us food and drug administration: 3856t1

8/14/2019 US Food and Drug Administration: 3856T1

http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 1/322

UNITED STATES OF AMERICA

FOOD AND DRUG ADMINISTRATION

+ + + + +

CENTER FOR DEVICES AND RADIOLOGICAL HEALTH

+ + + + +

OBSTETRICS AND GYNECOLOGY ADVISORY COMMITTEE

+ + + + +

SIXTY-FIFTH MEETING

+ + + + +

MONDAY

APRIL 22, 2002

+ + + + +

The panel met at 8:00 a.m., in Salons E

and F of the Gaithersburg Marriott Washington Center,

9751 Washingtonian Boulevard, Gaithersburg, Maryland,

at 9:00 a.m., Dr. Jorge D. Blanco, Chairman,

presiding.

PRESENT:

JORGE D. BLANCO, M.D., Chairman

CAROL L. BROWN, M.D., Member

GARY S. EGLINTON, M.D., Temporary Voting Member

JAY D. IAMS, M.D., Temporary Voting Member

NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS

1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com



PRESENT (continued):

KLEIA R. LUCKNER, J.D., M.S.N, Consumer Representative

MARY LOU MOONEY, R.A.C., Industry Representative

MICHAEL NEUMAN, M.D., Ph.D., Temporary Voting Member

MARY JO O'SULLIVAN, Member

SUSAN M. RAMIN, M.D., Temporary Voting Member

RICHARD E. RINGEL, M.D., Temporary Voting Member

DAVID B. SEIFER, M.D., Member

NANCY C. SHARTS-HOPKO, Ph.D., Member

ALICIA Y. TOLEDANO, Sc.D., Temporary Voting Member

ROBERT N. WOLFSON, M.D., Ph.D., Temporary Voting

Member

JOYCE WHANG, Ph.D., Executive Secretary





C-O-N-T-E-N-T-S

Introductions......................................4

Introductory Remarks..............................12

Colin Pollard, Chief,Obstetrics and Gynecological Devices Branch

Open Public Hearing

Raul Artal, M.D.................................17

Sponsor Presentations

Karl G. Rosen, M.D., Ph.D.......................24

Overview of STAN concept and Swedish RCT

Ingemar Kjellmar, M.D...........................53

Perinatal Care in Sweden

Karel Marsal, M.D., Ph.D........................58

Management of Labor and Delivery

Lawrence D. Devoe, M.D..........................64

Applicability/Usability of STAN in U.S.

FDA Presentations

Kathryn S. Daws-Kopp............................81

Overview of FDA Review

Julia A. Corrado, M.D...........................88

Clinical and Statistical Review

Panel Discussion.................................120

Open Public Hearing..............................278

Panel Deliberations and Vote.....................282





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

8:07 a.m.

CHAIRMAN BLANCO: All right, let's go

ahead and call the meeting to order.

I want to remind everybody that there are

signup sheets outside in the front. Please sign in

and let us know who you are and who you are affiliated

with.

Just a couple of housekeeping matters

before we start: As usual, let's not have any

outbursts from the audience. If you would like to be

recognized, at the appropriate time you will be

recognized; you can come to the podium and speak.

Always identify yourself and identify whether you are

associated with any particular entity, and whether you

have, at least the first time that you come up, you

need to state whether you have any possible conflict

of interest with the issues at hand today. That

includes any type of employee, employer, consultant,

travel, per diem, or any other type of relationship

with any of the companies that might have some

business before the panel.





At this point let's go ahead and have some

introductions of who the panel members are. If we

could start over here, please state your name and

affiliation.

MS. BROGDON: Good morning. I'm Nancy

Brogdon. I have been the Director of the Division of

Reproductive, Abdominal and Radiological Devices, FDA.

CHAIRMAN BLANCO: And next to her will be

Dr. Michael Neuman, who will join us very shortly.

Go ahead.

DR. RINGEL: Yes, I'm Dr. Richard Ringel,

Pediatric Cardiology at Johns Hopkins Hospital.

MS. TOLEDANO: Alicia Toledano, Center for

Statistical Sciences, Brown University.

DR. WOLFSON: Good morning. I'm Robert

Wolfson. I'm an independent maternal fetal medicine

specialist and obstetrician/gynecologist and engineer.

DR. SHARTS-HOPKO: I'm Nancy Sharts-Hopko,

Professor of Nursing, Villanova University.

DR. IAMS: Jay Iams, Professor of

Obstetrics and Gynecology at Ohio State University.

DR. WHANG: I'm Joyce Whang. I'm the





Executive Secretary of this panel.

CHAIRMAN BLANCO: I am Jorge "George"

Blanco. I am a perinatologist in private practice in

Odessa, Texas.

DR. RAMIN: Good morning. I'm Susan

Ramin. I'm a maternal fetal medicine specialist at

the University of Texas, Houston, Medical School.

DR. EGLINTON: Gary Eglinton, maternal

fetal medicine, Cornell and New York Hospital, Queens.

DR. O'SULLIVAN: Mary Jo O'Sullivan,

maternal fetal medicine, University of Miami.

DR. BROWN: Carol Brown, gynecologic

oncologist, Memorial Sloan-Kettering Cancer Center.

DR. SEIFER: David Seifer, reproductive

endocrinologist, UMDNJ, Robert Wood Johnson Medical

School.

MS. MOONEY: I'm Mary Lou Mooney, the Vice

President of Clinical Regulatory and Quality for

SenoRx, and I'm the industry rep. to the panel.

MS. LUCKNER: Kleia Luckner. I'm a

clinical administrator at Toledo Hospital in Women's

Health, and I'm the consumer rep.





CHAIRMAN BLANCO: Thank you very much.

Michael, I introduced you, but please do

the honors for yourself, if you would like.

DR. NEUMAN: I think you did such a good

job, Jorge, I think it's fine. I'm Mike Neuman from

the Memphis Joint Program in Biomedical Engineering of

the University of Tennessee Health Science Center in

the University of Memphis.

CHAIRMAN BLANCO: No, you did much better

than I did. Thank you.

(Laughter.)

DR. NEUMAN: Can't do it in one breath

though.

(Laughter.)

CHAIRMAN BLANCO: We'll have to train you.

We'll have to invite you back more, so we can train

you.

DR. NEUMAN: That's quite all right.

CHAIRMAN BLANCO: All right, at this point

I would like to introduce the FDA press contact, if

she would please stand. The FDA contact for this

particular meeting is Nancy Brogdon, Director,





Division of Reproductive, Abdominal and Radiologic

Devices. Thank you.

All right, at this point I will turn it

over.

DR. WHANG: Good morning. We have two

additional OB/GYN Devices Panel meetings scheduled for

this year. They are July 22nd and 23rd and then

October 21st and 22nd.

Today's panel includes seven temporary

voting members, and I will now read their appointment

to temporary voting status.

"Pursuant to the authority granted under

the Medical Devices Advisory Committee Charter, dated

October 27, 1990, and amended August 18, 1999, I

appoint the following individuals as voting members of

the Obstetrics and Gynecology Devices Panel for this

meeting on April 22nd, 2002:

"Gary S. Eglinton, M.D.; J. D. Iams, M.D.;

Michael Neuman, M.D., Ph.D.; Susan M. Ramin, M.D.;

Richard E. Ringel, M.D.; Alicia Y. Toledano, Sc.D.;

Robert N. Wolfson, M.D., Ph.D.

"For the record, these people are special





government employees and are consultants to this

panel. They have undergone the customary conflict-of-

interest review, and they have reviewed the material

to be considered at this meeting."

This is signed by David W. Feigal, Jr.,

M.D., M.P.H. He is the Director for the Center for

Devices and Radiological Health, and it is dated April

18th, 2002.

Now I will read the conflict-of-interest

in for the record. "The following announcement

addresses conflict-of-interest issues associated with

this meeting and is made a part of the record to

preclude even the appearance of an impropriety.

"To determine if any conflict existed, the

agency reviewed the submitted agenda for this meeting

and all financial interests reported by the Committee

participants. The conflict-of-interest statutes

prohibit special government employees from

participating in matters that could affect their or

their employer's 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 interest of the government.

"Therefore, a waiver under 18 USC

208(b)(3) has been granted to Dr. Richard Ringel for

his stockholding, between $5,001 to $25,000, in the

parent of a competing technology firm. The waiver

allows this individual to participate fully in today's

deliberations. Copies of this waiver may be obtained

by submitting a written request to the agency's

Freedom of Information Office, Room 12A-15 of the

Parklawn Building.

"We would like to note for the record that

the agency took into consideration certain matters

regarding other panelists. Drs. Gary Eglinton,

Michael Neuman, and Robert Wolfson reported current or

previous interest with firms at issue, but in matters

not related to today's agenda. The agency has

determined, therefore, that they may fully participate

in the panel's deliberations.

"In the event that the discussions involve

any other products or firms not already on the agenda

for which an FDA participant has a financial interest,





the participant should excuse him or herself from such

involvement, and the exclusion will be noted for the

record.

"With respect to all other participants,

we ask in the 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 on."

There will be transcripts and videos

available for today's meeting, and if there are any

presenters to the panel who have not already done so,

they should provide FDA with a hard copy of their

remarks, including overheads.

Kathy Daws-Kopp -- would you please stand?

-- will collect these from you at the podium. Thank

you.

CHAIRMAN BLANCO: Thank you.

It's a pleasure for me to introduce Colin

Pollard, Chief of the Obstetrics and Gynecological

Devices Branch, who will make some introductory

remarks.

Colin?





MR. POLLARD: Thank you, Dr. Blanco.

First of all, I want to welcome the panel.

We've got a few new faces, and we really appreciate

the time and trouble you all went to be here, and

especially for the new panel members, the training

that you went through yesterday and this morning.

I would also like to welcome the sponsor,

who has had to travel quite a distance to be here

today.

Before we get into today's agenda, I would

like to go over a few things with you. Since our last

panel meeting, FDA has approved two PMAs. In

September we approved the Novasure Endometrial

Ablation System. This is the fourth such device of

this type. As we get more experience with that, it's

less and less likely that we bring PMAs of this sort

before you, unless it's something new and different, a

new energy mode or some new safety issue, or something

like that.

Just last month, we approved the Lea's

Shield, which is vaginal barrier contraceptive device.

As Joyce just mentioned, we've got two





panel meetings scheduled for the remainder of the

year: July 22nd-23rd and October 21st-22nd. It's

quite possible we will use both of those dates, but

we'll see what the agenda holds for us.

I would like to talk a little bit about

post-approval studies. First of all the purpose of a

post-approval study, it needs to be understood that

there's already, before you even get into the post-

approval study, the determination on the part of FDA

that a reasonable assurance of safety and

effectiveness has already been established. However,

the post-approval studies may address either long-term

events or rare events. If the PMA was based, if the

pivot study supporting the PMA was based on surrogate

endpoints that FDA thought were reasonable, a post-

approval study might be done to validate those

endpoints or a post-approval study might answer

specific panel concerns.

I mention this because at our meeting in

July our Office of Post-Market Surveillance is

planning to give a presentation, and it is going to go

over a number of post-market activities that FDA





engages in, including an update on post-approval

studies.

Today we're going to bring before you a

PMA, which you have had a chance to review already,

for the STAN S21 Fetal Heart Monitor submitted by

Neoventa Medical. I just wanted to give a few remarks

about that.

First of all, this falls generally in the

category of electronic fetal monitors, and I would

just like to highlight that most electronic fetal

monitors are Class II devices and get to the market

through the 510(k) pre-market notification process

where the sponsor would show that they're

substantially equivalent to a monitor that's already

on the market.

However, if there is a new feature for

that fetal monitor, one that we believe has

significant implications, in that case we would

require a PMA. In the case of the PMA before you

today, we felt that the use of the fetal ECG waveform

in this monitor, the special analysis to identify ST

events, and the claims that it would improve





assessment, we felt that, when all taken together,

that this was something that required a PMA.

Just real briefly -- you have this in your

PMA -- the intended use of the STAN monitor is to use

the fetal ECG analysis with the cardiotocography to

obtain information on the impact of labor on the

fetus, and that is intended to improve the assessment

of fetal condition during labor. I'm not going to go

through all the indications for use that are listed in

the PMA, but it represents a fairly broad approach.

It's intended for use on a singleton fetus in the

vertex presentation with greater than or equal to 36

weeks gestation.

Real briefly, I know we went over this

yesterday for the new panel members, and I just remind

the more experienced panel members, the regulatory

framework for PMA reviews. I want to highlight three

elements: valid scientific evidence, safety, and

effectiveness.

With respect to valid scientific evidence,

FDA is given quite a bit of latitude has to what to

recognize for a given product, for a given intended





use, everything from well-controlled clinical studies,

partially-controlled studies, all the way to even

reports of significant human history.

Our assessment of safety -- in fact, this

must be based on valid scientific evidence. In the

case of safety, we must make a determination that the

benefits outweigh the probable risks, and for

effectiveness ultimately that the studies must have

shown a clinically-significant result when used for

the intended population and used the way it is

supposed to be used.

Joyce and Jorge are going to go over this

with you later, but your recommendation, which we

consider very seriously in the context of our making

our decision, should come in the form of a

recommendation, a panel recommendation, that would

take the form of one of those three aspects, either an

approval, a full approval, an approval with

conditions, or not approvable.

So, finally, our agenda, we are going to

hear first from the sponsor. After the open public

hearing, FDA reviewers will present their findings,





and you will have an opportunity to discuss this, hear

more from the sponsor and audience before you engage

in the questions that we've prepared for you.

Thank you, Dr. Blanco.

CHAIRMAN BLANCO: Thank you, Mr. Pollard.

The next item on our agenda is the open

public hearing. We have one speaker signed up to

present before the panel, Dr. Raul Artal, Vice

Chairman, ACOG OB Practice Committee.

Is there anyone, before Dr. Artal

addresses the panel, is there anyone else who would

like to participate in the open public forum at this

time?

(No response.)

All right, thank you.

Dr. Artal?

DR. ARTAL: Good morning. Dr. Blanco,

members of the panel, ladies and gentlemen, thank you

for giving me the opportunity to represent --

CHAIRMAN BLANCO: I'm sorry, Dr. Artel.

Can we start by stating your name, your relationship,

and whether you have any conflict of interest, and





then go ahead with your presentation? I apologize for

interrupting you.

DR. ARTAL: No, thank you. I appreciate

this. Thank you very much.

My name is Raul Artal. I'm currently the

Vice Chair of ACOG's Committee on Obstetric Practice.

I'm also the Professor and Chairman of the Department

of Obstetrics, Gynecology and Women's Health at St.

Louis University. I do not currently have any

conflicts of interest with this device or any current

device that is being considered by this panel.

CHAIRMAN BLANCO: I think you have a

conflict of interest with a computer, though, the way

they're working on them.

(Laughter.)

DR. ARTAL: Yes, well, I'm all prepared,

Mr. Chairman, for this eventuality, too.

(Laughter.)

CHAIRMAN BLANCO: Thank you. Go ahead.

DR. ARTAL: Thank you. Again, thank you

for giving me the opportunity to represent ACOG here

today.





The charge of the ACOG's Committee on

Obstetric Practice is to provide the ACOG membership

with objective, valid, scientific evidence and

guidelines for current practice, as well as existing

and emerging technology.

As to the device that is being considered

today by the panel, we had the opportunity to review

the following documents: The Summary of Safety and

Effectiveness Data of Neoventa Medical, the

publication listed in the summary, the detailed

analysis of the Amer-Wahlin, et al., the Swedish

randomized control trial, as published in the Lancet,

August 2001, and we also had the opportunity to review

a presentation of the lead author, Professor Rosen, at

the International Perinatal Society in Barcelona last

October.

The ACOG Committee on Obstetric Practice

bases its opinions on the fundamental principles of

evidence-based medicine. The extent of the evidence,

the benefits versus risks, patients' inconvenience,

cost, and patients' values.

As to the study presented and the adequacy





of the study design, the experimental study design was

considered to be appropriate for evaluating the

efficacy of cardiotocography plus ST analysis versus

cardiotocography only for intrapartum fetal

monitoring. However, questions remain about the

device's ability to detect either metabolic acidosis

or hypoxia, and certain improvements in future

validation studies will be required.

One concern about the study design is

that, while the main outcome variable was metabolic

acidosis at birth, very few contemporaneous fetal

blood scalp sampling determinations were conducted on

fetuses affected by metabolic acidosis. The overall

rate of fetal acidosis acidemia reported in these

studies was significantly -- significantly -- lower

than the one reported in our country.

In terms of adequacy of the materials,

methods, and procedures, the methods for identifying

eligible study participants, randomizing participants,

training clinicians to use the CTG or CTG plus ST,

gathering baseline, and follow-up measurements, and

analyzing the data are appropriate and clearly





described in the materials submitted.

However, I have to again emphasize the

overall very low incidence or rate of fetal acidemia,

significantly lower than in this country.

