UNITED STATES OF AMERICA + + + + + FOOD AND DRUG ADMINISTRATION + + + + + ORTHOPEDICS AND REHABILITATION DEVICES ADVISORY PANEL + + + + + PUBLIC MEETING

+ + + + + THURSDAY, JANUARY 10, 2002 The Advisory Panel met at 9:30 a.m. in the Walker/Whetstone Room of the Gaithersburg Holiday Inn, Two Montgomery Village Avenue, Gaithersburg, MD, Dr. Maureen Finnegan, Acting Chair, presiding. PRESENT: Maureen Finnegan, M.D. Barbara D. Boyan, Ph.D. Betty Diamond, M.D. John Doull, Ph.D., M.D. Edward N. Hanley, M.D. John Kirkpatrick, M.D. John Kostuik, M.D. Kinley Larntz, Ph.D. Leon Lenchik, M.D. Stephen Li, Ph.D. Sally Maher, Esq. Richard K. Miller, Ph.D. Sanjiv H. Naidu, M.D., Ph.D. A. Hari Reddi, Ph.D. Karen Rue Gene P. Siegal, M.D., Ph.D. Rocky Tuan, Ph.D. Hany Demain, M.S. Acting Chair

Executive Secretary

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TABLE OF CONTENTS PAGE Call to Order, Opening Remarks, Deputization,. . . . . .3 and Conflicts of Interest Statements Open Public Session Patsy Trisler...............................12 Dr. John McCullough.........................19 PMA for InFUSETM Bone Graft Cage Petitioner's Presentation Gerard Riedel...............................49 Scott Boden.................................69 Hal Mathews.................................84 FDA Presentation Aric Kaiser................................113 Peter Hudson...............................116 Barbara Buch...............................130 Telba Irony................................145 Guest Presenters Rocky Tuan.................................156 Richard Miller.............................165 John Kostuik...............................178 Panel Discussion Hari Reddi.................................185 John Kirkpatrick...........................189 Kinley Larntz..............................196 Public Session...................................308 Panel Discussion and Vote........................311

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P-R-O-C-E-E-D-I-N-G-S (9:41 a.m.) MR. DEMIAN: would first like to Good morning, everyone. you to this I

welcome

meeting.

We're ready to begin this meeting of the Orthopedic and Rehabilitation Device Advisory Committee. My name

is Hany Demian, and I'm the Executive Secretary of this Committee. I'd first like to remind everyone that you're requested to sign in on the attendance sheets which are available outside the doors. pick up an agenda and how information to find out You may also about about today's future

meeting,

including

meeting dates through the advisory panel phone line and how to obtain meeting minutes or transcripts I will now read two statements that are required to be read into the record. The first one is

the appointment to temporary voting member status and the conflict of interest statement. "Appointment to Temporary Voting Status; pursuant to the authority granted under the Medical Device Advisory Committee Charter, dated October 27th, NEAL R. GROSS
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1990 and as amended August 18th, 1999, I appoint the following individuals as voting members of the

Orthopedic and Rehabilitation Device Panel for this meeting on January 10th, 2002; Kinley Larntz, Sanjiv Naidu, Leon Lenchik, Gene Siegal, John Kirkpatrick, Barbara Boyan, John Doull, Betty Diamond, and Hari Reddi. For the record, these individuals are special

government employees and consultants to this panel or other panels under the Medical Device Advisory

Committee. They have undergone the customary conflict of interest review and have reviewed the material to be considered at this meeting. In addition I appoint

Dr. Maureen Finnegan to serve as acting Chairperson for the duration of this meeting", and this is signed by David Feigal, Director of CDRH. "Conflict of interest statement; The

following announcement addresses conflict of interest issues associated with this meeting and is made part of the record to preclude even the appearance of any impropriety. To determine if any conflict existed the

agency reviewed the submitted agenda for this meeting NEAL R. GROSS
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and

all

financial

interests

reported

by

the

committee's participants.

The Conflict of Interest

Statute prohibits special government employees from participating in matters that could effect their or their employer's financial interests. However, the agency has determined that the participation of certain members and consultants, the needs for whose services outweigh the potential conflict of interest involved is in the best interests of the government. Therefore, waivers have been

granted for Doctors Stephen Li, Kinley Larntz, Edward Hanley firms and that John could Kirkpatrick for be their interest by in the

potentially

effected

panel's recommendations. The waivers permit them to participate in all matters before today's panel. Copies of these

waivers may be obtained from the agency's Freedom of Information Building. Office, Room 12A-15 of the Parklawn

We would like to note for the record that

the agency also took into consideration other matters regarding Doctors Li, Larntz, Maureen Finnegan,

Barbara Boyan and Gene Siegal. NEAL R. GROSS
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Each of these panelists reported current or past interests in firms at issue but are not

related to today's agenda. therefore, that they may

The agency has determined, participate fully in all

deliberations. matters agency that has

Dr. Hanley has a past involvement with are related to today's agenda. that he The may

determined,

however,

participate in the panel discussions. We would like to also note that Doctors Rocky Tuan and John Kostuik are guests at this meeting and have reported interests in the firms at issue. the event that the discussions involve any In

other

product or firms not already on today's agenda, for which an 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 fairness -- in the interest of fairness that all persons making statements and presentations disclose any current or previous financial involvement with any firms whose products they may wish to comment NEAL R. GROSS
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upon". Before turning this meeting over to Dr. Finnegan, I would like to introduce our distinguished panel members for generously giving their time and effort to help FDA in matters being discussed at

today's meeting and other FDA staff seated at this table. So we'll go around the room and give your name

and affiliation and your current areas of research. Dr. Finnegan? CHAIRPERSON FINNEGAN: Maureen Finnegan,

I'm an orthopedic surgeon at Southwestern Dallas and I do -- my research is mainly fracture repair. DR. KIRKPATRICK: I'm John Kirkpatrick.

I'm an orthopedic surgeon and spine surgeon from the University of Alabama at Birmingham. DR. SIEGAL: I'm Gene Siegal, also from

the University of Alabama at Birmingham and I'm an anatomic pathologist. DR. HANLEY: Edward Hanley, orthopedic

spine surgeon, Carolinas Medical Center, Charlotte, North Carolina. DR. DIAMOND: Betty Diamond, Albert

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Einstein College of Medicine. rheumatologist. DR.

I'm an immunologist and

I'm on sabbatical at NIH. DOULL: I'm John Doull. I'm a

clinical toxicologist from the University of Kansas Medical School. DR. LI: in biomechanics and I'm Stephen Li. biomaterials. I'm interested I'm current

president of Medica Device Testing Innovations located in Florida. DR. Division WITTEN: of the Celia Witten. of which I'm the

Director and

Division Devices

General is the

Restorative

Neurological

reviewing division for this product for FDA. MS. MAHER: and Nephew Endoscopy Sally Maher. and I'm I'm with Smith the industry

representative. MS. RUE: I'm Karen Rue. I'm an R.N. I'm

consumer representative. DR. LARNTZ: Kinley Larntz, Professor

Emeritus, Statistics, University of Minnesota and I'm a statistician interested in clinical trials. DR. LENCHIK: NEAL R. GROSS
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Leon

Lenchik,

Musculoskeletal

Radiologist

from

Wake

Forest

University in Winston-Salem, North Carolina. DR. REDDI: I'm Hari Reddi. I'm a student

of bone morphogenetic proteins. DR. BOYAN: Barbara Boyan. I'm a

professor at the University of Texas Health Science Center at San Antonio and my specialty is bone and cartilage cell biology. DR. NAIDU: Sanjiv Naidu. I'm an

orthopedic surgeon at Penn State College of Medicine in Hershey and my interest is in biomechanics and orthopedic surgery. MR. DEMIAN: In addition, I'd like to

introduce our three guests who are seated over here, Dr. Richard Miller, Rocky Tuan and John Kostuik. CHAIRPERSON FINNEGAN: Thank you, Hany.

As I previously stated, I'm Maureen Finnegan and I will be the chair for this meeting. Today the panel

will be making recommendations to the Food and Drug Administration regarding a pre-market approval

application for a spinal fusion cage with a growth factor soak in a collagen sponge use to treat lumbar NEAL R. GROSS
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degenerative disc disease. I need to note for the record that the voting members present constitute a quorum as required by 21 CFR Part 14 and we will now proceed with the open public hearing session of this meeting I would like to ask at this time that all persons addressing the panel come forward and speak clearly into the microphone. The transcriptionist is dependent on this

as a means of providing an accurate record of this meeting. We would request that all persons making statements during the open public hearing of the

meeting disclose whether they have financial interests in any medical device company. Before making your

presentation, please state your name, affiliation and the nature of your financial interest if you have any. There's obviously someone who wishes to address the panel. MS. TRISLER: Patsy Trisler and I'm a Good morning, my name is regulatory a consultant at

PharmaNet, organization.

Incorporated,

contract

research

As an employee of PharmaNet, I have NEAL R. GROSS

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www.nealrgross.com

several

clients

who

are

orthopedic

product

manufacturers but I have no financial interest in any of them. CHAIRPERSON FINNEGAN: Ms Trisler, you had

made a request to make an oral presentation. MS. TRISLER: Yes. What we would like

CHAIRPERSON FINNEGAN:

to do is ask those people who had not made such a request, we do have two -a request for oral

presentations which we have put into the program and that's the next part of the program, so we would ask those people who had not made such a submission if they would like to make a presentation. MS. TRISLER: All right, I apologize. So if you'd give us

CHAIRPERSON FINNEGAN: one second.

Is there anyone else other than the two

parties who had made a formal request to make an oral presentation? (No response) CHAIRPERSON FINNEGAN: then we have had two requests. All right, if not,

One is from Osteotech

and one is from Striker Biotech and we will start with NEAL R. GROSS
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Ms. Trisler.

Go ahead. MS. TRISLER: Thank you and I apologize

for jumping the gun.

As I indicated, I'm an employee I would

of PharmaNet, Incorporated which is a CRO.

like to thank the Chairperson and the FDA Executive Secretary for providing the opportunity to speak to you today. The purpose of my brief presentation is to express some concerns in the form to review of the potentially combination by this

unanswered products of

questions the As type you

relating under

today been

committee.

know,

there

have

several

spinal fusion cages or systems approved by the FDA over the last five years. These products approved for

treating degenerative disc disease are to be used with autogenous bone grafts. Papers are being published reporting the successes observed with the use of the cages. It is

clear also that there remains some problems or issues such as subsidence. is not on the of The focus of my comments, though, but rather the on the biologic

cages

component

the

device,

bone

morphogenetic

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protein or BMP. As I'm sure you are aware even though BMPs have been under evaluation clinically now for about 15 years, only one has been allowed into the marketplace by the FDA. The approval is a limited one in the form

of a humanitarian device exemption for treating long bone, failed. non-unions when alternative treatments have

That product is human recombinant BMP-7 and

bovine bone derived collagen. This PMA before you today represents an important advance in medical device technology. BMPs

and other growth factors are potent compounds that offer significant promise in many therapeutic areas. Further, the potential of BMPs or other growth factors combined with traditional However, before medical the devices first is

significant.

combined

product of this type achieves market approval, it's very important to be certain all the appropriate

questions have been addressed, have been both raised and addressed and as I indicated, this is the reason I'm speaking. I do not know the full extent of Medtronic NEAL R. GROSS
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Sofamor Danek safety and effectiveness data.

However,

I do know this is a reputable company and my comments are by no means meant to challenge the capabilities, integrity of the data or quality of the studies

performed by them.

While we recognize that Center for

Biologic staff participates in reviews of products of this type along with the Devices Center, the issues posed by the biologic component are quite different from the issues typically presented to this committee. The standard of proof is different for drugs and biologics provided The than the for FDA devices. in those the Thus, areas the are

guidances different.

by

issues

that

prompt

following

questions, in fact, are not covered in the devices guidance document for spinal systems. As a member of

the public, I ask that you consider these questions in your deliberations. My promotion. first Cancer point is related by to cancer growth

promotion

cytokine

factors is well known, particularly when circulating blood levels are greater than normal or baseline as in the case of recombinant BMP. NEAL R. GROSS
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My question is, is

enough known about the cancer promoting capability of BMPs. I question the status if this growth factor,

BMP-2 as a cancer promoting compound. In my review this morning of the panel briefing surprised clinical approval. materials, that safety If FDA my has very quick review, I was nonpostadverse

agreed may

that be

certain

studies transformed

conducted or other

cells

events are seen after this implant has been released to the market, what is the surgeon to tell the

patient? I approved, that noted in the with BMP-7 a product that is are

patients

cancer

history

contra-indicated for the current -- for that product approval. Will it be necessary to similarly contra-

indicate this BMP that is before you today or is the risk to benefit fully profiled? My second point relates to the immunology area. Circulating antibodies to both Type I collagen I know the FDA has dealt with Are no

and BMPs are reported.

this matter in the collagen area for many years. enough data available to demonstrate there is

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correlation

between

these

antibodies

and

health

or

medical events?

Is the safety risk greater if a BMP

is inappropriately and perhaps inadvertently applied directly to the spinal canal? Has the autoimmune

reaction potential been fully evaluated? My third point relates to cardiovascular. Cardiac adverse events and increased blood pressure and body temperature have been reported in animal Is

studies.

The effects reported are dose dependent.

there sufficient assurance that benefits of the use of the BMP collagen mixture in a sensitive body area are outweighed by the potential risk to the cardiovascular system? The other BMP approved for orthopedic use and

this one are provided with collagen as a carrier. While I realize this may -- this question may not be particularly important, since there are potentially greater risks with the use of a growth factor in the spine than there are at a long bone nonunion site, are data available to show that collagen alone is not effective in improving the rate of spinal fusion? I believe this next point deserves

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particular attention.

As is well-known, the early

work of Dr. Urist demonstrated the ability of a bone inductive extract from adult bone to induce new bone formation at ectopic sites. Have the studies

published since that time sufficiently looked at the quality of the bone produced of bone and in at the risk of and

uncontrolled

growth

the

immediate

surrounding region of the implant?

I have heard of

one case in which bone grew into the spinal canal although I'm unaware of the extent of the problem. Has a full enough evaluation been

performed to be reasonably sure that if a large amount -- if a larger amount than indicated is applied in the spinal fusion area, the risk of in-growth won't occur. There is one final issue relating to a problem that is not limited to orthopedic devices, the expanded or off-label use in the medical community of a product approved for a very limited indication. While I believe the medical community, not the government, in should case control it the practice the risk of is

medicine,

this

seems

significant for off-label use of the BMP component of NEAL R. GROSS
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this device system.

Because of this, I feel that it

is important for the panel to, perhaps, give more consideration than is usually done to this issue. As

I noted earlier, many of the reported adverse events were dose dependent. Since BMPs are potent compounds that have systemic effects and this particular product is the first of a kind for this use, I am concerned that the pharmacodynamics may not be fully understood. After

this product type is out in the marketplace, if it is misused or misapplied, the potential for patient harm is great. In closing, I ask the panel to give

special attention to the potential for off-label use. I realize I have just scratched the surface of a number of areas and have or not data provided and you with

substantive

information

that

others,

perhaps, will raise some more concerns.

I am hoping,

though, that none of these topics remain issues after today's review. This concludes my comments. Thank

you for this opportunity. CHAIRPERSON FINNEGAN: Thank you for

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having the interest.

I did interrupt you when you Would you

were going through your financial interest. mind reviewing those? MS. TRISLER: I am employed by Yes.

No, I would not mind. which is a contract

PharmaNet,

research organization. many areas. product area. them. CHAIRPERSON consulting firm. MS. TRISLER: CHAIRPERSON

As such, I have clients in

I have several clients in the orthopedic I have no financial interest in any of

FINNEGAN:

So

you're

a

Yes. FINNEGAN: Okay. And I

believe our next presenter is from Striker Biotech. DR. McCULLOUGH: My name is John

McCullough and I'm an orthopedic spine surgeon from Denver, Colorado. I am not from Striker Biotech. I'm

here to offer an opinion regarding today's discussion on the BMP-2 interfix threaded fusion cage PMA and I thank the panel for granting me permission to speak. My travel has been paid for by Striker Biotech. I

have no financial interest in the company and I'm not NEAL R. GROSS
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a paid consultant. I've participated in the Striker Biotech pilot study using BMP-7 for to in the human my lumbar

intertransverse received study.

interval funds

which cover

institution cost of the

research

the

Contrary to questions by my colleagues prior

to this meeting, I am here in a positive relationship with BMP, not a negative relationship. Studies great promise for as of BMP-2 and BMP-7 osteo autograft and spinal have shown

potential crest

inductive for bone fusion

replacements healing in

iliac

appendicular

applications. inter-transfers effectiveness, meticulous

In working with BMP-7 in the lumbar interval, but I'm I am impressed impressed to with with its the the

also

technique

required

increase

likelihood of a solid fusion. It is a much less forgiving milieu for fusion than the interbody interval mainly because it is a soft tissue bed on which the body never intended bone to form. A solid anterior lumbar interbody

fusion is a relatively easy outcome to achieve but NEAL R. GROSS
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it's a technically demanding surgical approach fraught with serious complications. The lumbar It's an

intertransverse fusion is just the reverse.

easy, safe, posterior surgical technique but obtaining a solid fusion is much more difficult. As an example, allograft bone will often successfully incorporate in an interbody fusion model but it is useless in the adult intertransverse

interval.

The success of fusion with BMP-2 in a

collagen sponge with the interfixed threaded fusion cage, the subject of today's discussion, is well

established by the research of Boden's Zdeblick, Sandu and Hine. The researchers, the brave patients who submitted themselves to this largely successful pilot study and the company supporting the research are to be congratulated. It is not my purpose today to call

into question the efficacy of BMP-2 and its use in an interbody fusion with the interfixed threaded fusion cage. My concern, as with the last speaker's last

point, is the potential off-label use of BMP-2 soaked in a collagen sponge. NEAL R. GROSS
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There is a potential for surgeons to take an off-label approach if the panel does not carefully consider the labeling and packaging considerations

available with this product and provide the option that will prove to be the best direction and control of the product and its potential off-label use. One

off-label use for this BMP-2 collagen sponge model is the lumbar intertransverse interval. My concern for

such usage is found in the research work done by Martin Boden, et al in the posterior lateral

intertransverse fusion non-human primate model. The efficacy of the BMP soaked in a

collagen sponge, in this particular intertransverse fusion application was negatively impacted by the soft tissue and muscle compressing the sponge and thereby, compressing the growth factor out of the sponge. led to an unexpectedly high failed fusion rate. This It is

easy to conclude that this scenario would conclude in humans with BMP-2 and a collagen sponge carrier. this setting the potential is for the muscle In to

compress the collagen sponge and leak the BMP-2 away from where the bone is intended to form. NEAL R. GROSS
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To induce new bone formation, it is not currently feasible or practical to apply BMP directly into a bone void for the purpose of bone growth. carrier is needed for a number of reasons. A

One of the

main reasons is for the containment of the growth factor at a site where bone growth is needed. A

carrier is also needed for stem cell attachment and to provide a structural matrix for bone growth. Well, BMP-2 and BMP-7 have been shown to be two of the most effective BMPs in the bone healing cascade, the carriers used by these BMPs and

ultimately the orthopedic application site in which they are placed can effect their efficacy regardless of their potency. today has BMP-2 been sponge and used carrier the studies a being fibular in the

discussed hemostatic

with

collagen

placed

interfix titanium threaded interbody cage. In this application, liquid BMP-2, a

combination of BMP and sterile water, is applied into the collagen sponge inter-operatively and allowed to soak into the sponge. placed into the cage. The sponge is then rolled and In this application it is

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important combination

to is

note

that

the by

BMP the

collagen structure

sponge of the

protected

titanium cage. In the intertransverse interval, this same BMP-2 soaked collagen sponge would enjoin no cage

protection.

Rather as Boden et al suggested, its

compression by muscle would possibly lead to extrusion and dissipation of the BMP-2 and a failed bone

induction. Bone represents surgeons an and morphogenic exciting patients and alike protein new that research for may

opportunity over time

revolutionize the way we treat our patients.

Getting

rid of the bond graft harvest is an exciting concept and could possibly overrun the relative lack of

knowledge amongst my colleagues about this technology. There may be a temptation to push the envelope when it comes to indications and applications. opportunity, also comes the With this new and

responsibility

challenge of not only appropriate patient selection but also appropriate product labeling. My strong assertion and belief is that we NEAL R. GROSS
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need

to

make

every

effort

possible

to

insure

the

health and benefit of our patients through appropriate labeling in regards to this PMA. The BMP-2 collagen

sponge device has been tested in an IDE study for specific spine pathology with a specific type of

branded cage in the interbody interval. If approved, I hope the indication for use will be for this particular combination of BMP carrier and cage product. combination that they Since this product was tested as a cage with BMP, the the requirement they are This

product be

packaged

together

way

intended to be used is reasonable and logical.

provides an additional and important opportunity to further insure that the use of the growth factor will be used in an application where efficacy has been proven. Off-label posterolateral eliminated as use in areas fusion my such will as not the be but

intertransverse an option to

colleagues,

packaging the BMP and cage together will limit the product's use in an unproven and potentially flawed application. NEAL R. GROSS
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In concluding, I defer to commenting on the final approvability of this product. I am an

enthusiastic supporter of the BMPs but in the event it is voted to be approved, I would recommend that the combination specifically of the interfixed to be cage ordered and BMP-2 be and

required

together

packaged together to insure the product is used as has been tested. I would also recommend that off-label

use of BMP-2 and the collagen sponge in areas outside of the application such as the intertransverse

interval be addressed in the product labeling. Thank you. CHAIRPERSON FINNEGAN: Witten. DR. WITTEN: We also need to ask the prior Thank you. Dr.

speaker who paid her way, whether she paid her way or whether her way was paid for. CHAIRPERSON FINNEGAN: come back. Okay, I'll have her Ms.

Dr. McCullough, thank you very much.

Trisler, is she still with us?

While she's coming up,

are there any other persons who would wishy to make a comment? Go ahead. NEAL R. GROSS
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MS. question?

TRISLER:

I'm

sorry,

what

was

the

CHAIRPERSON FINNEGAN: to the meeting? MS. TRISLER: has. CHAIRPERSON FINNEGAN: to the meeting? MS. TRISLER: they paid my time. CHAIRPERSON FINNEGAN:

Who paid your way

As a consultant Osteotech

Has paid your way

Well, yeah, I live here but

Thank you.

All

right, if there are no other people wishing to make comments, Mr. Demian has received eight letters

regarding this meeting and he will now read them into the record. MR. DEMIAN: and seven of them are I've receive eight letters from spinal surgeons, all

letters regarding the use of BMP. from Dr. Regis Haid.

The first letter is

"I am currently the chief spine surgeon for the Department of Neurosurgery at Emory University in Atlanta, Georgia. I have no vested financial

NEAL R. GROSS
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interest in the product being discussed before the panel. various I've developed products for cervical spine for companies, including Medtronic, Codman and

Spinal Concepts.

These may be considered by some to I've

constitute an indirect conflict of interest. received no renumerations for my interest in BMP.

Our group has been involved in the use of BMP. We have been given presentation on fusion

techniques at national and international meetings and have briefly discussed the experimental use of BMP. We have actually published a paper in the Neuroscience Focus on the use of BMP. studies and presentations From my knowledge of the I've heard presented by

other spinal surgeons, I do believe that BMP offers a significant advantage in the practice of spine. It is very clear from my experience that the literature in neurosurgery and orthopedics state that autograft sites It do is present also iliac a well array of

complications. harvesting the

commonly crest

known

that to

autograft

adds

time

surgery and expense in the operating room and pain to the patient is always part of the harvesting autograft NEAL R. GROSS
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iliac crest. I would ask the panel to recommend to the FDA to expedite their approval of this product. This

would prevent further suffering of patients that occur with every autograft bone harvest as well as

potentially decreasing the time in the operating room and, thus, potentially decrease the total cost to the patient. Having reviewed the data from the academic

perspective, it seems very clear to me its efficacy is clear-cut in the use in lumbar interbody anterior

devices and that the product should be made available to the American public. Although I'm not an expert on the FDA, it is my belief that FDA required a small pilot study for this device under review and this was done before a large pivotal study could begin. the case, I believe a delay of the If this is indeed

this was unnecessary and prompted release of this product which

definitely benefits patients.

I would suggest that

the Orthopedic Advisory Panel recommend to FDA not to require these types of pilot studies for similar

issues in the future". NEAL R. GROSS
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The second letter is from David Malone. "I would like to add some information to the premarket approval application for a spinal fusion cage with growth factors soaked in a collagen sponge

intended for treatment of lumbar degenerative disease. I took part as one of the investigators in the

posterior lumbar interbody fusion BMP trial sponsored by Medtronic Sofamor Danek Corporation. Dr. Frank Tomecek was the lead

investigator for our small group.

There were a number Two of over-

of patients that were treated with the PLIF. the patients had significant on their posterior nerve roots bony

growth

impinging

requiring

additional surgery.

One patient, who was my patient,

required two surgeries to clear excessive bone growth from his spinal canal. over the past year. He has had no new bone growth

I am unsure as to whether or not

this data has been included in the application to the FDA. I've been told that the posterior lumbar in a body fusion cage trial was halted. I assume it With

was because of this bony overgrowth problem. NEAL R. GROSS
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www.nealrgross.com

regard

to

the

patients

with

bony

overgrowth,

I

personally experience -- my personal experience in reoperation on both of these patients, the bone quality from the BMP is robust and excellent. solid. The fusions are

I do feel that the BMP is a useful adjunct to

bony spinal fusion. However, BMP may lead to excessive bone growth and may cause significant neural impingement if placed in posterior lumbar interbody type of device. There does need to be at this point in time some type of barrier between the area where the bone can

overgrow and the neural elements. Frank Tomecek and Sofamor

I note that Dr. did further

Danek

experimental studies on the PLIF model but I do not have the data. helpful if you I know the data does exist and may be are considering approval of this

material for a posterior lumbar interbody fusion type of approach. If BMP is approved for spinal fusion, and I feel that it would be useful adjunct, the caveat is that it must be placed in such a manner that bony overgrowth cannot grow into the spinal canal as I NEAL R. GROSS
(202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com

think

this

would

cause

significant

problems

for

a

proportion of the patients whom it is used in". The next letter is from Dr. Robert Banco. "As chief of the spine section of the New England Baptist Hospital, my colleagues and I are pleased to have participated in the rhBMP-2/ACS/LT open clinical trial. Serving as the principal investigator, two co-

investigators and myself are members of the Boston Spine Group, four orthopedic surgeons and one

physiatrist with a practice dedicated solely to spine. As fusions iliac a group many we of perform which As are over 400 spinal by

annually

accompanied

crest

harvesting. iliac crest

you

know, the

harvesting risk of

patients

with

increases

complications, including but not limited to infection, nerve damage and possible damage to the muscles and vessels. Donor site pain is by far the most common

complication and patient complaint. BMP-2 supplants the need for harvesting the iliac crest and therefore, negates the risk of these complications. have heard many We at the Boston Spine Group and have read the

presentations NEAL R. GROSS

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www.nealrgross.com

literature regarding BMP-2. reported outcomes.

We are excited by the

We are anxious for this product to

get out of the lab and into the clinical practice and are looking forward to the use of InFUSETM in the clinical setting". The McCormick. next a letter full time is from Dr. member Paul at My

"I'm

faculty

Columbia University of Physicians and Surgeons.

practice is exclusively limited to the evaluation and surgical management of patients with spinal disorders. By the way of disclosure, I have no financial or other vested interest in the products that are being

discussed before the panel. As a full time spine surgeon at a major academic center, I'm well aware of active research that has been conducted for years regarding biological enhancement of spinal fusion. Like many other spine

surgeons, I look forward with great anticipation when effective agents will be commercially available for the utilization in spinal fusion. Spinal fusion is an

important technique for many patients who have lost their mechanical integrity of their spinal elements NEAL R. GROSS
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through

trauma,

degenerative

changes,

neoplasm,

or

disc herniations in prior surgery. A major problem related to the spinal

fusion is the harvesting of the autograft which is usually required for a vast majority of spinal fusions currently performed. The pain and morbidity

associated with autograft harvest can be considerable. Often this pain persists over time and may be

permanent. Further, despite significant advances in fusion techniques and spinal instrumentations, a

measurable number of patients continue to suffer from failed fusion or pseudoarthrosis. Therefore, any

useful adjunct that can be utilized to facilitate and enhance spinal fusion would be of tremendous benefit to patients with spinal disorders requiring this type of surgery. In essence, there's a tremendous need for

biological fusion enhancers such as BMP that diminish the reliance on autograft harvesting as well as

enhancing the rate and the success of spinal fusion. I'm also well aware of the research that is currently being conducted at numerous centers

NEAL R. GROSS
(202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com

regarding BMP.

To my critical review, BMP has shown

exciting promise in enhancing spinal fusion and bone incorporation. I fully appreciate the

responsibilities of the FDA in general and of your panel in particular in acting in the public interest through oversight on the approval and introduction of these request devices that and such agents. evaluation I be would respectfully on in an

carried

expedited fashion so that if BMP satisfies the FDA requirements for approval, we can utilize this

substance in a timely manner. Such an expedited approval would likely reduce the pain and suffering of future patients that are requiring spinal fusion". The next letter is from J.J. Abitol. a practicing spinal surgeon, also a current "I'm board

member of the North American Spine Society where I have been a past is scientific no current program official chairman. position

Although

there

statement from the Society, I would like to express my opinion about bone morphogenetic proteins or BMPs.

Being familiar with the research in this area, I can NEAL R. GROSS
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say with certainty that BMP has been one of the most heavily researched subject matters in all of

orthopedics. Since the late Dr. Marshall Urist first discovered these proteins of over 30 years and ago, and

unprecedented efforts proteins. have

amount been

publications to

research these

dedicated

studying

For all practical purposes, all of these

studies have demonstrated to the research and medical community that safe and new alternative to taking

autograft is now at hand. I strongly urge this panel to approve

these desperately needed proteins and make Dr. Urist's dream of having bone graft in a bottle a reality. It

is time to take these type of proteins out of research and make them available to surgeons to use in our clinical practice to treat patients". Our next letter is from Dr. John Peloza. "I'm a nationally recognized spine expert with a

tertiary specialty practice in Dallas, Texas.

In my

practice I perform many spinal fusion procedures on all levels of the spine from the skull to the sacrum. NEAL R. GROSS
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These fusions are done from an anterior, posterior and sometimes combined approach. I'm often challenged by difficult spinal reconstruction problems secondary to disease processes including spinal deformity, degeneration, trauma,

tumor and infection.

My team and I have been and are

presently involved in multi-center studies evaluating spinal surgical implants minimally invasive and nonsurgical technologies as well as biological

technologies for the treatment of spinal disorders. I'm an authority on bone morphogenetic

protein from my experience as a clinical investigator with rhBMP-2, professional presentations, knowledge of the scientific literature, national and specialty

meetings and think tanks. with the impressive

I have direct experience results on my own

clinical

patients utilizing this protein. Presently we have a number of bone graft alternatives. The gold standard is the patient's own It is osteogenic, contains viable transplantation, osteo inductive,

bone or autograft. bone cells at

actively promotes or enhances bone formation and osteo NEAL R. GROSS
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conductive, acts as a structural framework or scaffold for bone formation. Unfortunately, it is in limited

supply, e.g. the patient's iliac crest. In many cases we have very little or no autograft harvest at all. Additionally, the bone to graft post-

surgery

contributes

significantly

operative pain that can be permanent and can lead to other complications. When autograft is not available

or inadequate, surgeons use allograft, bone bank or cadaver bone. Allograft osteo bone is mainly and osteo no

conductive,

weakly

inductive

has

osteogenetic properties. Depending on the surgical construct,

allograft fusion rates are lower than autograft and take much longer to heal. Due to the massive demand

for bone graft worldwide, allograft bone is also in limited supply. Additionally, allograft bone has a Modern bone processing

risk of disease transmission.

is effective in eradication of bacteria and viruses. However, prions are very difficult to detect and no processing has been validated for their removal. After autograft and allograft, surgeons

NEAL R. GROSS
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can

use

bone

graft

extenders,

demineralized

bone

matrix.

These products are mainly osteo conductive,

poorly osteo inductive if at all, and not osteogenic. They are the last line of bone graft material and informed surgeons have little confidence in their

efficacy in obtaining a solid fusion. Recombinant human bone morphogenetic

protein is an attractive infusion surgery for many reasons. The fusion rates in animal models and in

human trials is the same or better than the gold standard autograft. With a production facility there RhBMP will

would be an unlimited supply of rhBMP.

eliminate the need for bone graft harvesting surgery which will eliminate the associated pain, potential complications and cost. There transmission. will be no chance of disease

The major cost of sponsored surgery is This can occur secondary to a as infection but the most

when the surgery fails. major complication such

common reason for failed surgery is the failed fusion or pseudoarthrosis. spinal surgeons. NEAL R. GROSS
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This is a problem that vexes all

A

product

that

markedly

enhances

our

ability to heal bone with few documented side effects is an extremely powerful tool in the treatment of spinal disorders. RhBMP is a breakthrough product

that represents the best of our research and advances technologies. It has been thoroughly tested in animal It has consistently proven It is

models and human trials.

better and safer than our present alternatives.

time to get rhBMP into the clinical arena where it is desperately needed for the optimum care of people. Finally, I would like to state I have no financial interest in the product rhBMP-2 nor do I have a financial interest in the company that is

sponsoring rhBMP-2". Second to the last letter from a trio, Stephen Sonntag. Barrow Papadopoulos, Curtis Dickman and Volker

"We practice primarily spine surgery at the Institute in Phoenix, Arizona.

Neurological

Our practice consists of regional and national and international referrals. interest in the We have no vested financial product being discussed

specific

before the panel. NEAL R. GROSS
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We have been aware of the field of BMP research for several and years through peer review, We of this

publications strongly product

scientific the clinical

presentations. availability will

believe in the

United

States

significantly

enhance patient care.

Graft site complications from

autograft harvest are well described and documented. The availability, quality and healing issues related to allograft is also well known. Fusion failure may result in chronic pain, deformity and the need for We additional believe spinal the

reconstructive

procedures.

that

approval of BMP will provide a significant advance in the patient outcome and satisfaction". The last letter is from Dr. Doug Morrow. "It is my understanding that you are about to discuss and vote on approval or rejection of rhBMP. I want my

voice to be one that you may not otherwise get in the sense that I am both a physician and a patient waiting on the approval of this enzyme to fuse my lumbar spine. wherein I have rather an unusual set of circumstances I got an infected disc in my lower back

NEAL R. GROSS
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because of an injection called a discogram. The infection all but destroyed two lumbar vertebrae, leaving me in constant pain for the

instability associated with the deformity.

I've been

keeping up with all the literature on the subject and especially this enzyme which speeds up the natural healing process of growing bone. I'm a perfect

candidate for this material to be used in surgery on my back. I've been waiting for its use for some time

delaying my surgery because of it. I have back pain every day all day. I

urge you prompt approval of this material so that my doctor can then use it on me as soon as possible. There are many people just like me who need help. Please help us. I beg you and thank you from the

bottom of my heart". That's it. CHAIRPERSON Demian. FINNEGAN: Thank you, Mr.

You may get an award for that.

We will now

proceed to the presentation of the pre-market approval application P000058, Medtronic Sofamor Danek InFUSETM bone graft/LT-cage lumbar tapered fusion device. NEAL R. GROSS
(202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com

I

need to remind the public observers at this meeting that while this portion of the meeting is open to public observation, except at public the attendees may of not the

participate panel.

specific

request

We will proceed first with the sponsor's presentation followed by the FDA presentation. I

would like to ask each speaker to state his or her name, their affiliation and I would ask everyone to please speak into the microphone so that people in the back of the so room that can hear you but can also hear most you.

importantly

transcriptionist

The sponsors, if they would like to come up, could start. DR. LIPSCOMB: Members of the Orthopedic

and Rehabilitation Devices Advisory Panel, my name is Bailey Lipscomb and I'm the Vice President of Clinical Affairs at Medtronic Sofamor Danek in Memphis,

Tennessee.

We have the pleasure and the long awaited

privilege to present to you the results of decades of research, development, and clinical studies. At the

outset, we would like to thank literally thousands of NEAL R. GROSS
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people who have worked over the years to make these presentations possible. For the next 90 minutes we

will present for the first time to an FDA advisory panel the culmination of work arising from a discovery made by Dr. Marshall Urist in 1965. Dr. Urist found that certain proteins

which he later terms as bone morphogenetic proteins, stimulate the formation of bone and these proteins can literally make bone where bone did not exist before. In the early in to 1980's researchers of Wyeth-Genetics developed these a

Institute method

Cambridge, synthesize

Massachusetts several of

bone

morphogenetic proteins using recombinant methods. The BMP-2 yields from these methods are much greater in quantity and much purer in nature than can be obtained from natural sources. The bone

morphogenetic protein that will be reviewed today is recombinant human bone morphogenetic protein 2 or more commonly known in its abbreviated form as rhBMP-2 and this is made by Wyeth-Genetics Institute. The rhBMP-2 is supplied as a sterile

freeze-dried powder that is reconstituted at the time NEAL R. GROSS
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of surgery with sterile water to a concentration of 1.5 milligrams per milliliter. The solution is then The sponge in the

applied to absorbable collagen sponge. provides the matrix to retain the

rhBMP-2

desired location sufficiently long to stimulate the formation of bone cells. The absorbable collagen sponge is a

commercially available product that is made by Integra Life Sciences of Plainsboro, New Jersey. FDA approved

the PMA application for the absorbable collagen sponge back in 1981. Medtronic Sofamor Danek has named the

combination of rhBMP-2 with the absorbable collagen sponge as InFUSETM bone graft. This PMA application

for InFUSETM covers this use with Medtronic Sofamor Danek's LT-cage lumbar tapered fusion device, not the interfix device that Dr. McCullough mentioned but the LT-cage device. The LT-cage device is a hollow fenestrated titanium alloy threaded interbody fusion device. FDA

approved the PMA application for this device over a year ago. Typically two cages are inserted in

parallel from an anterior surgical approach in lumbar NEAL R. GROSS
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spinal fusion procedures. bone graft is harvested

In current medical practice from the iliac crest, is

packed into the LT-cage devices. in the labeling of the device.

