of us, and so he just handed me this.  You want to know.  This is Paragraph 872.3930, and it's on tricalcium phosphate granules for dental bone repair.  The identification is tricalcium phosphate granules for dental bone repair is a device intended to be implanted in the upper or lower jaw to provide support for prosthetic devices, so it's granules, it's TCPs in general.

            DR. BURTON:  That's the CFR and not the PMA.

            CHAIR REKOW:  Oh, I'm sorry.  Yes, this is the CFR.

            DR. RUNNER:  I think Dr. Mulry has the indications from the Miter PMA.

            CHAIR REKOW:  So while they are looking that up, again, the discussion that's in the CFR is granules, all TCPs in the jaws to support prostheses.

            DR. COCHRAN:  Dianne, this is David Cochran.  I would interpret that to include sinus lift procedures.

            DR. BURTON:  Yes, so would I.  I mean, you could put that in to be -- I mean, you could do cleft grafts you know, cleft grafts on kids with this.

            CHAIR REKOW:  Yes.

            DR. BURTON:  Within and meet those indications.  So, I mean, my problem is that those are almost so broad that, again, you're sort of opening the door perhaps to some situations that would not be appropriate, in fact, because you could be doing that to support a prosthesis and you're taking out, you know, periodontally infected teeth that you want to preserve the ridge and putting this material into an infected site, and still would meet those indications.

            CHAIR REKOW:  Do you have the PMA?

            DR. RUNNER:  The PMA was originally cleared for periodontal alveolar bony defects.  That's very broad, but this is a very early PMA.  It was also indicated for use in fresh tooth extraction sockets and to provide additional stability to fill bony voids.

            DR. GLOWACKI:  Can you repeat the last part, because I didn't hear you?

            DR. RUNNER:  To provide additional stability and to fill bony voids.

            DR. GLOWACKI:  This is Julie Glowacki.  That statement, I think, we all can understand, but the other statement about to support prostheses is an incompatibility, and I, for one, would like a little bit of help on saying which are we looking at here?

            DR. RUNNER:  Well, unfortunately, the regulation is what it is and it was written some time ago, and it's very broad and it's open to a significant amount of interpretation.  I can tell you than in the Dental Branch, we have interpreted that not to include bone filling materials around endosseous implants and whenever endosseous implant, an indication for use around endosseous implants have been requested, we have asked for clinical data to support use around endosseous implants.

            DR. GLOWACKI:  Ms. Glowacki.  So as a follow-up to that then, is this an opportunity to help really sharply define what education --

            DR. PATTERS:  I don't even want to do that.

            DR. RUNNER:  I don't think that we can.  The regulation as it stands is as it stands.  I think you can make recommendations in terms of how you would like the Dental Branch to interpret that regulation, but I think as it stands, it stands.

            DR. PATTERS:  Mark Patters.  Susan, does the PMA, which the Panel has not seen, provide clinical data to show the effectiveness of TCP in periodontal defects?

            DR. RUNNER:  Yes, the original PMA did have clinical data.  I can't -- it was a very early PMA in the history of FDA, so I can't state that it was to the level of subsequent PMAs in terms of data, but it did have clinical data.

            DR. PATTERS:  To your knowledge, is that data published?

            DR. RUNNER:  I don't think so.

            DR. PATTERS:  That's why I don't know it, I guess.

            DR. COCHRAN:  David Cochran.  I think just to help explain the clinical indication is, I think, probably when that was written, it was used predominantly just to fill extraction sockets to help maintain the ridge to support complete dentures probably.  I would assume that's when that was done, and the endosseous implants came to vogue much later than that and probably weren't included early on.

            DR. RUNNER:  You know, the original data on that PMA was in 1980.

            CHAIR REKOW:  So if I understand it, we really have been given some direction in terms of how to focus, and that is on granules and TCP, because the reg doesn't limit it to Beta TCP.  Do you want to, as a Panel, add that limitation of Beta TCP, as opposed to TCP in general?  I'm sorry, yes?  Yes, please.

            MR. DRISKELL:  I would like to enlighten a few people on the Committee.

            CHAIR REKOW:  Would you go to the microphone, please, and identify yourself?

            MR. DRISKELL:  I'm Tom Driskell.  Well, actually, you might remind me of some of the things that you asked questions on, but I can speak to the indications to some degree.  First of all, I would like to point out that any type of a material or a device like this that we have ever put out, we had a package insert in there that said what it was to be used for, and it had plenty of contraindications in it, because we don't want this stuff to fail, and you see that package insert before you ever get -- I mean, when we apply for a 510(k), we would have a copy of that verbiage that was on the package insert.  It's to protect us and it's to protect the doctor.

            CHAIR REKOW:  Right.

            MR. DRISKELL:  And I think it's very important that you keep that in mind, because you don't really have to cite all the indications, but I think in the package insert, it's got to say what it's being used for or if that isn't in the regulations, it ought to be.  So then you have a chance to oversee what the manufacturer wants to do with it, and the original PMA when we did fill two sockets, what we had particularly in mind, at that point, was third molar sockets, which often really would benefit from being filled with something, so you generally get the defect back there that you, otherwise, might likely get.  So that was a very good use for it.

            In fact, my daughter was the first one that ever had it used on her, on anyone.  By the way, let me throw this in.  Speaking of sinus lifts, my wife had some periodontal disease and sinus infections, which she didn't even know she had for years, but the point is that she ended up with one and a half millimeters of bone in the maxilla, and we wanted to put implants in there.  We used tricalcium phosphate and we were able to put in 14 millimeter implants, which we no longer even bother to sell, because you don't need them that big, but in those days we still thought we did.

            So anyway, those have been in now for about 12 or 13 years and they still look like they did within a year of the time it was done.  So anyway, if you have some questions like this, I would be happy to give you my best information on it.

            CHAIR REKOW:  Thank you.

            MR. DRISKELL:  I don't want to -- well, excuse me.

            CHAIR REKOW:  Thank you.  I appreciate that and I think that our frustration is that there are a great many valuable clinical case studies.  The frustration that we're having is well controlled prospective studies, which of course have a different standard of information that may or may not be extractable from them, but we won't go into that category.  And it's the issue of what is the standard against which we're going to make our decisions, that's our frustration, because, clearly, there is lots of experience in positive results.  Thank you.  Susan?

            DR. RUNNER:  I just wanted to remind the Panel, as well, however, that the FDA regulations do state that the levels of evidence include case studies and all the way from experiential all the way to well controlled clinical studies.

            CHAIR REKOW:  Thank you for that reminder.  So we have focused ourselves a little bit.  We're talking about granules and we're talking about TCP.  Now, the question, I guess, is maybe the easier way to ask the question first is can we specify enough precautions or contraindications and not address what they are yet, but can we specify enough to make the Panel feel comfortable that the device could be reclassified?  Can I take a vote, David?

            DR. BURTON:  Yes.

            DR. PATTERS:  Yes.

            DR. GLOWACKI:  Glowacki, yes.

            DR. SUZUKI:  Suzuki, yes.

            CHAIR REKOW:  Well, Elizabeth is not voting.  Are you voting?  Okay.  So I don't have to break the tie, but I would say yes, too.  So before we go to what those precautions and indications need to be, I think I would like to take on the last issue of do you need training beyond that of a dentist to be able to use this stuff or is that intimately tied with the contraindications and indications?  Mark?

            DR. PATTERS:  Mark Patters.  I certainly don't know every product, but I know of no product that is specified in its labeling that can only be used by a specialist.  I know of no product that is labeled that way.  I don't think I would want to start one, do you?