No data is provided to determine false

positives and false negatives for the proposed method

to detect metabolic acidosis/hypoxia, such as

physiologic events, environmental factors, fetal

positioning, and so on. None of this has been

reported in the analyses.

ST segment deviations are known to be

caused by the following events: injury to the cardiac

muscle or ischemia, changes in the synchronization of

ventricular muscle depolarization, overload or strain

on ventricular muscle, drug or electrolyte influences,

and certainly could be observed also as a normal

physiological variant. It is this particular thing

that we have not seen any data reported in these

reports. Particularly, it's known that nested segment

deviation can appear as a normal physiological variant

during stressful events. In the studies completed and

data presented, have these factors been considered?





Other things of concern to the ACOG

Practice Committee was that, as reported on page 536

of the Lancet article, second column, first paragraph,

the interim analysis revealed protocol violations in

which the recommendations to intervene were

disregarded, and babies with cord arterial metabolic

acidosis were born. Indeed, the protocol violation

occurred in both arms of the trial, it appears. What

percentage of births were affected in each arm?

In terms of accuracy of interpretation of

the results, the results as presented in the tables

and text material reviewed are presented very clearly.

However, what is the sensitivity and specificity of

the CRT ST for detecting cord artery metabolic

acidosis or hypoxia? And more important, what is the

likelihood ratio?

Nowadays, for an evaluation of a

diagnostic or a screening test, likelihood ratio is

the appropriate effect size to describe the

performance of the test. So what is the likelihood

ratio?

In summary, we urge the panel to clarify





We'll open it up once again, if there's

any other members of the public who would like to

address the panel at this point.

(No response.)

Okay, not seeing anyone, we will move on

to the next item on the agenda. The next item on the

agenda is the presentation by the sponsor, and I

believe Professor Karl Rosen is going to begin the

presentation.

DR. ROSEN: Mr. Chairman, members of the

panel, ladies and gentlemen, my name is Professor Karl

Rosen. I'm a pediatrician/perinatal physiologist. I

am currently Medical Director of Neoventa Medical,

where I hold shares.

What I would like to start is to present

the way we can detect hypoxia during labor, but also

touch on the dissemination of knowledge as we see it

with the research we are doing currently in Europe. I

will be followed by Professor Ingemar Kjellmar, who

will present the current perinatal level of care in

Sweden, and then Professor Karel Marsal will draw

parallel observations with regard to the U.S. and





Swedish obstetric care, and Professor Lawrence Devoe

will follow with comparing or addressing the current

issue in the U.S.

Now to start this, we could look at a case

which is a term delivery where there's been ruptured

membranes for three days, induction. On the upper

part you see the heart rate trace, uterine activity,

and here you have something called the T/QRS ratio.

This is now the height of the T wave related to that

of the QRS. These are ECG complexes recorded from the

fetal scalp electrode. We could have a look at events

as they emerged in the heart rate trace as well as in

the ST with this case.

So we move forward. A baseline heart rate

of roughly 160 beats per minute. The mother has an

increased temperature. She's been given Parasetimol.

Still no ST events, and heart rate now in still first-

stage labor is constant with a tachycardia reactivity.

As we now start to enter the end of first

stage and approaching active pushing in the second

stage, deceleration starts to emerge, and with that we

have a first ST event, which is now the baseline rise





but the outcome seems to be good.

And this you are here to discuss is really

what happens when things like these emerge, and where

we know that there is sometimes some uncertainty about

how to interpret the heart rate rates, and where we

are looking for additional information now contained

in the ST wave form of the fetal ECG. But, at the

same time, to have a system that presents to everyone

what actually is taking place, so that delay factors

are avoided as much as possible.

So what we aim for is to identify fetuses

as risks of an adverse outcome, based on our

understanding of the path of physiology involved. We

know labor is a stress, and we know also that Nature

has provided the fetus with very good resources to

manage labor. Most fetuses are untroubled, although

we may find a lot of heart rate changes. Some are

troubled somewhat but managing and compensating fully,

in no immediate danger. But then there are a few

that's more troubled and forced to utilize key

resources in an attempt to compensate, and some may

not even be able to fully compensate, and we need to





know that the ST interval represents the time of

repolarization of the myocardium. This is now where

energy is required. The ion membrane pumps are

working hard, and metabolic events occur. So in case

of hypoxia, well, this is where we expect changes to

be seen.

Now then we need to quantify these

changes. As you noticed, there were marked peak T

waves. So we could look at the amplitude of the T

wave and relate it to that of the QRS. QRS, well,

that's a passive electrophysiological event, and its

QRS amplitude basically stays the same from the first

through the last heart beat. So by taking the ratio

of T/QRS, in this case in the normal, 5 versus 50, a

ratio of .10; then during hypoxia, 10 versus 50, so

the ratio increases to .20. We have a measure that we

can record and use.

Now the animal work that we have

conducted, starting in the seventies, initially were

observations on hemodynamic cerebral metabolic

function during experimental hypoxia, but also in

spontaneous labor in association with intrauterine





signal, allowing us to assess the specific components

of the fetal ECG.

So then the need for extractive clinical

work. In the eighties, observation started and

technological developments. In the nineties, we saw

the Plymouth randomized trial, fostering further

technological developments, verified in the EU

Observational Multi-Center Study, Nordic Observational

Multi-Center Study, with sensitivity/specificity

figures calculated, and you have then the Swedish

randomized trial, and currently the ongoing EU project

looking at the clinical implementation phase, being

equally important.

So if we look at the Plymouth randomized

trial, that was targeted to show safe reduction in

operative interventions for fetal distress, which was

achieved with almost 50 percent reduction for

operative deliveries for non-reassuring fetal status

with no increase for failure to progress.

If we look at the outcome, comparing the

heart rate only with the heart rate plus ST, meaning

in the STAN, the baby's outcome, whatever parameter we





choose, showed signs of improvements. If you take

metabolic acidosis, this didn't become significant

almost, but there were three cases in the STAN arm.

They had ST events, but they were not recognized. So

we saw the need to refine the technology with further

digital signal processing and automatic ST analysis.

Because we had the basic physiological

findings now verified in a large, randomized,

controlled trial, meaning that an ST rise, that is a

fetus responding to hypoxia, and biphasic ST, meaning

a fetus not fully capable of responding or has not had

the time to respond.

So we didn't want to change this approach

with a standard fetal scalp electrode and maternal

thigh electrode. We wanted to have a clear, nice

signal to work with. So we needed to develop the

computer, the digital signal processing, the software

engineering required, and, in particular, establish

what we call the ST log event log, automatic

identification of ST events, like in this case for its

1 centimeter a minute, but it is the only one showing

that, where you have a heart rate with a varietal





well, you had better be able to trust the data, then

perhaps the computer. So the user is taught how to

use the data also, regardless of what the computer is

saying.

Looking at the specificity issue here, I

want to use different ways to assess that, but the

positive predictive value is sometimes useful. We can

now look at how the STAN versus heart rate performs

with regard to different cutoffs in cord artery pH.

If we take the cutoff of 7.15, well, in 80 percent of

the cases where there are ST indications to intervene,

the cord artery pH was less than 7.15, whereas we had

a heart rate only in 43 percent of the cases. And

there were significant improvements, regardless of

what cutoff you choose. When it comes to sensitivity,

well, if we have metabolic acidosis, in this study of

573 cases, we did identify all of this.

So we take this forward now to the second

randomized trial, this one being multi-center in

Sweden, Gothenburg, Lund, and Malmo. These are all

large maternity unit, university departments with

between 3,000 and 4,000 deliveries. We have among us





here today Hakan Noren, Ingemar Kjellmer, and Karel

Marsal, being part of this study.

As you may notice, perinatal mortality

figures are reasonably low. Obviously, these are

tertiary referral centers, so they would have a little

bit higher perinatal mortality figures. If you look

at Caesarian section rates, you will find those vary,

as they would do between different centers, depending

on the culture of electronic fetal monitoring.

The objective of the study was to show a

reduction in number of newborns born with cord artery

metabolic acidosis by at least 50 percent. We

identified pH of less than 7.05 base deficit,

extracellular fluid greater than 12. Now this is not

a situation where the baby is severely affected.

Eighty percent of those had perfect normal outcome

innately. But this is a marker of an ongoing

anaerobic metabolism, and these are cases that need to

be discussed and identified.

While doing that we did not want to see an

increase in the rate of operative deliveries, but

rather a significant reduction without any increase





forcing an intervention, emergency C-section with a

normal outcome.

So we look at the clinical management of

these. The control group, they were managed according

to the standard practice, FIGO Guidelines for

interpreting the heart rate, allowing for fetal blood

sampling, and that practice varied between the

different centers somewhat. Obviously, if there was a

low cord arterial fetal blood sample, intervention was

required, as recommended.

You've seen the STAN guidelines, and just

to summarize those once again, in a case of pre-

terminal fetal heart rate, immediate delivery

regardless of ST; normal fetal heart rate, no

intervention regardless of ST.

In the interim analysis we found that in

the STAN arm there were deviations from the clinical

management guidelines, in that six babies had

metabolic acidosis with STAN changes and clear

indications to do something. When you discuss these

cases, well, the clinicians thought perhaps that

wasn't that much of a heart rate change, so they still





carried on as they were used to.

That focused an issue of repeated

training, which meant continuing case discussions,

because now we had samples from their own labor ward

settings. So we can bring those forward and show how

the ST information would affect the clinical

assessment in a neutral fashion.

Just to illustrate one of those cases, you

have a heart rate showing a somewhat increased

baseline, and then the deceleration, but good

maintained heart rate variability, and you find an ST

rise with a lot here stating a need for intervention,

but that wasn't a lot for a normal vagina delivery,

and you have a baby born 30 minutes later with a cord

artery metabolic acidosis.

So if we look at the characteristics of

this child, we find that there was more prima gravida,

more post-term cases. The epidural analgesia varies a

bit, but a lot with oxytocin augmentation. So,

clearly, a need for further information during active

labor.

Now when you develop a technology, you set





not knowing which arm of the trial the case belonged,

and identified 29 cases that he said these are

neonates affected by labor.

We had three cases that died, one in the

control arm because of asphyxia, one in the STAND arm

because of septicemia, Streptococci Group B, and one

because of asphyxia.

We can have a look at that case where you

have -- once again, we don't set up active pushing in

second stage, and ST rise coming with an ST event, and

as this now continues, heart rates become much more

alarming. At this point in time the trace is

discontinued because of vacuum extraction.

Then there is a delay for 24 minutes

before the baby is delivered. In that time the baby

is monitored by auscultation, and it's claimed that

there were normal heart rate sounds, and the baby is

born with Apgars 0-0-0 and does not respond to

resuscitation.

But looking now at that enter special

care, we had three cases on neonatal seizures, all in

the control arm; four cases of increased neuromuscular





we should look at deficiencies of that technology as

well. Among those 46 cases of metabolic acidosis

there were 15, now also including the control and the

STAN arm, where while there weren't any ST log

statements, 6 of those, yes, there was some reduction

in signal quality, but the ST changes were clearly

visually there. Sometimes they just emerge 10

minutes, 15 minutes, before delivering, in which case

there's not enough time for the computer to tell.

Then there are some in the control arm, in

particular, where there is also poor signal quality

that you couldn't do any ST analysis. But then there

are some where, yes, there are heart rate changes, but

they either regard them as not significant second-

stage events, perfectly healthy, vigorous newborn, and

we say, well, perhaps these are not that significant,

and sometimes you may not have data for the last 10

minutes, for instance, in which case, particularly on

metabolic acidosis, could emerge. But then in one

case, which was a case that died, Streptococci

septicemia, that had a pre-terminal heart rate trace,

and we know that these cases they are rare, but they





will not display ST events.

Another way of analyzing data here,

looking at potential deviations: 5,000 cases managed

by 300 obstetricians/midwives. So there are 46 cases

of metabolic acidosis, 8 in the STAN arm, you might

say potential deviations, 8 in the control arm, and we

can look at these. So we have in the STAN arm cases

where we say, well, in this case no deviations.

Because there were ST events, an action was done,

normal neonatal outcome, a bit of metabolic acidosis,

but that we would expect.

Then there are those where deviations,

probably ST events, no, but at the same time not that

much of a heart rate change, normal neonatal outcome.

But then, clearly, there are those where deviations

occur where we have ST events that were missed, and

these are the ones in the initial phase of the trial,

apart from this last trace that I showed you, the baby

that died with a vacuum and lack of data over the last

24 minutes.

If we look the situation in the control

arm, these are eight cases. There were some cases





where we can say, well, on the basis of heart rate

interpretation, there might not have been any

deviations. There were intermediary fetal heart rate

patterns, but then these got to ST events, and I

believe that is a significant observation, in that if

we add ST, we focus on the heart rate change that

emerged. Then we become more accurate in assessing

the heart rate and reducing the risk of an adverse

outcome. Clearly, there were those where there were

deviations from the standards of clinical practice and

a case, obviously, of no signals, then that's clearly

another cause of deviation.

So we can compare two randomized trials,

the Plymouth, the Swedish, and you'll find

similarities, perhaps a little bit more aggressive on

the reduction of operative deliveries, fetal distress

in the Plymouth trial. But if you look at metabolic

acidosis, the figures look identical.

So what to do next? Well, we have learned

a lot of experience, so we want to disseminate this

knowledge, focusing on education, training, use and

certification, quality control, using cord acid base





as routine, neonatal data, index cases, metabolic

acidosis. Take this up for discussion, provide

feedback, expert assessment.

This is now an EU-supported project,

initially with 10 Centers of Excellence. These are

all academic units across Europe, currently being 22,

who are becoming expert learning their own experience

and providing service to their regions in training,

education, and followup.

The aim is obviously to improve the

understanding during labor and to document consistent

improvements, based on the STAN monitor and a

dedicated teaching/training package. This, I believe,

is important, if we have in our database more than

10,000 cases that we can use in a sort of similar

environment to our STAN use, to our own experience,

before being exposed to real-life cases.

So now we can look at the experience from

STAN being used in routine obstetrics care. This is

now the City of Gothenburg, 16 months' experience. In

September eight STAN monitors were introduced, and

these are the rates of usage per month, covering this





in the national statistics. About 12 percent of the

mothers are immigrant mothers. In the three cities

taking part in the randomized control trial,

Gothenburg, Malmo, and Lund, the immigrant mothers are

around 20 percent, and they come mainly from the

Middle East, from Africa, and from former Yugoslavia.

Since we are talking about fetal

surveillance in term fetuses, the term perinatal

mortality rate, based on the two-year material, is 2.6

per thousand with very low rates of intrapartum death.

We have, since 1972, national guidelines

for resuscitation for asphyxiated babies. This is the

latest pamphlet from 1997 that is widely disseminated

among midwives, obstetricians, neonatalogists.

Now with a country where part is very

sparsely populated, one needs to have a program of

regionalization. This slide I have included to

demonstrate that we do have such a program. The

delivery hospital level refers to the equipment and

the staffing of the hospital. The hospital in the

Category 1 are the very small, rural hospitals with

obstetrics service only, no neonatal service. The





Category 2, the district hospitals with daytime

neonatal service. The Category 4 are the big regional

centers, and the Category 5 are the big university

centers that are fully equipped.

As you see from the first recordings, this

is material covering 12 years of deliveries in the

country, about 1.5 million deliveries, about 9,000

stillborn and neonatally dead babies. You see the

expected progression of the risk for cases accumulated

in the grade 4 and 5 hospitals. These are odds

ratios. You see that this is particularly effective

in cases where you can foresee the events such as

maternal disease and fetal disease, where there is

clear-cut gradient from the poorly equipped to the

very well-equipped hospitals.

But for conditions that are difficult to

foresee, such as obstetrical complications and

asphyxia in labor, the regionalization program

apparently is not enough to rid the smaller hospital

of these problems.

This slide demonstrates one often-

discussed final outcome variable when it comes to





between the use of fetal monitoring in labor in the

United States and in Sweden. I never worked as an

obstetrician in the United States, so I based my

information on the published statements and

recommendations from the American College of

Obstetrics and Gynecology and on my contacts with

American colleagues.

If you look at the staff providing during

labor in the United States, this is done primarily by

obstetricians. In uncomplicated pregnancies and

labors, the midwives are also involved. In Sweden, by

recommendation of the Ministry of Health, the

uncomplicated labors and deliveries are conducted

independently by midwives. It's their task to

recognize deviation from normality and to call upon

obstetricians who in that case will take over

responsibility for these patients. The complicated

pregnancies and the complicated labors and deliveries

are being conducted by obstetricians.

I mentioned the technical bulletin

published by the American College of Obstetricians and

Gynecology, the recommendation on the fetal monitoring





during labor. In Sweden the Swedish National Board of

Health and Welfare published in their database of

medical facts recommendations for the clinical

management of uncomplicated labors. It includes the

use of fetal monitoring. In addition, there are two

reference books which are used by all obstetricians

and midwives in Sweden, and there is rather big

consensus with regard to the use of the fetal

monitoring in labor.