This is stipulated

Autogenous bone graft augments the fusion of the treated segment and it is now considered a standard we're of care an graft material. Today, however, this

seeking

approval

recommendation

from

panel to use infused bone graft instead of autogenous bone graft to pack the central cavities of the LT-cage devices. Let's focus more closely on what is at issue

here today. It is not the LT-cage device. This

product is commercially available for the same medical indication, that is symptomatic degenerative disc

disease, and for the same manner of use, anterior antibody lumbar fusion procedures. It is not the

absorbable collagen sponge that has been FDA approved as an implantable hemostatic agent. It has a long

history of safe and effective use dating back over 20 years. The real of issue rhBMP-2 today when is used the safety the and two

effectiveness

with

NEAL R. GROSS
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previously

approved

products

and

whether

it

is

a

suitable replacement for autogenous bone graft, the gold standard, in antibody fusion procedures. We believe the years of basic research and development of this product have yielded considerable evidence to support the safety and effectiveness of the product. Further, the infused bone graft LT-cage

device is supported by clinical data arising from a large multi-centered prospective randomized clinical trial, a desirable scientifically valid study design, but one that is rarely used for orthopedic implants in the United States due to its difficulty in execution. This study embodies an idyllic scientific research. Eliminate as much of the variation as In

possible except for the variable being studied. this study that's exactly what occurred.

Patients met

the same study entrance criteria and received the same interbody fusion cage. 50/50 chance that a The only variable was the patient would receive either

infused bond graft or would receive autogenous bone graft in their surgery. It is our opinion that this study

NEAL R. GROSS
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presented objections voiced panel.

today to

overcomes trial by

virtually designs this as

all

of

the been

study

that

have

over

the

years

orthopedic well as

advisory the pre-

These

clinical

data

clinical test results, manufacturing information, and labeling were submitted to FDA as a modular PMA

application with the first module being submitted in April of 2000. review by FDA The PMA application has been under since then and presenting this

information to this advisory panel is part of the review process. As typical for these meetings, we plan to present overviews of the relevant information

contained in the PMA application.

Dr. Gerard Riedel,

the senior project director of the rhBMP-2 program at Wyeth-Genetics Institute, will make the first

presentation and he will cover the origin and biology of rhBMP-2 and the pre-clinical safety studies. Riedel will be followed by Dr. Scott Boden, Dr. an

orthopedic surgeon from Emory University.

Dr. Boden

will discuss the results of pre-clinical testing of infused bone graft in animal studies as well as the NEAL R. GROSS
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results

of

the

pilot

trial

involving

infused

bone

graft with the LT-cage device and that study supported the initiation of the larger pivotal trials. Dr. Hallett Matthews, an orthopedic spine surgeon from Richmond, Virginia, will review the

results of the large scale pivotal IDE trial of the infused Matthews bone was graft an with the LT-cage in the device. open Dr.

investigator

surgical

approach study.

I will then return to the podium for

concluding remarks. In addition to these speakers, we have assembled here today a group of physicians and

scientists who should be able to answer the questions you may have about the product under review. These

experts include several clinical investigators, the inventor of the cage, radiologists and immunologists, an OB/gyn physician, a histologist, a statistician, basic scientist and the discoverer of the rhBMP-2 that has been used in the study. So without further ado, I will now turn the podium over to Dr. Riedel. DR. RIEDEL: Thank you, Bailey. Good

NEAL R. GROSS
(202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com

morning.

My name is Gerard Riedel. Institute, a

I'm employed by company,

Wyeth-Genetics

pharmaceutical

that collaborates with Medtronic Sofamor Danek in the development of BMPs in spine surgery. In my

presentation I will briefly describe the origin and the biology of recombinant human bone morphogenetic protein 2. I will also summarize the pre-clinical

studies we have conducted that compliment the preclinical studies conducted by Medtronic Sofamor Danek. As a reminder, the letters rhBMP-2

represent recombinant human bone morphogenetic protein 2. Scientists at Genetics Institute use molecular

biology techniques to isolate the human gene in coding BMP-2. This gene was inserted into a chromosome of an

industry standard mammalian cell line and this cell line was subsequently engineered to enable it to

produce high levels of rhBMP-2 protein.

This cell

line can grow in large vessels and synthesize the protein as it does so. media, filled into RhBMP-2 is purified from the vials and subsequently

sterile

freeze-dried. RhBMP-2 is a member of a large protein NEAL R. GROSS
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family whose members all have activities associated with the growth and differentiation of tissues.

Endogenous rhBMP-2 plays a key role in bone repair and embryonic development. Recombinant human BMP-2 is a

homodimeric glycosylayted molecule with a molecular weight of approximately 30,000 Daltons. The protein This

is highly conserved and active across species.

conservation allows the use of recombinant human BMP-2 in all of the animal studies I will present rather than having to prepare specie specific versions of this protein. Finally, the biological activity of rhBMP2, that is the basis for its therapeutic development, is its ability to induce bone in both animals and humans. This slide demonstrates that bone

induction activity of rhBMP-2 in the classic in vivo assay known as the rat ectopic implant assay. assay was originally developed in Dr. This

Reddi's

laboratory.

In this assay, rhBMP-2 is implanted at a Typically bone is induced at this site The

non-bony site.

within seven to 14 days following implantation. NEAL R. GROSS
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www.nealrgross.com

photograph on the left shows the gross appearance of an ossicle of bone induced by rhBMP-2 in the

subcutaneous space of a rat's thorax.

Histological

analysis of this new bony tissue reveals extensive formation of trabecular bone corresponding to the dark pink regions in the photo micrograph on the right, a complete compliment of bone associated cells such as osteoblasts, highly osteoclasts and stromal with all cells bone and a

vascularized

structure

marrow

elements corresponding to the light pink regions in the photograph on the right. This activity in this rat model has been labeled osteo induction. other bone inducing BMP Only rhBMP-2 and several proteins exhibit this

biological activity.

No other protein or drug has Some of the

demonstrated this activity in this model.

biological events comprising bone induction have been identified. Following the implantation of recombinant

human BMP-2 cells initially migrate to the site and undergo several rounds of cell replication. Subsequently, mesenchymal cells fibroblasts into appearing osteoblasts.

differentiate NEAL R. GROSS

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www.nealrgross.com

Bone is formed, initially as woven trabecular bone and subsequently remodeled by the combined action of

osteoclasts and osteoblasts into lamellar bone. The vascularized as newly induced by tissue the is highly blood The

demonstrated

numerous

vessels in the photo micrograph on the left. entire sequence the of events physiologic induced by

rhBMP-2 of bone

recapitulates formation.

process

Considerable published about the

information of

has

also

been

mechanism

rhBMP-2

action.

Responsive cell types and major cell surface receptors have been identified. Additionally, elements of the

signal transduction pathway have been identified by which rhBMP-2 exercises its effects on cells.

Finally, and very importantly, it has been shown that it is necessary to apply rhBMP-2 locally in order to obtain bone induction in vivo. To facilitate the local application of

rhBMP-2, the protein is combined with a biomaterial that is generally called a matrix. The use of a

matrix with rhBMP-2 enables its surgical placement at NEAL R. GROSS
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the treatment site, facilitates retention of rhBMP-2 at that site and ideally provides an environment that is compatible with bone induction. The matrix selected for clinical

development in this specific program is an absorbable collagen sponge, abbreviated as ACS. This sponge was

selected after screening dozens of matrix candidates. The sponge in is the a commercially United States available since agent of safe 1981 and product as has a an The

marketed surgically extensive

implanted commercial

hemostatic experience

use.

sponge is composed of bovine tendon- derived type 1 collagen. Its manufacturer meets or exceeds all

regulatory requirements. This next slide shows an example of the dry absorbable collagen sponge in its original This The

packaging prior to the addition of rhBMP-2. diagram describes the preparation of rhBMP-2 ACS.

vial containing the freeze-dried powder of rhBMP-2 is reconstituted with an appropriate volume of sterile water, abbreviated WFI in the diagram. The resulting

sterile solution of rhBMP-2 is subsequently applied NEAL R. GROSS
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uniformly

to

the

dry

ACS,

generating

a

cohesive

pliable implant that can be readily manipulated in the operating room as depicted in this slide which shows that the wetted sponge can be rolled and subsequently inserted into an LT-cage. I mentioned before that one desirable

attribute of a matrix is its facilitation of rhBMP-2 retention at the site of implantation. This slide

describes one experimental system we used to assess this attribute. onto which we We generated rabbit ulnar osteotomies implanted labeled we measured rhBMP-2 rhBMP-2. the amount of ACS contained Following rhBMP-2

radioactively implantation,

retained at the implantation site over time by a noninvasive technique of gamma camera scintigraphy.

Basically, we measured the radioactivity remaining at the site over time and this method has been validated by several supplementary analyses including direct

explant measurement and biochemical characterization of the radio labeled BMP-2 derived from the explants. This slide shows the retention of rhBMP-2 in the rabbit ulnar osteotomy model. NEAL R. GROSS
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The Y axis

represents the percent of the rhBMP-2 initial dose remaining at the implantation site and the X axis represents time in days. The graph shows that the use

of ACS as a matrix facilitates the local retention of rhBMP-2 at the site, in contrast to the application of rhBMP-2 in buffer depicted by the line with black squares. the Significantly more rhBMP-2 is retained at site when it is applied in

implantation

combination with ACS depicted by the line with yellow diamonds. Radio-labeled rhBMP-2 can be detected at

the implantation site for as long as 14 days in this model. With this background information in mind, I will now discuss the non-clinical safety studies that have been conducted. The safety of rhBMP-2 alone

or combined with ACS has been assessed in a variety of studies. Implantation of rhBMP-2 ACS to assess its The absorption, of rhBMP-2,

implant safety has been conducted. distribution, metabolism and

excretion

abbreviated ADME, has been assessed.

Finally, the

safety of rhBMP-2 alone has been studied in a panel of assessments. NEAL R. GROSS
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The safety of rhBMP-2 ACS implantation has been evaluated in three anatomic sites, including a spine safety study conducted in Dr. Hanley's

laboratory.

The results of this spine study have The two other implant safety canine models with follow-up

already been published. studies used rat and

extending through six or 12 months.

In these two

studies we used rhBMP-2 dosing that greatly exceeded the specie specific therapeutic range and I should explain this. I have previously mentioned that

recombinant human BMP-2 is biologically active in all mammalian species. different However, different species require of rhBMP-2 within ACS for

concentrations

optimal bone formation and specifically the optimal therapeutic concentration of rhBMP-2 is lowest in

rodents, higher in canine and even higher in non-human primates and patients. We took advantage of this phenomenon to deliberate exceed of the rhBMP-2 species within specific ACS in optimal order to

concentrations

assess any toxic effects.

The safety results of all

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these studies were uniform.

There were no systemic

effects observed, no gross pathology or histopathology findings, no effects on blood chemistry, hematology or urinalysis and no incidents of bone formation distant from the site of implantation. Furthermore, the local effects observed in these studies were consistent with the bone inducing biological activity of rhBMP-2. We also looked at the

biodistribution of rhBMP-2 following its implantation. We used two implantation models in two species. results are similar. The

RhBMP-2 is slowly released from

the implantation site with a maximum of 0.1 percent of the implanted rhBMP-2 dose detected in the systemic circulation. This slide shows the retention of rhBMP-2 at the site of implantation but this time in a rat femur onlay model. RhBMP-2 can be detected at the

implantation site for as long as 14 days following surgical implantation in this model. In this same

study we measured rhBMP-2 levels in the blood and showed that the maximum amount detected was 0.1

percent of the total rhBMP-2 implanted. NEAL R. GROSS
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I've not

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graphed those levels on this slide because they would all cluster at zero on this scale. Nevertheless, because some small amount of rhBMP-2 was detected in the systemic circulation

following the product's implantation, we studied the fate of rhBMP-2 following systemic administration. We

used standard animal models of pharmacokinetics and biodistribution applied rhBMP-2 in rats and non-human in these cleared primates buffer models from and via we the

protein

dissolved In

intravenous observed

administration. rhBMP-2 is

that

rapidly

systemic circulation with a terminal half-life of 16 minutes in rats to seven minutes in monkeys. The clearance. liver is the the principal protein organ is of

Subsequently,

rapidly

degraded and excreted into -- completely degraded and then the remnants are excreted into the urine. This

graph shows the clearance of rhBMP-2 from the systemic circulation the protein following in rats. intravenous The Y administration represents of the

axis

percent of the rhBMP-2 initial dose remaining in the blood and the X axis represents time but now in

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minutes rather than in days as used in the previous graphs. This slide shows that rhBMP-2 is rapidly cleared from the circulation and contrasts

dramatically with its relatively slow clearance from the site of implantation. This slide summarizes the

net effect of the local and systemic clearance of rhBMP-2. Slow rhBMP-2 release from the site of

implantation combined with rapid systemic clearance, results systemic in very low has systemic exposure. for This the low

exposure

implications

safety

results described in the following slides. I switch now to a description of various safety assessments of rhBMP-2 alone beginning with

studies relevant to tumor formation or proliferation. Published studies have screened many different tumors and identified several tumor types that express either BMP-2 or BMP receptors. These published data do not

indicate any role of BMP-2 in the initiation or the promotion of tumor formation. We have also assessed rhBMP-2 in standard assays and determined that the protein is neither

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cytotoxic nor mutagenic. thorough histological

Additionally, we performed a assessment of the local

implantation site in the implant toxicity studies I previously mentioned. We detected no abnormal

cellular features at the site of implantation in any study at any time point. For example, in our rat

implant study, we implanted concentrations of rhBMP-2 on ACS that were 40 times higher than the optimal therapeutic concentration for this species. The histopathology assessment of the

implant site revealed no abnormal cellular features at any time point through the one-year follow-up period. These combined data suggest that rhBMP-2 has no role in the initiation or the promotion of tumor formation. To investigate the effect of rhBMP-2 on tumor cells that already We exist, we have our is conducted on to in in vitro vitro achieve

studies. assessments

focused it

efforts possible

because

relatively high exposure levels to rhBMP-2 in contrast to the very low systemic exposure levels that can be achieved in vivo. following slide. NEAL R. GROSS
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These studies are summarized on the

We have provided FDA with the results of series of studies including our own that investigated the effect of rhBMP-2 on the growth of human tumor cells in vitro. published. Most of these studies have been

In aggregate, these studies have assessed Three lines have

51 human tumor cell lines to date.

shown some growth promotion in the presence of rhBMP-2 as compared with growth in the absence of the protein. I will discuss these lines first. Two of these lines were derived from

pancreatic tumors. When these lines were cultured in the absence if serum, rhBMP-2 stimulated cell growth by 12 or 25 percent above that of the controls. Both

lines carried a mutation and a key component of the intracellular BMP signal transduction pathway. Other

pancreatic tumor cell lines were evaluated and showed either no effect or growth inhibition. The third tumor cell line demonstrating increased carcinoma. growth This was cell derived line from only a showed prostate growth

promotion in the absence of serum or the absence of androgen. When either of these components was added NEAL R. GROSS
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back to the medium, rhBMP-2 actually inhibited the growth of this cell line. In the remaining 48 cell

lines, the addition of rhBMP-2 had either no effect or resulting in the inhibition of tumor cell growth in approximately 50 percent of the cell lines tested. These lines included many different tumor cell types including three seven osteosarcoma pancreatic lines tumor as well as the four

additional

lines

and

additional prostate tumor cell lines. Besides testing rhBMP-2 on established

tumor cell lines, the protein has also been tested on primary tumor isolates generally obtained following surgical debulking procedures. Seventy-one

independent tumor isolates have been tested to date and all show either no effect or inhibition this time in approximately 25 percent of the isolates tested. Finally although inhibition of tumor

growth has been observed most dramatically in the cell lines and primary isolates of multiple myeloma cells, the degree of inhibition is not extensive enough to consider rhBMP-2 for therapeutic applications in

patients with these tumors. NEAL R. GROSS
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Over the course of the review of this PMA submission, we met with FDA on several occasions to discuss additional tumor biology studies that could be conducted. We mutually agreed to perform that

additional studies outlined in this slide as a postapproval commitment. compliment the These studies are intended to literature and to more

scientific

systematically assess rhBMP-2 effects on tumor cells that express the known BMP receptors. The first study is designed to screen

tumor cell lines for the levels of messenger RNA in coding complex. each known component of the BMP receptor

We are performing the screening activity by

using a sensitive polymerase chain reaction assay for each known receptor component component messenger and RNA comparing in the tumor

individual

levels

cells with messenger RNA levels in other cell types known to respond to rhBMP-2. We used this comparison

to operationally classify tumor cell lines as positive or negative for BMP receptor RNA. The representative second tumor cell cell lines line from evaluates the first

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experiment.

If possible, cell lines will be selected

that represent a variety of tumor types and different messenger RNA levels of BMP receptor components. The

growth of these cell lines will be assessed in vitro in the presence and the absence of rhBMP-2. In the third study, representative tumor cell lines from the second experiment will be assessed if relevant as xenografts in an appropriate mouse

model system in the presence and absence of implanted rhBMP-2. studies As I stated a earlier, these additional in

constitute

post-approval

commitment

agreement with FDA. I will now discuss additional safety

assessments of rhBMP-2 alone that have been performed. We have also in conducted formal studies animal of rhBMP-2

safety models.

well-characterized

toxicological

We studied the systemic safety of rhBMP-2 in

two species using intravenous administration to apply a single dose or doses repeated daily for 28 days at systemic exposure levels that greatly exceeded

anticipated human exposure. Similarly, because indigenous BMP-2 is

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active

during

embryogenesis, safety of

we

have

studied

the

reproductive

rhBMP-2

using

repeated

intravenous administration in standard rat and rabbit models that assess fertility or teratological effects again at systemic exposure levels that greatly exceed anticipated human exposure. studies, we assessed In these formal toxicity effects on clinical

rhBMP-2

signs, ophthalmic evaluations, electrocardiograms and blood pressure, bone marrow and hematology parameters, blood chemistry, urinalysis, growths pathology and

histopathology of all major organs. In the reproductive toxicity studies, we additionally assessed rhBMP-2 effects on maternal and paternal parameters, mating performance toxicity, and embryo reproductive lethality, The There

maternal

litter size and viability and fetal abnormality. results of all of these studies were similar. were no effects observed.

Studies were also conducted according to the tripartite biocompatibility guidelines for medical devices and a series of general safety pharmacology studies were conducted using systemically administered NEAL R. GROSS
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rhBMP-2. similar.

The

results

of

these

studies

were

also

There were no effects observed. In the course of the review of this PMA

submission, we have recently met with FDA to discuss issues related to an immune with response FDA, we to rhBMP-2. mutually

Following

consultation

have

agreed to perform the additional studies outlined in this slide as a post-approval commitment. These

studies are intended to more thoroughly assess the overall immune response to rhBMP-2. Our first commitment in this area is to develop a broader clinical antibody assay to detect human antibody isotopes in addition to the major IgG isotopes that we currently detect. Our second

commitment is to develop a valid assay to assess the ability of antisera to block or neutralize the

biological activity of rhBMP-2. Finally, we have also recently begun a discussion with FDA concerning experimental approaches to appropriately assess the to potential adverse of maternal on

anti-rhBMP-2

antibodies

have

effects

fetal development during pregnancy. NEAL R. GROSS
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In summary, the

www.nealrgross.com

safety

of

rhBMP-2

ACS

has

been

comprehensively

evaluated in a series of non-clinical safety studies that used either local implantation or systemic

administration.

The overall pre-clinical profile that

we have observed in these studies can be characterized as follows. There was no observed systemic adverse

effect of rhBMP-2 whether it was administered as an intravenous solution or implanted in association with the absorbably collagen sponge. lack of adverse effects to low We attribute this systemic exposure

caused by the gradual release of rhBMP-2 from its implantation site combined with a very rapid clearance of rhBMP-2 from the systemic circulation. Local

effects were observed with consistent with the bone inducing activity of rhBMP-2. dose limiting toxicity related We have observed no to rhBMP-2 in our

studies at amounts substantially exceeding anticipated human exposure. In conclusion, our pre-clinical safety

assessment supports the use of infused bone graft in patients. Thank you for your attention. NEAL R. GROSS
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I'll now

turn this presentation over to Dr. Scott Boden, who will review the data from several pre-clinical spine fusion studies and the results of the infused bone graft pilot clinical study. DR. BODEN: name is Scott Boden Thank you, Dr. Riedel. and I'm a Board in My

certified, Atlanta,

practicing Georgia.

orthopedic

spine

surgeon

I'm also a professor of orthopedic surgery I've written extensively on the proteins and I am

at Emory University. subject of bone

morphogenetic

familiar with the literature in this area. direct financial interest in the

I have no being

product

discussed today before this distinguished panel but I am a paid consultant for Medtronic Sofamor Danek. I also participated in the pilot study for the device being presented today which began five

years ago when recombinant human BMP-2 was first used inside the LT-fusion cage device in humans. I'd like to focus my remarks on the preclinical studies that led to the design and rationale and evaluation tools for the pivotal clinical trial which you'll hear about shortly. This slide

NEAL R. GROSS
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summarizes looking at

four the

of

the

key

pre-clinical BMP-2 protein

studies in an

recombinant

interbody spine fusion environment. Before I go into them individually, I want to point out the theme for these studies is that it was done in an animal model where the gold standard of the control had a less than 50 percent success rate in three of those four studies. And the empty cage or

without protein had a zero percent success rate in the a fourth of those studies. Similarly or in contrast,

the recombinant BMP-2 had a 95 or 100 percent success for inducing bridging bone in each of these

challenging animal models. The interbody fusion first with study a looks at cage single in a level sheep

titanium

model. In this study the cage was either filled with autogenous absorbable bone graft or the recombinant This BMP-2 slide

collagen

sponge

device.

highlights some of the challenges in non-invasively evaluating the presence or absence of bone formation in the interbody fusion area. In the autograft controls, plain

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radiographs

measuring

lucencies

of

the

primary

determinant of presence or absence of fusion suggested that rate. there might be 100 percent successful which which fusion

However,

histologic

analysis bone

directly is the

visualizes

bridging

trabecular

criteria for a solid fusion, show that only 37 percent of those animals actually had bridging trabecular

bone.

In the case of BMP-2, again, the plain x-ray

showed a very -- or indicated a very high success rate just using the lucency criteria but the difference here was that the histologic analysis showed bridging trabecular bone in each and every animal receiving BMP-2. These pictures illustrate that point.

Here is a micro-radiograph of an autograft control where there is clearly bone inside the cage but there are some areas that are not filled with bone and histology demonstrates that this is fibrous tissue

shown in the pink color as compared to bone shown in the blue. This can be contrasted with both a

radiograph and histology from one of the other animals in that study that had BMP-2 absorbable collagen

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sponge inside the cage rather than autogenous bone graft. One of the other relevant questions that has already been raised this morning is what is the mechanical quality of bone that is induced using BMP-2 as compared to bone that would be initially formed and remodeled And this using study autogenous shows iliac crest a the by bone graft? of

that

using that

variety

mechanical properties

testing of the

modes bone

mechanical BMP-2 were

induced

comparable comparing the red bar and the green bar to those seen with bone formed by autogenous bone graft from the iliac crest. The second study looks at single level interbody fusion with titanium cage this time in a goat model. The end point was again six months and Cage was either

the two groups were again the same.

filled with autogenous bone or recombinant human BMP-2 on the absorbable collagen sponge. the challenges of using just Once again, we see radiographs to In

plain

assess the presence of bone inside a fusion cage.

this case in the autograft group clearly less than 100 NEAL R. GROSS
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percent but more than the just under 50 percent that had an actual fusion based on histology, were assessed to be fused again using lucency as the primary

criteria. In contrast in the case of the BMP

animals, although 100 percent lacked lucency on the plain x-ray criteria, only 95 percent, which means all but one animal had continuous bridging bone as

measured by histology, the ultimate assessment of bone formation inside the cage. Once that there was again, no biomechanical testing in show the

statistical

difference

stiffness between the fusions that were formed with the autograft or fusions that were induced by the recombinant BMP-2. So, again, bone induced by BMP-2

absorbable collagen sponge functionally, inside the cage functioned similar to that of autograft bone. Now, one could argue that the presence of the metal cage might interfere with the ability to truly assess the quality of the bone and for that reason I'll just briefly show some mechanical assessment of bone with recombinant BMP-2 on the same carrier matrix, that's NEAL R. GROSS
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the

absorbable

collagen

sponge

but

from

a

posterolateral fusion model where there's no metal. The advantage of this model, which

incidentally the autograft once again fused less than 50 percent of the animals and BMP-2 absorbable

collagen sponge fused 100 percent of the animals but we can do testing that looks at just the strength and quality of the bone formed in the fusion without any confounding information from metal fixation. Once

again, in this case, the mechanical properties of the bone formed with BMP-2 shown in the green bars were essentially comparable to those in terms of relative strength and relative stiffness seen with autogenous bone. Now moving onto the non-human primate

studies which are extremely relevant as was mentioned earlier by Dr. Riedel, because of the close parallel of the required concentration of BMP-2 to get efficacy of bone formation in non-human primates and how that translates to human clinical trials. In this case an

allografted bone dowel or bone cage was filled with either BMP-2 and absorbable collagen sponge or with NEAL R. GROSS
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autogenous bone graft and inserted in a rhesus monkey single level, interbody fusions. These two x-rays show an example from a control and you can see that the intervertebral disc space, that black line, is still present and there was no bridging bone or fusion across the segment when the allograft bone dowel was filled with BMP-2. In

contrast, in this case you can see that bone has bridged the two vertebral segments completely

obliterating the disc space with the allograft dowel was filled with BMP-2 and in addition, the allograft dowel has been remodeled. These this point. microradiographs again highlight

Two controls shown on the to, in this

case, the remnant of the allograft dowel can be seen but bone is growing into and through it. In this case

the dowel has fallen out of the histologic section but you can see that bone has not grown completely through the specimen. In contrast, these are two examples

from animals that had BMP-2 with absorbable collagen sponge inside that cage and you can see that there's bridging trabecular bone across the interspace and

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remodeling of the allograft bone cage. The last pre-clinical study is the one that most closely simulates what was to take place in human -in the fact that this time BMP-2 with

absorbable collagen sponge was placed into a scaled down titanium fusion cage. This was inserted into

rhesus monkey at the lumbosacral junction with a sixmonth end point and the cage was either filled with the absorbable collagen sponge with buffer only, in other words, no BMP-2 or one of two doses, .75 or 1.50 milligrams per milliliter of recombinant human BMP-2. What we found was that the sponge alone did not result in any spontaneous bone formation

through the cage in either of those control animals. However, all of the animals that received either dose of recombinant BMP-2 on the collagen sponge had

histologic bone formation through the cage as can be seen on these two examples. This slide is important because it leads to the reliance and the importance of using CT scans to assess the presence of bone inside an interbody fusion cage. Here you can see that histologically in NEAL R. GROSS
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this case there was no bone forming inside the cage and on the CAT scan you can see that this dark area rather than a bright white area suggests that there is not a density consistent with bone inside the metal fusion cage. through the In contrast, in animals where bone grew cage, a CT scan revealed homogeneous

bridging trabecular bone through the center of the cage on the CAT scan. The quality of the bone and the normalcy in the non-human primates was as described earlier by Dr. Riedel in rodents and other animal models being entirely normal bone with osteoblast-line trabeculae remodeling and bone marrow elements. Now I'd like to briefly describe the pilot clinical study that was undertaken following that

rhesus monkey pre-clinical study as an introduction to validating the evaluation tools. was done at four In this study which sites, the LT-

investigational

threaded tapered fusion cage was filled with either autogenous bone graft in a small number of patients or with infused bone graft, that is recombinant human BMP-2 in absorbable collagen sponge. NEAL R. GROSS
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First

I'd

like

to

briefly

review

the

surgical anatomy for those who may be less familiar with the spine. The normal spine would have two

vertebra adjacent connected by the intervertebral disc cartilage and in the approach that's being put before the panel today which is an anterior surgical

approach, two cages are inserted from the front of the spine. It's important to note that there is residual

disc or annulus material that serves as a microscopic barrier creating that compartmentalization that Dr. McCullough was asking for earlier preventing gross

leakage of BMP-2 and carrier matrix into the area where the neuro elements would be. Looking at this in cross section, we can see here the normal or pre-operative and then postsurgical schematic of two cages inserted side by side again with residual annular tissue serving as a

macroscopic barrier. this is a

I should point out that while barrier and there can be

macroscopic

fissures, in none of the animal studies nor in the human studies have we seen formation of bone posterior to the cage outside the confines of the disc space NEAL R. GROSS
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when

the

anterior

surgical

approach

has

been

used

which is under consideration today. So the device before it goes in, has the wetted collagen sponge inside the taped fusion cage and in this clinical pilot study, 11 out of 11

patients were deemed by independent review of plain xrays and CT scans to have achieved bridging trabecular bone through and/or around the fusion cages. Two of

three of the autograft were shown to have successful bridging bone. Another issue is the impact on clinical outcome. disease which is In the Oswestry Disability Index is a

specific commonly In or

patient used

derived in

outcomes with lower

measure, low back is

patients a

problems. desirable

this

case

having of less

score or

indicative

symptoms

less

disability.

In the Oswestry scores from pre-op to 24

months, gradually decreased on both groups, in this case it seemed a little bit quicker in the infused group and it nearly reached statistical significance but in the end the clinical outcome was at least as good in patients that used infused and did not have to NEAL R. GROSS
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have a second site harvest with autogenous bone graft. Lastly, I think showing some

representative pictures are really important to bring home the fact that bone is forming in an area where there otherwise wasn't bone. The format of the next

several slides will look at a slice through the righthand cage, the left-hand cage and a coronal view of both cages or frontal view using reconstructed thin sliced CT scans. And the three columns represent

different points in time; six months, 12 months and 24 months. And you can see from this patient that

started with autograft bone, that in fact, there was incorporation of the autograft in this case and there is bridging trabecular bone through the cages both on the lateral and on the frontal view. Here's an example of another autograft

patient where you can see that there's less density inside the cage perhaps with resorption of the

autograft bone and over time there were lucencies that formed around the cage and absence of ridging bone suggesting a failure of bone formation and fusion. Contrast that with an example of some of the infused NEAL R. GROSS
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patients keeping in mind that the cage starts out without any bone in it and so when we see white bone growing through the cage, we know that it was induced as a result of infuser BMP-2. You can see here in both cages there's bone growing through the cages and as time progresses you can see secondary ossification which is a normal adjunctive finding in any solid fusion around the

cages through the disc space.

Another example of an

infused patient, again showing an increase in bone density in the cage over time and also the secondary healing around the cage normal for a solid interbody fusion. Another question is what happens to the bone inside these cages over a longer period of time and although this was a pilot study, these patients have continued to be followed and this is an example of one of the autograft patients at 48 months showing that when autogenous bone was put inside the cage, then in fact, it remains bridging through the cage and remodels similar to the density of bone in the

adjacent vertebral bodies. NEAL R. GROSS
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Looking at a patient that received infused we saw this same trend of preservation of bone in the cage, mature not disappearing of bone, fusion that's and continuing to the BMP

the

adjunctive So the bone

throughout induced with

interspace.

behaves ostensibly the same as bone that was put by autograft bone in the case of inside the fusion cage. And just one other example of a patient with BMP, again with longer term follow-up showing that the fusion is maintained even at four years with bone both through the cage and around the side of the cage. goals So I think it's important to summarize the of the recombinant BMP-2 absorbable collagen

device.

You've heard much about systemic safety and

toxicity in the first talk and I think at this point it suffice it to say very simply that we did not see any bone formation at a distance from the cages or in any place outside the caged in matrix in any of the animals or any of the pilot patients that have been discussed so far. Equally effectiveness. And important effectiveness to for safety this is device

NEAL R. GROSS
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really should be considered the ability to eliminate bone grafting morbidity which is substantial in these patients and to obtain equal or better healing success rate defined as bridging trabecular bone across the interspace and through the cage. stated more simply the goal of In other words, recombinant BMP-2

absorbable collagen sponge device is to make bridging bone. So in conclusion, based on a series of detailed pre-clinical and a clinical pilot trial, I believe that recombinant BMP-2 absorbable collagen

sponge has shown success in 95 percent or better in four animal studies, substantially better than

autograft controls in those models.

The bone formed

is normal and biomechanically equal to that formed with autogenous bone graft. CT scan analysis

correlates the best with the histology of bone and therefore, is an important indicator of the presence of new bone formation by BMP-2 inside fusion cages. And finally, the concentration of BMP-2 that was successful in the rhesus monkey pre-clinical study was also successful in the clinical pilot study NEAL R. GROSS
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with 100 percent success in humans at the same doses that were predicted by the rhesus monkeys. At this

point, I'd like to turn the podium over to Dr. Hal Mathews, who will describe the results of the pivotal clinical trial in greater detail. DR. MATHEWS: Distinguished panel members, My name is Hal surgeon from

ladies and gentlemen, good morning. Mathews. I'm a practicing spine

Richmond, Virginia. care. I'm an

My entire clinical focus is spine associate clinical professor of

orthopedics and neurosurgery at the Medical College of Virginia in Richmond. I have no direct financial

interest in this product under review here today and I'm not being paid for my participation in this

meeting.

I participated in the open surgical approach

study of this device as an investigator. I'm here today to present the results of the InFUSETM Bone Graft/LT Cage Lumbar Tapered Fusion Cage Device clinical trial. Before I discuss the

details, I want to report to this advisory panel and to the audience the top line findings from this open surgical approach study. First and foremost the

NEAL R. GROSS
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primary objective of the clinical trial as stated in the protocol was met, thus establishing the safety and effectiveness of the InFUSETM bone graft in the

treatment of degenerative disc disease. Secondly, the InFUSETM bone graft

stimulates the formation of bone which results in very high fusion rates. Thirdly, the InFUSETM bone graft

patients experience shorter operative times and less blood loss than the control patients. And finally,

patients who receive the InFUSETM bone graft avoided the complications and significant post-operative pain associated with bone graft harvesting in the control group. Let me offer a few additional observations that I believe will bring into sharper focus the

clinical trial results.

At the end of the day it is

our job as physicians to help our patients in the least invasive and least painful ways. For the

patients from whom a bone graft was taken from their iliac crest, at the time of discharge, 80 percent of patients registered a score of at least 10 out of 20 and nearly 15 percent of these patients had a score of NEAL R. GROSS
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at least five at 24 months. of these patients including

In addition, six percent graft site nerve

experienced bone

complications,

fractures,

injuries, infections and hematomas. Given its equivalent performance in

achieving fusion, the infused bone graft is clearly the most humane way to treat this painful condition. I will now elaborate on the clinical trial and the results and I will conclude with a brief review of the laparoscopic clinical trial that was also conducted showing equivalent rates of fusion as well as some other potential patient benefits. Let us now discuss the open surgical

approach for device implantation. prospective randomized treatment with control patients the

This study had a design. received bone the The LT

investigational cage device

filled

InFUSETM

graft.

Henceforth, I will refer to these patients as the InFUSETM group. The control patients were treated in a

similar manner with the LT cage device filled with autogenous harvested bone from the iliac crest. patients will be designated the autograft group. NEAL R. GROSS
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These

The

primary

objective

for

the

clinical

trial was to determine if the overall success rate for the InFUSETM is at least as high statistically as the rate for the autograft group. derived variable encompassing Overall success is a primary Secondary safety and

effectiveness

considerations.

objectives

focusing on equivalency and superiority of specific end points were also developed. Bayesian methods were used for statistical comparison of study outcomes. Patients admitted to

the study had a single level symptomatic degenerative disc disease as noted by back pain of discogenic

origin with or without leg pain with degeneration of the disc confirmed by patient history and radiographic studies. There are a number of additional inclusion

and exclusion criteria such as age, weight, mental competency, condition. Patients involved in the clinical trial were evaluated pre-operatively, at surgery and postoperatively months. at six weeks, three, six, 12 and 24 medical history, and existing medical

A total of 143 patients received the InFUSETM NEAL R. GROSS

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www.nealrgross.com

bone graft. with

There were 136 patients who were treated bone graft. Patient follow-up

autogenous

compliance at all post-operative periods exceeded 90 percent. Sixteen investigational centers contributed

to these patients. Patients in both treatment groups had very similar demographic characteristics and pre-operative medical conditions. interpret the This enhances one's ability to effects since potentially

treatment

confounding factors did not impact with the results. In terms of surgery results, the mean operative time for the InFUSETM group was approximately one-half hour less than that for the autograft group and this

finding was statistically different. The blood loss for the InFUSETM group was also statistically lower than that for the autograft group. The mean hospital stays of patients in both

treatment groups were slightly more than three days and did not have statistical difference. The results

of other surgical variables such as treated level, operative approach and type of orthosis were similar for both groups. The outpatient and inpatient

NEAL R. GROSS
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classification comparable. For

and

return

to

work

times

were

also

clinical

outcomes

I

would

like

to

emphasize that 24-month data are being used a primary supporting evidence of the safety and effectiveness of treatments. for spinal In order to satisfy the FDA's guidance implant studies, a composite variable

termed overall success was created and this variable is the primary end point of the entire study for PMA approval purposes. Overall success is comprised of the

effectiveness parameters of fusion, Oswestry success, neurologic success. It is also influenced by two

important safety considerations, the occurrence of any serious adverse events possibly associated with the device and the occurrence as a of a second The surgical overall

procedure

classified

failure.

success criteria is very demanding. The primary objective of this study was to determine if the overall success rate for the InFUSETM group was at least as high statistically as for the autograft group. As evidenced from this slide, the NEAL R. GROSS
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overall success rates for the two treatment groups at 12 and 24 months following surgery are very similar and stable over time. equivalent clinical at 24 These rates were statistically Therefore, was met, the primary

months.

trial

objective

thus

supporting

approval of this product. I will now discuss in detail the safety and the effectiveness parameters that were used in this clinical trial. Safety was assessed as a

function of the nature and the frequency of adverse events and second surgery procedures and the formation of antibodies to rhBMP-2 and collagen. Based on these

assessments, the infused group was found to be as safe as the autograft group. Now for more details. Reported adverse

events in each group were classified by their nature, their severity according and to the World Health Also

Organization

criteria,

their

duration.

Medtronic Sofamor Danek instructed investigators to report all adverse events that occurred whether or not the event was related to the treatment or the device. This conservative approach led to the reporting of NEAL R. GROSS
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many

unrelated

events

that

were

included

in

the

analysis.

