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TCBDEPARTMENT OF HEALTH AND HUMAN SERVICES

FOOD AND DRUG ADMINISTRATION

GASTROENTEROLOGY AND UROLOGY DEVICES PANEL

OF THE

MEDICAL DEVICES ADVISORY COMMITTEE

OPEN SESSION

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Thursday, July 29, 1999

8:48 a.m.

Conference Rooms G and H

Parklawn Building

5600 Fishers Lane

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Rockville, Maryland

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PARTICIPANTS

Anthony N. Kalloo, M.D., Panel Chair

Mary Cornelius, Executive Secretary

VOTING MEMBERS

Craig F. Donatucci, M.D.

Jenelle E. Foote, M.D.

Robert H. Hawes, M.D.

Joseph H. Steinbach, Ph.D.

Leonard L. Vertuno, M.D.

CONSULTANTS, TEMPORARY VOTING MEMBERS

Michael P. Diamond, M.D.

Patrick T. Hunter, II, M.D.

Naida Brooks Kalloo, M.D.

Richard E. Deitrick, M.D.

CONSUMER REPRESENTATIVE

Diane K. Newman, RNC, MSN, CRNP, FAAN

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INDUSTRY REPRESENTATIVE

Alan H. Bennett, M.D.

FDA

David Segerson

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C O N T E N T S

PAGE

Introductions 5

Executive Secretary's Statement 7

Open Public Hearing

Roger P. Dmochowski, M.D. 11

Dr. Thomas P. Gross 15

Donald St. Pierre 28

PMA P980053
Advanced UroScience Durasphere
(Urethral Bulking Agent)

Open Committee Discussion

Sponsor Presentation

Introductory Remarks/Product Description

Karen Peterson, M.S. 35

Study Design and Protocol

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Richard Holcomb, Ph.D. 39

Injection Procedure/Clinical Study Results

Jeffrey Snyder, M.D. 45

Concluding Remarks

Karen Peterson, M.S. 60

Open Committee Discussion

Clinical Overview of Incontinence

Jenelle E. Foote, M.D. 88

FDA Presentation

FDA Lead Reviewer

Rao Nimmagadda, Ph.D. 101

Clinical Considerations

Hector H. Herrera, M.D., MPH 111

Panel Discussion 134

Panel Deliberations and Vote 159

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Open Committee Discussion

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C O N T E N T S

PAGE

Recommendations for Revisions to Draft Guidance

for Preparation of PMA Applications for

Testicular Prosthesis

John H. Baxley 165

Status Report on Current Management of

Testicular Implants

Naida Brooks Kalloo, M.D. 183

Open Public Hearing 188

Open Committee Discussion (Continued) 191

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P R O C E E D I N G S

DR. A. KALLOO: Just to let you know we are

waiting on some of the panel members to get here. We still

don't quite have a quorum to proceed. So, as soon as they

arrive, we will begin the meeting.

[Pause.]

DR. A. KALLOO: May I have your attention, please.

Either because of weather or transportation difficulties, we

are still waiting on one or two members to arrive. So, the

plan is to reconvene at 9:15.

[Recess.]

DR. A. KALLOO: Good morning again. I think we

will proceed with this morning's session.

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I would like to call to order this meeting of the

Gastroenterology and Urology Devices Panel. I would to note

for the record that the voting members present constitute a

quorum as required by 21 C.F.R. Part 14.

Introductions

Would each member introduce himself or herself,

designate specialty, position title and institution and

status on the panel, voting member or consultant, starting

on my immediate right.

MS. CORNELIUS: I am Mary Cornelius and I am the

Executive Secretary of this panel.

DR. DONATUCCI: Craig Donatucci. I am Associate

Professor of Urology at Duke University.

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DR. N. KALLOO: Naida Kalloo. I am Assistant

Professor in Urology at National Naval Medical Center at

Bethesda. I am a pediatric neurologist there.

MR. SEGERSON: I am Dave Segerson, Associate

Division Director, Reproductive, Abdominal, Ear, Nose, and

Throat Radiological Devices. I am the FDA representative at

this meeting.

DR. BENNETT: I am Alan Bennett. I am a medical

consultant and Professor of Urology at Montefiore and Albert

Einstein College of Medicine.

DR. VERTUNO: Leonard Vertuno. I am a

nephrologist and Associate Dean at Loyola University School

of Medicine, Maywood, Illinois, and I am a voting member.

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MS. NEWMAN: I am Diane Newman. I am a nurse

practitioner in practice in Philadelphia in incontinence,

and I am the consumer representative. I am a non-voting

member.

DR. DIAMOND: My name is Michael Diamond. I am

Professor of Obstetrics and Gynecology at Wayne State

University in Detroit, Michigan, and I am a temporary voting

member.

DR. A. KALLOO: My name is Anthony Kalloo. I am

Associate Professor of Medicine at Johns Hopkins University

and the Clinical Director of Gastroenterology, and I am a

voting member.

I will now turn the meeting over to Mary, who will

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read the Executive Secretary statement.

Executive Secretary's Statement

MS. CORNELIUS: Good morning. Before we begin, I

would like to read a statement concerning appointments to

temporary voting status.

Pursuant to the authority granted under the

Medical Devices Advisory Committee Charter, dated October

27, 1990, as amended April 20, 1995, Dr. Richard E.

Deitrick, Michael P. Diamond, Patrick T. Hunter, and Naida

B. Kalloo have been appointed as voting members by Dr. David

W. Feigal, Director of the Center for Devices and

Radiological Health, for this meeting of the

Gastroenterology and Urology Devices Panel.

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As you are aware, we have some members coming that

have not arrived yet, and we can only surmise there may be

some problems at the airport. Dr. Foote, thank you. You

are not the only one who had trouble getting here.

To determine if any conflict existed, the agency

reviewed the submitted agenda and all financial interests

reported by the committee participants. The Conflict of

Interest Statutes prohibits special government employees

from participating in matters that could affect their or

their employers' financial interests. However, the agency

has determined that the participation of certain members and

consultants, the need for whose services outweighs the

potential conflict of interest involved, is in the best

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interest of the government.

A waiver is on file for Dr. Leonard Vertuno and

waivers have also been granted to Ms. Diane Newman, Drs.

Michael Diamond, Craig Donatucci, and Patrick Hunter for

their interest in the firms that could potentially be

affected by the panel's deliberations. The waivers allow

these individuals to participate fully in today's

deliberations.

A limited waiver has been granted to Dr. Jenelle

Foote that allows her to participate in the discussion, but

not vote on the PMA before the panel today.

A copy of these waivers may be obtained from the

agency's Freedom of Information Office, Room 12A-25 of the

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Parklawn Building.

We would also like to note for the record that the

agency took into consideration certain matters regarding Ms.

Newman and Drs. Diamond, Donatucci, Foote, and Hunter.

These panelists reported current and past interest in firms

at issue, but not in matters related to what is being

discussed today. Since these matters are not related to

specific issues of this meeting, the agency has determined

that they may participate fully in today's deliberations.

In the event that the discussions involve other

products or firms not already on the agenda for which the

FDA participant has a financial interest, the participants

should excuse him or herself from such involvement and the

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exclusion will be noted for the record.

With respect to all other participants, we ask in

the interest of fairness that all persons making statements

or presentations disclose any current or previous financial

involvement with any firm whose products they may wish to

comment upon.

Dr. Kalloo will ask all persons making statements

either during the open public meeting or during the open

committee discussion portions of the meeting to state their

name, professional affiliation, and disclose whether they

have any financial interest in any medical device company.

Finally, I would like to remind you that the

remaining panel meeting scheduled for 1999 is November 18th

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and 19th. This meeting is only tentative. The tentative

panel meetings for 2000 are January 27 and 28, April 13 and

14, August 31 and September 1, and November 30 and December

1. If the panel meeting is going to be held, I will notify

panel members at least two months in advance of the meeting.

I will turn the microphone back to Dr. Kalloo.

DR. A. KALLOO: Thank you, Mary.

I would like to ask Dr. Foote to just introduce

herself, her specialty.

DR. FOOTE: My name is Dr. Jenelle Foote. I am in

private practice in Atlanta with clinical affiliations with

Emory University and Morehouse School of Medicine. My

specialty is that of general urology with subspecialty

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training and expertise in neurourology and female voiding

dysfunction.

DR. A. KALLOO: Thank you.

Open Public Hearing

We will now proceed with the Open Public Hearing

section of this meeting.

I would ask at this time that all persons

addressing the panel come forward to the microphone and

speak clearly, as the transcriptionist is dependent on this

means of providing an accurate transcription of the

proceedings of the meeting.

Dr. Hawes, welcome, glad to see you. If you could

just introduce yourself and your title and specialty.

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DR. HAWES: My name is Rob Hawes. I am a

Professor of Medicine at the Medical University of South

Carolina. I am a gastroenterologist.

DR. A. KALLOO: And your voting status?

DR. HAWES: I am a voting member.

DR. A. KALLOO: Before making your presentation to

the panel, please state your name and affiliation, and the

nature of your financial interests in that company. Let me

remind you that the definition of financial interests in the

sponsor company may include: compensation for time and

services of clinical investigators, their assistants and

staff, in conducting the study, and in appearing at the

panel meeting on behalf of the applicant; direct stake in

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the product under review, that is, inventor of the product,

patent holder, owner of shares of stock, et cetera; owner or

part owner of the company.

Of course, no statement is necessary from

employees of that company.

I would ask that all persons addressing the panel

come forward to the microphone and speak clearly as the

transcriptionist is dependent on this means of providing an

accurate transcription of the proceedings of this meeting.

Before making your presentation to the panel,

state your name and affiliation, and the nature of any

financial interest you may have in the topic you are going

to present.

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The first speaker as listed on the agenda is Dr.

Roger Dmochowski from the AUA, American Urologic

Association.

Roger R. Dmochowski, M.D.

DR. DMOCHOWSKI: Good morning. My name is Roger

Dmochowski. I am a practicing urologist in Dallas, Texas.

I am here to represent the opinions of the American Urologic

Association in this research. I have a clinical appointment

both at the Uniformed Services University and also at the

University of Texas Southwestern. I have no financial

affiliations with either of the companies bringing forth

their products today.

I would like to make just some general supporting

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statements from the American Urologic Association regarding

ongoing industry-sponsored research in incontinence.

The Executive Committee of the Board of Governors

of the American Urologic Association, as well as those with

specific interests in neurourology and female neurology,

such as Dr. Foote and myself, feel strongly that

industry-supported research is crucial for the development

of new and novel techniques for the delivery of incontinence

treatment for patients other than surgical techniques.

It has become obvious from our improved

understanding of the pathophysiology of stress urinary

incontinence in both females and males that surgery is not

the only nor the best option for a significant percentage of

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patients. We better understand the intrinsic urethral

mechanism, and there are now several methods by which we can

deal with the intrinsic urethral mechanism other than pure

surgical techniques.

Basically, those method involve two essential

types of therapeutic delivery. One is the utilization of

various injectable or bulking agents of which there are

basically three categories. The three categories are

biologics, either autologous or non-autologous, and

synthetic materials.

The other broad option for treatment of the

intrinsic urethral mechanism other than surgery is the

utilization of various device-based technologies, such as

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intraurethral mechanisms, mechanical mechanisms, and/or

injectable delivery mechanisms.

It is the opinion of the AUA that development of

these mechanisms and also the injectables represents the

next significant frontier in development in the treatment of

stress urinary incontinence other than surgical techniques

which continue to evolve.

We are very much in favor of the development of

these techniques. Specifically, in the injectable market,

the development of the biologics really holds great promise.

We have a gold standard, which is bovine collagen, which is

limited both due to durability and allergic phenomena.

We are continually seeking new and better options

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with more longevity and durability in terms of response and

also less antigenicity and allergic reactions.

In terms of mechanism technologies that we are

looking for, we are looking for small mechanical devices

that can be utilized by patients without significant

discomfort, with relatively broad spectrums of time delivery

in terms of not having to be removed every one to two weeks,

but rather can dwell for anywhere from 30 to 90 days with

relative stability of response and stability of mechanical

support to the patient.

So, from the standpoint of the American Urologic

Association, both the injectable and device-driven

technology represents a frontier for the future in the

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treatment of the intrinsic urethral mechanism, and we

support it in its entirety from the general standpoint.

Thank you very much.

DR. A. KALLOO: Thank you.

Dr. Hunter just arrived, so while he settles down,

I want to just ask him to introduce himself, his title,

specialty, and his voting status. Sorry to pull you to the

table so quickly, Dr. Hunter.

DR. HUNTER: Pat Hunter, Clinical Assistant

Professor, University of Florida. I am also in private

practice in Orlando. I have no affiliation with any of the

companies or products being discussed, no financial

interest. I am a voting member.

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DR. A. KALLOO: Thank you.

Next, Dr. Thomas Gross will give a presentation on

Postmarket Evaluation at the FDA's Center for Devices and

Radiological Health.

Dr. Thomas P. Gross

DR. GROSS: Good morning. My name is Tom Gross.

I am the Director of the Division of Postmarket Surveillance

at CDRH. This morning I would like to take a few minutes of

your time to talk about postmarket evaluation at CDRH.

We, in the Office of Surveillance and Biometrics,

think that it is important that advisory panels are aware of

postmarket programs and activities because they may directly

relate to your deliberations about a product's safety and

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effectiveness.

[Slide.]

The objectives of this presentation are threefold:

one, to describe a few of the key methods of device

postmarket evaluation; present challenges in better

accomplishing postmarket evaluation; and describe the

pivotal role that the advisory panels can play in this

arena.

[Slide.]

This slide, entitled "From Design to

Obsolescence," makes three key points. One, it depicts the

natural history of medical devices from design to lab/bench

testing, clinical testing, FDA review, and importantly,

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postmarket evaluation.

Secondly, it depicts the continual feedback loops

throughout the process leading to product improvements.

Postmarket evaluation has an important part to play in that

process, and the rest of this talk will focus on three

programs within postmarket evaluation - the MDR program,

postmarket surveillance under 522, and post-approval under

PMA.

Thirdly, the clinical community including the

advisory panel has a crucial role to play in this process of

continual product improvement.

[Slide.]

As products move into the marketplace, questions

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of potential public health interests may arise. There may

be questions about a product's long-term safety, about the

performance of the device in community practice particularly

as it moves outside the confines of clinical trials.

There may be concerns about effects of change in

user setting, going from professional to home use, for

instance, or concerns about effects of incremental changes

in technology.

There may be concerns also about adverse events or

unusual patterns of adverse events.

[Slide.]

Now, let's focus on some of the programs that may

address some of these questions starting with the Medical

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Device Reporting program or MDR.

MDR is a national surveillance system of voluntary

and mandatory reports. The mandatory portion started in

1984 under the Medical Device Amendments, requiring

manufacturers to report deaths and serious injuries if a

medical device may have caused or contributed to the event.

They were also required to report malfunctions.

Beginning in 1990, under SMDA, all user

facilities, particularly nursing homes and hospitals, had to

report deaths to the FDA and serious injuries to the

manufacturers.

[Slide.]

All told, in the history of the MDR program, we

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have received slightly more than 1 million reports in our

database. However, it was only in the early 1990s that we

started receiving huge numbers of reports, and currently we

receive about 100,000 reports per year.

These are submitted on standardized forms which

capture several data elements including device specifics,

event description, pertinent dates, and patient

characteristics.

Reports unfortunately often have very limited

information, even information on age and gender is missing

from many, many reports, but they also provide critical

signals to the FDA, signals that we take action on.

[Slide.]

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Now, what are some of the actions prompted by the

MDR program? Upon further investigation of these adverse

event reports, we may be doing directed inspections of

manufacturers or user facilities. It may ultimately lead to

product injunctions or seizures, product recall, namely, an

example of a recent recall involving blood tubing associated

with leaking of infected blood into dialysis machines.

We have had several patient and physician

notifications over the past few years, again, many related

to dialysis machines and, in particular, dialyzer membranes.

Actions may also lead to additional postmarket study.

[Slide.]

We at CDRH have two authorities by which we can

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conduct postmarket studies. One is a statutory authority

under FDAMA, Section 522, entitled "Postmarket

Surveillance." Another is our post-approval authority under

PMA regulation.

Section 522 was originally mandated in SMDA 1990,

and was changed significantly in FDAMA 1997. The 1990

version had categories and lists of devices, the

manufacturers of which were required to do postmarket

studies on regardless of whether there were any pertinent

public health questions.

Those categories and lists were deleted and they

are no longer part of the FDAMA 1997 version. However, the

'97 version retained FDA's discretionary authority to order

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postmarket surveillance on products for which we had public

health concerns.

Now, post-approval refers to PMA products and it

is reserved strictly for PMA products and the studies

conducted under post-approval are referred to as conditions

of approval studies. Section 522 extends our authority to

cover Class II and III 510(k) products whose failure may

present a public health problem.

Now, both authorities are seen as a complement to

the premarket efforts to continually assure product safety

and effectiveness in the marketplace.

[Slide.]

Now, in implementing the FDAMA version of Section

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522, we developed criteria to help guide our deliberations

about when to impose postmarket surveillance on Class II and

III products. The principal criterion is that there has to

be a critical public health question.

This can result from a "for cause" issue, such as

a notable adverse event or patterns of adverse event. It

may be linked to concerns about new or expanded conditions

of use, or concerns about safety related to the evolution of

the technology.

The second criterion has to do with consideration

of other postmarket strategies, 522 may not be the

appropriate strategy to answer the public health question of

interest - perhaps an inspection, perhaps some aspect of the

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quality systems regulation would better handle the issue.

Thirdly, the studies have to be practical and

feasible to conduct. For instance, for long-term studies we

need to be somewhat assured that sufficient patient follow

up is there.

A related question - how will the data be used?

This is especially important for rapidly evolving

technology. By the time the studies are done, the data may

be obsolete.

Lastly, it has to be of a high priority for the

center, for yourselves, and for the manufacturing community.

[Slide.]

Once we decide to impose postmarket surveillance

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under 522, there are several approaches we may use. We

should attempt to choose the appropriate study design to

match the public health question of interest and to choose

the least burdensome approach.

Now, that may mean something as least burdensome

as a detailed review of the complaint history and

literature, non-clinical testing of a device, use of

existing databases, or telephone or mail follow up of

patients. It may require something more sophisticated, such

as use of product registries, case control studies, and

rarely, we might turn to randomized trials.

[Slide.]

Now, what are some of the frustrations we have

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experienced in conducting postmarket surveillance in the

postmarket period?

I have mentioned before that the rapid evolution

of technology may make studies obsolete. We should

anticipate that. There are lack of incentives for industry

to conduct these studies. Industry may view these studies

as being the bearers of only bad news for their products.

We need to change the paradigm and make it useful for

industry to conduct these studies.

There may be lack of interest in the clinical

community. Clinicians may be much more interested in

studying cutting-edge technology as opposed to issues

related to mature technologies.

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As in the case of SMDA 1990, there may be lack of

clearly specified public health questions.

[Slide.]

Now, what is the challenge to the advisory panel

and really the challenge to us all?

When considering postmarket studies, whether they

are post-approval or 522, we need to ensure that these are

of primary importance, that they are just not nice to know,

that they are central to the issue of the safety and

effectiveness of the product, that they justify the

resources, that they are practical and feasible.

We need to clearly specify the public health

question, and we need to note the clinical and regulatory

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relevance of answering the question - what will do with the

data? Are the data there to assure us that what we see in

the postmarket arena is what we have seen premarket, are

they there to address residual concerns about the product,

are they there to capture untoward events?

[Slide.]

Lastly, this is my last slide, just a look into

the future of MDR and postmarket surveillance.

For medical device reporting, we are moving more

and more away in terms of efficiency from individual

reporting to summary reporting of well known and well

characterized events, and we are also looking into a

sentinel reporting system. Rather than having the universe

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of hospitals report to us, we are working on establishing a

subset of hospitals who are well trained, well informed

about recognizing medical device issues, so that we can

obtain much more timely and higher quality reports.

We are also working on submission of reports

electronically. Today, we get them hard copy. We are

looking to integrate trend analyses with the quality system

regulations, and we are also in the process of exchanging

reports internationally and globally.

Under postmarket surveillance, I have mentioned

there are a wider variety of design approaches that we

should choose from. There should be more collaboration with

industry and the clinical community, and there should be

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expanded access to relevant data sources.

That finishes my brief talk, and I will take any

questions if there are any.

DR. A. KALLOO: Any questions?

DR. DONATUCCI: I just have one question. How

many devices have actually been recalled under the

postmarket registry program? In other words, how many times

--

DR. GROSS: Have we instituted postmarket

surveillance?

DR. DONATUCCI: No, that you have instituted, but

that has resulted in the disapproval or revocation of

approval of a device.

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DR. GROSS: I think it's fair to say never. I am

not sure about the PMA side of the house, but I don't think

it has ever resulted in a product withdrawal, and somebody

on the OD side can correct me if I am wrong.

With regard to the Section 522 authority, that is

a relatively new program, and it underwent significant

changes last year, so we have a very brief history, and it

has not resulted in any product withdrawals.

The purpose, if I didn't make it clear, is not

really to recall a product. The purpose is to set up

studies to address either "for cause" issues or potential

issues about the safety of a product.

DR. DONATUCCI: Right, but the public health

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question ultimately is that a device was approved and placed

into use before an unanticipated problem arose. I mean I am

thinking of an analogous situation to drugs, such as the

anti-obesity drugs that were then pulled because of the

possible cardiac toxicity.

So, as of today, there is no analogous situation,

no device has actually be subject to that?

DR. GROSS: Not under those authorities. We

recall products under different mechanisms, but not under

those authorities, but let me give you a more concrete

example. Polyurethane foam-coated breast implants. They

were marketed a few years back, and some years into its

marketing, there were questions raised about its possible

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carcinogenicity based on animal studies.

We ordered the company to do a study to help

resolve that issue, and they did a small-scale study

involving humans, blood testing and urine testing, and the

upshot of that study was that there was no significant risk

of carcinogenicity based on those data.

So, in that instance, it helped reassure us that

at least for that particular issue and for that particular

product, there was no long a major public health concern.

So, that is one concrete example. Of course, it didn't

result in any product withdrawal.

DR. DONATUCCI: I guess the thrust behind my

question is that regardless of whether it's PMA 522 or other

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mechanism, the process that you have in place now for device

approval has served the public well. There hasn't been

major problems that have not been identified through this

process. Am I correct in that assumption?

DR. GROSS: Well, I think it has served us well,

and you still have the authority to conduct these condition

of approval studies. There are several other mechanisms by

which we monitor products. I alluded to one, the Medical

Device Reporting mechanism where we received adverse event

reports, and there are multiple things that we can do based

on those adverse event reports.

One of them -- maybe I should bring the slide back

up -- is ordering additional postmarket studies. The other

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things we can do is we could directly inspect a firm, we can

ultimately seize the product, we can ultimately recall the

product, and this is absent any postmarket study.

DR. DONATUCCI: Those are what you can do. My

question actually was how often have you actually done that.

DR. GROSS: Well, absent a postmarket study, we

conduct recalls at least -- I am talking about the entire

agency -- I know for a fact several thousand a year. This

is absente postmarket studies. This is using other

mechanisms by which we surveil products.

The agency, as a whole, including drugs and

biologics and devices, conduct several thousand recalls a

year.

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DR. DONATUCCI: I guess the thrust of my question

again is devices and how often does that happen.

DR. GROSS: Devices, I wish I had the exact

numbers, but I believe several hundred. I can clarify that

if anybody else has more current information, but it is a

substantial number.

DR. A. KALLOO: Any other questions?

DR. HUNTER: I have one. Having been a panel

member for a number of years, I have helped recommend

postmarket approval studies, and I am wondering what your

routine is to help check on those, and then I think some of

them are commerce. I am now looking back, and the

marketplace is very shrewd at finding a device that although

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it's not dangerous, is no longer effective, and if you have

a system in place to say, hey, enough, or have a review and

say enough, we can stop these studies, or do you have a

routine way of doing that, because it would be cumbersome on

the agency to continue every study that we recommend.

DR. GROSS: Well, there is a mechanism, at least

on the PMA side, where they get annual reports, and they are

required to look at the information submitted on these

interim reports, and basically follow through to make sure

that those studies are complete.

We are starting a process right now on reviewing

how well that process works. Now, on the 522 side of the

house, a related authority, as you can gather, we have

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changed the program significantly because of the statutory

changes. I mentioned the 1990 and 1997 version.