Looking at the definitions of hypoxemia,

hypoxia, and asphyxia, I have found that these are

identical in both countries. The fetal heart rate

evaluation during labor is recommended for all

patients both in the United States and in Sweden.

In pregnancies with absence of risk

factors, auscultation is accepted as the only way of

fetal monitoring both in the United States and Sweden.

However, more and more often the electronic fetal

monitoring is applied also in the low-risk

pregnancies.

In the United States, one-to-one nurse-to-

patient ratio is recommended in the cases of





auscultation. In Sweden the ratio is about one to two

or three patients.

During the active phase of the first

stage, the control of fetal heart rate is recommended

in this stage at least every 30 minutes after a

contraction, and during the second stage at least

every 15 minutes. In cases with risk factors present,

the frequency of recommended controls is higher, risk

control every 15 minutes during the first stage and

every 5 minutes during the second stage.

In Sweden, during the active stage of the

first stage of uncomplicated pregnancy and labor,

auscultation for a minimum of 15 seconds every 15

minutes after a contraction is recommended, and during

the second stage with active pushing after each

contraction.

The electronic fetal heart rate monitoring

is performed using the commercial monitors of similar

makes both in the United States and Sweden. There is

a difference in the speed, which is 3 centimeters per

minute in the United States and 1 centimeter per

minute in Sweden. Also, the heart rate scale differs,





being 30 to 240 beats per minute in the United States

and 50 to 210 beats per minute.

The recommendations for the use of scalp

electrodes as been mentioned in Professor Rosen's

description of the Swedish study, and these

recommendations are practical identical in both

countries. The documentation, either as a paper strip

or electronically, is also similar in both countries.

The absence of risk factors, when using

electronic fetal monitoring, the elevation of the

heart rate is recommended in the United States every

15 minutes during this first stage and every 5 minutes

during the second stage. In Sweden, practically all

pregnant women admitted to the labor ward are using

the admission test, the recording of the heart rate

for 15 to 20 minutes. Afterwards, in those

uncomplicated cases, intermittent recording is done

every two to three hours and, alternately,

auscultation may be used. During the second stage a

continuous recording of the heart rate is recommended

during the pushing stage.

In cases with risk factors present, the





blood sample for the pH, and if indicated, to perform

operative intervention. The operative interventions

used are emergency Caesarian section or the

instrumental vaginal delivery, comprising both forceps

and/or vacuum extraction. These indications are

identical in both countries.

So, to summarize, after looking on these

similarities or differences in the use of fetal

monitoring during labor, I came to the conclusion that

the United States and Swedish national guidelines are

very similar, including even liberal use of electronic

monitoring in normal pregnancies.

Thank you for your attention.


DR. DEVOE: By way of introduction, I am

Dr. Lawrence Devoe. I'm Professor and Chairman of

Obstetrics and Gynecology at the Medical College of

Georgia. I'm also a consultant for Neoventa, who paid

for my expenses and travel to attend this meeting.

I would like to kindly thank the panel and

its Chairman for their attention for the remarks that

I am about to make, which deal with the issue of where





nonrandomized trials? The answers to that I think are

very obvious. The early nonrandomized control trials

had less antepartal screening and, consequently, fewer

compromised babies were excluded from labor.

The care in randomized control groups is

very intense, featuring to one-to-one bedside nursing

care, and in turn, during the period in which these

randomized control trials evolved, the neonatal

intensive care unit performance improved.

Consequently, there were fewer neonatal deaths and

much larger groups than those included in almost all

the trials would have been needed.

There are three issues that really affect

the performance of electronic fetal monitoring today

in the United States. These are well-known. They are

the issues of observer reliability and

reproducibility, the issues of fetal heart rate

interpretation per se and its clinical correlates, and

the use of ancillary assessment methods.

As far as the first issue, many studies

have already shown wide ranges of intra- and inter-

observer agreement, and the lack of observer





reliability applies to visual and auditory

identification of fetal heart rate patterns. This is

a summation of best-case studies which is inter-

observer studies simply featuring the same tracings

being presented to individual observers at different

times and showing that cap levels of agreement vary

widely, but definitely fall far short of the gold

standard of 1.0.

Things are clearly much worse when one

gets to the inter-observer agreement, and the

parameters of fetal heart rate baseline, such as rate,

accelerations, decelerations, and variability, all

degrade as more observers are brought into the mix.

The reliability of fetal heart rate

assessment also decreases as you ask the observer to

discriminate more different types of patterns or

categories. In fact, even applying a standard

criteria with standard terminology to visual

inspection may not improve reliability or agreement.

The targets for electronic fetal

monitoring are to make some assessment of fetal

oxygenation and acid-base balance, as well as try to





predict cases in which these are disturbed, and

endpoints have been used such as scalp or cord blood

gases in neonatal outcomes, as you have already heard.

Going back, in fact, as early as the late

1960s, it became very obvious that certain patterns of

fetal heart rate monitoring tended to be more closely

associated with lower pH values, and these

particularly were persistent, severe, variable, or

late decelerations.

But we look at two retrospective studies

which were published in the 1980s. Both of these

identified that the main significant alteration in the

fetal heart rate tracing, when examined visually, was

the occurrence of late decelerations which was

associated with an increased risk for metabolic

acidosis in the study published by Low, and also an

earlier occurrence of decreased fetal pH in a study

published by Fleischer in the same time period.

As far as pathophysiologic correlates of

intrapartal fetal heart rate patterns, there have been

numerous retrospective and few prospective studies

that have ensued in the last 20 years with limited





linkage with adverse CNS outcomes, and to determine

whether the causal relationship between fetal heart

rate outcomes could, in fact, be affected by

interventions using fetal heart rate interpretation as

a clinical guide.

It came to four main conclusions: that no

consensus on strict guidelines for management using

fetal heart rate patterns alone could really be

recommended until evidence-based algorithms could be

developed.

Secondly, that normal fetal heart rate

patterns do exist, that they confer high likelihoods

of well-oxygenated fetuses at the time of observation.

Third, there are several patterns that

predict current or impending fetal asphyxia with

increased risk of injury to the neurologic system or

death.

Fourth, there are many fetuses, possibly

as many as 30 to 40 percent of those being monitored,

that fall between these extremes, and this group would

experience the most benefit from the results of the

recommended research.





Computerized processing of raw fetal heart

rate data might be able to improve point No. 2, but

still by itself gives a limited picture of fetal

adaptation.

And, finally, FECG analysis moves one step

closer to the intrapartum fetal adaptive or

maladaptive responses when hypoxia is present.

Thank you very much.

CHAIRMAN BLANCO: Thank you, Dr. Devoe.

Anything else, Dr. Rosen?

DR. ROSEN: I'm fine with this

presentation, and thank you very much for your

attention. Thank you.


Thank you to all of the speakers.

It is now, by the official clock, 9:45.

We're going to take a 15-minute break, and we will

reconvene promptly at 10 o'clock. Thank you.

(Whereupon, the foregoing matter went off

the record at 9:45 a.m. and went back on the record at

10:01 a.m.)

CHAIRMAN BLANCO: All right, if we could





go ahead and reconvene?

I think that we will start at this point

with presentation by the FDA, and I believe that Ms.

Daws-Kopp will be starting the presentation.

MS. DAWS-KOPP: Hi. Good morning, ladies

and gentlemen, distinguished panel members, and

guests. I'm Kathy Daws-Kopp, the lead reviewer for

FDA on this PMA, and I'm here to give you a brief

overview of the review process we've gone through on

the PMA.

This is a PMA for a specialized perinatal

monitor that includes a feature for ST analysis of the

fetal ECG.

First, I would like to acknowledge the

review team. As you can see, a number of people have

been involved in the review of this PMA application in

the areas of clinical, statistical, epidemiology,

software, hardware, fire research, monitoring, and

manufacturing.

Before I go over our efforts in review of

this file, I am going to give a brief overview of our

interactions with the company leading up to the PMA





inspection is required.

Dr. Corrado, whose presentation follows

mine, will address clinical and statistical reviews

during her presentation.

One of the review issues we're addressing

is that of signal quality. Here the device monitors

signal quality, providing an indication on the display

when signal quality is poor. The sponsor provided the

information regarding an ongoing retrospective visual

assessment of signal quality being conducted on the

strip charts from the Swedish randomized controlled

clinical trial.

This partial assessment identifies the

percentages of low, medium, and high quality signals

in the study as defined by the size of data gaps.

That is, for ST information, signals with data gaps

larger than four minutes are considered low quality,

and signals with maximum data gaps of two minutes or

less are considered high quality. It is not clear

whether the device uses a similar criteria for its

signal quality indicator.

The labeling and training provide some





guidance on management of data gaps such as advising

the user to reapply the fetal ECG electrode or to do a

manual assessment of the ECG complex, that is, to

estimate the T/QRS ratio by eye. We haven't finished

this review and will work with the sponsor and expect

that we will obtain the descriptive information and

test data we need.

I would also like to mention another

aspect of signal quality because it relates to the

analysis of the data for primary and secondary

endpoints. Analysis II, which Dr. Corrado will

discuss in her talk, excluded cases that did not meet

the sponsor's requirement for adequate recordings.

The database includes reasons why specific cases did

not meet these clinically-based criteria. A large

portion of these excluded cases, about 42 percent,

were to attributable to signal or technical problems.

As mentioned in my last example, our

hardware and software reviews are ongoing. We

currently have some information from the sponsor that

describes the device design requirements and

verification/validation. As I outlined in my previous





slide, we don't have as many details about the design

of components, features, and algorithms for the device

as we would like to answer all of our questions about

how the device works. Likewise, we would like further

information on verification and/or validation testing

that was done to confirm performance issues that may

not come out in the clinical testing. We are still in

the process of describing our needs in this area to

the sponsor.

Bioresearch monitoring and manufacturing

reviews are also still ongoing. The inspections in

Sweden have not yet been scheduled. We will continue

to work with the sponsor on these issues.

Now I will turn the floor over to Julia to

discuss clinical and statistical findings of our

review.


DR. CORRADO: Thank you, Kathy. Good

morning, everybody.

As we all know by now, the subject of this

PMA is the STAN fetal ECG monitor, and its use is that

of fetal ECG analysis and that includes standard fetal





heart rate plus ST waveform data to obtain information

on the impact of labor on the fetus, to evaluate the

status of the fetus during labor.

The sponsor's proposed indication for use

is for a term fetus in vertex presentation who is a

singleton, and there are additional criteria, all of

which contribute to an indication for fetal scalp

electrode monitoring.

I'm going to cover the following subjects

during my presentation. I'm going to emphasize the

results of the Swedish randomized controlled trial.

I'm going to talk about clinical issues that arose

during our review of this trial, and then I'm going to

summarize some other clinical experience with the STAN

monitor in European countries, and then try to bring

us to focus on the questions FDA has identified for

the panel.

Very briefly, as Dr. Rosen indicated,

there have been multiple studies of the STAN monitor

in European countries. The Plymouth study was in

England. There was a multi-country trial called the

Fetal ECG Analysis During Labor Trial that was





relatively small. There was then the larger Nordic

Observation Multi-Center Trial. The Swedish RCT is

what we're going to be talking about, and then there

are data from the City of Gothenburg, which she has

summarized and I will summarize very briefly as well.

I am afraid that I accidentally hit the

"end" button. Sorry. I'm sorry. I'll be real

careful not to press that "end" button there.

Finally, I wanted to highlight that

there's an ongoing study that is sponsored the

European Union. It involves obstetrical units in 10

different countries, and the primary focus is the

training and clinical results from a Center of

Excellence and dissemination of knowledge program.

So the point I've just tried to make with

the last couple of slides is, although we're going to

be focusing on the results of the Swedish RCT, there

is a very large body of data from this device that has

been accumulated over the last 10 years, clinical

data.

One of the reasons that we focused on the

Swedish RCT is that we felt that it met the criteria





We don't know the cause of this. We,

nevertheless, thought it was interesting to note that

for some reason that excluded population seemed to

relatively concentrate those subjects who went on to

C-section for fetal distress.

We, at this time, would just like to point

out possible significance of the definition of

metabolic acidosis in this study. The sponsor's

prospectively defined criteria were a pH less than

7.05 and a base deficit of greater than 12. This was

established prior to the carrying out of the study.

So this was an entirely prospective definition.

We thought it would be interesting to

stratify the results for different pH cutoffs, for

example, ACOG in a 1995 technical bulletin described

the pH of less than 7.00 as possibly being significant

with respect to fetal hypoxia. When you look at the

differences between the STAN arm and the control arm

at that pH level, 7.00, you see that the differences

between the two arms are less impressive. For the

7.05 cutoff, it was 15 and 30 versus 31 in the control

arm; for the pH cutoff of 7.00 the numbers were 11 and





most clinically-relevant here. It is very easy to see

that there were no cases of modern encephalopathy in

the STAN arm of the study.

I again want to point out that I'm making

a distinction here between babies who had confirmed

metabolic acidosis and babies who either did not have

metabolic acidosis or the cord blood data just weren't

adequate to confirm metabolic acidosis.

In the control arm there were three

infants who had confirmed metabolic acidosis plus

moderate encephalopathy. There was one additional

infant in the control arm who had modern

encephalopathy, but the cord artery data were not

available. So we don't know whether or not that

encephalopathy occurred in conjunction with metabolic

acidosis. So there is a difference in these two arms

of the study for modern encephalopathy. It was zero

in the STAN arm and 4 in the control arm.

Regarding severe encephalopathy, there

were three cases in the control arm of severe

encephalopathy. There were none in the STAN arm. I

think it's important to note, with regard to severe





encephalopathy, that none of those cases in the

control arm had confirmed metabolic acidosis. As a

matter of fact, two of the cases had evaluable cord

blood and those infants did not have metabolic

acidosis.

One of those infants underwent a mid-

cavity vacuum delivery. This was, I believe, a prima

gravida subject who -- and the baby turned out to be a

little bit over 4,000 grams. Unfortunately, a

shoulder dystocia was encountered, and about 8 to 10

minutes elapsed before delivery of that infant.

In another one of the cases of severe

encephalopathy in the control group the infant also

had an operative vaginal delivery. I believe it was a

vacuum delivery, and there was evidence of trauma,

possible trauma, from that delivery.

The third case is one I believe where the

cord blood data was not available to say whether or

not metabolic acidosis was present.

With regard to intrapartum and perinatal

deaths, there was one perinatal death in the control

arm of the study. Unfortunately, that was a subject





our review, you will find all of you have in your

package today a list of questions that the FDA staff

put together for the panel. One of these is the lack

of automatic ST event signals. The second is

deviations during the Swedish RCT from the patient

management protocol. Another issue has to do with

retraining of clinicians during the trial, and the

last is intercountry differences in clinical practice

between Sweden and the U.S., and whether or not that

has any implications in our review of the PMA.

These are cases where there was not an

automatic ST event signal. Now it's important to note

here that, in all fairness, we only looked at the 46

cases of metabolic acidosis as well as a few other

cases of bad outcomes. We definitely did not look at

every tracing from this study of 4,966. It wasn't

practicable.

So, again, these cases of lack of ST event

signal really only apply to the 46 total cases of

metabolic acidosis in the study. So there's no way we

can draw any conclusion as to whether or not this

occurred in the other 4920-or-so subjects.





There were seven cases in the STAN arm, 7

out of 15, and 8 out of 31 in the control arm. What

you see on the lefthand side of the slide is just

apparent or confirmed reasons why there was no

automatic event signal. In several cases the STAN

monitor hadn't been on for the required 20 minutes.

In other cases poor signal quality probably

contributed to a failure to register an automatic

event.

The last two categories are more difficult

to confirm. Nevertheless, it appears possible that

some sort of acute hypoxic event took place sometime

after the scalp electrode was removed and actual

delivery. We believe that there is one case where

pre-existing severe hypoxia was responsible for

failure to record an automatic ST event because a

myocardium that has been exposed to severe chronic

hypoxia may not respond similarly to hypoxia during

labor, as an infant, a fetus, who is not.

What else did I want to say about this

slide? I think we can go on to the next slide. Oh,

one last thing. I'm sorry.





The management of normal labor by midwives

is one characteristic of OB management in Sweden

that's different from the U.S. As it has been pointed

out, midwives manage normal uncomplicated deliveries

in Sweden.

Mid-cavity operative vaginal deliveries

were interesting in this study in that in the STAN arm

about 50 percent of the operative vaginal deliveries

were mid-cavity deliveries. That's probably a higher

percentage than we would see in the U.S., but, in all

honesty, I don't have statistics on that. In the

control arm it was slightly lower; around 40 percent

of those operative vaginal deliveries were mid-cavity

deliveries.

In looking through the cases, the tracings

for the cases of metabolic acidosis and other adverse

outcomes, we noticed a few examples of what might be

differences in labor management, including management

of chorioamnionitis, duration of the second-stage, and

management of uterine hyperstimulation, the presence

of a non-reassuring fetal heart rate, but I can't make

generalizations here. I could point to specific cases





where I believe that patients might have managed

differently in the U.S.