For the InFUSETM group only 17 patients or

11.9 percent had an event that was possibly related to the device and only 11 of these patients or 7.7

percent were the events considered serious. Overall, a total of 113 InFUSETM patients had at least one adverse event with a substantial majority not being related to the device. As you can

see from this slide, these rates are very similar to those rates for the autograft group. Adverse events

were also categorized according to their nature and comparisons groups. were made between the two treatment

There were no statistical differences for all

reported categories of adverse events except for two. These categories in which differences were noted were graft site events and urogenital. of the autograft These patients Nearly six percent had graft included site bone

complications.

complications

fracture, nerve injuries, infection and hematoma. Obviously, adverse events for the there were not graft This site fact

InFUSETM

group.

clearly supports the use of InFUSETM bone graft since NEAL R. GROSS
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it

eliminates

the

need

to rates

harvest favor

bone the

graft.

Urogenital group.

complication

autograft

The difference in rates was mainly due to

urinary retention following surgery and these events resolved in all patients prior to discharge from the hospital. Overall the occurrence of adverse events in the clinical trial were considered typical for a patient population having an anterior lumbar interbody fusion procedure and were not unanticipated. component nature of of safety assessment surgical is the Another and

number

additional

procedures

performed

after the initial study surgery.

This slide lists the

classifications of additional surgical interventions. According removals and to the protocol, are revisions, considered level

supplemental at

fixations the

significant

procedures

treated

spinal

that effect the assessments of the treatment outcome. Therefore, a patient having one of these procedures is considered a treatment failure for study purposes. the other hand, re-operations and other On

surgical

procedures that are believed to have no effect on the NEAL R. GROSS
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treated level are therefore, not considered failures. The second surgery rates for both groups were

comparable and there were no statistical differences for any of the additional surgery category

comparisons. Because of the proteinaceous nature of

both rhBMP-2 and the absorbable collagen sponge the development of antibodies was assessed as part of the IDE clinical trial. each patient Serum samples were taken from to establish months their

pre-operatively and at

baseline surgery.

condition

three

following

These samples were analyzed for the presence

of antibodies specific to rhBMP-2 and to bovine type I collagen. If a patient had a positive response to

bovine type I collagen, the serum was also tested for antibodies to human type I collagen. Antibody levels

were checked in both InFUSETM and autograft patients, even though the latter group was not exposed to the InFUSETM product. The rates of antibody formation were not different for the two treatment groups. InFUSETM patient and one autograft There was one who had

patient

NEAL R. GROSS
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authentic incidents percent.

positive rates were

responses very

to at

rhBMP-2. less than

The one

low,

There were no adverse events that appeared

to be related to these findings. Approximately 13 percent of patients in both treatment groups had authentic positive responses to bovine type I collagen. These antibody responses

did not appear to result in any clinical manifestation nor impact the overall success rates of the study. None of the patients who tested positive for bovine type I collagen had a positive result for human type I collagen. those from These other antibody Medtronic findings Sofamor are similar to

Danek

clinical

trials involving the InFUSETM bone graft. Since I've presented a lot of information, I want to briefly review the impressive safety profile of the use of the InFUSETM bone graft with the LT-cage device before moving onto the effectiveness results. Adverse events and second surgery procedures for the InFUSETM treatment were very similar to the autograft treatment. The rates of antibody formation were not In addition,

different for the two treatment groups. NEAL R. GROSS
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any positive antibody response appeared to be without clinical manifestation. The eliminated graft use of the InFUSETM adverse bone events graft that

harvesting

occurred in approximately six percent of the autograft patients and significant graft site pain in

approximately 80 percent of patients peri-operatively. This finding is significant since it supports a major reason for using the InFUSETM bone graft. There were also no cardiovascular adverse events associated with the use of the InFUSETM bone graft. Therefore, based on the data, the InFUSETM bone

graft LT-cage device is safe for its intended use in the anterior lumbar interbody fusion procedures to

treat degenerative disc disease. Now, we'll focus on device effectiveness. Briefly InFUSETM in bone summary, graft these patients received the high

experienced

exceptionally

fusion rates, pain relief, maintenance or improvement in neurologic status. Let's review specific

effectiveness results in more detail.

We consider

fusion to be the primary end point since the intended NEAL R. GROSS
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use

of

the

infused

bone

graft

is

to

induce

bone

formation in spinal fusion procedures. For this clinical trial, CT scans and

radiographs were used to assess fusion.

These films

were evaluated at the University of California San Francisco under the direction of Dr. Harry Genant, a board certified radiologist. There were two teams of reviewers who were masked to patient treatment. Each team worked independently of each other. If their

overall fusion conclusions differed, a third reviewer would adjudicate the findings. However, this occurred

in frequently since the percent agreement between the two primary review teams exceeded 98 percent at all time points. Fusion spanning segments, the two was based on evidence of the of bone,

vertebral CT scans

bodies and

treated In

using

radiographs.

addition, segmental stability and lucent line criteria also had to be met to be considered fused. having second surgical procedures reported Patents by the

investigator as due to pseudoarthrosis or non-union were also considered as fusion failures regardless of NEAL R. GROSS
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independent radiographic findings. This later condition dramatically impacts fusion rates for both treatments. For example, at 24

months post-operatively, all non-unions in the InFUSETM group were due to second surgery criteria and not the radiographic treatment following the criteria. were The high fusion at 12 rates and for 24 both

groups

months

surgery. fusion

At 24 months following surgery rate was 94.5 percent and was

InFUSETM

statistically equivalent to the autograft rate of 88.7 percent. Frankly, for the study the most important aspect of the fusion criteria is whether bone,

spanning the two vertebral bodies at the treated level could be detected by the independent radiologist.

This would be indicative of whether the InFUSETM bone graft was effective in stimulating de novo bone

formation.

It is noteworthy that in all patients in

both treatment groups with CT scans available, such spanning bone was detected at 12 and 24 months. scans bone. were particularly findings important are in detecting of CT the

These

considered

prime

NEAL R. GROSS
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importance since fusion cannot exist unless bone is connecting the treated segment. In addition, these findings agree with the data previously presented by Dr. Scott Boden. The

Oswestry Low Back Pain Disability Questionnaire was used to measure ability the to effects manage of back pain life. on a The

patient's

everyday

Oswestry Questionnaire has 10 questions and is selfadministered. Oswestry scores are expressed as a

scale ranging from zero to 100 points with a lower score indicating less pain and disability. As seen with this slide, the mean Oswestry scores for the two treatment groups were very similar at all time periods. At 24 months following surgery,

the mean improvements in Oswestry scores from preoperatively were approximately 29 points for both

treatment groups.

These findings are quite gratifying

and represent an approximate 55 percent improvement. This slide illustrates the distribution of patients demonstrating pre-operative to post-operative improvements in Oswestry scores of at least 15 points, which is a very rigorous condition mandated by the NEAL R. GROSS
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FDA.

This is termed Oswestry success. scores, for both the Oswestry success At

Like mean rates 24 were months were

Oswestry similar

treatment the

groups.

following

surgery

Oswestry

success

rates

found to be statistically equivalent with rates of 73 percent in both groups. The neurologic status of patients was also assessed pre-operatively and post-operatively and at every follow-up visit and is considered an indicator of safety and effectiveness. of The neurologic of motor

evaluations

consisted

measurements

function, sensory, reflex, and degree of straight leg raise producing pain. A successful outcome for each

parameter was based on the post-operative condition being no worse than the pre-operative condition. Overall neurologic success for a patient in any given post-operative time period was based on having successful outcomes for all four neurologic

parameters.

This slide shows the overall neurologic

success at 12 and 24 months following surgery for the two treatment groups. The rates are very similar The 24-month neurologic

across time and treatment.

NEAL R. GROSS
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success rates for the InFUSETM and autograft groups were determined to be statistically equivalent. In contribute to addition overall were made to these end points that

success, during

other the

effectiveness of this

measurements study. pain,

course

These measurements included back pain, leg disc height maintenance and general health

status via the SF-36 survey.

The 24-month results for

these parameters were comparable for the two treatment groups and statistically equivalent between treatments was demonstrated for all but two comparisons. They

were back pain and mental component summary or MCS of the SF-36. I will not focus on the MCS finding since the difference between the two treatment groups was less than four percentage points and this is not

considered clinically significant.

For back pain the

success rate favored the autograft group and it is believed to be due to arbitrary cut-off assumptions of the analysis, since a mean improvement of back pain scores for the InFUSETM group was actually higher,

showing more improvement than that for the autograft NEAL R. GROSS
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group. Another very important effectiveness

parameter that was assessed was graft site harvest pain. This was measured in autograft patients using

two numerical rating scales, one for pain intensity and the other for duration. The composite pain score

ranged from zero to 20 with a lower number signifying a better outcome. pain for autograft This slide shows a mean graft site patients from time of hospital

discharge to 24 months post-operatively.

At hospital

discharge the mean score was 12.7 and approximately 80 percent of patients had scores of at least 10. expected, the harvest site pain improved over time. However, nearly 15 percent of patients had a score of at least five at 24 months postAs

operatively.

Aside from the pain approximately 16

percent of patients indicated they were still bothered by the appearance of the graft site at one and two years following surgery. When these rates are coupled

with the adverse events associated with harvesting the bone, a very compelling case can be made for using infused bone graft in spinal fusion procedures since NEAL R. GROSS
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it eliminates the negatives of graft site appearance, pain and morbidity. There is additional good news about the InFUSETM bone graft. Another clinical trial was

performed examining the laparoscopic implantation of the device and the results are just as compelling as for the open study. The data from the laparoscopic

study augments the safety profile of the device and support approval of The that surgical method study treated of had with cage one the

implantation. treatment group,

laparoscopic patients

those

InFUSETM bone graft and the LT-cage device.

Other than

this, the protocol was identical to that of the open study. A investigational centers total of 134 patients received the

laparoscopic the

treatment. There

Fourteen was no

contributed

patients.

overlap in surgeons between the open and laparoscopic studies. laparoscopic On average was the hospital stay two for days

patients

approximately

shorter and statistically different than for patients of either treatment group of the open study. NEAL R. GROSS
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Further, nearly 45 percent of laparoscopic patients were treated on an outpatient basis as The

compared to virtually none in the open study.

laparoscopic patients also returned to work some 20 days sooner than for the open study patients. These

surgery, hospital stay and return to work findings for the laparoscopic patients may suggest that there is a synergistic effect of the use of the InFUSETM bone graft and the laparoscopic insertion of the LT-cage device. The overall success rate at 24 months

following surgery for laparoscopic patients was more than 68 percent and nearly 12 percentage points higher than for the autograft rate of 56 percent. was not only statistically equivalent This rate to the

autograft, but statistically superior, a finding that more than satisfies a primary objective of the

laparoscopic study. The safety profile of the laparoscopic use of the device was also comparable to the open surgical treatment groups. As expected retrograde ejaculation

rate was higher than with the open surgical treatment NEAL R. GROSS
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due to the transperitoneal approach for laparoscopic patients. However, the rate was lower than previously

noted in other large studies using the laparoscopic implantation of the LT-cage device. The laparoscopic impressive. effectiveness results patients for were the also

investigational

This slide shows statistical equivalence

can be claimed for all comparisons to the autograft group from the open study. At 24 months the fusion

rate was virtually identical to that for the open InFUSETM bone graft treatment at approximately 94

percent, these compared to an 88.7 percent value for the autograft group. in all evaluated Again, bridging bone was noted at 12 and 24 months

patients

radiographically. Since seeing is believing, I want to spend the next few minutes showing a few slides of some study patients using CT. According to the protocol

criteria, these patients had not responded to nonoperative treatment for at least six months prior to being included in this study and had significant

amounts of pain.

The first case is an example of a NEAL R. GROSS

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successful patient.

radiographic

fusion

in

an

autograft

The patient is a 37-year old female that had an L5/S1 fusion procedure. Since cortico

cancellous autogenous bone chips are placed in this autograft patient's cages, it appears radio-opaque

immediately after surgery.

Over time the bone chips

begin to bridge and consolidate to form bridging bone through the cages. The second patient was a 38-year This

old female who had an L5/S1 fusion procedure.

particular patient's cage were filled with autograft. The patient was not a successful fusion. As a result of the failed fusion and lack of stabilization bone across undergoes the some disc space, the that

surrounding

absorption

becomes evidenced by radiolucencies and black lines around the cages. female who had an The third patient is a 42-year old L4/5 fusion procedure with the

InFUSETM bone graft placed inside the cage. In contrast to the autograft filled cages, when InFUSETM bone graft is placed into the cage, it is not initially radioopaque. The InFUSETM bone graft starts out as a dark NEAL R. GROSS
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appearance

within

the

cage,

so

as

to

increase

whiteness, this is due to new bone formation. The CT scan clearly shows evidence of new bone formation at six months, evidenced by the radioopacity. And over time this bone becomes denser. In

addition, anterior bridging bone can be seen in front of the cage and around the sides of the cage. This is

further evidence of mechanical stabilization across the disc space. One question you may be considering is do these impressive CT scans infusion results hold up over time and the answer is yes, and this is based on four-year post-operative CT scans from the same

InFUSETM treatment that Dr. Boden previously presented. So to summarize, as demonstrated in both animal and human studies CT scans are the most practical and definitive method of detecting new bone formation

within cages and determining fusion status. The scientific data I have presented has been impressive and we believe the results certainly support approval of the product. Science aside, So

patients need to be satisfied with their results. NEAL R. GROSS
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study visits

patients to

were

asked to

at

their

post-operative related to

respond

three

questions

satisfaction.

This slide vouches for the high levels

of satisfaction at 24 months following surgery for both InFUSETM bone graft LT-cage device treatments and for the autograft group. Generally 75 to 82 percent of the patients offered positive responses which are very gratifying findings considering the complex nature of low back pain and degenerative disc disease. In conclusion,

the primary objective of the prospective randomized study of the open surgical implantation of the InFUSETM device was met. The overall success rate of the

InFUSETM bone graft LT-cage device was found to be statistically equivalent to the autograft treatment. The InFUSETM treatment was associated with shorter operative times, less blood loss than their autograft control patients. Two of the primary

benefits of InFUSETM bone graft are that it induces bone formation and that it eliminates the need to harvest autogenous bone graft in spinal fusion

procedures.

The autograft group results attest to the NEAL R. GROSS

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need for InFUSETM bone graft treatment since 80 percent of the patients had significant perioperative graft site pain and nearly six percent of these patients had an adverse event associated with graft harvesting. Further, the laparoscopic implantation of the infused as device well. produced The very positive success clinical rate was In

results

overall

statistically higher than the autograft group.

addition, the patients had hospital stays that were two days shorter than the autograft group and they returned to work some 20 days sooner. Therefore, the

results of this study of the open and laparoscopic implantation of the InFUSETM bone graft with the LTcage lumbar taper fusion device showed the device to be safe and effective in the treatment of degenerative disc disease. Thank you very much. DR. LIPSCOMB: conclusion as clearly and the in PMA Members of the panel, in demonstrated the information more in that than these was a

presentations, submitted in

application,

reasonable assurance of the safety and effectiveness NEAL R. GROSS
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of InFUSETM bone graft with the LT-cage device has been presented. We understand that following our

presentations the FDA will pose several questions to this panel. We believe that our presentations have

provided much information to address FDA's questions. For the sake of clarity, let me summarize what you have just heard as it relates to some of these questions. issue One of question rhBMP-2 pertains stimulating to a

theoretical

cell

proliferation from existing tumor.

A comprehensive

review of the literature provides a preponderance of evidence that rhBMP-2 has either no effect or an

inhibitory effect on tumor cell proliferation. We believe that ongoing laboratory testing at Wyeth-Genetic Institute as well as precautionary labeling statements will address any remaining

theoretical concerns. pertains solely to

Again, to emphasize, this issue the effects of rhBMP-2 on an

existing tumor and there is no scientific evidence to suggest that rhBMP-2 transforms a normal cell into a tumor cell. Another FDA question to the panel involves NEAL R. GROSS
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an immunology issue, specifically, what effects, if any, do antibodies to rhBMP-2 have on a developing fetus and the mother. Again, this is a theoretical issue that has not been manifested in either animal studies or in our human clinical trials. The rate of

authentic rhBMP-2 antibody response was less than one percent and was similar to that in the control group in our InFUSETM clinical trials that you heard about this morning. We adequately statements do believe via that this issue can be

addressed and

precautionary to females

labeling of child

instructions

bearing age.

Also we intend to discuss further with

FDA the necessity for a pregnancy register. Another line of questioning to the panel pertains to radiological issues. functioning bone inside the cage? One aspect, is there The answer is yes.

Histological results from animal studies have verified that InFUSETM bone graph causes normal bone to form and that accompanying CT scans show that the appearance of the bone radiologically. similarly reveal the Our clinical study CT scans of bone where none

presence

NEAL R. GROSS
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existed before in the InFUSETM bone graft patients. This bone also remains intact and dense over time as evidenced from the CT scans that have been presented to you some of which are out as far as four years following surgery. Finally, the major panel consideration, is the use of InFUSETM bone graft with the LT-cage safe and effective in the treatment The of valid symptomatic scientific

degenerative

disc

disease?

evidence presented here today unquestionably provides an affirmative response to that question. A multitude

of pre-clinical in vivo and in vitro studies attest to the safety of InFUSETM bone graft. Functional animal

model testing and clinical data from a pilot study as well as two large scale pivotal studies demonstrate InFUSETM bone graft safely stimulates the formation of bone. The data from nine animal species and from humans are consistent. are convincing. normal bone They are compelling and they

InFUSETM bone graft can safely form none existed before and is an

where

effective substitute for autograft bone. NEAL R. GROSS
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These data

www.nealrgross.com

provide

more

than

a

reasonable

assurance

that

the

device is safe and effective for its intended use and this is the criterion for PMA approval. that you will of acknowledge this the We believe and the this and

importance and to

validity

information available

make surgeons

breakthrough

technology

their patients by recommending approval of this PMA application. This concludes Medtronic Sofamor Danek's presentations. your questions. We are available to respond to any of Thank you. FINNEGAN: Thank you.

CHAIRPERSON

Actually, I think we'll do the questions later on today. will We are going to take a 10-minute break. return at 12:00 o'clock for the We

FDA's

presentation and then we will break for lunch. (A brief recess was taken.) CHAIRPERSON FINNEGAN: We are going to

have the FDA presentation and this is in two parts. The first of part the is the FDA staff panel. who Those will are the

members

FDA

give

their

presentations and the second portion will be three NEAL R. GROSS
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guest reviewers that the FDA has asked to look at particular portions of this PMA. And the FDA

presentation will be started by Dr. Aric Kaiser. DR. KAISER: Good morning. I'm Aric

Kaiser, an expert reviewer in orthopedics and the lead reviewer for the PMA. I would like to first introduce

the other members of the primary review team for this PMA who will be making the FDA presentations this morning. reviewer, Peter Barbara Hudson Buch, was the the lead pre-clinical reviewer and

clinical

Telba Irony, the statistical reviewer.

I'd also like

to acknowledge the expertise and efforts of a number of other people involved in this project both from the Center for Devices as well as valuable input from the Center for Biologics. The sponsor has gone into detail

describing the product, their pre-clinical data and the clinical results. panel that the device And I'd like to remind the that we're seeking your

recommendations on today is the InFUSETM bone graft LTcage lumbar tapered fusion device which is a threecomponent spinal fusion device that consists of a

NEAL R. GROSS
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spinal implant, a growth factor and a carrier. The first component, the cage component, is a titanium alloy tapered spinal fusion cage and as the sponsor has already mentioned, it has received PMA approval for use in the treatment of degenerative disc disease when filled with autograft. The other two

components, the InFUSETM bone graft consists of rhBMP2, the growth factor which is soaked into the ACS collagen sponge carrier. From a pre-clinical standpoint, there were two areas that we looked at, those having to do with the cage itself and those having to do with the BMP and carrier. Since the fusion cage has already

received PMA approval and has not been changed since that approval, and there we was no additional be review any

necessary information presented.

will the

not sponsor

presenting not

that

has

already

The BMP and carrier will be the focus of the FDA presentations and our presentation will focus primarily on the issues having to do specifically with our questions and not repeat the full review that the NEAL R. GROSS
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sponsor has already given.

The same thing will occur

for our analysis of the clinical and statistical data. The sponsor has given a detailed presentation and

we'll focus our comments on those issues having to do with the questions. After the last FDA presentation, I'll get up and go through an overview of what our questions are, but beforehand, I'd like to just give you an idea of the general areas of concern so that when you're listening to our presentations, you have some idea of where to focus. on issues We will be asking you for your input to do with reproduction and

having with

teratogenicity

tumorigenicity,

radiographic

effectiveness, end point interpretation, issues having to do with instructions for use and we'll also be looking studies. And with that, I'd like to introduce Peter Hudson, who will be giving the pre-clinical for some input on potential post-market

presentation. DR. HUDSON: Hello, I'm Peter Hudson and

I'm the lead pre-clinical reviewer for FDA regarding NEAL R. GROSS
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this

product.

I'd

like

to

acknowledge

the

collaborative effort of colleagues in the Center for Drugs, Biologics and Devices for review of this

application. the review

They have provided critical input into of the pre-clinical and manufacturing

information.

It's important to note that review of

the manufacturing information of this application has met the full standards of review that the Center for Biologics uses for review of recombinant reproduced growth factors. I'm going to briefly go over the pre-

clinical evaluations and identify the issues that FDA believes need further evaluation. The sponsor has been informed of FDA's concerns and in part has either begun to address some of these concerns or is committed to addressing some of the concerns as post-market commitments. know, we would greatly appreciate your As you and

input

guidance regarding the issues that remain as concerns. I'll first go over the extensive

toxicology and biocompatibility testing conducted on the produce although not as detailed as Dr. Riedel has done. Then I will discuss the experiments used to NEAL R. GROSS
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demonstrate

bone

inductive

ability

of

the

product.

Finally, I will present questions that have arisen in the course of I review would of like the to pre-clinical stress that due to test these the prethe

information. questions did

not

arise

specifically from the We of

experimental clinical questions literature. or in

observations clinical

sponsor's have posed

studies.

consideration

relevant

research

As has already been described, part of the device consists of recombinant human bone morphogenic protein 2 in an absorbable collagen sponge or matrix. The rhBMP-2 ACS is placed within the lumbar tapered cage or fusion device. acute single and RhBMP-2 alone was evaluated in dose general toxicology

multiple

experiments.

The results of those studies indicated

that the cytokine did not cause toxicity except for the occurrence of injection-site related tissue

thickening. To cytokine in assess a the chronic toxicity canine one-year of the

sponge, defect

six-month and a

mandibular rat femur

maxiofacial

study

NEAL R. GROSS
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onlay study were conducted. observed.

No toxic effects were

The cytokine sponge combination as well as

the fusion cage itself was tested in accordance with internationally recognized standards of

biocompatibility testing.

The cytokine sponge product

passed all the tests shown here. Studies of the ability of rhBMP-2 on a collagen carrier to induce bone included critical size defect repair models and fracture repair models on various monkeys. entopic sites in rabbits, rats, dogs and

Histologic analysis of a monkey ulnar defect

model and other studies suggest that bone formation in response to rhBMP-2 ACS occurs through a process of spindle or mesenchymal cell infiltration, vascular

invasion and a combination of endochondral and direct bone formation. Histologic analysis indicated that the

bone formation process temporally extended from the outside of the implant towards the center until the implant was replaced by trabecular bone. Many of the

animal bone induction studies included dose ranging studies and from these results a broad therapeutic NEAL R. GROSS
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dose range was identified.

The effective dose range

is bordered on one side by inadequate bone formation and on the other by excessive bone formation. The therapeutic rhBMP-2 concentration Higher

range shifts with the animal species tested.

concentrations are required in canines than in rats and higher concentrations are required in non-human primates. the The ability of rhBMP-2 ACS contained within cage to cause interbody sheep and fusion and was goat cage

fusion in

evaluated studies.

non-human cytokine

primates, collagen

The

fusion

combination device cause more fusion in comparison to autograft control and the fuse bone than was not

significantly fused bone.

different

mechanically

autograft

These results indicate that the bone

induced by rhBMP-2 in combination with ACS and/or the fusion cage is comparable to autograft induced bone and mechanically is not significantly different. As conducted a I have of summarized studies the to sponsor has the

number

establish

biocompatibility and safety of the product and has used various animal, non-human models to demonstrate NEAL R. GROSS
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bond inducing capability of the product.

However, the Again,

FDA has two questions related to the safety.

these questions don't arise due to pre-clinical and clinical observations of adverse effects due to the product but due to consideration of the potential for adverse effects that might occur. The rhBMP-2 to questions regard the potential bearing for for BMP an

stimulate to

transformed and the

cells

receptors

proliferate

potential

immune response to rhBMP-2 to cause adverse effects in developing fetuses in pregnant women. I'll first go

over the question for the potential for rhBMP-2 to stimulate transferring cells in a patient's body. Bone morphogenetic proteins form a subfamily within a transforming growth factor a super family of cytokines. Cytokines within the TGF beta

family and BMP specifically have been shown to play crucial roles in embryogenesis. In addition members

of the BMP sub-family have been shown to influence growth, differentiation and apoptosis of various cell types including osteoblasts, condroblasts, neuro cells and epithelial cells. BMP is type 1 and type 2, serum

NEAL R. GROSS
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kinase receptors in order to induce cellular signal transduction. Like other members of the TGF beta family, BMPs may elicit various types of responses in cells due to the cell type and/or receptor type expression. It is reasonable to attempt to investigate the

potential for BMP-2 to stimulate transformed cells. Some pre-clinical testing was conducted to address

this issue previously by the sponsor.

Now I will

review the information contained within the sponsor's application that is relevant to the topic. Then I'll

go over the additional studies or actually, I'll kind of briefly go over that since Dr. Riedel has pretty adequately discussed that already, the studies that were recommended by us. First pharmakinetic of all, I'll pretty go over the The

information

quickly.

experimental observations indicated that the systemic availability of rhBMP-2 is low. The prediction is

based upon pre-clinical evaluations and assuming a one milligram per kilogram dose suggested systemic

exposure to rhBMP-2 would be in the low nanogram per NEAL R. GROSS
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NL range.

The experiments indicate that the clearance

of rhBMP-2 from the systemic circulation is rapid and that the residents time and tissues involved and

clearance is brief.

However, individuals implanted

with the device will likely have some low exposure to rhBMP-2 outside the implant site. To address -- to more directly address concerns regarding carcinogenicity or for lack of a better term, of tumorigenicity transformed or cells, promotion the or

stimulation

sponsor

conducted the Ames mutagenicity assay in which they found that the results with that were negative. In

addition, they evaluated the product in a one-year chronic toxicity the study in the rat to and they have the

evaluated

product's

ability

influence

proliferation or growth of a limited number of tumor cell lines and primary tumor cell isolates. No carcinogenic effects were observed in the one-year rat femoral onlay study. In in vitro

tumor cell growth experiments, BMP-2 was observed to inhibit two prostate carcinoma tumor cell lines, one breast tumor cell line, one tongue cell line and one NEAL R. GROSS
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lung tumor cell line and not to effect the growth of four osteocarcinoma lines. against found primary that of tumor 65 In assessing BMPs activity isolates, Soda, et 16 al, were

cell

available

specimens,

inhibited.

No tumors were observed to be stimulated.

In neither in vitro cell study did the investigators evaluate the cells for BMP receptor expression. We cannot state that these studies

demonstrate a lack of stimulatory effects of BMP-2 on tumor cells or tumor cell lines the expressing two-year BMP-2 rats

receptors.

Traditionally,

carcinogenicity study isn't recommended for evaluation of implanted devices. We don't believe this assay

would adequately assess for the potential of rhBMP-2 to stimulate transformed cells. In consultation with

the sponsor we devised a series of experiments that Dr. Riedel has already gone over. FDA believes that the studies can be done as a post-market commitment. You will be asked to

comment on the concern of the ability of rhBMP-2 to stimulate transformed cells and whether you believe additional studies are necessary. NEAL R. GROSS
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Now I'll go over FDA's question regarding the potential for an immune response to rhBMP-2 to cause adverse effects. in I'll the briefly discuss the

information

contained

application

regarding

anti-rhBMP-2 immune response findings and then I'll present research literature regarding BMP-2 knockout mice. I'll mention what post-market commitments the sponsor and FDA have discussed with respect to revisions of the Elisa used to detect anti-rhBMP-2 antibodies. Finally, I'll tell you what we'd like you

to think about in preparation for our questions at the end. Enzyme link immune absorbants and assays were established to measure anti-rhBMP-2 anti-collagen type 1 antibodies in animals and patients implanted with the device. antibodies monkeys were Anti-rhBMP-2 and collagen type I screened on In rats, the dogs femur and rhesus rat

pre-clinically.

onlay

models, serum samples were obtained pre-operatively at four weeks, 26 weeks and 52 weeks. No rats

demonstrated a positive anti-rhBMP-2 or anti-collagen NEAL R. GROSS
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type I response. In at 28-day daily IV injection beagle dogs' toxicity study, three of eight animals receiving a high does of rhBMP-2 were determined to have a positive immune response. No animals exhibited an In non-human primate to rhBMP-2 were

anti-collagen immune response. studies the antibody

responses

evaluated pre-operatively at four, eight, 12 and 16 weeks post-operatively. Antibodies to rhBMP-2 were

detected in 35 percent, 7 of 20 of the animals treated with the device. The antibody responses were

transient of a low titer. No control animals exhibited an anti-BMP-2 response. Eight percent of the animals exhibited an These studies

anti-bovine collagen type I response.

suggest that immune responses to implanted rhBMP-2 can be expected. The type of responding antibody was not In addition, we don't

determined in these studies.

know if the antibodies cross react with endogenous BMP. In undefined as addition, to whether the it antibody was of a response was

neutralizing

NEAL R. GROSS
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character. would

For clarification, a neutralizing antibody prevent the BMP-2 from inducing

effectively

signal transduction in responding cells.

The sponsor

plans to revise the Elisa to better characterize the immune response elicited by implantation of rhBMP-2 as a post-market commitment. In the clinical study the immunologic

findings of which Dr. Buch will further discuss, two of 277 patients implanted with the cage contained One

rhBMP-2 exhibited a positive immune response.

control patient exhibited a positive immune response to rhBMP-2. The incidents of antibody formation

observed in this limited clinical study was very low and did not correlate with adverse clinical findings. In other clinical applications of rhBMP-2 and in the pre-clinical evaluations done in non-human primate

models, the incidents of the immune response to rhBMP2 was higher. FDA's concern about immune responses to rhBMP-2 regard to two issues; throatigenecity (ph) and restimulation restimulation of of an -and the response potential in the for women

immune

NEAL R. GROSS
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during pregnancy. experimental

This concern is driven chiefly by obtained from research Again, I

observations

literature regarding BMP-2 deficient mice.

want to stress that these concerns were not raised by observations of adverse effects in the pre-clinical or clinical evaluations done by the sponsor. Also it should be stated that pre-clinical evaluations were not specifically designed to evaluate these issues. The sponsor conducted teratology (ph)

and fertility pre-clinical evaluations of rhBMP-2 but these studies were designed to assess if exogenously added rhBMP-2 itself would have deleterious effects on the development of fetuses or if it adversely effected performance parameters of reproduction. These studies did not investigate whether the deletion of rhBMP-2 cause due to antigen-specific morbidity. In

antibodies

would

embryonic

addition experiments were not done to investigation a fetal expression of BMP-2 in pregnant females immune responsive mother. to rhBMP-2 could cause toxicity in the

It is important to be cognizant of research

and literature regarding the role of that cytokine NEAL R. GROSS
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plays

in

normal

bone

physiology

as

well

as

in

embryogenesis in order to anticipate potential safety issues. The reason why we pose these questions is based upon experiments conducted in mice deficient for BMP-2 or BMP-2 knockout mice. In these mice

investigators noted that a deficiency of BMP-2 was embryonically lethal. The embryos were noted to have

failed to close the pro-amniotic canal which cause the malformation tissue. defect in of the amniotic cavity and chorionic a

BMP-2

deficient

embryos

also

exhibited by

cardiac

development

manifested

the

abnormal development of the heart and the exocelimic (ph) cavity. Homozygous deletion of BMP family

members has resulted in other embryonic lethal events as well. and mice BMP-2 had For example, as shown in this slide, BMP-7 deficient defects in mouse the embryos, BMP-7 of deficient eyes and

development

kidneys. BMPs obviously, play significant critical roles during were embryonic to cross development. the placental If antibodies they

rhBMP-2

barrier,

NEAL R. GROSS
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theoretically

could

adverse

effect

embryogenesis. A

This diagram captures the essence of the issue. woman of child bearing potential is treated

with

rhBMP-2 to fuse vertebrae. cytokine elicits an immune

The implantation of the response. During a

pregnancy, fetal expression of BMP-2 restimulates the anti-rhBMP-2 immune response would have potentially adverse effects for the embryo as well as the mother. We would like you to discuss this issue and look forward what to of your animal address recommendations. models the do you of

Specifically, believe would

type

sufficiently

question

whether maternal antibodies to rhBMP-2 can cross the placental barrier and cause deleterious effects on the developing fetus, also what type of animal models

would you recommend to answer the question regarding fetal expression of BMP-2 and its potential for

adversely effecting maternal or embryonic development in women who have anti-rhBMP-2 antibodies. We would like you also to consider the use of a registry for women of child bearing potential in order to monitor for these potential effects. NEAL R. GROSS
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Thank

you. DR. BUCH: Good afternoon. My name is

Barbara Buch and I'm the FDA's clinical reviewer for this PMA. assistance Yahiro. I'd like to thank my colleagues for their with As this review, has especially already Dr. Martin a

the

sponsor

presented

detailed account of the results regarding safety and effectiveness of the clinical trial, I will not repeat that but I would like to start by highlighting some of the key points relating to the effectiveness and the safety of this device based on the data that was presented by the sponsor in PMA. review some additional studies in Then I will briefly in this and the

considerations the PMA

supporting

regarding

interpretation of radiographic data specifically. Given all this information, I will then as you, as the panel, issues the to focus on the lead radiographic you into a

interpretation discussion of

which

will

radiographic

panel

question. I'd

Overall, this clinical trial was well conducted.

like to point out that Bayesian statistical analysis were used and there was a high patient follow-up and NEAL R. GROSS
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data

accountability. adverse event

In

addition, As

there

was

meticulous

reporting.

previously

been discussed many times, there were two arms of the randomized portion and one non-randomized laparoscopic clinical trial. I'd like to also point out that the

follow-up rates, again, are very high and that in the laparoscopic group the follow-up rate does not take into account those patients who are not yet evaluated for that 24-month evaluation. Dr. Mathews has already explained in

detail these clinical end points that were evaluated to determine overall of safety patient and success for of the this

determination combination

effectiveness randomized

device.

For

the

clinical

trial, as I've said, the accountability of patients and the data at 24 months was greater than 85 -greater than 87 percent. This included the antibody

testing for anti-rhBMP antibodies and for anti-bovine collagen antibodies. In the randomized group there was very little difference in the co-variates between groups pre-operatively. This included a strong correlation NEAL R. GROSS
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of the pre-operative SF-36 obtained in the Oswestry evaluation scores. I'd like to briefly highlight some In the randomized portion of

of the clinical results.

the trial, the investigational group had less blood loss and less overall operative time than the control group. This is in part attributable to the lack of

bone graft harvest as has been mentioned. The laparoscopic group, as expected, had a shorter hospital stay when compared to the randomized treatment time. groups and also had a shorter operative

I'm sorry, the operative time was equivalent. antibody testing, as been explained

Regarding

previously, the patients were tested for the presence of antibodies to rhBMP bovine type I collagen and then to human type I collagen. In each of the three

treatment groups, including the laparoscopic, there was only one patient that had an authentic positive response to rhBMP antibodies for a total of three in the entire clinical trial. The overall study outcome was a success for the control patient that was positive and failures for the patients in the investigational and

NEAL R. GROSS
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laparoscopic treatment groups.

However, because of

the low rate of occurrence, the significance of this finding relative cannot low be rate determined. of authentic There is also a

positive

elevated

antibody responses to bovine collagen in each of the three treatment groups. Of these greater than 60

percent of the patients in the randomized groups were overall success. groups has a No patient in any of the treatment response to type I human

positive

collagen. What's important to know is that analysis was completed comparing clinical outcomes with

antibody responses.

There were no correlations of any

of the rhBMP and bovine antibody results with the overall outcome individual end point success or One the

failure or the occurrence of adverse events. other interesting final result both is sets that of in

randomized

treatment

groups

patients

returned to work in an average of approximately 64 days following in the surgery and not arm unexpectedly returned to the work

patients

laparoscopic

faster than those in the open procedure groups. NEAL R. GROSS
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This clinical trial has demonstrated that the outcomes for patients treated with the

investigational device were as effective as those in the control treatment group. As this table shows, for

the results of the primary effectiveness end points, the investigational treatment group were equivalent to the control. The same can be said about the majority

of the secondary end points. When looking at the adverse events in

general, the incident of any adverse event in either of the randomized treatment arms was high. This is,

in part, due to the detailed reporting of the adverse events and the nature of the surgical procedures.

Specifically, there was one death in a patient in the control group who had a history of cardiac disease. The most significant finding was the incidence of

graft site related adverse events aside from pain that occurred only in the control treatment group and were absent in the investigational treatment group. These included fractures, nerve injuries, infection and hematoma. immediately Donor site pain was high but as we've seen

post-operatively

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significantly

resolved

by

six

months

to

a

year.

Finally, important to note is that there were six pregnancies in women in this clinical trial. five pregnancy in the two investigational Of the device

treatment groups, that is the laparoscopic and the open investigational group, there were two early

trimester miscarriages, both in the laparoscopic group and three healthy births. In the overall analysis of adverse events in randomized treatment groups, there were 12

categories which -- in which both groups had a greater than five percent occurrence rate. had Of a those the

investigational

treatment

group

slightly

numerically higher rate of non-device related events including back and leg pain, GI symptoms, retrograde ejaculation, spinal events, incidents of trauma, one vertebral fracture and urogenital events. Of these only the urogenital event rate was statistically significant as a difference compared to the control. events Approximately involved half of those urinary

urogenital retention.

post-operative

This is not an unexpected event following NEAL R. GROSS

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www.nealrgross.com

spinal surgery.

All these events resolved prior to

discharge from the hospital. Other kidney stones, events bladder in and this category included and

rectal

symptoms

erectile dysfunction. six weeks

These events occurred at least a period unrelated to was

post-operatively, procedure. in five this

surgical documented patient

Retrograde investigational difference was

ejaculation and not one

control

but

considered

statistically significant.