So, we have a limited history with the new

approach, but our intent is, as you say, is to monitor these

studies to see if they are being conducted, to see how

useful they are ultimately, and to change our approach if

that doesn't work.

DR. BENNETT: Following up on Craig's issues, and

being the industry rep, I understand that the annual reports

are done, however, I would encourage you and the agency to

really fine-tune that as rapidly as possible.

I have rather direct experience in a very

prolonged postmarket study that will never, ever be able to

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be completed on a product that has been on the market for

almost a decade, and going back to the issue that Craig

brought up, there are other mechanisms, and I would behoove

the FDA to try to step in and when you find and realize that

a postmarket approval study really is not adding anything,

then, be proactive rather than wait for the study to be

completed.

DR. GROSS: I would second that. You should be

aware of reengineering efforts that have been going on

within the center, and there is one initiated recently on

postmarket reengineering, and that is one of the topics for

the reengineering.

DR. BENNETT: If you need a specific example, I

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will be more than happy to give it to you.

DR. GROSS: I am sure you would and I would

appreciate that.

DR. A. KALLOO: Thank you, Dr. Gross.

Next, Don St. Pierre will bring us up to date on

the progress made on matters previously presented before the

panel.

Don.

Donald St. Pierre

MR. ST. PIERRE: Good morning. I am Donald St.

Pierre, the Branch Chief of the Urology and Lithotripsy

Devices Branch. As is customary, I will give a brief update

regarding our past panel meetings, which is not terribly

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customary, I am going to actually follow a script this time.

Our last meeting was held on October 29, 1998. At

this meeting the panel made a recommendation of approval

with conditions on a PMA Supplement from Cypress Bioscience,

Inc., for an extracorporeal immunoadsorption device called

the Prosorba column indicated for use in the therapeutic

reduction of the signs and symptoms of moderate to severe

rheumatoid arthritis in adult patients with long-standing

disease who have failed or are intolerant to

disease-modifying anti-rheumatic drugs. FDA agreed with the

panel's recommendation and issued an approval order on March

15, 1999.

I would now like to update you on some other

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activities that were subject to earlier panel meetings.

First, on July 30, 1998, the panel made a recommendation to

down-classify extracorporeal shock wave lithotripters from

Class III to Class II and also provided recommendations on a

special controls guidance document for extracorporeal shock

wave lithotripters.

This was an FDA-initiated down-classification.

FDA agreed with the panel's recommendations and issued a

proposed rule on February 8, 1999, to down-classify these

devices. On the same date, FDA also issued a Level 1 draft

guidance document in accordance with our internal good

guidance practices. The comment period on these documents

ended on May 10. We are in the process of addressing the

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comments and preparing the final rule and final guidance

document.

Going back a little further, on February 12, 1998,

a closed panel meeting was held to discuss a product

development protocol, commonly referred to as a PDP, for

American Medical Systems' penile inflatable implants.

I am pleased to announce that the company

completed their PDP and was given marketing approval on

November 2, 1998. This represents the first ever completed

PDP for the agency and will ensure the continued

availability of these types of products when the final rule

is published calling for PMAs or PDPs.

For those of that are unfamiliar with the PDP

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process, it is an approval process that has always been in

the regulation, but has never been used successfully until

now. As part of CDRH's reengineering efforts, this process

was given new life. For more information on the PDP

process, I suggest that you check out CDRH's web site.

The next couple of notable device approvals that I

will discuss involve implantable stimulators. Although not

subject to a previous panel meeting, I mention these because

the agency used guidance that was provided by the panel in a

previous panel meeting.

This panel met on August 6, 1997, to provide

recommendations on Medtronic's Implantable Sacral Nerve

Stimulator for the treatment of urinary urge incontinence in

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patients that failed or could not tolerate more conservative

treatments.

Based on the panel recommendations, FDA approved

this device on September 29, 1997. Subsequent to that

approval, Medtronic submitted a PMA supplement to expand the

indications to include urinary retention and treatment of

patients with significant symptoms of urgency/frequency.

The agency determined that based on the panel's

deliberations at the August 6, 1997, panel meeting on the

original PMA application provided sufficient guidance and we

did not bring this before another panel. The device with

the expanded indications was approved on April 15, 1999.

The agency has also approved two humanitarian

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device exemptions for an implantable stimulator. Like the

PDP, the HDE is another fairly new program which is directed

at devices that treat conditions affecting less than 4,000

patients a year.

This is CDRH's equivalent to orphan drugs. An HDE

requires that the sponsor demonstrate that their device is

safe and has probable benefit.

FDA used the knowledge gained from the August 6,

1997, panel meeting and applied it to the review of

NeuroControl Corporation's VOCARE Bladder system which is

indicated for the treatment of patients who have clinically

complete spinal cord lesions with intact parasympathetic

innervation of the bladder and are skeletally mature and

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neurologically stable, to provide urination on demand and to

reduce post-void residual volumes of urine.

The VOCARE system was approved on December 28,

1998. NeuroControl Corporation submitted another HDE to add

a secondary indication to aid in bowel evacuation. This

secondary use was approved on February 19, 1999.

I would now like to follow up on a couple of

issues that Dr. Gross just discussed regarding two specific

post-approval studies that have been completed in urology.

As you may know, in December of 1988, the panel

recommended that all original PMA approvals for

extracorporeal shock wave lithotripters have as a condition

of approval, a requirement that a post-approval study be

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conducted to study the relationship between lithotripsy and

hypertension.

The condition of this post-approval study

requirement has resulted in a labeling change for

extracorporeal shock wave lithotripters that changed the

statement that the risk of hypertension is unknown to the

statement that hypertension is not a long term risk of

lithotripsy.

This was further emphasized at last year's panel

meeting on the down-classification of extracorporeal shock

wave lithotripsy.

The second successful completion of a

post-approval study involves a device for the treatment of

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BPH. On May 3, 1996, FDA approved EDAP Technomed's PMA for

the Prostatron which is a microwave thermal therapy system

for treating BPH.

This device was discussed at a panel meeting on

October 20, 1995, and the panel recommended approval with

conditions. One of the conditions was the completion of a

post-approval study to assess the long-term effects, that

is, five year years posttreatment, including durability and

re-treatment rates.

The sponsor completed the study and modified their

labeling to include five-year follow-up data. Both of these

studies demonstrate the benefits of a well-thought-out

post-approval study.

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This concludes my update on past panel activities.

Thank you.

DR. A. KALLOO: Thank you. Any questions for Don?

If there is anyone else wishing to address the

panel, please raise your hand and you may have an

opportunity to speak.

[No response.]

DR. A. KALLOO: Since there are no other requests

noted, we will now proceed to the open committee discussion

of the premarket approval for P980053 Advanced UroScience

Durasphere (urethral bulking agent) as indicated for the

treatment of stress urinary incontinence due to intrinsic

sphincter insufficiency. This device is injected into the

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urethral submucosa under endoscopic vision to achieve

urethral bulking and coaptation.

I would like to remind public observers at this

meeting that while this portion of the meeting is open to

public observation, public attendees may not participate

except at the specific request of the panel.

The first speaker for the sponsor is Karen

Peterson.

I was just told that we have more panel members,

Dr. Deitrick and Dr. Steinbach. If you could please

introduce yourself, your specialty, and your voting status,

please.

DR. STEINBACH: My name is Joseph Steinbach. I am

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at the University of California at San Diego. I am an

engineer/biostatistician, and my voting status, I am a panel

member, I vote.

DR. DEITRICK: I am Richard Deitrick, Chairman of

the Department of Ob-Gyn at Mercy Hospital in Pittsburgh.

DR. A. KALLOO: And your voting status?

DR. DEITRICK: Panel member, yes.

DR. A. KALLOO: The first speaker for the sponsor

is Karen Peterson.

I would like to remind the speakers please

disclose whether they have financial interests in any

medical device company and, if so, please state your

financial interest.

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PMA P980053

Advanced UroScience Durasphere

(Urethral Bulking Agent)

Sponsor Presentation

Introductory Remarks and Product Description

Karen Peterson, M.S.

MS. PETERSON: Good morning, Mr. Chairman and

distinguished panel members. My name is Karen Peterson and

I am the Vice President of Regulatory, Clinical and Quality

Affairs for Advanced UroScience.

[Slide.]

I would like to begin by introducing the other

individuals in attendance today who are representing

Advanced UroScience. Dr. Jeffrey Snyder, urologist from

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Denver, Colorado, who is one of the investigators in the

clinical trial. Dr. Aaron Kirkemo, consulting urologist

from St. Paul, Minnesota. Attending from Advanced

UroScience today is Dean Klein, our President and CEO;

Richard Holcomb, our biostatistician, and Tina Wittchow, our

Clinical Research Manager.

[Slide.]

We are very pleased today to present our marketing

application for Durasphere Injectable Bulking Agent for the

treatment of stress urinary incontinence due to intrinsic

sphincteric deficiency, or ISD.

[Slide.]

Our presentation today will be conducted in four

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parts. I will summarize the prevalence of urinary

incontinence, and I will provide you with the product

description. Richard Holcomb will present an overview of

the clinical trial study design and the protocol.

Dr. Jeffrey Snyder will summarize the injection

procedure and present the safety and effectiveness results

from the clinical trial. Then, I will present some

concluding remarks.

[Slide.]

Urinary incontinence is a common condition.

According to the U.S. Department of Health and Human

Services, urinary incontinence plagues 11 to 35 percent of

adults and at least half of the 1.5 million nursing home

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residents in the United States.

At least 13 million American adults suffer from

some form of urinary incontinence, and 85 percent of them

are women. Urinary incontinence is generally recognized as

one of the major causes of institutionalization in the

elderly.

[Slide.]

Stress urinary incontinence due to ISD is a

condition where the bladder neck does not close properly.

Involuntary loss of urine occurs during a stress event such

as coughing, sneezing, laughing or other physical activities

that increase the abdominal pressure.

Durasphere is injected trans-urethrally under

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direct visualization, through a cystoscope or endoscope into

the mucosal lining of the bladder neck or urethra.

Durasphere is injected using a commercially available

injection needle. Durasphere is designed to create

increased tissue bulk and subsequent coaptation of the

bladder neck or urethra to prevent involuntary loss of

urine. Here you can see the demonstration of the increased

tissue bulk.

[Slide.]

Durasphere is a sterile, injectable bulking agent

composed of pyrolytic carbon-coated beads suspended in a

water-based beta-glucan carrier gel. Durasphere is

dispensed in a commercially available, individually packaged

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one-milliliter syringe.

[Slide.]

The size range of the beads is 212 to 500 microns,

which has been deliberately chosen to be well above any

known threshold for migration. Published studies in the

urology literature have reported that migration has been

associated with particles less than 80 microns in size.

The carrier gel consists of 2.8 percent beta-

glucan in water. Beta-glucan is a simple polysaccharide and

has a well-established role as a nutrition supplement and as

an agent to facilitate wound healing. The combination of

water and beta-glucan in this ratio produces a viscous,

biocompatible carrier gel suitable for suspending the

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pyrolytic carbon-coated beads.

[Slide.]

Injectable bulking agents and injection techniques

for the treatment of stress urinary incontinence due to ISD

are not new. Contigen, manufactured by Collagen Corporation

and distributed by C.R. Bard, was introduced for use in the

United States in 1993. Contigen is currently the only

injectable bulking agent available in the U.S. for the

treatment of stress urinary incontinence due to ISD.

Durasphere was specifically designed to be

biocompatible, non-immunogenic, non-migratory, and

non-absorbable.

[Slide.]

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I would now like to introduce Richard Holcomb, who

is going to provide you with an overview of the study design

and the protocol.

Study Design and Protocol

Richard Holcomb, Ph.D.

DR. HOLCOMB: Good morning. My name is Richard

Holcomb. I am a biostatistician for Advanced UroScience,

and I am pleased to present highlights of the study design

for the Durasphere clinical study.

[Slide.]

The goal of this IDE study was to evaluate the

safety, effectiveness, and performance of the Durasphere for

the treatment of stress urinary incontinence due to ISD in

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male and female adults.

The specific objectives of the study include:

1. Evaluating the effectiveness of Durasphere in

improving the patient's incontinence over a one-year period

commencing with their first treatment.

2. Assessing the safety of Durasphere by

quantifying any adverse health effects during and after the

transurethral injectable procedure.

3. Comparing the safety and effectiveness of

Durasphere for the treatment of stress urinary incontinence

with the safety and effectiveness of the control.

[Slide.]

This study was designed as a multi-center,

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double-blinded, randomized, controlled trial. Patients were

assigned to receive either the Durasphere or the

market-released control product, Contigen.

The randomization was one-to-one between

Durasphere and control and was stratified by the gender of

the subjects and blocked within clinical sites to achieve a

balance between study centers.

The study was a double-blind trial. Due to the

nature and treatment and anatomy involved, patients would be

blinded to the treatment they received. Treating physicians

could not be blinded, however, due to the differences in the

study material, because of the different appearance and

handling characteristics, as well as packaging. However,

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study staff and non-treating physicians who performed the

follow-up evaluations were blinded to the therapy.

[Slide.]

The study had two primary efficacy endpoints.

The first endpoint was the change in the

continence grade score of the patient from baseline to the

12-month posttreatment interval time point. This endpoint

was used to determine the required sample size. A decrease

in the continence grade of one or more grades was considered

a success for purposes of evaluating this endpoint.

[Slide.]

The continence grades used for the study and

involved in the success criteria were defined by Stamey in

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1979 and have been used frequently in incontinence studies

including the prior Contigen clinical trial.

This is a four-point scale from zero to 3, with

zero indicating a continent or dry status of the patient;

Grade 1, some loss of urine with increases in abdominal

pressure; Grade 2, a worsening of incontinence associated

with physical activities; and Grade 3, associated with total

incontinence and urine lost without any relation to activity

or position.

[Slide.]

The second primary efficacy endpoint for the study

was based on urine loss during pad weighing testing, and

also evaluated the improvement from baseline to 12 months

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post-treatment.

[Slide.]

This pad weight endpoint was measured by

evaluating the urine loss of patients who underwent a

prescribed set of activities included in the protocol that

led to stress incontinence. This urine loss was quantified

through the use of pads, which were worn by the patients and

then weighed at the completion of the activities.

[Slide.]

The primary endpoint of safety was evaluated

through an analysis of morbidity and complication rates

associated with the use of Durasphere, and the evaluation of

those risks.

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Safety was assessed by the physician through

physical examinations and by questioning patients

immediately post-injection and at all subsequent follow-ups.

Symptoms and complications were recorded for all

patients. The investigators were instructed to report any

symptom or adverse event, and to rate each experience for

the intensity, duration, possible cause, and eventual

outcome of that adverse event. All reports of adverse

experiences were reviewed and classified additionally by the

nature and severity of the event, as well as the

relationship of the event to the device or the treatment

procedure.

[Slide.]

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Investigators classified these adverse events as

mild, moderate, or severe: mild events being defined as

those requiring minimal medical treatment; moderate events

being associated with temporary disability or other medical

or surgical interventions; and severe events defined as one

that were associated with life-threatening episodes.

[Slide.]

A number of secondary endpoints were also

evaluated statistically in the study. These included the

following:

1. The number of patients who had improved in

continence grade at follow-ups before and after one year.

2. The number of patients who were dry, that is,

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an incontinence grade of zero at each follow-up interval.

3. The total number of treatments required

including re-treatments.

4. The volumes of the Durasphere and control

materials injected.

5. Changes in an incontinence-specific validated

quality of life instrument.

[Slide.]

Initial sample sizes were calculated for

evaluation of the primary study endpoint of incontinence

grade change based on the Blackwelder approach through

equivalence trials, with a design criteria of a Type 1 error

alpha of 0.05 and an 80 percent statistical power. This led

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to an estimate of 232 patients to be followed for one year.

[Slide.]

Summary statistics were calculated for all study

variables. These included the common summary measures of

mean,s, standard deviations, standard errors, and the like.

Differences in continuous variables between the

treatment groups or between phases of the study were

evaluated using two-sample tests, such as Student's t-tests.

Within-patient differences were evaluated using paired

tests, and where there was evidence of non-normality of any

of the responses, appropriate nonparametric tests were used

or evaluated including Wilcoxin and Mann-Whitney tests.

Evaluations of more than two independent groups,

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such as evaluation of clinic differences, employed analyses

of variances or their nonparametric equivalent. Comparisons

of categorical variables employed Fisher's Exact Tests,

thereby not depending on the distribution of the responses,

and in either the report or subsequent communications with

the FDA, multiple analyses, multiple regression analyses,

and other multivariable analyses were performed including

logistic regressions and repeated measures analyses.

Unless otherwise indicated, all statistical tests

were two-sided, with p-values of less than 0.05 or equal to

0.05 considered evidence of statistical significance.

[Slide.]

Upon enrollment into the study, baseline patient

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and medical history data relevant to the diagnosis of stress

urinary incontinence were collected. At baseline and

follow-up visits, data were also collected on the results of

laboratory blood and urine testing, abdominal leak point

pressure testing, pad weight tests, seven-day voiding

diaries, and Quality of Life instruments.

In addition to the assessment of changes in

continence grade at scheduled follow-up visits, data were

recorded on any procedure- or urology-related symptoms, side

effects, and safety issues seen by the physician or reported

by the patient.

A maximum of four re-treatments was allowed in the

study, consistent with the labeling for the control device.

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Re-treatment was to occur when the patient had not improved

or when the investigator believed that another treatment

would be beneficial to the patient.

[Slide.]

At this point, I would like to introduce Dr.

Jeffrey Snyder from Denver Colorado, who will summarize the

injection procedure and the clinical study results.

Thank you.

Injection Procedure and Clinical Study Results

Jeffrey Snyder, M.D.

DR. SNYDER: Good morning, Mr. Chairman and panel

members. I am very pleased to have this opportunity to

advance what I believe is a safe and effective treatment for

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stress urinary incontinence due to intrinsic sphincter

deficiency. The urology community anxiously awaits an a

non-immunogenic urethral bulking agent.

First, let me disclose that I have no financial

ties with Advanced UroScience other than that as a clinical

investigator and as a consultant.

[Slide.]

I am going to begin my presentation today by

showing you a video of an actual injectable procedure that

was performed from one of our sites that occurred during the

clinical trial, to demonstrate the simplicity of this

injectable technique.

This is an example of a cystoscopic view looking

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into the bladder. At the 5 o'clock position, we see the

injection needle. This is quite an intuitive procedure for

any urologist or gynecologist who performs cystoscopic

procedures. We have an open bladder neck. The needle is

advanced into the submucosal region. The needle has been

primed with the Durasphere, and you can see, with

infiltration and implantation, you get bulking of this area

in the submucosal region, a bulk mass effect, and you see

closure of the bladder neck region.

This is quite a simple procedure with a very short

learning curve, and this is quite easily accomplished and

was demonstrated by all our sites, and you can see closure

of the bladder neck.

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It is very interesting to look at the device. As

you can see, although there is a puncture site here with the

implants, it does not, because of the impregnation in the

beta-glucan gel, does not leak out of this area, and it is

surmised and believed that this will be something that is

important for the long-term durability of this very

biocompatible and non-immunogenic implant.

A second puncture site is created at the 7 o'clock

position. The sites of puncture are very operator-dependent

and what we are looking for is just coaptation and decrease

of this lumen in the bladder neck.

One starts very proximally in the urethra and

works more distally. This is an analogous situation in the

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male patient, as well, and this is obviously a female

patient.

[Slide.]

In summary, this minimally invasive, simply

injection procedure takes less than a half-hour and is

easily accomplished in an outpatient setting. For

physicians experienced with injectable bulking agents, this

procedure is routine and quite intuitive to begin.

[Slide.]

In June 1996, Advanced UroScience began this

investigational study of Durasphere injectable bulking

agent. A total of 377 patients were injected with either

the Durasphere or the control bulking agent at 10

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investigational centers. The data includes all patients

treated in the study as of December 1, 1998, and all

follow-up data received up until May 21, 1999.

This IDE study was open to both men and women. Of

these 377 patients, 355 patients were female and 22 were

male. Based upon anatomical and etiologic differences in

their incontinence, it was expected that the treatment

outcomes would be gender specific. Thus, study results were

reported separately for men and for women.

The male patients experienced less improvement

than the female counterparts. However, these improvements,

as well as the overall clinical results, were similar in

male patients between Durasphere and the control.

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I will now be presenting the results from the

female population in the study.

The Durasphere female population were followed in

the study for a mean of 10.7 months with a cumulative study

time of 1,997 months. As required, at least 232 female

patients were evaluated at one year post-injection.

[Slide.]

This busy slide displays the baseline

characteristics of the patients receiving Durasphere and the

control product. There was no significant difference

between the Durasphere and the control patients for any of

the baseline variables. This was a very well matched group

of patients.

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[Slide.]

The first primary endpoint is the percentage of

patients improved by greater than or equal to 1 continence

grade based upon the Stamey system at 12 months. As shown

in the slide, 66.1 percent of Durasphere patients and 65.8

percent of the control patients demonstrated an improvement

in the continence grade of greater than or equal to 1 at 12

months. No significant difference was observed between

Durasphere and the control group.

This primary endpoint was also evaluated using the

Blackwelder method, in which the Durasphere device was found

to be equivalent to that of the control, with a p-value of

0.007.

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[Slide.]

The second primary endpoint is the change in pad

weight from baseline to 12 months. As shown in the slide,

the mean change or decrease in weight in pad weight from

baseline to 12 months was 27.9 grams in the Durasphere group

and 26.4 grams in the control group. No significant

difference was observed between Durasphere and the control.

In summary, what we can say is there is no

significant difference in the two primary efficacy endpoints

between Durasphere and the control group. It is therefore

concluded that the effectiveness objective of the study has

been met and that Durasphere's effectiveness is equivalent

to that of the commercially available control group.

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[Slide.]

I would now like to present the results of the

safety data of the primary safety endpoints, namely adverse

events experienced during the clinical trial. It is

important to point out that Advanced UroScience included all

symptoms and observations reported on the case report forms

regardless of whether or not they were related to the study

product. Many of the events were unrelated to the study,

but were included by the sponsor for completeness.

This slide demonstrates all of the mild, moderate,

and severe adverse events by severity distribution. The

mild category consisted of 87.6 percent of Durasphere

events, 11.6 percent as moderate, and 0.8 percent of severe

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events.

The three events considered severe for the

Durasphere patient included patients with chest pain, renal

failure, and myocardial infarction. All three events were

deemed unrelated to the device or to the procedure by the

clinical investigators.

There was no significant difference seen in the

distribution of severity of events between Durasphere

patients and the control group.

[Slide.]

This slide shows the incidence of the adverse

events that were reported by 10 percent or more of the

Durasphere patients.

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There were a total of 31 different categories of

adverse events reported during the study. Once again, there

was no significant difference in the incidence of events

between the Durasphere and the control group for 29 of the

31 groups.

However, there was a significantly higher

incidence of urgency and acute urinary retention, defined

for duration less than seven days, for Durasphere for the

control patients, with the p-values of 0.002 and less than

0.001, respectively, and I will address these two different

categories in my next two slides.

[Slide.]

With regard to urinary retention, 30 Durasphere

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patients experiences symptoms of acute urinary retention,

defined as inability to void or the sensation of incomplete

bladder emptying, following treatment.

Twenty cases were resolved after short-term

catheterization, and one case the treating physician chose

to remove 2 ml of material by aspiration in a transvaginal

fashion, thereby allowing the patient to void. Nine cases

resolved on their own without any intervention.

All cases of acute urinary retention were resolved

on an average of four days with a maximum of seven days

post-treatment. No untoward consequences were experienced

by any of these patients, nor was there any adverse impact

on continence improvement.

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[Slide.]

With regard to the urgency issue, 44 Durasphere

patients experienced urgency some time in the study.

Thirteen of these patients reported symptoms of urgency

prior to entering the study, therefore, we are discussing 31

patients who experienced de novo or new onset of urgency.

The vast majority of these urgency symptoms that

were reported were resolved and required limited medical

intervention. Eighteen cases resolved on their own without

any intervention, and 12 of the remaining 13 were resolved

with medication.

All urgency events treated with medications were

considered mild. Twelve of the 13 events resolved on an

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average within 57 days. One patient remains on Ditropan, a

bladder antispasmodic, for the treatment on urgency at the

time the database was closed in May.