With respect to biostatistical issues,

there are no FDA biostatistical issues regarding the

presentation of the efficacy data for the primary and

secondary endpoints. The numbers and the percentages

and the statistical significance are not being

contested.

As I said earlier, I just wanted to

summarize some outcomes of the other clinical studies

using the STAN monitor, in part to give credit for

what is a vast body of clinical experience with this

device in Europe. The Plymouth study enrolled 2,400

subjects. These were high-risk labors. It was not

designed or powered to evaluate metabolic acidosis.

There was a significant reduction in operative

delivery for fetal distress and Caesarian section for

fetal distress in the arm of the study that used the

STAN device.

At that time -- that was in the early

1990s -- there were some differences between the

device used then and the one used in the Swedish RCT;





for example, in automatically identifying biphasic

events. There was also in that study a trend toward

reduction of metabolic acidosis in the STAN arm, but

that was not statistically-significant. As you see,

the cases of asphyxia were approximately the same in

each arm.

The European multi-center trial was a

relatively small trial which, as I understand,

prospectively recruited subjects. However, the ST

data was blinded, and the subjects, the tracings were

evaluated retrospectively. Eleven out of 12 of those

cases with evidence of hypoxia or asphyxia did have ST

changes when the tracing was unblinded for that data.

The Nordic observational study was larger

than the EC multi-center study. Management was based

only on the fetal heart rate data, although ST data

was available, and the results showed that following a

retrospective evaluation, the tracings blinded to

clinical outcome of 100 percent sensitivity for the

STAN guidelines to recommend intervention for cases

with neurological symptoms and/or metabolic acidosis.

The City of Gothenburg experience was what





tracings of some cases using the STAN monitor. The

first three cases I would like to show, for those of

you who might not have gotten your disks working,

actually, they're from a training CD, a collection of

cases that are used to train clinicians using the STAN

monitor. The purpose of showing these case studies is

just to illustrate different aspects of the STAN

monitor, but it is not to comment on management per

se.

The first case that I'm going to show you

isa VBEC patient at 41 weeks -- I'm sorry, 42 weeks,

one day, who was dilated 5 centimeters at the time

that the monitor was applied.

These tracings go relatively quickly. So

I'm just going to back up very briefly.

Again, what you see on the bottom of the

screen is the T/QRS data here. So this is the line

that we would be looking at during cases recorded with

the STAN monitor. For those of you in the audience

who might not be obstetricians, this line up here is

the fetal heart rate, and this line down here reflects

the uterine contraction pattern.





So what I'm going to ask you to do is

mentally be evaluating how you think the fetal heart

rate tracing is going, and bear in mind what's going

on in the bottom of the screen, where we are getting

our T/QRS data.

I'll try to speed this up to what I think

is the punch line.

There's reasonable variability here with

some reactivity, and then we're going to evolve into a

slightly different pattern.

So what we had here -- I'm just going to

back that up for a second -- drop in baseline, and

again some drops in baseline that look to be -- it's

difficult to evaluate the fetal contraction pattern.

We're losing some variability. We're

losing reactivity.

And what I am looking for here is an ST

signal event marker.

(Member of the audience begins to speak.)

CHAIRMAN BLANCO: I'm sorry, please, no

comments from the audience. If you need to make a

comment, you need to identify yourself, okay?





DR. CORRADO: What might be happening here

is that the point that I was trying to illustrate from

this case is that there was an ST event, an automatic

ST event, that occurred approximately 40 minutes prior

to delivery. It would have signaled an intervention.

The infant was born with Apgars of 1-5-5 and a cord

arterial pH of 6.82 and a base deficit of 17.

The reason I selected this case was to

illustrate that if the ST event data had been

available and the case intervened according to the

STAN monitor, we very likely would have gotten a

better outcome.

Can I just interrupt this for a second,

please, and ask if maybe the sponsor can tell me, are

we not going to see the actual ST event automatic

signals here? Because that was what I was trying to

illustrate.

(Sponsor representative speaks privately

to Dr. Corrado.)

Well, given that I need a slightly

different directory, what I will do here is, regarding

these training cases, what I would like to do is just





definition of metabolic acidosis as prospectively

identified by the sponsor clinically meaningful?

Question No. 2 has to do with the outcomes

in the study. I showed a couple of slides just

presenting the outcomes. We would ask the panel to

discuss the clinical significance of these results,

first for the intent-to-treat group -- that was

Analysis I -- and then for the adequate recordings

group.

As I just summarized -- I apologize, this

is very difficult to see on the screen. It's

virtually impossible to see. So I just, again, point

out for everybody that you've got these questions in

the handout for the meeting.

This is panel Question 3, and we would

like the panel to discuss the implications of a number

of issues in relation to the clinical significance of

the results that were described under Question 2.

First, deviations from the patient

management protocol. Second, no registration of an

automatic ST event in certain cases. Third,

exclusions of subjects in the study based on





inadequate recordings. Fourth, intercountry

population and management differences. Then, lastly,

whether or not there's any significance to the

retraining that occurred in the middle of the study.

We would like the panel to weigh the other

body, the large body of clinical data outside of the

Swedish RCT and determine to what extent do the

results from those studies support the safety and the

efficacy of the monitor.

We haven't said much about labeling and

training, but it's one of the most important things

that we do here at FDA. We would like the panel to

comment on the appropriateness of the indication and

whether or not the PMA data support this indication

for use, and whether or not the professional labeling

and training materials are sufficient to ensure

appropriate use of the STAN monitor.

If the panel votes to recommend approval

of the monitor, we would like the panel to comment on

whether or not there's a need for post-approval

studies.

With that, I'm going to retire here,





unless there are any questions for me specifically

regarding the FDA review, and let the panel begin its

deliberation.


We'll go ahead and begin the deliberation portion of

the meeting.

We've already read the discussion

questions, and, Panel Members, they are in your

handout folder, so you can look at that.

What I would like to begin with, and we

started doing this, is we would like to try to address

if the panel members have any questions of fact that

they might like for the company, the sponsor, or FDA

to address, if we could bring those up during the time

that we have before lunch, so that would give them

some time over lunch and prior to the last open public

hearing portion to try to address those specific

issues. Is that kind of clear with everybody?

All right, I'm going to ask Dr. Ramin, as

the lead reviewer, to go ahead and start us off on the

discussion.

DR. RAMIN: I'm Susan Ramin. I'm the lead





umbilical cord occlusions, trying to simulate the

dynamic changes that occurred during labor.

What the authors concluded is that

monitoring must include the T/QRS height as well as

the waveform analysis. I was wondering if you could

clarify, does the STAN monitor evaluate the height of

the T/QRS as well as the waveform analysis?

There were also approximately 14 percent

of the cases, roughly about 600 cases, where there was

no cord gas data available. I know that part of the

trial requirement was to have both an artery and a

venous sampling. I was wondering if you have the

numbers of how many cases had just an arterial sample

and how many cases had a venous sample, and whether or

not there were any cases of metabolic acidosis based

on one artery or venous sample.

I was wondering if the sponsors could

provide their definition of mid-pelvic operative

delivery, and whether or not -- what is utilized for

that definition in Sweden and what was utilized for

the trial.

CHAIRMAN BLANCO: Your implication there





being a comparison to what may be the definition in

the United States, correct?

DR. RAMIN: Correct.

There were the 46 cases of metabolic

acidosis out of the entire population. In the

randomized clinical trial, as was brought out by the

FDA, the STAN monitor did not register an ST event in

7 of the 15 cases in the STAN arm and in 8 of the 31

cases from the control arm. My question would be,

what is the sensitivity and specificity of this device

in detecting metabolic acidosis and hypoxia?

Likewise, in the randomized controlled

trial, there were inadequate tracings or inadequate

recordings in almost 12 percent of the cases. My

question is, is the 11.6 percent inadequate recording

rate satisfactory?

In the United States there is a tendency

toward less operative vaginal deliveries, marked

increase in Caesarian delivery rates, and there's a

limited use of fetal scalp blood pH. Given the lower

Caesarian delivery rate in Sweden, roughly 13 to 15

percent, compared to the United States, which is over





20 percent, is there any evidence that the use of the

information from the ST event or the ST waveform

analysis during the second stage of labor would result

in obstetricians not to intervene when it's

appropriate?

CHAIRMAN BLANCO: I'm sorry, could you

clarify that a little bit more?

DR. RAMIN: Sure.

CHAIRMAN BLANCO: Because I'm not sure I

understood that one.

DR. RAMIN: You gave the example of that

recording where there was good variability, beat

variability in the fetal heart rate tracings, but

there was also an ST event, and a Caesarian delivery

was performed. The cord gas was normal, and thus

intervention was done based on the ST event recording.

And the question is, how many times did that occur

where an intervention was done based on ST events even

though the fetal heart rate tracing was reassuring and

the cord gas status was normal?

Yes, you have a question?

DR. ROSEN: Could I ask for clarification?





I understand that it's observational, but I was, I

guess, curious about whether these were commercially-

acquired devices by the hospitals that then did the

study or were they provided by the company? What was

the training like? How much was this like a study as

opposed to how much was this like clinical practice?

Because I think that has a lot of implications for how

the device would be used once sold in the United

States.

And I don't think it was reviewed in his

presentation by Dr. Rosen, but I was curious about the

results in the Gothenburg trials. It appeared that

the decrease in metabolic acidosis was not as good in

the STAN group as in the CTG group in the latter half

of the trial, October to January, 2001 to 2002. So it

appeared as if the greater improvement was in the

patients monitored by traditional technique rather

than by the STAN, I think.

Then my final question was regarding

alarms. Does the system come with any alarms? Are

there alarms that can be set, or is it all totally

dependent on observation of the treating physician or





nurse?


MS. TOLEDANO: Alicia Toledano from Brown.

I had the same question about audible

alarms, and I had a question about how much experience

you have with breach presentation.

My main question is, how much do you think

you would have an effect on labor management if you

just retrained people on the current -- you know what

I'm trying to say. If you retrained people on using

the current fetal monitoring techniques, would you be

able to effect the same change as retraining them

including the STAN?

I'm done.

CHAIRMAN BLANCO: Okay, thank you.

DR. WOLFSON: I'm Bob Wolfson.

My question is actually a couple of

questions. One, why the 20-minute interval? What is

the statistical basis of that? I presume it has to do

with signal-to-noise ratio, but could you please

explain why that was derived?

Also, the issue of mid-forceps, my





impression is that is a relatively rare event in the

United States. Therefore, one could at least crudely

move the mid-forceps rate either by vacuum or by

forceps formally that's reported in the Swedish study

into the Caesarian section column for assessment in

the U.S.

I'm interested if you have any specific

information on IUGR. The low birth weight rate

clearly in the United States is substantially higher.

Granted, a significant portion of that is due to pre-

term births because our pre-term birth rate obviously

is approximately twice that of Sweden, typically

running around 10 percent.

But, specifically, because IUGR represents

a fetus at risk for metabolic acidosis, and you've

demonstrated, at least my understanding of the

physiology, you're reporting that this is specifically

an area in which the biphasic T wave is important. I

would like to know if you can tell us a little bit

more about the predictive value specifically in IUGR,

since I think that's a major impact in the population

differences.





Oh, and could you please clarify for me, I

still remain confused as to which is the primary drive

in this study or in the way of using this device.

When you're monitoring an individual, are you using

the electronic fetal monitoring information that would

be, I'll say, conventional information as your primary

tool, where the ST segment information now becomes

secondary in making a decision? Or are you really

utilizing the ST segment information, and when that is

of question, you then look to the electronic monitor?

So which is the primary tool here?

CHAIRMAN BLANCO: But what you're asking,

by primary tool, you mean, what was supposed to be the

trigger that caused, that would have caused an

intervention in the patient? Is that what you mean?

DR. WOLFSON: Well, Jorge, it's not just

the intervention. The thing that I find myself doing,

and just in looking at the images that were put up on

the screen, my mind always looks for more information.

I found myself rapidly watching the T wave

information, and when I saw the segment rise or become

biphasic, I merely looked to the EFM part of it, the





traffic signal with a green light and a red light

that's made by a decision in the machine some way or

another. I'm not sure I understand what that decision

is, and it worries me a bit.

So I would like to ask the proposers and

the FDA if they could comment a little more about

that, particularly the issue that Dr. Wolfson brought

up, namely, about the 20-minute period where we don't

know what's going on. Yet, in one of the

presentations the mention was made that 30 cardiac

cycles were averaged to do the analysis, and I get

that to be about 15 seconds or so. So I'm wondering,

what else is going on?

The second thing is the robustness of the

analysis routine in terms of signal distortions,

either arising from the electrode itself or from some

of the technical issues in terms of signal matching,

which I don't think we should get into here. But at

least we should hear a little more about how robust it

is and what constitutes the gaps in the data that we

see. What does the monitor decide as non-analyzable

data?





I believe somewhere in the documentation

that was a comment that this data, in fact, can still

be visually analyzed. I would like some more

information on that.

The final question I have is with regard

to the lead configuration, and probably my colleague

on my left could better ask the question than I can,

but it is my memory from the distant past that the

configuration of the T wave is very much dependent on

the particular lead that you're using to monitor it.

I'm curious if anyone knows what the spiral electrode

on the fetal scalp is in terms of cardiographic lead,

and even more important, is there the possibility that

-- and I have to use a technical term here -- the lead

vector changes during labor as the position of the

fetus changes, and that this could result in some ST

changes?


Dr. Sharts-Hopko?

DR. SHARTS-HOPKO: Okay, Nancy Sharts-

Hopko.

I was also concerned about lead placement





and diagnostic tracings. So thank you.

I am also concerned about the

comparability of how women are attended during labor

in Sweden versus the United States. We can typically

two registered nurses to six laboring women, thanks to

central monitoring. So there has to be a person there

watching for these ST events, so that intervention can

happen within 20 minutes, and I'm pretty worried about

that.

I am also concerned about in Book 1,

Section 2, page S-4, we have a list of complaints from

people who purchased 96 units. There were 57

complaints. I am interested to know how those have

been addressed, and I'm assuming that these complaints

the data that we've been given.

Thank you.


Jay?

DR. IAMS: Jay Iams, Ohio State.

I have a couple of study questions that

can probably be best found by looking at Dr. Corrado's

presentation on pages 8 and 9 regarding infants who





were excluded in Analysis II. Is there any reason to

think that infants who were excluded due to inadequate

cord blood might have a different incidence of

metabolic acidosis than infants who remained in the

study? Were they so profoundly depressed and had such

poor cardiac output that the cord samples

preferentially perhaps would have revealed babies who

were sicker? And if so, or regardless, do you have

any data on those babies regarding their Apgars

scores?

The next one was on the next page, Dr.

Corrado's slide No. 17, on page 9. The percent of

removals, she listed them as removals according to

what percentage of removals were 1.3 percent, 37

percent. Those are percentages of the removals. I

was wondering more about in each group, the STAN

versus the CTG alone, if those percentages within each

group were approximately the same.

Let's see, we also learned that the STAN

is not completely sensitive in detecting pre-terminal

or being coincident or in agreement with pre-terminal

tracings. What is the degree of concordance when





there's a pre-terminal tracing? Does the STAN

virtually find that always?

And then the last question is regarding --

it's somewhat theoretical. When you're looking at

myocardial hypoxia, myocardial acidosis, how

reflective of that, in animal studies perhaps, how

much does that reflect hypoxia and acidosis elsewhere?

Is it so sensitive to the heart that, in fact, it's

not necessarily applicable to the systemic

circulation?


Gary?

DR. EGLINTON: I'm still thinking about

mid-pelvic operative deliveries and wondering about

the definitional difference. It's probably in here

and I just can't remember it. I would like to know

what the frequency of mid-pelvic operative delivery is

in this sequence of studies, if it's relatively

uniform in all these studies or especially in the

Swedish RCT.

Since I've been a chairman for three years

and been looking at credentials packages, a third of





my staff that has joined my staff in the last three

years, almost none of them apply for privileges for

mid-pelvic operative delivery. They just skip that

box on the credentials sheet. I think there's

probably a major cultural difference here between the

European Union and the U.S.

Thank you.

DR. O'SULLIVAN: Mary Jo O'Sullivan,

Miami.

I have a question regarding the

training/retraining. I would like to know (a) what

were the differences between the initial training and,

after the first interim analysis, the retraining, if

there were any differences at all and how that

training was done, other than I realize that

individual hospital cases were used for the retraining

purposes, and they were, therefore, retrained on their

cases. Was that the only difference that occurred in

the whole retraining process? If it was not, then

what were the characteristics of the original versus

the retraining? I ask that because of the differences

between the interim analysis and the subsequent





analysis.

DR. BROWN: Carol Brown, New York. I have

a couple of questions.

One was about the correlation between

cardiac ischemia and specifically the effects on the

central nervous system. Is that a correlation, again,

in an animal model, specifically to metabolic acidosis

and encephalopathy, any type of fetal model?