            DR. SUZUKI:  Jon Suzuki.  I agree with Dr. Patters and, in fact, even dental implants are not specified just for certain specialties either.

            CHAIR REKOW:  Okay.

            DR. BURTON:  Richard Burton.  I would like to agree.  I think that the kinds of indications that I can see for the product would fall within the realm of the general practitioner as being appropriate for it.  There are going to be conditions that they are going to be treating, as well as specialists.  So, I mean, I think that to limit the availability of it in that arena would be inappropriate.  Yes, cruel of them to say that.  I know you will.

            CHAIR REKOW:  I am being suggested that we go onto the classification questionnaire, because that will answer lots of the questions that need to be resolved.  Does that also tie in enough with your risk table or do you want us to address the risk table specifically?  Let's do the questionnaire first and then we can see if we can go back and redo the -- where is the questionnaire?

            SECRETARY ADJODHA:  I believe that would be in the --

            CHAIR REKOW:  It was in your stuff.  Okay.  So for the Panel, who also don't remember, it's in the last pieces of what we were given in Section 7, which is at the very bottom of the pile of the reading, and the general device questionnaire.  The first question is who is the petitioner, and then this is the one, right, this one?

            SECRETARY ADJODHA:  I think we need to refer to Marjorie Shulman.

            CHAIR REKOW:  Marjorie Shulman.

            MS. SHULMAN:  I'm handing out new forms, too, and we're going to get one up on the overhead.

            CHAIR REKOW:  Got it.  Good.  It's nice to have somebody keeping us on track properly.  Oh, I see.  Got it.  So, Mark, let me turn it over to you, please, to guide the discussion.  While she is getting that set up, are there any compelling things that any of the Panel would like to say?  Mark?

            DR. PATTERS:  Yes, Mark Patters.  I would just like to address the petition from Dr. Morgan where under Number 4 in his petition, indications for use in the device labeling, and he has his indications as bone substitute material for dental alveolar procedures.  I would have to say that I personally think that is way too broad, dental alveolar procedures.

            DR. COCHRAN:  This is David Cochran.  Just listening to what Mark said, I think what we're actually doing is reclassifying the original PMA is my understanding, and the language that's in there is what is going to be what we're really discussing.

            CHAIR REKOW:  What exactly are we reclassifying, the original PMA?

            DR. RUNNER:  The tricalcium phosphate for dental bone repair with the indications as indicated in the PMA and in the CFR notes.

            CHAIR REKOW:  Both?

            DR. RUNNER:  Both.  It includes --

            CHAIR REKOW:  Okay.

            MS. SHULMAN:  My name is Marjorie Shulman.  I work for the Program Operations Staff, and we'll walk you through the forms.

            DR. GLOWACKI:  May I interrupt?

            MS. SHULMAN:  Sure.

            DR. GLOWACKI:  Just to follow-up on that, Susan, Ms. Glowacki again, if we do a reclassification of the original PMA and put the specifications in, so that it only applies, it really only applies to pure Beta TCP for certain uses, what happens to the other whole field that we don't talk about here?

            DR. RUNNER:  The regulation would be split such that Beta TCP could potentially be Class II and other forms of tricalcium phosphate would remain as Class III if that's what you so suggested.

            DR. GLOWACKI:  Thank you.

            CHAIR REKOW:  So that's part of our charge today, first to look at the original PMA and then to talk about --

            MS. SHULMAN:  Yes, just as a matter of --

            CHAIR REKOW:  Okay.

            MS. SHULMAN:  Marjorie Shulman.  Just as a matter, we're not looking at the PMA, so to speak, to reclassify.  We are reclassifying looking at the reclassification of the reg in which the PMA was classified under.  So we're looking at the intended use for that PMA, and any supplements that may have been cleared under that, because if the vote was to go for reclassification, that would then become a Class I or a Class II device.

            CHAIR REKOW:  Okay.

            MS. SHULMAN:  So the first thing we want to do is agree upon exactly what intended use we're looking at from the intended use from the reg and the PMA, and you, as a Panel, would have to decide do you want to split it right off the top and go through the sheets two times and see where you end up or do you feel comfortable enough to go all as one group?

            CHAIR REKOW:  This is Diane Rekow again.  My understanding then from what you said is that the PMA is a subset of the reg, and we should just focus on the reg and by default, all of the things that we have discussed are included as long as it applies to the ridge.

            DR. RUNNER:  Right.  I think you also need to consider, however, that if you split off Beta TCP, that would mean that other forms of tricalcium phosphate would come in with the PMA.

            CHAIR REKOW:  Yes.

            DR. RUNNER:  If that's what you so desire.  You can also realize if you reclassified the entire group, tricalcium phosphate, FDA would also consider the other forms, because we don't have any experience within requiring clinical data in most instances, as well.  So that's --

            CHAIR REKOW:  Okay.  So --

            DR. PATTERS:  Excuse me.  Mark Patters.  Susan, isn't there an alternative that makers of other forms of TCP could ask for reclassification, rather than have to come in as a PMA?

            CHAIR REKOW:  So we're talking about granules and we're talking about TCP in general?  All right.  Is the Panel willing to do that as the general group for going through this questionnaire form?  Do I hear any objections to doing so?

            DR. BURTON:  Could you restate that again?

            CHAIR REKOW:  Yes.  We're going to keep all the TCPs in their granular form as a group, and address this questionnaire for that group of products, I guess.  Is there an objection to doing so?  Hearing none, I'm going to give it back to you again.

            MS. SHULMAN:  Thank you.  Marjorie Shulman.  We'll start with the form then.  The first part is just housekeeping, the Panel name and petitioner and everyone is able to fill out their own form, but the Panel Chair will keep the main form.

            The generic type of the device is the regulation.  Is that what we agreed upon?

            SECRETARY ADJODHA:  Yes.

            MS. SHULMAN:  Okay.  The first question --

            SECRETARY ADJODHA:  Marjorie, can you explain to them what they should put in there for generic type of device?

            MS. SHULMAN:  You can just put in the regulation.

            SECRETARY ADJODHA:  Oh, the exact name?

            MS. SHULMAN:  Okay.

            SECRETARY ADJODHA:  Okay.  So the exact name is tricalcium phosphate granules for dental bone repair.

            MS. SHULMAN:  Okay.  Question 1, and we can do this, you can go around and tell us yes, no, and then vote.  Is the device life sustaining or life supporting?

            CHAIR REKOW:  David?

            DR. COCHRAN:  David Cochran, no.

            DR. BURTON:  Richard Burton, no.

            DR. PATTERS:  Mark Patters, no.

            DR. GLOWACKI:  Julie Glowacki, no.

            DR. SUZUKI:  Suzuki, no.

            MS. HOWE:  Elizabeth Howe, no.

            CHAIR REKOW:  Dianne Rekow, no.

            MS. SHULMAN:  Okay.  Number 2, is the device for a use, which is of substantial importance in the preventing impairment of human health?

            CHAIR REKOW:  Now, we'll go backwards this time.  Jon?

            DR. SUZUKI:  No.  Suzuki.

            DR. GLOWACKI:  Yes, only because, I mean, Ms. Glowacki, I thought implanting anything into the body is done for a substantial clinical reason, but maybe I don't understand these words.

            CHAIR REKOW:  Let's finish the vote and see if we need to have that discussion.  Mark?

            DR. PATTERS:  Mark Patters, yes.

            DR. BURTON:  Richard Burton, no.

            DR. COCHRAN:  David Cochran, no.

            CHAIR REKOW:  My read would be the same as Julie's, so I would say yes, which I guess splits it.  So could we have some clarification from FDA about what this means?  Mark?