It is certainly worth noting that the proportion

of Durasphere urgency events that were resolved were

significantly better than that of the control group. As of

the time of the database closure, 90 percent of the urgency

events for Durasphere were completely resolved as compared

to 65 percent of the urgency events for the control group.

The p-value for this difference was 0.021.

[Slide.]

The mean duration and resolution of all adverse

events are displayed on the slide.

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The duration of an adverse event was calculated by

subtracting the onset date from the date that the event was

documented to be resolved. As shown in this slide, the

overall mean duration of all adverse events was

significantly lower or better clinically for Durasphere

compared to the control group, with a p-value of 0.032.

Overall, 91 percent of the Durasphere events were

resolved as of the database closure as compared to 87

percent of the control group events.

[Slide.]

Our adverse event summary. This slide

demonstrates the overall adverse event profile of Durasphere

patients and the control group patients is actually quite

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similar. This is based on the evaluation of the four

adverse events attributed as just discussed - the severity,

the incidence, duration of the events, and resolution of the

events.

There was no difference between groups in the

severity of the events. If you multiply the number of

events by the duration of events you obtain total adverse

event days. Although the number of events was higher for

Durasphere, the duration was longer for the control group.

Therefore, the combined total adverse event days was similar

between the two groups.

Finally, there was no difference between groups in

the resolution of these events. We conclude, therefore,

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that the overall adverse event profile is similar between

Durasphere and the control group.

[Slide.]

Looking at our secondary endpoints now, in the

next few slides I will summarize the secondary endpoint

results of the study. This slide demonstrates and displays

the improvement in continence grade at the various follow-up

periods of one month, three months, six months, 12 months,

and 18 months for the Durasphere patients.

As can be easily seen by this bar graph, the mean

continence grade was significantly and consistently improved

from baseline to follow-up, all the way across all the time

periods for the Durasphere patients. The p-value was 0.001.

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Interestingly, at the 12-month period, the mean

continence rate for Durasphere was significantly improved

from 1.8 at baseline to 0.97. This represents a 48 percent

improvement in the mean continence grade.

No significant difference in mean change of

continence grade was observed between Durasphere and the

control group at any of the follow-up visits.

Secondary endpoints improvement of greater or

equal to one continence grade.

[Slide.]

This table displays the proportion of Durasphere

and control group patients who have improved by one or more

continence grades from baseline to the time of their

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follow-ups. No significant difference was observed between

the proportion of Durasphere and control group patients who

demonstrated improvement by greater than or equal to one

continence grade at anytime in the follow-ups. These are

very equivalent groups at all follow-up areas up to 18

months.

Previous studies on the control population

reported the proportion of patients demonstrating

improvement at some time during the study. For comparative

purposes, 90 percent of Durasphere patients and 89 percent

of the control patients demonstrated an improvement of equal

to or greater than one continence grade at some time during

the study.

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[Slide.]

There was no significant difference in the

proportion of patients who achieved a continence grade of

zero, defined as dry, between the patients in the two groups

at any time in the follow-up visits.

[Slide.]

This slide depicts pad weight test by time. This

next figure displays the improvement in pad weight of the

Durasphere population in the time periods, and what we can

observe is a decrease in pad weight test at all parameters

of one month through 18 months.

The mean pad weight was significantly improved or

reduced from baseline to follow-up at all time periods for

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Durasphere patients, with a p-value of less than 0.001.

These results parallel the graph recently shown for

improvement for continence grade.

The mean pad weight for Durasphere patients was

significantly improved from 47.2 grams at baseline to 19.3

grams at the 12-month period. This also represents a 59

percent reduction in pad weight at 12 months.

No significant difference in pad weight was

determined between the Durasphere group and the control

group.

[Slide.]

Patients were required to complete a voiding diary

once week prior to each follow-up visit. This figure

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displays the improvement in incontinence episodes per week

by time periods for the Durasphere population.

The mean number of episodes per week was

significantly improved from baseline to follow-up at one,

three, six, and 12 months for the Durasphere patients, with

a p-value of 0.001.

I want to bring your attention to the improvement

at all these time parameters and the similarity in the

parameters they were measuring in the secondary endpoints.

There is quite a bit of consistency in this product.

At 12 months, the mean number of episodes per week

was significantly improved from 20.8 episodes per week to

10.2 episodes per week at 12 months. This represents an

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improvement of 51 percent.

No significant difference in change in number of

incontinence episodes from baseline to follow-up was

observed during this trial between Durasphere and the

control group.

[Slide.]

This slide depicts Quality of Life and the Quality

of Life survey scores that were determined during the time

periods of the Durasphere study population. The mean

incontinence Quality of Life score was significantly

improved from baseline to follow-up at all time periods for

the Durasphere patients. The p-value was less than 0.001.

At 12 months post-treatment, the mean score of

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Durasphere patients was significantly improved from 55.5 at

baseline to 73.7 at the 12-month period. This represents an

improvement of symptoms of 33 percent in the incontinence

Quality of Life score at 12 months.

No significant difference in the mean change of

incontinence Quality of Life scores from baseline to

follow-up was observed between the two groups at any of the

follow-ups.

[Slide.]

Number of injections. The distribution of the

total number of treatments that each patient received during

the study is displayed on this graph. The mean number of

Durasphere injections per patient during the clinical trial

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was 1.69. There was no significant difference in the number

of treatments between the Durasphere patients and the

control patients.

[Slide.]

Injection volume. This table represents the mean

volume of material injected at the initial treatment for

Durasphere and control patients, as well as the total volume

of material injected for patients during the study.

The Durasphere patients had a mean of 4.8 ml of

material injected at the initial injection as compared to

the control group of 6.2 ml. The total mean volume of

material injected during the study was, on average, 7.6 ml

for the Durasphere patients and 9.6 ml for the control

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patients. Thus, Durasphere patients had significantly less

material injected at the initial injection time, as well as

total injection material, less was injected during the

study. The p-value of this was 0.001. Whether this

difference is clinically significant still remains to be

determined.

[Slide.]

Durability. One of the potential advantages of

Durasphere over the control group material is the fact that

Durasphere beads are non-absorbable, whereas, collagen is

absorbed by the body over time. In theory, one would expect

the Durasphere implants to be more durable.

My final two slides give some insight into the

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durability of Durasphere compared to the control.

The fact that the re-treatments were allowed to

occur throughout the study confounds the results of the

durability tests. If one were to evaluate the patients who

received a single injection during the study, it would show

how these patients endured over time without additional

treatments.

This slide shows the improvement in continence

grade by follow-up for all patients who received a single

injection during the study for both Durasphere and control.

At one year post-treatment, 83.7 percent of Durasphere

patients as compared to 71.4 percent of control patients

were improved by greater than or equal to one continence

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grade compared to baseline. Remember that these are

patients who received only one single treatment. The

p-value for this difference is 0.166, which is suggestive

but clearly not significantly different.

[Slide.]

My final slide shows the results as if were to

analyze the data in a slightly different way, or the

retrospective way, that is looking at improvement one year

after the last injection was received and looking back.

This table demonstrates that 80.3 percent of the

Durasphere patients and only 69.1 percent of the control

group patients were improved by one continence grade one

year after their last injection. The p-value of this

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difference is 0.162, which is again suggestive but clearly

not significantly different.

[Slide.]

This concludes my presentation of the clinical

studies. Thank you for the opportunity. I will now call

upon Karen Peterson to provide you with her concluding

remarks.

DR. A. KALLOO: Question. Was there any

relationship between the development of urinary retention or

other side effects on the volume or frequency of injections?

DR. SNYDER: I am going to defer that to Tina.

MS. PETERSON: We are going to do two more slides

and then we will get into the questions and answers. I will

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be brief.

DR. A. KALLOO: Sure.

Concluding Remarks

Karen Peterson, M.S.

MS. PETERSON: Final two slides coming up here.

[Slide.]

The objectives of the clinical study have been

successfully met.

This includes the evaluation of the two primary

efficacy endpoints, which were improvement in continence

grade and pad weight a 12 months post-treatment. Both

continence grade and pad weight were significantly improved

from baseline to follow-up for Durasphere patients, and the

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results are found to be equivalent to that of the control

group.

For the primary safety endpoint, few differences

were found between Durasphere patients and the control group

patients in the severity, incidence, duration, and

resolution of all adverse events. No new or unique safety

issues were identified for Durasphere.

No significant differences were found between the

Durasphere patients and the control group patients in any of

the secondary endpoints at any of the follow-up intervals.

Lastly, the durability of improvement for

Durasphere was found to be not significantly different from

that of the control group, however, the results are

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suggestive of potential longer term durability of Durasphere

compared to the control material.

[Slide.]

The following conclusions from the study have been

drawn:

1. Durasphere injection is safe to use for

treating the symptoms of stress urinary incontinence. No

safety issues arose that limit its application when used

according to its instructions for use.

2. Durasphere injection has been effective in

reducing stress urinary incontinence as measured by

improvement in continence grades, pad weight tests,

incontinence episodes, and validated Quality of Life

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instruments.

3. The effectiveness of Durasphere was found to

be equivalent to that of the commercially available control

device in a prospective, controlled, randomized clinical

trial.

This study has demonstrated the safety and

effectiveness of Durasphere in the treatment of stress

urinary incontinence due to ISD.

I thank you very much for your attention.

DR. A. KALLOO: I had a specific question. Any

questions from the panel? The question I had, was there a

relationship between side effects, specifically, urinary

retention and the volume or frequency of injections?

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MS. PETERSON: We looked at that, and there is no

relationship between those two.

DR. STEINBACH: Question. How much of the bulk

was due to the pyrolytic graphite at the day of injection or

the instant of injection and at long-term follow-up, because

the handout we read said that most of the bulk is being

provided by tissue reaction rather than the pyrolytic

graphite itself? I may have misread the handout.

DR. SNYDER: If I can repeat your question, you

want to know, the bulking effect, how much was due to the

actual pyrolytic beads as opposed to the transfer agent

beta-glucan?

DR. STEINBACH: Right.

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DR. SNYDER: The percentage of pyrolytic beads

that is infiltrated in the beta-glucan is right now

proprietary information, and I am sure will be opened up

later on.

DR. STEINBACH: It might take studies that you

couldn't do in people to know how much is pyrolytic and how

much is tissue material at 12 months, or is that also

proprietary?

DR. SNYDER: No, I don't believe so. I think that

is an excellent comment, and I think that information

actually will be available at some point in the very near

future in laboratory animals.

DR. DIAMOND: I think that is a very good

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question. I read that also. I thought the reason that you

have the bulking was collagen growth stimulated by beta-

glucan, and some of what I read talked about how beta-glucan

is also used in wound healing, but again, from the

presentation, what I heard was that the bulking is due to

the particles.

So, I think a question of which it is, is

important, particularly if you deal with issues of

durability and why it is there and why repeated injections

might have been necessary if it is due, in fact, to the

particles.

DR. SNYDER: Well, I don't believe that one can

absolutely say, there is clearly no data to say that it is

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the particles versus the transfer agent, the beta-glucan,

that is providing the bulking. I think it is probably safe

to say at this point, with the science that we have, that it

is a combination of both agents and possibly the reduction

in the effectiveness following one injection may very well

be due to absorption of beta-glucan.

DR. VERTUNO: Do you have an explanation for the

increased incidence of short-term urinary retention compared

to control?

DR. SNYDER: We looked at those issues because

clearly, there was a difference in those 2 out of 31 groups.

There were certain things that we looked at. We looked at

anesthetic agents, first of all. A variety of anesthetic

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agents were utilized during the procedure from local

anesthesia with lidocaine, lidocaine with epinephrine, up to

a more invasive general anesthetic. That analysis showed no

difference between anesthetic agent and the incidence of

urinary retention.

We do feel that possibly some of the incidence of

urinary retention was due to the size of the needle, which

is larger in the Durasphere group than the control, the

technique which takes a little bit longer than the control,

and irritation from the cystoscope.

DR. FOOTE: I understand through the protocol that

you did follow-up urodynamics at one year. Was there a

difference in the urodynamics in those patients who had

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experienced the prolonged urinary retention or the bladder

irritative symptoms from the patients who did not?

Specifically, I am interested to know if those

patients at one year demonstrated a bladder outlet

obstruction.

MS. WITTCHOW: As shown on the urodynamics, we did

not show evidence of bladder outlet obstruction. In this

patient population, they had a lower post-void residual than

our general population of patients.

DR. SNYDER: Also, interestingly, there was --

which is consistent with the majority of the literature --

there was difference in Valsalva leak point pressure of

these patients, and, Dr. Foote, you had a very eloquent

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article back in the mid-nineties in paraplegia, I believe,

which did show some increase in Valsalva leak point

pressure, but we did not show that in our population.

DR. A. KALLOO: Could the prior speaker identify

herself, please.

MS. WITTCHOW: My name is Tina Wittchow, and I am

the Manager of Clinical Research for the sponsor.

DR. HUNTER: Were any of the control group

patients injected with periurethral, like a spinal needle,

or was it all transurethral injection?

DR. SNYDER: This was purely a transurethral

procedure done via the cystoscope.

DR. HUNTER: Just some clinical questions. It

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looks like that the gel doesn't leak out as well as the

control. Is that the experience of the investigators?

DR. SNYDER: Yes. I believe that, and that is

what I tried to demonstrate in the initial video. It

appears that although it takes a slight bit more effort than

the control to implant the device, one of the advantages is

there is also a decrease in the leakage rate post-treatment.

Another observation that we made is something

called urethral molding. Following the implantation of the

control group, if you were to catheterize the patient, you

tighten up the bladder neck in a very nice fashion with the

control, but when you catheterize the patient, and you look

back in with the cystoscope, you see that the area has

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opened up slightly, there is a little bit of molding. It's

a softer material.

With the Durasphere implant, we did not find that

molding present at all.

DR. HUNTER: One investigator showed you can

actually aspirate the material out?

DR. SNYDER: This is a one-site, one-patient

treatment of what the investigator felt might possibly have

been an abscess causing urinary retention, and this was done

through a transvaginal route, aspirate of 2 ml. This is

certainly not something that we recommend on a routine basis

for patients.

DR. HUNTER: Did anyone experience rupture of the

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submucosal bleb with either the control or the Durasphere?

DR. SNYDER: Yes, I think it is fair to say that

that occurs somewhat frequently depending upon the depth and

volume of implant that you put in no matter what type of

injectable you use, and I think the basic tenet would be to

go to another area that will capture the implant.

DR. HUNTER: So, your study included the rupture

because -- well, they just kept track of the total, and they

just put in whatever it took?

DR. SNYDER: Yes, absolutely.

DR. A. KALLOO: What were the indications for

repeat injections, how did you decide which patients you

were going to do a second and a third injection?

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DR. SNYDER: At follow-up visit, the patients were

seen by the study coordinators and the blinded physician.

The normal parameters of quality of life and incontinence

pad weight tests in all the follow-ups, that were standard

in the protocol, were measured.

It was then determined based upon the patient's

desire and these tests, a discussion was made with these

people to decide who would be re-treated.

DR. HUNTER: Would you inject the material

routinely without doing a skin test? That is an open-ended

question.

DR. SNYDER: Are you talking about future use?

DR. HUNTER: Yes.

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DR. SNYDER: Yes, we saw absolutely no

antigenicity or this implant, and were quite impressed by

it, and I think this is a major advantage.

DR. N. KALLOO: Did you exclude patients with

cystoceles or any other gross visible signs?

DR. SNYDER: According to the protocol, we did not

include patients with Grade 4 cystoceles or significant

cystoceles that were contributory to obstruction. So,

patients in the population did have Grade 1's, maybe Grade 2

cystoceles, and Grade 3's and 4's were eliminated.

DR. N. KALLOO: Were there any cures? I note that

you mentioned greater than one continence grade. What was

your absolute cure rate with absolute dryness?

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DR. BENNETT: It was on one of the slides.

MS. PETERSON: Right.

DR. BENNETT: Between 20 and 25 percent, the same

in both groups.

MS. PETERSON: It was roughly a third at 12

months. Turn to page 36 of your clinical reports. It is

there.

DR. STEINBACH: I noticed two of the slides you

showed to the public with pad weight and with injection

volume, these parameters are normally tested with the

t-test, and you reported the p-value by the Fisher's Exact

Test on your slide. It's not that way in the handout.

DR. HOLCOMB: There were, as you rightly assert,

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most of these tests of continuous measures were Student

t-tests unless there was some reason not to, example,

non-normal distribution of the data, but we had quite a

large sample size, so that wasn't an issue for us.

There were cases where there was classification of

patients, for example, in terms of severity of incontinence

or whenever, where it was appropriate.

DR. STEINBACH: Could it be a typo?

MS. PETERSON: The pad weight, we used a two-sided

Student's t-test.

DR. STEINBACH: It wasn't that way on the slide.

MS. PETERSON: Okay. If you look on page 38 of

your report.

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DR. A. KALLOO: Could you tell us the data on the

male patients?

DR. SNYDER: I am sorry. Could you repeat that?

DR. N. KALLOO: Your results on male patients.

DR. SNYDER: Once again, it should be obvious that

our male population was quite small.

MS. PETERSON: That was included in your

appendices on the males. We do acknowledge that there was a

small sample size for the males, however, some males did

benefit, and there were no safety issues.

So, what we have done is in our labeling, we have

acknowledged that and we have a precaution statement that

reads like this: "The improvements in the male patients

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experience were less than that of the females, but similar

to that of the commercially available control device." We

have that as a precautionary statement.

DR. A. KALLOO: And the incidence of adverse

effects in the males, were they any different even though

it's a small group?

MS. PETERSON: It's a very small group, and it is

your appendix, but you will see it is actually very

comparable to the females, if not less. So, there were no

new or safety issues there.

DR. HAWES: What did you learn from the repeat

injections when you went in to repeat the injection, what

was the appearance, and can you derive any information of

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why the repeat injections failed?

The second question is did you reinspect anybody,

not just urodynamics, but actually reinspect anybody at the

end of the study period to look morphologically at what the

injection looked like?

DR. SNYDER: To answer your first question, which

was what were the observations of the clinical implanters on

reinjection, I think similar findings that we found with the

control group, which were there were several areas of

mucosal erosion where there was some denuded mucosa, where a

blebbed area of a mass had actually just busted open and

been excreted out in the urine.

In none of my patients -- and I injected 34

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primary patients, I had a total of 70 patients of Durasphere

and controls -- did we find any beads left in the bladder in

any patients, which actually surprised me a little bit. I

was concerned that maybe some beads would be left in the

bladder, and this was never reported by any of the

investigators.

In other areas, we found the beads to be present

embedded in the submucosa with some effect, but there

appeared to be, one of the observations I made at

termination of primary treatment was what percentage of the

urethra did I close off, did I get 80 percent, 100 percent,

and at reinjection, there appeared to be no correlation

between the degree of closure that we made versus the degree

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of continence.

So, in some patients that we got an 80 percent

closure of the urethra, who we anticipated would probably

need another injection, when we looked at the data, we saw

that some of those patients were quite dry, and other

patients where we had had 100 percent closure, at three

months, six months, 12 months, those patients required

reinjection.

As far as the second question -- does that

adequately answer your first one?

DR. HAWES: Yes.

DR. SNYDER: As far as the second question, all

patients at all follow-up visits underwent routine

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examination, and there were no morphologic problems that

were visualized on vaginal pelvic examination.

DR. HAWES: But they didn't undergo re-cystoscopy.

DR. SNYDER: Patients did not routinely undergo

cystoscopy on follow-up evaluations.

DR. DONATUCCI: Were all the episodes or urinary

tract infection simple cystitis, or did any patient have an

upper tract infection?

MS. PETERSON: Tina, do you want to answer that?

MS. WITTCHOW: All the events of urinary tract

infection were simple cystitis. I can give you some

specifics as to the urinary tract infections and the ability

to resolve the infections. For our patient population, 88

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percent of those UTIs were cured with one treatment of

antibiotics or one course of antibiotics, leaving about 8

percent that needed to use two courses of antibiotics to

cure, usually a switch in the type of antibiotic that was

being used, and 4 percent of the patient population had UTIs

resolved on their own, either because the patient chose not

to take antibiotics or chose to use other methods like

increase their fluid, changed their practices to see if they

could resolve it on their own.

So, they were fairly routine in the cure rate or

resolution of those UTIs.

DR. A. KALLOO: Ms. Newman.

MS. NEWMAN: I have two questions for you. You

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said that your primary outcome variables have been change in

continence grade and pad weight, but you said your

reinjection criteria was quality of life.

Were those the same variables you looked at for

reinjecting women?

MS. WITTCHOW: Reinjection, to reiterate what Dr.

Snyder had said previously, reinjection was considered after

an entire follow-up. For instance, the criteria for a

follow-up would have been evaluating the continence status,

doing a pad weight, doing a quality of life only after six

and 12 month follow-up, doing a diary, and then evaluating

all of those in coming up with Stamey continence grade, as

well as discussing the need for re-treatment. So, all of

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those factors were taken into consideration for

re-treatment.

MS. NEWMAN: The second question I have is you

have data on 18 months. What numbers do you have longer

term, what numbers as far as reinjection rate, how many

women you have long term, after 18 months, and what are you

doing with that?

MS. PETERSON: So, are you asking after 18 months,

how many?

MS. NEWMAN: What numbers you have on that, and

how long out are there?

MS. PETERSON: Right now we have about 30, a

little over 30 in each group, so about 65 patients that have

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hit their 18 month in the report.

MS. NEWMAN: No, but I mean beyond 18 now.

MS. WITTCHOW: We have about 30 patients at the

24-month follow-up, as well as about 9 more at the 30-month

follow-up, and we have been, while the study has been open,

we continue to follow them every six months.

MS. NEWMAN: Do you have data beyond 18 months

then? Do you have data beyond those 18 months in a certain

cohort?

DR. SNYDER: That data is currently being

collected, but has not analyzed for purposes of this talk

today.

DR. N. KALLOO: Were you doing any ultrasound

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evaluation for volume of post-void residuals?

DR. SNYDER: The standard BVI ultrasound or

catheterization were the standards by which sites used for

measuring post-void residual.

DR. N. KALLOO: Were you able to see the spheres

on ultrasound, did they have a typical pattern on

ultrasound?

DR. SNYDER: My personal experience was that,

number one, I didn't do the follow-ups because I was a

blinded physician, but there was no mention of that on the

ultrasound, but remember, this is not high-resolution

ultrasound.

DR. N. KALLOO: Like a bladder scanner?

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DR. SNYDER: This was a bladder scanner, yes, and

my guess is, is that had one done intravaginal ultrasound

with a high resolution, 5 megahertz or so, that you would

have seen the particles.

DR. N. KALLOO: My concern would be certainly in a

male, for example, who still has his prostate in, how would

that patient be monitored? Were you able to feel any

difference on digital rectal exam in males?

DR. SNYDER: In my site, we had no

non-post-prostatectomy males, no TUR males who participated

in the study. In fact, we had no male patients in my study

at all, my site, so I can't answer that question.

DR. N. KALLOO: Is there anybody that can answer

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that?

MS. WITTCHOW: The inclusion criteria for our

protocol required the male patients to be

post-prostatectomy, so we did not have any males in the

study that still had their prostate.

DR. SNYDER: So, TUR incontinence after a benign

prostate operation would not be a part of that cohort.

DR. N. KALLOO: I am thinking in terms of sort of

spinal cord injury patients or neurologic etiologies.

DR. SNYDER: Neurologically impaired patients were

excluded from the study.

DR. DONATUCCI: Pardon me if you have already

answered this, but there was a statistically significant

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difference between the time to first re-treat and between

Durasphere and the control, at least as I read it in the

handout.

Was there any anatomic differences between the two

groups when you looked inside for the first re-treatment?

DR. SNYDER: Dr. Donatucci, can you just tell me

what -- rephrase your question again?

DR. DONATUCCI: I am referring specifically, let

me find it for you --

DR. HOLCOMB: Is that Table 33 on 45?

DR. DONATUCCI: No, actually, there is another

table a little later. Yes, I am sorry, it is 33 on 45, I

was looking at the wrong table, exactly. The time to first

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and second injection was statistically different between the

two groups, and I am just asking whether there was anything

you found at the time. That just struck me, and I was

wondering what that was.

DR. SNYDER: I don't believe so. I believe what

this represents is a scheduling factor between the follow-up

visit and when the -- there was no defined time period when

the patients had to be injected following that evaluation,

so many times patients couldn't come in during certain

months of the year or at certain vacations, and so certain

patients were just put off for several weeks.