And as would be expected

and has been mentioned many times, the incidents of graft related adverse events were statistically and numerically worse in the control group. In groups, reviewing all of was only three higher treatment in both

retrograde

ejaculation but

investigational

groups

statistically This There

different in the laparoscopic treatment group. is, again, attributed to the surgical approach.

were no directly linked immune related adverse events. There were five possible or potential events that may be considered immune related and none of these

patients had authentic positive responses to either NEAL R. GROSS
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anti-rhBMP antibodies or anti-bovine collagen type I antibodies. There were two cases of cancer diagnosed during the clinical trial. cancer was diagnosed in One case of pancreatic a patient in the

investigational treatment group and a case of breast cancer was found in a control group patient. were no cases of osteogenic cancers reported. There The

overall occurrence of device related events, as we have seen, was similar between the investigational

control and laparoscopic groups.

What I'd like to

point out is that this includes malpositioning of the device, migration, loosening and subsidence in

addition to non-unions.

When non-unions are removed

from this scenario the incidents is low, falls to less than one percent which is expected for the caged

devices. When compared to the control group, the laparoscopic group had a higher occurrence rate of migration, malpositioning and related anatomic

difficulties as well as has been discussed retrograde ejaculation. These occurrence rates probably relate NEAL R. GROSS
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to the procedural approach and are consistent with other spinal literature. surgeries Although is the similar rate of in The occurrence of second both randomized was higher of groups. in the

removals the

investigational

group,

rate

supplemental

fixations was slightly higher in the control groups. The relative rates of occurrence, however, are very similar with eight percent in the investigational

group, 10 percent in the control group, and seven and a half percent in the laparoscopic group. Based on the clinical data provided in this trial, patients receiving the investigational

device achieved equivalent fusion and clinical scores compared to the patients receiving autograft control while eliminating the possibility and necessity of

bone graft donor site and its attendant morbidity. Again, they were mostly equivalent adverse event

profiles and occurrences. Now, I'd like to turn your attention to the question of radiographic interpretation. This

question arises because this clinical trial was the first to use both x-rays and thin sliced CT scans with NEAL R. GROSS
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reconstructions

to

determine

fusion

which

is

an

important primary end point.

The sponsor has provided

the results of an x-ray versus CT validation study as part of the IDE and Dr. Irony will discuss this in her presentation. All the radiographic results of this

clinical trial, both plain radiographs and CT scans were presented in order to assess fusion. One other of our concerns is whether or not we can interpret the radiographs of patients

treated with this combination device in the same way as we do the radiographs of those treated with

autograft given that the fusion sites may calcify at different rates and the progressive rate diffusion may be different. To this end, I will review the current

definition of fusion in this trial, show you some examples of radiographs from this trial and discuss some issues and interpretation within this trial and other studies presented in the PMA. Plain films were reviewed for the presence or absence of translational motion and angulation.

They were then reviewed for the presences of bridging trabecular bone. If there was trabecular bone present NEAL R. GROSS
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and no motion on fluction extension films, the patient was considered to be fused. If there was no bridging

bone apparent on the plain films, the CT scans were assessed for bridging bone. If there was bridging

bone on CT, no motion on plain films, no lucencies, the patient was determined to be fused. utilized both plain radiographs and The sponsor CT scans to

determine the presence of bridging trabecular bone in the assessment of fusion. There were no instances where there was bridging bone on plain films that was not seen on CT scan. However, there were many instances of false

negative plain films, that is cases where the CT scan showed no bridging bone when the plain film did not. I'm sorry, there were no cases -- there were many instances of false negative plain films, that is cases where the CT scan showed bridging bone and the plain radiograph did not. This phenomena could potentially inflate the success rate in the open investigational group. As seen on this slide, the table compares the

determination of bridging bone by x-ray and CT scan at NEAL R. GROSS
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various

time

points.

At

six

and

12

months,

the

proportion of disagreement between the x-rays and the CT scans was high. This problem was minimized at 24

months which was the end point of the clinical trial. You will also notice that as the study progressed from six months to 24 in all three groups, there's an actual decrease in the number and rate of patients with bridging bone detected. At 24 months, however, only 8.3 percent of the patients who were considered failures by plain xray became successes by CT. In the control group,

approximately five percent of the patients who were failure by plain radiographs, became successes by CT. I'd like to direct your attention now to the next series of CT scans which are examples of patients in the clinical trial. The slices are taken through the center of the fusion cage and while I realize the determination of bridging bone and fusion are naturally determined by multiple serial axial to sagittal and

reconstruction views, these views are an attempt to provide you with some representative examples of the NEAL R. GROSS
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patients

in

the

trial

which

can

supplement

those

presented by the sponsor.

When reviewing these scans,

consider, if possible, the progression of fusion and differing densities of the material within and around the cages at different time points. The first series are patients considered successful fusions in the trial. The second set I'm

represent patients who were considered failures.

going to ask you if you were able to determine which side represented the investigational device and which represented the control. On the left side of the

slide the cuts represent patients who were in the investigational group and on the right represent the control. Now let's look at what information we've learned from prior animal studies and human studies that looked at radiographic These subjects results compared looked to at

surgical animal

findings. and human

studies

that

implanted

with

spinal

devices using autografts -- autograft only and then were taken back to surgery. Fusion was determined at

the time of surgery by manipulation and histologic NEAL R. GROSS
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analysis and then compared to pre-operative x-ray and CT fusion status analysis. A summary of these studies showed the CT scan correlated in most cases to the findings at

surgery and that the CT scans specifically had higher sensitivity and specificity for determining fusion

status compared to the plain radiographs. where BMP was used in surgical fusion

In the case in animal

subjects, a similar analysis was done at second look surgery to determine fusion and then compared to preoperative x-ray and CT radiographic fusion analysis. In summary the CT scans again highly

correlated with the surgical findings and histological analysis. and rate In addition, it appeared that the density of progression of repair or remodeling

differed somewhat in comparison to what's known about autograft and allograft. In this clinical trial there

was an extremely high fusion rate in all treatment groups when using both x-ray and CT to make the

determination of fusion. When considering the data from other

studies regarding the radiographic interpretation of NEAL R. GROSS
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fusion, you should bear in mind a few key points. First, in the x-ray and CT validation study that was done by the sponsor, autograft was the basis for the conclusion used to consider this method for

determining fusion in this PMA. Second, we may not be able to extrapolate the information from animal trials to potential human responses. potentially And finally, we need to recognize that the rate and extent of radiographic With

changes between autograft and rhBMP may differ.

all of this in mind, you'll be asked to comment on the interpretation of radiographic data in this clinical trial. issues Please keep in mind the following additional when commenting in on the determination with of this

successful

fusions

patients

implanted

combination device. This includes the presence and absorption rate of the collagen sponge, the identification of progression of bone repair processes in the presence of rhBMP and the ability of bone formed at various time points to accommodate applied loads. And

finally, I'd like you to consider the implications of NEAL R. GROSS
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all

of

these

factors and

on

the

interpretation training in

of the

radiographic future.

fusion

physician

Thank you for your attention. DR. IRONY: My name is Telba Irony and I'm

going to comment on the statistical issues relevant to your consideration for the questions presented by the FDA. I have discussed two statistical issues. report about the analysis of I will and

briefly

safety

effectiveness in this submission and these analysis were made through Bayesian methods. And second, I

will talk about the statistical comparison of the use of x-rays and CT scans in assessing spinal fusions. First, with respect to the Bayesian

methods that were used here, as was said before, we have two main studies. surgery study and which One was an open study -- open was a multi-center There were study 143 The

prospective

randomized.

like

investigational devices and 136 control devices.

second study was a laparoscopic study which was nonrandomized and in this statistical comparison we made a comparison with the same control as we did in the open surgery study. NEAL R. GROSS
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Well, Bayesian methods were used and I will very briefly explain the methodology that was used in this submission. First, non-informative prior

distributions were used and I'm just stressing that because usually when Bayesian methods are used, in many cases they use prior information meaning

information from other studies. here.

That was not the case

We computed posterior probabilities instead of

p-values and predictions of results for 24 months were made from some cases in which the patients had only some data; in the cases of the patients for which the 24 month values of some end points were missing or some patients that were lost to follow-up and patients that were not yet due for their 24-month visit. Such accountability at conditions 24 months improved was already the high

especially for the open study and as a consequence it enhanced the accountability and improved the precision of the estimates at 24 months. Just to give you a

brief idea of what was done here, let's think that for each endpoint, P
0

will be the chance of success for
1

that point, endpoint in the control group and P NEAL R. GROSS
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will

www.nealrgross.com

be the chance of success for the endpoint in the treatment group. So if you think about the difference
1 0

between zero minus P , you will conclude that if P minus P better
1

is large, that will mean that the control is than the treatment small, and the if P
0

minus

P

1

is be

negative,

meaning

control

will

considered worse than the treatment. So we are going to look for a large

probability that the difference is small enough and that will provide us evidence that the treatment was not inferior than the control and then will declare equivalent. probabilities. endpoint. For So we Small each are going to look depend had a at on this the

enough endpoint,

will we

minimal

clinically significant difference and high probability or large probability was in this case 95 percent. So

here are the results for effectiveness endpoints for the open surgery control group -open surgery

compared to the control group. That's the table. For instance, for

fusion, the chance of success in the treatment group and that chance is already corrected for the loss to NEAL R. GROSS
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follow up and for patients that for instance didn't come at 24 months was 92.8 percent and for the control group was 88.1 percent. The probability of

equivalence, in other words, the probability that this difference was small enough was basically 100 percent. And you can see for all of the effected endpoints, the probability of equivalence was considerably high. There were two endpoints which was back pain and the MCS. I put a little red star there to

say that that probability was high but was not 95 percent. Now, for the laparoscopic group we have a The values are different and basically

similar table.

for all endpoints the probability of equivalence was larger than 95 percent. And for this group there was

a higher -- the group started late, so there were more patients that had not yet reached 24 months by the end of the study, so predictions was -- were made for more or less 25 percent of the patients. Now the second issue I'm going to assess which is the statistical comparison for the use of xray and CT scans in determining fusion. First I'm

going to talk about a validation study that was done NEAL R. GROSS
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independently on the submission and second, I'm going to talk about the scenario in the current submission and how it compares to the validation study. Our problem was the false positive rates. We don't want to have false positive rates because that will inflate the results on fusion and

consequently on overall success which was the primary endpoint of this submission. So in the validation

study, it was done, I will stress, independently on the study in this PMA. There was a surgical

exploration of 53 spinal fusion methods in humans in order to assess sensitivity and specificity of both xrays and CT scans for determining fusion. So before the surgical exploration, which was the gold standard; they opened the patient, they could see if the patient was effectively fused or not, the fusion status was determined by both x-rays and CT scans and the relevant parameters evaluated in the study with respect to this PMA are the sensitivity which is the probability of testing positive, in other words, determining fusion when in fact there was

fusion, the specificity which was the probability of NEAL R. GROSS
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testing negative, determine there was no fusion when there was no fusion and a false positive rate, the probability of saying that there was fusion when in fact, there was no fusion. These are the results of the study. are point estimates. These

And for instance, for x-rays,

the sensitivity was 79, about 79 percent, specificity 86 percent, so the false positive rate was about 14 percent. For the CT scans both sensitivity and

specificity were higher resulting in the lower false positive rates. In that study there was a third

method to determine fusion, which was a combination of x-ray and CT scan and in that case, the patient was determined fusion -- fused only if both x-ray and CT scan determined fusion. method. The conclusion for this validation study is that sensitivity and specificity is higher for CT scans and for x-rays. False positive rate is lower That's a very conservative

for CT scans and the smallest false positive rate is from the combined x-ray/CT scan method. That's very

conservative and was not used in this submission. NEAL R. GROSS
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Now, the validation study characteristics were different than the ones in the current PMA and that's an important point for consideration for the people that are trying to answer the questions that FDA has posed. First, the patients in this study did

not have cages, they did not have spinal fusion cages. The inclusion criteria in this study was different. The patients or in this study pain were patients with

continued lumbar

worsening for

following or

instrumented disc

fusion

instability

degenerative

disease requiring surgery. Given that, we will expect that we'll have a higher prevalence of known fusions in this study but however, the distribution was even, where 24 patients that were fused and 29 patients that were not fused. Second, the time a year flexion is period after of the exams The There the were x-rays was no of

approximately examined presence were of

surgery.

extension. study and

BMP

the

method

performing CT scans was different than the one in the present PMA. Now, what happened in the current

NEAL R. GROSS
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submission? determined. evaluations.

I will briefly explain how fusion was It was it actually was based on in several of

First,

based

evidence

bridging bone and the determination was first made by x-ray. If bridging bone was not detected, then CT

scan was used and if bridging bone was detected by at least one method, either x-ray or CT scan, then the evidence After of bridging bone was considered bone, on these present. other

evaluating were

bridging made based

evaluations

x-ray;

segmental

stability, and lucent line criteria and in addition if there was a second surgery due to pseudoarthrosis, that will be a failure and the patient was not

considered fused. Now, as a consequence, the actual

comparison that we are making is in the methods of detecting bridging bone. The other factors are the The adopted way

same in both methods of evaluation.

of detecting bridging bone is not conservative because it's sufficient to have evidence of bridging bone with one of the methods. And finally, in the submission

there was no case in which the presence of bridging NEAL R. GROSS
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bone was detected by x-ray and was not detected by a CT scan. So I'm going to present a table in which I will show the disagreement between the x-rays and CT scans in the examination of bridging bone. But before

I do that, I will note some important considerations. First, again, in all disagreement cases the CT scans indicate that fusion and x-rays did not agree. There

is much less disagreement at 24 months than at 12 months and the relevant point for this submission is actually 24 months. the disagreement. So this is the table that shows For instance, at 12 months there In other was CT

was disagreement in 52 patients out of 130. words, 40 percent between of the the patients

there through

disagreement

determination

scans and x-ray. In the control group, that disagreement was also high and the same with the laparoscopic

group.

When we go down to 24 months, the disagreement It's about seven percent for the

is much smaller.

open group, five percent for the control group and there was no disagreement for the laparoscopic group. NEAL R. GROSS
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Now, what is the effect of this disagreement in the success rates of fusion? At 12 months, for instance,

an open group that will be determined by x-ray to have only 57.3 percent of success whereas if it was

determined by CT scans the success rate will increase to 96.9 percent. The same behavior was seen in the control group; by x-ray the success rate will be about 30 percent and by CT scan will be about 92 percent and the same with the laparoscopic group. However, at 24

months which, again, I will insist is our final and primary endpoint, this disagreement is much smaller. You cannot -- I put in red just to say that in a few cases actually the success rates decreased but they decreases slightly. Now, overall success. impact as well. what's the impact of that in the

Of course, there will be a large The impact will be more pronounced at For instance in the open

12 months with x-rays.

group, the success rate will be about 32 percent and with CT scans will raise to 59.7 percent. Again, at

24 months, primary endpoint this difference basically NEAL R. GROSS
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disappears, it was just reduced to a much smaller difference. As bridging bone a has conclusion, impact on the the determination determination of of

overall success and the impact is much more pronounced at 12 months than at 24 months. The validation study

was performed in patients at approximately 12 months after surgery and in the study both the sensitivity and specificity of CT scans were higher than for the x-rays, but the characteristics of the study were

different than the ones in the PMA and should be taken into account by the panel members. my presentation. CHAIRPERSON FINNEGAN: Thank you. Aric, And that concludes

we're going to actually ask you to do yours after lunch so that right we can have We're the panel to looking have at

questions

away.

going

three

short, five to 10 minute presentations from our three guest presenters and the first one is going to be Dr. Rocky Tuan who is a -- who has expertise in the BMPs and their biological effect. DR. TUAN: So the purpose of my

NEAL R. GROSS
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presentation is to give you an overview of the biology both in vitro and in vivo, of BMP as a group of molecules. My talk will be divided into four topics. The

The first one has to do with the protein itself.

second part has to do with its molecular mechanism action. activity The third part has to do with its biological both developmental applications and and also then in post-natal some

pharmacological

finally

discussion on issues related to potential biological complications related to the usage of BMP. As already has been described and detailed by previous of speakers, bone the BMP or bone morphogenic actually

protein

morphogenic

activity

was

first discovered quite awhile ago.

In fact, more than

100 years ago the work of Nicholas Sen at Rush Medical College who used bone grafts to treat osteomyelitis was in fact, the first indication ever of bone The

inductive activity coming out from bone itself.

pioneering study of Dr. Marshall Urist, of course, was instrumental in identifying, discovering activity from the demineralized bone matrix. Later on the work of

Hari Reddi and Dr. Huggins in the early '70's with the NEAL R. GROSS
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subcutaneous implantation of demineralized bone matrix substantiated all of these earlier findings. Later on, Urist, Sampath, Reddi and

several other groups isolated in at least a certain degree of purity, these bone morphogenic molecules. Partial sequences were obtained and then these were then used to and generate nucleotide these probes BMPs to screen cloned.

libraries

subsequently

were

And at this point there are at least 20 BMPs and they belong to the larger family of transforming growth factor beta super family which was originally isolated from tumor cell extracts and called transforming

growth factor beta for that reason. The only exception is BMP-1 which is

actually an enzyme. actually, so it

It's a procollagen C peptidase belong in the same group

doesn't

although it's called BMP-1. sub-families of the BMPs.

There are at least four There's a BMP-2,4, BMP-3,

the OP1 BMP-7 and then finally the cartilage derived morphogenic protein which are also called growth and differentiation factors. These are -- and there are

others that have not been neatly fallen into specific NEAL R. GROSS
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sub-categories. The structure of BMP as already has been described by other speakers. homodimer, sometimes It's a dimer, some time They are

heterodimer.

synthesized originally as larger precursor forms which are then photolytically processed into carboxyl and into yield a mature product. It contains canonical 7

cysteine residues, one of which is involved in a very critical disulfide knot (ph) structure important for its activity. Okay, the second part now, the molecular mechanism action; BMPs because they are in the family of TGF beta super-family, they are actually signalling molecules, that's the best way to describe them. interact with cell surface receptors. They

There are at

least two receptors, each of which, of course, also has cousins and relatives. These are the BMP receptor

1 and BMP receptor 2, both of which are also enzymes. They are kineses. Upon binding of BMP to the BMP receptor 2, BMP receptor 1 is then phosphorylated. This then This

activates a whole series of signaling events. NEAL R. GROSS
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www.nealrgross.com

receptor

complexed

and

interacts

with

a

family

of

molecules known as SMAD or S-M-A-D.

MAD stands for

Mothers Against Decapentoplegic, which is actually a fly protein and which is also a member of the BMP super-family. Again, I just want to also reiterate

that the BMPs have been found across all species so far. So at any rate, the SMAD, these are the signaling partners, SMADs 1, 5 and 8 interact in a sequential manner. Later on they then interact with a

common partner called SMAD 4, which then removes the entire complex into the nucleus of the cell to

activate specific genes, so that's basically how this whole thing works. There are also anti-SMADs.

They're also called SMADs. They's called SMAD 6 and 7. So these are the inhibitory SMADs. emphasize one point in this Now, I want to of the

description

molecular mechanism of action is that this signaling pathway does not work in isolation. Nature being the way it is, there is

tremendous cross-talk between one signaling pathway and other signaling pathways. Recent data from many

NEAL R. GROSS
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laboratories have shown that this particular -- from the outside of the cells to the surface receptor and then to the nucleus, this particular pathway, this access, actually interacts with other axes, such as the extracellular matrix and receptor complex

signaling mechanism via intergrins and fibronectin and collagen, et cetera, as well as most recently the wind-signaling pathway. Again, that's another distant Again, the function growth, proliferation, So when we

relative of some fly protein. there is to stimulate cell

differentiation, morphogenesis, et cetera.

consider BMP family as a family of signaling molecule, we have to consider what they also do with other signaling pathways. All right, the third topic is activity, developmental as well as post-natal. One thing I want

to emphasize again is that BMP action is highly cell specific. There we should get it out of our mind that

there is one cell that is -- all cells react to BMP the same way. That is absolutely not true. BMP --

the same BMP can do different things to different cells depending on its own repertoire of receptors and NEAL R. GROSS
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also all the signaling molecules inside the cell. Now, during development as Dr. Hudson

already pointed out earlier, BMP is absolutely crucial for survival is and ample development at this of the If fetus. you The have a

evidence

point.

knockout, i.e. deletion of BMP genes, you will get embryo lethality. transgenic If you also are missing, again by the receptors for BMP, you

methodology,

also get embryo lethality. things happen way before

So now, remember these there is any bone or

cartilage or anything like that. So where BMP works is actually depending on the developmental during very stage early of the animal. For during

example,

development,

gastrulation, BMP works be defining the polarity of the animal, particularly the dorsal-ventral polarity, who's on top, who's on the bottom, and again, nothing to do with bone or cartilage at that point. And a very crucial example would be the specification of the formation -- of the development, the differentiations of the paraxial mesoderm. In

fact, those are the cells that ultimately give rise to NEAL R. GROSS
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the spine. that are

So before you even have a spine, the cells precursors to the spine already are

responsive to BMP.

Whether it's in the same manner or Nevertheless, if

not, we do not know at this point.

there is a perturbation in the distribution of BMP, the dorsal aspect and the ventral aspect would get all mixed up. In the development of a limb, which of course has bones and cartilage, et cetera, again BMP is very, very crucial. It is important for the

initial differentiation event of forming cartilage as well as the death of cells in the interdigital area. So it can be a positive factor in the sense that it makes cells, becomes something else or it can make cells undergo apoptosis and die so that there will be a space between the fingers. And also member of the BMP family, TGF-5, is absolutely crucial for joint development. Without

that, there would be a decrease in the number of joints. There would be a fusion of joints, mainly the So

joint never will actually form in the first place. that's developmental. NEAL R. GROSS
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www.nealrgross.com

In terms of post-natal, we have already seen many pieces of data on the or results of

pharamocological application of BMP

application to a

therapeutic animal, the

post-natal

historical findings of osteochondroinductive activity, of course, is obvious. Fracture repair, critical size

defect, feeling, spine fusion, we saw many pieces of data and also recently in terms of osteointegration and that is how bone cells interact with an implant bio-material. In this case it may be relevant to the

topic at hand, namely that there is a piece of alloy that is part of this device. Now, how the presence of BMP may influence the interaction between the neighboring cells and the metal alloy is something for us to think about. Finally, potential biological

complications; one thing that needs to be considered is the distribution of the BMP that has been placed into a particular site and also retention of this material once it has distributed to other places. notice the low systemic level. We

However, exactly where

the BMP finally ends up is something that perhaps to NEAL R. GROSS
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think about. Tumor inhibitory or induction stimulatory in in terms terms of of either cell

proliferation for transformed or not yet transformed cells, hematological perturbation has been shown for the grandfather The of the TFG of beta TGF super-family, beta-1 can TGF

beta-1.

presence

cause

hematological perturbations. Teralogical discussed later, for effects, example, which the will BMP be can

whether

cross the placenta, the window of time in terms of its action, whether the effect can be transgenerational is also something worthy of consideration and finally

immunoreaction which has also been discussed, so I think I'll stop here. CHAIRPERSON much, Dr. Tuan. FINNEGAN: Thank you very

Now, Dr. Miller is going to talk to

us generically about animal models and the use of registries for teratogenicity. While he's setting up,

the really bad news is we do not need to have a closed session, so we will go to lunch once Dr. Kostuik has finished his presentation. We do need to start back

NEAL R. GROSS
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immediately at 2:00 o'clock, so I would ask you to make it a short lunch. Consider it a way to get over

your Christmas indulgences. DR. MILLER: make it brief. Good afternoon. I'll try to

You have a handout so some of the

slides have been eliminated in the interim to shorten it a bit. and I've been asked to look at some principles The developmental toxicology animal

concepts.

testing is how it is done.

The evaluation of biotech

products which really introduces a whole new question into the reproductive and developmental area and then post-marketing pregnancy registries and I'll try to do that all within 10 minutes. I am offering a course at the FDA next month that takes four hours to do this, so I'm putting it in perspective. Different molecules will produce a

different spectrum of malformations depending upon the mechanisms of action as one sees here with Accutane, with valporic acid in terms of spina bifida and methyl mercury down below. We know that the pregnant female We don't study products in

is a pharmacologic orphan.

them by choice necessarily and that we really are NEAL R. GROSS
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treating two different organisms and that's actually one of our questions. Dose is the problem, threshold concept is critical to the area of developmental toxicology and usually we say where is that threshold there is a toxic effect? Well, in many instances when we're

looking at it there are doses that won't produce that toxicity and maybe that's what we should be looking at as well. Along those lines, dose, length of exposure

and time during gestation are our critical areas of evaluation important and when this one will is certainly talking become more

about

different

surgeries and what time they may be occurring in a woman if she is pregnant. There are certainly sensitive windows

along these lines and I've borrowed this from Keith Moore, where you see in red here many different organ systems that are sensitive from the brain down to limbs and other organs. If we move just a little

earlier, the whole pre-implantation, implantation area is one also of equal concern. the last moment. I added this just at However, when we

I had removed it. NEAL R. GROSS

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www.nealrgross.com

are thinking of mechanisms of action, the National Academy of Sciences just completed their work in the past year and of published a volume called Risk I

Assessment

Developmental

Toxicology,

which

recommend to you and have been using the 17 different signal transduction pathways to look across species to see the commonality for agents and I do have an

asterisk up there; one for transforming growth factor, because obviously, that is the family cluster in which BMPs are found. So if these are some of our concepts, what are the animal testing that we must undertake and follow guidelines on? being fertility and And there are three areas, one early embryonic development,

usually performed in the rodent, the rat; embryonic and fetal development, sort of the teratogenic period, that is done in two species; one the rat, the other the rabbit or some other species that is a non-rodent. And then some pre/post-natal developmental studies to look at behavioral and functional changes. Along those lines, studies are conducted according to these guidelines and these are sort of the minimum NEAL R. GROSS
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requirements

that

we

really

need

to

think

about.

Treatment via the likely human route with obviously some exceptions but we would like to perhaps more closely mimic that. Results should permit identification of a NOAEL and a LOAEL and also look at a maternally toxic dose. Maybe the compound one is looking at doesn't

get to a toxic dose that one can demonstrate in the mother but at least you've tried to go there.

Extrapolation from the most sensitive species unless there is evidence that the species is inappropriate might, in fact, be reason to look at another species based upon drug and a metabolism, then formation we of reactive to have

metabolites, clarity of

obviously, about

need

thought

detection

versus

characterization. If these are our primary roles, then we're looking at the identification of hazard and we're

looking at the identification of risk. these lines, hazard really is an

And along studies

animal

agenda, especially with a new agent because we don't have human case reports to rely upon in many instances NEAL R. GROSS
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and if we generated that, the dose response model from animal studies is what we would need to utilize in trying to identify phenomena risk. we need And to probably consider the here most is

important

biological plausibility. And biological plausibility really

encompasses all of what we know about pharmacology and about actions in pregnancy and is that, in fact,

reasonable what you are seeing. the risk assessment model

So here in terms of we're outcome talking and the

toxicokinetics, toxicokinetics

toxicodynamics becomes an

and

extremely

important

component here to try to extrapolate among species. Range finding studies are important as

well as doing the definitive study as listed below here and in that one would certainly stop at delivery, actually before around 21 days to do a Caesarean

section to evaluate the animals and in other studies doing the follow-up post-natally to see survival and what may, in fact, be happening in terms of behavior. In the rabbit, one usually starts with the non-

pregnant dose ranging study and then does a pregnant NEAL R. GROSS
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one to see if there is enhances sensitivity and then going on to embryo fetal developmental studies,

exposures between seven and 25 days to look for those types of problems that may be associated with the agent under study. So selective reproductive toxicity can be detected in range finding studies and if there aren't any, usually one would perform according to the ICH guidelines and do sort of the minimum requirements. However, if you have found toxicity, you would

certainly want to characterize it better by doing the dose response relationships looking at the critical periods and looking at the adverse effects in terms of both structural and functional but also emphasizing again, this toxicokinetics in terms of the critical periods and determining whether the agents are formed and delivered in fact, to the conceptus. In understand the vitro models can be used So to better in an

toxicity

itself.

identification of risk, we have a decision tree and these you need for to keep risk in mind. Is the Are species there

appropriate

assessment?

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differences species risk?

in

pharmokinetics trying to

and

dynamics to

among human

especially Are

extrapolate in

there

differences

reproductive

physiology or timing of development which should be taken into account? What is the likelihood humans

will be exposed and treated under the conditions one has used in these animal studies for critical periods and characteristics of the patient population? And potential of finally, the agent conclusions to produce about the

reproductive

toxicity, is that similar to other agents and in this case you sort of have a unique agent and you may not be able to look across therapeutic classes. One of

the main questions here is though early in pregnancy and I show here a Doppler where you can see the heart in red here in the early embryo and you can also see the blood flow in the mother. Along these lines, this is the time we really want to know what is going on inside. in fact, having our compound arrive at Are we, site?

the

Well, here in a more schematic diagram we are looking at the early embryo and we can see the exocoelomic NEAL R. GROSS
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cavity and the amniotic fluid cavity.

Now, these, in

fact, can be sampled very early on and Eric Jauniaux over in London has done such. And I want to share

just a bit of data with you to help put some of your deliberations in perspective. Now, neither you nor I can read this from this distance but what it indicates is that mother villous tissue, decidua and embryo all are producing different products. And, in fact, if we sample them, And Eric

can we find some of those products there?

has done a very nice job of looking at this and I have circled two in particular, IgG and IgA. And if you

look at the maternal serum, you will find that there is substantial IgG there and also certainly

substantial IgA. If we though, look at the celomic fluid, we find very little IgA and non-detectible in amniotic fluid but still the IgG tends to get across. And one

of the reasons for this is, in fact, that the placenta does have receptors that will allow for that to occur. In this particular study you can see also that HCG is produced and tremendous amounts are ending up in the NEAL R. GROSS
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conceptus. So one can say do IgGs get to the early embryo and the answer is, yes. In terms of our

evaluation of biotech products, we're really on the horizon here of unique agents to try to evaluate and how do we try to assess that? proteins. Well, we have many new

Now cytokines are not new but Fab fragments

which are used clinically such as RheoPro have, in fact, been unique agents. Do they cross into the

conceptus, anti-sense (ph) compounds? The issue here is the difficulty in

testing in rodents and lagamorphs because if it's a human protein you might get a heterologous response. Also extrapolations from human are often difficult to do and the biological plausibility issue comes forward with SARs and pharmacokinetics and pharmacologic

action.

Well, what can we do to look at this and I'd

like to leave two thoughts with you along those lines. One is again, returning to the non-human primate

model, and in the non-human primate model there are some studies that have been undertaken with

recombinant cytokines, G-CSF and stem cell factor and NEAL R. GROSS
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they have looked at these in terms of whether they transit the placenta and enter into the fetus. And to abbreviate which was a very

extensive study, is that when they administered it to the mother and these were recombinant cytokines, they found insignificant transfer even though they had huge concentrations circulation. of materials in the maternal

They also did not find any fetal effect.

However, when they directly administered it to the fetus, counts. they found rapid rises in fetal neutrophil

So you can see that in terms of some agents,

they may or may not be transiting and having fetal impact. So the non-human primate model may be a good one to explore in the reproductive area as well. Another possibility is looking at human placental

profusions where you isolate a lobule and you have a maternal circulation and a fetal circulation and the maternal circulation you can add your agents to and see if they cross into the fetal side. you can quantitate how much one has seen. If they do, I just give

you a list of examples here of a few that might be of NEAL R. GROSS
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interest to you and here is G-CSF again and you find very little really transferring across in four or five hours in the Gregor study published a couple of years ago. Interleukin-8 was not detected when it was given to the maternal side. Epidermal growth factor

had a very, very small amount of the maternal dose appear in the fetal side, as also with recombinant erythropoietin where they really did not find any

significant levels on the fetal side.

And the same So there

with the RheoPro which is an FAB fragment. are examples.

Now, how do you explain this particular

issue and one is the placenta is a wonderful machine for breaking down proteins and if you aren't bound to a receptor mediated process, such as IgG being bound, the rest of them may, in fact, be catabolized and reutilized as basic amino acids to support the

placenta as well as the embryo fetus. So many of these are being broken down and recycles. So if these are going on, then if we make a

decision that a compound has survived all of the preclinical analysis, what do we do in terms of postNEAL R. GROSS
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marketing evaluations. reasonably undertaken

And in fact, this has been in about the last 10 years

mainly because of Accutane.

And that has been the

most rigorous registry by the Boston group headed by Alan Mitchell but along those lines, these are some of the issues that one needs to think of whether you're doing an in-house one using the university center or using the Organization of Teratology Information

Services. But along these lines, pregnancy

registries are epidemiologic studies and therefore, you have to think about what is an appropriate control group when you are of initiating exposed from those? Prospective based health upon care

identification voluntary

pregnancies or

contact

patients

providers, i.e., the referral bias that can often come in; follow-up of exposed pregnancies to obtain times, at is many not

complete

information at the

because FDA as

often well as

unfortunately, pharmaceutical

companies,

that

information

completely collected. When should pregnancy registries be

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conducted?

And perhaps the best time is when a new

molecule entity is being introduced such as live virus vaccines or an entity like this one, BMP, expectations of high use in pregnant women or of women of child bearing associated age, with agents high necessary morbidity or for conditions that

mortality

cannot be discontinued as a recognition of pregnancy and an agent's suspected adverse effects during

pregnancy based on SAR, pharmacology and laboratory findings and agents known to be harmful during

pregnancy which obviously was an issue with Accutane when it was first marketed. So what design of the pregnancy

registries; one, you need a preparation of written protocol, you need to explore consent issues, you need to have incentives to promote voluntary reporting and have a preparation of information documents which is a means to communicate with the public and also have a major advertising campaign. And with these, the

initiation at the time of marketing for new products is probably the optimal time. Window of opportunity for collecting

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reports is really within the first five years; quickly identifying any potential risks and not likely to be used for agents on the market for an extended period of time due to diminution of voluntary reporting. with that sort needs publish of to background, be done is the to next part So that

obviously reports,

provide

annual and

occasions

of

interim

results

really get the care providers involved. So I hope we've reviewed that in as quick an amount of time as I can possibly do. CHAIRPERSON FINNEGAN: We thank you both Thank

for the quality of information and the time. you. Dr. Kostuik?

Dr. Kostuik is going to give us

generics on different ways to image the spine. DR. KOSTUIK: name is John Kostuik. Thank you, Dr. Finnegan. My

I'm the director of spinal

surgery at Johns Hopkins and as I was preparing this talk in the last few hours, since I was only notified that I would be asked to do this yesterday, I realize that I have been a spinal surgeon for 35 years. in itself, is 40 frightening percent of since the it That,

constitutes since spinal

approximately

time

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fusion was first introduced to mankind so I am getting old. What is the problem in assessing a fusion? It's a difficult proposition. It is far more

difficult today than it was when I was an embryonic spinal surgeon because of the advent of rigid internal fixation. This is particularly true in posterior

approaches to the spine.

There is no doubt today that

the implants used are much better than they were even seven to 10 years ago. It has been relatively easy to

assess fusion from an anterior interbody approach up until the development of metallic interbody cages. It has been stated that expiration of the fusion mass is the gold standard. One, of course,

would be very reluctant to explore a fusion mass on the anterior side of the spine because of scarring and potential risk to vascular structures could result in serious problems. But even on the posterior side of

the spine, it is not a very valid technique because a bone graft regardless of how it may be stimulated, may fuse to itself but not fuse to the underlying host and therefore, you have a pseudoarthrosis which is very, NEAL R. GROSS
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very

difficult

to

ascertain

in

any

form

of

radiological

investigation,

including

three

dimensional CT scanning. When should one do plain x-rays following a spinal fusion? course, I think that they should be done, of post-operatively, probably at

immediately

about 10 days after that.

Those are for medical-legal

reasons and not pertinent, I think to this group; then I think probably at about eight weeks, four months, six months, nine months, one year, 18 months, two years, after that depending upon the problem, for

instance deformity cases, on should follow those for life. Now, it has been stated also that flexion/ extension x-rays are valid. They are not valid since

the introduction of rigid forms or internal fixation. If you have gross motion on flexion/extension, that is fine but generally that is not seen particularly with modern implants. their use. Therefore, I rarely ever recommend

I do recommend, however, at least four

views, including oblique views, which are frequently not done but which can be of great value in looking at NEAL R. GROSS
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the spine from other angles. There are many, many false positives with flexion/extension x-rays which brings us next to the question of CT scanning. as well. This has been controversial

There is no doubt that I think that the CT

scans as presented here today are of more value with the sponsor's product than it would be with autograft since there is no intercage density at the beginning. However, it isn't the beginning that we are interested in. It is the end point that we are interested in and

we do not know or at least I don't think there is sufficient data to tell us when we see significant enough ossication or it has been called bridging

within the cage.

Moreover, the bridging we see is

within the cage only. There has been studies done, including

some of our own work, to show that if you take a cage and fill it with bone and take a CT scan, the first day post-operative, it looks like it's fused. So I

think CT scanning has a lot of potential error and although I do admit that it may be more valuable with this product. NEAL R. GROSS
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What about the type of CT scans?

There's

no doubt that the modern new thin scans are much better. There are -- there is software available that However,

allows you to subtract the metal artifact.

it is still inaccurate and recently has been thrown out in a court of law where it was presented as a means of assessment in a particular patient where a legal suit arose. Probably one of the most difficult radiologically to tell whether or not you have a

fusion is the question of radiolucency or loosening. Particularly loosening I think is obvious.