            DR. PATTERS:  If we answered no to this question, and we're sure we answered no to the question after it, this then could be classified as a Class I device.  I'm not sure this Panel wants to do that.

            DR. BURTON:  Well, could we go through the Question 3, which would sort of, at that point, render that discussion null and void.  Okay.  If you split Question 2, if we go to Question 3 and the majority on Question 3 comes up yes, then we're already, then it would appear to me, moved over to it being a Class II and then looking at some --

            CHAIR REKOW:  Okay.

            MS. SHULMAN:  Marjorie Shulman.  As a matter of clarification, too, you could answer no to the first three, get to the question is general controls enough, say no, and then you get back to 2.

            DR. BURTON:  Okay.  I would go through Question 3.

            CHAIR REKOW:  Excuse me?  I'm sorry?

            DR. BURTON:  I would move that we go through Question 3, which I think would --

            CHAIR REKOW:  Yes, let's do that, and I have also had some other clarification, which may resolve this.  So let's do Question 3, which is does the device present a potential unreasonable risk of illness or injury?  David?

            DR. COCHRAN:  Cochran, no.

            DR. BURTON:  Burton, yes.

            DR. PATTERS:  Patters, no.

            DR. GLOWACKI:  Glowacki, yes.

            DR. SUZUKI:  Suzuki, no.

            DR. BURTON:  Dianne?

            CHAIR REKOW:  So the general vote is no.  I'm told I only have to vote if there's a tie.  So if that's the case, does that resolve Number 2?

            DR. BURTON:  No.

            CHAIR REKOW:  Let's redo the vote on Question 2, please.  Jon?

            DR. SUZUKI:  Suzuki, no.

            DR. GLOWACKI:  Glowacki, yes.

            DR. PATTERS:  Patters, yes.

            DR. BURTON:  Burton, yes.

            DR. COCHRAN:  Cochran, no.

            CHAIR REKOW:  So the answer to that is yes?

            MS. SHULMAN:  Correct, Question 2 is yes.

            DR. COCHRAN:  Do I have to have my opinion or their opinion?

            CHAIR REKOW:  Okay.

            MS. SHULMAN:  Okay.  Number 4, did you answer yes to any of the above questions?  The answer is yes.

            CHAIR REKOW:  We don't have to vote?

            MS. SHULMAN:  If yes, we go to Item 6.  Is there sufficient information to establish special controls, in addition to general controls to provide reasonable assurance of safety and effectiveness?

            CHAIR REKOW:  Okay.  And the implications of this, of course, and the comments is that if you say yes, you can classify it as a Class II and if you say no, it remains a Class III?

            MS. SHULMAN:  Correct.

            CHAIR REKOW:  So, Jon, shall we start with you?

            DR. SUZUKI:  Suzuki, yes.

            DR. GLOWACKI:  Glowacki, yes.

            DR. PATTERS:  Patters, yes.

            DR. BURTON:  Burton, yes.

            DR. COCHRAN:  Cochran, yes.

            CHAIR REKOW:  Okay.  Good.  So that's unanimous.  So now, we go to Item 7.

            MS. SHULMAN:  Number 7, if there is sufficient information to establish special controls to provide reasonable assurance of safety and effectiveness, identify the special controls needed to provide such reasonable assurance for Class II.  And the guidance document can include a lot of the discussion from earlier, so you can say that.

            CHAIR REKOW:  Okay.  So the choices, of course, are guidance document performance standards, device tracking or testing guidelines or other things that we may deem appropriate.  Could you, please, for me, and I apologize if you had this discussion earlier, differentiate the difference between the content of a guidance document and a performance standard.  Is a performance standard like an ASTM or an ISO standard?

            MS. SHULMAN:  It could be recognized standards like that.  Performance standards are also recognized by a rule and it goes through a rule making.  A guidance document may have standards in it that you abide by.  A company does not have to go 100 percent to the guidance document.  However, they would just have to explain why they deviated, how they deviated and what they used instead.

            CHAIR REKOW:  Okay.

            MS. SHULMAN:  So the performance standard is rule making.

            CHAIR REKOW:  Okay.  Could we poll the Panel and see if there is substantial places that we need to do that at, as opposed to initially taking a vote?  David, can I put you on the spot and ask you your preference first?

            DR. COCHRAN:  I'm sorry.  Repeat your request.

            CHAIR REKOW:  Just rather than voting on which one we need to do first, can we have a discussion by each of you of what your preference of that ranking should be, and then have an open discussion about that if it's clear that we need to.  I think it's going to throw out a few options.

            DR. COCHRAN:  Okay.  This is David Cochran.  My feeling is that we want to be least restrictive if we can, and I think the guidance document, from my understanding, would do that and it sounds like from what the FDA can do in a guidance document, they can help direct the issues, which we have concerns about.

            MS. SHULMAN:  If I can just clarify one thing, too.  Dr. Betz just reminded me.  There was the risk table that was discussed earlier in the presentation.  If you want to refer to that or we could put it back up there.  It may help identify the risks or what could mitigate them.

            CHAIR REKOW:  Okay.  What is the preference of the Panel?  Do you want to do that or you want to try to sort through it first, and then go back to the risk table?

            DR. BURTON:  Keep going, I think.

            CHAIR REKOW:  Keep going this way and go back to the risk table?  Make sure to use that as our backup check.  Okay.

            MS. BLACKWELL:  Do you want to see the risk table?

            CHAIR REKOW:  No.

            DR. BURTON:  No.

            CHAIR REKOW:  Not right now.  We will go back to it though, because I think it's a useful piece.  Richard?

            DR. BURTON:  I would agree with that.  I think that in looking at what those guidelines are, I think that the guidance document, I think, is what people are really, truly going to look at.  I think that that's really just the way to go, and I think the way we can address that most effectively.

            CHAIR REKOW:  Mark?

            DR. PATTERS:  Patters.  I think, obviously, the guidance document is necessary, but I would give some consideration to device tracking if we are not 100 percent satisfied that adequate studies have been done to show safety.

            CHAIR REKOW:  Okay.

            DR. GLOWACKI:  Glowacki.  I think from the general discussion that's going on, that it should be possible that guidance documents would cover it all.

            CHAIR REKOW:  Jon?

            DR. SUZUKI:  Suzuki.  I believe I agree with everybody else that the guidance document is probably -- that that's the way to, at least, approach this question, and I don't really believe, at this point, that device tracking is that critical of testing.  That's just my opinion at this point.

            CHAIR REKOW:  So clearly, everyone is pretty comfortable with the guidance document, and we need to probably come back to whether or not we need some special tracking.  Can we do that as we go back to the risk table or how would you like us to proceed?

            DR. RUNNER:  I would just -- Marjorie, could you comment on tracking in terms of what kind of devices, at this point in time, are tracked, as opposed to not?

            MS. SHULMAN:  I didn't do my homework.  Very few devices are tracked actually.

            DR. RUNNER:  I think, in general, tracked devices actually put quite a burden on the manufacturer in terms of keeping records of who devices are sold to and who they are they implanted in.

            MS. SHULMAN:  Correct.

            DR. RUNNER:  And I think that for a device, usually, for example, TMJ implants, which have had a history of having significant problems are tracked devices, and there are very few other ones.  In my opinion, it would probably be very unwieldy to track a device, such as this, which may potentially be implanted in quite a number of patients.

            MS. SHULMAN:  Correct.

            DR. BURTON:  Burton.  I would agree with that, because when I think of a tracked device, first of all, it would be something that could be potentially explanted, at some point in time, so that, you know, you could recover something.  Whereas, you know, hopefully down the road, there is nothing here to explant.