DR. DONATUCCI: Artifactual then.

DR. SNYDER: I think they are artifactual, yes.

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DR. A. KALLOO: Was there a difference in the

quality of life scores between the two groups? I saw your

zero in one year, but compared to the two groups, was there

a difference?

DR. HOLCOMB: No, there wasn't, not any of the

follow-ups, and not at the 12-month follow-up between the

two groups.

DR. A. KALLOO: Is that surprising given the fact

that the urinary retention, et cetera, was higher?

DR. HOLCOMB: I don't know if it's surprising. It

probably reflects the fact that those didn't impact

significantly on the people's feelings.

DR. SNYDER: I think when you look at the quality

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of life issues, it all is based upon or much of it is based

upon the expectations of the individual patient and how much

improvement that individual expects to make to be happy, and

for some patients, completely dry would be the only

acceptable result, and in other patients, a significant

reduction in incontinence and use of pads, et cetera, would

be a significant quality of life improvement.

DR. DIAMOND: I would like to go back to the

tissue reaction question. Can you tell me a little bit

about beta-glucan, how long it resides in the body, how it

is cleared? Is there anyone that has that information?

MS. PETERSON: Sure. I would like to have Dr.

Kirkemo answer that.

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DR. A. KALLOO: If you could please introduce

yourself.

DR. KIRKEMO: My name is Aaron Kirkemo. I am a

urologist in private practice in St. Paul, Minnesota.

The beta-glucan, we do not have an enzyme in our

body, a glucanase enzyme to digest it, so if you look at the

histologic data from the animals, what happens is this

material is phagocytized, and you ultimately just see it

sitting in macrophages and histiocytes. It is just kind of

encapsulated as a foreign body.

The thing that is interesting, if you kind of look

at the tissue reaction over time, it looks very bland within

a very short period of time.

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DR. DIAMOND: What is the time portion over which

it is phagocytized? Are we talking days or --

DR. KIRKEMO: If you look at the basic response at

least from the animal models, at seven days there is a bit

of an acute inflammatory response with both

polymorphonuclear leukocytes -- with both leukocytes and

lymphocytes.

If you look at the three-month data, by that time

point it is basically early deposition of collagen, mostly

histiocytes and a few macrophages, and by the time you get

out to six months it's basically just bland collagen. It

looks very benign.

DR. DIAMOND: So, at three months or six months is

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there any beta-glucan that is not yet phagocytized?

DR. KIRKEMO: I can't say exactly. At least with

all the histology that I looked at, everything looked

incorporated.

DR. A. KALLOO: Could you state your financial

interest, please.

DR. KIRKEMO: I am a consultant for them.

DR. DIAMOND: Going back to the questions I was

asking earlier, then, about what is it that is providing the

durability, the comments, if it is gone pretty much at three

to six months, then, it is probably the particles where

collagen that develops, that is, what is acting is it is not

something that at least components of the device are not

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persistent.

MS. PETERSON: And I think you are precisely

right, it's a combination of what you just said.

DR. SNYDER: And the pyrolytic beads obviously

composing --

DR. KIRKEMO: You see a volume of beads, and you

see mature collagen.

DR. DIAMOND: So, what then happens in those

patients who have continence or who get some improvement in

a month, but don't have improvement six months, a year, 18

months in the data that were presented to us?

DR. SNYDER: Clearly, that is a multifactorial

type of problem that may relate to changes in bladder

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function, maybe not seen initially at one month, but

certainly at six months down the line, you can change the

compliance of the bladder, create some de novo urgency.

You can see disruption of the bleb and loss of the

implant, as you can with the control.

DR. DIAMOND: But the changes in the bladder, you

should have picked up on urodynamics. Did you see

differences like that?

DR. SNYDER: Urodynamics was performed at 12

months.

DR. DIAMOND: Right, and baseline beforehand.

DR. SNYDER: We did not see --

DR. DIAMOND: So, it is not changes in bladder

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function then.

DR. SNYDER: No, it's not, but you are asking for

a theoretical of any given patient, what could potentially

be the cause, and what I am trying to say is that it may be

loss of implant bulk, it may be changes in the urethra, or

it may be other factors, such as pelvic relaxation that we

don't measure it is difficult to measure.

Clearly, there are multiple factors that could

cause that.

DR. DIAMOND: I was trying to be more than

theoretical in that part of the presentation described the

product as non-absorbable, and looking at the data over

time, 7.3.5, it looks like continence decreases actually.

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Now, whether it is significant, I don't know, because I

don't think that analysis was done. Section 7.3.5. I am

sorry, that's not right. I am sorry, it's Table 19. I was

looking at the wrong place.

Analysis has been done there, comparing Durasphere

with control, but if you look at continence grade, you have

greater improvement in continence grade early on than you do

later on. At one month it is 1.1, and at 12 months and 18

months it is about 0.9, so you have about a 20 percent

reduction in continence grade from one month to 12 months.

DR. SNYDER: Yes, and it seems to be similar in

the control group, as well, and I once again would propose

that the mechanisms are not completely understood. We do

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acknowledge that there is a decrease in continence grade,

and there is some loss in continence control that is gained

on initial injection that clearly happens over time. We do

lose some.

DR. A. KALLOO: What I would like to propose -- do

you have a question?

DR. N. KALLOO: I do. I actually have two

questions. Did you notice any granulomas in the area of the

injection?

DR. SNYDER: No.

DR. KIRKEMO: No. It was very interesting that

there really were not giant cell granulomas, granulomas like

you might see with lipid or something like that. It was

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quite remarkable to me there was basically just bland

collagen within a period of about three months on.

DR. N. KALLOO: The other question that I had is I

noticed on your movie, on the video portion, you saw some of

the beads actually come out. You mentioned that the glucan

didn't come out, but I actually saw beads that came out, and

my concern would be these are biodegradable, is that

correct, the beads themselves, the spheres, the

carbon-coated spheres?

DR. KIRKEMO: Correct, they are not biodegradable.

DR. N. KALLOO: How would you go about monitoring

that, for example, over time, if those came out into the

urethra and sort of stuck around in that area, over time

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that might set up a chronic reaction, and we know that the

tissue in that area was chronic reaction. Certainly, we are

concerned about things like squamous cell and that over

time.

So, my concern would be how would that be

monitored over time - or stone formation, for example?

DR. SNYDER: Sure. I think that is a very

thoughtful question. As I made a comment before, where I

was really surprised that we didn't run into problems was in

the bladder, that the dependent position of a bladder with a

mild Grade 1 cystocele, that one might see beads in the

bladder. At no point in any of the sites in any of the

patients was there free retention of carbon particles of

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beads either in the urethra or in the bladder.

These beads are small enough that they get

excreted out with voiding, and the patients would report

that they had some sand, because to the naked eye it looks

like sand, when they voided, and they looked in the toilet.

DR. KIRKEMO: And then also from the standpoint of

kind of a chronic inflammatory sort of reaction, again, what

was seen is you would see macrophages kind of wrap around

the thing, an early granuloma formation, but then by six

months all the inflammatory cells were gone, and all you

would see would be a bead with just mature collagen around

it, and no signs of any chronic inflammatory process going

on whatsoever.

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So, there was really no appearance of any chronic

foreign body reaction, you know, seen within a very short

period of time.

DR. SNYDER: And on follow-up, it is fair to say

that when one looked back into a urethra that had been

implanted for a secondary procedure, both the Durasphere

group and the control group showed amazingly well-healed

urethral mucosa except in the areas that had recently burst

blebs, and you saw some fraying of the mucosal tissue.

DR. KIRKEMO: And that is a phenomenon you see

with any bulking agent. If the mucosa becomes disrupted,

you will see sort of a roughened area.

DR. A. KALLOO: One final question.

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DR. FOOTE: One quick question, and it kind of

goes back to the discussion before about why some patients

got better than others. Did you look back in your

demographic data of your initial groups to see if there were

some things in terms of demographics, in terms of what

patients did better than others?

DR. SNYDER: Sure. Would you address that?

MS. PETERSON: We did a logistic regression

analysis, and Rich will give you the result, and it is

actually in your book, as well.

DR. HOLCOMB: Dr. Foote, it's in Appendix A of the

panel pack that was presented, and we obviously were

interested in identifying which patients would tend to do

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better than others, and as part of that, we did a

multivariable analysis and identified actually five baseline

factors that were associated with better success, and the

details of that analysis is presented there, but it's those

things that you would expect - people with worse

incontinence, that was a predictor for how well they did.

DR. A. KALLOO: One very last question.

DR. HAWES: For a rather ignorant

gastroenterologist, put things into a little bit of

perspective for me. The average age of these individuals

was 57 years old. You have provided us data that looks good

for 12 months.

What happens to these people long term? I mean do

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you anticipate needing to reinject all these people after

two years? If you do reinject them, is there just fibrous

tissue, so you can't enter that subcutaneous space any

longer?

It seems to me that this whole area of injection

for incontinence begs for more long-term studies, and I am

wondering what your perspective is on that. I know your

data just addresses 12 months, but to me, as I assess this

as a treatment for patients, it seems to me that a longer

term perspective needs to be provided.

DR. HOLCOMB: Let me just address maybe two

subpoints. First of all, with regard to effective age of

patient, that did not turn out to be a predictor for success

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in the study, so younger patients and older patients had

similar success profiles.

DR. HAWES: For 12 months.

DR. HOLCOMB: For 12 months. Actually, the data

in the tables, for example, Table 19, that was referred to

earlier, goes out to 18 months, and after that initial

decline after the first month, to date -- and, of course,

you are always limited by how far that you look out -- but

to date, it looks like we have a relatively stable

performance profile for patients out to 18 months and the 24

months, the initial data there suggests that, as well.

So, you can't say what will happen in five years,

but certainly the data we have to date suggests that you

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have got a stable persistent response with the Durasphere

patients.

DR. SNYDER: I think based upon previous

intra-urethral implant bulking agents, such as teflon and

Contigen, we don't typically see fibrosis. It would be a

very unusual thing to see in the urethra looking out beyond

a year.

The potential of this device, the advantages

besides the decrease and immunogenic nature of it, is the

fact that the carbon beads may stay long enough to give a

longer lasting result, and that is yet to be determined, but

as Rich just stated, at 18 months it look like there is some

durability at this point, but this is stopping the clock at

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one moment, and we will have to see.

DR. A. KALLOO: We will now take a short,

10-minute break and reconvene promptly at 11:20.

[Recess.]

DR. A. KALLOO: If I could have everyone please

take their seats.

The meeting will now reconvene with an open

committee discussion. Dr. Jenelle E. Foote will give a

clinical overview of incontinence.

Dr. Foote.

Clinical Overview of Incontinence

Jenelle E. Foote, M.D.

DR. FOOTE: I am very happy to be here. I

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appreciate this opportunity to address the panel and address

guests, and I felt that today it would be important to put

the current discussions in the framework of the work that

has been done on incontinence of all sorts, not just stress

incontinence, and so what I have prepared for this morning

is a review of the evaluation and treatment of urinary

incontinence in the female.

[Slide.]

As was mentioned earlier, urinary incontinence is

a big problem affecting about 13 million Americans, most of

which are women. A quarter of these women are in this age

group, and incontinence affects 50 percent of the elderly.

[Slide.]

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There are implications in regard to incontinence

to include emotional problems, social activity, skin

problems, as well as cost, and this cost is not only in

terms of medical treatment, that that individual may get

from a physician or from a hospital or another health care

provider, but also in the use of pads and padding and

bedding that need to be changed to deal with this problem.

[Slide.]

Incontinence occurs because there is problems in

regards to the storage of urine and urinary tract,

specifically, the lower urinary tract, the bladder and

urethra.

[Slide.]

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If you can remember this little summary here, this

will help you understand many of the times when urologists

discuss continence, remember that is a function of normal

bladder function plus normal sphincteric function. You need

to have both of them working well to allow for continence.

[Slide.]

Keep in mind also that the neurologic control over

the lower urinary tract is essential to allow for

continence, hence, the problems with continence in

individuals who have neurogenic problems.

[Slide.]

In terms of the etiologies, including neurogenic

etiologies, trauma either from surgery or obstetrical

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trauma, as well as certain congenital conditions and

hormonal conditions, can be associated with incontinence.

[Slide.]

In regards to the diagnosis, the workup for the

typical urologist or other health care provider evaluating

incontinence, a good history, as well as a physical

examination is necessary, a urinalysis with a culture and

sensitivity being done if there is worry of infection, with

urodynamics being the functional test that is done in many

cases to help determine the type of incontinence and so

guide therapy.

[Slide.]

There are four basic types of incontinence, and I

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show this slide to illustrate that there is overlap, and so

the evaluation of a patient with incontinence can be quite

complex as you can have a patient with more than one type.

I am going to be talking specifically this morning about

urge incontinence, then briefly about overflow incontinence,

and lastly, stress incontinence.

I am not going to specifically talk about

functional incontinence, but suffice as to say that

functional incontinence is associated with individuals who

have problems with the habit of toileting. This includes

individuals who have physical disabilities, as well as

cognitive disabilities that make toileting difficult.

[Slide.]

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In regard to urgency incontinence, this woman's

face says it all. Essentially, an overactive bladder is

acting without the owner's permission, if you will, and

contracting, allowing for the expulsion of urine. If the

external sphincter is not competent enough to prevent the

flow of urine, if the external sphincter is tight enough to

prevent the leakage of urine, the individual can experience

suprapubic discomfort, as well as pain and a feeling or

urgency.

[Slide.]

These patients can be characterized as having the

so-called overactive bladder. When you see this term, this

refers to a situation where the individual experiences these

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symptoms without any known neurologic or metabolic cause.

[Slide.]

In terms of the treatment for the overactive

bladder or to instability or to hyperreflexia, there is a

lot of different terms that you will see used for this.

Another term is hypertonic bladder. They include the use of

pads, of course, behavioral modification, pharmacologic

therapy is the mainstay of therapy in 1999. Also, used is

electrostimulation, as well as a variety of other surgical

treatments.

[Slide.]

As I mentioned before, drugs are the mainstay of

therapy. These drugs tend to be anticholinergic and a

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spasmodic in character.

[Slide.]

The three main generically available drugs are

seen here. In the last two or three years, we have seen a

number of other drugs that have been recently developed to

cut down on the side effects associated with these drugs,

which are predominantly anticholinergic. These patients

many times have a dry mouth and constipation.

One of the newer treatments for urgency and

urgency incontinence is use of sacral nerve stimulation, and

as Mr. St. Pierre talked earlier, this procedure was

recently approved.

[Slide.]

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This form of therapy allows for stimulation of the

pelvic nerves that go to the pelvic floor.

[Slide.]

Via the S3 nerve, and in doing so, affects

incontinence.

[Slide.]

The next type of incontinence I would like to

review if called overflow incontinence. In contrast to the

previous type of incontinence, this incontinence is

characterized by a bladder that can't empty either because

there is some element of obstruction at the level of the

bladder neck or that the bladder has lost its tone and does

not push adequately to empty.

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Essentially, what empties out in this individual

is the amount of urine that exceeds the capacity of the

bladder, hence, the word overflow.

[Slide.]

In this condition, this is seen not uncommonly in

long-standing diabetes, as well as certain neurogenic

dysfunction, and in able-bodied individuals, bladder habits

that delay voiding, the so-called nurses' bladder.

[Slide.]

Treatments for this include bladder training, not

exactly as you see here, but basically, the individual is

taught or prompted to void on a regular basis.

[Slide.]

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Timed voiding for patients who are not cognitively

impaired by teaching the patient to go by their watches, of

how they feel, can be very useful for this disorder.

[Slide.]

And for individuals who cannot empty despite those

types of programs, catheterization is the preferred method

of treatment.

[Slide.]

Stress incontinence is the type of leakage that we

think about when we think about stressful maneuvers like in

this little cartoon, the woman lifting the groceries out of

the back of a car, coughing, sneezing, laughing, jumping,

there is pressure from the abdominal muscles that is exerted

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on the bladder. If the bladder is full, and the bladder

neck or supportive structures are incompetent, there can be

leakage of urine.

[Slide.]

In this condition, generally, the individual

reports small losses of urine when doing these so-called

stressful maneuvers, and typically, the individual is dry at

night or when they are not engaged in stressful maneuvers.

[Slide.]

In regards to the evaluation of stress

incontinence, one is concerned about how much pressure it

takes to open up the bladder neck, and this has been

described a number of ways. Closure pressure has been used

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to quantify this, as well as leak point pressure.

[Slide.]

In terms of the treatments, the include pelvic

floor exercise training, use of prostheses, and what I call

the patches and the plugs, as well as various surgical

options, and we are going to go over those briefly.

[Slide.]

The use of pelvic floor exercises is recommended,

and I certainly recommend it for the primary treatment in

most women presenting to me who have stress incontinence,

because you may not need to do this if the person can

strengthen the pelvic floor and decrease incidents of

incontinence.

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[Slide.]

These so-called Kegel exercises have been

rejuvenated and --

[Slide.]

-- are being done with a variety of aids to make

them more effective. This, for example, is the use of a

type of weighted cone that I call barbells for the pelvic

floor, that can be used to help make these pelvic floor

exercises more effective.

[Slide.]

In addition, the use of biofeedback and

electrostimulation can also make these exercises more

effective.

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[Slide.]

There have been a number of studies looking at the

benefit of electrostimulation for the treatment of

incontinence. If you look here under stress incontinence,

although the success rate in regards to cure is moderate,

there is a variety of improvement rates that run the gamut

from 20 to 100 percent.

[Slide.]

As regards to certain patches and plugs, I have a

couple of them here that I am showing to you, that are not

commercially available right now. The panel may be hearing

about some in the future. I do know that there are some in

commercial development.

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[Slide.]

The purpose of these devices is to stem the flow

of urine by using a device either inserted in the vagina or

in the urethra to effect continence.

[Slide.]

Next, I would like to talk briefly about something

that you may have heard about, and that is the types of

stress urinary incontinence. Classically, urinary

incontinence has been graded from a Type zero to a Type III.

You are hearing less and less of that in the literature

these days.

[Slide.]

Suffice as to say the type of incontinence that

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you have heard about the most often is the so-called Type

III incontinence, also known in today's parlance as

intrinsic sphincteric deficiency, and you heard that term

discussed at the discussion earlier today.

In terms of causes of Type III stress incontinence

or ISD, it includes previous pelvic surgery, radiation

therapy, neurogenic dysfunction, as well as other kinds of

causes to include the lack of estrogen in women who are

postmenopausal.

[Slide.]

In regards to the current thinking, again, at one

time we were very rigid and tried to put patients in one

camp or the other, i.e., patients who have Type zero to II

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stress incontinence in which anatomic malposition or

weakness of the pelvic floor supporting the bladder was felt

to be the problem, and the other camp being that of ISD Type

III incontinence or that of the dysfunctional urinary

sphincter being the cause.

What we understand now is that it is more of a

combination of the two in most patients, and so that we are,

in terms of urologists, are changing our ways in terms of

how we are approaching patients, appreciating that patients

will likely have a combination of these two types of factors

contributing to stress incontinence. I am talking

specifically about women in this regard.

Next, in regards to the typical and classic

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bladder neck suspensions that have been suggested and are

still done for the treatment of Type zero through Type II

stress incontinence, they are called a variety of different

names. Those of you in the audience may recognize the name

of some of these operations that are named after surgeons.

Surgeons are egotistical, so they like to put their names on

procedures.

[Slide.]

Just to show you what these operations try to do

by restoring the anatomy of the pelvic floor. In this

little cartoon, you can see a bladder here with a bladder

neck and urethra here in this side view of a woman's pelvis.

Note here the pubic bone and note that there is a distance

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in between the bladder neck and the pubic bone.

This distance is theoretically felt to be due to

something called pelvic relaxation or weakness of the pelvic

floor, such that the bladder neck is a fair distance away

from the pubic bone.

[Slide.]

What the surgical action attempt to do is to

restore this anatomy, i.e., to bring the bladder neck close

to the pubic bone.

[Slide.]

What I would like today is just to briefly talk

about a study that was commissioned by the AUA to look at

the long-term results. There was a question, and an

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excellent question, earlier today about what is the

long-term benefit of these different types of technologies

that are being proposed for stress incontinence, and, as

urologists, we have recognized the importance of looking at

long-term data.

[Slide.]

In this particular study, I am just going to

highlight two slides from this study. There were two types

of operations that were felt to have the best long-term

success rate. In this study, they looked at a number of

studies in the literature that were felt to be good studies,

that had some objective measures for inclusion, their

criteria, as well as success, and they found that the

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retropubic suspensions, known as the MMK's, the Birch

procedures, as well as the Richardson repairs, were felt to

have fairly good long-term success rates, about 90 percent

going at greater than 48 months.

[Slide.]

For those non-surgeons in the audience, what these

operations do is to bring the bladder neck close to the

pubic bone, as I mentioned earlier. This is a picture

showing a Birch procedure with the foot of the patient being

here, the head of the patient being here. Here is the

bladder, here is some fascia on either side of the bladder

that is being sutured up to this ligament on either side of

the pelvis, so-called Cooper's ligament.

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You can see that the bladder is being suspended by

this fascia and therefore, the bladder neck is being brought

close to the pubic bone.

[Slide.]

On the side view you can see a little bit more

dramatically in this cartoon how that is represented.

[Slide.]

In the next category of this study that showed the

procedure having the best long-term success rates was that

of the so-called sling procedure, and at 48 months you can

see this procedure had a median of probability of cure, dry

or improved, of 87 percent.

[Slide.]

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In this particular operation, a piece of fascia or

other material is placed underneath the bladder neck with

the purpose of lifting the bladder neck in addition to

restoring the anatomic proximity of the bladder neck to the

pubic bone, also giving some coaptation of the bladder neck

area and proximal urethra.

[Slide.]

The artificial urinary sphincter is a device that

has been popularized for the treatment of stress

incontinence or ISD. It is used mostly in men. In women,

there is a relatively high rate of erosion with these

devices. As you may know, this is a hydraulic device that

involves the use of fluid that is cycled through a pump

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device to a cuff that is placed around the urethra that

affects continence.

[Slide.]

In regards to the injections that we are

discussing today, the way that those are felt to work is

through a bulking action, and you saw some fairly dramatic

pictures earlier in the presentation, but in this cartoon I

wanted to just demonstrate that in the before picture there

is non-coaptation of the bladder neck and such that the

leakage or urine can be pretty significant.

[Slide.]

Where the bulking agent is used, essentially, you

fill in the gap at the bladder neck and proximal urethra,

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thereby increasing resistance at this area and affecting

continence, and as you know, there are several agents that

have been tried in the past and are currently being

investigated for the use of continence in these patients.

I would like to take any questions if there are

any.

DR. A. KALLOO: Thank you, Dr. Foote.

DR. FOOTE: Thank you.

DR. A. KALLOO: Next, we will proceed with the FDA

presentation. I would like to remind the panel that they

may ask for clarification of any point included in the FDA's

presentation, but the discussion should not go beyond

clarification.

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The first speaker for the FDA is Dr. Rao

Nimmagadda.

FDA Presentation

FDA Lead Reviewer

Rao Nimmagadda, Ph.D.

DR. NIMMAGADDA: My name is Rao Nimmagadda. I am

a chemist in the Urology and Lithotripsy Devices Branch and

the Lead Reviewer for the Durasphere PMA.

My presentation is an overview of the Durasphere

PMA and does not go into the details as the sponsor has

already made a detailed presentation. In my presentation, I

shall only outline the various aspects covered in the PMA

and point out some of the issues that are still under

review.

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[Slide.]

The PMA was first submitted in December 1998 to

document the safety and effectiveness of Durasphere, and

updated in June 1999 to include additional clinical data.

The PMA contains information about: the device description

and how the device improves or cures incontinence,

manufacturing and device specifications, preclinical testing

including a two-year dog study, clinical studies, summary of

safety and effectiveness, device labeling, post-approval

study proposal.

Let me now briefly discuss each section to draw

your attention to some important points and issues.

[Slide.]

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Durasphere is a sterile, nonpyrogenic, injectable

bulking agent composed of pyrolytic carbon-coated zirconium

oxide beads suspended in an aqueous beta-glucan carrier gel.

The pyrolytic carbon-coated beads have a size range of 212

to 500 microns. The carrier gel is approximately 97 percent

water and 2.8 percent in beta-glucan.