Radiolucency around a device screw cage can be a bit more subtle. It is my opinion that any lucency means

non-union if there is still the presence of pain which may be different than the original pain the patient presented with. If there is a lucency and pain then I think investigation probably should lean towards

injections of dye to see if it flows freely or semifreely and, perhaps, the addition of local anesthetic for pain relief. radioactive bone Bone scans are very little value, scans are very little value in

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assessing fusion mass since most fusions will remain warm or hot until two years approximately two years from the time of fusion. indicates otherwise. The real way, I think with anterior to body fusions with metallic devices to tell whether you have a solid fusion is the presence of an anterior sentinel graft, that is anterior to the cage. Now, a pseudoarthrosis Hot after that probably at least unless proven

the big question comes up is how thick should that anterior bridge be and that is not known

scientifically. experience on

I have certainly had the personal many occasions to remove a few

millimeters of solid looking anterior bone definitely fused to the vertebral bodies to find a significant underlying pseudoarthrosis. So I think we do need to know the answer to how thick should an anterior bridge be? Should it

be eight millimeters, five millimeters, 10 centimeters -- 10 millimeters rather. I don't know. A question

also which has not been announced and I'm perhaps unclear here is, what about more than one level of NEAL R. GROSS
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fusion, if the devices are to be placed at more than one level because it is far more common to do a twolevel fusion than it is to do a one level fusion and then when do you decide when you have a

pseudoarthrosis. That is about all I have to say. you very much. CHAIRPERSON FINNEGAN: Thank you so much. Thank

All right, we will reconvene at 2:00 o'clock. (Whereupon, recess was taken.) at 1:38 p.m., a luncheon

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

S-E-S-S-I-O-N (2:13 p.m.)

CHAIRPERSON

FINNEGAN:

Ladies

and

gentlemen, I do think we are ready to begin if you would take your seats. you. Dr. Reddi, we'd be waiting for

We are now going to have the panel reviewers The panel reviewers are

give their presentations. three.

Dr. Hari Reddi is going to give his review of Dr. Kirkpatrick is going to give

the pre-clinical.

his review of the clinical and Dr. Larntz is going to give his review of the statistics. DR. REDDI: Madam Chairman, I would like

to do you a favor and finish my comments in five minutes. I'll give you an extra five minutes. CHAIRPERSON FINNEGAN: Well, your comments

are very valuable, so you actually get as much time as you'd like. DR. REDDI: Chairperson. I just want to help out the

First, as far as the biological problem

is concerned, we are going into a stage where how can we improve on nature, that is bone itself. So the

autograph has three main ingredients; the cells, the NEAL R. GROSS
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matrix, and the signals.

It turns out these are the

same three ingredients which are needed in manmade approaches for tissue replacement, what is generally referred to as tissue engineering. Now, I want to make some comments

concerning this isolation of BMPs and some of the questions which were posed by FDA and what comments I can make in relation in general, not specifically. First, the BMPs during evolution they have been found not just in mammals but in other organisms. tell you what ways I to mean get by that. out the First, Let me are

there

several

signals

during

development. bone.

One can isolate it from a tissue like

One can look at other organisms and find out if

they are found in other tissues. In the case of BMPs, it happens to be a rather unconventional from bone method which in is which really signals one of were the

isolated

ingredients in the graft itself, so bone morphogenic proteins are natural substance. Dr. Tuan mentioned I want

the history for about 100 years Nicholas Sen.

to take it back further that the idea that normal NEAL R. GROSS
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substances present in human body could be used as therapeutic agents was first propounded by none other than our old friend Hippocrates. He said 23 centuries

ago the best therapeutics are therapeutics mined from the human body. Next. from bone, in it These signals, although isolated out in this case was later the

turns

described

other

organisms.

This

addresses

issue of possible immunity.

Of course, I can see one

should keep in mind but I want to make a point that because it has been conserved in evolution, the insect BMPs could be equally effective and safe in humans. The other point which I want to make upon which

considerable effort has been directed mainly because of some misunderstanding about the transforming growth factor, it terrifies people because it is something called transforming growth factor and if one reads the literature, it's only the name and the name is a misnomer. Although it's considered as involved in cancer research, it is really due to an in vitro artifact that this particular factor was called

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transforming

growth

factor.

In

effect,

all

these So

proteins are very important to normal physiology.

the point which I want to make is, one needs to be careful but not to worry too much about the I'm a

teratogenicity which, of course, will come up. making general BMP. comments, I'm not specifically about for

particular molecules.

talking

signaling

These are normal constituents to the human

body and the word here is moderation. And the point which I want to make in response really to certain at the tests is again, one is needs to

look

physiology.

This

normally

present.

I want to add one other point.

BMPs are not

just in bone.

It turns out this particular family of

molecules are involved long before bone formed during the pattern formation. That is, for example, your

right hand and left hand are the same, yet the DNA is the same but the right hand is a mirror image of the left hand which is involved in a subject called

pattern formation. Simply put for a lay person, if you want to build a building, you need to have architecture. NEAL R. GROSS
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This

is

usually

referred

to

in

the

parlance

of

developmental biology as pattern formation.

The point

which I want to make is long before bone and cartilage appeared, BMPs have arose in defining where particular tissue forms including that your heart is placed on the left side so that is very important, the pattern formation having that it is involved in the initial differentiation of tissues such as cartilage in the lumbar. For example in the developing spine it is

involved in the early stages. So in effect, what we are looking at in terms of repairing is really a recapitulation.

Finally, these same molecules play a very important role in the maintenance of tissues and finally in the regeneration and repair. So in summary then, in

conclusion, I want to point out that BMPs are normal natural substances, normally found in the human body and it is not surprising they may have therapeutic implications. CHAIRPERSON much. Dr. Kirkpatrick. DR. KIRKPATRICK: Thank you. I was FINNEGAN: Thank you very

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beginning to fear that not only did I need to have prompting for what I was going to say but I was going to prove the orthopedic surgeon still is not

technology proficient but fortunately with the aid of our gentleman there. I'm going to provide an overview from a clinician's standpoint of the clinical results that we heard about today. The device basically we know

pretty well by this time.

It's a combination product

with a titanium fusion cage, recombinant human BMP-2 and an absorbable collagen sponge. The study groups,

from my standpoint, appear to be reasonably similar. There was an open arm with a surgical placement of the device for the control, fairly evenly divided and

randomized. The laparoscopic arm was basically a nonrandomized group but compared again to the controls that were done. There was -- it was multi-center,

which is one of the things that we always like to hear and there were roughly 135 patients in each group meaning the numbers were reasonable from my standpoint but, of course, the statistician will add to that and NEAL R. GROSS
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blinding wasn't possible, obviously, because of the graft site implications. The indications for the surgeries were

degenerative disc disease at L4 to S1, single level disease, Oswestry scores of greater than 135. For

Spondylolisthesis had to be grade 1 or less.

those of you that don't recall, that means just a little bit of subluxation but not more than 25 percent of the size of the vertebral body and then failure of non-operative treatment for four months, although I heard it was six months. So maybe they could make

sure that the paperwork -- just confirm whether the paperwork is right or what you said was right would be appreciated. I do want to remind the panel that many of us have been away from spine surgery for a little while and maybe don't do spine surgery. Degenerative

disc disease as an indication in itself, is a fairly controversial subject. thought to be a Degenerative disc disease is source of low back pain.

Unfortunately we cannot attribute it specifically as the source of low back pain. And so when we look at

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clinical results in here, 70 percent range, we wonder if that means that they're really doing better for back pain. So from a panel consideration issue I

think we need to have the clinical understanding that most of the patients that have degenerative disc

disease and are having fusions for degenerative disc disease, it is for back pain and not for the disease that they're getting fused. Many people have degenerative disc disease without having evidence of discomfort or clinical

limitations or functional limitations.

And in fact,

one of our panel -- I mean, not our panel experts but one of the applicant's experts, in fact, has published well on asymptomatic degenerative disc disease. can't equate fusing degenerative disc disease So we with

eliminating pain which may be a consideration that we have to raise later with our discussions. At any rate, the other indications are all appropriate and for their device it may have been the only reasonable one that they could get us a defined population for. excluded Sorry, I went the wrong way. things, prior fusion at They the

appropriate

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level, significant co-morbidities, inorganic behavior, that's people that are trying to fake out the doctor about their pain, what for those of you that aren't be,

familiar

with

inorganic

behavior

would

substance abuse and then a few others that made a lot of sense as well. The patient populations were very similar in the three groups and so beyond just stating that once again, I don't think we need to belabor that point. The primary outcomes, radiographic fusion, Dr. I

Kostuik pointed out exactly why I put it in quotes. don't think we need to go on with that. scales, success the were neurologic the function and

The Oswestry the overall Secondary

primary

outcomes.

outcomes, of course, were the back pain, leg pain, the PCS and MCS of the SF-36 and then they also had

another issue of this type early on to see about subsidence, I believe was the main target of that. Basically, they found either equivalent or superior results. I would attribute the Oswestry

superior rating there as being simply because they didn't have to take the bone graft is in my mind one NEAL R. GROSS
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of the bigger things as well as the limitation of the surgical exposure. Surgical exposures do lead to some

patient symptoms and some problems down the road and I think that's the main reason that we're seeing a

difference there. the device itself.

I don't think it's attributable to

As far as the secondary outcomes that they were looking at, again, we didn't find a great deal of benefit there or difference there between all the

groups, but you do notice that there was really in the open procedure for back pain we're getting back into that clinical problem, I think, where even the

morbidity of the exposure may be enough of a problem to give them a bad result from a back pain standpoint. And then, of course, as you see the PCS on the SF-36 was superior. Antibodies, I really didn't

find anything in the data to attribute a problem with the antibodies either from the BMP or the bovine

collagen antibodies.

I will be asking the applicants

if they wouldn't mind taking the question now and writing it down so that I can have an answer later. I'm just curious as to why -- how would you explain NEAL R. GROSS
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the fact that you would get bovine collagen antibodies in the control group when they did not apparently get exposed to the bovine collagen? an answer prepared for that. your explanation. Let's see, so in summary, the device in my review of the data appears as safe as a cage with autograft for a single level fusion in degenerative disc disease. It appears to be as efficacious as well And I'm sure you have I'd just like to hear

again with the quantification of the fusion data and I really have to reserve the comment on some of the embryological effects and that sort of thing for our other experts on the panel. Discussion issues again, will be a

radiographic evaluation of the cage fusion from my standpoint, the immune response, the tumorigenicity and the time course of the BMP-2 presence and just to reiterate again, the quality of the films that we were provided on our CD roms, failure or success, I have no idea how to tell this as a clinician, which one is the failure and which one is the success. I'd be interested to know if the audience NEAL R. GROSS
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could pick those out.

Similarly with the CT scans,

I'm not convinced that they could tell me which of these were study or control and so from a radiographic standpoint, we have those questions and I thank you for your time. CHAIRPERSON much. Dr. Larntz. DR. LARNTZ: all right. many. I'll just sit here if that's FINNEGAN: Thank you very

I've got a few comments, actually not very

First, let me say I don't know if anyone said

it but compliments to the company and the FDA for their presentations. I thought they were very good

presentations and very clear and well, I'll just say that, that's true. Compliments randomized open study. to the company for their

The device clearly meets the As a statistician I

criteria set up in the protocol.

should just stop there and maybe you should say please do. Not only in inferiority or equivalence or

whatever you call it, the device clearly establishes that with respect to the to primary from endpoints the and

actually

comes

close

this

secondary

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endpoints.

I mean, that's pretty good.

Some of us

have been involved in studies where that's not always true. as the So I think it's a very clear case that as far protocol criteria is concerned, the device

meets the specifications. Again, has anyone seen is compliments. what we have quite The up documentation, here? but The it

documentation

actually

extensive,

actually gives me good confidence in what was done and even down to providing some interesting programs which gave me great confidence in how the calculations were carried out. I appreciate that. Okay, enough of that. Now, one issue that I'm a those

seems to be coming up are CT scans and x-ray. statistician. I don't know anything about

things. I don't know anything about lots of things but I do know it's important to take measurements in a blinded fashion and to have adjudication and

remeasurement and a process that allows multiple looks at these x-rays or CT scans. the company did that. respect to some issues, It appears to me that

It appears to me that with with respect to that, it

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doesn't matter much in the sense that the -- all of the conclusions wouldn't change whether you use the xrays or the CT scans. So I feel very comfortable that with

respect to the clinical aspect, we can talk about what fusion is or is not, I'm not going to deal with that. That's not a statistical issue but I don't think

there's an issue with respect to the data or the conclusions with respect to that issue. So I would

like to say that the study conclusions don't depend on that issue. How is that, don't depend on whether CT

scans or plain films are used. A terribly small point and this is only because data. doesn't the documentation, there are some missing

It's not all perfect. collect all the data

The world sometimes and there are some

methods given in the documentation which no one talked about today which is fine, called intent to treat and I'm just going to say for the record, that particular method of dealing with missing data is not

appropriate.

We need to do some kind of sensitivity

analysis, that is some kind of analysis that says, if NEAL R. GROSS
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the control group did better than the treatment group by a certain amount, would it change our conclusions. There wasn't, as far as I could tell, and it's a question, if any sensitivity analysis of that sort was done, I didn't see that and I think we saw a lot of what was done. But I don't think it would change the

conclusions much in this case because again, I think, as I said, the criteria set up and protocol, were met and met fairly convincingly. is I don't know how much Another question which analysis was done of

covariates to find out if there are sub-groups of the patients that do better on one -- on the device, not comparatively but are there sub-groups of patients for whom this procedure is better indicated, "the overall success rate", quote, unquote, I realize it's a very stringent criteria, but they're not very high, so are there ways to pick out sub-groups that have higher overall success rates for instance, and I don't know the answer to that. Again, a small minor point, this is not necessarily for the company, maybe for the FDA, a NEAL R. GROSS
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number of these measures are scales.

The Oswestry, is

that how you say it, is a scale, back pain are scales and they're analyzed as success/failures because of some arbitrary criteria and actually the company

mentioned -- I was actually pleased.

The company

mentioned that they might have some slight difference on back pain because they actually have a higher

average but their success proportion was lower. And I think that when we have scales like that we lose information when we go to arbitrary cut points. That's a comment, it's actually a comment I

made before and it probably -- if you're on this panel again with another study, it will be a comment I'll make again because it seems there seems to be this drive to call it success or failure rather than trying to measure the size of the effect and the amount of change, and I'd prefer to see the continuous variables analyzed as continuous variables and there was, of course, some of that analysis done in the reports. Okay. So that's the open randomized study. Now, randomized study. the laparoscopic study is not a

It's an extra arm, right? NEAL R. GROSS

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done as an extra arm and when you have -- but the comparison was done to the control group in the open study. careful. When you do that, you've got to be very

And here I think we haven't been so careful

because I do think there are differences between the patients. It was minimized, I think, at various

points, but there are differences if I read it right and, of course, again, I'm just a statistician so I might not have read it right. But if I understand right, the

laparoscopic patients had less previous back surgery. What does that mean to me? to the doctor so much. Well, they haven't been in They're

I mean, that's good.

maybe at an earlier stage because they're on more nonnarcotic as opposed to strong narcotic medications. Okay. They have better pre-op neurological scores,

better SF-36 MCS scores, better leg -- they look like they're a healthier as an population, -just I from think my I'm

perspective

unbiased

well,

unbiased, as a statistician looking at it, how is that? I'll say that. Now, if you have differences in a group NEAL R. GROSS
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and you want to make a comparison to control and you have differences of some sort, you really should think about making some adjustment for that and I didn't see any adjustment. So that's a question I have. The

results look very good.

In fact, in some cases,

they're called superior but I don't think any of those analysis I know of made adjustments for perhaps that the laparoscopic patients were better to begin with. I don't think that happened. So with respect to laparoscopic, I think we're in a situation where there is a possibility that an adjusted analysis would change the conclusions

somewhat but I don't feel, given they had reasonably good results, I don't feel it would change it so much that we should discard the good results we have. You

do have some what I would say advantage there because at least the laparoscopic patients that were better turned out to do better, that's at least comforting. But I do think an adjusted analysis might give us a slightly different story there. I think I'll stop. Thank you. NEAL R. GROSS
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And so on that note,

CHAIRPERSON FINNEGAN: was, as usual, very enlightening. do now is I'm going to ask

Thank you.

That

What we're going to to put up the

Aric

questions and then we're going to go around the panel and I'm going to ask each panel member with their expertise and their comfort level, to discuss their concerns, questions and perhaps, some thoughts they have on what's been presented so far, and just to warn you, Stephen, we're going to start with you. DR. KAISER: Okay, as I mentioned earlier,

we've got some general topic areas where the questions are coming from and as we move into the first area, reproduction, teratogenicity, we have several

questions that we would like you to discuss in this area and would you like me to go through all the questions in the topic and then come back to the beginning? Okay. In this area, the first thing we'd like you to do is discuss the potential for an immune response in the mother to effectively block BMP-2

expression in the developing fetus.

We'd also like

you to discuss the potential that the fetal expression NEAL R. GROSS
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of BMP-2 could restimulate a maternal immune response and cause adverse effects in the mother. I'll go back to the first question. CHAIRPERSON FINNEGAN: Actually, I'm going

to have you run through them all, all the questions. DR. KAISER: Okay, all right, the next

category, tumorigenicity, we'd like you to discuss the potential for rhBMP-2 to stimulate growth of

transformed cells.

Now, I want to mention and it's

been mentioned previously that this category and the previous category are based on potential issues,

hypothetical issues.

These were not things that were

seen in the clinical data set presented by the sponsor but these are things based on information from the literature that could happen in the presence of the growth factors. Okay, next radiographic effectiveness and this is a question that comes actually from the data presented by the sponsor. Given what you've seen from

the sponsor data and from our presentation, we'd like you to comment on interpretation of the radiographic findings at various time points in view of the

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following factors; the presence and resorption rate of the collagen sponge, the carrier for the BMP, the progression of bone repair in the presence of rhBMP-2 in the case of the investigational patients and the absence of rhBMP-2 in the control patients and the relative ability of bone formed at various time points to withstand the applied loads. Now, we move onto some things that based on the data we'd like to get some input on some of the labeling issues with this product. The first thing,

with respect to instructions for use, we'd like you to provide with some suggestions to the for adequate instructions so

respect

radiographic

interpretates,

based on the previous question if there's anything that we should be putting in the labeling. In addition, we'd like you to discuss any other specific training that should be implemented

with respect to this product. questions The that are related to do to

We have a number of post-market studies. in

first

has

with

reproduction

teratogenicity.

FDA believes that additional animal

studies may be useful for assessing an immune response NEAL R. GROSS
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effect on fetal growth and development and so we'd like you to comment on the need for these studies. If

you decide that these studies are necessary, the types of studies that should be performed as well as

appropriate animal models. In the area of tumorigenicity, we've

described and the sponsor has described that there's been an agreement to conduct some additional studies -additional non-clinical studies to evaluate

potential for rhBMP-2 to stimulate transformed cells. And what we would like you to do is comment on whether there are any additional studies beyond those ones that we've already agreed to, to address this issue and if you believe that there are, we'd like some comment on the type of studies to be performed as well as the appropriate animal models. And then finally we'd like to have your comments on the use of ongoing post-market registry data bases to further assess potential for congenital abnormalities. questions, if And you as with the previous registries two are

believe

that

recommended, we'd like to have some input on the types NEAL R. GROSS
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of data to be captured. CHAIRPERSON FINNEGAN: Okay, thank you.

Just to clarify for the panel, I would like you to give your opinions. If you have questions for the

sponsor, you might give them a heads up but we're going to go around a second time with specific

questions for the sponsor, so this is mainly a generic discussion of your concerns and any thoughts you have on the questions. DR. Dr. Li. KAISER: I'll leave this first

question up and then let me know when you want me to pop to the next one. CHAIRPERSON FINNEGAN: copy. DR. engineering LI: Yeah, doesn't my materials equip me and to I think we've got a

background

exactly

answer this question directly.

A heads up maybe to

the FDA or experts or the sponsor, I guess my question would be, are there any examples of any agent,

pharmaceutical or otherwise, that actually passed all the in vitro tests that you've done on tumorigenicity or teratogenicity or the other things that you've

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tested that actually in vitro did not cause any ill effects but actually turned out to actually have a clinical effect? Because if the answer is yes, then

I'm really stuck with this question. CHAIRPERSON FINNEGAN: DR. DOULL: Yeah, Dr. Doull. my question is

peripheral also, and it's a heads up.

When Dr. Hudson

was talking about BMPs he mentioned the fact that there's a lot of variability in specie sensitivity to these agents. That also was brought up a couple other

times and it's in our book and my concern is usually when you have intraspecies variability like that, you also -- or interspecies variability, you usually also have intraspecies variability. it, you're talking about Yet, as I understand a vial of this

taking

material, a standard dose, diluting it up, putting that on the sponge and putting it in the cage and it's the same dose for everybody; old, young, male, female, whether they are immuno compromised. And if that's true, it makes it a little hard to look at the worst case kind of assumption that one would like to make to evaluate systemic toxicity NEAL R. GROSS
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as opposed to local toxicity. CHAIRPERSON FINNEGAN: DR. DIAMOND: Dr. Diamond?

I guess my concerns have to

do with the antibody assays because I'm concerned that they represent arbitrary numbers with a definition of authentic response but no definition of a biologically significant response and I think that, you know, one doesn't know what a neutralizing antibody titer is and -- unless there are studies that haven't been done and we certainly do know that antibodies, maternal

antibodies can cause problems in a developing fetus and the IgA antibodies may not get across the placenta but they certainly get into milk and get into neonate. So it's about the antibody assay. CHAIRPERSON FINNEGAN: DR. HANLEY: Dr. Hanley, sir.

Yes, I'd like to preface my

comments by saying that I've been to many of these meetings before and served as the chair of many of these. I'm a non-voting member at this meeting

because of my previous involvement in studies on the spine and particularly in some of the initial studies with BMP use on the spine prior to what is going on NEAL R. GROSS
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here, some with Genetics Institute but not with the current sponsor Medtronic Sofamor Danek. Several years ago we had a meeting of the Food and Drug Administration Orthopedic and

Rehabilitation Advisory Panel with regard to spinal conditions in an attempt to set some criteria such that sponsors would have a good idea of what was needed for us to pass scientific judgment on what they did. Heretofore, I have personally not seen studies

put together in a fashion that we could do it well. I would compliment the sponsors on meeting all the criteria which were set down several years ago and I don't know if anyone's here who participated in that but what they have done is exactly what we've asked people to do so that we could make our job easier and not spend all afternoon saying, "What did you mean by that", or trying to make up for things that weren't there. So I applaud them on their issues. spine surgeon, a clinician and I view I'm a as

myself

reasonably knowledgeable with regard to the issues; spine surgery, the selection of patients, the

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performance

of

the

procedures

and

the

use

of

the

implants and materials under discussion here. We will not and cannot solve the enigma of back pain in the selection of patients for surgery for it here. It is not part of this discussion. I do not

believe that radiographic issues brought up have great pertinence to this presentation. They are what they

are and our opinions on what's better if any of CT, regular radiograph, bears not on -- in my opinion, on decisions that should be made here. the clinical practice. It's nice to see that they included CT. It just means they're trying to give us everything that could be meaningful but I don't think it matters in the long run if the device is deemed to be approved and is approved, that the criteria be set up for what a practicing clinician should do. That's a study issue. I'm sure plain Those are part of

radiographs are just as satisfactory and the patients, ultimately if this were approved, operated on with a device that should not be -- need not be subjected to CT unless for specific instances such as a clinical NEAL R. GROSS
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failure. Some of the other things that might not be apparent to non-clinicians are issues like blood loss and blood loss is so small in all the groups that it makes no difference. The length of stay, however, has

some import and this is one time where not taking a bone graft probably does dramatically improve the

length of stay issue, particularly in that other arm that we criticized a little bit, laparoscopic arm. I'm not an expert on teratogenicity and tumorigenicity and that sort of thing. I think we'll I

let others who have more expertise work that out.

think the issue here at the table today is mainly one of labeling, indications for use, trying to put in the proper perspective for -if approved for people

utilizing a device, how best it can be controlled and doing some appropriate follow-ups on it. This is --

it's been a good experience, one of the easier ones I've seen. Thank you. CHAIRPERSON FINNEGAN: DR. SIEGAL: Gene.

Well, if there's a good cop,

I guess there has to be a bad cop, too. NEAL R. GROSS
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CHAIRPERSON FINNEGAN: a smile. DR. SIEGAL: do think that the

You said that with

I have a number of issues. sponsor did everything

I

that

reasonably could be done as far as the radiology, especially by acquiring the expertise of Dr. Genant and his associates, who is a world renowned authority and I feel very confident that everything that could be done radiologically has been done. However,

histology/pathology has been eluded to multiple times, both in the pre-clinical and the clinical. And it was used as the gold standard, if you will, to validate the radiology. I have a multi-

part question depending on the answer and the question goes something like this. Were those veterinary or

human pathologists that did those studies, neither or both? Did they work for the company or was there an Were bone

independent vetting of the pathology results? the pathologists recognized as experts in

diseases? Changing carcinogenicity subjects, two as I understand cell the

issues,

pancreatic

lines

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showed increased proliferation in the presence of BMP2 and one patient developed pancreatic carcinoma while receiving the therapy. I would like to hear that I wonder too, way

coincidence or a potential problem.

off the topic perhaps, that at the time of surgery, the rhBMP-2 must be rehydrated, if I could use that term, with sterile water and then must be, quote, "applied evenly" end quote to the ACS which is loaded into the cage. Why was it not discussed pre-loading

the BMP-2 sponge to maximize even distribution, either requiring hydration by perhaps emersion in water or pre-hydrating it and packaging it to keep it intact? And to come full circle back to the

pathology question, I wonder would it not be of value to do a carefully controlled radiology histopathology study with pathologists to see, in fact, if there is a gold standard one against the other? DR. KIRKPATRICK: I'd like to echo some of

the other panel comments, that that was quite a wellprepared presentation and a substantial data set to review. A few questions that I'd like to see

addressed are, you mentioned that you have data beyond NEAL R. GROSS
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24

months.

How in

complete the we

is

it

and

did

you which

see is

deterioration something techniques? that

clinical see

results with

often

other

fusion

I would like to see if you could provide me with some general insight with the expression of BMP-2 normally in the time course of the fusion. In

other words, do we have any information on when BMP is normally produced in the fusion healing process and whether the application of the BMP-2 at the onset is coincident with what it would be in the autograft group, for example? data. You mentioned that the metabolic pathway of BMP was through the liver but I did not hear a specific of what that pathway was in the liver and the package insert, as I recall, indicates that no liver studies were done. I'm wondering since one of your I imagine you already have that

explanations about the toxicity was the fact that it was rapidly metabolized, what liver impairments would prevent it from being rapidly metabolized and as such, what liver enzymes should be checked prior to giving NEAL R. GROSS
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the device or using the device. And the next question is perhaps one, if we find it approvable, in light of the history of the pedicle screw off label use, how would you recommend guarding against off-label use of this product,

especially the rhBMP-2?

Thank you. I basically have

CHAIRPERSON FINNEGAN:

two areas that I would sort of like to see discussed. One is there were some very nice elution studies of the BMP but you didn't look at elution or I didn't see any data for elution from -- of the BMP inside the cage and I would suggest that that's probably a

different pattern than just BMP in a sponge. And the other thing that fascinated me that I couldn't find anywhere is why did the cases that failed fail. You picked pretty straightforward

pretty simple spine problems and I was wondering if you have any feeling for why the ones that failed failed. DR. congratulate outstanding the study. NAIDU: sponsors I I'd for like to comment an was --

doing it

excellent very well

thought

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presented.

The

data

showed

that

the

device

is

effective and with regards to safety, I will hold on. I'm an orthopedic I will surgeon defer with that a biomechanics to the

background.

question

biologists on the panel, but in general, from what I've heard at least, the antibody response was

detected in only three of the patients and from Dr. Miller's comments, it appeared as if hardly any cross the placenta barrier nor the amniotic cavity and our respected panel member, Dr. Reddi, goes on to comment that this is a normal substance. concerned about it. We should not be too

And so I will defer that thought

to Dr. Reddi and the rest of the biologists on the panel. But as far as the radiographic findings, I think that it appears as if at least from the CD Roms, the CDs that I got, the disks, the fusion mass started to show up at six months as the sponsor stated, and the thing is I don't have any time zero CT scans to judge as to what it would look like. I can only

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that.

So I think that there is bone forming, but I

don't know the mechanical integrity of this bone. And Dr. Kostuik stated that at least eight millimeters of bone must be needed to -- a thick -eight millimeter thickness of bone must be needed to stabilize an intersegmental fusion. And the other

thing is in light of Dr. Kostuik's comments where he stated that it is hard to judge on flexion/extension views mainly because of the superior instrumentation that we have developed today, such as segmental spinal fusion devices such as pedicle screws, it's hard to depend on flexion/extension views. Those are the

words that I recall from Dr. Kostuik. These are not -- you don't have pedicle screws here. You just have two cages. And so I would

assume that the flexion/extension criteria that you guys used would be credible at least. That's what But I

common sense would dictate to me at least.

think that's all to an issue to discuss further is just the stability of these devices. to these pedicle screw Are they similar that

constructs

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considered credible as a radiographic criteria. I think that you guys have shown a pretty reasonable product here that seems to be safe and efficacious but obviously, there are some issues as far as packaging and I'm also assuming that -- this is actually seeking a question to the this sponsor, for that you are disc

approval

for

degenerative

disease with less than grade one spinal disc thesis (ph) for single level fusion. That's what I'm

assuming that this device is up for.

If I'm wrong as

far as that goes, I would appreciate clarification but thank you very much. CHAIRPERSON FINNEGAN: DR. BOYAN: Dr. Boyan.

I have just two issues that

have come up in my reading of the documentation and the discussion today and overall I, too, want to

compliment the applicant.

It truly was a beautiful

package to read, but the two comments I want to make have to do -- one with mineralization and the other one has to do with antibodies. And the mineralization has to do with how the use of CT and x-ray. I would like to echo the

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comments from down at the end of the table that it's very difficult at least early on to determine whether or not something is bone or if it's just remineralized collagen and given that you're using a collagen

sponge, even x-ray or CT isn't able to discern whether or not that's bone, bone or if it's a graft that was fortuitously structurally remineralized. And I say that only as informational

because the only way you could ferret that out is with histology and you're not likely to take a nicely fused human and do histology but to bear that in mind in interpreting the data. The other comment has to do

with antibodies and while I may not be as concerned as some people are about this future consequence to a pregnant person and her fetus, I am somewhat concerned about elderly individuals and people who are likely to have more than one experience with this device in their lifetime. And if there has been any consideration given to people that might have multiple surgeries at different times and whether or not we're sensitizing them to be BMPs and sensitizing them to type 1

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collagen. CHAIRPERSON FINNEGAN: Reddi. DR. REDDI: Yes, thank you for giving me Thank you. Dr.

this opportunity, Madam Chairman. First, I'd like to also compliment the sponsors for giving us a good package but however, I have some questions which I was not sure whether I should outlay while I made a brief presentation or not because I'm a novice at this but I will very soon learn. But I would like to ask as far as the tumorigenicity is concerned, whether the sponsor or some of their contractors have done studies because we are really interested in induction of tumors as I

opposed to stimulating growth of transformed cells.

found copious amounts of data on about 60 cell lines. A lot of cancer research today in the United States has shied away from cancer research because it doesn't mean anything for the human patient, because you can get whatever you want in a cell line, it might please some FDA regulators, but we are really -- it's a very important issue from the point of your patient. NEAL R. GROSS
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If

you

really

want

to

study

tumorigenicity, it needs to be done in a living animal and I wanted to find out if such attempts are being made or being thought about by the sponsor, so I'd like to find out whenever the time is opportune for that. The other question concerning the

antibodies, I wanted to find out if the sponsor in their volumes of study have developed antibodies to the native BMP-2 as opposed to anti-peptide antibodies or monoclonal antibodies because you might make an antibody to a peptide by one of the scientists in Wyeth-Genetics Institute but I would like to see if there is such data and if such data is available, I would like to strongly recommend that the

transplacental passage of these antibodies to native recombinant BMP-2, does it cross and does it have any adverse effects on the fetus. That's a very important thing because we have been dancing around this issue. I think we need

to do definite studies in order for both the -- to allay the fears of both the patients as well as the NEAL R. GROSS
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surgeon. CHAIRPERSON FINNEGAN: Thank you. Now

we're going to get a definitive answer about x-rays and CT scans, right? DR. LENCHIK: I thought we were still

talking about teratogenicity.

I don't have much to

say about that but to your preview, the sponsor, I have a couple of questions relating to CT. The CDs

that we were given, the quality of the CT really varied widely from having real quality CTs with

beautiful coronal and sagittal recon to other CT scans that were virtually uninterpretable. So my question to Harry Genant in

particular is what was your experience in the study in terms of CTs that were potential equivocal because you couldn't -- because of metal artifact perhaps or due to reconstruction artifacts. again to the sponsor, And the second question, do you think the

what

explanation is why there were fewer patients fused by CT at 24 months compared to 12 months? CHAIRPERSON FINNEGAN: DR. LARNTZ: Dr. Larntz?

I don't have any more to add

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than I already did. CHAIRPERSON FINNEGAN: MS. RUE: I have a Ms. Rue? couple questions.

They're points of discussion I guess.

One was there

was an agreement made with the women in the group for them not to get pregnant and they talked that there were six pregnancies anyway, not to get pregnant for 16 weeks and it doesn't say at what time these women got pregnant. So I'm wondering what effect that

agreement held. And also, if there's going to be a

pregnancy registry board, that it include miscarriages of the fetus or embryo at any stage and also some pathology on that to see if there's any effects on the fetus. And also, the fact that the majority of

pregnancies are not planned and most women don't know that they are pregnant for the first at least five to six weeks, a lot longer than that, what is going to be done as far as that goes prior to surgery. CHAIRPERSON FINNEGAN: Maher? MS. MAHER: I don't have much to add above Thank you. Ms.

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and beyond what everybody else has said and I thought what I heard was very well put together. I would ask

the panel to be cautious about trying to mandate the practice talking of medicine as you're that going forward and when

about

labeling

would

determine

fusion has occurred. fusion has occurred

I think most surgeons know when and will be making that

determination on their own no matter what's in the labeling. So I would ask us to all be cautious and think about that. I would go the same way towards the I think labeling can go

concerns about off-label use.

into the labeling but there's -- mandating packaging or something like that will increase the cost of the product to the consumer without probably stopping much of what you're probably trying to stop. CHAIRPERSON FINNEGAN: Thank you.

All right, we'll

now start back around the table and you can ask your questions and we'll get them to answer them one at a time. Dr. Li. DR. LI: Do I ask the same question? FINNEGAN: Yeah, the same

CHAIRPERSON

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question or a new one if you have another one. DR. LI: Yeah, I guess my original

question was, if you've done a variety of in vitro tests to test tumorigenicity, teratogenicity and other possible complications. My question actually was

either the sponsor or the FDA or panel members, are there examples of any agent that actually would pass all these tests, yet turn out to be clinically

something you'd want to avoid? In other words, how -- the fact that you passed all these tests, is that actual assurance that these things will not happen clinically? CHAIRPERSON FINNEGAN: I don't know who

the most appropriate -- probably, Dr. Riedel, did you want to answer that or did you -DR. RIEDEL: and the knowledge of To the best of my knowledge my colleagues is no who example are of

professional

toxicologists,

there

such an agent.

It would be just hypothesize. Okay, my question did ask earlier

DR. LI:

because I was limiting myself to teratogenicity, was on the x-rays versus CT. I guess my question on that

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is, was the determination of whether or not there was a bone bridge, is that just a yes or no determination? And if it was just a yes or no determination, there's like one spicule or one trabecula that goes from side to side, does that count as a bone bridge or was there some threshold amount of bone that had to be in there to be qualified as a bone bridge. And a follow-up question to that is, no matter how you determined whether or not it was fused or not fused by radiographic approaches, how

predictive of clinical failure were those radiographic approaches? For instance, were there cases where

there was a radiographic failure but the patient was perfectly happy with it and conversely, were there clinical failures that radiographically looked great? CHAIRPERSON FINNEGAN: I think, Dr.

Miller, did you want to address the question about whether there's been an example of -- in something not showing any signs in vitro but turning out to have some effects in vivo? DR. MILLER: Thank you. Some of the

estrogens might fall into that category, being diethyl NEAL R. GROSS
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stebesteral (ph) originally and probably that might be out closest that we might look at along those lines both being tumorigenitic birth defects and for quite awhile one didn't have that understanding because the right tests weren't done but -CHAIRPERSON least one example. FINNEGAN: So there is at

All right, Dr. Doull, did you want

to ask your question? DR. GENANT: Can we answer? Oh, yes. Well,

CHAIRPERSON FINNEGAN:

actually, I think that was -- oh, radiographic, I'm sorry. DR. GENANT: I'm Harry Genant from the I have no I'm a paid

University of California, San Francisco. vested interest in the product and

consultant. in the past.