Another question about the

training/retraining: Was there any assessment of the

baseline experience and familiarity with using CTG at

your centers? In Sweden I obviously you have, I would

assume, a much higher proportion of nurse midwives for

managing most labors. Was there an assessment of what

their baseline experience and interpretation of CTG

was before retraining, before training and retraining?

And specific numbers in terms of the percentages of

these traces that were managed by nurse midwives

versus OB/GYNs, proportionately, because I would

suspect there would be a big difference in the United

States in terms of the number of nurse midwives

proportionately who would be managing these cases.





One other question was, it was mentioned

in some of the background information about ST segment

depression specifically. I just wanted to clarify how

ST segment depression, is that incorporated in the

biphasic assessment or is it possible that that could

be a separate thing that would or would not be picked

up by this system?


DR. SEIFER: David Seifer, New Jersey.

Two questions: One is the inadequate

recordings of 12 percent, is a number that one would

expect with a new technology, looking at these

endpoints? Also, so would one in actual practice, as

opposed to a study, expect to see 12 percent

inadequate recordings?

I would imagine that part of the answer to

that question might include what clinical information

investigators have to understand if this greater than

50 percent of greater than 20 minutes between the

device and delivery, if we have an explanation of why

that might have occurred and whether or not that would

be preventable in a clinical setting? Also, with





MS. LUCKNER: Thank you. That's it.


I have one question I would like them to

address and clarify, the utilization of 7.05 as the

definition of metabolic acidosis, how was that arrived

at, and why the decision was made to use that value?

It's not, I believe, the common value used in the

United States. That was the one question that I had.

What we're going to do now -- there are a

lot of questions that folks have. I would like to

encourage the sponsor and FDA to be very brief. Most

of these are actually addressed to the sponsor. Be

concise and to the point because we need to not be

spending all the time listening to the answers. We

need to discuss what we think. So we would like

clarifications, and many of the questions are similar,

so you might want to join them together on there.

DR. WOLFSON: Jorge?

CHAIRMAN BLANCO: Yes, go ahead.

DR. WOLFSON: Can I add an additional

question?

CHAIRMAN BLANCO: Sure.





DR. WOLFSON: Could you clarify the basis

by which the actual management guidelines were

derived? There were specific differences in the rise

of the ST segment based on the CTG information. It

wasn't clear to me, though I think you had one slide

that suggested, but I didn't understand the

differences as to why in one case it's greater than .1

where in the other case it's greater than .15. Is

there actually specific statistical information that

demonstrates the value of those specific thresholds or

was this based on clinical grounds and then simply

prospectively moved forward?

The other question that occurred to me in

the midst of the discussion was, could you clarify

again the use of fetal monitoring in Sweden compared

to the U.S.? My impression certainly in my own venue

is that electronic fetal monitoring will be used

somewhere in 80 to 90 percent of labors. Granted,

typically, this is external monitoring through the

bulk of the labor and not an internal monitoring?

My impression was that your data suggests

that the internal monitoring takes place in about 40





percent of your labor. So you have different

criterias. I would just appreciate a clarification.

Thank you.

CHAIRMAN BLANCO: All right, so let's be

concise, and let's try to put some of the questions

that are fairly similar together, so that we can get

some discussion of the questions that FDA would like

for us to address.

The other thing that we're doing, I think

we only have 30 minutes under the current agenda. I'm

going to take the Chairman's prerogative and go ahead

and close the meeting now for lunch and reconvene a

bit early, so that we don't have to break the

discussion up into a small amount of time, if that's

all right with the panel. Okay?

So it is right now, by the official clock,

11:30. We would reconvene at 12:30 and begin the

discussions at that point. Thank you very much.


the record at 11:31 a.m. for lunch and went back on

the record at 10:54 a.m.)





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

12:34 p.m.


ahead and see if we can get started, please. All

right, let's go ahead and begin the afternoon session.

The way that we're going to try to do this

is we would like to, first of all, address the

discussion questions that the FDA has posed to the

panel. Panel Members, you should have a copy of these

in your panel booklet.

If some of the questions that were asked

by the panelists of the sponsor are included in this

particular questions for the FDA, then we'll ask them

to come up and answer it at that time, but if not,

then we will wait until the time that we have allotted

for the open public hearing later this afternoon

again, and at that time we'll bring up the company,

the sponsor, to answer some of the questions that the

panelists posed.

All right, well, let's go ahead and begin

then. Let me just read the first question, and it's

also up on the screen for everyone.





Discussion question, safety and

effectiveness. No. 1: "The pivotal clinical study

supporting this PMA is a large multi-center randomized

controlled trial conducted in Sweden. The Swedish RCT

was designed to compare several fetal and maternal

outcome measures between women managed with STAN

monitor technology and women managed by conventional

monitoring technology."

A: "The primary endpoint for the study is

metabolic acidosis. Is this endpoint appropriate?"

And I guess I'll go ahead and turn to Dr.

Ramin to start off the discussion on 1A.

DR. RAMIN: I think the primary endpoint

using metabolic acidosis is appropriate and reasonable

to utilize, given the pathophysiology behind this

device.

CHAIRMAN BLANCO: Okay. Any other

comments? Anybody else want to address the issue of

the metabolic acidosis?

DR. IAMS: I'll just make one comment. It

has to be recognized; it's the best surrogate endpoint

you can use, but metabolic acidosis is not, in and of





itself, an endpoint. It's a marker for the ultimate

endpoint, which is neurologic injury, presumably. We

all know the difficulties inherent in using that as an

endpoint. So it's an appropriate choice for a

surrogate endpoint.

CHAIRMAN BLANCO: Well, let me throw out

some things on this. I mean, they may be an

appropriate endpoint as surrogate, but in looking at

how it was defined in this particular study, there

seems to be a significant number of neonates that,

although had the definition, really didn't have very

much of a significant, were not affected in any way

that was reported. So I don't know if part of that

might have been what FDA had in mind, but to me I had

some concern about whether the definition of that

really reflects, and is a good surrogate for,

something bad happening in the fetus and neonate.

DR. RINGEL: Our markers of a bad outcome,

if you just look at the neonate, are perhaps weak. So

that stress that occurred during delivery might not

show up for a year, two years, five years. So that

you have to use some marker; otherwise, the studies





would never get completed. Then you won't even be

able to link it to later events, learning

disabilities, and so forth. So I think that metabolic

acidosis is a reasonable marker.

DR. IAMS: I would just add I think the

best marker, and I certainly defer to the pediatric

colleagues around the table, but the best clinical

actual marker of long-term performance that's

measurable in the neonatal period is seizures. If you

have seizures in the newborn period, I think that's

still the best clinical marker, not laboratory marker.

CHAIRMAN BLANCO: I'm sorry, was there a

comment over here?

DR. O'SULLIVAN: Yes, I was just going to

say, a lot of kids with seizures, Jay, don't have any

problems at all.

DR. IAMS: Well, true, they don't, but if

you're looking for a marker that's not a laboratory

event, subject to the vagaries of where you set the

threshold, et cetera, seizures I think are the one

that's been used in most trials trying to predict

who's going to have neurologic injury. That's not





perfect by a long shot, I agree, but I think that's

the one that's in most common use.

DR. RAMIN: I have a comment just about

your statement about metabolic acidosis and a fair

number of these babies didn't have any adverse

outcome. We have seen that in a lot of studies where

two-thirds of babies with metabolic acidosis go to the

newborn nursery and do perfectly fine. But I think we

have to have some endpoint in this study, and it would

be an immediate marker. I mean, ultimately, what we

need is long-term neurological outcome, but that's not

the purpose of this study.

CHAIRMAN BLANCO: Gary, you had a comment?

DR. EGLINTON: That's okay.

DR. O'SULLIVAN: Maybe the difference

should be in terms of what is metabolic acidosis.

CHAIRMAN BLANCO: Well, that's part of the

next question, so that's why I was leaving for that.

I just wanted to make sure. I think it's important to

point it out, as Jay did, that it is a surrogate

endpoint for what you eventually want to do.

DR. WOLFSON: My only comment was that I





think that we all would agree that metabolic acidosis

is not a natural state and, therefore, it's a state of

physiology that we want to avoid. While we may not

have all the information on its actual impact, both

short-term and long-term, on an individual, I think

it's still a worthwhile endpoint to choose in a study

of this nature because it's a space we don't want to

be in for a fetus or, for that matter, the mother.

CHAIRMAN BLANCO: All right. Any other

comments on 1A?

(No response.)

All right, well, let's move on to 1B,

brought up as well by Dr. O'Sullivan. "The definition

of metabolic acidosis in this study was an umbilical

cord arterial pH less than 7.05 and a base deficit

greater than 12 millimeters per liter. Is this

definition of metabolic acidosis clinically

meaningful?"

Would you like to go ahead and start, Dr.

O'Sullivan?

DR. O'SULLIVAN: I think that the data

that was pointed out by the FDA showing the





think it may be appropriate at this point maybe to

have Dr. Rosen, whoever is going to answer the

question about, why was the definition of 7.05

utilized, if somebody could come up and address that?

Maybe to the podium might be better.

DR. ROSS: I'm Michael Ross, Professor of

OB/GYN at Harbor UCLA, and I'm a consultant to the

sponsor. My travel has been reimbursed for today.

The issue of the 7.05 and the base excess

is a great question. Firstly, although, Dr. Neuman,

as you suggested, pH and base excess are continuous

variables, it appears from really the best literature,

and that's largely derived from the extensive work of

Jim Low in Canada, indicates that really there are

threshold levels, and that base excess is probably the

best single individual level to assess the risk of

newborn neurologic disease.

So I would argue that, rather than looking

at either pH or base excess as a continuum, it appears

that babies have a minimal to negligible risk of

neurologic disease from an acute event unless their

base deficit is 12 or greater. And at that point





the harvested umbilical cord?

DR. O'SULLIVAN: They're taken from the

umbilical cord --

DR. RINGEL: But the CO2 is changing then?

DR. O'SULLIVAN: Hum?

DR. RINGEL: The CO2 is changing as --

DR. O'SULLIVAN: Not significantly.

DR. RINGEL: Not significantly?

DR. O'SULLIVAN: No.

DR. RINGEL: Because it's clamped on

either end.

DR. RAMIN: There have been studies that

have shown that it doesn't change dramatically.

DR. RINGEL: Thank you.

DR. ROSS: Right. So I think that the

minor differences in procedures or rapidity of doing

samples are not going to change the value

significantly.

CHAIRMAN BLANCO: All right, thank you.

All right, any other comments on the

definition, and we do we think the definition is

clinically meaningful?





(No response.)

I guess there is no comment on that.

DR. EGLINTON: Jorge? Jorge, let me be

the naysayer then. I mean, everybody is familiar with

probably 25 publications by Dr. Low on base deficit.

That's fairly straightforward, fairly clean. I don't

think anybody, answering Michael's original question,

I don't think anybody has performed a receiver

operator characteristic curve analysis of pH, which is

probably what we would like to see. But I think that,

based on clinical outcomes, a bunch of the things that

have been published, and a lot of it by Larry

Gilstrap, has focused on a pH under 7 as being more

clinically important in terms of longer-term outcome.

If we look at the slide that Dr. Corrado

provided for us, slide 21, at a pH of less than 7,

there was no difference between the STAN and control

arms. They're really identical proportions.

So it seems subtle, 7.0 versus 7.05, but

it may actually be clinically important. The 7.05 may

not front-load the population with enough risk to be

clinically useful. It may require a pH lower than





that in order to have enough risk in the resultant

population, enough risk of long-term injury.

CHAIRMAN BLANCO: Well, I think it goes

back to the original issue of, is the definition --

you know, we said metabolic acidosis as a term is a

good surrogate endpoint for damage, but, yet, you

know, that's part of the problem: Is 7.05 enough of a

definition that it a surrogate marker or should a

lower number have been used to have been a better

marker of actual damage to the neonate or the fetus or

neonate? I think that's the question that needs to be

addressed.

Dr. Wolfson?

DR. WOLFSON: Two things: One, if we're

looking back at other studies, we've got to be

consistent in terms of what the outcome is. What's

the gold standard here that the pH is being compared

to, and what level of damage are you requiring in

those studies? We also know that many of those older

studies didn't take into account that a lot of the

damage that was observed was not based on metabolic

issues. It was anatomic disorders in the individual.





to show?

MS. TOLEDANO: Let me focus for a second

on damage to a neonate and what's clinically

significant. We have on Dr. Corrado's slides on page

12, her slides 23 and 24, and those show us the babies

with moderate and severe encephalopathy. There are

seven of those babies. What was their core blood pH?

Was it all less than 7 or were there some of them that

fell between the 7.0 and the 7.05 that within the

United States we would not have considered to have

metabolic acidosis?

So maybe if people are interested to find

that out, how many of those babies fell below 7.0

versus within 7.0 and 7.05 --

CHAIRMAN BLANCO: Well, why don't we see

if they're able to address that. I think along with

that, Dr. Ramin had asked a question about the 46

cases that were defined as having metabolic acidosis

and what was the sensitivity and specificity of this

device in identifying those particular cases. Maybe

we can have someone from the sponsor try to address

those two questions at this point.





Dr. Rosen, come to the podium, please.

DR. ROSEN: So the issue is very much,

what babies are affected by the process of being born?

And we did an attempt in analyzing those cases by

using the neonatal records, looking at what happened.

Did they have increased neuromuscular tone? Did they

have neonatal seizures? What we found was that some

of them had metabolic acidosis and others were exposed

to the forces of labor applied by vacuum/forceps

deliveries.

I think the issue is very much on how we

manage, learn to manage labor more appropriately. As

Dr. Corrado demonstrated, there were no cases in the

STAN arm that suffered severe or moderate

encephalopathy, whereas there were seven cases in the

control arm that did this. I believe that monitoring

is very much a managerial issue and how you relate to

the changes.

To what extent there were metabolic

acidosis of greater than 7, I have to look at the

data. You have all the data presented to you in your

folder. We have a detailed analysis of all these





cases.

CHAIRMAN BLANCO: Well, that's why I would

ask you if you could have someone maybe in the next 30

minutes or so -- I mean the seven cases with

encephalopathy were either moderate or severe, and see

what their pHs were.

DR. ROSEN: Well, I know that in some of

these the pH was quite reasonable.

CHAIRMAN BLANCO: Well, let's see if we

can figure that one out.

DR. ROSEN: Yes.

CHAIRMAN BLANCO: Okay? And then how

about the issue of the sensitivity and specificity in

the 46 cases?

DR. ROSEN: Well, we haven't done that

analysis simply because in those 46 cases we

intervened, obviously. We did sensitivity/specificity

analysis on the Nordic observational data, where no

intervention was done, according to the STAN protocol.

So, clearly, whether one should go for

automatic ST assessment or whether we should use what

the educational program says, and the way the user is





taught to handle the information by visual analysis as

well -- and as I showed you, yes, there were cases

where metabolic acidosis did emerge with no ST events,

in one case with a pre-terminal heart rates where the

guidelines said there was a need to do something, but

there will be the occasional case where there may not

be that dominant heart rate change and there will be

no ST, or there may be a period of time, of 10

minutes, where we don't have data available to us.

CHAIRMAN BLANCO: All right, well, thank

you for your answer. I think we ought to add the

question of, if you could see if you can have your

data and have someone look to see what the pH of the

seven cases with encephalopathy were. We would

appreciate it.

All right, any other comments on 1B? No

other comments? Dr. Wolfson?

DR. WOLFSON: Just one more question: If

part of the outcome issue is neonatal outcome with

respect to neonatal encephalopathy, then can we not

consider that the outcome that was created, since

that's the long-term outcome, was one that was





Okay, well, let's move on to Question 2

then: "List the outcomes from the Swedish randomized

control trial. Please discuss the clinical

significance of these results, essentially looking at

the primary endpoint as metabolic acidosis. In the

Analysis I, which is the intent-to-treat group, you

have a significant difference from 0.69 percent to 1.5

percent with a P value of 0.02, and in the Analysis

II, the adequate recording group, you have a 0.57

percent versus a 1.4 percent with a P value of 0.01."

Any comments on those results and the

clinical significance?

I think it's kind of what we've been

discussing, which is the definition, whether you

accept the definition of metabolic acidosis, as was

done in the study, and then show the difference.

Anybody else want to say anything else?

Jay, do you want to add something?

DR. IAMS: I was thinking of something

else when you were asking that question, but the

bottom line comes down to the number of individuals

with an adverse event. Although the almost 5,000





patients is a lot, by the time you get down to the

final endpoint, you're dealing with numbers that, for

other tests, other populations, would perhaps be

considered simply not enough.

That's a concern I think that I have about

the -- I'm not sure what the right word is, but the

durability of these relationships is evident. As Bob

said, the P values are fine. The design of the study

was appropriate. I don't disagree with the choice of

endpoints. I think the response that Dr. Ross gave

was appropriate. But when you get all finished with

that, you end up with not very many patients in those

cells, which is troubling. If you add to that other

issues that we'll talk about regarding trans-Atlantic

transplantation, it just gets a little concerning.