When Durasphere is injected submucosally in the

periurethral tissue at the bladder neck, it increases the

tissue bulk and produces coaptation of the bladder neck

and/or urethra. By increasing urethral resistance to urine

flow, this coaptation reduces and in some cases even

eliminates urine leakage.

Durasphere is formulated Advanced UroScience from

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the components, pyrolytic carbon-coated zirconium oxide

beads and beta-glucan powder received from the vendors.

The sponsors prepares the beta-glucan gel, adds

the pyrolytic carbon-coated beads to the gel to produce the

desired concentration of the beads, fills 1 ml syringes with

the material, packages each syringe and steam sterilizes the

packages.

[Slide.]

The manufacturing of the pyrolytic carbon-coated

zirconium oxide beads reproducibly according to

specifications (212 to 500 micron size range) to ensure the

absence of small particles below 80 microns by sieving the

beads and removing carbon soot on the beads by washing and

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to ensure the purity of beta-glucan gel is critical for the

safety of Durasphere.

If there are particles below 80 microns in

Durasphere, they may migrate to distant sites, such as

liver, kidney, and lung, and cause serious complications.

If beta-glucan has higher levels, that is, greater than 2.5

percent of impurities such as protein, it may increase the

risk of sensitization reaction in patients.

The carbon-coated beads account for a specific

percentage of Durasphere's volume and the sponsor maintains

the bead concentration within narrow limits. If the beads

occupy less than the specified volume, the bulking effect

per ml of Durasphere would be less than that found in the

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clinical study.

Since Durasphere is a permanent implant, it has to

be sterile and nonpyrogenic. The firm's manufacturing

procedure is designed to ensure conformance to these

specifications.

[Slide.]

Biocompatibility testing. The firm had conducted

both short-term and long-term biocompatibility studies. The

short-term studies include: pyrogenicity, Guinea pig

sensitization, cytotoxicity, systemic toxicity, hemolysis,

muscle implantation (45 days) and Ames mutagenicity tests.

These tests showed that Durasphere is not toxic.

Other tests include 7-day and 28-day dog studies, as well as

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a 2-year dog study, in which Durasphere was injected in the

periurethral tissue.

The injection sites revealed mild to moderate

granulomatous inflammation/subacute inflammation in the

7-day dog study and trace to mild granulomatous inflammation

in the 28-day dog study.

Dr. Herrera will address a possible consequence of

this inflammation in his presentation. After this initial

phase, the tissue response from the carbon-coated zirconium

oxide particles was found to be a normal tissue response to

the presence of foreign material.

The sponsor has adequately addressed any potential

concerns regarding the migration of carbon-coated beads to

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distant sites and organs, providing reasonable assurance of

the safety of these beads.

The clinical section covers various topics: study

objectives, study design, study protocol, description of

patient population, effectiveness and safety results,

summary and conclusion.

You may remember from the sponsor's presentation

that a total of 578 patients were tested for skin

sensitivity at 9 U.S. sites and 1 foreign site, and 355 were

treated. All of these patients I am referring to here are

female patients, and my presentation discusses the study

results only on females, because there were very few males.

Eighty percent of the patients treated are

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Caucasian and 19 percent of the patients are Hispanic,

primarily from the Costa Rican site. Afro-Americans

accounted for only 1 percent of the treated population.

Of the 355 patients found eligible and treated,

178 patients were treated with Durasphere and 177 with

Contigen, the control. The patients are well matched

between Durasphere and Contigen arms in regard to a number

of baseline characteristics.

The protocol required at least a 12-month

follow-up. Although several parameters, like pad weight

urine loss, incontinence episodes, change in Quality of

Life, were used to monitor the effect of treatment on the

patient's incontinence, improvement of greater than or equal

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to 1 grade at 12 months by Stamey incontinence grade scoring

system was chosen as the primary endpoint for effectiveness.

For this primary endpoint, 115 patients in the

Durasphere arm and 120 patients in the Contigen arm had

12-month follow-up All adverse events observed or reported

by patients were considered in the safety analysis.

Although there are still some issues that require

clarification or explanation by the sponsor, we are in

general agreement with the firm that the clinical

performance of Durasphere is equivalent to that of Contigen.

I would now like to draw your attention to the

following information presented in the PMA.

[Slide.]

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Skin sensitivity testing. In the skin sensitivity

test, none of the 485 U.S. patients tested positive to

Durasphere, that is, to beta-glucan. In contrast, 19 of the

93 Costa Rican patients tested positive to Durasphere in the

initial testing, but only 1 tested positive on retesting

using a revised protocol by an allergist/immunologist sent

from the Mayo Clinic.

The sponsor attributes the initial high

sensitivity rate to the desire of the Costa Rican medical

personnel to be overconservative in rating the skin test

results. The protocol used in retesting is a valid

protocol. FDA is in the process of reviewing whether there

were any differences in the purity of beta-glucan lots used

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in the testing and retesting that could have caused the

variant results.

However, based on Dr. Herrera's clinical review,

which will be presented later, hypersensitivity to

Durasphere does not appear to be a significant clinical

concern.

In contrast to the low reactivity of Durasphere,

Contigen exhibited a positive skin reaction rate of 15

percent in the Costa Rican patients, although the overall

rate of 3.5 percent observed in the U.S. patients is within

the limits of 1 to 5 percent reported in the literature for

Contigen. A potential advantage of Durasphere is that it

may not require skin testing.

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[Slide.]

In regard to effectiveness, as you have seen from

the sponsor's presentation, both Durasphere and Contigen has

the same effectiveness profile at 12 months. Sixty-six

percent improved by one grade with 31 percent reporting

dryness. Similar decrease in pad weight urine loss, and

similar decrease in incontinence episodes per week, similar

change in Quality of Life scores.

[Slide.]

Durasphere performed obviously equally well when

the improvement of incontinence grade at 12 months was

analyzed as a function of the number of treatments.

[Slide.]

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With 1 treatment, Durasphere showed 83.7 percent

improvement versus 71.4 percent improvement. In regard to

dryness, 46.9 percent dryness versus 51.9 percent.

With the 2 treatments, 54.4 percent showed

improvement for Durasphere versus 65.4 percent for Contigen.

For dryness, 21.7 percent for Durasphere versus 15

percent for Contigen.

With 3 treatments, 60 percent of Durasphere

patients improved versus 33 percent for Contigen. The

dryness rate is 20 percent for Durasphere versus zero

percent. You should note that there were very few patients

who received 3 treatments.

[Slide.]

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Issues under review regarding effectiveness.

Improvement and dryness should evaluated as a function of

baseline incontinence grade since most patients had a

baseline grade of 1 and 2. Very few patients at Grade 3.

Improvement should be evaluated as a function of

baseline urine loss by pad weight, and there is very little

data available regarding improvement and dryness beyond 12

months.

Dryness observed by Stamey incontinence grade of

zero at 12 months should be correlated with other criteria

such as pad weight urine loss, number of incontinence

episodes and change in the Quality of Life.

Did the patients who were dry by Stamey grade

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scoring have zero urine loss and zero number of incontinence

episodes at 12 months? If not, what was the average urine

loss and average number of incontinence episodes for these

dry patients?

There is also a pooling issue for the primary

effectiveness endpoint. Significant differences among

centers were observed for the primary endpoint of

improvement equal to or greater than 1 grade at 12 months.

In conjunction with significant differences found

between centers regarding a number of baseline

characteristics such as incontinence grade, pad weight urine

loss and incontinence episodes, the center to center

differences in the primary endpoint may require further

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justification for pooling.

Dr. Herrera will note in his talk that there are

of no clinical concern, these differences are not of

clinical concern.

[Slide.]

Safety/adverse events. All adverse events were

separately categorized, depending on whether they lasted

less than or greater than 24 hours. A comparison of the

adverse events lasting more than 24 hours shows that the

rates for a variety of complications, such as non-acute

retention, frequency, respiratory, and other infections,

musculoskeletal, and cardiac events, outlet obstruction,

allergic reactions were comparable for Durasphere and

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Contigen. However, as you heard before, for urgency and

acute retention, the rates were higher for Durasphere and

statistically significant.

Thirteen of the 44 patients with urgency in the

Durasphere group required medical intervention with drugs

and antibiotics.

[Slide.]

In the transient symptoms category notable rates

of hematuria, retention, urgency, and dysuria were reported

for the Durasphere group. However, these transient symptoms

do not raise significant clinical concerns. Another

positive aspect for the Durasphere is, as you will hear from

Dr. Herrera in the next talk, the KUB x-rays at 12 months on

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100 patients show that Durasphere beads were confined to the

pelvic region with no significant migration.

There are also equipment and procedure related

issues, such as needle occlusions 3.3 percent, difficulty to

inject 3 percent, and syringe occlusion 2.2 percent

associated with the Durasphere injections.

This is the current status of our review. Dr.

Herrera will now discuss the risks and benefits of the

Durasphere implant in treating intrinsic sphincter

deficiency patients.

If you have any questions, please hold them until

the conclusion of Dr. Herrera's presentation, after which

the company or FDA will address them.

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Thank you.

Clinical Considerations

Hector H. Herrera, M.D., M.P.H.

DR. HERRERA: Good morning. My name is Hector

Herrera. I am a urologist within the Urology Device Branch.

The previous speakers have done an excellent job.

Therefore, I will be very brief and only present a couple of

clinical issues that I believe warrant further discussion.

The first issue that I would like to discuss is the

demographics.

[Slide.]

Nearly all patients enrolled and treated in the

study were females, all of which were over 25 years of age.

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Since there were too few men treated to statistically

evaluate, my discussion is limited to the female population.

After my discussion, you will be asked to address this issue

as pertains to the device indication.

Regarding the racial make-up in the study

patients, there were 81 percent for the Caucasians, 18

percent for Hispanics, and only 1 percent for the

Afro-Americans. Based in the demographics of the general

United States population, Afro-Americans appears to be

under-represented. However, the clinical significance of

this disparity is not clear, but not appears a significant

issue.

Next, I would like to touch upon the issue of

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pooling that Dr. Nimmagadda discussed in this presentation.

As pointed out, differences among centers were observed for

the primary endpoint of improvement of 1 grade or more at 12

months.

Likewise, several key baseline characteristics,

such as incontinence grade, pad weight urine loss, and

number of incontinence episodes, were significantly

different between sites. While these differences are worth

noting, I believe that they are due to the natural

variability among these groups of patients, and, therefore,

are not of clinical concern.

[Slide.]

As described in the presentations of the

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manufacturer and Dr. Nimmagadda, the effectiveness of the

two products were similar at one year in: improvement of

continence 1 grade, changes of continence grade, achieving

continence, improvement in pad weight, and changes in the

number of incontinence episodes per week.

The safety of the two products was also similar,

except in the incidence of urgency and acute retention. One

possible reason for this urgency rate is the larger size of

the needle needed for injection.

The vast majority of these cases were resolved

with the administration of antispasmodics. The retention,

as mentioned by Dr. Nimmagadda, could be the result of

inflammatory reaction as was seen during the early periods

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in the dog study.

After self-catheterization the retention was

resolved on average in four days. There were no trends in

laboratory values noted for either Durasphere or Contigen

patients or differences seen between the treatment groups.

In the 12-month KUB, no evidence of significant

migration was observed in Durasphere patients at 12, 18, and

24 months.

Dr. Foote's detailed overview of the treatment of

urinary stress incontinence was very illustrative. As a

reminder of the present modalities of treating, I am

presenting this slide.

[Slide.]

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Treatments are behavioral, pharmacological,

periurethral bulking agents, and surgical.

[Slide.]

The advantages of the Durasphere are: no need for

skin test prior to injection, no apparent risk for

hypersensitive reactions, to the coated beads are

non-absorbable, the beads are not prone to migration due to

their large size, significantly less volume of Durasphere as

compared to the control material was injected. However, I

do not believe that this difference in the amount of

material injected clinically is significant.

[Slide.]

My main concern is the durability of the implant

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past one year is largely unknown at the present time.

This is an issue which the panel will be asked to

address during your deliberations.

[Slide.]

Durasphere has equivalent effectiveness to the

only legally marked injectable bulking agent and similar

safety profiles. There is an increased risk of urgency and

retention, both of which were resolved. This difference

must be balanced against Durasphere's benefits.

The fact that the injection of both products can

be performed as an outpatient is an important feature for

the patients considering a surgical approach for their

incontinence.

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For urologists, the injection procedure for

Durasphere is familiar. This fact is evidenced by the short

learning curve observed in this study.

The beads permanently reside at the injection

site. Therefore, reabsorption may be less of an issue.

However, some Durasphere patients needed reinjection, and

this re-treatment rate was similar to that of the Contigen.

As I stated earlier, the long-term effectiveness of

implantation of these non-resorbable beads is not yet known.

No skin testing is necessary, and there is less

risk for long-term immunological complications.

In light of all the available treatments for

stress urinary incontinence, Durasphere's risk-benefit ratio

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appears to be comparable.

Thank you very much.

DR. A. KALLOO: Thank you.

Are there any questions from the panel at this

time?

DR. DIAMOND: I have two questions for Dr.

Nimmagadda and I have one for Dr. Herrera.

Last week in Detroit, we had a patient --

actually, we didn't have a patient, it was another hospital

-- had a patient, a 57-year-old delivered a baby, and while

most of the patients in this group are menopausal, the age

range went into the premenopausal range. So, it caught my

eye that when you looked at the biocompatibility testing,

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reproductive toxicity was not mentioned.

Was that done and it wasn't on the slide?

DR. NIMMAGADDA: I can't really -- the

biocompatibility testing I already mentioned, but the tests

showed Durasphere to be nontoxic.

DR. DIAMOND: What about reproductive toxicity?

DR. NIMMAGADDA: Yes.

DR. DIAMOND: Was that tested, to your knowledge?

DR. NIMMAGADDA: Right.

DR. DIAMOND: And did not show any?

DR. NIMMAGADDA: No.

DR. DIAMOND: The second question was in the

presentations given today, and what I saw here, I didn't see

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any breakdown on patients who either had had, on the outcome

specifically, the patients who had a prior suspension

procedure, of which there were about 10 or 15 percent in

each group, or any breakdown as a function whether women had

had hysterectomies.

Were there data like that available for your

review?

DR. NIMMAGADDA: Maybe the company can answer that

question.

DR. A. KALLOO: Company, do you have the

information on the question about previous surgery?

DR. HOLCOMB: I am not sure that we have really

looked that, so that we can't address what impact, if any,

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prior hysterectomies or prior suspensions would have caused.

They weren't exclusions for the study, so to the extent that

they were represented in the normal patient population, they

would have been included in the study.

DR. DIAMOND: I would think they would be sizable,

and I would think that would be something worthwhile looking

at, because it may have impact one way or the other on

outcomes that you observed.

DR. HOLCOMB: Only through, you know, as a

surrogate, we have examined the effect of age on outcomes,

and didn't find any effect there.

DR. DIAMOND: That's a good issue, but it's

probably a different one in my mind.

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The last question I had for I think probably more

for Dr. Herrera, was it started out each group had about 230

patients, and ends up -- sorry -- about 170 in each group,

and ends up each group having about 120 patients.

So, basically, there is only one year follow-up on

about two-thirds of the original patients in the group or

one-third of the patients were lost, and primary endpoint

analysis and secondary endpoint analysis not available.

Are there ways to try to statistically correct for

that, or how do you -- when you do a statistical analysis, a

relevant statistical analysis, how do you control for that

large loss of patients in your study population?]

MR. BAXLEY: I am John Baxley. I am Acting Branch

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Chief in the Urology and Lithotripsy Devices Branch.

I think that a lot of those patients hadn't

reached 12-month follow-up, and if the firm could comment on

that.

DR. HOLCOMB: Well, that is exactly right. They

weren't really lost, they just haven't reached the follow-up

time.

DR. DIAMOND: Maybe you can enlighten me then

about the rate of enrollment. I thought the study started

in '96, is that right?

MS. PETERSON: Yes.

DR. DIAMOND: I don't know when enrollment closed

and you put together your package, but it would seem

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one-year follow-up, you should have had a lot more patients,

unless you had a ballooning of enrollment at the very end of

the study.

DR. HOLCOMB: The study was not atypical in that

respect. It started slow and ramped up with the majority of

the patients in the latter part of the study. As has been

alluded to earlier, some of the patients actually we have

two-year data on, so those early patients in the study, we

do have long-term follow-up on.

There were also two phases for the study, and that

should be pointed out. The first group of patients that

were done, were done in the early part of the study, prior

to starting the pivotal, so only a small number are out at

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that longer period of time.

DR. STEINBACH: A question for Dr. Herrera. Is

there a controlled clinical trial in the literature on men

and Contigen or not?

DR. HERRERA: Yes, there is, but there were not

enough patients in this particular trial for evaluation.

DR. N. KALLOO: Excuse me. Dr. Herrera, I had a

question about your advice about not skin testing. My

concern would be certainly if this is done in America, and

you do it on more African-Americans, and there is a history

of keloid formation with skin healing, does that apply, or

does anybody know if that applies internally, as well, and

would they tend to get more or a different type of healing

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with the biosphere as compared to, say, whites?

The other question is would that apply to Asians

or other groups of Hispanics, as well? I am wondering if

excluding skin testing overall, in all groups, is

necessarily a good idea.

DR. HERRERA: I cannot answer that question.

Really, in this study, we didn't have enough patients,

Afro-Americans. As you can see, there was only 1 percent of

the population, so it is something that is a question for

the panel to decide.

DR. A. KALLOO: Just from the company, was there a

reason why there was such a disparity in the accrual? Was

it because of the sites of recruitment? Do you know?

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DR. HOLCOMB: I don't think so. I think it is

difficult. There was an attempt to enroll a cross-section

of patients, as you can see from the description of where

the centers were, there is a variety of geographic

locations, urban/rural. It just happened that way, and

unfortunately, happens that way in many studies.

DR. N. KALLOO: I had one other question. You did

KUBs only? Were there any chest x-rays that were done to

look for migration?

DR. HERRERA: Yes, there were patients that they

had the KUB and chest x-ray.

DR. N. KALLOO: So, it was both, the KUB and --

DR. HERRERA: Yes.

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DR. A. KALLOO: Any other questions?

DR. N. KALLOO: I have one more question, I am

sorry.

My question is sort or directed to the Grade III

stress urinary incontinence, and I notice that in Appendix

A, they have about 40 percent achieved a Grade zero, and

maybe Dr. Foote could address this, as well.

What is the cure rate or roughly the cure rate for

Grade III stress incontinence, with, say, a sling procedure?

DR. FOOTE: That's a good question, because I

think when we look at new technology, we have got to compare

it to what we have got in regards to traditional technology,

and the cure rates for Grade III incontinence, I can't quote

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specifically, but as you can see from the meta-analysis that

was done at the AUA, all comers, keeping in mind that most

of those patients did have Grade III incontinence, was about

80, 85 to 90 percent, so that the success rates in regards

to sling would be higher.

DR. N. KALLOO: And from what I can recall, at our

institution, most people with sling procedures are actually

out in less than 24 hours. I am not sure if they are all

outpatient, if you consider that outpatient, but I think for

billing and DRG, I think less than 24 hours is considered an

outpatient procedure, so actually, the injection is done as

an outpatient procedure and also the slings at our

institution I know are done as an outpatient procedure.

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DR. FOOTE: That's true. Certainly, the

postoperative recovery period would be longer for an

individual having a sling although there are some newer

technologies that are allowing the slings to be done with

less and less morbidity on the part of the patient.

The postoperative period to return to full

activity may be on the order of three to six weeks depending

on the type of procedure, the type of methodology used for

performance of the sling.

DR. N. KALLOO: So, for surgery it would be three

to six weeks, and for the injection, are they going right

back to work?

DR. FOOTE: I can only speak -- I am not familiar

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with the current study product. The company may want to

respond. I am familiar with the use of GAX collagen, and

these patients are back to work the following day.

DR. SNYDER: I just want to point out, if I may,

that you are comparing success rates of Grade zero on these

patients, but we are talking about, in the index, five

patients, and two of five patients, so the sample is

extremely small, and so it really isn't a comparative group.

It's not fair to compare 200 sling patients to 5, because

here, two of five achieved a Grade zero, giving you 40

percent. So, I think the sample size really doesn't make

that comparison quite fair.

MS. NEWMAN: Also, the success rate in what you

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showed was cure, dry, or improved, correct?

DR. FOOTE: Yes.

MS. NEWMAN: So, we are not still talking about

dryness in that end either, okay?

DR. SNYDER: In the literature, the cure means

many different things.

MS. NEWMAN: That's right.

DR. SNYDER: And that's fair, yes.

DR. HOLCOMB: Chairman Kalloo, we do have someone

here that might be able to shed some additional light on the

issue of ethnic background and immunogenicity. If I could

introduce him, he is Dr. Roy Ritz, who may be familiar to

some of you. He is a former head of the Immunology Panel,

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Advisory Panel for the FDA.

DR. A. KALLOO: If you could please state your

name.

DR. RITZ: Yes, it's Ritz [phonetic]. I am an

emeritus Professor of Microbiology and Oncology at the Mayo

Clinic. I am emeritus Executive Director of the King Faisal

Specialist Hospital in Riyadh, Saudi Arabia, and I have no

financial interest in the company, but a desire to have my

hotel room paid and perhaps get a Ferrari.

As to the question you addressed, Dr. Foote, about

the skin testing, the first thing is that nonliving, aqueous

antigens in blacks and whites, in my experience of about

over 30,000 patients, probably shows no significant

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difference. A difference would be in the living antigen,

such as smallpox, where you do see keloid formation.

In the case of this particular product, the issue

of immunogenicity and antigenicity arose by someone either

misreading or misunderstanding a paper on beta-glucan

written by Nick DeLusio in the seventies, and no theoretical

or practical immunologist would suspect that glucan would be

immunogenic, but the company has done a series of studies

which show that it is not. The skin test material would not

in any event contain the beads since their immunogenicity

are antigenicity is not a question.

The beauty of having a nonimmunologic reactive

material, such as this, and I can tell you this from many of

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our oncology studies, is that you eliminate a two-day period

that brings patients and brings extra cost to the patient,

extra expense of personnel to put down the skin test, read

them, when very often, and unless someone is fairly expert,

there is a lot of ambiguity to begin with.

So, I think the cost saving and the economic

aspects, as well as the lack of nuisance factor to both

physicians and patients is a positive aspect of this.

DR. A. KALLOO: Could you explain the discrepancy

with the Costa Rican patients in terms of the initial

testing and then subsequent?

DR. RITZ: It was my view when I looked at the

data sent to me by E-mail, I guess, or maybe before I left

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Minnesota, that the responses were being wildly overread,

and I think that is reflected in the rate of responses read

in Costa Rican patients for Contigen, which is about three

times my understanding of what has been in the literature,

and I might point out that how can I, in the fifties, were

the first to demonstrate antigenicity to tropocollagen, so I

think there was reading, and Dr. Adele Taylor, from Mayo,

went and reviewed those patients, and the only one that she

did find who was positive, she ascribed a variant of the

hypersensitivity to, which is her opinion.

My opinion is that that doesn't exist, but the

opportunity to address one patient that seemed to have what

I believe is a factitious or an idiosyncratic reaction would

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have been to take a biopsy. So, we don't know about that

one patient, but I believe that the non-physician reader of

the test was extravagant.

DR. A. KALLOO: Was that one patient of African

origin?

DR. RITZ: I am not able to tell -- Hispanic? I

don't know if it was African origin or not.

DR. A. KALLOO: Any other questions?

DR. NIMMAGADDA: I am clarifying the question

about the genotoxicity testing. I believe they did, but I

want to doublecheck. I don't want to be on the record that

they did, but even if they didn't, considering that these

are a pyrolytic carbon-coated zirconium oxide beads, and the

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other component is beta-glucan, I don't see any reason or

rationale of requiring genotoxicity testing. That is what I

wanted to say.

DR. DIAMOND: I am sorry. Genotoxicity is a good

question. Reproductive toxicity is what I was asking.

DR. A. KALLOO: Dr. Hawes.

DR. HAWES: I would sort of like some advice,

maybe from Dr. Foote. There were a few people who were in

this study reported that were Type III, and you mentioned in

your meta-analysis that most of the people undergoing a

sling operation were Type III.

Is there a reason to believe that these

implantable bulking agents will be less effective in Type

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III patients, and should the panel, in your opinion,

consider that group separately? Is there not enough data in

the Type III's, I guess specifically?