I've also been a consultant with Ostech

Now, with regard to the predictability of the radiographic features, that is either plain films or the CT in relationship to success, we have to keep in mind here that at 24 months we did have a very high success rate. And so we're talking about relatively NEAL R. GROSS
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small numbers of cases. that were re-operated

The majority of those cases were not re-operated

specifically with the suspicion that they were, in fact, unstable, but rather related to other symptoms and findings that were being addressed. So I would say that there was not a strong or tight correlation in those small cases between the radiographic and/or CT features of fusion and the

presence, for example, of a need for re-operation. DR. LI: Were there cases where there

appeared to be radiographic failures either by x-ray or by CT but were clinically -- had no complications? DR. GENANT: There were cases in which

lucencies had been observed in which there were no clinical manifestations. DR. LI: Thank you. Oh, yeah, the issue

Thank you.

about how you determine whether or not there was bone bridging. DR. GENANT: Yes, the question with regard

to the amount of bone that might be relevant for bridging and in I particular would point based out upon by the 12 CT and

observations,

that

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particularly by 24 months, one observed not only the bony bridging within the cage, but in the majority of cases one observed also substantial bridging of bone either in front, behind or on the sides adjacent to the cage. I'm not certain that we made a

determination of what the minimum amount for thickness of the bridging this to would be be necessary in order but to we

consider

clinically

relevant,

essentially made the assessment of whether we could judge there to be solid bony union across either

within or outside of the cage. DR. BODEN: point about the I just want to expand one between radiographic

dissociation

outcome and clinical outcome which I believe was the subject of your question. in treating patients It is not at all uncommon with spinal disorders,

particularly patients that have so-called degenerative disc disorders, to or which is the subject yet of these

patients, symptoms

have cases

solid where

fusions symptoms

persistent and it

improve

doesn't correlate with the radiographic outcome. NEAL R. GROSS
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So that's inherent with the disease, the disorder and even accomplishing a fusion by any means independent of whether it uses bone graft or infuse. That's particularly why it's important to focus on the more direct or primary outcome and goal of something like infused, which is to generate bridge in bone. When you start to add the overall success factors, there's a lot of other things multi-factorially that go into that that go well beyond the device in

question. DR. LI: So you're saying that the -- if I

understand what you told me, that the presence of bridging bone is not just a biomechanical benefit, but it's actually a reflection of other things that are going on with the device? DR. BODEN: No, I don't think that I was

trying to say that at all. DR. LI: Okay, sorry. So let me follow,

just maybe to pinpoint this again; do you have any correlation from animal data or any other data that correlates the amount of bridging bone in any

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Is there any number that you -DR. BODEN: Well, we showed -- we showed

in the cases of the animals that the biomechanical properties of those fused segments were equal to or greater than those with autogenous bone graft at the same point in time and so, if anything, there's a trend to possibly achieving bony union a little bit faster and more consistently with infused compared to with autograft. Unfortunately, there's -- the fusion

can occur through the center of the cage, which is typically the way it occurs with autograft and is considered solvent. There's no clinical definition in humans of how much bone is enough bone. It's empiric. clinically to be mechanically solid and

However, I will say that it tends to be a more than all or none response and I think that kind of case that Dr. Kostuik highlighted where there was some bone but it turned out to be not good bone, is more the exception than the rule and we tend to clinically think of fusion bone as a binary it event, remodels either solid of

bridging

and

then

because

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continued mechanical stress whether that bone was put there by autogenous bone graft or InFUSE actually

wouldn't effect the ultimate remodeling. And so on the other hand, the clinical problem is you never get that union of bone. sees load and then it never remodels. clarify? DR. LI: Yes, thank you. Go ahead. It never

Does that help

CHAIRPERSON FINNEGAN: DR. GENANT:

Yes, I wanted to address the

question that Dr. Lenchik had. CHAIRPERSON FINNEGAN: Well, we'll get

around to him in a second. DR. GENANT: Oh, okay, it was relevant to

this topic with regard to the -CHAIRPERSON ahead. DR. GENANT: the CT and the quality And that was with regard to of the images that were FINNEGAN: All right, go

reviewed, and I sympathize with you to some extent with regard to the review of the CDs. I think that in

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that we looked at with the direct hard copy images but on the other hand, in some reproductions they did not capture the original image quality. I would say that overall the CT quality of the images that we viewed were reasonable. There was

some range in that quality but I think by and large, were acceptable for most -- the vast majority of cases and of course, we had, in general, excellent

radiographic imaging. CHAIRPERSON FINNEGAN: Doull. DR. DOULL: Well, as you know, in order to Thank you. Dr.

answer the question about safety, you need to ask whether the quantity and the quality of the tox

studies were sufficient to provide one the ability to be reassured about safety and as I indicated, we have two kinds of safety questions here. There's the

systemic toxicity and the local toxicity. I think in terms of these studies, they were well-described and well-done. The doses looked

fine and they are standard studies, so that I find those reassuring in regard to the systemic safety. NEAL R. GROSS
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I'm not exactly sure what additional studies you're talking about that you might do to focus on the

question of local toxicity transformation and so on. DR. RIEDEL: question, Dr. Doull. If I can respond to that

This is Gerard Riedel speaking.

You had raised earlier the question of intra-species variability raising the issue of -- I'm sorry, interspecies variability raising the issue of intra-species variability and if I might, I'd like to address that question first -DR. DOULL: DR. RIEDEL: relevant to this question. Fine. -- because I think it is What we have observed is

that it is the local concentration of BMP-2 applied on the absorbable collagen sponge which correlates with efficacy within a species and that that efficacy which is defined by that local concentration is consistent across all the anatomic sites where we've tested it in that species, and is independent of the total volume of the material that's implanted or in other words, independent of the total volume -- of the total dose of BMP that's implanted at that site. NEAL R. GROSS
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A more specific application -- example is the following. If we implant rhBMP-2 in critical size

defects in long bones or in periodontal defect pockets in a canine what we have found is that the optimal therapeutic concentration of BMP-2 on the sponge is identical in those two anatomic sites, but of course, the volume that's implanted in those two bony defects is very different. So that's the empirical

observation. Then to address the question about how does one appropriate dose in order to assess local toxicity, what we took was the strategy that we -- we tried to use as high a concentration as was feasible in terms of manufacture. And in the case of the rat

implant toxicity study that I described to the panel earlier this morning, we applied a concentration of BMP-2 to the absorbable collagen sponge that was four milligrams per mil. That's the highest we can

manufacture and put on the sponge. Now, that's in excess of the concentration that's used in the human clinical setting which is one and a half milligrams per milliliter. NEAL R. GROSS
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However, it is

somewhere between 40 and 80 times in excess of the optimal therapeutic concentration in rats, which is somewhere in the range of 50 to 100 micrograms per milliliter. We took this approach in order to drive

the concentration in order to look for some effect of cellular abnormality or toxicity at the local site. So we didn't take a total mass of protein to total body weight approach, but rather this local concentration approach and that's the approach that we took. DR. DOULL: You're on the low end below

the threshold for a lot -- in the net conclusion of all your tox studies was no effect and that conclusion of many of your pharmacology studies were no effect, which, I guess it's for a little those hard kind to of talk things, about but

therapeutic

index

that's, I guess the way the ball park is. DR. correct. RIEDEL: Your observations are

We tried very hard to find dose-limiting We were unable in any of our studies

toxicity doses.

no matter how high we drove the dose to identify a dose limiting toxicity. NEAL R. GROSS
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DR. BODEN: intra-species variability?

Can I add a word about the or inter-species

variability

CHAIRPERSON FINNEGAN: DR. BODEN: Stated

Certainly. another way, the

definition of the minimally effective dose for any given species was the dose which took out of play and intra-species variability. defined as the dose that in In other words, it was would yield 100 And percent because

consistent

response

that

species.

there is a pretty wide range of therapeutic excess, in a sense, if you lower the concentration below what we've defined as the minimally effective concentration for a given species, you will see animal to animal variability but the way those are defined for each species is to take that out of play. DR. experts. and DOULL: I was struck by our BMP

They're all telling us about the variability of different organs, of different

sensitivity

cells, for example, and it just seems that that kind of variability between species, between cells, between -that surely there must be a little difference

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between an immunal compromised patient for example, what she really needs. What you did in the rat was figured out how much you need in order to get that bone response and what is the maximum that increasing the dose no longer increases that response, which gives you that nice therapeutic range in your animal studies.

Whether one can extrapolate that to humans, it leaves me -- I don't know, interesting question. CHAIRPERSON FINNEGAN: want to add anything? DR. point. that I TUAN: Sure, just around that one Dr. Tuan, did you

Just along that same direction, a question think ought to be addressed is also that

different cells respond to BMPs in the cell types and therefore, the different tissues respond to BMP with a different type of dose response, generally, in a

nanogram for mil range or lower even.

So I'm just

thinking with -- about a couple milligrams at the site and then about one percent out there in the

circulations. maybe it will

I can't do the math that quickly but be useful to give the panel some

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information as to, if you have the data that is, what is the local concentration of BMP at various tissue sites as a function of time, what the concentration may be and perhaps that may address some of the

concerns of the panel. DR. speaking again. RIEDEL: This is Gerard Riedel

This is a topic which I started to Dr. Tuan is

address in my summary this morning.

correct in terms of the exposure that comes from the -- to the body from BMP implantation. that we've observed in several of one animal percent And that is models of the that BMP

approximately

one-tenth

that's implanted at a local site becomes systemically available and is detected in the circulation. This exposure. predicts a very low systemic

But to address the issue that Dr. Tuan

raised, that is that BMP has effects on different cell types, we administered BMP-2 protein in buffer by an intravenous administration to these animals and we did so with doses of BMP that were thousands of time higher on a per kilogram body weight basis than what was anticipated to be the human exposure as a result NEAL R. GROSS
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of implantation of BMP-2 and the results that we found were uniform and they were striking in their

uniformity. We saw no effects. Now we know that there

are cells that could respond, but we saw no effects and when we explored that further by looking at the pharmokinetics and the bio-distribution of BMP-2 in these animal models, we found that BMP-2 was very rapidly cleared from the circulation, principally by the liver and that it was rapidly degraded by the liver and cleared through the kidney and excreted in the urine within 24 hours and that's the explanation we think will -DR. important point. DOULL: Yeah, I think that's an

In order to define exposure, you

need to talk about not only the dose but also the time and your kinetic studies have clearly shown that in 16 minutes it's gone in a rat and it's even less in a monkey. that. So in a human it's probably even less than So if you're defining exposure correctly in

terms of both dose and time, then you're exposure is indeed, trivial. NEAL R. GROSS
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CHAIRPERSON FINNEGAN: ahead. Microphone, microphone. DR. TUAN:

If I could -- go

This might also address some

concerns of another panelist and that is have you looked at the same thing in a pregnant animal and how much of the BMP that's administered to the pregnant mother is found in the fetus as a function of time, the pregnancy period? DR. RIEDEL: I think it's very important

for the panel, we'll keep the issue of the protein versus an antibody to the protein. those as separate issues. We try and keep

We have only administered

unlabeled BMP-2 protein in our reproductive toxicity studies but we did administer that protein over the duration slides that per was the described ICH by Dr. Miller for in his

guidelines

performing

reproductive toxicity studies both before and during the early portions of gestation. And in those cases, at exposure levels, again, that were calculated to be many times greater, more than a thousand fold greater than the anticipated exposure in humans. We saw no observations on any of NEAL R. GROSS
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the parameters that were evaluated. CHAIRPERSON FINNEGAN: floor is yours. DR. DIAMOND: I have a few questions but Dr. Diamond, the

can you just clarify for me something that I think I just heard but I'm not certain. You put in a total of

five milligrams at a concentration of one and a half milligrams per mil; is that correct, into the sponge? DR. RIEDEL: DR. DIAMOND: DR. RIEDEL: Diamond. DR. DIAMOND: DR. RIEDEL: Okay. Depending upon the volume of I'll be happy to clarify. But it's not -It's not quite correct, Dr.

the sponge, we soak the sponge with a solution of BMP that contains one and a half milligrams of BMP-2 per milliliter of that solution. The reason why I can't

give you a straightforward answer is that the total volume of solution that we use depends upon the size of the sponge. DR. DIAMOND: But are you suggesting that

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matter if the total amount of protein you give is 10 milligrams or five milligrams in that reasonably

little space? DR. RIEDEL: What we have advised surgeons

and in all of our animal models was to fill the space with the volume of the wetted absorbable collagen

sponge and not to over-pack it. defects that required small

And so, yes, in small of the wetted

volumes

absorbable collagen sponge, the concentration of the applied BMP was the same but the total dose was

different. total dose.

So for small defects, they got a smaller Large defects in our animal studies got a

larger total dose and what we found correlated with optimal therapeutic efficacy was the concentration of BMP that was applied to the sponge. That's the

empirical observation. DR. DIAMOND: I guess that's a little

surprising, I think, but so I guess I had a question that was raised previously about are there studies with liver dysfunction? can receive this? DR. RIEDEL: From a pre-clinical Is there limitations on who

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perspective we have not looked at the pharmacokinetics nor the bio-distribution of BMP-2 in a liver

impairment model and any animal model. DR. DIAMOND: And do you know if the

pancreatic tumor was receptor positive, the one that developed in the individual who got the -DR. LIPSCOMB: DR. patient. DR. You're talking LIPSCOMB: about Wait a minute, were wait. DIAMOND: They were negative. And can I ask -the

whether

they

positive

antibodies? DR. DIAMOND: DR. LIPSCOMB: DR. RIEDEL: No. Okay, I'm sorry. Just to clarify the question,

I think you were asking whether or not the patient in the clinical study who had a pancreatic tumor was positive for receptors for BMP-2. DR. DIAMOND: DR. RIEDEL: Right. Well, the patient is still We don't have

alive about 13 months after diagnosis. any materials to assess. NEAL R. GROSS
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www.nealrgross.com

DR. DIAMOND:

I see, okay.

That's a fair

answer, a good answer even. Can antibody studies? I ask some questions about the

I guess it begins with were the

studies in animals with the serum diluted one to 50 when I don't know, 30 percent of the dogs or whatever got -- or monkeys got antibody or was there different dilutions in the animals where there seemed to be more antibody? DR. RIEDEL: I think it's appropriate to

call one of my colleagues to the podium to address this answer. DR. Institute. RUP: Bonnie Rup, Wyeth-Genetics

So the question is -DR. DIAMOND: Were the dilutions of serum

the same in the humans and in the animal studies? DR. RUP: They're basically the same

starting dilutions -DR. DIAMOND: DR. RUP: to get to a titer. DR. DIAMOND: Why did you start at a one So what --

-- and we diluted out in order

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to 50 dilution?

I mean -Yeah, it's our experience that

DR. RUP:

generally below that concentration one often sees very high background readings that gives you something that could be more variability in the background of your baseline which could be attributable to antibodies, perhaps. It could be interpreted as being

attributable to antibodies but it's more likely to be due to just background high reactivity and especially in dogs. We had a lot of problems with high

background. DR. DIAMOND: So did you do any assays

either in the animals or in human serum to look for neutralizing activity? I don't know what the most So I don't know

sensitive cell line to BMP-2 is.

which would be the most sensitive assay to look for neutralizing antibodies, but I assume that there are others here and elsewhere who know that. for -DR. RUP: about developing a We have been talking to the FDA neutralizing antibody assay and Did you look

we've made some attempts to start trying to look at a NEAL R. GROSS
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cell line, the same cell line that's used as the bioassay to determine potency of BMP-2, which obviously, is a logical choice. development. But there is -- that assay is in

There has been some difficulty in trying It's a cell

to use serum on it, as you can expect.

line that produces alkaline phosphatase in response to BMP-2 stimulation and obviously, we'd be looking at a reduction in alkaline phosphatase production. The serum itself also inhibits the cell line's alkaline phosphatase production. So we need to

work on ways of reducing that as an issue. DR. DIAMOND: Using your control, is your

control, positive control, is it monoclonal? DR. RUP: few antibodies that We have looked at -- we have a were generated as reagent

antibodies, both monoclonal and polyclonal antibodies and those, obviously, we can test in a purified

fashion, and we haven't seen any evidence that those are neutralizing. DR. DIAMOND: But do you have -- can you

calculate based on those how many micrograms per mil of antibody you have in the serum? NEAL R. GROSS
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DR. RUP: anything like that

Well, we've avoided trying to do because, as you know, antibody

potency is really a function of both concentration and affinity. like And there -- yeah, and so on, so we feel out nanograms per mil would be

reporting

misleading because obviously, if you test it against a high affinity antibody, you get low numbers and if you test it against a low affinity antibody, you get high numbers and we just feel like that would be misleading and, you know, obviously, it's just relative to what you use to begin with, so we've never tried to do that. DR. DIAMOND: the antibody testing I guess my concern is with as you know, an ELISA

that

depends how much antigen you put on the plate, what your starting dilution is, if you don't reduce the IgM antibodies and there are lots of IgM antibodies, you may not see the IgG antibodies that are present in the serum. And it's I guess a very artificial assay until

it is validated with a gold standard of a biologic assay because do you know what kind of titer you would call at this point a clinically significant titer? NEAL R. GROSS
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DR. RUP:

Well, that's always a difficult

thing to do because the intention of the assay was just to set up something that was very sensitive and would be able to give us a very reproducible assay during the duration of a long study. And so one

always goes in with the intention of just developing a sensitive assay and you really don't know whether your assay is sensitive enough to pick up clinically

relevant antibodies until you get clinically relevant responses. DR. DIAMOND: Have antibodies been given

to gestating animals or have gestating animals been immunized? DR. RUP: No. And I guess I have another This

DR. DIAMOND:

question that will reveal what I don't know.

pregnancy registry certainly sounds like an appealing idea but how many pregnancies would you have to see to have a degree of fetal loss or teratogenicity that is important and how many child bearing -- women of child bearing age a year come to this kind of procedure. So over the five years we were told is realistic, are NEAL R. GROSS
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numbers,

the

kinds

of

numbers

that

will

give

meaningful information going to be available? And the answer may be clearly yes or I just don't know this. DR. LIPSCOMB: Well, on that particular

question I did try to run the numbers to see, you know, what you could come up with just based on the demographics of patients that were in our clinical trials and then taking some information that's

available in the literature about how often do women get pregnant during the course of a year and I came up with this calculation. DR. DIAMOND: DR. Tennessee. (Laughter) DR. LIPSCOMB: But anyway, if you look at Once. As a whole. Not in

LIPSCOMB:

the slide here that's on the screen, for every 10,000 patients a year that would receive treatment, and I'm talking about all patients, not just women, based on our demographics from our clinical trials, about 5,000 of them will be women. And then if you look at the

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age distributions that are in our study, then about half of those or about 2500 of them would be women of child bearing age. And then this where the statistic comes in, I think we received out of a document that came from the FDA, in which this 11 percent of women of child bearing age in the general population would So

maybe become pregnant during the course of a year.

you multiply 11 percent times 2500 and you get down to a factor of about 275 women a year -- 275 women during the course of a year out of 10,000 people treated, would get pregnant in our patient population. Then if you look at our antibody rate that we had in our clinical trial and you multiply that, you know, roughly -- surely less than five but the numbers calculate out to about two per year out of 10,000 people treated may be positive for antibodies they get pregnant. So you can see the number is

pretty small, and even if you put safety factors, let's say -- well, not a factor of five. you up to 10. And at the bottom of that slide, the Let's get

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population rate, this would be -- what would be the adverse event that you would expect in the general population, whatever, the birth defect or whatever you would be looking for, if it occurs at one percent or three percent or 10 percent, and if you look at a relative risk of two, which would be the doubling of the rate versus the control, then you'd need those numbers that are underneath that patient. So if it's one percent, you'd need 2,000 patients or 700 patients for three percent. So you

can see by the numbers generated in the population and then what it would take in a registry, then to do anything statistically meaningful, it's kind of a hard thing for me to come to, you know, grips with when you start talking about a registry. takes taking into -account assuming a situation women And this also, too, where are you're to just get

that

going

pregnant.

That doesn't take into account that, you

know, women that have had back surgery which will probably lower that number some and it's also probably -- you know, you might tell them not to get pregnant, you know, for some period of time, so that will reduce NEAL R. GROSS
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it even more. In our clinical trial, only about 1.5

percent of the people got pregnant.

I know there was

a question, you said, you know, when did these people get pregnant and everybody got pregnant in the study after 16 weeks except one. There was one, I think, at

about eight weeks and that pregnancy went to a normal delivery. So the other thing, too, that was

mentioned, I think, in Dr. Miller's talk this morning when he was going through the registry concept, tell me when to be quiet, but he gave several reasons why you might want to do a registry, I think at the end of this talk and it seems like to me some of those points that you made wouldn't fit our particular situation which was, say maybe a registry wasn't appropriate here. So question. DR. DIAMOND: I guess it seems to me that's -I hope that answers your

though that the numbers of patients who are going to accrue over five years and the number of anticipated pregnancies is probably at the low end of where you're NEAL R. GROSS
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going to be able to detect teratogenicity for sure and even fetal loss and so I think that makes it all the more important to look in animal models to see whether these antibodies have a potential negative effect on pregnancy outcomes. DR. RIEDEL: piece of information. I just wanted to add one We have looked very hard in

making monoclonal antibodies to recombinant human BMP2 to make an antibody that would neutralize the

activity of the protein and we've tried for now eight, nine years and we have yet to make a neutralizing monoclonal antibody against this protein. So we do

have some technical issues that we have to address as we work with FDA on this matter. CHAIRPERSON FINNEGAN: Are you comfortable Dr. Hanley,

-- you're comfortable with the answers? questions? DR. HANLEY:

We have one question and that

relates to one of those letters that was read earlier about putting the BMP adjacent to the nerve for a posterior approach. It doesn't relate to the

indication being sought for here but any comments from NEAL R. GROSS
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people on that? DR. BODEN: Obviously, the risks and

complications of the device are that of the surgery, the insertion of the cage and what's inside the cage, and this specific application before the panel today is through an anterior approach, either an open or a laparoscopic and to talk about safety issues that are related to a different surgical approach seems to me to be outside the scope of what we ought to be

focusing on today. CHAIRPERSON FINNEGAN: Actually, I'll take

a little bit of exception to that because you know that in the skilled hands of the people who did your trial, that was placed where it was supposed to be placed, but if it goes out into the free market it's going to be probably placed close to nerve roots and I think that's a really valid question. DR. BODEN: Okay. We can go into it in a Why don't we go to slide

little bit more detail then. 36? study

The issue with the study that's been raised was a where the cage of the was inserted Why through don't we the go

posterior

aspect

spine.

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forward one slide actually? And so there was no longer a barrier, in fact, between the cage and the InFUSETM bone graft and the neuro elements. One of the other things that

happens when you insert cages from behind is, in fact, that you have roughened surfaces of bone. You can

have hematoma, sometimes hemostatic agents are put in place. cage, As we see from the anterior insertion of the it is in fact, not uncommon to see bone

formation in front of the cage from the direction of the surgical approach. Somebody sentinel sign. referred to it earlier as a

I think it might have been Dr. Kostuik Why don't

and in fact, that's a very positive thing. we move forward another slide?

So the notion that

there would be bone forming in front of the cage, and this is, of course, a patient from the application we're discussing today which is from the front of the spine, the notion that you would have a bump or bone in front of the spine, otherwise known as the sentinel sign is, in fact, a normal and a desirable finding. However -- why don't you back up one for a NEAL R. GROSS
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second

--

if

that

sentinel

sign

occur

--

if

the

insertion of the cage is through the canal and that sentinel sign, if you will, is a reverse sentinel sign, and occurs encroach posteriorly, into an area then where that there can are

potentially nerves.

Forward. So I would say that it's not at all an

unexpected finding.

It's something that, in fact,

with posterior lumbar interbody fusion with the same cage filled with autogenous bone graft we see variable amounts of bone formation and the patients in that study were analyzed in great detail looking at how often that occurred and it was with an intermediate degree of frequency and to differing degrees or the size of the bump, just like we would expect from that anterior approach, but I think the most important

thing in that trial was that the presence or absence of that little bony bulge did not correspond with any clinically measurable differences between the groups. So it was a radiographic observation that I would say is not at all unexpected based on our experience from putting them in from the front of the NEAL R. GROSS
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cage and it is something that, you know, when you look at the groups as a whole, groups of patients that had, you know, a little bit of bone versus no bone, there was really not a clinically detectable difference in their outcome. Does that -Could I follow up just from

DR. LARNTZ: that statement? analysis of that? DR. BODEN: DR. LARNTZ: say. DR. BODEN: Dr. Hanley?

Did you actually do a statistical

No. Okay, that's all I wanted to

Does that answer the question,

CHAIRPERSON FINNEGAN:

Just one addendum

to that; was the PLIF -- I don't think you were part of it. Was the Sofamor Danek PLIF study with the cage

not stopped because there were some problems? DR. BODEN: Yeah, the trial was put on

hold and that was actually a somewhat controversial decision which I can take some personal responsibility for because I was not one of the participating

surgeons in that trial and the surgeon group met and NEAL R. GROSS
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analyzed people

this were

when

it

first it and

became

apparent felt

that very

observing

actually

strongly about continuing the trial. I, as a consultant, wanted to actually watch these patients longer and make absolutely

certain that this was not going to be of clinical consequence and made the recommendation to Medtronic Sofamor Danek that they consider holding the study until there could be more follow-up and a better

determination of the extent of what this observation meant. And it was after that deliberation that the study was put on hold merely to follow these patients. DR. DIAMOND: Can I ask something

following up on this? CHAIRPERSON FINNEGAN: DR. DIAMOND: Yes.

Didn't we hear in a letter

that there was one patient who had bony ingrowth into the spinal canal? CHAIRPERSON FINNEGAN: Dr. McCullough still here? NEAL R. GROSS
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I think Dr. -- is

A VOICE:

No. He left but I think from using the

CHAIRPERSON FINNEGAN: Dr. McCullough's presentation

had

material posterially with a -DR. DIAMOND: That was post -It was in a letter.

CHAIRPERSON FINNEGAN: DR. DIAMOND: Right.

CHAIRPERSON FINNEGAN: DR. WITTEN:

Yes.

Yeah, I just want to mention

that to the extent that these things -- you know, these other studies relate to the effectiveness of this indication, then I think asking questions is

appropriate but to the extent that they're just about some other use, we really want to focus the discussion here on the particular indications sought by the

sponsor. CHAIRPERSON FINNEGAN: Understood,

understood, but I think there is some relative safety as far as leaving some space. you want to add to that? cleaning his glasses. DR. MILLER: While he's cleaning his Yes, Dr. Kostuik, did Yes, Dr. Miller. He's

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glasses, perhaps Dr. Diamond and the group here could address an issue I've been fumbling with. We have

three patients who are positive on antibodies; one an experimental, one in the control and another

experimental that was, in fact, positive before they -- in the pre-op stage. have a small segment Now, does this mean really we of the population that is

carrying these antibodies not associated at all with your giving BMP-2. If you took 500 women, pregnant women and screened antibody? CHAIRPERSON FINNEGAN: Well, I think that them, how many of them would have that

relates to Dr. -- to Barbara's question, too, so hang on a second and we'll get around there. DR. SIEGAL: Gene.

I'd like to go back to the You the

pancreas because I did not understand the answer. said the patient was still alive. Certainly

diagnosis was made by either open biopsy, by fine needle aspiration or perhaps by radiologically guided brushing. Any one of those should give you enough

cells to seek the answer that was requested. NEAL R. GROSS
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DR. LIPSCOMB: this gentleman. DR. SIEGAL:

They performed surgery on

So you do have tissue. Yes. I don't think the

DR. LIPSCOMB:

receptor has been looked at though. DR. SIEGAL: Okay. So let me then go back

and ask that question I asked before which is two cell lines appeared to show increased mitogenesis and one patient developed pancreatic cancer, the first two

were pancreatic cell lines. cohort of data? DR. BODEN:

How do you interpret that

When we looked at the expected

frequency of tumors in the population of this size and age and demographics, it turns out that the number of tumors is actually less than what you would expect in the population. The issue that the -- you know, that

one of the tumors happened to be pancreas, I think at this point it would be hard to make any statistical case that would be more than just coincidence. The other thing is -DR. SIEGAL: not, two cell lines, one? NEAL R. GROSS
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There was two, were there

DR. BODEN: DR. SIEGAL: DR. BODEN:

No, no, in the cell lines. Two cell lines, one patient. There were two cell lines.

There were also pancreatic cell lines that did not have that response and also when you look at tissues from tumors which Dr. Riedel presented earlier in none of the transformed tumor cell lines, so none of the live tissue that came out of patients with tumors was it ever observed that there was that increase in

division. DR. SIEGAL: Okay, thank you. Now, I want

to go back to my question about whether or not there were pathologists involved in any of these studies. DR. clarification? DR. SIEGAL: DR. RIEDEL: Yes, please. Are you referring to the RIEDEL: Can I just ask one

animal studies that looked at spine fusion or the animal studies that looked at the safety of the

implanted product? DR. SIEGAL: I guess I would ask in any

studies were there board certified veterinary or human NEAL R. GROSS
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pathologists involved? DR. RIEDEL: For the animal safety studies

the implant safety toxicology studies were conducted at a contractor, -in Clinical Canada. Trials On Bioresearch were in

Centerville

staff

board To

certified pathologists and veterinary surgeons.

the best of my recollection, I can't remember at this moment and will have to get back to you on whether the histologist was a board certified veterinary

histologist but I believe he was. DR. SIEGAL: And so you don't know either

whether they have any expertise in bone pathology. DR. RIEDEL: Oh, no, I'm sorry, I should We did specifically ask

follow up with that point.

for people with specific expertise in bone biology to assess the histological samples from these studies. DR. LIPSCOMB: We also have here Dr.

Jeffrey Toth, who has done histological reports as well on samples. DR. TOTH: associate Medical professor College of Yes, I'm Jeffrey Toth. of orthopedic surgery also I'm an at the the

Wisconsin,

direct

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biomaterials

laboratory

for

orthopedic

surgery.

I

have no financial interest in the company or product being reviewed here today nor any other company or product. I am not a pathologist. over the last 10 years that I have done work involved bone

has

histology as a method of analysis for biomaterials and bone implants. I have about 25 publications and peer

review publications and book chapters in that area especially dealing with spinal implants. There were four pre-clinical studies that Dr. Boden talked about his morning. Our laboratory

actually did histology on two of those, so I don't know exactly which ones you're referring to. could have slide number 13, please. If I

Our laboratory

actually produced the histology for the -DR. SIEGAL: I don't wish to in any way

impugn your reputation but I just want to make sure you said you're not a pathologist. DR. TOTH: I am not a pathologist. Thank you. Dr. Siegal, my colleague just

DR. SIEGAL: DR. RIEDEL:

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corrected me and I should correct for the record, the folks that did the work for us at Clinical Trial were not boarded histologists. They were boarded

veterinary pathologists. DR. SIEGAL: In the human studies, were

there any human pathologists involved? DR. RIEDEL: Well, Dr. Toth did the

analysis in the human explants. DR. SIEGAL: Okay, thank you. Then the

next question, I guess, out of order if you will was, would there then not be value in performing a study comparing the radiology to the pathology in animals with appropriate expertise in pathology and radiology? DR. ZDEBLICK: Tom Zdeblick. of I'm an Good afternoon, my name is orthopedic I do surgeon a at the

University interest.

Wisconsin.

have

financial

I'm the inventor of the LT-cage and I have

patents on the LT-cage and one of the four studies that were quoted this morning was the original one that I did with goats using a different cage, titanium cage, using BMP-2 and that was performed at our School of Veterinary Medicine at the University of Wisconsin. NEAL R. GROSS
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And that correlated the radiographs and the pathology read by a certified veterinary pathologist, two of the mechanical results that we found in that study. And there was very good correlation

between what we saw in histology, the radiograph and the mechanical performance. DR. SIEGAL: Thank you. The last question

I have had to do with whether you consider preloading the cage with already hydrated BMP-2 in the sponge, to minimize the amount of handling required at the time of surgery. DR. consider obstacles that to RIEDEL: but there Yes, are to Dr. Siegal, we did

significant manufacturing

technical such a

generating,

preloaded material.

We have chosen to go with aseptic

manufacture of the protein in order to preserve the integrity of the protein and avoid any problems

associated with damage to the protein due to terminal sterilization of the product. The collagen sponge is terminally We wanted protein

sterilized with ethylene oxide treatment. to avoid the potential damage to the

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associated Consequently,

with we

that have

terminal

sterilization. studies

performed

validation

using radiolabeled BMP-2 to validate that the method that we use for instructing the surgeons to apply the protein results in a uniform application of protein across the entire volume of the wetted sponge and that information has been provided to the agency in the application. DR. SIEGAL: Thank you very much. Dr. Kirkpatrick.

CHAIRPERSON FINNEGAN: DR. KIRKPATRICK:

I think a couple of my

questions can be dispensed with fairly quickly but first with a yes or no question with regard to my question raised during the presentation. Have you

identified the specific reason that the patients in the control group developed an antibody to the bovine collagen? Was it because the surgeon used a

hemostatic agent during the surgery? DR. BODEN: There's no way to know that

for sure, but certainly people are exposed to bovine products in many aspects of life in addition during surgery, and so any gelatin-based product of some

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kind, you know, sutures and things. DR. KIRKPATRICK: So as a yes or no

question, it's no, you don't know? DR. BODEN: that. DR. KIRKPATRICK: Right, that's all I We have no way of confirming

wanted to make sure. DR. BODEN: No. Thanks. Sorry, Scott,

DR. KIRKPATRICK:

but there's a lot of people trying to catch planes tonight. With regard to the radiographic data beyond

24 months and the clinical data beyond 24 months, can you just give me again as short an answer as possible, did you see the deterioration continue that you

demonstrated between 12 and 24? DR. BODEN: No. In other words, we can would be a smaller

DR. KIRKPATRICK: assume that even though

there

number of patients beyond 24 months, that we would find percentage of fusions approximating the ones that you saw at 24, no more than a five or 10 percent -DR. BODEN: Understand that the 48-month

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follow-up is really limited to the pilot study which had 11 investigational patients and three autogenous bone. DR. KIRKPATRICK: a number at 36 however? DR. BODEN: It wasn't part of that study. So once the 24 months Would you not also have

DR. KIRKPATRICK:

was up those patients are no longer studied? DR. BODEN: trial or the clinical? DR. clinical groups. trial LIPSCOMB: between the I'm open talking -the about two the open Are you talking in the pivot

You didn't do them all in the first month of

the trial. DR. BODEN: No, I mean, there -So I know you've got

DR. KIRKPATRICK:

patients beyond 24 months that might be at 36. I'm wondering since you showed in your data that you

deteriorated I think it was like four percent between 12 and 24, did you continue to see that between 24 and 36 even though you're probably down to what, 50, 75 patients at that time? NEAL R. GROSS
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DR. BODEN:

The best long term follow-up

going out to four years is in eight of the 14 patients from the pilot trial which is essentially the same protocol. And in there, there was five

investigational and three control and at the 48-month follow-up five out of five in the investigational were still deemed as fused radiographically and the same two out of the three of the control were rated fused. So there was no change in the primary outcome variable which was radiographic fusion at 48 months. What happens to change in the overall

success rate that you're observing is not a change in the radiographic or CT determined fusion success.

It's patients that over time may, with their surgeons, decide to have another operation or may require So the that if

another operation for an adjacent problem. definition of success was very strict in

anything occurred. And so what you're seeing with that quote, unquote "deterioration", is not really a change in the hard core result of bridging bone but rather that those other criteria that go into the more clinical NEAL R. GROSS
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fusion rate. DR. KIRKPATRICK: What I saw in at least

one of your case reports of a failure was that between 12 months they were deemed a fusion and at 24 they were a failure because of a pseudoarthrosis, okay, specifically in your case example. is, did that happen after 24 months. DR. BODEN: surgery, reading. not because That was because of a second of a radiographic change in So what I'm asking

That patient was -DR. KIRKPATRICK: The clinical report that A an

I saw said he had a pseudoarthrosis, period, okay. pseudoarthrosis is a failure even if it took

operation to discover it. DR. LIPSCOMB: That was the reason for the

second surgery that was filled out on the adverse event form. That's why the second surgery was

performed. second there.

It was a diagnostic reason for why a We take a conservative approach

surgery.

Regardless of what the radiograph show on the

fusion criteria, if a patient is still having pain or whatever and the physician says that I had a suspected NEAL R. GROSS
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pseudoarthrosis here, then they -- and if they do a second surgery, they may put pedicle screws on the other side, we count that as a fusion failure, just because the surgeon called it a suspected or a

possible pseudoarthrosis, even though it may not jive at all with the radiographs. DR. KIRKPATRICK: I'm sorry, I didn't

memorize the number of the patient so we could discuss it specifically. say possible However, the report I read did not It says he was If

pseudoarthrosis.

reoperated on because it was a pseudoarthrosis. that data is not correct, I'd like to know.

If it

was, I'd like to know if you followed the patients that are now beyond 24 months and found if you have any more. DR. LIPSCOMB: The protocol for the

pivotal trials specify that patients are seen after 24 months and then bi-annually which means every other year, thereafter until every person in the study has gotten two years. That's the criteria, so there is no

36-month visit for patients to come back in according to the schedule. Forty-eight would be the next one NEAL R. GROSS
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provided meantime.

that

everybody

didn't

get

to

24

in

the

I am aware, I think there's been a couple of second surgeries after 24 months, though. DR. KIRKPATRICK: If you had said that in If I

the beginning, my question would have stopped.

knew you weren't looking at anybody from 24 until 48, that was -- you can't answer my question. I think You

you've already answered my question on the liver. don't know, correct? DR. LIPSCOMB: That's right.

DR. KIRKPATRICK:

I think in the interest

of time, the expression of the BMP in a normal is probably not worth discussing. I would like,

however, to know your specific recommendations as far as my other question on the off-label use, which is, in light of the history of the pedicle screw issue and the off-label use there and resulting litigation, how would you guard against off-label use of this product especially with rhBMP-2? DR. LIPSCOMB: pedicle screw situation. Well, you mentioned the That is -that's an

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interesting concept because when we, as a company, were dealing with that the issue, years and with in FDA, discussing when we

labeling

throughout

started talking about a warning or a precaution or some statement like that about, "Don't use a screw in the pedicle", it came back that if you tell somebody not to use a screw in the pedicle, that's in essence an indication. So a contra-indication or a warning would be an indication. So we couldn't basically do that.

I think we could propose labeling or would propose labeling. We'll discuss it more with FDA when we're

discussing the final labeling, but statements could be made or -along the fact that safety and

effectiveness of InFUSETM bone graft and other spinal applications has not been established. DR. KIRKPATRICK: CHAIRPERSON Kirkpatrick. questions. All The Thank you. Thank a couple you, of Dr.

FINNEGAN: just of

right, question

short the

elution

within

titanium cage, has that been looked at and a second part of that question is, do you know if there's any NEAL R. GROSS
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affinity for titanium ions and the BMP? DR. RIEDEL: Neither Medtronic Sofamor

Danek nor we have looked at the bio -- the clearance of BMP implanted in a titanium cage. We have,

however, looked at several animal models that have used different geometries of the implanted rhBMP-2 ACS and in general the clearance from the implantation site follows the same time course and the same general pharmokinetics from the site. With respect to your second question about interaction with titanium ions, we have done no

studies to look at interactions with any metal ions and the BMP-2. CHAIRPERSON FINNEGAN: The next question I

is, any idea why the ones that failed, failed? mean, it's a pretty simple standard -DR. LIPSCOMB: by fail.

It depends on what you mean

If you're talking about overall success,

failure, why that rate is what it is? CHAIRPERSON FINNEGAN: fuse. Actually, did not

The other back pain patient population problem

we're not that interested in but didn't fuse. NEAL R. GROSS
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DR. BODEN:

Actually, there's very few, if

any, that did not fuse based on using the CT criteria, bridging trabecular bone. The ones that are -- and

this is a bit of a confusion because of the way the protocol is defined and the way it's presented, a radiographic failure technically could be somebody who is fused but had another operation because they had persistent pain or had adjacent segment degeneration. And that would be shown as a radiographic failure. definition If you separate out the radiographic -- the of radiographic success as bridging

trabecular bone, I think Dr. Genant will say that every patient met that criteria. CHAIRPERSON FINNEGAN: No, but at least I

know there are two women over 50 who had migration of their cage and one of them very definitely. rays and CT scan I could see -DR. BODEN: Yeah, that's -- I'm sorry, Those were Those x-

that's a completely different situation.

early failures because of technical problems with the cage insertion irrespective of whether the cage is filled with autogenous bone graft or infused bone

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graft.