            And again, I think also, you know, if you're looking at this type of product and the cost factor involved, most of those that have been tracked are, I would say, expensive devices, but they are also things, which would be an overhead where the manufacturer could afford to have a tracking system.  You know, this is broadly or at least potentially as broadly as this could be used in terms of the potential indications would be very, very difficult, because if you were in practice, you would be tracking, literally, it could be hundreds of patients with this and probably, I'm not sure what you would really gain from that.

            CHAIR REKOW:  Susan?

            DR. RUNNER:  I think, in addition, it would be significantly different from any of the other bone filling materials that are on the market presently without that requirement.

            CHAIR REKOW:  I see that there is also this check box of other, and to specify either any special things that are done in the other bone filler materials that we might think of that perhaps address some of the concerns that Dr. Patters has.  Are they simply included and integrated into the guidance document?  Is there a guidance document for the bone filling materials in general?

            DR. RUNNER:  There is not.  That's one of the reasons why we gave you the risk and mitigation table, because that could potentially be used in such a guidance document.  The only guidance documents that the center has put out so far is the one that you have seen for orthopedics in terms of bone filling materials.

            CHAIR REKOW:  So does it seem that it might be appropriate for us to go to the risk table now?

            DR. COCHRAN:  Dianne, this is David Cochran.  I have a question for maybe Susan.  I think on the market, there are so-called bio-active classes that are sold.  What are they classified as?

            DR. RUNNER:  All of the other dental bone filling materials are presently unclassified.

            MS. SHULMAN:  We could continue on this sheet, and in the next sheet we get into the risks of health and that way it would be more helpful.

            CHAIR REKOW:  Okay.  So can we leave the other for the moment, Mark?  Are you comfortable with that, just making the recommendation at the moment, a guidance document, knowing that we are likely to come back and revisit at least a part of this?

            DR. PATTERS:  Yes, I'm comfortable.  My concern was if the Panel had doubts, that was -- but if you don't, you don't.

            CHAIR REKOW:  Okay.

            DR. PATTERS:  My personal concern is that the lack of reports of adverse reactions may just stem from the lack of broad base use, and once it's in broad base use, we maybe can see them and will we recognize the problem without any type of control?

            CHAIR REKOW:  Okay.  Thank you.

            MS. SHULMAN:  Number 8 is regarding the Regulatory Performance Standard, but that was not chosen, so we can skip that.  Number 9 is also a question about the performance standard, so we can skip that.  Number 10 is a question if it was to be classified or stay in Class III, which is wasn't, so we can skip that.  So we can go to the next page.

            Number 11, identify the needed restrictions.  There are three other restrictions and another.  The first one is the basic prescription labeling, and the other two used only by persons with specific training or experience in its use and use in only certain facilities adds upon the prescription labeling.  So the first question is identify the needed restrictions, and the first one is only upon the written or oral authorization of a practitioner licensed by law to administer or use the device, and then the other two.  We have been on those.

            CHAIR REKOW:  Okay.  I have forgotten which way we were going.  David, do you want to go first?

            DR. SUZUKI:  Jon Suzuki.  Oh, sorry.

            CHAIR REKOW:  Go ahead.

            DR. PATTERS:  Jon Suzuki.  Answer 1, which is only upon written or oral authorization of a practitioner licensed by law to administer or use the device.

            DR. GLOWACKI:  Julie Glowacki, yes to the authorization with the licensed practitioner.

            DR. PATTERS:  Patters, I agree with that.

            DR. BURTON:  Burton, concur.

            DR. COCHRAN:  Cochran, with a question.  Does that mean like a licensed dentist or are we talking about a prescription, per se?

            MS. SHULMAN:  A prescription per se.

            DR. COCHRAN:  I don't think that's our understanding on the Panel.

            CHAIR REKOW:  No, I don't think so either.

            DR. RUNNER:  I think what -- this device would not be -- you would not write a prescription for this device and give it to your patient to go get it.  In other words, you wouldn't need a licensed practitioner to obtain the device to implant it.

            CHAIR REKOW:  I think, if I may, rather than taking another vote, I know I'll be corrected if I'm not correct, that a person who is a licensed dentist with all of the abilities and assurances that they can practice dentistry could use this product.  Is that the consensus of the Panel?  So however you have to say that.

            MS. SHULMAN:  That would be the first block.

            CHAIR REKOW:  That's what we thought.

            DR. COCHRAN:  Well, then my answer is affirmative.

            CHAIR REKOW:  Okay.  All right.

            MS. SHULMAN:  Okay.  Now, we can move on to the supplemental data sheet and the generic types of device, Question 1, was whatever you said.  Question 2, the Advisory Panel is the Dental Products Panel.  Question 3, is device an implant?

            CHAIR REKOW:  Can you read us whatever 21 CFR 860.3?  I don't know how I survive with all these numbers.  So we have a definition of an implant.  An implant means a device.  For those of you who have the handouts, that's on page 11.  An implant means a device that is placed into a surgically or a naturally formed cavity in the human body.  The device is regulated as an implant for the purpose of this part only if it is intended to remain implanted continuously for a period of 30 days or more unless the Commissioner determines otherwise in order to protect human health.

            What does that last phrase mean?  Like in an emergency, something can happen?  So if it's in the body for over 30 days, I guess it's an implant.

            DR. PATTERS:  Right.  Yes.

            MS. SHULMAN:  Correct.

            CHAIR REKOW:  So the breakdown products that we have seen, that's everything is over 30 days, right?  I'm getting an affirmative nod from the corporate people, so I guess that makes it an implant.

            MS. SHULMAN:  Number 4, the indications for use in the device's labeling.  We can fill out what was in the regulation and approved PMA.

            DR. RUNNER:  I actually have the actual list now of what was approved in the PMA, and I could read them for you again if you would like.  The Miter PMA had five indications, use in defects after extrication of dental alveolar cysts.  In periodontics, for filling of two-wall bone pockets, as well as bifurcations and trifurcations of the teeth.  Three, augmentation of the atrophied alveolar ridge.

            CHAIR REKOW:  Say that one again.

            DR. RUNNER:  Augmentation of the atrophied alveolar ridge.  Four, defects around an apicoectomy and five, filling of bone defects after surgical resection of impacted teeth.

            SECRETARY ADJODHA:  Susan, seeing that the Panel has recommended so far Class II, shouldn't we use the indication for the intended use in the reg?

            DR. RUNNER:  I believe the intended use in the reg is just a description of the generic class of device.

            SECRETARY ADJODHA:  Okay.

            DR. RUNNER:  These are the indications that would be --

            MS. SHULMAN:  Right.  So it's the intended use of the reg and the indications that were cleared.

            SECRETARY ADJODHA:  Okay.  Thank you.

            CHAIR REKOW:  So that does not -- does it or does it not include sinus lifts?

            DR. RUNNER:  It does.  I will read them once again.  Use in defects after extrication of dental alveolar cysts.  In periodontics, for filling of two-wall bony pockets, as well as bifurcations and trifurcations of teeth, augmentation of the atrophied alveolar ridge, defects around apicoectomies and filling of bone defects after surgical resection of impacted teeth.

            CHAIR REKOW:  So to you periodontists, does augmentation of an atrophied ridge include a sinus lift?

            DR. BURTON:  No.

            DR. RUNNER:  We have not interpreted it as such.

            CHAIR REKOW:  Thank you.

            DR. BURTON:  Burton.  I would say that it wouldn't.  The other thing is though that that's even more restrictive than, at least, what I have been hearing at least from manufacturers, because, I mean, there it limits it down to saying, you know, surgical extractions of third molars, which would then not make an indication for use, let's say, in general surgical -- just general extractions for ridge preservation would not be an indication within what was given there.  You know, that's a pretty tight limitation to say that it has to be surgical extraction of third molar or an impacted tooth.  I mean, that's, you know, an impacted cuspid.