DR. FOOTE: That is a very good question. It is

also a very complex question, and I am going to go back to a

slide that I showed earlier in the discussion that I had to

show that as clinicians and as researchers, we are impressed

that there is a lot of overlap, you know, a pure Type III

patient, you know, is really in the minority now in terms of

what we are thinking now as opposed to what we thought years

ago.

So, when you talk about a patient who is pure

intrinsic sphincteric deficiency without any problems with

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prolapse, for example, that patient is really in the

minority now in terms of what we are thinking, and because

of that, I think it would be difficult and I think

inappropriate to try to pin down a therapy based upon a

designation which as time goes on is going to be used less

and less.

In regards to one of the points of information

that I found interesting was the fact that for these groups

of patients -- and by the way, that we have also found for

Contigen -- is that the leak point pressure, which is a

quantification of the amount of pressure that it takes to

allow your leak from the bladder was not significantly

different between responders and non-responders, and you

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might say, well, if leak point pressure can let you know to

what degree the individual has incontinence, is that

predictive, well, that has not been really predictive

either.

So, you know, it would be wonderful if we did have

something in regards to a diagnostic test or in regards to

something in regards to the history to be able to allow us

to predict which patients were going to be responders and

which patients would not be responders, but I am afraid that

the level of our understanding at this point in regards to

the diagnosis of the different classes, if you will, of

incontinence, is not to the point that it really would be

beneficial to do so at this time.

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DR. HAWES: As a point of clarification for the

company, you are asking for approval for all, irregardless

of the grade scores?

DR. SNYDER: If I may just address your previous

query, one of the things that makes discussion, as Dr. Foote

stated just now, difficult is that one creates a mixup

between grade and type, and using two different systems and

measuring two different processes.

In reality, when one does a study of stress

urinary incontinence due to intrinsic sphincter deficiency,

one is including 100 percent of the patients are Type III

patients, so Type III would include all the grades of what

we are grading.

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So, all patients in the study who received

implantation are Type III patients. Now, within the Type

III intrinsic sphincter deficiency, we have different

gradations of how much activity causes it.

So, we are looking at a new definition of

intrinsic sphincter deficiency at a time when Type III

didn't -- there was no intrinsic sphincter deficiency for

Type III. We now acknowledge or are in general agreement

that Type III urinary incontinence includes stress urinary

incontinence with mild activity, with moderate activity, and

severe.

So, the Grade III of Type III are what you

classically I think are talking about, but they are actually

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all Type III patients. It is my feeling that the company is

talking about all types of Type III urinary incontinence.

DR. HAWES: But my question was on the grade. I

understand the Type III. There were very few Grade III in

your trial, very, very few, and my question is are you

asking, are you making any discrepancy about their grade in

terms of the efficacy of your treatment.

DR. SNYDER: No.

DR. HAWES: So, you are asking for approval for

all grades within Type III patients?

DR. SNYDER: Yes.

DR. HAWES: Again, I would bounce it back to you.

That seems reasonable?

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DR. FOOTE: Well, in regards to that specific

point, I personally feel the numbers were not high enough to

contraindicate the use of this therapy for patients with

those most severe types of incontinence, and generally, what

happens is that the market tells the tale. I mean as the

numbers get more, and you have more investigators using it,

it will become apparent what grades, if you will, of

incontinence are best treated by this device.

DR. HOLCOMB: Dr. Hawes, maybe I could just add

one additional comment. There is a table in Appendix A, the

very first table, which shows improvement by baseline grade.

DR. HAWES: I was looking for that.

DR. HOLCOMB: Page A-1. Two things are worthy of

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note. The classification in the Grade II or Grade III, as

Dr. Foote mentioned, had in our patients a significant

overlap. There were people who fell sort of in the gray

area potentially between, and could have gone one way or

another in terms of the grade that they were assigned.

The other thing that you will notice there is that

even among those people that were classified as the most

severe in Grade III, they had comparable success rates, all

small numbers aside, they had comparable success rates to

what we saw with Grade II.

The last thing that I think is worthy of note in

that table is that that effect was also present in both

groups, both Contigen and Durasphere had a similar profile.

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DR. A. KALLOO: Any other questions?

DR. DIAMOND: Could I just get clarification, were

genotoxicity and reproductive toxicity tests done?

MS. PETERSON: Genotoxicity was done in our

biocompatibility.

DR. DIAMOND: But not reproductive toxicity?

DR. HOLCOMB: Related to ability to become

pregnant?

DR. DIAMOND: And outcome of fetuses that are

conceived or that are carried by a woman who has these

implants in place.

MS. PETERSON: No, we didn't do that.

DR. DIAMOND: Or I mean animal equivalent studies,

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obviously.

DR. HOLCOMB: Those studies were not done.

DR. BENNETT: Jenelle, you may want to magnify on

this, but it is rare for a urologist to treat a childbearing

person with a bulking agent.

DR. A. KALLOO: But it is also important to know

whether or not that --

DR. BENNETT: But it is not commonly done because

you don't want to deliver a child through the vagina with a

bulking agent because you are going to let it go every which

way, and it will destroy whatever effect you are going to

have on the treatment.

MS. NEWMAN: But you have a cross-section of quite

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of quite a few young subjects in the study. Your age span

here was these came to urology offices, and they decided

that they should enter into the study, so it seems like that

there are urologists who are doing that, correct, on

childbearing women?

DR. FOOTE: Yes, correct.

MS. NEWMAN: And not just in the 50s, which is an

aberrant, I hope, but women who are 40 or maybe 30, who are

coming in with this type of incontinence, that may have

babies, and they decided they would get a bulking agent.

DR. FOOTE: Yes. As a matter of fact, and I will

speak for my clinical experience, for women who are still

interested in having children, of childbearing age, a

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bulking agent may look more attractive than doing something

like a pubovaginal sling, although there would be the

possibility that either procedure may be affected by a

vaginal delivery, clearly, the effect on the surgical

procedure, like a retropubic suspension or pubovaginal sling

would be greater than in a bulking agent.

DR. HOLCOMB: Just one specifically in the

inclusion/exclusion criteria, Ms. Newman, it was a patient

who had been pregnant in the past 12 months or was scheduled

to become pregnant in the succeeding 24 months was excluded

from the study.

MS. NEWMAN: But there are women who become

pregnant that don't schedule it. Okay?

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DR. A. KALLOO: Any other questions?

DR. N. KALLOO: Is there any indication that this

would prevent surgery in the future if it was unsuccessful?

DR. SNYDER: There is no concern regarding this.

Prior bulking agents, most urologists have fairly good

experience in using a more conservative therapy, such as

bulking agents, and then going in and either doing a sling

procedure with autologous or non-autologous tissue, as well

as other procedures, such as an artificial urinary sphincter

in men post-prostatectomy, and there appears to be no

contraindication for this and no further fibrosis that

occurs.

DR. N. KALLOO: So, basically, similar to the

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collagen.

DR. SNYDER: Very analogous.

DR. A. KALLOO: We will now take a lunch break for

45 minutes and return at 1:15.

[Whereupon, at 12:32 p.m., the proceedings were

recessed, to be resumed at 1:15.]

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AFTERNOON PROCEEDINGS

[1:20 p.m.]

DR. A. KALLOO: Good afternoon and welcome back.

Panel Discussion

We will now reconvene the open committee

discussion with the FDA charges; while this portion of the

meeting is open to public observation, public attendees may

not participate except at the specific request of the panel.

We have had a fair amount of discussion. I think

Dr. Diamond has a couple more questions he wants to ask, and

then we will move along to the specific questions that we

are charged with by the FDA, and then answer these questions

in turn.

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DR. DIAMOND: I would presume after the agent is

placed, if you did a pelvic exam, you would be able to feel

the bulking agent when you palpated the interior vaginal

wall vaginally, is that correct?

DR. SNYDER: I would presume so.

DR. DIAMOND: Is there any discomfort women have

with intercourse, any dyspareunia once it has been done, was

that reported by any of your patients?

DR. A. KALLOO: Would you step up to the

microphone, please.

DR. SNYDER: You can if you inject and implant

enough of the device, you can feel it through the anterior

vaginal wall. We had no reports of dyspareunia, and

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patients were asked if they had pains, vaginal pains at all,

and this was not reported, so this was not a concern for us.

DR. DIAMOND: Presumably, all the surgeons that

were participating in the study had lots of experience with

prior bulking agents that were on the market. For surgeons

that were not that experienced with those, is there going to

be a steep learning curve there?

DR. SNYDER: Tina, can you just describe the

population of surgeons? Not all surgeons were

overqualified, some had minimal experience with bulking

agents. Can you just define the groups a little bit?

DR. DIAMOND: Would less experienced physicians,

if you had some, did they have greater failure rates?

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MS. WITTCHOW: We did not see that. Our Costa

Rican physician had no experience with Contigen whatsoever,

and he had, as you see in the report, had a nice success

rate with both products.

DR. SNYDER: I must say personally I who have had

huge experience with bulking agents was in the middle of the

pack, and sometimes my stuff looked good, and it was just --

I had a 0.64, and I was right in the middle of the pack of

all sites.

DR. DIAMOND: The last question I had is when

actually were patients randomized? First, they were given

the forms, they saw who was included and excluded, you did

the skin testing, but when in the process were the patients

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actually randomized to the treatment or control groups?

DR. SNYDER: That's a great question. Patients

were randomized in the operating room. Patients were

prepared for surgery or if the procedure was done in the

office, they were prepared at the time.

A monitor was present for every single

implantation case, a sealed envelope was present, and at the

time the patient was up in position, the seal was broken,

and at that point we knew, the implanting surgeon knew what

he or she was going to implant.

DR. DIAMOND: You were ready to go with either

one, you had them both available, and whichever one?

DR. SNYDER: Exactly.

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DR. DIAMOND: That's great.

DR. SNYDER: And just normally, we would do more

than one procedure often on the same day, so we would have

all product available.

DR. N. KALLOO: These were all urologists?

MS. WITTCHOW: We had one gynecologist. That is

our Seattle site.

DR. A. KALLOO: Thank you.

The first question is based on the patient

population enrolled in the clinical investigation of the

Durasphere Implant and reported in the PMA, should the

intended use statement be limited to adult women, that is,

exclude men and/or patients under 21 years of age?

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Question 2. Given the rates of improvement in

effectiveness outcome measures and the rates of adverse

events observed during the clinical trial and reported in

the PMA, does the panel believe that the Durasphere Implant

has a favorable risk/benefit profile?

Question 3. Is the post-approval study outlined

in the PMA adequate to document the long-term safety and

effectiveness of the Durasphere implant?

Question 4. Should physician training be required

prior to use of the Durasphere Implant?

Question 5. Are the proposed "Directions for Use"

accurate and comprehensive?

We will go back to Question 1. What we will do is

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to have each panel member comment on the question, at the

end of which Dr. Donatucci will summarize the panel comments

at the end of each question.

We will start with Dr. Foote on the first

question.

DR. FOOTE: I personally feel that the product

should not be restricted. Although the study did not

include a significant number of male patients, there

certainly may be male patients in the clinical situation

that that may potentially benefit from the device, and I

would say the same thing for pediatrics. It does not appear

to me that there had been any contraindications that I could

see for use in the pediatric age group.

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DR. A. KALLOO: Dr. Diamond.

DR. DIAMOND: I would make basically the same

observations, but I would probably come to the opposite

conclusions. I would think since there is a paucity of data

on men and a paucity of data on children, that its use

should be restricted to not include those groups. Once it

were approved, if it were approved for adult women, a

physician and a patient would have the option of going ahead

and using it off-label, and I think that would probably be a

better way of going than approving its use for something

where we don't have data or a large enough volume of data to

show that it is safe and effective.

That might be something in a postmarketing study

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that if the company wanted those specific indications, they

could enroll additional patients to do that.

The other caveat that I would throw in here is

about the use in women who are either of reproductive age or

desiring further reproductive potential, and whether in

those individuals, there ought be labeling to that degree or

even excluding its use in women in those situations who

potentially desire future childbearing is one way of

phrasing it, or otherwise who are of reproductive potential,

natural reproductive potential.

DR. A. KALLOO: Ms. Newman.

MS. NEWMAN: I don't think there is data in men,

but I really do think it can be used in adult women and men.

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I am not sure about pediatrics because I don't think there

is enough data, and they don't have enough long-term data on

this product yet.

But I agree that I think its potential in

premenopausal or childbearing women is of concern, and if

women, even though they may not be pregnant in the next 12

months, but can possibly become pregnant, you know, in the

next so many years, I have a concern about this injection.

DR. A. KALLOO: Dr. Vertuno.

DR. VERTUNO: I have no objection to it being used

in men, but I think it should be clearly labeled that what

modest data there is shows it to be less effective. I would

like to see some data before it is approved in the pediatric

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age group. I am concerned about that.

DR. STEINBACH: I do not object to using it in

men, but I agree with Dr. Vertuno that the labeling should

reflect that it doesn't seem to be as effective.

DR. A. KALLOO: Dr. Bennett.

DR. BENNETT: Yes, I concur to what Dr. Foote has

already said.

DR. A. KALLOO: Dr. Hunter, to comment on this

question.

DR. HUNTER: Handle it with labeling.

DR. A. KALLOO: Dr. Deitrick.

DR. DEITRICK: I would agree with what has already

been stated. I think that we need to handle with labeling

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as far as men are concerned, and I would still, until we had

more documented evidence, that I would restrict it to those

women of reproductive age.

DR. A. KALLOO: Dr. Hawes.

DR. HAWES: My opinion would be that we should

manage the male population with labeling, that it should not

be restricted. I personally don't think that it should be

approved for the pediatric population since there is no

data, and I am concerned about the long-term situation with

this.

I would agree that in terms of women of

childbearing age, my own personal feeling is that it would

be managed by labeling, that it shouldn't be automatically

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restricted, but that labeling should be appropriately made

in that regard.

DR. N. KALLOO: I agree with what everyone else

has pretty much said, that labeling should take care of the

male population. It can be used, but definitely mention

that it is not effective, and again long-term studies before

it is approved for pediatrics.

DR. A. KALLOO: Dr. Donatucci, can you summarize

the comments of the panel?

DR. DONATUCCI: Well, it appears that the panel in

summary feels comfortable with handling the paucity of data

in men by addressing that in the labeling. I think, in

summary, that the panel feels that the pediatric population

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should not be included in the intended use because of the

paucity of data, and at least my read of the panel here is

that there is a little bit of a difference in terms of women

with reproduction.

Several panel members feel fairly strongly that

that should be stated, that it should not be used in that

population until data are available. Others feel that that

precaution can be included in the labeling.

DR. DIAMOND: I was probably the most vocal about

the women of reproductive age, but the way you phrased that

was actually not the way I was intending. The way you

phrased it was that women of reproductive age should not be

using it, and I am not in favor of that. I am just in favor

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of the indication being in women who are beyond reproductive

age as opposed to putting the negative there for that group

because I don't know anything that says it is bad, I just

don't know anything, this is not an issue.

DR. A. KALLOO: Dr. Hunter.

DR. HUNTER: I would handle it a different way. I

would say there is no data on it, which is what you see in

the PDR on any drugs, and so forth. There is no data on it,

so safety has not been proven.

DR. DONATUCCI: I would point that actually that

is exactly how it is handled in the directions for use. It

says there are no data.

DR. A. KALLOO: Do you need to resummarize that

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last point?

DR. DONATUCCI: I think the feeling of the panel

is that the problem in terms of reproductive women is a

problem that is addressed in the labeling, that the

indication should be for women who are beyond reproduction,

but the precaution could be handled in the labeling.

DR. BENNETT: Craig, could you repeat what your

concept is concerning pediatric age group? The reason I

bring that up is bulking agents are often the court of last

resort for urologic disasters in the pediatric age group,

and very small amounts sometimes produce a remarkable

improvement in symptoms, and there is no immunologic data

that we have seen that there is any danger in giving this

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product to anybody.

So, I just want to hear what you --

DR. DONATUCCI: Well, let me first give you my

opinion, which I didn't give it, I just summarized what the

panel felt. My personal opinion about pediatrics is that

there are two issues. First, the bulking agent can be used

for incontinence in the pediatric population. There is also

a potential use as a bulking agent for reflux.

DR. BENNETT: But the indication is ISD, so that

is different.

DR. DONATUCCI: But that has to be clear.

DR. BENNETT: Well, it will be clear in the

labeling I would assume. It's not an anti-reflux product.

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DR. DONATUCCI: You want me to restate --

DR. BENNETT: I just want to hear what you think

the opinion of the panel is concerning the pediatric. I

would also like to know the pediatric age group, I would

like you to define the age of a pediatric age group, as

well.

DR. A. KALLOO: Dr. Kalloo, any comments?

DR. N. KALLOO: Pediatrics can go all the way up

to 21, but again, you can buy beer at 18, and you can vote

at 18, and you can use sometimes puberty as the cutoff. If

you have got an adult body, then sometimes you can do adult

things. I know for certain hospitals, if they are over a

certain weight, they can be 14 and 110 pounds, but if you

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are over a certain weight, you can go on the adult ward.

So, the definition sort of can be skewed.

DR. A. KALLOO: What about the use of bulking

agents in the pediatric --

DR. N. KALLOO: For the use of bulking agents, I

would probably say puberty.

DR. DONATUCCI: But the summary of the panel

appears to be -- and this is my concept of the summary of

the panel -- I will restate it now taking into account what

Dr. Diamond said.

The indication should be for adults and there

should be no comment about excluding children. There should

be a comment about the absence of data with children.

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DR. A. KALLOO: Good.

DR. HUNTER: And pregnancy.

DR. DIAMOND: Women desiring.

DR. A. KALLOO: Question 2. Given the rates of

improvement in effectiveness outcome measures and the rates

of adverse events observed during the clinical trial and

reported in the PMA, does the panel believe that the

Durasphere Implant has a favorable risk/benefit profile?

Dr. Foote.

DR. FOOTE: I think yes although the rates of

bladder irritative symptoms and urinary retention were

higher in the Durasphere arm, those effects were

self-limited and did resolve in a reasonable period of time.

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DR. HUNTER: Yes.

DR. A. KALLOO: Dr. Diamond.

DR. DIAMOND: In most cases I don't think there

was much difference with the control group other than two

items that were mentioned, so I would say that it does, yes.

MS. NEWMAN: Yes.

DR. VERTUNO: Yes.

DR. STEINBACH: Yes.

DR. BENNETT: Yes.

DR. DEITRICK: Yes.

DR. HAWES: Yes.

DR. N. KALLOO: Yes, for the short term.

DR. DONATUCCI: Yes as an individual, and yes for

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the committee. In summary, I think the panel believes the

answer to the question is that the profile is favorable and

in favor of it.

DR. A. KALLOO: Question 3. Is the post-approval

study outlined in the PMA adequate to document the long-term

safety and effectiveness of the Durasphere implant?

Dr. Foote.

DR. FOOTE: I would have to defer on this because

I didn't have the chance to read the entirety of that, and I

would like to review that while you are going around.

DR. HUNTER: I would match the control. Whatever

the control did historically with the FDA -- and I can't

remember what that was -- but I would match that.

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DR. DIAMOND: I have a couple thoughts. First of

all, I think it is hard to know, to be able to answer this

until we know for sure what the labeling and full

indications that we are going to approve are going to be.

But with that caveat, I think 188 patients is

probably too small. I think it also needs to be segregated

into different populations, such as women who have had prior

surgical procedures, women who have had hysterectomies, and

perhaps some other groups, as well, that if we had further

discussion, we can identify.

DR. A. KALLOO: Ms. Newman.

MS. NEWMAN: I think it is adequate.

DR. VERTUNO: I think it's adequate, as well, but

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I would like to see some data on the populations that we

have discussed.

DR. A. KALLOO: Specifically?

DR. VERTUNO: Men, women of childbearing age, and

young people.

DR. STEINBACH: I agree with Dr. Vertuno.

DR. BENNETT: I wasn't privy to the post-approval

study because I am the industry rep, but I would not

recommend what Dr. Hunter recommended because that study,

number one, was designed because of the potential

immunologic aspects of GAX collagen, and that does not

apply, and the bar to the Contigen study is a totally

different study. It's looking for rheumatologic disease, et

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cetera, so it certainly has no application whatsoever to

this product. So, those are my comments.

DR. DEITRICK: I think it's adequate.

DR. HAWES: I think it is adequate with again the

comments that were made regarding the specific groups that

we are concerned with, i.e., the question of whether they

should address the pediatric population and women of

childbearing age. Otherwise, I think it is adequate.

DR. N. KALLOO: I think my concern still lies with

those patients who have total incontinence, and I think we

need more numbers and more long-term data on those specific

patients.

DR. FOOTE: After my review of the PMA, I would

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say yes with the comments that were made earlier.

DR. DONATUCCI: I think it's adequate personally

and I think that, in summary, in terms of the safety

question, I think the panel's feeling is that the

post-approval study is adequate, but there is definitely a

feeling that the panel would like to see more data on

subpopulations in that study.

DR. A. KALLOO: Would you just go over the

subpopulations?

DR. DONATUCCI: The subpopulations that have been

mentioned earlier are patients with Grade III incontinence,

we previously mentioned -- that's in terms of effectiveness,

we want more data on the Grade III population in terms of

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safety -- we previously mentioned pediatric population and

women of reproductive age.

DR. STEINBACH: And men.

DR. DONATUCCI: Men, yes.

DR. HUNTER: Dr. Donatucci, so you think there

should be more study, a long-term study on patients that

really aren't even indicated for use of the drug, you are

asking the company to do studies that they didn't really try

to get approval for?

DR. DONATUCCI: I was just summarizing the panel.

DR. HUNTER: Oh, okay.

DR. DONATUCCI: In fact, I think it's adequate as

it is personally.

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DR. A. KALLOO: Okay. Question 4. Should

physician training be required prior to use of the

Durasphere Implant?

DR. FOOTE: My answer is yes, I think as an

initial requirement, physicians should have evidence of

training and expertise in the use of the cystoscope, and

then there should be some documentation of their ability to

perform the injection. Although many urologists are

familiar with the use of Contigen, for example, not all

physicians are, and I think if a physician does not have

that type of experience, some type of training should be

documented.

DR. HUNTER: Well, I guess I am biased because I

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am a urologist, but this is a very easy technique and maybe

if they could look at a video, let's say they looked at a

video, that would be sufficient. It's not a difficult

procedure.

DR. DIAMOND: I would be in favor of training.

MS. NEWMAN: I think that if they are trained in

cystoscopy, I feel that is adequate, too.

DR. VERTUNO: I will defer to my urologic brethren

on this one, but I think anybody trained in urology should

be able to do this quite readily.

DR. A. KALLOO: Dr. Diamond.

DR. DIAMOND: Part of the reasons I think training

is required is that all these procedures, once this product

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were to be approved, would not necessarily be done by

urologists. Many might be done by gynecologists, and while

there are some urogynecologists who are extremely familiar

with other bulking agents and maybe others who are not, and

for them I think training aids would be important.

I think another question that might come up at

some point in the future, would this be a thing that a

physician assistant or a nurse practitioner might do, and

again, then, the level of training of individuals who are

going to be utilizing the device, I think is important.

DR. A. KALLOO: But specifically, we are asking

about physician training, number one, and secondly, do you

think that the ability to do cystoscopy qualifies in itself

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as was mentioned? Dr. Diamond, do you?

DR. DIAMOND: Well, I would like someone to be

able to do more than diagnostic cystoscopy.

DR. FOOTE: And I would agree, because there are a

lot of, for example, gynecologists who do do diagnostic

cystoscopy, but are not familiar at all with doing things

therapeutically through cystoscope, and I think that having

a requirement for -- and it's hard to be specific about

that, but clearly, for someone who has not been trained in

Contigen, for example, there were specific training

protocols for Contigen injection, for example, and if

someone had passed that, I think that that would be

adequate, but if someone did not go through that, I think

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that it would be prudent to make sure that the success rates

that are experienced in the community are the same ones that

were experienced in the study to have some type of training

documented.

DR. STEINBACH: I have no competence with this

question.

DR. BENNETT: I would hate to see us revisiting

what happened probably seven or eight years ago with the

anger and the angst that occurred both at the AUA level and

the company level with the Contigen issue.

I think this can be dealt with, with labeling.

The great majority of urogynecologists and urologists in the

United States are trained, and I would just leave it that

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the product should be used by physicians trained in the use

of bulking agents.

DR. DEITRICK: I would agree with that because if

you exclude the urogynecologists, there is not too many

local gynecologists doing this. Secondly, they are usually

curtailed somewhat by the delineation of privileges in their

local hospital bylaws.

