U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES

FOOD AND DRUG ADMINISTRATION

CENTER FOR DEVICES AND RADIOLOGICAL HEALTH

MEDICAL DEVICES ADVISORY COMMITTEE

MEETING OF THE

DENTAL PRODUCTS PANEL

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.

[PRESENT]{.underline}:

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

[FDA PARTICIPANTS]{.underline}:

M. SUSAN RUNNER, DDS, MA, Captain, USPHS

KEVIN P. MULRY, DDS, MPH

ROBERT S. BETZ, DDS, Captain, USPHS

MARJORIE SHULMAN

[SPONSOR PARTICIPANTS]{.underline}:

VINCENT J. MORGAN, DMD

THOMAS DRISKELL

JOHN R. LONG, Ph.D.

**[AGENDA ITEM]{.underline}** **[PAGE]{.underline}**

[CALL TO ORDER]{.underline}:

Michael Adjodha 3

[CONFLICT OF INTEREST SURVEY]{.underline}:

Katherine McComas 7

[RECLASSIFICATION OF TCP]{.underline}:

Kevin Mulry 9

[RECLASSIFICATION PETITION]{.underline}

Robert Betz 13

Vincent Morgan 28

Thomas Driskell 33

John Long 46

[AMERICAN ACADEMY OF PERIODONTOLOGY]{.underline}:

Mark Reynolds 58

[CURASAN AG CORPORATION]{.underline}

Gunter Uhr 69

[REGULATORY CONSULTANT FOR CURASAN AG]{.underline}:

Thomas Arrowsmith-Lowe 84

[PANEL PRESENTATION/DISCUSSION]{.underline}:

Jon Suzuki 121

Julianne Glowacki 123

[CLASSIFICATION QUESTIONNAIRE]{.underline}:

Marjorie Shulman 153

[ACTION TAKEN]{.underline}:

Dianne Rekow 207

P-R-O-C-E-E-D-I-N-G-S

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]{.underline} 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]{.underline} 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.)