            DR. RUNNER:  But it's also a combination of the intended use, which sort opens the door wide if you look at the intended use definition in the CFR, because the intended use in the CFR says tricalcium phosphate granules for dental bone repair is a device intended to be implanted into the upper or lower jaws to provide support for prosthetic devices.  So our interpretation of that couldn't be --

            CHAIR REKOW:  Okay.

            DR. BURTON:  But not sinus lifts.

            DR. PATTERS:  Patters.  I am somewhat disturbed about those periodontal indications.  It's my understanding that if we include an indication, we are saying that there is scientific data to support that use, are we not?  If there is scientific data that shows any bone filling material to be effective in the treatment of bifurcations and trifurcations, it has escaped my notice.

            CHAIR REKOW:  Yes.

            DR. COCHRAN:  This is Cochran.  I'm not sure that probably any device has scientific data for every particular indication in the world out there that it's used for, and it sounds like the regulation is to use for dental alveolar surgery, and I would hope that we would allow the clinician to have some say in how the product is used if they think it's going to benefit the patient.  I favor the regulation.

            CHAIR REKOW:  Mark?

            DR. PATTERS:  Patters again.  I think that if it's labeled for this use, that that states that there is scientific data to support it.  So I am very uncomfortable with filing a label that says this is useful in periodontal defects and bifurcations and trifurcations.

            DR. RUNNER:  Unfortunately, when this came and it was approved back in the '80s, I assume it went  before a Panel, at that time, it was determined that there was scientific evidence to support that indication and it was approved, at that time.  We have to --

            DR. PATTERS:  But that's not like getting the Ten Commandments though, is it?  I mean, just because it was carved in stone in 1980 doesn't mean that the pillars have not been broken, does it?

            MS. SHULMAN:  Those were the approved PMA indications.

            DR. PATTERS:  But further data might show in the future that those indications were not appropriate.  Is that not true or is it like the Ten Commandments?

            DR. RUNNER:  I believe that if we were to take an indication off, we would probably have to have some evidence of medical device problems with the issue that would be submitted to the Agency that this indication should be eliminated, and to date, we don't have that data, so it is sort of like the Ten Commandments.

            DR. PATTERS:  You know, I have no problem with the clinician making a determination as to how to use the device, but I have a problem with labeling it.  That is when you label it, you are stating that it has been shown to be effective, and perhaps there were data in 1980, but it has escaped my notice.  That's all I can tell you.  Perhaps David could recite it for us.

            DR. COCHRAN:  No.

            DR. PATTERS:  Or perhaps Dr. Suzuki who is very familiar with that literature.

            MS. SHULMAN:  Marjorie Shulman.  Right now, that is an improved indication that is out.  Maybe it's not being marketed, at this time, but it's an improved indication that is out on the market.

            DR. SUZUKI:  This is Jon Suzuki.  I do tend to agree with Dr. Patters' concerns about the labeling, but I think if we go the route, as already alluded to by Dr. Cochran, it really is up to the clinician jurisdiction, clinician judgment, and if he feels he can utilize them in these types of defects like bifurcations and trifurcations, then more power to him.

            But in their education, they learn the risks and the benefits, and most astute clinicians would probably go to the literature and know that it doesn't work in certain situations.  So I do see Dr. Patters' concerns, but I would like to see us accept them the way they are, I guess.

            DR. PATTERS:  Well, again, I would like to see it say that it can be used in periodontal defects and leave it to the clinician to decide what type of defects, rather than say that it is labeled for use and treatment of trifurcation and bifurcation involvements, because that's very different to me.

            DR. SUZUKI:  This is Suzuki.  What would it take to add that clause?

            MS. SHULMAN:  A more specific indication?

            DR. COCHRAN:  I guess, a procedural question would be are we really -- is this language with those indications, is that going to be on the labeling of this product or will it just fit into the regulations as whatever that CFR thing is you're talking about?

            MS. SHULMAN:  Marjorie Shulman.  It would not only be on the label of a product if a company came in for that indication for the labeling of their product.

            DR. PATTERS:  But there is nothing to prevent them from doing so if it's in the labeling.  They don't even have to show data, I mean, if it's in the regulation.

            MS. SHULMAN:  Under pre-market notification, under Class II, we could ask for data.  We could ask for clinical data.

            DR. RUNNER:  And you could --

            DR. PATTERS:  But if it's already a known indication, why would you do that?

            MS. SHULMAN:  It's a known indication.

            DR. PATTERS:  Because, like I say, I'm uncomfortable with it.

            MS. SHULMAN:  It's an improved indication for the one company who has the approved PMA.  Anyone else who is to introduce this into the market would require a new 510(k) and would require anything that was to be in the guidance document, any clinical data that we might need, any special labeling, anything like that.

            DR. RUNNER:  And I think you could recommend to us that you feel that it would be important to specifically require data when they were making a claim for bifurcations and trifurcations, and we could certainly ask for that.

            DR. PATTERS:  You guys always have a way out.

            CHAIR REKOW:  Richard?

            DR. BURTON:  Richard Burton.  One of the things that has changed in the world since 1980 though, which concerns me a little about this is we have split off in so many areas, pediatrics.  I do a lot of pediatric surgery, and my concern is that this also opens -- I mean, again, I would say it's one thing in adults, but, you know, I would have a lot of heartburn with people using this type of material in some pediatric situations that would fall within those accepted guidelines.  I mean, is there any way you can add this, you know, for -- I would say things now oftentimes have a young age limit sometimes built into it, but, you know.

            MS. SHULMAN:  Marjorie Shulman.  I would have to look at the labeling that was actually cleared in that PMA.  If it wasn't cleared for pediatric, pediatric use is a new indication for use.  New indications for use require new 510(k)s, and there would be a new 510(k) and we would get data.

            DR. BURTON:  Because again, you could have -- it might be a fine product if you want to put it in a cyst.  I'm not sure you would want to put it into a cyst in an 8 year-old kid, because I think that, again, you know, they are not the same use.  We didn't split those things out.  It was sort of a little more across the board, but I don't know whether that could be looked at.  At least, I would certainly recommend doing that.

            CHAIR REKOW:  Okay.  I guess on the form under indications for use, we say whatever is in the regulation and the PMA with concerns as noted in the discussion, especially relating to pediatric and periodontal.

            DR. PATTERS:  Treatment of bi and trifurcations.

            CHAIR REKOW:  Okay.  Let me write that before I forget.

            DR. BURTON:  It would be a lot easier if you could have just pulled them out and got rid of them, just pull them out and put it in.

            CHAIR REKOW:  Any other things that people want as noted concerns?  Okay.

            MS. SHULMAN:  Okay.  The identification of any risks to health presented by the device.  Did you have an overhead for that?

            CHAIR REKOW:  Maybe this is when we go to the risk table.

            MS. SHULMAN:  It was on the risk table, but there's an overhead.  We can put it up.  Okay.  We can put it up there and then you can vote as is or you can add or subtract anything that you see fit.

            CHAIR REKOW:  Okay.  So the first risk is those associated with surgical treatment procedures and the thought is that the indications for use and labeling would deal with those.  Is that adequate?  Yes?

            DR. GLOWACKI:  I have a question about the failure to osseointegrate.

            CHAIR REKOW:  Can we go down to the --

            DR. GLOWACKI:  Oh, I'm sorry.

            CHAIR REKOW:  We'll go one by one.