DR. DIAMOND: Unless it's done in the office

procedure room.

DR. DEITRICK: Those same gynecologists probably

would not venture into that, but, yes, there is all kinds of

people.

DR. HAWES: My thought would be that it should be

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done by people who are trained in therapeutic cystoscopy and

any further, quote, unquote, "training," can be handled by

booklets, videos, et cetera.

DR. N. KALLOO: I agree. In the labeling, it

should say somebody who is trained in therapeutic

cystoscopy.

DR. DONATUCCI: I agree with Dr. Kalloo's comment,

and I think the majority of the panel feel that this can be

handled in the labeling with a statement saying that it

should be used by people familiar with therapeutic endoscopy

although we have dissension.

DR. A. KALLOO: Okay. The final question is: Are

the proposed "Directions for Use" accurate and

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comprehensive?

DR. FOOTE: Yes.

DR. HUNTER: Yes.

DR. DIAMOND: I am going to have to pause as I

read through it again after all of today's discussions.

DR. A. KALLOO: Ms. Newman.

MS. NEWMAN: I think they are accurate, but we

don't get to talk about the patient information brochure, I

guess, is my question.

DR. A. KALLOO: No. The patient information

brochure -- what is the question? I am sorry.

MS. NEWMAN: I just wanted to comment on something

that I want them to put in, we can't do that?

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DR. A. KALLOO: Sure. Do you want to make a

comment?

MS. NEWMAN: They have got to say that -- they

don't answer the question will I feel pain, and I want them

to answer that question. It isn't answering that question

on this brochure. Okay?

DR. A. KALLOO: Okay.

DR. VERTUNO: Yes.

DR. STEINBACH: Yes.

DR. BENNETT: Yes.

DR. DEITRICK: Yes.

DR. HAWES: Yes.

DR. N. KALLOO: Yes.

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DR. DONATUCCI: Yes.

DR. A. KALLOO: Can you summarize?

DR. DONATUCCI: I think the summary of the panel

is the answer to the question is yes.

DR. A. KALLOO: Now, Dr. Donatucci, if you can do

a complete summary of the panel's recommendations.

DR. DONATUCCI: I think the summary concerning the

five questions raised, basically, in the labeling we wish to

see that the indication to be for intrinsic sphincter

deficiency in patients over 21 years of age with a further

statement saying that there are no data in the pediatric

population, there is few data in men, and we have no

specific data concerning the safety in women in pregnancy.

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It was felt that the post-approval study is

adequate as designed, however, we want you say on the

effectiveness side, further information on the patients with

Grade III incontinence, and on the safety side, segregated

data looking at the pediatric population, women of

reproductive age and also in men, and the directions for

labeling are adequate as presented to the panel -- let me

rephrase that -- directions for use are adequate as

presented to the panel.

DR. A. KALLOO: Physician training?

DR. DIAMOND: Yes. And it was felt that the

physician training issue would be handled also in the

labeling with the statement that the device should be used

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by physicians familiar with therapeutic endoscopy.

DR. A. KALLOO: Thank you.

Before we take a vote, if anyone wishes to address

the panel, please raise your hand and you may have an

opportunity to do so.

MR. SEGERSON: Dr. Kalloo, before you go into

that, I would like to make a clarification. We outlined

five specific areas that we wanted you to address, but we

are also asking you to deliberate and make recommendations

on the whole premarket approval application.

So, if there is any issue that you would like to

raise, we would like to hear them especially if it affects

your recommendation on safety and effectiveness.

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DR. A. KALLOO: Could you repeat specifically,

other than the five questions, what would you like us to do?

MR. SEGERSON: You are not limited to those five

questions. When Diane brought up that other issue, I just

wanted to let you know that you are welcome to bring up

anything else that is of concern.

DR. A. KALLOO: Panel, here is your chance. If

there are issues that you are concerned about other than the

five questions that we were asked, here is your chance.

DR. HUNTER: What is the shelf life?

DR. A. KALLOO: There is a question with respect

to the shelf life. If one person can come up to the podium,

please.

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DR. HUNTER: Six months?

MS. PETERSON: Our current shelf life is at six

months.

DR. HUNTER: Temperature problems, storage?

MS. PETERSON: None.

DR. HUNTER: Obviously, we are going to make this

less expensive than the alternatives, please.

DR. A. KALLOO: Any other issues or questions?

MS. NEWMAN: The thing about the patient brochure

again, I think you need to answer the question will I

experience pain, because I don't think you are answering

that, and I do think that women experience pain even if it

is from the anesthetic, and you, evidently your adverse

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effects was over time.

The other question I just was wondering, why did

you do it with PVR less than 100, where we in the AHCPR, we

used a higher number. Was there any reason, you just wanted

to be real safe? And whenever you talked about acute

retention, then, what was it, a total not able to void, or

what did you see then?

DR. SNYDER: To answer your first question, some

definitive number has to be ascribed to bladder volume.

There has never been a study which associates post-void

residual with disease state, and so somebody who carries a

post-void residual of 250 cc, who goes to the bathroom once

every four hours, and has no urinary tract infection nor any

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deterioration of renal function is a perfectly normal person

although a finding of elevated post-void residual is

present.

So, one needs to just remove the patients who are

the neurogenics, and we created 100 cc as being a very

critical, and overly critical number to make sure that we

weren't anywhere near patients who had neurogenic bladders.

MS. NEWMAN: Then, when you did your acute

retention, what were your figures there then?

DR. SNYDER: Acute retention was actually defined

somewhat loosely. It included the patients who completely

could not urinate and the patients who felt, that they had

the sensation of incomplete bladder emptying.

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Had we used a pure diagnosis or a pure symptom

complaint of urinary retention, absolute no urination, our

numbers for urinary retention would have been much, much

lower, but we included the patients in a sense of fairness

who said, you know, I just don't feel like I empty my

bladder well, and I feel like I have to go to the bathroom

again in 15 minutes as urinary retention.

So, we tried to actually be very critical on our

post-procedural results.

DR. A. KALLOO: Thank you. Any other comments or

issues?

[No response.]

DR. A. KALLOO: Before entertaining a motion

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recommending an action on this PMA, Mary will remind the

panel of our responsibilities in reviewing today's premarket

approval application and of the voting options that are open

to us.

MS. CORNELIUS: Before you vote on a

recommendation, please remember that each PMA has to stand

on its own merits. Your recommendation must be supported by

the data in the application or by publicly available

information. You may not consider information from other

PMA's in reaching your decision in this PMA.

The Medical Device Amendments to the Federal Food,

Drug, and Cosmetic Act, as amended by the Safe Medical

Devices Act of 1990, allows the Food and Drug Administration

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to obtain a recommendation from an expert advisory panel on

designated medical device premarket approval applications

that are filed with the agency.

The PMA must stand on its own merits and your

recommendation must be supported by the safety and

effectiveness data in the application or by applicable

publicly available information.

Safety is defined in the Act as reasonable

assurance, based on valid scientific evidence that the

probable benefits to health (under the conditions on

intended use) outweigh any probable risks.

Effectiveness is defined as reasonable assurance

that, in a significant portion of the population, the use of

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the device for its intended uses and conditions of use (when

labeled) will provide clinically significant results.

Your recommendation options for the vote are as

follows:

1. Approval - if there are no conditions

attached.

2. Approvable with conditions. The panel may

recommend that the PMA be found approvable subject to

specified conditions, such as physician or patient

education, labeling changes, or further analysis of existing

data. Prior to voting, all of the conditions should be

discussed by the panel.

3. Not approvable. The panel may recommend that

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the PMA is not approvable if the data do not provide a

reasonable assurance that the device is safe, or, if a

reasonable assurance has not been given that the device is

effective, under the conditions of use prescribed,

recommended, or suggested in the proposed labeling.

Panel Deliberations and Vote

DR. A. KALLOO: We will now consider the panel's

report and recommendations concerning approval of P980053

Advanced UroScience Durasphere indicated for the treatment

of stress urinary incontinence due to intrinsic sphincter

insufficiency together with the reasons or recommendations

as required by Section 515 Part C(2) of the Act.

The underlying data supporting a recommendation

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consists of information and data set forth in the

application itself, the written summaries prepared by the

FDA staff, the presentations made to the panel, and the

discussions held during the panel meeting, which are set

forth in this transcript.

The recommendations of the panel may be approval,

approval with conditions that are to be met by the

applicant, or denial of approval.

Dr. Donatucci, will you summarize the panel

discussion and make a motion?

DR. DONATUCCI: Yes. In summary, the panel finds

that there is a favorable risk-benefit analysis for the

Durasphere implant; that the indications for Durasphere

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implant should be in patients with intrinsic sphincter

dysfunction over 21 years of age, with further

qualifications that there are minimal data in men and no

data available in the pediatric age group and reproductive

women; that the device should be used by physicians who are

familiar with therapeutic endoscopy; further, the panel

feels that the post-approval study is adequate as designed,

but would like to see specific data in terms of

effectiveness on patients with Grade III incontinence and

specific data in terms of safety in the pediatric

population, the male population, and women of reproductive

age.

Finally, I would like to move that the panel

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approve the PMA with the conditions as I have just

summarized.

DR. A. KALLOO: Will all those voting members in

favor of approval with the conditions as stated by Dr.

Donatucci, raise their hands.

Before you vote, I need someone to second the

motion by Dr. Donatucci.

DR. HAWES: Second.

DR. A. KALLOO: Good. Now, may I have all the

members who are in favor of the motion as proposed by Dr.

Donatucci to raise their hands, please.

[Show of hands.]

MR. SEGERSON: Would you announce the count?

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DR. A. KALLOO: Can you raise your hands once

more?

[Show of hands.]

DR. A. KALLOO: Eight in favor of approval of the

motion.

DR. DIAMOND: Seven. You can't vote, I don't

think, unless there is a tie.

DR. A. KALLOO: Seven then in approval.

How many members in denial of the motion that has

been set forth?

[One hand raised.]

DR. A. KALLOO: One.

Dr. Diamond, could you put forth your reasons for

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denial?

DR. DIAMOND: Sure. In principle, I agree with

most of the statements that were reviewed. I find, though,

that I cannot vote for approval with that inclusion of males

in that group, when just reading from what it says, there

has not been a reasonable assurance that the device is

effective in that group, and not only is there only a

paucity of data of effectiveness or of safety, but even in

the introduction that the company has provided to us, the

very last sentence is that based on anatomical and

etiological differences, it is expected that treatment

outcomes would be gender specific.

So, despite lack of efficacy data, the company's

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acknowledgment and presentation to us that there is

difference in mechanisms, the vast majority of the members

of the panel have recommended that it be approved for use in

men.

I would rather see it not be approved for use in

men and let a physician decide to do that if he or she so

chooses.

Other than that, I think the safety profile, the

efficacy profile is equivalent to the control group, and

would be in favor of its approval.

DR. A. KALLOO: Starting with Dr. Hunter, could

you please give your reasons for approval as we go around

the panel.

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DR. HUNTER: The safety and efficacy was supported

by the data. I continue to be impressed by what a good job

our agency people do in preparing the information for us,

and I think it was a well done study, and I think that what

the labeling issue does, it states that there is not enough

information on men, women of childbearing age, and pediatric

patients. So, you are not saying that it is approved for

that use or that group, and you are not telling people how

to practice medicine either.

DR. DIAMOND: A point of information. If the

product is approved, is that not approving it for those

groups?

DR. A. KALLOO: We are making recommendations to

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the FDA. This is the recommendation.

The next voting member.

DR. VERTUNO: I think the safety has been

demonstrated. I also think efficacy has been demonstrated.

I think the remaining questions can be adequately handled in

the labeling.

DR. STEINBACH: I think the safety and efficacy

has been demonstrated.

DR. BENNETT: The only comment I have is

concerning the male issue. I think that physicians who

don't treat males with post-prostatectomy incontinence

should probably not be making decisions on issues related to

that disease, which is very specific.

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There are many males who respond to bulking

agents, and denying them what is really the only option --

DR. A. KALLOO: I am sorry, Dr. Bennett. Are you

a voting member?

DR. BENNETT: I am not a voting member.

DR. A. KALLOO: The comments are just for the

voting members who approve. Sorry.

DR. BENNETT: I am sorry.

DR. DEITRICK: I agree with the other panel

members that approve.

DR. HAWES: I agree, as well. I think safety and

efficacy has been shown, and I am comfortable with the male

issue.

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DR. N. KALLOO: I agree with the others, and just

to sort of bring in what Dr. Bennett said, I think that if

you have a person, even though it is not necessarily

approved for that person, but it might be the safest and

best option for that patient, whether they are a male or a

pediatric patient, and the safety and efficacy profiles have

been good based on the data that we see, I think that that

should be up to the physician and the patient to discuss,

and it should be an option.

DR. DONATUCCI: I voted approval because, one, I

think the safety and efficacy data as presented warrants

such an approval, with the qualification that we have

minimal data in men.

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I would also say the reason I am comfortable with

that is because this is not the first bulking agent.

Urologists have vast clinical experience with bulking agents

in the radical prostatectomy patient, and so the physicians

who will be using it in that population are familiar with

limitations of bulking agents in that population.

So, I don't feel that there is an undue -- I

really feel there is no risk really in going ahead the way

we have done.

DR. A. KALLOO: Based on the majority position,

the recommendation of the panel is that the motion is

carried with the stipulations as stated by Dr. Donatucci.

This concludes the reports and recommendations of

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the panel for Advanced UroScience Durasphere.

Thank you.

We will have a 10-minute break before we move on

to the second portion of the session.

[Recess.]

DR. A. KALLOO: Welcome back. I would like to

call to order for this session of the meeting to discuss

revisions to the Draft Guidance for Preparation of PMA

Applications for Testicular Prosthesis.

I would like to note for the record that the

voting members present constitute a quorum as required by 21

C.F.R., Part 14.

We will being the open committee discussion with

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John Baxley presenting the recommendations for revisions to

Draft Guidance for Preparation of PMA Applications for

Testicular Prosthesis.

Mr. Baxley.

Open Committee Discussion

John H. Baxley

MR. BAXLEY: Good afternoon. I am John Baxley, a

biomedical engineer in the Urology and Lithotripsy Devices

Branch. I am before you today to present some preliminary

thinking within the agency regarding changes to our clinical

data recommendations for testicular implant PMAs.

We currently have a guidance document in effect

regarding PMA submissions for testicular prostheses, the

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clinical data recommendations contained within that guidance

are general to any design.

The aim of my presentation this afternoon is to

propose clinical data recommendations for three particular

designs of testicular implants: solid elastomer, elastomer

shells filled with saline, and elastomer shells filled with

silicone gel.

The goal of developing these design-specific

recommendations is to establish clinical testing

recommendations which are least burdensome to manufacturers,

and at the same time sufficient to demonstrate the safety

and effectiveness of each of these particular device

designs.

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Before proceeding further, I want to emphasize

that the information being presented are only our

preliminary thoughts, which have not yet evolved to the

stage where they can be written down as draft guidance to

the industry or public.

Therefore, since these thoughts are in the infancy

of their development, I eagerly and openly invite the

panel's comments on this matter. I also want to note that

we are only proposing changes to the clinical testing

section of the guidance document.

A significant portion of this document addresses

preclinical testing regarding material chemistry, toxicity,

and mechanical characteristics, which we do not intend to

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alter substantially. After today's recommendations, we will

develop and issue a draft guidance document for public

comment following the agency's internal "Good Guidance

Practices" as a Level 1 document. We hope to have this done

in the fall. Ultimately, we foresee this updated guidance

document supplanting the March 1993 guidance that is

currently in place.

Before jumping into our proposed clinical testing

scheme for testicular prostheses, I feel that it is

necessary to understand the regulatory history of these

devices as well as the clinical recommendations section of

our current guidance document.

After the Medical Device Amendments in 1976,

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testicular prostheses were classified into Class III. By

law, this classification meant that FDA would eventually

require testicular implant manufacturers to submit safety

and effectiveness information regarding their device in PMA

applications unless the device is first down-classified.

These devices were not down-classified, so in

January 1993, FDA issues a proposed regulation calling for

PMAs. Following publication of this proposed regulation,

FDA issued the March 1993 guidance document of which you

each have a copy, and presented it to the panel in April.

Although the proposed regulation and the guidance

document were applicable to all device designs, both

documents contained detailed testing recommendations

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specific to the silicone gel-filled design as this was the

predominant type of testicular implant on the market at that

time.

After reviewing the comments received on the

proposed rule and noting that no petitions for

down-classification were received, FDA issued a final

regulation in April 1995 requiring PMAs for all testicular

implants.

At the same time, however, each manufacturer

ceased production of their testicular prosthesis. Since no

PMAs were received, there have been no legally marketed

testicular implants in the U.S. since 1995.

Although several companies have since proposed

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clinical investigations of new testicular implant models

that do not contain silicone gel, these trials were either

not started or proceeded much slower than expected due, in

part, to difficulties in applying the clinical

recommendations of the March 1993 guidance with its heavy

emphasis on silicone gel-filled designs.

With this regulatory history in mind, let me

briefly describe the clinical study recommendations of the

March 1993 guidance document.

The clinical study objectives recommended in the

guidance are to demonstrate the safety and effectiveness of

the testicular implant when used for cosmetic replacement of

a missing testicle.

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The document recommends that safety be evaluated

through assessment of all complications related to the

implant, including any potential material-related adverse

events. The guidance document primarily discusses this

issue of "material-related adverse events" in terms of the

potential toxicity of silicone gel and polyurethane foam

coating. Unlike silicone gel, however, polyurethane foam

was only briefly used as a coating of testicular prostheses,

after which it was discontinued following reports of

increased infection and tissue reaction.

Regarding the effectiveness endpoints, the

guidance document recommends evaluation of the implant's

cosmetic effect, either by the physician or patient, as well

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as assessment of the patient's "psychological well-being,"

which is more appropriately referred to today as "quality of

life."

As for study design, the guidance document only

recommends that studies be prospective using an appropriate,

concurrent control population. Likewise, specific sample

sizes are not stated; rather, the document states that the

number of patients enrolled should be statistically

calculated.

The recommended follow-up duration prior to PMA

approval is five years or physical maturity, whichever is

later.

Post-approval follow-up is also recommended,

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although the sample size and duration of follow-up are not

specified. The recommended objectives for this

post-approval study are to assess the rates of any longer

long-term complications, such as rupture, revision, and

material-related adverse events.

Lastly, the guidance document makes general

recommendations to manufacturers on the design of an

epidemiological study to evaluate the connection between

testicular implants and material-related and other long-term

adverse events, which could be submitted either in support

of PMA approval or in lieu of the stated post-approval study

recommendations.

Having summarized this background information, I

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would like to go over the proposed changes to the guidance

document's clinical study recommendations. In general, our

proposed changes involve the following concepts:

First, development of design-specific clinical

recommendations. As stated at the outset of this

presentation, we would like to device clinical study

recommendations for each of the specific designs that

manufacturers are most likely to propose for market.

Two designs that we believe are likely to come

before the agency are solid elastomer implants and

saline-filled designs. Although silicone is the elastomer

material that we would most likely expect to see used in

each of these designs, other polymers could be potentially

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be used.

The third design that we believe should be

included in our revised guidance document is the elastomer

shell filled with silicone gel. While we currently don't

have an indication that manufacturers are interested in

pursuing PMA approval of the gel-filled design, we feel that

it should be considered since this was the dominant design

during the seventies and eighties and is still used abroad.

Since polyurethane coatings were rarely used in

the past, we will not specifically address them in the

revised guidance document. At this point I want to briefly

make a distinction between the solid and the gel-filled

devices.

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In designing the solid device to feel as natural

as possible, some manufacturers use a softer consistency

elastomer for the implant's core, which is less cross-linked

than the external surface of the device. Since at some

degree of cross-linking the distinction between a soft

elastomer and a gel blurs, our future guidance will define

the minimum material characteristics that can be considered

a solid elastomer.

For the purposes of today's discussion, however, I

propose that we just assume that any material used in a

solid device will not flow in the event of implant rupture,

whereas, a gel filler material will.

The second general concept is reliance on the

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literature. We have reexamined the available literature on

testicular implants to determine what is and what is not

known regarding the safety and effectiveness of each of the

various designs.

While published information is not sufficiently

complete to support either PMA approval or

down-classification of any particular device design, there

is a significant amount of information regarding the

surgical technique and short-terms risks and benefits which

can be included in each PMA a supplementary information to

confirm the validity of the clinical results.

The last general concept in these recommendations

is that patients should serve as their own control. Since

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there is no alternative treatment for cosmetic replacement

of a missing testicle, baseline control should be

recommended for the clinical evaluation of all device

designs.

Now, for the specifics. For PMA approval of the

solid elastomer prosthesis, we proposed manufacturers submit

data on 50 patients followed for a minimum of six months.

Since there is information available in the literature

regarding the implantation technique and acute effects of

solid and gel-filled testicular implants, and assuming that

this information is equally applicable to the solid design

that I described earlier, which we believe it is, the

objectives of this study would be to simply confirm that the

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proposed device requires similar surgical technique and has

a comparable short-term adverse event profile.

Of course, if the implantation procedure or

clinical results deviate significantly from those reported

in the literature, a larger clinical trial will be needed to

sufficiently characterize this information for the labeling.

Following approval, we recommend that the

manufacturer collect one-year follow-up data on 50 patients

to assess the incidence of adverse events after the early

post-implantation period, such as erosion or migration.

For the saline-filled testicular implants, we

recommend that PMA approval be based on a minimum of 100

patients followed for six months. As with the solid design,

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the objectives of this study should be to confirm that the

implantation technique and short-term adverse event profile

is similar to that described in the literature for

gel-filled and solid devices.

However, since the saline-filled device will

likely require unique device handling, filling, and

implantation procedures, and could potentially be associated

with different rates of rupture or other adverse events as

compared to the gel-filled and solid designs reported in the

literature, we believe that 100 patients should be followed

to provide higher statistical confidence for each measured

endpoint than what we are currently recommending for new

solid implants.

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Again, if the reported results deviate

significantly from the literature, a larger clinical trial

should be performed. Following approval, we recommend that

the manufacturer collect five-year follow-up data on 100

patients to assess the rates of long-term adverse events,

primarily rupture and revision.

Alternatively, the manufacturer could choose to

maintain a patient registry to record information on the

rates of rupture and revision. We believe that these

additional post-approval study recommendations are warranted

due to the absence of published information on saline-filled

testicular implants.

For approval of a silicone gel-filled testicular

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implant, we recommend that PMAs contain the results of 100

patients followed for 12 months. As with solid devices, the

study objectives should be to confirm that the implantation

technique and short-term adverse event profile are similar

to that described in the literature.

However, since this design carries the additional

risk of rupture with associated potential material-related

adverse events as compared to the solid design, we believe

that a minimum of 12 months of follow-up data should be

obtained premarket.

As with the proposed study design for

saline-filled devices, we believe that the proposed sample

size of 100 patients is necessary to provide adequate

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statistical confidence for the key safety endpoints.

Following approval, we recommend that the

manufacturer either follow 250 patients for 10 years to

document the rupture, revision, and long-term adverse event

rates, or maintain a patient registry to record this

information for all patients.

The objectives and follow-up duration proposed for

these post-approval recommendations are designed to

precisely evaluate the rate of rupture and the effects of

subsequent release of silicone gel into the body, and is

consistent with the agency's post-approval study

recommendations for breast implants.

The remainder of our clinical study

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recommendations are relatively straightforward. As in the

current guidance document, we believe that the effectiveness

of the testicular implant is best evaluated by physician

assessment of the cosmetic effect, and assessment of patient

satisfaction and quality of life.

However, we recognize that assessments of patient

satisfaction and quality of life are typically only valid

for adults and older teens. Therefore, for younger

subjects, this information may need to be obtained from

parents or guardians and analyzed separately.

We still plan to recommend that the safety of the

testicular implant be assessed through analysis of all

reported adverse events. However, we propose removing the

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recommendations on the design of epidemiological studies, as

they would not be practical to perform due to the limited

numbers of patients receiving this implant.

This concludes my presentation. At this point I

would like to turn the discussion of these proposed changes

to the panel. But before I do so, let me take this

opportunity to answer any questions regarding my

presentation.

DR. A. KALLOO: Any questions?

DR. DONATUCCI: Let me ask you first you said

earlier that you hadn't changed the -- I was there in March

of 1993, and I remember the preclinical testing

requirements, which were rigorous. I have two questions.