That's a cage technique insertion problem that

surgeon technical irregularity. CHAIRPERSON FINNEGAN: Because one of them

was not approached surgically again, but still did not fuse, so I would assume that the material is still there and the BMP is still in the cage. DR. BODEN: The BMP is going to be gone And there

from the cage presumably within in 14 days.

are a number of different animal studies and a variety of different venues to support that, as well as

somebody asked earlier about the -- or it's one of the questions about the collagen sponge. be resorbed in four to six That's going to most likely,

weeks

depending on the animal model. So I think if a cage was sticking out front what you have is a situation where you don't have the adjacent bone in order to develop blood So

supply and have a continuous or connecting bone.

that particular cage in a sense would be an isolation, but if there's a case where -CHAIRPERSON tissue there. NEAL R. GROSS
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FINNEGAN:

You

have

soft

DR. BODEN: CHAIRPERSON tissue around it.

Huh? FINNEGAN: You have soft

Anyway, never mind. You obviously My last question, I think, for

haven't looked at it.

your vice president is, when I looked at the materials that you sent it looked like these were all packaged together, that is the cage, the BMP hydrated and there was one picture that had sort of what this was

supposed to look like.

And I guess my question is, if

you have different sized cages, do you have different sizes of the sponge but the same -- this is like somebody else's question -- but the same amount of BMP? DR. LIPSCOMB: Yes. The key point as Dr.

Riedel said is the concentration of 1.5 milligrams per milliliter and depending on the size of the cage, it would take different sizes of vials of BMP. CHAIRPERSON FINNEGAN: size and the vial size differ. DR. LIPSCOMB: the inner lumen. Right, because it would be So both the sponge

It would be the inner lumen of the

cage that would dictate what size sponge to put in. NEAL R. GROSS
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CHAIRPERSON FINNEGAN: to my question about packaging.

So that goes back

So then for each size

cage are you going to have an associated size vial of the BMP and associated size of the sponge? DR. LIPSCOMB: Well, the BMP kits will be

sold with a certain size vial with the sponge inside the kit. The cage will be sold separately or will be,

you know, not packaged with that. DR. RIEDEL: There is a volume to volume. Right, but if your

CHAIRPERSON FINNEGAN:

cage volume is different then you have to match the cage volume to the sponge size and to the volume of your -- okay, and the consumer is going to know this by -- so I guess two questions then. going to be sold as a separate unit. with the cage. DR. LIPSCOMB: That is the plan, yes. Okay, and so then The InFUSETM is It's not sold

CHAIRPERSON FINNEGAN:

how is the consumer to know which size of InFUSETM goes with which size of cage and how do you control that? DR. labeling. NEAL R. GROSS
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LIPSCOMB:

It

would

be

in

the

CHAIRPERSON FINNEGAN:

All right, but then

the surgeon could, in fact, use more or less at his or her discretion because they could just buy a different size package. DR. LIPSCOMB: Well, the inside of the

cage would dictate what size kit would be required to fill the cage. question but -CHAIRPERSON FINNEGAN: Actually, I think I guess I'm not understanding the

you're not understanding the creativity of orthopedic surgeons, that's my concern. (Laughter) CHAIRPERSON FINNEGAN: question. Dr. Naidu? DR. NAIDU: questions. Yes, I have a couple of short You answered the

The question about excess bone formation, Dr. Boden

you guys talk about surgical technique.

goes into in detail but just looking at your manual, nowhere do you describe the preservation of the

posterior annulus, just be careful about not -- you know, you talk about not perforating through, but is that going to be addressed in a manual in more detail NEAL R. GROSS
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as to how not to place it too close to the nerve roots or -- I mean, as far as the technique, the surgical technique? DR. ZDEBLICK: The surgeon technique

manual is pretty specific about templating for size and the templating takes into account the area of the disc space and how far away from the posterior

longitude and the ligament you need to stay and then second, when you're preparing the channels for the cages with the reamer, they're depth specific and

depth stop will keep you in that range so that you inadvertently don't go too far posterior. So at several steps in the technique

manual it addresses that concern. DR. NAIDU: Okay, thank you. And the

second question is, the size ranges of your cages, what were the size ranges, small to the largest, the diameter of the cages? DR. MATHEWS: Yeah, the cages range from

14, they go to 16, 18 and 20 millimeters. DR. diameter? NEAL R. GROSS
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NAIDU:

So

14

is

your

smallest

DR. MATHEWS:

Yes, and they have different

lengths from 20 to 26 millimeters in length. DR. NAIDU: Okay, now, so when you're

seeing these -- this bone formation at 12 months on CT scans, what we get are a couple of reconstructions at 12 months and 24 months and you're saying that the dowel of bone that forms between the two segments is, at best 14 millimeters thick -- I mean, I'm sorry, at best 22 millimeters thick and if you use the smallest cage it's about 14 millimeters thick. those radiographic data mean? DR. BODEN: Yeah. Scott, you need to Is that what

CHAIRPERSON FINNEGAN:

state your name for the record, so the transcript shows it. DR. BODEN: I'm sorry, Scott Boden. What

-- the early fusion tends to be through the cage. That's the way the device works whether you're using autogenous bone graft or InFUSETM. So this is a

question that really is, in a sense, independent of what is causing bone to form. However, what you see

over time is bone forming around the cages or what is NEAL R. GROSS
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secondary bridging across the interspace.

It can be

in front of the cage or the sentinel sign, that we discussed earlier. We showed examples of it going

around the sides of the cages. We see a clear trend that in the case of InFUSETM, which seems to have more reliable bone form earlier based on measuring units on CT scans, that we tend to see more reliably this bone around the cage. So, if anything, I would say that you get additional bone sooner and more reliably in the InFUSETM cases but that's not a statistical observation. official endpoint. It was not an

It's a empiric observation, but it

ultimately gets to the same endpoint in appearance if you had used autogenous bone graft, but it appears to get there quicker with some of those additional areas and zones of bone formation. DR. NAIDU: Okay, thank you. And the next

question that I have is more directed towards our experts, Dr. Kostuik mainly. Dr. Kostuik, you talk

about flexion/extension views not being too reliable with the advent of this posterior instrumentation

world that we're in today.

Would you say that the

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flexion/extension

criteria

that

the

sponsor

has

established such as less than three millimeters of translation and less than five degrees of angulation, with the use of these cages is a valid radiographic criteria since -- if you could expound on that. DR. KOSTUIK: not valid. I would say that they are

There's too much variation in how the

patient is positioned, how the x-ray is taken, slight location of patient during taking the lateral view, but the most particular reason for my saying that is that these implants provide very significant rigidity at least within the first few months, and it's

certainly been, I think, well-shown and a long-term practice with other forms of anterior cages that

flexion/extension x-rays are not statistically valid in assessing motion. DR. NAIDU: questions I have. CHAIRPERSON FINNEGAN: Boyan? DR. BOYAN: question. Well, I don't really have a Thank you. Dr. Thank you. Those are all the

I just wanted to state again -- maybe my NEAL R. GROSS

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question is really for Integra. HelistatTM sponge, you clearly

On the -- in the have had 20 years

experience with that clinically, have you found that patients have become sensitized to the type I collagen in the sponge where or if that particular had type of type I

collagen

they've

repeated

procedures,

that they don't develop an immune response? DR. O'GRADY: O'Grady, Regulatory Good afternoon. Integra Life I'm Judy Sciences

Affairs,

Corporation.

We're the manufacturer of the absorbable

collagen sponge which is also known as HelistatTM, also known by other names. Let me start off by saying that there is a 21-year history, as you mentioned, of this -of

approvals through FDA and marketing of the absorbable collagen sponge. In our experience in marketing this

product as an implantable medical device, and also in numerous involve clinical often trials and the clinical and trials multiple

repeated

application

applications of the collagen product, not necessarily the HelistatTM but we -all our products are

manufactured from the same source of collagen and also NEAL R. GROSS
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undergo the same purification process. To this date, in 21 years, both in

marketing the product and in clinical trials, we have never seen any immunogenic response or allergic

reaction to the product. DR. BOYAN: Okay, thank you. And then not

to cause a problem but, Dr. Riedel, I'm going to turn it over to you on the BMP side of things and the only reason why I do this is just to clear the air but BMP, you know, it revs a lot of things up and it does, in fact, rev up some times immune cells. They're there

and it isn't a -- I mean, it's -- they're not unhappy but they're energized. And so have you done -- in any of your animal studies have you looked at this specifically? DR. RIEDEL: Other than performing a

histological assessment at the site of implantation, we have not looked at specific immunological markers in any of our studies. DR. BOYAN: Okay, thanks. Thank you. Dr.

CHAIRPERSON FINNEGAN: Reddi. NEAL R. GROSS
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DR. REDDI:

Yes, my questions and issues

are for the folks from Medtronic Sofamor Danek and their collaborators and Wyeth-Genetics Institute. far as the tumorigenicity in which the FDA As has

specifically charged the panel to provide guidance to the FDA, I'd like to follow up with one of the experts from the sponsors. In addition to studying the

effects of recombinant human BMP-2 on transformed cell lines from one of your grantees in Texas, has there been any direct long-term effects on either mice or rats to see whether there might be any in vivo

tumorigenic actions, positive or negative? DR. RIEDEL: I'll start just by

summarizing the results that I presented this morning and that is that we conducted in canines and in rats a chronic toxicity study with endpoints at various time points to either six or 12 months of follow-up and did extensive histological assessment of the implantation site in those animal models. Using they've greatly local exceeded concentrations the of BMP-2, optimal

therapeutic

concentration, local concentration, for those specific NEAL R. GROSS
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species and in both of those animal models, we saw no evidence of any abnormal cellular events that would be suggestive of tumorigenicity in those models. DR. REDDI: All right, I take it, it was

mostly confined locally to an osseous environment. DR. RIEDEL: correct, Dr. Reddi. In both instances, you are The implant resulted in a

formation of an osseous environment at the site of implantation. DR. REDDI: Yes. I was most impressed by

your presentation and description of the effects or recombinant human BMP-2 on the femoral onlay model. Now, in your extensive pre-clinical studies at

Medtronic, either Scott Boden or some of the other three centers, has there been an attempt to do the same experiment of placing such a device, InFUSETM in the environment of the disc? DR. RIEDEL: I'll start the answer by

referencing a safety study that was done in a canine model in which the safety of BMP-2 on the absorbable collagen sponge was assessed when it was applied

directly to the dura of the spinal cord following an NEAL R. GROSS
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laminectomy procedure. GLP study in an

This study was conducted as a laboratory and it was

academic

actually Dr. Hanley's lab that performed this study and the results of that study have been published and there were no significant findings in that study. DR. REDDI: There is a lot of panel

members at various times have asked already questions about the antibody and the transplacental passage and I had given you a heads up to tell me whether you have antibodies to the native recombinant BMP-2 and what happens if such antibodies are administered to rats or mice. DR. RIEDEL: I'm going to defer to my

colleague to address this question. DR. Institute, Wyeth. were made as RUP: I'm Bonnie Rup, Genetics

You're referring to antibodies that antibodies? Yeah, the only

reagent

antibodies that we were able to make by immunizing were actually or against Ecoli-derived, conjugated onimeric to (ph)

BMP-2,

against

peptides

immunogen

proteins. DR. REDDI: And when you administered --

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did you administer to pregnant mice or rats and what effects did it have on the embryos? DR. RUP: them to animals. We never tried to administer

I can't tell you that we've tried to

look to see whether they have neutralizing effects in cell-based bioassay and they don't seem to neutralize. DR. REDDI: Yes, and it is also well-

known, even the best antibodies made by Wyeth-Genetics Institute the recombinant BMP-2 cross-reacts with BMP4. Would there be a concern that these antibodies in patients might effect functions which are

these

directed in the embryo or elsewhere by BMP-4 or do you think it would be a concern that we should address? DR. RUP: I think that the antibodies that

-- you know, the few antibodies that can be generated in humans, they might cross-react with BMP-4 since they're very homogenous. DR. BOYAN: Chairman? CHAIRPERSON FINNEGAN: DR. BOYAN: You may. May I make a comment, Madam

I think that we're all dancing

around about the antibodies and I'm going to take the NEAL R. GROSS
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risky

thing

of

saying

something

out

loud

scientifically and hope that I'm right but it isn't easy to make an antibody to native recombinant BMP-2 and I think everybody needs to know it's not easy to make one and it isn't easy for humans to make one. This is a highly conserved common protein that we have in our bodies all the time. Generating an antibody to it is not a

small feat and that's why they've had to go through such extensive things to generate them to peptides and hook them onto stuff to get the antibodies made. DR. RUP: that. DR. DIAMOND: though? CHAIRPERSON FINNEGAN: DR. DIAMOND: Yeah. Can I just say one thing, And we definitely concur with

I think that the experience

with recombinant human proteins in people is that when you give it to enough people, you get antibodies. DR. BOYAN: I agree. And that we know this with erythropoietin, these are

DR. DIAMOND: thrombopoietin, with

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recombinant

human

proteins.

They

shouldn't

be

immunogenic and I think it really depends on having an assay that can look for an interference with biologic function and that's very important because, you know, very immunogenic, not very immunogenic, eventually it will be immunogenic. DR. BOYAN: impossible. I agree. I didn't say it was

I said it isn't easy. CHAIRPERSON FINNEGAN: DR. REDDI: Dr. Lenchik (sic).

The last question I have for somebody else from Medtronic

perhaps

Dr.

Boden

or

Sofamor is that since when you first put the cage with the InFUSETM device, the cells which are going to see it are either the nucleus palposa (ph) cells and/or the annular cells, has there been some basic studies to find out the responsiveness of these cells at what you might call a therapeutic index concentrations?

How do they respond? CHAIRPERSON FINNEGAN: once there? DR. histologically BODEN: not Scott any Boden. changes We in have the Don't all jump at

observed

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surrounding

cartilage.

As

part

of

the

procedure,

obviously the cartilage is removed in order to create the crevice or the tunnel that the cage goes into. And the cells that really grow into the sponge, which is where the BMP is and if the BMP elutes into the adjacent bone because of circulation, tends to be more of an exchange with bone cells and marrow cells than the relatively acellular and quiescent intervertebral disc cells. In most cases these discs are very

degenerative and so the cellular activity is somewhat low. There are a number of in vitro studies looking

at BMP-2 and others effects on disc chondrocytes and again, those are in vitro studies. There have not In fact,

been any deleterious effects that I know of.

many of them are thought to be beneficial and whether or not that would be possible with a single dose application, as in this case to make any difference I suspect probably not. Most of those beneficial attempts at

intervertebral disc cartilage therapeutics are more with longer term exposures or gene therapy approaches. NEAL R. GROSS
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DR. REDDI:

Thank you. Dr. Lenchik? have a couple of

CHAIRPERSON FINNEGAN: DR. LENCHIK: I

questions, hopefully it will be brief. that question of posterior anatomical

To get back to barrier that

exists behind the cage, what do you do about patients that have annual tears or worse disc herniations? Is

the labeling going to be such that this device is contra-indicated in those patients or how do you keep them from ossifying the spinal canal? DR. BODEN: Scott Boden. I think that's a

very appropriate question and, in fact, as you know and others know, the normal population has a very high frequency of annular tears. Some of them are

microscopic, many of them are macroscopic.

Patients

can have defects in the annulus because they've had previous disectomy or current herniated discs. We believe that all of that existed

because this is a normal disc population and remember that in order to form bone at a distant site away from the implantation site, it requires not only the

elution of recombinant BMP-2 protein but it requires a NEAL R. GROSS
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matrix or a substrate in order which to form the new bone on. So in none of these hundreds of patients

which inevitably, based on pathologic studies we know from the prevalence of annular fissures and tears was that an issue in the pilot clinical or in the pivotal clinical trials. DR. LENCHIK: So there was not a single

patient that formed bone posterior to the cage? DR. BODEN: -- Scott Boden again. There was not a single patient There was not a single patient

that formed bone posterior to the cage outside the confines of the disc case. confines of the disc case, Remember bone in the anterior, posterior,

laterally to the cage is a normal finding that we see even with successful autograft fusions over time. DR. LENCHIK: to what I asked A second question, a repeat what do you think the

earlier,

explanation is for why the number of patients fused by CT criteria were less at 24 months compared to 12 months? Were these initial false positives at 12

months and did you look at that group specifically to see if there was any correlation with clinical

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symptoms in that small group? DR. BODEN: Scott Boden again. That drop

in the apparent fusion rate was all due to the second surgery criteria. Those were all people that had

operations, for reasons as I stated earlier, that may have either been persistent pain, new pain, adjacent segment degeneration. So it was not a change in the

radiographic reading or appearance or the grading of the CT scan. So in a sense, in terms of positivity, false or otherwise, the numbers and the statistics that you're probably thinking of were radiographic

fusion rate, include in it the requirement that there not have been a second surgery in order to be

considered a fusion success as the study is currently defined. because So the apparent drop in that percentage is of some patients that are getting second

surgeries. DR. LENCHIK: that. I guess you confused me by

So what you're saying is that actually the

number of CTs that were fused was not less at 24 compared to 12? NEAL R. GROSS
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DR. BODEN:

That's correct. The other question is also

DR. LENCHIK:

somewhat a repeat of what was asked earlier but I'm not sure I heard an adequate of response. either Was by CT the or I

radiographic

assessment

fusion

plain films, was there any quantitation of that?

thought somewhere in the document I read that it was graded one through four and A through D, and if so, how much of it did you need before you called it fused, either on plain film or CT? Was one trabecular bridging across

sufficient or how much of it was required? DR. BODEN: This is Scott Boden again.

The grading system you're referring to was created in the pilot study as a means of assessing whether or not that type of quantitative analysis would be helpful or not since this was broaching somewhat new ground. was determined in that the effectively pivotal the criteria that It as that

outlined

protocol

quantitation of that sort was not useful in coming up with an all or none binary answer that was meaningful. So there wasn't, as Dr. Genant mentioned NEAL R. GROSS
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earlier,

formal

quantitation

but

there

were

two

independent readers and I think that if there had been one little spicule, that they would not grade that as bridging trabecular bone. It would have to be

meaningful but if you want further clarification, then we can get Dr. Genant back. DR. LENCHIK: That's all right. The last I have

question is perhaps the easiest to answer.

read several times in the documentation that patients -- plain films were evaluated first and if they were fused by plain films then they were basically Does

considered fused.

If not, they had CT scan.

that mean that the CT scans were not evaluated in the patients who were fused by plain films or were CT scans actually read in every single patient from whom they were obtained? DR. BODEN: Boden. CT scans were -- this is Scott

CT scans were read in every single patient.

That was only the decision algorithm as to whether or not they were classified as fused. DR. GENANT: This is Harry Genant again.

Yes, Leon, that is correct, that basically we did an NEAL R. GROSS
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evaluation of the CT in all of the patients in whom CTs were available and that was a vast majority. DR. LENCHIK: Since you're up there,

Harry, what about the issue of artifact coming off the metallic cage on CT, were there any patients in whom you thought you simply couldn't tell whether there was bridging across or this is a hypothetical that just exists in my head and not in real life? DR. GENANT: Well, indeed, that is an

issue. Although that we recognize that in this case we're dealing with titanium cages and clearly if we had other metal alloys that would be -- would almost preclude the evaluation. But nevertheless, we found

that with the combination of the axial images with the coronal and with the sagittal reformations, that we were able to make an estimate of the intracage

ossification in virtually all the cases. CHAIRPERSON FINNEGAN: Dr. Larntz? DR. LARNTZ: question is, was any Just one question. analysis done to The one the Okay, thank you.

adjust

laparoscopic results for the difference in baseline NEAL R. GROSS
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variables? DR. LIPSCOMB: The answer is yes. In

anticipation of your question, Dr. Larntz, we did do a co-variant adjustment analysis comparing the Next and

investigation of lap group to the control group. slide, please. We looked at 25 demographic

preoperative conditions and also some of the surgical variables to get out base of what other possible covariants and from a logistic regression, we identified eight that seemed to be -that had the most

significant effect. Next slide, please. And those are the Some

eight that came up from the logistic regression.

of them obviously, make a lot of sense when you start thinking about what maybe would effect the outcome. Next slide. And then when you do the Bayesian

analysis, comparing the lap to the control with the adjustments, established Oswestry, you in all and be see the that major an equivalence is

categories; and

fusion, in fact, them,

neuro

overall claimed

success in

superiority

could

three

of

Oswestry, neuro and overall, so yes, we did. NEAL R. GROSS
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DR. LENCHIK:

Thank you. Ms. Rue.

CHAIRPERSON FINNEGAN: MS. RUE:

I think my other questions and

comments were pretty much discussed but I do have one. You had a very nominal amount of patients that had hepatitis. Was there anything specifically different

about their outcomes? DR. LIPSCOMB: there's anything. I'd have to look to see if

I think there's only just one or

two patients that had that and if you can give us a second, we can -MS. RUE: I think there was like three in It was just nominal. Yeah, if you can give us a

one and two in the other. DR. LIPSCOMB: second we can check.

CHAIRPERSON FINNEGAN: MS. MAHER:

Ms. Maher?

I have nothing further to add. All right, if you

CHAIRPERSON FINNEGAN:

will all -- while he's looking that up -- hang on a second. Yes. DR. KOSTUIK: May I ask a question? Microphone.

CHAIRPERSON FINNEGAN: NEAL R. GROSS
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DR. KOSTUIK:

It's John Kostuik.

It's my

understanding that there was statistically significant difference in urological or urogentic problems between the InFUSETM group and the controls and that these

were mainly retention and that they all resolved, but I do have some concerns. It's my understanding,

probably wrong, that there may be some influence BMPs in the prostate. I would like to know the breakdown

between sexes and ages as to who had the significant problems with urinary retention because this could

lead in the older population to some difficulties. DR. MATHEWS: Kostuik. Hal Mathews. Thank you, Dr.

We did not urogenital issues in the patients We tried to look at

in the investigational group.

specific mechanisms for that and we didn't really come up with anything specific to that but Dr. Kostuik's point is well-taken. We're currently searching for

the distribution of age and sex. We discussed this clinically amongst the investigators and we thought that there were two

issues which were really pretty obvious in treating these patients. Number one was the fact that the NEAL R. GROSS
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patient

that

received

the

investigational

control

device did not have a bone graft harvest; and hence, when the surgery was over, if they were treated

laparoscopically, they were going home in 45 percent of those patients. If they were treated as an open surgical patient, they wanted to get up because they didn't have much pain. harvestation. They didn't have the iliac crest

And hence if one is up and mobile, one

will typically ask the nurse, "May I have my catheter removed", because as you know, the catheter insertion and Foley catheter drainage during and alift procedure (ph) is paramount to that procedure. the bladder deflated. And hence, if you didn't have an iliac crest harvestation, you had your catheter taken out very early and you were up and mobile. However, we You want to have

still always know that that's an anterior procedure and that anterior approach still has the risk of

having ileus and also urogenital complications just from being there and hence those patients may have had reinsertion of a Foley catheter later because of this. NEAL R. GROSS
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However, it is important to note that all of these retention issues did resolve before they went home and no patients needed additional catherizations. CHAIRPERSON FINNEGAN: you. All right, thank

We're going to have to proceed to questions, to

the FDA questions but I think Dr. Li had one question. DR. LI: to ask earlier. I just have one question I failed

In one of the summaries, it compares

the results of nine of the investigators who had a financial interest in the product versus the

investigators that did not have a financial interest. And I was taken by the fact that the surgeons that had the financial interest had a better overall success rate in both your control and your test group, almost by a factor of two in the test group, versus those physicians that did not have a financial interest. So I don't really raise this at all to impugn anybody's integrity but my question is, is Was

there something that we can learn about that?

there something that your nine investigators that had a financial interest, did they have a higher

experience level, did they have a better technique? NEAL R. GROSS
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Is there something that we can take away from that that you could put into the labeling or instruction or manuals than that would basically make everybody's -or you could give everybody a financial -(Laughter) DR. LIPSCOMB: only thing I can say Well, what a question. about that is we did The the

analysis, as you had in your packet, and it just speaks to the beauty of having a prospective

randomized control trial because if you look at the results that were presented, yes, those with the

financial interest did better than those that didn't on the numerical -- different numerical parameters, but they also did equally well in the control group as well. So when you start making those comparisons,

that's where those kind of wash out. DR. LI: Yeah, I guess my question is, did I mean, was there from that to teach

you investigate why that was? something that we could take

everybody across the board to have the same -DR. LIPSCOMB: past that point, no. NEAL R. GROSS
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We didn't specifically look

CHAIRPERSON FINNEGAN:

Time out.

If you

will bear with me, we need to actually officially have a second open public session, so I would like to proceed with that at this time. I would ask that all

persons addressing the panel come forward and speak clearly into the microphone so that the

transcriptionist can have a valid means of providing an accurate record of this meeting. And we request that all persons making statements meeting during the which open public session of the and

disclose

company

they

represent

whether they have financial interests in any medical device company. the panel, in Before making your presentation to addition to stating your name and

affiliation, please state the nature of your financial interest, if any. the panel? Please. DR. PATEL: I'm Tushar Patel. I'm a Is there anyone wishing to address

service consultant to Depuy Acromed as well as Striker Biotech. for by And I'm here with my travel expenses paid Depuy Acromed. I'm a clinical assistant

professor at Yale University and a private practice NEAL R. GROSS
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spine surgeon, limited to spine surgery, orthopedics. This is a two-part question, a follow-up of that to Dr. Finnegan, of who commented upon the I Dr.

endless plead

resourcefulness guilty. How comments

orthopedic one

surgeons. given

does

insure, about

McCullough's

earlier

off-label

application, different carriers, et cetera, and this is a particularly important question. I would be

delighted to see BMPs approved in the sense that I think that's a tremendous advance in treating spinal disorders, but I think it is important to address the off-label issue. The second is for the people from Integra Life Sciences, in which the question was asked, have any antibodies been seen. Knowing that it's been

approved 29 years ago, were any tests done to look for the antibodies? I understand that nobody's ever

reported any immune response but did anybody ever look for an immune response and specifically the

antibodies?

Thank you. CHAIRPERSON FINNEGAN: Would you guys like

to answer the first question? NEAL R. GROSS
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MR. DEMIAN:

He's just giving a comment.

You don't have to specifically answer the questions. This is open public session where he's providing his comments to the panel, so that's it. CHAIRPERSON FINNEGAN: time I would like to ask the All right, at this sponsors, Medtronic

Sofamor Danek if they have any final comments before we proceed with reviewing the questions. MS. RUE: Dr. Finnegan, I'd like them to

answer the question about -CHAIRPERSON hepatitis. DR. LIPSCOMB: We did a quick analysis of FINNEGAN: Oh, certainly,

the patients that had hepatitis and if you'll just look at the overall success, bear with us, the data that we could garner quickly, three out of five of the open investigation patients were successes at their last visit, overall successes. Sixty-six percent or

virtually 60 versus 66 percent in the control were successes and then 100 percent in the lap group were successes. MS. RUE: Thank you.

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CHAIRPERSON FINNEGAN: make any final comments? DR. LIPSCOMB: CHAIRPERSON No. FINNEGAN:

Would you like to

Oh,

thank

you.

Aric, if you would go ahead and put up the questions, please. MR. KAISER: to do with reproduction Okay, the first question has and teratogenicity and we

would like the panel to discuss the potential for an immune response in the mother to effectively block BMP-2 in the developing fetus. CHAIRPERSON FINNEGAN: panel. DR. DIAMOND: I think we have to say it's Comments from the

a potential hazard and that this study so far doesn't prove the null hypothesis, so it's a potential

concern. CHAIRPERSON FINNEGAN: DR. LENCHIK: Any other comments?

I've got one. Yes. talking about the

CHAIRPERSON FINNEGAN: DR. LENCHIK: We're

pregnancy registry.

Why not just make it a contra-

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indication

in

women

who

are

pregnant,

no

one

has

brought that up as an option. CHAIRPERSON FINNEGAN: DR. WITTEN: Can All right. I provide some

clarification to that question, just in response to that, which is as Peter Hudson explained during his presentation, it's not the -- what we're concerned about potentially is a potential concern, it's not something demonstrated in the study. the product itself when administered It's not that is causing a

problem in developing fetus but that the problem -that the product that may at cause some an immune not response in

another

could

time,

necessarily

related to you know, the time point at which it was implanted, cause a problem. So then, you know, the question would be if a woman had it which would be suggesting a contraindicating event. So that's just something to keep in

mind, you then contra indicate it or -- you know, there's a sort of -- it's not clear what the time limit would be of that contra-indication. DR. BOYAN: Madam Chairman?

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CHAIRPERSON FINNEGAN: DR. BOYAN:

Yes, Dr. Boyan.

The -- I guess I would argue

against that contra-indication because I don't think we have enough information one way or the other except to say that the incidents of an immune response in the mother was exceedingly low in the clinical trial and based on the information that was given to us would be very low in the general population, but I don't think we should ignore it. I think that we need to make it clear in the labeling somewhere that it's a potential issue and that I guess I might even go as far as to say that there may be some wording to suggest that the patient be made aware of that not just in some vague

discussion but should they then get a second or a third treatment using BMP-2 in some sort of device, that they maybe want to pre-test to see if they have antibody titer at that time. DR. comment? CHAIRPERSON FINNEGAN: DR. KIRKPATRICK: Go ahead. I KIRKPATRICK: Dr. Finnegan, may I

John Kirkpatrick.

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would just suggest that as a surgeon, and I hope my colleagues would agree but I can't read their minds, that I would not plan to do an elective surgery on a pregnant woman anyway. indication practice. DR. DIAMOND: I think the concern, the is kind of So putting it as a contranot relevant to medical

caution would be for women who want to get pregnant, who plan to get pregnant and I think that maybe there should be some post-marketing continued studies of

these antibodies in gestating animals. CHAIRPERSON FINNEGAN: And actually I

strongly support that as well. Dr. Witten, is that one of

One of my questions, the studies that is

proposed or no, because I don't see that as a -DR. WITTEN: That's actually one of the

studies that we're asking you to make a recommendation on. If you do propose such a study, we'd like to know

that and what it would look like. CHAIRPERSON FINNEGAN: ahead. MR. KAISER: All right, the next question, Okay. You can go

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same

topic,

discuss of BMP-2 and

the

potential

that a

the

fetal

expression immune

could cause

restimulate adverse

maternal in the

response

effects

mother, which was the question that Dr. Witten had brought up. CHAIRPERSON FINNEGAN: All right. Dr.

Diamond, do you have any comment on this being as you are our resident immunologist? DR. DIAMOND: You know, I think that I

don't know if that transplacental model that we heard about goes in both directions and whether you can actually see whether fetal protein goes into the -- I mean, I think it's an interesting question. concerned the other way. CHAIRPERSON FINNEGAN: You need a microphone. DR. MILLER: There certainly are data that Okay. Dr. Miller. I'm more

suggests in mouse models that the decidua is they're producing tremendous amounts of RNA about day seven and perhaps, influencing where implantation will be occurring in that process, Dr. Day out at the

University of Kansas in a group. NEAL R. GROSS
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So it may not just

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be fetal.

It may be maternal reaction to generating a It may not be transplacental. I guess I would be worried I mean, I also would be

large amount.

DR. BOYAN:

about it going the other way.

in favor of worrying about unborn fetuses but there's lots of us that are like already born and there is a certain healing amount even of in use of BMPs in normal I fracture it is

micro-fractures.

think

important to know that and since the company is more than willing to investigate that and FDA is willing to let it be investigated after a post-approval moment, I think we should encourage them to do so and suggest that study -- I have to admit this is not my field, so I don't know how to suggest a study, but I'm willing to put my thoughts to it. CHAIRPERSON FINNEGAN: MR. tumorigenicity, potential for we KAISER: would like to Thank you. With you to Okay. to the of

respect discuss growth

rhBMP-2

stimulate

transformed cells. DR. DIAMOND: You already recommended the

study of primary isolates that are receptor positive NEAL R. GROSS
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and receptor negative, correct? CHAIRPERSON FINNEGAN: So the question is

do we agree with the proposed study? DR. DIAMOND: I think that's a good study. Dr. Reddi, did you

CHAIRPERSON FINNEGAN: have any comment on that? DR. REDDI: not enthusiastic on

No, I think I'm very -- I'm wasting time on looking at It for

transformed cells. only enriches the

Cell lines are a dime a dozen. contractors and it who do research any vivo

Genetics

Institute I

doesn't to

give in

useful data.

information.

would

like

see

Although Dr. Riedel has mentioned that he has done some dog studies, I still would like him to keep his eyes open, ears open and senses open to see if

anybody's talking about it and it should be brought t the attention of FDA and it's the duty of every one of us in this room, like Dr. Miller here, he has Dr. Day's studies in Kansas City. It should be brought to

the attention, especially our hard working colleagues in FDA. CHAIRPERSON FINNEGAN: NEAL R. GROSS
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Okay.

MR. KAISER: effectiveness, we'd

With respect to radiographic your comment on the

like

interpretation of the radiographic findings at various time points in view of the following; the presence and absorption rate of the ACS, the progression of bone repair and the presence or absence of rhBMP-2 and the relative ability of bone formed at various time points to withstand the applied loads. CHAIRPERSON FINNEGAN: Well, actually, I

think I'm going to take this and I think that Dr. Kostuik and Dr. Hanley and Dr. Lenchik probably all together have told us that none of them work and it's probably not worth fussing about. DR. KIRKPATRICK: If I could add, John

Kirkpatrick, with regard to the last point that you had about to withstand applied loads, I believe that the loads will be shared between the graft and the titanium cage. The titanium cage is more than

adequate to withstand the loads even after the graft is formed. DR. LENCHIK: Can I just make a comment?

I think the way you have the questions broken down NEAL R. GROSS
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don't make a lot of sense to me because we've heard from the sponsor that the ACS is gone by six weeks or two months and the first set of radiographic studies were at six months. So I'm not really sure how we can

answer the first part. The second part, I think, we can answer. I think you can see bone ingrowth at the rate that you would expect to see it. I think that has been shown So whether they not I think the

with both plain films and with CT. included the CT in the study or

efficacy of the system would have still been proven. The fact that they included CT is interesting. don't think it makes any difference from I the

standpoint of patient evaluation and some people will still use CT. films. I wouldn't regulate how you evaluate So Other people will still use plain

radiographic fusion in the labeling of the device.

I agree with everything that's been said previously. I think the third question you simply can't answer from any of the data that's been provided because nobody's really told us what kind of loads were applied at what NEAL R. GROSS
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time points, so I'm not exactly sure how to answer that third sub-question. CHAIRPERSON FINNEGAN: Witten. DR. WITTEN: MR. KAISER: Okay, thank you. Okay, instructions for use. That's a no, Dr.

We would like you to provide suggestions for adequate instructions for use with respect to radiographic

interpretation and also to discuss any other specific training that should be implemented with the product. CHAIRPERSON Hanley. DR. HANLEY: These questions are part of FINNEGAN: Go ahead, Dr.

the normal clinical practice of medicine and are not specific to any particular device. I don't see the

relevance for this particular issue personally. CHAIRPERSON packaging or not? FINNEGAN: Can we address

I have some serious concerns about

packaging but you haven't actually asked about that and I was going to try and cheat and put it under instructions for use but I don't know if that will work. NEAL R. GROSS
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The question has been brought up by our toxicologist about the volume inside the cage,

basically what he's saying is the amount of medication or drug that's available. You have different sizes of

cages, you have different sizes of sponges, you have different concentrations of BMP and they're all going to be packaged separately and somebody gets to figure out how much of what they put in where and I have serious concerns about that. DR. WITTEN: And the concern is -The concern is that

CHAIRPERSON FINNEGAN:

the amount of BMP that gets to a specific disc space may be inadequate, may be over adequate or may be appropriate and there's no guidance to the user. It

would seem to me to make much more sense to package a size of cage with an associated size of sponge with an associated size of BMP as one package that came

together because then you know you've got a controlled amount of everything. MS. MAHER: give a response to that? help out. NEAL R. GROSS
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Dr. Finnegan, can I actually I'd also like the sponsor to

CHAIRPERSON FINNEGAN: MS. MAHER: I

Sure. by having them

think

packaged together, you would be adding a tremendous extra expense to the consumers of the because of the

sterilization

methods

different

products,

because of the different sizes and how they're going to be used, but I think Medtronic Sofamor Danek can better answer the question as to how it will be

controlled. DR. BODEN: This is Scott Boden. From the

standpoint of an operating surgeon and in the interest of patient care, the reality of it is that you need the ability to mix and match cage sizes and sometimes you change something. You think you're going to use a

certain size and while we template these patients, it's hard to predict in advance what we're going to actually need and sometimes you need a different cage size on one side than on the other depending on the shape of the spine. So the practicality of having that

together would be difficult in terms of feasibility, in terms of what goes on in the operating room. NEAL R. GROSS
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I

should mention that once you've figured it out, then the 15-minute wait for reconstitution. it is there's only actually that's one 1.5 to The reality of of per the

concentration milligrams rehydrate

recombinant milliliter

BMP-2 and the

and

instructions

lyophilized powder (ph) are effectively the same. The only variable is what size the sponge is and that's based on the size of the cage and the little, you know, template that says how to cut it, and then therefore, the volume that appropriately

fills up the size of the sponge, based on the sponge. It is difficult, if not impossible, to -- the sponge can only hold so much volume. you know, large excess, So in terms of putting, too much on, it's

full,

technically not really possible. I mean, this thing ends up like a wet little, sort of mushy thing, cigar, and even if you went and doubled the volume you put in, it wouldn't hold it. The volume that it's designed for is a

wetting volume that's appropriate for the sponge so that when you handle it, it doesn't go squeezing out all over the place and all those have been worked out. NEAL R. GROSS
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CHAIRPERSON FINNEGAN:

But then what would

stop someone from taking, once you've squeezed it up to put two of those sponges in? I mean, the cage, it

does really compress down and so the cage could take two of them. I mean, I really don't see that you're

controlling dose exposure. DR. BODEN: I guess it's based on

concentration and so if you take 1.5 milligrams per milliliter and put it in half the size of the cage, it will make bone in that half of the cage. And if you

take another sponge and put it in the other half of the cage, then it would still make the bone. I guess

I'm not sure why a surgeon would try and use twice as much of something that's been shown to work using the instructions. I mean, I don't understand how this is

different than -CHAIRPERSON FINNEGAN: DR. BODEN: You've never --

-- any other drug, you know,

where you have instructions, and you know, if you use twice as much of an anti-inflammatory you might get an ulcer risk. I don't know why -- if you're getting,

you know, effectively a 100 percent bone induction, NEAL R. GROSS
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why even would in the mind of a creative orthopedic surgeon, which I'll subscribe also to that group of people, it just wouldn't go through my mind to think to use more of something that's not inexpensive. CHAIRPERSON FINNEGAN: Okay, next. MR. KAISER: studies, the first In the area of post-market question has to do with Any other comments?

reproduction and teratogenicity.