            DR. GLOWACKI:  Oh, I'm sorry.

            CHAIR REKOW:  Okay.  I'm sorry.

            DR. GLOWACKI:  Yes.

            CHAIR REKOW:  Infection of the soft tissue and/or bone, the guidance document could deal with that, as well as the sterility review question.  What is the sterility review?  Is that like a specification?

            DR. RUNNER:  It's a guidance document.  Well, first of all, we would review all information about sterility of the device, and guidance on how the company --

            CHAIR REKOW:  Okay.

            DR. RUNNER:  What about performing those tests.

            CHAIR REKOW:  For adverse tissue reactions, aside from failure to osseointegrate, which may be a separate issue.  The FDA has an ISO standard and there is biological information of medical devices and evaluation and testing, which is standard procedures, which would again be in the guidance document, I assume.  Adequate?  I'm getting affirmative nods from everybody, just for the record.

            Incomplete or lack of bone formation, and here the data would be obtained either through performance testing, animal and/or clinical data, as well as directions for use.  Is that adequate?  My, what an accommodating group we have here.

            MR. SCHECHTER:  Dianne?

            CHAIR REKOW:  Yes, sir?

            MR. SCHECHTER:  This is Dan Schechter.  With, I guess, the last four categories on the risk table, it talks about performance testing.  Is it FDA's position that every 510(k) under this category regardless of indications is going to require clinical data, either animal or human?

            DR. RUNNER:  No.

            MR. SCHECHTER:  Okay.  Just checking.

            CHAIR REKOW:  So having said that, can

you --

            DR. RUNNER:  I think that would depend on the indication for use that was proposed by the company.

            CHAIR REKOW:  Okay. 

            DR. PATTERS:  Susan?

            CHAIR REKOW:  Yes, Mark?

            DR. PATTERS:  Patters.  Susan, can the performance testing be put in the guidance document?

            DR. RUNNER:  Yes.

            CHAIR REKOW:  Okay.  The next one is a failure to -- let me go back and make sure that we took care of incomplete or lack of bone formation.  Everybody is okay with that?  Okay.  Failure to osseointegrate, to be controlled again by performance testing, directions for use in animal and/or clinical data.  Julie had a question about that.

            DR. GLOWACKI:  This is Julie Glowacki.  I'm not sure that that concept has any relevance, osseointegration, if we're talking about resorbable materials.  Now, I may in a spiralling argument here with respect to are we talking about resorbable forms or biphasic and so forth?  So I just wanted to raise that as a point of clarification.

            CHAIR REKOW:  Yes.  It's an interesting one.  If it's in for 30 days, but it's going away, does it osseointegrate?  Dr. Betz, you have a comment?

            DR. BETZ:  This is Dr. Betz.  Unfortunately, this is my baby right here and I stole it from the draft guidance that the orthopedic people did.  Failure to osseointegrate maybe doesn't have anything to do directly with the bone itself, with the grafting material itself, but my concern in putting in and separating to get out from incomplete or lack of bone formation was related to the fact that the bone that is generated therefrom may or may not osseointegrate and, therefore, I threw it in just to make sure you guys were on your toes and you would want to consider that as a possibility.  It may not apply in your opinion.  That's your choice.

            CHAIR REKOW:  Can you help me understand better the difference between lack of bone developing and lack of osseointegration?

            DR. BETZ:  Well, my concern was that the bone that is generated may or may not have properties that would permit it to osseointegrate.

            CHAIR REKOW:  Permit what to osseointegrate?

            DR. BETZ:  It's a big unknown.  We don't know whether bone generated like this will osseointegrate as such.

            CHAIR REKOW:  With the natural bone that is remaining?  Osseointegrate with what?

            DR. BETZ:  With the dental implant.

            CHAIR REKOW:  Oh.

            DR. BURTON:  Burton.  I know what Dr. Betz is alluding to.  There have been some various studies at different times looking at both autogenous and allogeneic materials, and whether the bone that seems to be developed from that doesn't seem to have quite the same capabilities as some native.  That has been one of the tradeoffs between autogenous bone and various allogeneic, you know, various allogeneic materials has been -- yes, it sort of forms bone, but it doesn't seem to function quite as well or whatever as that.  And I think what you're saying is does the bone -- you know, there's a risk from this that the bone that would be generated by it may not be of the same quality that would support osseointegration that native bone would.

            DR. BETZ:  This is Betz again.  I agree 100 percent.  That is also related to weakness, newly formed bone, you know, at the bottom.  We don't know a lot about the nature of the quality of bone that you get, and the last thing I would want to do is have somebody and my wife, especially my wife, sink a brand new implant in some very freshly generated bone and have to go heck in a hand basket and then have to explain to her why, my dear, you have to do this again.

            CHAIR REKOW:  Julie?

            DR. GLOWACKI:  Julie Glowacki.  Then I think it's a matter of grammar, rather than anything else, because the way this table is set up, I think you're talking about this implant material.

            DR. BETZ:  Right.

            DR. GLOWACKI:  So could I make a suggestion to say failure to support osseointegration of devices?

            DR. BETZ:  This table is yours to do with as you see fit.  That's fine with me.

            DR. GLOWACKI:  Let's make it go back.

            DR. COCHRAN:  I would like to make a comment.  This is David Cochran.  In a lot of the more recent literature, we understand that the quality of the bone is fine that's being stimulated, but a lot of it has to do with the nature of the implant surface itself, and that may be a lot more overriding a factor whether you actually have osseointegration of the implant or not.  So I am not sure.  I would agree with Julie.  I think it's a matter of what we're saying, because the way it's sort of stated now is like does this new bone integrate in the old bone?  But you mean it to be a dental implant.

            DR. BETZ:  Yes, sir.

            DR. COCHRAN:  Yes.  And I'm not sure if we should really comment.  I mean, I think what you're trying to say is if you want to use it in support of a dental implant, that you need to have data that suggests that when you use it, you do enhance osseointegration of the implant.

            CHAIR REKOW:  And you could go one step further to the last item.  It's stiff enough to do that.

            DR. COCHRAN:  I don't know if stiff is the right word.

            CHAIR REKOW:  Right, it isn't.

            DR. COCHRAN:  But osseointegration is bone to implant contact at a light microscopic level, but I think that's a little different issue.  So I would think we just need to work on the wording of that to get the meaning across of what you really want to say.

            DR. BETZ:  Yes.  This is Betz again.  I just want to make sure you guys were awake.

            CHAIR REKOW:  While you're standing there, you want to help us with the last item, because it's going to be the same issue?  When you talk about the weakness of the newly formed bone, is that also relating to in support of endosseous implants or are you talking about in general there?

            DR. BETZ:  In my opinion, I would consider it in general.

            CHAIR REKOW:  Okay.

            DR. BETZ:  But including related to implants.

            CHAIR REKOW:  Okay.  Thanks for the clarification.  We'll get there.  So if we make the change to, say, something like failure to support osseointegration of endosseous implants or something like that to clarify.

            DR. BURTON:  It would seem to me that we could almost take all three of those, the areas incomplete or lack of bone formation, failure support osseointegration, weakness in newly formed bone are really all sort of one thing, and they all have the same outcomes across from there.  They all say performance testing, animal and/or clinical data, that those could be rolled into maybe one statement, which was just really, you know, incomplete or weak bone formation, which may fail to support osseointegration, make it into one.  I mean, you have just brought out a bunch of lines.

            CHAIR REKOW:  Say incomplete or inadequate maybe.

            DR. COCHRAN:  I would have the opinion that we ought to get rid of the last one.  I don't think we do any testing for weakness of the bone.  I don't think that's the appropriate language at all there.