So it's hard to say I'm really concerned

about this question or this question so much, but in

the end the number of babies who had problems is a

genuine concern.

CHAIRMAN BLANCO: I thank you.

Gary?

DR. EGLINTON: I wanted to talk just a





wouldn't come out of this trial, the RCT.

CHAIRMAN BLANCO: Any other comments from

any panel member?

DR. BROWN: Yes, I just had kind of an

informational question for the maternal/fetal medicine

people around the table in terms of translating this

data. Someone made the comment earlier that the

incidence of metabolic acidosis, I guess you all were

saying, defined as less than 7.0, is much higher in

the United States.

Can you comment on that in terms of the

numbers, if you were to sort of extrapolate this data,

in terms of the numbers of patients you would expect

to see if you were using this intervention in the U.S.

population? Or if you're going to use the cutoff of

7.05, which is what the indication is, do you have any

sense or can you give us a sense of what comparable

expectations of percentage of babies born, say, at

Jackson Memorial who have less than 7.05 and base

excess of greater than 12 are?

DR. O'SULLIVAN: Very low. Very low.

DR. BROWN: So it's still very low?





DR. O'SULLIVAN: Uh-hum.

CHAIRMAN BLANCO: Any other comments?

MS. TOLEDANO: I've got my hand up, as

usual.

CHAIRMAN BLANCO: Any other comments?

MS. TOLEDANO: I've got my hand up.

I'm used to a screening setting in

radiology usually where we look at very rare outcomes.

When I sit here, I see us talking about, are there too

few of these babies? Is this too rare of an outcome

to really worry about?

I think the decision has already been made

by clinical practice where we are worried about that

outcome because we go after operative deliveries and

any indication of fetal distress to try to avoid the

metabolic acidosis, to try to avoid the neurological

damage. So every single one of those 45 babies or 50

babies or 90 babies in the United States that could be

saved by this, I think it's worth considering. And,

yes, it's a low number, but it's an important number.

That's just my personal opinion.

CHAIRMAN BLANCO: Dr. Ross, do you have





the pH use? Is that what you've got? All right, come

on up and let us know.

DR. ROSS: My appreciation to Dr. Corrado

for helping me with these cases here. Again, there

were three cases in the moderate encephalopathy group,

all of whom were from the control arm. Their values

were 6.78 with a base deficit of 12.8, 6.73 with a

base deficit of 21.8, and 6.87 with a base deficit of

16.9. Clearly, those three cases would meet anyone's

definition.

In the severe group there were two cases,

again severe encephalopathy, again two cases, both

from the control group, and those both have a little

interesting twist. One was born and a cord gas

obtained only from one vessel, and it's not noted

which vessel. That baby was born after 8 to 10

minutes of a shoulder dystocia. You're aware that

that sort of marks your point in time and then you

have 10 more minutes of now acidosis. So that baby's

single cord value was 7.17 with a base deficit of 3.7.

However, the immediate newborn blood, which was done

at 13 minutes of age, essentially just following the





shoulder dystocia, was 6.79 with a base deficit of

16.5, consistent with encephalopathy.

Then the final case speaks to this issue

of the importance of base deficit rather than pH, and

that is the severe encephalopathy case, the second one

from the control group, had a pH at birth of 7.1 but a

base deficit of 13.7. That likely was possibly due to

some loss of carbon dioxide in the sample or some

absence of respiratory acidosis. But, again, it

speaks to the base deficit being the key issue.

So I don't think there's any real

difference in this prediction whether you use 7.05 or

7.0. Thank you.

CHAIRMAN BLANCO: Thank you. All right,

how about the secondary endpoints and other measures

in the intent-to-treat group? We haven't addressed

the issue of operative intervention and C-section.

We've been mainly on the metabolic acidosis. Anyone

care to make some comments on the data for the

secondary endpoints and other measures?

(No response.)

Not particularly overwhelmed by the





panel's response here.

(Laughter.)

DR. SEIFER: Only to reiterate Dr. Iams'

concern about the small margin of difference here.

It's even slimmer, and it becomes more of an issue

when we get to the next question.

DR. O'SULLIVAN: I think that the only

thing I would add here is that, since mid-cavity

delivery is whether they're forceps or vertex -- I'm

sorry, forceps or ventouse -- are extremely rare in

this country. Now it's not that they don't happen,

but it is extremely rare.

CHAIRMAN BLANCO: It's extremely rare, so

you think it's not that applicable to the United

States situation? Is that what you're saying?

DR. O'SULLIVAN: Yes.

MS. TOLEDANO: But what would have

happened to them? Would they have ended up being

operative abdominal?

DR. O'SULLIVAN: They would have fallen

into the all operative interventions, which includes

Caesarian section.





MS. TOLEDANO: Okay, so they still would

have been C-section?

DR. O'SULLIVAN: Right.

CHAIRMAN BLANCO: So I guess the question

is, you know, later on to think about in the vote, so

I'll go ahead and bring it up, eventually, if the

device is approved, the company will have indications

for which the device has been proven to be clinically

useful. Does the fact that P value is somewhat small,

and you have the issue of the difference in operative

delivery rates in terms of vaginal versus Caesarian

section in Europe versus in the United States, do you

think that that makes any difference? Would someone

like to make a comment about the validity of operative

intervention differences for this particular device?

DR. RINGEL: Just before we get to the

issue of how they're delivered, I'm just thinking this

through. The STAN doesn't fix anything. All it does

is indicate that you've got to get the baby out

sooner. So in a certain group of patients that the

STAN identifies as being at risk, you will increase

the number of C-sections, or whatever, you know,





operative interventions.

So if we have accepted the metabolic

acidosis as the endpoint, the small difference in

operative interventions shouldn't bother us because,

hopefully, the ones that are being intervened on are

more appropriate candidates, so that we are swapping.

We are taking jeopardized or at-risk babies and doing

operative intervention, and taking healthy babies out

of that group. So we wouldn't expect a huge

difference in C-section rate, just in the metabolic

acidosis rate.

CHAIRMAN BLANCO: Well, actually, I was

going in a totally different area. I was going

exactly the opposite. One of the things that's always

of interest is being able to say that you've got a

fetal heart rate monitoring tracing that may look non-

reassuring, but you have a STAN tracing, if you will,

that is reassuring, so you can keep going and maybe

end up with a non-intervention vaginal delivery.

If you look at the numbers down here in

the first part, in the bottom part of the first page,

the rate of operative delivery was actually lower in





the STAN group.

DR. RINGEL: Right, I agree, yes.

CHAIRMAN BLANCO: What I was really

addressing was just exactly the opposite of what you

said, which is, you know, if the company is interested

in saying that they can lower Caesarian section rates

by identifying the non-reassuring fetal heart rate

tracings, that the STAN monitor says it's okay to keep

watching. Is that data that we have before sufficient

to be able to allow that statement to be made. That's

what I was trying to get at. Okay? Do you

understand?

DR. RINGEL: Yes.

CHAIRMAN BLANCO: Okay. Anybody want to

address that?

DR. BROWN: Well, I just think it's

problematic because, although you would have to then

make the assumption that all the patients that had

mid-forceps in Sweden would be patients who would have

C-sections here, is that really a valid assumption

without actually knowing? I mean, you're making a

jump in the data to make that statement. So I would





personally have some concerns about making that

statement, because you don't actually have the data in

the labor management culture that you're saying the

indication would apply for.

DR. IAMS: That's a reasonably comfortable

jump, I think, for most of us doing obstetrics in the

United States. We don't do mid-forceps very often, as

has been discussed. So that's a concern -- I mean

that is not as much a concern for me as the issue of

we operate with nearly almost twice the rate of

Caesarian sections in the first place, many of which

are done for presumed fetal compromise when, in fact,

no such thing exists.

So in this marketplace that's a very

appealing endpoint. It wasn't the primary endpoint in

this trial, but it is a very appealing endpoint

because we know we do more Caesareans than we would

like to do. So that's a concern. Our culture takes

devices like this, and it's on the next page, I guess,

as questions, and we do have a hard time using

information like this to reduce the Caesarian section

rate.





I think culturally caregivers in this

country are more likely to look at this as another way

to find babies, especially given the primary endpoint

of the study, babies who wouldn't be identified with

traditional cardiotocography. It might further raise

our C-section rate, maybe appropriately, as you said,

but we already have a perhaps even bigger problem with

injury to many mothers and complications with many

mothers. So we really are in a very different

cultural environment to use this technology than what

was done, I think, in Sweden.

CHAIRMAN BLANCO: Jay, I've got to kind of

call you a little bit on that because you started out

sort of saying you were comfortable with the fact that

there's a difference in Caesarian section rates in the

United States and Sweden, but you kind of ended with

sort of implying, or at least to me making me think

that you're really not comfortable with trading the

data to necessarily have that indication.

DR. IAMS: Let me see if I can say it

quickly and clearly again. The simple issue of the

data in this study using operative delivery as a





descriptive term for operative vaginal and operative

abdominal deliveries, that doesn't bother me. That's

nice. So end of comment.

I guess the second point was what I was

trying to say, maybe not clearly, is that in our

culture, marketed and promoted for its primary

indication, this device has some significant potential

to increase the Caesarian section rate, looking for

babies who have got problems. So we may decrease it;

we may increase it, but we're more likely perhaps in

this culture to increase it.

CHAIRMAN BLANCO: All right. Any comments

from anyone else?

DR. O'SULLIVAN: I think it's kind of

interesting that we are talking about, on the one

hand, decreasing the Caesarian section rate and, on

the other hand, now people can come in and ask for a

Caesarian section for any reason they want.

CHAIRMAN BLANCO: Yes?

DR. WOLFSON: I don't think we have the

data, but I think that we have to be very careful in

making the comparisons to look at, again, obstetrical





management because, as I recall in some of the early

work that was done on one of the NIH panels, one of

the principal reasons or one of the areas of concern

was that Caesarian section rates were increasing

because of, for example, breach delivery.

I don't know -- when we're looking here,

we're looking specifically at delivery for fetal

distress. I don't have a way of comparing raw

Caesarian section data or operative delivery data

between the two. My anticipation is that the overall

incidence of Caesarian delivery for fetal distress is

going to probably be uniform among most populations,

given that the individuals come relatively healthy

into the laboring process.

We talk about the translation between

countries. That may be the key point, that in many of

our academic centers, many of our urban facilities,

that the individual coming in in terms of the level of

pre-natal care, the knowledge of what's going on with

the infant, or I should say the fetus, are not going

to be comparable to the Swedish system, where they may

have much more information and have their patients





better defined than we do.

So I think that for fetal distress I think

we're okay. I don't think that the differences in

section rates is going to make a big difference.

CHAIRMAN BLANCO: Let me bring it back,

because I really started this as an adjunct to, in

other words, what the sponsor and company can claim

that their product does. Let me get not necessarily

the definition, but if you're comfortable with the

lumping together and if you're comfortable with the

differences between Sweden and the United States in

terms of operative deliveries, is this level of data,

this level of significance sufficient to make the

panel comfortable that they can make a claim that

they've lowered the rate of operative interventions

for fetal distress?

Did I make that specific and clear?

DR. RAMIN: It's only 1.6 percent

difference.

Can you hear me?

CHAIRMAN BLANCO: No.

DR. RAMIN: When you look at it, it's only





about 1.6 percent difference. So it's questionable if

it really ultimately decreases, at least clinically

significant.

DR. WOLFSON: Okay, but you have to look

at it from a proportional standpoint. It's 1.6

percent out of 7.7. So, proportionately speaking,

it's a relatively large number if you then project it

into a general population. I know we're sort of maybe

splitting hairs here, but even though it looks like a

small number, the fact that it's statistically-

significant says that you should be able to expand it

to a larger portion.

CHAIRMAN BLANCO: All right. If there are

no other comments, I think we probably beat that one

to death. So let's move on.

Let's go on to No. 3. Hang on, we're

going to No. 3.

"Several issues identified in the FDA

review may affect the results. Please discuss the

implication of each issue in relation to the

clinically significance of the results presented in

Question 2."





You can see that there are five items, so

let's go ahead and take it with the first side of 2A,

deviations from the randomized clinical trial patient

management protocol. Anybody want to start the

discussion? Maybe Dr. Ramin?

DR. RAMIN: Right.

CHAIRMAN BLANCO: Do you think that the

fact that there were deviations once patients were

identified as having an event, but yet the management

protocol was not followed, does that create a problem

in your understanding or support of the data? Or do

you understand what I'm getting at?

DR. RAMIN: My opinion would be that, yes,

there would be a significance clinically in the fact

that there was deviation in the clinical management

protocol, in defining an ST event but not intervening,

especially in cases of non-reassuring fetal heart rate

tracing, and you take the opposite approach as well.

So I think there are implications.

CHAIRMAN BLANCO: Okay. Anyone else want

to make a comment on that? Agree or disagree?

DR. EGLINTON: Yes.





CHAIRMAN BLANCO: Gary?

DR. EGLINTON: I would like to

congratulate the sponsors on in one case at least a

30-year career working on this and translating some

basic science research. This is translational

research here now, bringing this into the delivery

room.

But I'm worried about a second

translation. These are services that are very tightly

controlled, very high-level excellent care, people who

are very bright, coached by zealots who are also very

bright, and now we're talking about trying to

translate this across an ocean.

When we have some people who really have a

lot of trouble understanding basic fetal heart rate

patterns at this point, I don't see this as a question

on piece of paper here, but it is a question -- maybe

this is it; this is the best place for it, deviations.

I mean, they had deviations from their management

protocol. I'm just trying to imagine the deviations

from this management protocol in my own labor and

delivery unit, if I'm trying to introduce this





technology. I don't see that this is going to

translate.

We don't have any evidence that this

management protocol is doable in the United States,

that this can be implemented in the United States.

CHAIRMAN BLANCO: Yes, Dr. O'Sullivan?

DR. O'SULLIVAN: Well, I think there are

two issues. First, I think that the investigators

pointed out, and they have to answer this question for

me, what were the differences in education before and

after? I mean prior to the protocol violations, when

they first got started, versus after the protocol

violations.

I would hope that eventually, with the

right education, and starting out from ground zero,

that we could teach our people in this country to

perform adequately. I think that it will be

difficult, but I think it can be done.

I think the big issue here is, what was

the difference in the educational process as it was

introduced versus after the first 1600 patients were

done and the interim analysis were looked at that made





the difference here? How come there was such a

difference? Or how come it appears there as such a

difference?

MS. TOLEDANO: I want to be devil's

advocate for a moment and just to notice that when we

evaluate safety and effectiveness as members of an FDA

panel, it's for the device used in accordance with its

indications. While looking at the way the device

would be used in our culture is certainly very

important to all of us, that is not necessarily what

we are supposed to be looking at when we are

determining whether the device is safe and effective.

DR. RINGEL: Just to comment on the

deviations question that you're asking us to comment

on, I thought the deviations were equal in the control

group and the STAN group, so I actually think it's a

moot point. People deviate from protocols, people

deviate from accepted medical practice. They were

just showing that the deviations were equal in the two

groups. It may be a high number of deviations, but

they were equal. So I think it's a wash.

CHAIRMAN BLANCO: Yes, I think the





question was really aimed, and it's because of what

you said, in terms of how the FDA has to evaluate

things. The question was more, does the fact that

there were so many deviations invalidate the results?

Your point is they were probably randomly in both

groups, or maybe not randomly, but at least they were

the same numbers. So probably it didn't affect it one

way or another. Correct?

DR. RINGEL: That's the way I look at it.


comments? Anyone else want to say something?

DR. SHARTS-HOPKO: Well, I have to recall

that we've had experience in this panel with devices

that were not used according to the written

instructions and with adequate training. The chicken

came here home to roost. So I think that is something

that we have to be concerned about, and I'm concerned

about that.


comments?

(No response.)

All right, what about B, no registration





go and look for the ST event marker and it's not

there. So where does that leave you?

DR. RAMIN: Which one do you rely on?

DR. IAMS: Yes, and that gets back to one

of the questions we asked before the break, about the

number of pre-terminal tracings that were also marked

as being abnormal by the STAN.

DR. RINGEL: But, in fairness to the

company, they very clearly, even in their brief

summary, state that a pre-terminal ECG, you don't look

at the ST analysis.

DR. IAMS: Right, that assumes that pr-

terminals are all that easy to identify, which is one

of the tracings that we were shown this morning

reminds me of, sometimes they look pretty good. It

depends on where in the process you come into it, I

guess. If you come in at the end, it can get

confused. So we're just looking to see if there is a

correlation there, and then what degree of

correlation.

CHAIRMAN BLANCO: Well, yes, I think

that's a very important point. I think we ought to





spend a little bit more time on it, because I think

this is an issue with some other things that have come

before this panel as well.

You wonder, going back to A, if you'll

allow me, how many of the deviations went, because it

wasn't clear in terms of the indications, if you look

at the little box thing where you act on it, I mean it

wasn't totally clear to me, you know, exactly where

you needed to go.