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One, fortunately, six years have passed, there is a large

body of data now, and the anxiety attendant to 1993 has

subsided to a certain extent.

If the material is the same as the same material

that is used for the breast implant for example, do they

have to repeat all that stuff?

MR. BAXLEY: Referencing the biocompatibility

data, for instance, of the material in another application,

that was used in another --

DR. DONATUCCI: I mean it is just a different

anatomic site, it's the same thing, but it's a different

anatomic site.

MR. BAXLEY: Right, we would consider whether that

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was valid to do, and would probably take that

biocompatibility data or take that assurance of

biocompatibility based on approval of some other

application. That is certainly an option.

DR. DONATUCCI: Secondly, we heard earlier a

presentation from FDA about the registry. There is a lot of

experience with the gel-filled prosthesis. How many adverse

effect complaints relative to rupture of a testicular

gel-filled prosthesis have come in to FDA over the 20 years

that they were available?

MR. BAXLEY: There are on the order of tens, not

many, relative to, say, the adverse event reporting for

breast implants.

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DR. DONATUCCI: A final question. Is the process

that led to classification as Class III, they were included

in the 1976 law because they were an implant basically, a

permanent implant, in 1976, all of them were automatically

Class III with the provision that at some point, FDA would

ask for a PMA. Is that how --

MR. BAXLEY: Yes, but it wasn't just because it

was an implant. There were specific risks raised regarding

adverse tissue reaction that were raised by the panel that

classified the device.

DR. DONATUCCI: But you also said that no requests

for reclassification arrived. Does that mean there is a

mechanism to ask for reclassification?

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MR. BAXLEY: Yes, a device that is in Class III

can be down-classified regardless of whether it was

pre-amendments or not. I mean this device existed prior to

1976, which is why it is a pre-amendments device.

DR. DONATUCCI: But you can't do that, that has to

come at a request of someone?

MR. BAXLEY: That is a petition from the public,

which could include --

DR. DONATUCCI: Does it have to be for an existing

device? In other words, do the people who had a device at

that time have to request that this should be reclassified,

or is it a category of devices?

MR. BAXLEY: Oh, no, you request the category, not

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one particular.

DR. BENNETT: John, have you had any --

MR. BAXLEY: Oh, and FDA can initiate a

reclassification, too.

DR. DONATUCCI: You can initiate it.

MR. BAXLEY: The case of the lithotripter that you

heard about last year, that was FDA initiated.

DR. A. KALLOO: How did you get to the sample

sizes?

MR. BAXLEY: Sample sizes are based on the comfort

level with the confidence intervals on the adverse events

that we would expect to see from the literature, so for a 5

percent adverse event rate, we know the confidence interval,

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and that is a comfort level on that confidence interval.

DR. BENNETT: John, has the FDA been in contact

with the one company that used to make testicular prostheses

or is this an internal process?

MR. BAXLEY: Right now this is right off the

press, and so it is before we have put it out for public

comment. The public comment will follow immediately after

this.

DR. BENNETT: I mean if there is no interest from

the point of view of the sole manufacturer, isn't it just

kind of a -- or are you looking to the future?

MR. BAXLEY: We are looking to the future and are

hopeful this will stimulate interest.

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DR. HAWES: Assuming these are done now, what is

happening now?

DR. DONATUCCI: They are not done now.

DR. HAWES: They are not done. There have not

been any done since 1995.

DR. BENNETT: If the child or an adult wants a

testicular implant today, they go to Europe.

DR. HAWES: Are you serious?

DR. DONATUCCI: That's not entirely true. We, at

one of our grand rounds recently, presented a product that

is a silicone block that can be used as a testicular

prosthesis coming from Europe. I forget the company that

makes it.

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DR. FOOTE: I would like to make a comment on

that. My partner put one in, and will never put in another

one. It just doesn't feel real.

DR. DONATUCCI: Fine, but I was referring to Alan

that you don't have to go to Europe, Europe has come here,

and as I understand it, because it is not a "testicular

prosthesis," but a silicone block, it doesn't fit into this

discussion today. It's semantics.

DR. BENNETT: So, Jenelle, what do you do?

DR. FOOTE: My partner had an experience in using

one of these things, and it didn't feel real, it felt like a

rock.

DR. BENNETT: Like the old ones used to feel.

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DR. FOOTE: Yes.

DR. DONATUCCI: In fact, Alan they have already

been shaped.

DR. FOOTE: Yes, they are shaped, but it doesn't

feel good.

DR. HAWES: So, we went from 4,000 per year before

1995, to zero, none.

DR. BENNETT: Yes.

DR. N. KALLOO: I did a literature search, and in

Ontario, they are using them, and they actually were

reviewing their data, old data, this is from '93, but they

are doing some old data, and they used the gel-filled, and

they actually had rupture in those, who had significant

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trauma, so they sort of went over their profile for rupture,

and a lot of these were in transsexuals, male and female,

and one was in a bicycle rider, and another was in somebody

who did various things to excite himself.

So, they ruptured under extreme conditions. Now,

there is an article that is from the Netherlands, from

Amsterdam, that came out in February, and they are using the

-- which one are they using -- I believe they are using the

solid ones, but with sort of the less cross-linking, which

makes them softer, but they have had no evidence of any

complications whatsoever, but they are still being used, but

not in this country, because -- you know, Canada and Europe.

DR. STEINBACH: The problem with devices of this

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kind is we have trouble convincing the public and maybe

ourselves that there is any benefit -- I am just saying, so

this is what I am saying, that he is proposing not a

controlled trial where it's just, you know, how you felt six

months ago, to how you feel now.

I think we really ought to allow the manufacturers

to be creative as to what might be a control group. One

suggestion I will toss out, and I certainly wouldn't require

it, is that if it was like a jock strap, you know, that was

purely external, and was not an implant, might serve as a

control group.

DR. DONATUCCI: In terms of satisfaction you mean?

DR. STEINBACH: Yes.

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DR. DONATUCCI: Obviously not in terms of safety.

DR. STEINBACH: But in terms of satisfaction, and

because of the perception in the public, I mean there will

be adverse events, and do the benefits justify it.

DR. DONATUCCI: I would say first there is a

population out there that is waiting for something. I get

calls frequently, requests frequently for this, so there is

a demand out there. However, it is low, and in a sense, we

talked earlier today, FDA mentioned kind of an orphan device

equivalent to an orphan drug, and this is essentially that

situation because there is a demand, but it's not that

large, never will be.

DR. A. KALLOO: I wonder, too, about the numbers

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that you are requesting, is this going to be doable with the

amounts of the population. I have no idea. I guess it's a

question I am putting to the urologists.

DR. DONATUCCI: Is the study doable from a company

point of view or from just accrual of patients?

DR. A. KALLOO: Just accrual of patients.

DR. DONATUCCI: I think, yes, I mean 50 patients

is doable.

DR. HUNTER: Yes, it's doable.

DR. A. KALLOO: I guess we should go on to the

clinical presentation, and then consider more questions.

Next, Dr. Naida Kalloo will give a status report

on current management of testicular implants and will lead

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the discussion of the FDA charges.

Naida Brooks Kalloo, M.D.

DR. N. KALLOO: I want to start this off by saying

that a lot of people will know a lot more than me about all

this stuff, and this is less than 24 hours notice that I am

doing this, so I just wanted to sort of make that clear, and

again, a lot of this will be repetitious.

As I mentioned before, implants were first

introduced in the sixties, and were introduced as rock-hard,

solid silicone rubber tips to give a prosthesis that went

over like a lead balloon.

Then, over time this gel-filled testicular

prosthesis was introduced in 1972 by Dow Corning. There

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have been several cross-linking changes made between '72 and

'88, and there are at least four other companies that make

them - Mentor and some other ones that were making them at

that time.

The indications for a prosthesis in the

prepubertal population would be a person who is born without

a testicle, perinatal torsion, some intersex disorders that

require gonadectomy because of the risk of tumors later on,

tumors, both benign and malignant, and then post-surgical

atrophy after hernia repairs and after orchidopexies.

Post-pubertally, patients who have Klinefelter

syndrome, who have very small, hard testicles like them

replaced for something that is more appropriate, and female

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to male transsexual operations, peripubertal torsion, and

again for tumors.

In most cases, the surgical procedure is either an

inguinal, an inguinal scrotal, or a scrotal approach for

implanting the procedures or implanting the testicular

prosthesis.

Complications from historical data, from the

literature, include wound infections, discomfort from the

devices, inadequate size at puberty for those who are

implanted prepubertally, rupture again with extreme force,

wound dehiscence, and extrusion through a dehisced wound.

Also, I would include on here migration to an extrascrotal

position.

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In 1992, right around the same time that we were

going through all the hoopla with the breast implants, the

AUA had a position paper and basically indicated that

silicone, gel-filled testicular prostheses should not be

used, however, they stated that the use of silicone

elastomer-filled implants may be considered when the

benefits to the patient outweigh the possible risks.

Right about the same time, Dow Corning suspended

their production of testicular implants right after the AUA

had their position paper.

Now, in the literature again, mostly associated

with breast implantations, they were concerned about

systemic disorders, and in the literature, there is

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absolutely no evidence that testicular implants are

associated with any systemic abnormalities. There is one

paper again, like I mentioned before, in Ontario, there were

34 males. There was a mean follow-up of at least five years

postoperatively, and there were no systemic disorders noted

that could be related to the silicone.

Again, in the current literature, again, from the

Netherlands, in February, an article mentioned that they use

the silicone elastomer envelope of highly cross-linked

semisolid medical grade, silicone elastomer filling, and

none of the patients had any complications from that.

In those that were ruptured, they mentioned

various ways of identifying the rupture with both ultrasound

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and MRI, and they went into a lot of those details, but what

they found is that, unlike the gel-filled prostheses before,

these prostheses did not spill the contents either with

rupture or with puncture of the envelope.

In essence, I think right now, people are being

very creative with how they are putting in testicular

implants. I know that Dr. Kogan, who is sort of the liaison

with the AAP, is doing a mentor-sponsored study, and they

are supposed to come up with about 267 patients, but with

all the problems going on, they are unable to get the

adequate numbers to get those patients for approval.

So, that is one thing that is actually going on

right now. Other than that, I know that plastic surgeons

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often use tissue expanders, and those are silicone based,

that you fill with water.

DR. A. KALLOO: Any questions?

DR. DONATUCCI: So, there is a trial ongoing at a

single site in the pediatric population?

DR. N. KALLOO: That is my understanding based on

information that I received today, but I have put them in

with tissue expanders, that are used by plastic surgeons,

and you can get them to shape them any way you want to, and

you just call the company, and they will shape them in an

ovoid shape, and you fill them with saline.

I have done it for people who want two big

testicles, and I have had no complications. Of course, that

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is anecdotal, and I have put them in sort of a peripubertal

male who was, you know, sort of a petite type of male, and

was always being pushed around, was always being kind of

knocked around, and his level of self-esteem came up tenfold

once he had a matching pair because then he wasn't, you

know, One Eye, and all the other sort of things that he

mentioned he was being called.

So, I think you are going to get a lot of

anecdotal studies about that, but certainly I don't think

any one place is going to have a large number of these

particular patients, especially with those indications.

There just isn't one place that has a lot of them.

If anybody has anything about the status, you are

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more than welcome to bring it up. That is certainly all

that I have available.

Open Public Hearing

DR. A. KALLOO: Does anyone outside the panel wish

to address the panel? Please raise your hand.

DR. HOLEBRUE: I am Dr. Logan Holebrue [phonetic]

from the American Urological Association. I am Chairman of

the Health Policy Council and former President of the AUA,

an I have no financial interest in any of the companies that

manufacture any of these, and neither have I spoken to any

of the industry representatives. I might also add that the

AUA has not revisited this issue since its pronouncement

back in 1993.

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I would like to make several points. First of

all, we applaud the Food and Drug Administration in its

efforts to protect the public and to assure efficacy in the

various products it reviews. It is extremely important,

first, to do no harm.

The second point I would like to make is that this

is a very rare condition, and a study that was advocated

here would have to be a multi-center study, indeed, I would

suspect it would have to include every children's hospital

in this country.

It would be a multi-year study. I don't know how

many of these operations would be performed a year were

there prostheses available. Neither do I know how many were

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performed back when they were available. A figure of 4,000

a year has been bantered around. I think those are the

production and sales. My own hospital would have an array

of different sizes on the shelf because what is suitable in

size for a six-year-old would not be suitable for a

21-year-old, and what would suit a 21-year-old would, of

course, be grotesque in the scrotum of a 6-year-old.

So, there are lots of sales. I don't know how

many implants there are, we simply have no data. Now, I

have a feeling that given the minimal number of these

implants that are going to be done in a year, even if there

were to be approval, I wonder if any company or companies,

plural, would be interested in embarking on such a study

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given the meager numbers of sales available.

I am not in industry. I don't know that I can

answer that question. I simply raise it.

I think there is serious question whether the

cost-profit ratio would be such that they would want to fund

and embark upon and support a study of this magnitude

involving so many different centers, which is always costly,

and over so many years, which is also costly.

Now, having said all of that, I would be very

happy to go back to the AUA and to ask our board of

directors to reevaluate the position it put forward in 1993,

and perhaps we should do that.

I think that the facts having been stated, as I

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have just given them, I think we all have to admit that no

young man or young male child dies because they have an

empty scrotum, but I think that, on the other hand, there

are emotional issues involved, and we all know that young

children and young adolescents compare the appearance of

genitalia, we know that, and the young man with an empty

scrotum I am sure is at considerable psychological

disadvantage amongst his peers.

So, having said these things, I think that this is

an open issue, and I think we have to therefore balance the

risks of these devices. If we know of anecdotal situations,

if we -- I was interested to hear that there were 10 cases

reported of problems, I would certainly like to know what

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those were. I would love to see that data.

We have to balance the risks of this versus the

potential psychological benefit we glean of a young man and

children who are in need of this procedure. It is a very

small number, and very honestly, I would think that the

study proposed here would probably be near nigh to

impossible, and I doubt that industry would ever be

interested in funding it.

You might ask industry. I don't represent them,

so I don't know.

Thank you very much.

DR. A. KALLOO: Thank you.

Open Committee Discussion (Continued)

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Any questions from the panel with regards to this?

DR. DONATUCCI: To anyone?

DR. A. KALLOO: Yes.

DR. DONATUCCI: I have one more question to the

FDA. If these devices, say, the saline-filled testicular

implant is essentially the same as a saline-filled breast

implant except that it's a different size and it is placed

in a different anatomical location, what issues are

different about putting the same prosthesis that is already

approved for placement underneath the skin of the chest

wall, demand a clinical trial when it's placed in the

scrotum? Is there a substantial difference in the potential

risk in terms of materials and rupture? I just don't see

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it, and that's why I am asking.

MR. BAXLEY: Well, we want certainly the labeling

or its directions for use be able to be clear enough that a

physician knows how to put it in, and there are no reports

in the literature of this version of a device to give you

that information. That is one thing in our minds.

Another thing is we like the labeling to tell the

physician and patient what likelihood it has of rupturing,

which means that you probably would have to get a

reoperation, not being satisfied with a ruptured implant.

DR. DONATUCCI: But the data from the chest wall

is not sufficient for this scrotum?

MR. BAXLEY: No, because its rupture rates depend

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on its geometry, and it is also dependent on location, being

in an area which I guess a child, who is rough in playing,

could very easily break it. It's hypothetical, but in this

area, it seems like it might, because of the anatomic

location, might have different forces received.

DR. DONATUCCI: But you couldn't gather that data

by postmarket? I mean record ones that were ruptured.

MR. BAXLEY: Yes, and what we are proposing is to

study the patients premarket for six months, and probably

not have any rupture data in that time period, and then

postmarket, get the rupture data, and the option is we are,

at least at present, equally open to the ideas of

post-approval follow-up with that patient population, of a

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specific patient population, or a patient registry, which

doesn't include follow-up, but tracks all patients.

DR. N. KALLOO: I would like to just address that.

There is an article here, this one from Amsterdam, from

February of '99, and what they are mentioning is that -- I

will just read this one paragraph -- "As opposed to the

subpectoral location of many prostheses, the scrotum is said

to offer a position with low tension, low friction, and

lower temperatures. Testicular prostheses are also more

mobile, allegedly making them potentially less vulnerable to

pressure injury. These factors may contribute to the lack

of demonstrated implant failure."

So, they are actually suggesting that the scrotum

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is actually an advantageous place. Now, certainly, if you

are performing extreme acts, like bicycle riding and things

like that, then, you certainly might put it at risk, but I

think the two cases that they mentioned were actually

extreme cases.

DR. BENNETT: I see a representative from AMS in

the room. Is there anyone here from Mentor? I mean again,

there are none being made in the United States. Is there

any interest from any company here to revisit the issue

vis-a-vis down-classification or whatever?

DR. A. KALLOO: Please state your name and

affiliation.

MR. PURKATE: My name is Bobby Purkate [phonetic].

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I am from Mentor Corporation. I am the Senior Vice

President for Science and Technology.

To answer your question, yes, we do have interest

both on the saline testicular as well as the solid

elastomer. Currently, we have completed a clinical study,

about 100 patients, on the saline testicular, and on the

solid elastomer, we do not have any clinical data, but we

have extraordinary amount of preclinical data, which we

believe would be sufficient to show the safety and

effectiveness. So, we are very interested.

DR. BENNETT: But you haven't discussed this with

the FDA?

MR. PURKATE: We have opened the dialogue with

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John Baxley and Don St. Pierre. They are pretty familiar

with what we have. We are continuing to work with it,

hopefully, we will bring the data to them for their review

very shortly, and we will take it from there.

DR. A. KALLOO: I think I would like to move on

and look at the specific questions that the panel will be

asked.

The first question is: Does the panel believe

that the proposed scheme for stratifying the clinical

testing recommendations for the testicular prosthesis by

solid, saline-filled, and silicone gel-filled designs is

clinically sound?

Question 2. Should adult and pediatric patients

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be analyzed as separate cohorts, or are the general issues

of safety and effectiveness sufficiently similar to permit

these two populations to be pooled for analysis?

The third question is: Does the panel believe

that the proposed pre-/post-approval follow-up

recommendations are necessary and sufficient to demonstrate

the safety and effectiveness of the three testicular

prostheses designs currently being considered?

So, those are the three questions and what we will

do is I will pose each question to each of the panel

members, and Dr. Kalloo will summarize the panel comments at

the end.

The first question, we will start with Dr. Foote,

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if you could please comment.

Does the panel believe that the proposed scheme

for stratifying the clinical testing recommendations for the

testicular prosthesis by solid, saline-filled, and silicone

gel-filled designs is clinically sound?

DR. FOOTE: Yes.

DR. HUNTER: Yes, but I think it's a waste of time

for the last one, because of the lawyers.

DR. DIAMOND: Yes.

MS. NEWMAN: Yes.

DR. VERTUNO: Yes.

DR. STEINBACH: Yes.

DR. DEITRICK: Yes.

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DR. HAWES: Yes.

DR. DONATUCCI: Yes.

DR. N. KALLOO: Yes, and I think the consensus is

yes.

DR. A. KALLOO: The second question is: Should

adult and pediatric patients be analyzed as separate

cohorts, or are the general issues of safety and

effectiveness sufficiently similar to permit these two

populations to be pooled for analysis?

DR. FOOTE: I would pool the analysis of the adult

and the pediatric populations. I don't think there is going

to be a whole lot of difference in regards to how they do.

DR. HUNTER: Ditto.

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DR. DIAMOND: I would think they could be pooled.

MS. NEWMAN: I agree.

DR. VERTUNO: Yes.

DR. STEINBACH: No, I think children behave

differently than adults, and may stress them more.

DR. N. KALLOO: I am sorry. Would you repeat what

you said?

DR. STEINBACH: I think the children are more

likely to put them to higher mechanical stress.

DR. DEITRICK: Yes, I agree they could be pooled.

DR. HAWES: I think they could be pooled.

DR. DONATUCCI: I think they can be pooled, and in

response to your comment, again, we do have prior clinical

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experience, and it just wasn't an issue.

DR. N. KALLOO: And personally, I think they can

be pooled. There are very few things that they are going to

be doing that really put that much stress -- they are so

mobile, and they are so little.

DR. A. KALLOO: And the summary?

DR. N. KALLOO: In summary, I think the majority

have agreed that they can be pooled.

DR. A. KALLOO: Question 3. Does the panel

believe that the proposed pre-/post-approval follow-up

recommendations are necessary and sufficient to demonstrate

the safety and effectiveness of the three testicular

prostheses designs currently being considered?

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DR. FOOTE: In regards to the recommendations, I

guess my only concern was that, as I recall, for the solid

prostheses, it was recommended that a size 100 was used, but

for the other two, was it 250? Am I correct?

MR. BAXLEY: No, it was 50 for solid.

DR. FOOTE: 100 for the saline and for the gel.

DR. N. KALLOO: 250 at 10 years for the gel.

DR. A. KALLOO: Postmarket.

DR. FOOTE: 250 postmarket. Yes, that's fine.

DR. HUNTER: It's either acceptable or I would

simplify it to a registry only. I think that is more

realistic.

DR. DIAMOND: I am not sure you can really assess

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effectiveness in this sort of model, but in view of the

small number of patients, I think it probably is going to be

the most realistic and best that you are going to be able to

do in any reasonable amount of time. I would be in favor of

it the way it was proposed.

MS. NEWMAN: I think it's fine.

DR. VERTUNO: Yes.

DR. STEINBACH: I still would like to see some

kind of control group for effectiveness.

DR. N. KALLOO: Would that be psychosocial

effectiveness?

DR. STEINBACH: Yes.

DR. BENNETT: I have no problem with the early

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follow-ups, but I would eliminate totally the post-approval

studies. I think they are unrealistic and past history

would indicate that they need -- there is not requirement

especially if the only thing that you are really concerned

about is rupture. I think that that information can be

gleaned within the first few years.

DR. DEITRICK: I agree with the proposal as it is.

DR. HAWES: I think the study is sufficient and

can demonstrate safety and efficacy. I would agree with Dr.

Hunter. I would just simplify the follow-up to a registry,

and not require a formal study.

DR. DONATUCCI: The way I look at the

post-approval studies, 5,100 and 250, it seems like there

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is still some concern long term about gel-filled prostheses.

Again, I question whether, in an adult population, the fact

that it is placed in the testicle and leaks in the scrotum

as opposed to leaking in the body wall, would make any

difference in the long-term toxicity, and I think there are

data already about the toxicity of gel in an adult

population.

Now, I don't think we have any information about

the risk of leakage of saline gel in the pediatric

population. It just doesn't exist as far as I know. I am

not necessarily overly concerned, but the way you stratify

that, 1,500 and 250, says to me that you are still more

concerned about the gel-filled prostheses than the other two

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in the potential toxicity of the gel.

I just wonder whether that needs to be a fear in

the scrotum as opposed to any other anatomic location in an

adult given the data that we have available.

I would say, I have to agree I think the registry

would probably be the most logical way to handle that.

DR. N. KALLOO: I think that a summary would

indicate that the majority would say yes, that the proposed

pre- and post-approval follow-up recommendations are

sufficient to demonstrate safety and effectiveness of the

three types with the caveat that they should probably be

reduced to a registry, and again, other comments would be

that there should be a control group for psychosocial

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effectiveness, that again, the post-approval studies are

probably excessive, and the registry would probably address

those issues.

DR. A. KALLOO: Before I ask the panel to vote on

whether they agree with this or not, would you like to have

the summaries restated? No.

Those in agreement with this final consensus, if

you could raise your hands, please.

[Show of hands.]

DR. A. KALLOO: Unanimous.

Mary, do you want to read the letter?

MS. CORNELIUS: I would just like to read into the

record some comments sent to me by Dr. Kogan.

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Dr. Stanley Kogan, representing the Urological

Section of the American Academy of Pediatrics, submitted a

letter to the agency that will be added to the panel record.

To summarize Dr. Kogan's comments, he states there

is a need for a legally marketed testicular implant in the

United States and would like the FDA to ensure that this

device is available to patients who are in need.

I have one final comment before we adjourn.

Please leave your books on the table and put your trash in

the trash can before you leave.

DR. A. KALLOO: This concludes the meeting. I

would like to thank all the members of the panel and the FDA

for making this a very successful day.

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The meeting is now adjourned.

[Whereupon, the meeting was adjourned at 3:08

p.m.]

- - -

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