            DR. BURTON:  Yes.  I mean, that's really an orthopedic term, because what it is is when they used this to deal with a gap issue was whether it was strong enough to support function.  It would appear that we're really not doing that.

            DR. COCHRAN:  We don't do that.

            CHAIR REKOW:  Especially with granules.

            DR. COCHRAN:  Right.

            CHAIR REKOW:  It's a good trick if you can do that.

            DR. COCHRAN:  We would drop that last one.  I don't think that's appropriate.

            CHAIR REKOW:  So what if we just made that heading incomplete or inadequate bone formation?

            DR. COCHRAN:  Yes.

            CHAIR REKOW:  Because that then gets you to the applications.

            DR. COCHRAN:  Yes.

            CHAIR REKOW:  It addresses some of the alveolar ridge stuff underneath prostheses, and it lets the test be driven by what the application --

            DR. COCHRAN:  In that Number 4 that we have, the fourth block down.

            DR. BURTON:  Yes.  But I would say, you know, incomplete or what was the other word you used?

            CHAIR REKOW:  Inadequate.

            DR. BURTON:  Inadequate bone formation, which may not support osseointegration.

            CHAIR REKOW:  No, I would actually go back, if I may, I'm sorry.  Sometimes I get too pushy.  Take the first, the second and the fourth one and collapse them into just saying incomplete or inadequate bone formation, and let the application drive the decision and the test for what that needs to be, because if it's inadequate, it can't support the endosseous implant.  If it's too weak, it can't do the other stuff it's supposed to do.

            DR. COCHRAN:  But we don't measure weakness in bone.

            CHAIR REKOW:  No, I know we don't, but that's why I would just say get rid of the word entirely, and just put all three of those into one category that says incomplete or inadequate.

            DR. RUNNER:  So you're going to get rid of 5 and 7?

            CHAIR REKOW:  Oh, I'm sorry.  I would like to get rid of -- collapse together the incomplete, the failure to osseointegrate and the weakness.

            DR. COCHRAN:  I would vote against that, Dianne.

            CHAIR REKOW:  Okay.

            DR. COCHRAN:  The reason for it is that Number 4, the incomplete or lack of bone, can apply to other indications in this material.  A lot of times we have placed in an intraosseous defect without an implant.

            CHAIR REKOW:  Right.  I agree completely, but the point that I was trying to make is that if we make it more generic, then it becomes a decision process for every application, because you need either complete or adequate bone for whatever application you're thinking about.  If you're going to enhance the ridge, if you're going to do it around an implant, if you're going to replace a cyst, all those things needed to be adequate and they needed to be complete.

            DR. COCHRAN:  My feeling is, in the experience I have had, is that we are really looking at very different indications when we put it around an endosseous implant.

            CHAIR REKOW:  I agree.

            DR. COCHRAN:  Versus when we use it as a bone augmentation material in a ridge.

            CHAIR REKOW:  Okay.

            DR. COCHRAN:  So my preference would be to keep them separate.

            CHAIR REKOW:  Okay.

            DR. COCHRAN:  Because I think you're going to see, the FDA is going to see very different data in the performance testing in those kinds of things.

            CHAIR REKOW:  Okay.  We just want it to work.  Any comments, changes, suggestions?  Okay.  We have the device migration or extrusion and there, the answers that are given are the performance testing, animal and/or clinical data and the directions for use.  I would like to motivate a tiny bit of conversation about whether or not it's appropriate and needs to be specified what the breakdown product dynamics are.  Dynamics is probably the wrong word, but to be able to characterize the breakdown products as a function of time.  Does that need to be more completely specified than it is or is it already taken care of in the data that you would collect under this?

            DR. RUNNER:  We typically collect that data as a part of these applications.

            CHAIR REKOW:  Okay.  Never mind.

            MS. SHULMAN:  That would be under adverse  tissue reaction.

            CHAIR REKOW:  Okay.  Jon?

            DR. SUZUKI:  This is Suzuki.  I guess I'm not reading it the same way you are, Dianne.  Device migration or extrusion to me means lost out of a site or a pocket, as opposed to degradation of products.

            CHAIR REKOW:  Okay.  Okay.

            DR. SUZUKI:  And I getting mixed up?

            CHAIR REKOW:  You are probably right.  Okay.  So does that take care of the risks?

            SECRETARY ADJODHA:  Well, you need to go through and list each one.  You should agree on it.

            CHAIR REKOW:  Okay.  Okay.  So will you write and I'll see if I can summarize them?  So the first one, maybe we can just tie it to Angela's table.  The first one is the risk associated with surgical and treatment procedures and that is as it appears.  There were no modifications.  Yes, we're talking about Question 5.

            MS. BLACKWELL:  Question 5?  Okay.

            CHAIR REKOW:  The second point -- Angela, maybe you can number those, so that Michael can --

            DR. RUNNER:  Dr. Rekow?

            CHAIR REKOW:  Yes, ma'am?

            DR. RUNNER:  Maybe we could just say see table, table of risks.

            SECRETARY ADJODHA:  But they modify the tables.

            DR. RUNNER:  See table as modified.

            CHAIR REKOW:  So maybe we can mark up your table.  The second one is fine.  The third one is fine.  The fourth one we decided.  What did we decide?  The incomplete or lack of bone formation, we said we would leave or did we want lack to be inadequate?

            DR. SUZUKI:  Suzuki.  Lack to be inadequate, I think, is what we agreed.

            CHAIR REKOW:  Okay.  So, Angela?

            MS. BLACKWELL:  What does it say?

            CHAIR REKOW:  The next one up from where your finger is.  Change lack to inadequate.

            MS. BLACKWELL:  Okay.

            CHAIR REKOW:  And the next one down, I think we modified that to say failure to support osseointegration of endosseous implants.

            DR. BURTON:  Endosseous dental.

            CHAIR REKOW:  Dental implants?

            MS. BLACKWELL:  Yes, we'll use the one from this.

            CHAIR REKOW:  Okay.  The next one was fine, and the we were going to eliminate the last one, the last row, yes.  Okay?

            DR. RUNNER:  Okay.

            SECRETARY ADJODHA:  Okay.

            MS. SHULMAN:  Perfect.  On the form, we can move to Number 6, the recommended Advisory Panel classification of priority.  Classification is Class II.  The priority you would vote on a high, medium and low, and all that means is how fast would you like us to work on the regulation reclassifying the device?

            CHAIR REKOW:  Yesterday afternoon would have been good.

            MR. SCHECHTER:  This is Dan Schechter.  Do we get to ask the petitioner what priority they like?  As industry representative, I endorse high priority.

            CHAIR REKOW:  Do you ever get anything that isn't high priority?

            DR. BURTON:  You could try carbon dating.

            CHAIR REKOW:  Excuse me?  What did you say, Rick?

            DR. BURTON:  I said we could try carbon dating.

            CHAIR REKOW:  Do you ever get anything that isn't high priority, Susan?

            MS. SHULMAN:  I can tell you.  Marjorie.  We do get some things that are low priority if they are Class III already undergoing 510(k), so it's not a change in the regulatory path, PMA versus 510(k).

            MR. SCHECHTER:  This is Dan Schechter.  In all seriousness, given that there aren't many or any, at this point, products in this category on the market and, although, the studies we have may not be gold standards studies, it does seem to be a very helpful product.  I would just push for a high priority, so that these products can actually get back out there on the market.

            CHAIR REKOW:  Is there anyone that would argue otherwise?

            SECRETARY ADJODHA:  Did we vote on what classifications?