I wonder if some of the deviations might

have been the STAN monitor was identifying an

abnormality or an event, but, oh, hey, the tracing

looks great, so I'm just going to keep on trucking and

keep laboring the baby, even though I should be

delivering it, according to the protocol.

So I think this is an important point in

trying to give some guidance to the sponsor as to how

they need to specifically word the actions. I mean,

what are we trying to do here? Are we saying that

this particular monitor is going to be useful when you

have a non-reassuring fetal heart rate pattern, and

then you use the fact that you have an ST event as





your point at which you say, well, this baby's in

trouble, so we've got to deliver this baby pretty much

immediately, or are we going to say, or is the sponsor

going to say, well, you know, I've got a reassuring

fetal heart rate pattern, but we know that may not

mean that much, so you've got an event, an ST event,

being flashed by the STAN monitor; you still need to

deliver that baby?

Some comments on that?

DR. IAMS: Well, let me follow up on that

comment I made about Dr. Wolfson's comment before and

guess what the answer will be from the sponsors about

the question of which one goes first.

My sense is you will probably answer that

by, with experience, you integrate the two of them

together. I don't know, maybe that's the answer.

CHAIRMAN BLANCO: Well, I don't know that

that gives them a lot of guidance, Jay, but --

DR. IAMS: I'm not asking for guidance or

trying to give them guidance. I really would like to

know the answer to that question before we deliberate

a whole lot further, I guess.





CHAIRMAN BLANCO: All right, well, Dr.

Rosen? All right, Dr. Ross?

DR. ROSS: Michael Ross again.

That's not the answer, Jay. It is really

a sequence of looking first at the fetal heart rate

tracing and, secondarily, at the STAN. As indicated

on the little package insert, if the tracing is

entirely reactive and reassuring, there is no need,

nor request, to look at the STAN. If the tracing is

pre-terminal, then one has to act upon that. In fact,

because of the physiology of T/QRS in a pre-terminal

baby, the T/QRS actually decreasing with ultimate

hypotension just prior to cardiovascular collapse, you

may not see it. Again, of course, that's assuming

that you start at the STAN relatively late in the

process, which was the case in the examples shown.

For all other heart rate tracings, those

that are non-reassuring in our terminology or,

according to the FIGO terminology, somewhat the

different levels of concern, then the STAN becomes the

secondary level.

DR. WOLFSON: Dr. Ross, then explain to





me: So if you have a reassuring electronic fetal

monitoring tracing, and because the display shows you

your ST segment, and you're seeing either ST event,

because I'm still not sure which one to focus on more,

the rising or the biphasic. The biphasic certainly

sounds more ominous.

So if you see an ST event, you're going to

tell me you're going to ignore the ST event because

the electronic fetal monitoring tracing is

reassuring --

DR. ROSS: That's correct, and, in fact,

it may be an episodic rise. I mean, let's assume that

we have a completely reactive, reassuring tracing. In

looking at hundreds of these tracings, one may have an

occasional deceleration with an episodic rise that

does or doesn't meet criteria for what would be an

abnormal tracing, as indicated on here. Those would

be ignored and viewed as a short-term event.

So you're correct, look first at the

tracing; ignore some short-term events in the ST, if

they occur, which is infrequent at best.

CHAIRMAN BLANCO: Any other comments from





the panel? Go ahead, Gary. Go ahead.

DR. EGLINTON: I wanted to ask about this

card. The system, I may not understand it.

Obviously, I don't understand it well enough, but it

appears on the surface of it to be impossibly complex,

because there's an algorithm on this side where

there's a normal CTG, an intermediary which is other

places labeled suspicious, an abnormal CTG, which

other places is labeled pathological, and then pre-

terminal.

So there are six boxes in here that

require a great deal of interpretation along the

horizontal axis with intermediary and abnormal. Once

one pigeonholes the strip into one of these four

lines, then one turns this over here and watches each

individual EKG complex that shows up on the right side

of the screen, or at least that's what I was trying to

do, watching the strips, because you either have a

biphasic ST for continuous for greater than five

minutes or more than two episodes of coupled BP2 or

BP3 in the case of an intermediary CTG, but it also

could be an episodic T/QRS rise of greater than .15 or





a baseline T/QRS rise greater than .1.

Is the computer doing this in real-time

continuously, and that's what puts the little ST event

marker down on the bottom channel?

DR. ROSS: That is. You do not look at

the ST waveform. That's in fact just displayed on the

computer. It's not displayed on the monitor paper.

So the computer will integrate that.

I could see at first glance that this

looks confusing, the grids on both sides, which speaks

in part to the need for an education program, but it

actually is not that dissimilar from what we use. We

could all agree on a normal definition of CTG, pretty

much can agree on pre-terminal CTGs. What this is

attempting to do is define in fairly objective

criteria what is the intermediary and the abnormal.

So it is really breaking our suspicious tracing into

two categories, one being suspicious or intermediary

and one being abnormal. But the computer does the

rest of that calculation.

CHAIRMAN BLANCO: I'm glad that Gary found

it confusing because I'm always happy when I find





something confusing that I'm not the only one. I find

it's very confusing, and I don't think it was clear at

all, the episode or the sequence of events that should

occur in terms of the assessment, what you've

clarified for us at this point.

I think you need to, I guess addressing

the sponsor, I think you need to do a lot of work on

clarifying it. I guess if you forgive my being --

well, anyway, if you just forgive me --

DR. EGLINTON: Being from east Texas? Is

that what you're trying to say, Jorge, from east

Texas?

CHAIRMAN BLANCO: Yes, from west Texas.

(Laughter.)

But you've got to Americanize it. This

isn't very Americanized, and it's not very much the

way practice is done in the U.S. This is going to be

confusing. This is confusing.

Thank you, Dr. Ross.

Any other comments?

DR. WOLFSON: Jorge?






DR. WOLFSON: I just want to get one thing

that still isn't clear to me, going back to this.

What does the machine actually show us? In other

words, just the basic question, when there is an ST

event, does an alarm go off audible, visible? Do we

know so that it at least alerts the attendant to the

patient to look at the tracing, if nothing else?

DR. ROSEN: Karl Rosen.

The attempt that we are doing is to verify

when the fetus is forced to respond to the stress of

labor. We're utilizing the ST and we're asking the

computer to verify when there is a change from the

situation that occurred prior to this event, and, in

particular, with contractions, obviously, coupled

contractions with illustration of where you then would

see an episodic rise which is identified, and it has

strict rules in the software to tell what type of

change is required to achieve an episodic as well as a

baseline change, as well as a set of biphasic STs.

CHAIRMAN BLANCO: I'm sorry, Dr. Rosen, I

don't think his question was addressing that. I think

his question was addressing, you've got some bells and





whistles when this bad thing happens --

DR. ROSEN: All right, yes.

CHAIRMAN BLANCO: -- bells and whistles to

call somebody to look at this. Is that right, Dr.

Wolfson?

DR. WOLFSON: Yes, that was question one.

Just does it go off?

DR. ROSEN: It doesn't go off. It's

there. It's written. There is a flag raised on the

screen, and you would have to go and verify that, sort

of recognize that, that that is a possibility. We

have not included bells and whistles.

We try to bring knowledge more, but, I

mean, it might a cultural thing here that you like

bells and whistles, in which case it will have it.

DR. RINGEL: We would like a sign that

flashes, "C-section now!"

(Laughter.)

That would be good. That would be good.

CHAIRMAN BLANCO: All right, thank you,

Dr. Rosen.

DR. WOLFSON: I would just like to go back





to the other questions. Why 20 minutes? What is

the -- do you want to wait for that?

CHAIRMAN BLANCO: I'll tell you what, I

think that's maybe not necessarily in here. That's

one of the questions that you asked that we said we

were going to handle later on.

DR. WOLFSON: Okay.

CHAIRMAN BLANCO: So I don't see the exact

applicability to the issue. So let's make sure we

finish with these before we go into the others. We'll

get to that one, I promise.

DR. WOLFSON: Well, I asked the question

relative to how it made the decisions it did, but I

will be glad to wait.


All right, anything else on B?

(No response.)

If not, let's move on to C. Any concern

about the exclusions based on inadequate recordings?

Remember that the way the protocol was set up, if you

had an inadequate recording, you were supposed to

reinsert so that you could get an adequate recording.





And there was a significant number, or maybe not

significant, but there were large numbers of folks who

had exclusions based on inadequate recordings.

Yes, sir?

DR. WOLFSON: I was going to ask a

question of my colleagues, since I haven't been in the

delivering process for many years. What actually is

the incidence of failure of standard electronic fetal

monitoring, of getting an inadequate signal?

CHAIRMAN BLANCO: A scalp electrode?

DR. WOLFSON: In other words, in a scalp

electrode, what proportion of the time does it

actually fail when you're just doing regular

monitoring?

CHAIRMAN BLANCO: I think I'm hearing from

my left very low.

DR. WOLFSON: Because in this group it

would be about 5 percent, if you look at it from a

purely technical perspective. Only 5 percent of

failures of where it would have been replaced. I

don't know what it is in the U.S. history.

CHAIRMAN BLANCO: Was it 5 percent? I





thought it was more.

DR. WOLFSON: It is. The total number is

about 11 percent, but when you actually look at the

technical issues of poor signal where the system

couldn't operate, that's only about half that. So

it's about 5 percent. It's around 5 percent.

DR. SEIFER: On slide 17 she says less

than 20 minutes on the STAN monitor. Of that, less

than 12 percent, 37 percent, and greater than 20

minutes removal of device and delivery at 56 percent.

CHAIRMAN BLANCO: Congratulations on

getting the 20 minutes back into the discussion.

(Laughter.)

Dr. Wolfson?

DR. WOLFSON: That was not intended,

Jorge.

CHAIRMAN BLANCO: That's okay. We're

going to talk about it now. We're going to deal with

it. So be prepared.

All right, so the issue is it is overall

12 percent, but then if you break it down, what

percentage --





required for the computer to do automatic analysis,

and you need a baseline consisting of approximately 10

minutes to verify where you are to start with, and

then you start to look for a change. Obviously, you

do a minute-by-minute basis, but after an additional

10 minutes, calculating the median value change. Then

you are significant and you can demonstrate

automatically by mathematics.

DR. WOLFSON: So it needs about 1400

samples or 1200 samples?

DR. ROSEN: Well, in this process we

require 10 T/QRS data for a median to be calculated.

DR. WOLFSON: Okay.

DR. ROSEN: So you could do that in a

shorter space of time tentatively, but to be able to

secure the accuracy of this data, according to the

software mathematics that the machine is using, there

is this 20-minute guidelines to secure.

It is also a function of how the electrode

stabilizes, because sometimes a few minutes are

required for this calculator to just settle down and

provide us with a clean signal.





Now on the issue of exclusions --

CHAIRMAN BLANCO: Before you go onto that,

because I'm still not clear, I mean do you have data

that you looked at that said that 20 minutes was what

you needed for the mathematical model? I'm

remembering Dr. Neuman's comment, and somewhere in the

presentation, somewhere in the data it was that you

needed 30 QRS complexes, and then you've got some

information.

DR. ROSEN: But --

CHAIRMAN BLANCO: Wait a minute. Wait a

minute. Let me finish.

Then that 30 QRS complex in a fetus is a

fraction, a fraction of a minute. So could you

elaborate a little bit more on the 20 minutes?

DR. ROSEN: I mean the 30 beats, now we've

got to separate the beats from QRS data.

CHAIRMAN BLANCO: Okay.

DR. ROSEN: So 30 beats, high-quality

beats, are required, and the system looks for that

high quality. So it will disregard those that are

poor quality. Then we say we need at least 50 percent





of the time covered with acceptable half-beats to say

this is a reasonable quality recording.

Because the thing I don't want to see is

erroneous data being entered into the T/QRS plot. So

our software is very much focused on avoiding that

issue and using modern digital signal processing to

sort of take noise out of this problem.

I think from the traces you have seen you

might have recognized the quality of the ECGs has

actually been displayed, where you can identify a P

wave, a QRS, and a T wave very accurately.

Then we have T/QRS ratios that in a normal

case -- and now I'm talking about 90 percent of all

recordings, where we have a continuous; that means up

to four QRS data plots per minute, and that is the

norm. We may address that now looking at the

Gothenburg experience, where, according to the

information I had here, it's only 1 percent now of the

cases where we don't obtain an ECG. It is obviously a

reflection of the motivation of the staff to apply the

scalp electrode correctly, but also the software

engineering is continuing, and we learn and we improve





the technology. It is part of the process.

CHAIRMAN BLANCO: Dr. Wolfson, have you

gotten your questions on the 20 minutes answered by

that?

DR. WOLFSON: I think so, yes.

CHAIRMAN BLANCO: Now several people

brought up the 20 minutes. So does anybody else have

any comments on the 20-minute window?

DR. NEUMAN: I still have a question

regarding the fact that you used 30 good QRS

complexes. Is there a maximum number of bad QRS

complexes in between? If I can be a bit sarcastic,

you wouldn't want to choose just 30 QRS complexes over

the entire 20 minutes.

DR. ROSEN: Sure. There are also are

rules that in that case would turn the system on. I

mean we have set strict rules, and I don't have those

in my pocket today to show you, but they are part of

the software engineering, the quality control, the

safety aspects. We have spent 15 years of software

engineering time to develop, having had access to the

ECG. As you can imagine, it is a bit of a challenge





to record an ECG where you have a reference electrode

placed on the maternal thigh. This is required to

obtain the vector to identify the T wave, which is

different from the standard ECG monitoring procedure,

where we don't need ST; we only rely on QRS. It's

very simple to measure that, but with ST it is

becoming more of a challenge.

So we need a unipolarity configuration.

We need the maternal thigh. The mother is moving.

That creates a problem. We've got to spend a lot of

energy and time and skills in developing the software.

Today, with the latest software there is, it appears

there's only 1 percent of the cases we obtain a

signal.

You should also remember in the Gothenburg

database, that's all intention-to-treat. The only

guidelines have been 20 minutes of recording, and it's

all intention-to-treat. There are no cases taken out

of that. So that really shows how the current

technology works in clinical practice.


Go ahead, Mike.





DR. NEUMAN: I would just like to get on

the record for the FDA -- I don't think it needs to be

discussed here -- that it will be important to look at

the criteria for selecting the "good" QRS complexes to

make sure that it doesn't bias the results in any way.


Any other comments, going back, now that

we have the 20-minutes issue? Go ahead.

MS. BROGDON: Dr. Blanco, Dr. Corrado has

tallied some data that may help to answer some of your

questions.

CHAIRMAN BLANCO: Please, Dr. Corrado.

DR. CORRADO: We used the spreadsheet of

the results from the entire study that the sponsor

provided us, and we tried to evaluate what the precise

causes for recordings of less than 20 minutes on the

monitor, categories of deliveries that occurred more

than 20 minutes after disconnection, and I'll

certainly defer to the sponsor, but I will share the

information with you that we have been working from.

For recordings that were excluded,

patients who were excluded because the STAN was on for





less than 20 minutes, we counted about 111 in the STAN

arm and 105 in the control arm. Of those, 94 in the

STAN arm and 76 in the control arm were identified

with the word "partus," P-A-R-T-U-S, which we

interpreted to mean perhaps the patient had delivered.

Is that -- that is the case?

So for the STAN arm, out of 111, 94

weren't included because they delivered sooner than 20

minutes, and then 76 out of 105 in the other group.

There was something called signal, which was

identified as a problem in 14 of the STAN patients and

21 in the control arm.

Technical problem, question mark, "TOCO"

occurred in four patients in the CTG arm. The rest of

the numbers are very small. They're less than three

or four. So the overwhelming majority of the category

of STAN on for less than 20 minutes was due to

delivery.

CHAIRMAN BLANCO: So, basically, 60

percent, I mean roughly -- I don't know the exact, but

70 or 80 out of the 100, a little over 100, were

because they delivered before the 20-minute window was





up?

DR. CORRADO: Correct.

CHAIRMAN BLANCO: Okay. So I think that,

I don't know, to me at least it sort of puts an end to

the exclusions based on inadequate recordings issue.

DR. CORRADO: Well, that is just for less

than 20 minutes. There were also a bunch of cases,

133 in the STAN arm, 130 in the control arm, that were

excluded because, for some reason, the monitor was

disconnected, and more than 20 minutes elapsed between

the time it was disconnected and delivery.

I will just quickly summarize those

numbers for you. Our analysis showed that there was

apparently a signal problem in 80 out of 133 in the

STAN arm and 85 out of 130 in the control arm. There

was a category identified as technical that included

20 patients out of 133 in the STAN, 15 out of 130 in

the control.

There is a category that "user error," six

and seven, respectively, in the STAN and the control

arms, and a category that was just labeled "unknown."

I'm not sure if that is our label or the sponsor's.





There were 19 of those out of 133 in the STAN arm and

16 in the control arm. So in that category, that is,

it was disconnected more than 20 minutes before

delivery, the overwhelming majority comes under a

category of signal problems.