FDA believes that

additional animal models may be useful for assessing an immune response effect on fetal growth and

development. for these

And we'd like your comment on the need studies and if you believe they're

necessary, the type of studies to be performed and the type of animal models. CHAIRPERSON FINNEGAN: MR. REDDI: So comments. I just want

I'm Hari Reddi.

to echo the comments made by Dr. Betty Diamond from Albert Einstein College of Medicine. I hope I'm sort

of giving sort of combined views, but if you have good antibodies for recombinant BMP-2 that it be used to study in a mouse model to see, number one, does it NEAL R. GROSS
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effect after administering it, prior to implantation, which is four to five days, after implantation between nine days and 10 days when the first skeletal elements begin to form and then again after implantation and after limb bud formation, and during the joint

formation such as -- and also spine formation in the embryo, say 16 days or 17 days to see what it does. Can you agree, Dr. Diamond? DR. DIAMOND: CHAIRPERSON sounds like that's -MR. KAISER: Okay. In the area of Yes. FINNEGAN: All right, that

tumorigenicity, FDA and the sponsor have agreed to conduct additional non-clinical studies to evaluate the potential for rhBMP-2 to stimulate transformed

cells.

We'd like your comment on the need for any

other non-clinical studies and if you believe they're necessary, the types of studies and the appropriate models. CHAIRPERSON FINNEGAN: Dr. Reddi, if I

understand you correctly, you feel that there are some clinical studies that should be done. NEAL R. GROSS
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DR. REDDI: MR. KAISER: DR. REDDI:

Non-clinical studies. Non-clinical. Yes, I would like to -- I I wanted somebody else

didn't want to speak up first.

in the panel to -- I have very strong views, I think people already know, at the risk of repeating, adding these substances to 60 other transformed cell lines is worthless. It should not be done. But instead I

recommend to these sponsors a very careful study be done using again simple animal like mouse and

administer -- the studies about tumorigenicity is not that you give one big bolus and go off to Miami for vacation. You've got to take these mice and you have to see these mice every day. You've got to have such

good technicians and they should be administered the dose equally distributed over about three to six

months.

If the mouse has a longevity of two years, I

don't buy the study in which they say we give 1000 times the dose and the mouse was fine at six months. That's not a useful study in cancer research. Cancer research is the dose distributed NEAL R. GROSS
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over a period of time and see what happens.

This

should be done and I strongly recommend such a nonclinical study be implemented. DR. DIAMOND: But I think the study that

you suggested -- they're really are two questions. One is promoting tumor growth and one is inducing tumors and the question Dr. Reddi is addressing is inducing tumors. Promoting tumor growth would also be an unfortunate outcome. So I think, I agree that tumor Primary isolates

cell lines are not the way to go.

are and to have them identified as receptor positive so because it may be that of the 71 primary isolates looked at or whatever, only three were receptor

positive. DR. BOYAN: I would agree with both of you

except that I'm not sure I would limit it to receptor positive primary isolates because BMP induces its own receptors. So it can be that you just take your best and -DR. DIAMOND: DR. BOYAN: But identified -The you know one way or

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another if it was or not. DR. DIAMOND: DR. BOYAN: Yes, yes. And I must stress again no

more cell lines because we could take -- just the people sitting at this table could pick one cell line each and we could get the cells to proliferate or not proliferate or inhibit or whatever we wanted them to get depending on how confluent they were in the

culture, how we set up the experiment.

I think an

animal study is the only acceptable way to go. MS. Institute to MAHER: on Can I just ask Genetics to Dr.

give

one-sentence

response

Reddi's comments on the cell -CHAIRPERSON FINNEGAN: Well, I think this

is basically for the panel to make its decision, so you can go onto the next. MR. KAISER: Okay. We'd like you to

comment in the use of ongoing post-market registry data bases to further assess and the if potential agree for that

congenital

abnormalities

you

registries are recommended, discuss the types of data to be captured. NEAL R. GROSS
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CHAIRPERSON this? DR. LARNTZ: do.

FINNEGAN:

Any

comments

on

Registries are just hard to Hard for people to --

They're hard to follow.

it's a serious undertaking and you have to be very specific about what you want to find out. It would

seem like for this particular issue it's going to be difficult worthwhile. DR. DIAMOND: You won't get enough I think that's the point. numbers to get statistical to get enough patients to make it

significance. DR. LARNTZ: But it's hard to do anyway

and if you're not going to get enough people, why bother? CHAIRPERSON FINNEGAN: around the table? All right, I need the panel to listen very carefully because this gets really complicated. want to ask her if we've adequately answered Do I the Any other comments

questions? more.

I don't think she wants to hear us any

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DR. WITTEN:

Yes. Dr. Witten, have we

CHAIRPERSON FINNEGAN: adequately answered the questions? DR. WITTEN:

Yes, thank you. All right, we are For the panel, your

CHAIRPERSON FINNEGAN: now going to move to a vote.

instructions; the options are that we do not approve the PMA. Second option is that we approve with

conditions and the third option is that we approve with no conditions. obvious. The first and the third are

The second one for each condition, we have

to vote, so this is -- it's actually -- if you've been here before, this is a very good way to deal with this -- if this is the way we go, a good way to deal with the conditions, but you have to be patient and you have to understand that for each new condition, we have to have another vote. So I would ask Dr. Kirkpatrick, who is the panel's clinical reviewer for this, if he would like to make a motion. DR. KIRKPATRICK: I'd like to move that

it's approvable with conditions. NEAL R. GROSS
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CHAIRPERSON FINNEGAN:

All right, we will

go around the table and see if that is comfortable with people and if it is, that's fine. could give your reasons. DR. LARNTZ: before we -CHAIRPERSON FINNEGAN: all right. DR. LARNTZ: I second it. All right. Dr. Li? He needs a second, Dr. Li. He needs a second for that If not, if you

CHAIRPERSON FINNEGAN: DR. LI: I concur.

CHAIRPERSON FINNEGAN: DR. DOULL: I concur.

Dr. Doull?

CHAIRPERSON FINNEGAN: DR. DIAMOND: Also.

Dr. Diamond?

CHAIRPERSON FINNEGAN: DR. HANLEY:

Dr. Hanley?

Non-voting. Oh, he's -- you're

CHAIRPERSON FINNEGAN: not voting. Dr. Siegal? DR. SIEGAL: I concur.

CHAIRPERSON FINNEGAN: vote. Dr. Naidu? NEAL R. GROSS
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DR. NAIDU:

I concur. Dr. Boyan?

CHAIRPERSON FINNEGAN: DR. BOYAN: here because I would

And are we actually voting have wanted to vote for no

conditions. CHAIRPERSON FINNEGAN: You're allowed to

say that you would like to vote against this and vote for no conditions. DR. BOYAN: for approval. second. CHAIRPERSON FINNEGAN: go around you and come back. DR. REDDI: All right, let me Well, I don't want to not vote

Let me just give this a thought a

Dr. Reddi?

Yeah, I would like to proceed

with the rest of the group. CHAIRPERSON Lenchik? DR. LENCHIK: Concur. Dr. Larntz. FINNEGAN: All right, Dr.

CHAIRPERSON FINNEGAN: DR. LARNTZ: I concur.

CHAIRPERSON FINNEGAN: DR. BOYAN:

Dr. Boyan?

Oh, yeah, the crowd is for

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this.

I'm going with approvable with conditions. CHAIRPERSON FINNEGAN: Thank you. conditions. All Dr.

right,

we

have

approvable

with

Kirkpatrick, would you like to add conditions or would you like others to add conditions? DR. KIRKPATRICK: come back? CHAIRPERSON FINNEGAN: You can defer. Dr. Can I defer and then

Diamond, would you like to add a condition? DR. DIAMOND: I would like to add the

condition that there be some testing of the effect of anti-BMP-2 antibodies on all stages from implantation to birth in a rodent model for fetal development. CHAIRPERSON FINNEGAN: All right, so your

condition is that there be further studies on the reproduction teratogenicity and you're comfortable

with the studies that were proposed? DR. KIRKPATRICK: Dr. Finnegan, if I may. You may. already passed

CHAIRPERSON FINNEGAN: DR. KIRKPATRICK:

We've

notes on exactly how to word the condition. CHAIRPERSON FINNEGAN: NEAL R. GROSS
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Go for it.

DR. KIRKPATRICK: BMP-2 which to promote been growth of

Assess the potential for primary for tumor isolates reception

have

analyzed

BMP-2

expression. CHAIRPERSON FINNEGAN: DR. DIAMOND: DR. different one. Okay.

That's a different one. Sorry, that was a

KIRKPATRICK:

I missed the first one. All right, would

CHAIRPERSON FINNEGAN: you like to reword the first one? DR. potential reproductive for DIAMOND: anti-BMP-2 problems with Okay,

to

assess to

the cause with

antibodies --

problems

implantation or fetal development. CHAIRPERSON FINNEGAN: DR. KIRKPATRICK: wrong line. want it? CHAIRPERSON FINNEGAN: DR. KIRKPATRICK: Okay. All right.

I'm sorry, I read the

Can I make sure we've got it the way we

Study anti-rhBMP-2 in

systemic administration mouse model for antibodies at conception, implantation and limb bud formation time NEAL R. GROSS
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points. DR. DIAMOND: That's fine. All right. Do we

CHAIRPERSON FINNEGAN: have a second for that condition? A VOICE: I second it.

CHAIRPERSON FINNEGAN: DR. LI: Concur.

All right, Dr. Li?

CHAIRPERSON FINNEGAN: DR. DOULL:

Dr. Doull?

Yeah, I like that. Dr. Diamond, you'd

CHAIRPERSON FINNEGAN: better like it. Dr. Siegal? I concur.

DR. SIEGAL:

CHAIRPERSON FINNEGAN: DR. KIRKPATRICK:

Dr. Kirkpatrick?

I agree. Dr. Naidu?

CHAIRPERSON FINNEGAN: DR. NAIDU: Concur.

CHAIRPERSON FINNEGAN: DR. BOYAN: I concur.

Dr. Boyan?

CHAIRPERSON FINNEGAN: DR. REDDI: I concur.

Dr. Reddi?

CHAIRPERSON FINNEGAN: DR. LENCHIK: Concur.

Dr. Lenchik?

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CHAIRPERSON FINNEGAN: DR. LARNTZ: Concur.

Dr. Larntz?

CHAIRPERSON FINNEGAN: condition, Dr. Kirkpatrick. DR. KIRKPATRICK: Reddi's condition.

All right.

Next

I believe it was Dr.

Study the mouse model with equal

dosing and multiple dosing over long periods of time to compliment the large dose at a single time data. Is that correct, Dr Reddi? DR. REDDI: CHAIRPERSON Yes. FINNEGAN: Do I have a

seconder for that, Dr. Reddi? DR. REDDI: I would second it. All right.

CHAIRPERSON FINNEGAN: DR. KIRKPATRICK:

He can't move and second

the same thing so I'll second it for him. CHAIRPERSON FINNEGAN: DR. LI: Concur. Dr. Doull? I All right. Dr. Li?

CHAIRPERSON FINNEGAN: DR. DOULL: want to hear that again. DR. KIRKPATRICK:

Could you read it again?

Study the mouse model

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with equal dosing of the rhBMP-2 and multiple dosing over a long period of time to compliment the data we've already heard which was single large dose at a single time. DR. DOULL: Yeah, I agree. Dr. Diamond?

CHAIRPERSON FINNEGAN: DR. DIAMOND: Yes.

CHAIRPERSON FINNEGAN: DR. SIEGAL: CHAIRPERSON you already seconded it. DR. NAIDU: Yes. FINNEGAN:

Dr. Siegal?

Dr.

Kirkpatrick,

Dr. Naidu? I concur. Dr. Boyan?

CHAIRPERSON FINNEGAN: DR. BOYAN: I concur.

CHAIRPERSON FINNEGAN: DR. LENCHIK: Concur.

Dr. Lenchik?

CHAIRPERSON FINNEGAN: DR. LARNTZ: Concur.

Dr. Larntz?

CHAIRPERSON FINNEGAN:

All right.

Dr.

Doull, did you want to make a condition on toxicity? DR. DOULL: been covered by that No, I think that issue has condition. The question is

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whether the previous chronic studies they've done were adequate to indicate reasonable assurance of safety and I think this study clearly would strengthen that position a lot. CHAIRPERSON FINNEGAN: And Dr. Siegal, do

you have any conditions on pathology? DR. SIEGAL: I do not except to say as a

friendly suggestion that those studies be done with the use of a pathologist who has expertise in those areas, especially a perinatal pathologist with those embryo/fetal studies. DR. LIPSCOMB: ask one point of Dr. Finnegan, can I just Are these these -I postmean,

clarification? or are

approval

recommendations

what's the -CHAIRPERSON FINNEGAN: These are the

conditions attached to the approval. DR. LIPSCOMB: I know, but are they post-

approval conditions, post-PMA approval conditions? CHAIRPERSON FINNEGAN: I think we give the

FDA the freedom -- they're post-approval, right. DR. WITTEN: I'm assuming you're

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recommending them from the way they've been worded as post-approval. DR. KIRKPATRICK: It was my understanding

that these would be -- you would have the approval and then these studies would be required of you after the approval. DR. clarification. CHAIRPERSON Naidu, did you have FINNEGAN: conditions All right, you Dr. were LIPSCOMB: I just wanted

any

that

concerned about? DR. question. NAIDU: No, I just have a quick

This is strictly for single level fusion, I just want to clarify that. That's being done.

am I correct?

CHAIRPERSON FINNEGAN: Dr. Boyan? DR. BOYAN:

I have nothing further. Dr. Lenchik, any --

CHAIRPERSON FINNEGAN: Dr. Larntz? DR. LARNTZ: CHAIRPERSON

I have nothing further. FINNEGAN: All right, Dr.

Kirkpatrick, your next one? NEAL R. GROSS
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DR.

KIRKPATRICK:

Yeah,

I'd

like

to

propose two conditions that would be regarding -- one is regarding the labeling and one is regarding the packaging. the One is that the labeling be specific for approach and I guess it's in there

anterior

already as I understand it and a single level is in there, as I recall. I would like to restrict it to only

tapered cages and I believe that that will prevent a majority posterior of surgeons from applying fusion this from a and Not

lumbar

interbody

perspective

therefore getting in the canal bone formation.

many of us would try and put in a tapered cage from the back and give induced lordosis, so I would trust that judgment of surgeons would prevent that because that is a concern that I have. And I think if we

restrict it to the tapered cage, we'll solve that, so we'll leave it at that specific thing and then I have another one after that. DR. WITTEN: Can I just point out the

device is a three-component device that includes a lumbar tapered cage. NEAL R. GROSS
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CHAIRPERSON

FINNEGAN:

But

it's

the

tapered cage that is his concern. DR. KIRKPATRICK: tapered cage. DR. WITTEN: product. CHAIRPERSON FINNEGAN: So that's That's a component of the I'm making sure it's a

officially in the title and does not need to be a condition? DR. WITTEN: is the description of Well, it's officially -- that the product that's under

consideration. CHAIRPERSON anybody if -DR. WITTEN: No, you can put it in. All right, okay. FINNEGAN: Will it upset

CHAIRPERSON FINNEGAN: Do I have a seconder for that? DR. SIEGAL:

I'll second it. Thank you. Dr. Li?

CHAIRPERSON FINNEGAN: DR. LI: though I know the

I'll just raise this issue even rest of the panel members may

disagree, but with all due respect to Dr. Larntz, the NEAL R. GROSS
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idea of not doing a registry because it's difficult in this case is a little peculiar to me. I understand

the difficulties of that but the alternative right now is to do a mouse study, which I agree with, but at the end of that mouse study, even if it turns out to be an immune response it's going to be, well, that was a mouse, will it happen in a human. So I think if you don't do some kind of registry, if you don't look for sure you're not going to find anything. And if you have some sort of

registry where you make an honest attempt to look for a certain set of conditions and the immunologist and biologist could probably set the type of things to look for, I don't really understand how you could not do it in this case where you have a small potential for not a very good effect. CHAIRPERSON FINNEGAN: Why don't -- I'm

going to ask you to make that as a condition but we'll vote on this condition about the tapered cage first. DR. LI: Sorry. No, perfect. I'm

CHAIRPERSON FINNEGAN: glad you brought that up. NEAL R. GROSS
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DR. LI: condition?

So do you want me to make that a

CHAIRPERSON tapered cage. DR. LI:

FINNEGAN:

Isolated

to

the

Well,

for

the

device

that's

described in the application, I would like a postmarket surveillance registry of -- I guess you want a definition of what the registries would include; is that correct, or what you should look for? CHAIRPERSON FINNEGAN: back to you on that. DR. WITTEN: asking for -CHAIRPERSON condition. DR. WITTEN: -- a vote on the condition --- of only using FINNEGAN: A vote on the Right now, Dr. Finnegan is I'm going to come

CHAIRPERSON FINNEGAN: the tapered cage. DR. LI: Oh, well, fine.

CHAIRPERSON FINNEGAN: what I need. DR. LI: Yes. NEAL R. GROSS
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I need a yes, is

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CHAIRPERSON FINNEGAN: DR. LI:

Thank you.

Yes, sorry, I got all excited. Dr. Doull? does that include

CHAIRPERSON FINNEGAN: DR. DOULL: Yeah,

information on the dose? CHAIRPERSON FINNEGAN: just trying to keep it out of there. DR. DOULL: I agree. Dr. Diamond? No, no. That's

CHAIRPERSON FINNEGAN: DR. DIAMOND:

That's fine. Dr. Siegal?

CHAIRPERSON FINNEGAN: DR. SIEGAL: DR. DOULL: DR. NAIDU: Yes. Dr. Naidu?

Yes, I concur. Dr. Boyan?

CHAIRPERSON FINNEGAN: DR. BOYAN: Yes.

CHAIRPERSON FINNEGAN: DR. REDDI: I concur.

Dr. Reddi?

CHAIRPERSON FINNEGAN: DR. LENCHIK: Yes.

Dr. Lenchik?

CHAIRPERSON FINNEGAN: DR. LARNTZ: Yes.

Dr. Larntz?

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CHAIRPERSON FINNEGAN: your condition? DR. LI:

Okay.

Now, Dr. Li,

My suggested condition is that

the sponsor does conduct a post-market surveillance by way of a registry and I'll let, perhaps, some

biological colleagues determine what they should look for in that registry. CHAIRPERSON FINNEGAN: DR. SIEGAL: information? CHAIRPERSON FINNEGAN: DR. SIEGAL: Yes. All right.

Can I ask just a point of

Isn't there going to be a

required adverse reporting to the FDA anyway? CHAIRPERSON FINNEGAN: Do you want to

touch that with a 10-foot pole, Dr. Witten or -DR. WITTEN: Sorry, I missed the context

but the question was is adverse event required? CHAIRPERSON FINNEGAN: FDA. DR. WITTEN: Adverse event reporting for Reporting to the

-- is required and it will happen for things that are recognized to be related to the product. NEAL R. GROSS
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CHAIRPERSON FINNEGAN: yeah, but not -- yes, Dr. Li. DR. LI:

Problem but not --

Yeah, can I comment on that?

I

guess in total hips and total knees which is subject to the same adverse reporting schedule, it's estimated that somewhere only about one or two percent of actual adverse events actually get reported in that system. So my own experience is in the absence of a separate pre-determined mandated sort of post-market

surveillance, it isn't going to happen. DR. LARNTZ: Can I ask a question? Do I have a -- go

CHAIRPERSON FINNEGAN: ahead. DR. LARNTZ:

No, the question is you're I wasn't

talking about a registry of all patients? clear on that before. DR. LI: in the context of

Is it an all patient registry? That's a good question. our discussion today, I guess it would

obviously be a registry that would at least be of -minimally would be of women of child bearing ages. CHAIRPERSON FINNEGAN: ahead. NEAL R. GROSS
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Do I have -- go

DR. KIRKPATRICK: about

I have just a question Are we

kind of thing we're asking them to do.

basically asking them as the sponsor to maintain sales records on who gets the implant because they are not going to be responsible for following up those

patients once they've had the implant. DR. WITTEN: Well, they're not

responsible, no, for following up patients who've got an implant that's commercially distributed, no. To do

a registry you'd -- it's similar to doing a study. They'd have to design it and describe how they would be recruiting patients and what kind of data they would be collecting. I mean, that's the kind of thing

we'd want recommendations from you all on. CHAIRPERSON FINNEGAN: like them to do this registry? DR. LI: I guess the biologist and How long would you

radiologist would have to tell me what a reasonable time course would be. MS. MAHER: Can I make a comment? I think

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cents in a little early.

But if you're going to -- I I'm not

mean, I saw the numbers they threw up there.

sure that a registry would capture any information but it would be very expensive for the company to maintain and I think as a panel we need to be very careful not to throw cost, which ultimately goes down to the

consumer, there's no way around it, the consumers bear the cost in the long run, that aren't going to provide any relevant information at all. So I just would like

you all to think about that as you're deciding whether to second it. CHAIRPERSON FINNEGAN: But with

information systems on the internet that's available now, the registry may not be as difficult as it was say five or 10 years ago. DR. LARNTZ: I would disagree totally.

It's very difficult to do a registry, do it right. So many registries are so sloppily done and then you get our garbage at the end and someone says, "Nothing happened" but there wasn't good enough -- it's very difficult to do. It's important to do it right and I Dr. Witten

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said that and she's right, it's a study, so we're requiring another study to be done. effort. It requires serious work. I don't -- I like registries if they can be done well, but I see too many that are done so poorly and then the information misused out of them, that that's my concern. DR. BOYAN: I actually -I mean, we It's a serious

haven't had too much discussion after any of these conditions and it hasn't been good. we're having this. This is good that

I would like to go ahead and

second it so we can vote it down or just -- or agree not to do it. And I really would -while I

appreciate your reasons for doing it, Steve, I have to say that I think it's something that is -- we're going to get the answer we want from the mouse study. If something comes out of the mouse study -this company has distinguished itself by being

willing to get a tremendous amount of science done before they've come forward with the product. think that we would run in -I don't I don't a

foresee

problem developing.

If the data should come out from NEAL R. GROSS

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the mice in an unfortunate way, I think that the rest will follow naturally. DR. LI: Are you comfortable then that

just as a follow-up question, if you do the mouse study, and it turns out there's no negative effects of the BMP-2, then you would be comfortable that we will never see an effect in humans? DR. DIAMOND: I think the issue is that it

will take more than five years, more than 10 years with the kinds of numbers of patients to be able to see what are generally small -- I mean, they can be two-fold increments, but you still need to look at thousands and thousands to see. And so I think the

problem is that it's very costly and very difficult to keep the effort going over that time frame and the chance of actually reaching numbers where you can say with confidence it's not teratogenic is vanishingly small. I think that's the issue. DR. LI: this out, number Well, and again, I just throw one, so we could have the

conversation and if you want to vote it down -CHAIRPERSON FINNEGAN: NEAL R. GROSS
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It's on the record.

DR. LI:

Okay, and that's fine.

I guess

my only negative on this product is this potential problem for which we actually have no evidence for. Right? And I'm just not completely comfortable that

the only way we're going to answer that is with a bunch of mice. CHAIRPERSON FINNEGAN: All right, Dr.

Kirkpatrick, your next condition. DR. KIRKPATRICK: next condition. Actually, it's not my

I just want to amend a condition that

we've already talked about because Dr. Reddi provided me with specifics on the studying of the mouse model with equal dosing and multiple over a long period of time. He suggests monthly over a one-year period and

since we're going to add that, I need to make sure that everybody agrees with that. CHAIRPERSON FINNEGAN: Well, we don't want

to tell them how to do their study, do we? DR. KIRKPATRICK: yeah. Or we can delete it,

I'm just saying he provided me with this extra Okay. CHAIRPERSON FINNEGAN: NEAL R. GROSS I don't think we

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want to tell them how to do their study. DR. LI: Madam Chairman, I think Dr. Boyan If nobody else wants

actually seconded my condition.

to vote on it, that's okay, but -DR. BOYAN: I only seconded it in the

event that we were going vote for it and then I was going to suggest in my seconding that we vote

negatively, but -DR. LI: That's okay, that's okay. But if there's no second, we

DR. BOYAN: don't have to vote. DR. LI:

That's okay, I just want you to That's okay. Great. Are you formally

put me away on this one. DR. BOYAN:

CHAIRPERSON FINNEGAN: seconding -DR. BOYAN:

No, no, if there's no other

second, then we don't have to worry about it. DR. DIAMOND: Can I ask, did we actually

vote on assessing the potential for promoting tumor growth? CHAIRPERSON FINNEGAN: NEAL R. GROSS
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We did, yes.

All

right, Dr. Kirkpatrick, your next one. DR. KIRKPATRICK: condition which in all due Okay, I do have another deference to inventory

issues and the difficulty that will require my implant supplier to come into the operating room with an

entire tote full of product, I would like to propose the condition that the cage and the infused must be packaged together. CHAIRPERSON seconder for that? FINNEGAN: Do I have a

Am I allowed to second? No. Okay, do I have a

A VOICE:

CHAIRPERSON FINNEGAN: seconder for that? DR. DIAMOND:

Well, I'll second so there

can be discussion but I don't -CHAIRPERSON Comments? DR. KIRKPATRICK: Would you like me to -Go ahead. order to give a FINNEGAN: All right.

CHAIRPERSON FINNEGAN: DR. rationale to KIRKPATRICK: this, we've In

already

heard

several

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on the package insert.

In addition, we have heard the

vice president of the company indicate not directly but between the lines that while he would not

encourage off-label use of the InFUSETM by itself, it sounds like he would welcome its use because it would be an issue where people would be able to use the InFUSETM without the cage. I'm not sure that they

would be adequately policing that. MS. MAHER: sir. DR. KIRKPATRICK: Between the lines he I never heard them say that,

mentioned that they would be packaged separately as separate components and we'd have to match them in the operating room. appropriate dose. We'd have to match our cage with the What I am suggesting is, is that if

they know the dose for each cage that's right, they can package the two together and that way we don't have the burden in the operating room of saying, "I need a 14 millimeter by 20 cage, what dose do I need to apply to it". If it's already pre-determined and prepackaged that way, we don't have that problem. NEAL R. GROSS
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You

also will stop the problem of a surgeon taking just the InFUSETM without the cage and applying it in an off-label use if that is a concern at this time. DR. BOYAN: May I comment on that? Uh-huh.

CHAIRPERSON FINNEGAN: DR. BOYAN: that for another

I would like to see us not do and that's because things

reason

happen and as a consumer myself, I'm thinking right now but things do happen in the operating room and there is a change in the cage size, a dropping on the floor of the sponge. I think it's important that the

surgeon have the opportunity to buy the sponge with the BMP as a separate entity just because of the sheer -the complexities of this, the end stage

sterilizing. I was very much taken with the fact that they explained how they decided to prepare the BMP under sterile conditions rather than ethylene oxide. That's very important to me as a biologist and it means that they're able to use a lower dose of BMP than they would have had to have done if they

sterilized it another way and these are large doses NEAL R. GROSS
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but they're not as large as they could be if they had to start off with the ethylene oxide sterilizing. So there are some really compelling

reasons for me that they be able to package them separately and -CHAIRPERSON FINNEGAN: But they can

actually sterilize them differently and package them together. DR. BOYAN: Well, okay, I'll just go on

record as saying that it would be my intent to vote against that. CHAIRPERSON FINNEGAN: the volume concern, then? DR. BOYAN: How do I address it? Yeah, I mean -How do you address

CHAIRPERSON FINNEGAN: DR. BOYAN: Well, I --

CHAIRPERSON FINNEGAN:

-- as a scientist

how would you address the fact you don't know what concentration you're getting to -DR. BOYAN: Well, you would. I mean, I

just can't believe that the surgeons are not -- and their staff are not intelligent enough to say, "I have NEAL R. GROSS
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a cage from column A and I'm going to match it with a package from column B that is B .
A

I think they can do

that, but I also think there is times when they have to make decisions and sometimes those -- they need the flexibility of that decision. Now, potential for I agree with and you, I've there already is a

off-label

use

been

sitting over here thinking of the 15 ways I would do it if I had the opportunity, you know, once that went into my brain, but I also think that there's

consequences for making those decisions and they know what they are. And we have to trust that they would

use their brain activity. MS. MAHER: You also have to consider that

if you package them together if something falls on the floor and it becomes contaminated, you're going to open up a whole new package which is -from an

industry standpoint, that's another sale, but I don't think that the hospitals are going to be particularly happy with that. Or if you open them up and say, "Oh,

damn, I need another size", it's going to mean that you go back and you have to open everything up again NEAL R. GROSS
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as opposed to one at a time. another problem. DR. KIRKPATRICK:

So I think that's

With

regard

to

the

second issue about sizing, do we not use a size before we open the implant? In other words, are we not doing

a specific tapered reaming and a specific tapping for this implant? I haven't reviewed the specifics of the

implantation protocol, but I believe that you do size it before you open the implant. DR. MATHEWS: you're correct. Hal Mathews. In general,

However, there are times when the

position of the cage for some reason isn't optimal, the anatomy of the approach isn't optimal and for some reason the cage will tend to migrate towards one side of the intervertebral space. That migration may cause

the need to up-size the cage after you've already opened the cage. And that up-sizing would then

generate a whole another second BMP being brought onto the table that wouldn't have had to happen if you could do it individually with cage sizing and then once you determine the appropriate cage size, then actually getting the BMP and putting it in

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secondarily. DR. KIRKPATRICK: Can you provide me with

an incidence of when that happens or how often that would happen because I can provide you with the

relative incidence of dropping things in our ORs being very low fortunately. DR. MATHEWS: Well, I would love to know I can tell

that incidence historically in the study. you that it happened to me. double-barrel cage insertion

I was not able to use a device which for the

panel members is a device that actually lets you come down on the spine and actually have the channels for the reaming already established. We had to use what's

called a free-hand technique which, in my hands, being somewhat more experienced than others, it did not

allow for that cage size to go in and I had to up-size the cage on the table. Now, I've never dropped one on the floor, I can give you that, but I've had to up-size a cage. DR. KIRKPATRICK: And you had that cage

open before you recognized that? DR. MATHEWS: I had that cage open, saw

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the migration in the insertional process and had to make an adjustment during surgery. DR. KIRKPATRICK: the cases were in your hands? DR. MATHEWS: There were 13 of the And roughly how many of

investigational patients in my hands. DR. KIRKPATRICK: than 10 percent at least. DR. MATHEWS: That happened in my hands. Yeah, but less than 10 So we're talking less

DR. KIRKPATRICK: percent. DR. MATHEWS:

That is the math, correct. Okay.

DR. KIRKPATRICK: DR. NAIDU:

Can I just make a comment?

You know, I don't think that packaging together is going to discourage off-label use because, you know, if the guy wants to use the BMP off-label, he's going to use it anyway. For example, in fact, it could turn

out to be a more expensive proposition because if you look at the small finger joints that we use nowadays, they package it with titanium grommets which they

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don't even use the grommets and we throw them out. We just put in the implants for finger joints. I mean, you know, the lower end on the totem

pole, but still the suggestion that the guy's not going to use that BMP off-label by packaging them together is probably not a good, you know, issue to package them together. CHAIRPERSON FINNEGAN: Actually do we have

a second for this before we go any farther. DR. DIAMOND: it. CHAIRPERSON FINNEGAN: it, okay. Yes, Dr. Witten? DR. WITTEN: Yeah, I just want to make one Oh, you seconded Yes, I believe I seconded

comment because people keep mentioning off-label use which is we're on really this asking you and to its focus safety your and

discussion

product

effectiveness as the label indication -CHAIRPERSON FINNEGAN: DR. WITTEN: -Okay. not, you know,

and

speculate on what other uses might not be safe of, you know, a portion of the product or some other product. NEAL R. GROSS
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CHAIRPERSON FINNEGAN: do a vote on the packaging. DR. TREHARNE:

All right, we will Sir.

Dr. Li?

May I make one point? I guess, yeah.

CHAIRPERSON FINNEGAN: DR. TREHARNE:

My name is Rick Treharne.

I'm with the sponsor and I just want to remind the panel that this It's cage already is in already hundreds commercially of hospitals

available.

around the country and if this is packaged together then people who have those cages would not be able to use those. They'd have to throw them away and buy a There's a lot of

new one, so it's just not practical.

other -- a number of other reasons why this can't be done, different shelf lifes. They have different

methods of sterilization and it's just not a practical thing to do. I just wanted to add that. CHAIRPERSON FINNEGAN: DR. LI: No. Dr. Doull? Okay. Dr. Li?

CHAIRPERSON FINNEGAN: DR. DOULL:

I guess I could support the

idea of a recommendation but conditions are mandates and I don't -- would not approve of a mandate. NEAL R. GROSS
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CHAIRPERSON FINNEGAN: DR. SIEGAL: No.

Okay.

Dr. Siegal?

CHAIRPERSON FINNEGAN: DR. NAIDU:

Dr. Naidu?

I disagree. Dr. Boyan?

CHAIRPERSON FINNEGAN: DR. BOYAN: No.

CHAIRPERSON FINNEGAN: DR. REDDI:

Dr. Reddi?

This is to package -Package, yes.

CHAIRPERSON FINNEGAN: DR. REDDI:

-- in one single package? Yes.

CHAIRPERSON FINNEGAN: DR. REDDI: CHAIRPERSON Lenchik? DR. LENCHIK: No.

I disagree with that. FINNEGAN: All right, Dr.

CHAIRPERSON FINNEGAN: DR. LARNTZ: No.

Dr. Larntz?

CHAIRPERSON FINNEGAN:

All right, so are

there any other conditions to attach that the panel wishes to attach to this? vote which will be If not, we'll do our final with the listed

approvable

conditions and I'll ask Dr. Kirkpatrick to list the NEAL R. GROSS
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conditions. DR. KIRKPATRICK: conditions, number one was Summarizing the approved study anti-rhBMP-2 in

systemic administration mouse model for antibodies at conception, implantation and limb bud formation time points. This was approved as a post-approval study.

The next was study mouse model with equal dosing and multiple compliment dosing the of large rhBMP-2 dose at over a long time time, to also

single

approved as a post-approval study. Assess the potential of BMP-2 to promote growth of primary tumor isolates which have been

analyzed for BMP-2 receptor expression, also a postapproval study. condition. And tapered cages only was the other

The other two that were brought up were

not approved. CHAIRPERSON FINNEGAN: Li, we are voting on whether All right, so Dr. we approve with

conditions and with all of the conditions that were just listed. DR. LI: I vote to approve the device with

all the conditions just listed. NEAL R. GROSS
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CHAIRPERSON FINNEGAN: DR. DOULL:

Dr. Doull?

That's three conditions. Three conditions.

CHAIRPERSON FINNEGAN: Four. DR. KIRKPATRICK: tapered. CHAIRPERSON FINNEGAN: DR. DOULL: Yes.

Three studies and one

You're still a yes?

CHAIRPERSON FINNEGAN: DR. DIAMOND: Yes.

Dr. Diamond?

CHAIRPERSON FINNEGAN: DR. SIEGAL: Yes.

Dr. Siegal?

CHAIRPERSON FINNEGAN: DR. KIRKPATRICK: Yes.

Dr. Kirkpatrick?

CHAIRPERSON FINNEGAN: DR. NAIDU: Yes.

Dr. Naidu?

CHAIRPERSON FINNEGAN: DR. BOYAN: Yes.

Dr. Boyan?

CHAIRPERSON FINNEGAN: DR. REDDI: Yes.

Dr. Reddi?

CHAIRPERSON FINNEGAN: DR. LENCHIK: Yes.

Dr. Lenchik?

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CHAIRPERSON FINNEGAN: DR. LARNTZ: Yes.

Dr. Larntz?

CHAIRPERSON FINNEGAN: happy? DR. WITTEN:

Dr. Witten, are you

I'm happy.

I think, does the Yes,

panel need to go around and state their reasons?

I'm happy except you still have that one last step to do. CHAIRPERSON FINNEGAN: for -DR. WITTEN: vote. Is that right? CHAIRPERSON FINNEGAN: We haven't spent State your reasons for your State our reasons

like the last eight hours talking about the reasons for our vote? DR. WITTEN: You -- well, yes, you have

and if someone summarizes them, other people can -you know, don't have to repeat the same reasons. mean, you can -DR. LI: I'll start if you want. Okay, go ahead. I

CHAIRPERSON FINNEGAN: DR. LI:

I voted for approval because a

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method criteria for safety and effectiveness for this device. CHAIRPERSON FINNEGAN: DR. LI: And And the conditions? conditions are

the

appropriate to make the device safe and effective. CHAIRPERSON FINNEGAN: All right. Dr.

Lenchik, if you agree, we can just agree. DR. LENCHIK: Agreed. Dr. Reddi?

CHAIRPERSON FINNEGAN: DR. REDDI: I agree.

CHAIRPERSON FINNEGAN: DR. BOYAN: I agree.

Dr. Boyan?

CHAIRPERSON FINNEGAN: DR. NAIDU: I agree.

Dr. Naidu?

CHAIRPERSON FINNEGAN: DR. KIRKPATRICK:

Dr. Kirkpatrick?

I agree. Dr. Siegal?

CHAIRPERSON FINNEGAN: DR. SIEGAL: I agree.

CHAIRPERSON FINNEGAN: DR. DIAMOND: I agree.

Dr. Diamond?

CHAIRPERSON FINNEGAN: DR. DOULL: I agree.

Dr. Doull?

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CHAIRPERSON FINNEGAN: DR. LI: I agree.

Dr. Li.

CHAIRPERSON FINNEGAN: DR. WITTEN:

Dr. Witten? I thank all

And I thank you.

the panel members here, the guests of the panel, the sponsors and particularly the FDA staff and also the chairperson. (Whereupon, at 5:30 p.m. the above-

entitled matter was concluded.)

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