            CHAIR REKOW:  Oh, I guess Michael has just brought up that we didn't formally vote on which classification --

            MS. SHULMAN:  We'll vote on the sheets when completely done.

            CHAIR REKOW:  Okay.  I'm sorry.  So I'm hearing the priority should be high.  David?

            DR. COCHRAN:  I think medium would work, as well, for fairness to the FDA, but I don't really care how we go on this one.

            MS. BLACKWELL:  We can't go any faster.

            DR. BURTON:  It's sort of like the mule.  It only has one speed.  You can dangle carrots or a whip.

            CHAIR REKOW:  Rather than putting anyone on the spot, is there anyone who will --

            DR. GLOWACKI:  I'll go on the spot.

            CHAIR REKOW:  Go ahead.

            DR. GLOWACKI:  Julie Glowacki.  I think, you know, having made this recommendation for reclassification is absolutely no reason to suggest any delay, and I think we ought to say high.

            CHAIR REKOW:  Any other comments, suggestions?  All right.  I will take that as affirmation.

            MS. SHULMAN:  Okay.  Number 7, if device is an implant or is life sustaining or life supporting and has been classified in a category other than Class III, explain fully the reasons for the lower classification with supporting documentation and data, and we may say as discussed in the Panel meeting if you so wish.

            CHAIR REKOW:  Is there anyone that would like to explicitly state all of our things, as opposed to saying as discussed in the Panel meeting?

            MS. SHULMAN:  Okay.  Number 8, summary of information, including clinical experience and judgment upon which classification recommendation is based.  You can also say as discussed in the Panel meeting.

            CHAIR REKOW:  Anyone want to say other than that?  Hearing nothing, we'll go on.

            MS. SHULMAN:  Number 9, identification of any needed restrictions on the use of the device, for example, special labeling, banning prescription use, anything else besides what has already been discussed in the risk to health?

            DR. BURTON:  Children.

            MS. SHULMAN:  Pardon me?

            DR. BURTON:  Children, children.

            MS. SHULMAN:  Oh, pediatric?  All right.

            CHAIR REKOW:  Julie brought up a list.  I'll have to write and talk at the same time.  That never works.  Julie brought up a series of questions.  Do we want to go with any of these?  If I remember her list, it was not doing infected sites, being careful about overfilling, discontinuous defects.

            DR. GLOWACKI:  Discontinuity.

            CHAIR REKOW:  Discontinuity defects, I'm sorry.  I guess now that we have only granules, we won't worry about the block and the machinability.  Concurrent use with implants, I guess we have taken care of that.  One that we haven't addressed is the suitability of mixing it with other materials, and that might be either inert materials and/or biologic materials, but I guess under this umbrella, it would be with other inert materials, perhaps HA, perhaps other forms of the TCP, and whether or not we need to explicitly say to avoid various tissue types, including the blood stream, and I think you mentioned soft tissue and nerves and the dental pulp and those sorts of things.

            So do we need to go with a conversation in any of those?  David?

            DR. COCHRAN:  This is David Cochran.  My comment is even on the pediatric one, we really don't have any data to say anything about these or any of these, at this point, and I think we almost have to rely on the FDA that when they get the applications or the 510(k)s, that the data they get supports whatever indication you're going to use, and I would just vote that we allow that to happen.

            CHAIR REKOW:  So I guess we don't have a burden of proof to be able to prove that it is an issue.  It's a concern that we have, but there is no proof and there is plenty of practical usage proof that suggests otherwise.  Do we need to worry at all about the mixing and combinations or does more than 50 percent --

            DR. PATTERS:  The guidance document should cover that.

            CHAIR REKOW:  The guidance document can cover it?

            DR. RUNNER:  The mixing has already occurred in cleared 510(k)s in terms of --

            CHAIR REKOW:  Okay.

            DR. RUNNER:  However, if that's something that you think we should look more into in terms of concerns, you know, the Panel transcript is reviewed and your concerns are looked at when we do write the guidance document.

            CHAIR REKOW:  Okay.  So I guess the answer to Number 9 is nothing other than what has already been discussed.

            MS. SHULMAN:  Perfect.

            DR. GLOWACKI:  This is Glowacki.  Since pediatric was brought up, I wonder about the geriatric, extreme geriatric population, where there-- you know, with the prevalence of diabetes and inadequate healing responses of diabetics and geriatric patients that we may also want to think about an upper end of the age or health status just as we begin on the lower level.

            CHAIR REKOW:  Mark?

            DR. PATTERS:  Mark Patters.  I think that's the clinician's judgment about the surgical risks involved for any given patient, and there is no reason to believe that in a perfectly healthy 80 year-old patient, this device would not be helpful, so it has nothing to do with their age.  It's just surgical judgment.  Some patients are not candidates for surgery.  I'm not sure it's device related.

            CHAIR REKOW:  The same would be true for biologic, pathologic conditions and various disease states, I think.  Okay?

            MS. SHULMAN:  Okay.  Number 10 we get to skip, because it's not a Class I device.  Number 11, if the device is recommended for Class II, recommend whether FDA should exempt it from pre-market notification.  That's a yes and a no.  A Class II device can be exempt from pre-market notification and we would not see, so you would vote yes or no.

            CHAIR REKOW:  Can I have a vote, David?

            DR. COCHRAN:  Cochran, no.

            DR. BURTON:  Burton, no.

            DR. PATTERS:  Patters, no.

            DR. GLOWACKI:  Glowacki, B, no.

            DR. SUZUKI:  Suzuki, no.

            CHAIR REKOW:  You have it.

            MS. SHULMAN:  Okay.  Number 12, existing standards applicable to the device of assemblies, components or device materials.  We can say what we have discussed earlier, though it has been presented or if you wanted to add any.

            CHAIR REKOW:  Does anybody have any compelling standards that we have overlooked so far in our conversation?

            DR. SUZUKI:  Suzuki, nothing to add.

            CHAIR REKOW:  Angela?

            MS. BLACKWELL:  I think there is an ASTM standard that's out there.

            CHAIR REKOW:  Can we say this is as discussed?

            MS. SHULMAN:  We can, as discussed in the Panel meeting.

            CHAIR REKOW:  Okay.  And if there are new ASTM standards and ISO standards, I would assume that those would be applied as part of the guidance document anyway.

            MR. SNIDER:  Those would be reviewed and applied.

            MS. SHULMAN:  Then you will take one final vote on the forms as filled out and voted upon as a Class II device reclassification.

            CHAIR REKOW:  Okay.  So the question is should this be reclassified as a Class II device.  Jon?

            DR. SUZUKI:  Suzuki, yes.

            DR. GLOWACKI:  Glowacki, yes.

            DR. PATTERS:  Patters, yes.

            DR. BURTON:  Burton, yes.

            DR. COCHRAN:  Cochran, yes.

            MS. SHULMAN:  Thank you very much for your time.

            CHAIR REKOW:  Is there any other comments or statements that anyone has a compelling urge to make?  Hearing none, I thank you all, and it has been fun, as always, Susan.

            SECRETARY ADJODHA:  Onto the closed session now.

            CHAIR REKOW:  Now, we have a closed session.  Sorry.

            DR. BURTON:  Can we take a break first?

            DR. COCHRAN:  Take a break.

            SECRETARY ADJODHA:  Yes.

            CHAIR REKOW:  No.

            DR. BURTON:  I'm going to have to take my own.

            DR. COCHRAN:  Yes, me, too.

            CHAIR REKOW:  Why don't we take a 10 minute break, and then we'll come back for a closed session.  Thank you all.

            (Whereupon, at 3:04 p.m. a recess until 3:17 p.m., when the Panel resumed in Closed Session.)