DR. CORRADO: I hope that helps.

CHAIRMAN BLANCO: Yes. Thank you very

much.

Yes, go ahead.

MS. TOLEDANO: Just a point of

clarification: Were the signal problems at all

correlated with the removal of the electrode to do

forceps or ventouse deliveries?

CHAIRMAN BLANCO: Go ahead, Dr. Rosen.

DR. ROSEN: That was not the common

situation. The more common situation was that they

would then would not reapply the scalp electrode and

they would switch to a standard electronic fetal

monitoring device.


All right, any other comments? Questions?





Issues on 3C?

DR. IAMS: Jorge, is this a good place to

ask about the exclusions based on cord blood?

CHAIRMAN BLANCO: Okay, go ahead.

DR. IAMS: Because you're talking about

exclusions.

CHAIRMAN BLANCO: We're talking about

exclusions, so go ahead.

DR. IAMS: That was a lunchtime question.

Is there any additional data about that?

CHAIRMAN BLANCO: This is a question where

you did not have both the arterial and venous cord

blood or didn't have, or you didn't have any on some.

Dr. Rosen?

DR. ROSEN: I did a quick look at these

data where there was the cord artery sample and then

there were in the STAN arm about 170, and 190 in the

control arm, where there were additional cord vein

samples. In the STAN arm there was no case with

metabolic acidosis or cord artery pH of less than

7.05, whereas in the control arm there are two cases,

a cord vein, metabolic acidosis, and where the cord





vein pH are less than 7.00.

DR. IAMS: Okay, my concern before was

that babies with metabolic acidosis might have been

particularly difficult to sample for some reason. So

it sounds like that was not the case.

DR. ROSEN: Well, it's probably true.

There were two cases in the control arm where they

couldn't obtain a cord artery sample. So they were

actually excluded from the cord metabolic acidosis

group. They obviously are included, because they had

the clinical symptoms, so they are included in the

adverse outcome cases, one of those, and the other one

is not included. So you have those represented in the

material, in the neonatal outcome of the study.

DR. IAMS: Thank you.

CHAIRMAN BLANCO: Thank you. Any other

comments on the exclusions?

(No response.)

All right, let's move onto 3D then, and

this has somewhat been alluded to, but maybe we can

spend a little bit more time. 3D, "The intercountry

population and management differences." Anybody want





to make a statement about that?

DR. O'SULLIVAN: I think that, depending

upon the facility on the labor floors as to whether

there is central monitoring, one, and, two, that

somebody actually looks at a central monitor, which is

not common, and, three, if there are alarms and the

alarms go off and everybody is still sitting at the

desk. All of these are issues when we talk about

bells and whistles. The whole idea of bells and

whistles, and whatever you can do, red lights, et

cetera, is to get the staff to pay attention to them,

but the answer is usually, "It's not my patient."

I have grave concerns where you have

individual labor rooms with individual delivery room,

labor and delivery suites, with a nurse usually taking

care of anywhere from four to six, although the floor

will tell you it's one to two. When you actually look

at it, between lunch breaks, coffee breaks, union

breaks, all kinds of breaks, it's one nurse to four to

six patients. So I have a lot of concerns about it

from that perspective in terms of practicality.

Yet, I also wonder if the educational





process somehow or another will make a difference,

since there was such a difference in what you all

showed before with your education. I come back to

that. I keep coming back to that because of the

importance that I think it has in introducing this in

the United States at all. It's going to be a major

educational process, and it's going to be

desensitization with resensitization.

CHAIRMAN BLANCO: Well, let me play a

little devil's advocate. I mean, I totally understand

what you're saying in terms of you have a concern.

You know, you've got a 1-to-4, 1-to-6 ratio, and

whether somebody's going to pay attention to this, but

that's really not a problem with the device.

DR. O'SULLIVAN: No.

CHAIRMAN BLANCO: That's really a problem

with our system, and actually you might be better, you

know, if you've got something that records, so that

when they do come around and pay attention to the

patient, that they will notice that this event

occurred. They may not have gotten to it on a timely

basis, but the other option is simply to central





monitor and not showing that.

I'm not sure that that necessarily to me

makes me against the device.

DR. O'SULLIVAN: No, but I think in terms

of, when you're talking about marketing it in this

country, and its useful utilization in this country,

to do what it did in Sweden, for example, it is going

to be important. Otherwise, it won't do what it is

supposed to do. It's subsequent failure.

DR. IAMS: Jorge, my concerns about

transportability don't reflect very well on this

country. I was struck by one of the comments Dr.

Rosen made in this beginning of his discussion, that

there is a general consensus in Sweden about the

interpretation of cardiotocography and some other

issues about management.

I'm not so sure that you could make that

statement about any manner of fetal surveillance in

labor in this country. It varies tremendously;

interpretation varies tremendously.

The natural inclination of even the least

technological American obstetrician, most of us as we





talked about this, did you look at these tracings?

We're all looking at that little EKG thing over there.

We're not supposed to look at that, but that's what

American obstetricians do. We're looking -- I didn't

see the ST wave go up or down. If I were going to

redesign the equipment for an American user, I would

take out everything except the ST event marker. Why

do I need the rest of it? Because we will want to

analyze and argue with the computer. That's what we

do.

CHAIRMAN BLANCO: Don't forget the light

and the bells and whistles.

DR. IAMS: Well, I don't need a bell and

whistle. Maybe a little bell, but really take out the

data that supports when the ST monitor goes off,

because the nature of the American physician -- I

won't necessarily just indict obstetricians -- is to

argue with, well, I didn't see anything go on there.

I'm sure I am right, and the computer algorithm that's

taken you 15 years to develop is wrong. That might be

a reason maybe in Sweden why you had to re-educate

people. I don't know. But in this country it would





be a big problem, I think, something you could easily

fix.

CHAIRMAN BLANCO: Well, let me pin you

down a little bit, and Dr. O'Sullivan as well. Is

that an issue that's sufficient enough that you are

concerned about the introduction of this device into

this country?

DR. O'SULLIVAN: Absolutely.

CHAIRMAN BLANCO: Really?

DR. O'SULLIVAN: Because, again, if the

device is introduced into this country without that

whatever it is secret he has about education, and that

education is not done universally, widespread, it is

doomed to failure.

CHAIRMAN BLANCO: Jay?

DR. IAMS: The second issue I brought up

about changing what is displayed, I think you could

change that fairly easily. The larger issue is trying

to get American physicians to buy into (a) there's a

problem with our current system and (b) this is the

answer. I think, unfortunately for you guys, after

all your fine work, the answer to that is probably





going to be an American study.

MS. TOLEDANO: The No. 2 question on my

page, from reviewing all these materials last night,

was, how will the knowledge be disseminated in the

United States? Because I definitely agree with the

importance of the question, but, if I recall

correctly, Ms. Daws-Kopp was telling us that the

sponsor is prepared to set up a program similar to the

Centers of Excellence that they have in Europe, so

that they would be coming into harvest, disseminating

the knowledge, doing the educational program,

reviewing cases, and monitoring the way that this

technology is marketed and distributed in the United

States. So, to me, that alleviates some of the

concern.

DR. SHARTS-HOPKO: I share the issues that

Dr. O'Sullivan raised, and we mentioned earlier a

concern about, how are women attended? When a woman

is attended by a midwife in the United States,

typically, that person stays with her pretty

constantly throughout the labor and the delivery.

That's only 1 percent of our births that are midwife





happen agree and I feel very uncomfortable with any

piece of medical equipment that does not have

appropriate alarms, so that when it is reading a value

that they consider out of bounds, the fact that there

is no alarm I think makes it personally unmarketable

in this country, because you can't have a piece of

medical equipment attached to a patient without alarm

parameters. So in that way I agree.

DR. WOLFSON: Yes, but a lot of our fetal

monitors, you can have recurrent late decelerations;

nothing goes off. You're supposed to look at it.

DR. RINGEL: Ah, but that's an

interpretation. I'm being told that people interpret

this differently. They are specifying an out-of-

bounds value for their ST or T waves -- excuse me --

for their T wave QRS ratio. That is part of their

premise. They have an out-of-bounds ratio, and that

they have an automatic detection. So if we don't want

the alarms, then we go back to displaying just the QRS

pattern and, like any electrocardiogram, where we

would then interpret it ourselves, or if you're going

to say there's automatic detection and you set





boundaries, and they have set boundaries, then I think

you have to have an alarm.

DR. WOLFSON: I would agree. I would like

to see some type of alarm because part of what I see

the power of this tool is, is that it's another factor

that's going to come back and alert people to go back

and re-evaluate the status of the patient, the status

of the tracing in the context of interpreting it.

Because the other feature relative to

outcome is, what's the time to delivery? If the time

to delivery is felt to be under 5 to 10 minutes, or

even some people might even argue as far as 30

minutes, then, clearly, you're going to go for a

vaginal delivery, and the patient is not going to fall

into an operative category. Otherwise, you're going

to go in the other direction.

CHAIRMAN BLANCO: I think we have sort of

gotten off 3D here and we're going back to the fact

that, again, and the word I was looking for before was

to be so provincial, but I think you need to

Americanize the device a little bit as to what the

practice here is.





But let's try to go back into 3D and 3E.

In a way, we've also talked about retraining. I think

training is coming out as an extremely important

adjunct to this particular device.

But, Nancy, go ahead.

DR. SHARTS-HOPKO: Thank you. I

remembered my point.

The Swedish study looked at applying the

device to women that had some risk indicator, and we

monitor everybody pretty much here. So we don't know

what kind of false findings we're going to find in a

normal population, a general population. I'm

concerned about that.

DR. BROWN: Another point is we don't

know, in terms of comparing the populations, the

incidence of pre-existing conditions that might be

undiagnosed or unknown or even that are known.

Someone mentioned the contrast in prenatal care. Was

there a comparable rate of women with diabetes, IUGR,

pregnancy-induced hypertension, smoking, drug use,

whatever, in this population? I mean, I have some

concerns about that.





Then I think, getting back to Dr. Iams'

point, if you're talking now about the management

differences, I think the question about, can this be

marketed to reduce the operative rate is a valid

point, because if the indication of this is that your

company wants to market as a way to avoid operative

deliveries by letting you use this for that gray area

of fetal heart rate tracing, and sit on that patient,

that needs to be very clear. Because to me, just

reading it, not having done obstetrics in a long time,

it is a little confusing.

Is that really the primary point of this

device, to allow you to sit on the questionable

tracing, if there is not an ST flag on the screen or

an alarm?

CHAIRMAN BLANCO: I think that was sort of

what was addressed, that that's one of the ways that

the fetal heart monitoring is not reassuring, is non-

reassuring; you then look at the ST events or ST

changes.

DR. BROWN: Because that will require a

whole complete change of culture and education.





CHAIRMAN BLANCO: Well, I think some

people think so.

The other issue that you brought up, and I

think it's important to bring up, because it's been

talked about immeasurably, is when it applies to

Caesarean section rates in terms of comparing, say,

Ireland versus the United States, the United States is

a very heterogeneous population. I'm sorry I've never

been to Sweden, but my understanding is that it is a

very homogeneous population, very much like Ireland.

So other than your percentage -- and I

don't have my hands on it right now -- of folks that

were from the Middle East and Africa and former

Yugoslavia, and most everybody else is pretty

homogeneous, and that percentage was 20 percent --

DR. O'SULLIVAN: Twelve percent.

CHAIRMAN BLANCO: -- 12 percent. So I

think that that is a concern in trying to extrapolate

the data from Sweden into the United States. I think

there really are different populations.

DR. O'SULLIVAN: But the other thing to

keep in mind, too, when you're looking at that, at





least based on our own experience in this country, is

the initial immigrant who comes in is generally the

healthier individual. That's why they're here. And

they generally do better than our own U.S.-born

individuals do.

CHAIRMAN BLANCO: I'm sorry, but I don't

understand your point.

DR. O'SULLIVAN: I was just saying that

because somebody is an immigrant into the country

doesn't mean that they are going to perform more, that

something's going to happen that's going to be more

complicated in terms of the obstetrical outcome for

that index pregnancy.

CHAIRMAN BLANCO: Okay, so what you're

saying is that, even though they have a 12 percent

population that is not what would be classified as

homogeneous, they may not be as homogeneous as some of

the population in the United States?

DR. O'SULLIVAN: Oh, absolutely.


comments? Yes, Ma'am?

MS. MOONEY: I think one of the things we





should keep in mind with this particular area question

is that, if we think the data we have in hand

essentially supports the safety and effectiveness,

answering these types of questions may be the things

we talk about in the post-approval study area. So to

keep cognizant of the fact that we can separate out

the inherent safety and effectiveness in the data we

have and make that judgment call versus what we could

look at entertaining the post-market study.

CHAIRMAN BLANCO: While I don't disagree

that you may need to look at it in a post-market

study, I'm not sure -- I think the point is that there

is some concern that the difference in populations may

mean that the safety and effectiveness may not be the

same. We're not talking about something that's

showing an 80-versus-20 percent difference. We're

talking about something that shows a very small

difference, significant but very small. So I think it

may still be applicable, an applicable point.

DR. WOLFSON: Jorge?

CHAIRMAN BLANCO: Yes, sir?

DR. WOLFSON: Going back to the





differences in the populations, the device, it says,

"indications for use." "Is indicated where there is a

planned vaginal delivery and there is need for close

surveillance during labor or there are maternal

disorders and/or uterine placental dysfunction with

potential adverse influence on fetal oxygen and

nutrition supply, or deviation from the normal course

of labor, including induction, augmentation of labor,"

et cetera.

So I think that the actual use of the

device in terms of who it is going to get applied to,

when you turn on the ST segment, let's say, is

probably going to be the same in both countries, in

that you're using it as an augmentation to standard

monitoring. A great deal of our clinical monitoring

that we see -- I guess I'll speak for my own venue in

Colorado Springs. External fetal monitoring is what

is used early in labor, clearly, because the membranes

aren't ruptured generally, and even if they are it is

still the simpler thing to do, and our labors are

generally attended by the nursing staff. The

obstetrician is called in when there is a concern of





what is being seen on the strip. So the nursing staff

is making the decision, and they are generally going

to utilize external monitoring. When internal

monitoring is required, then they're going to call the

obstetrician in.

So I think that the difference in makeup

of the populations relative to whether it is the

heterogeneity of the American population, that as long

as we are using it where we think there is a specific

need for this additional information, it's not going

to differ from population to population.

CHAIRMAN BLANCO: All right, let's move on

to 3E, retraining during the Swedish randomized

controlled trial. I think we've kind of addressed

that. Does anybody want to summarize it or say

something?

DR. IAMS: I don't want to summarize it.

I have one question about it.

It's this sort of event that made me

wonder why the investigators did not decide, since we

didn't execute the interventions according to our

original plan, why didn't you restart the study





basically and then get your end from that point on?

It's powerful actually that you were able to achieve

the P values you got when the first, what, third of

the study was not totally compliant with the original

protocol. So why not repower it at that point? There

must have been some thinking along those lines at some

point.

CHAIRMAN BLANCO: I think there is some

disagreement with you on that. Do you want to make a

comment? I saw you shaking your head.

MS. TOLEDANO: You can't do that. You now

have to turn --

DR. IAMS: Yes, you can. You can do what

is basically a run --

CHAIRMAN BLANCO: Wait a minute. Let her

have a chance to finish. Go ahead.

MS. TOLEDANO: That would be so sorely

frowned upon, because basically you would have to

report the first study, that you terminated it early

for the protocol deviations. Protocol deviations

happen in all sorts of studies that are used by any

governing body in this country and in the European





Union and other areas as well.

As far as it is ingrained into me with

that all the ethics training that we are required to

take during studies and holding NIH grants, you can't

just stop a study because you don't like the protocol

deviations that people make. If there are protocol

deviations, you do your interim look. You can try to

fix it, but you finish up the study. You don't just

stop the study.

DR. IAMS: I don't disagree with that, but

all I can say is that you can, because we do it all

the time in NICHD-funded trials --

MS. TOLEDANO: Well, we don't do it in

cancer --

DR. IAMS: -- look at the performance and

then decide that you do not have enough in that has

followed the protocol. You just continue for longer;

that's all. You don't really deny the existence of

the first 1600.

MS. TOLEDANO: Right.

DR. IAMS: You report them. You're

completely honest, but you say, "We haven't achieved





our end, and so we're going to have to continue this

study in order to make sure that we have the results."

MS. TOLEDANO: They did that actually.

They recalculated the total sample size. It wasn't

based on protocol deviation. It was based on the

baseline rate of metabolic acidosis. So they did go

at the 1600 and calculate that they needed more than

the original 3200.

DR. IAMS: Okay, I missed that part,

but --

MS. TOLEDANO: Yes.

CHAIRMAN BLANCO: And the other point is

they showed more of the difference now. So I think

they showed that, with the retraining and re-

education, they actually did better off than without

it, before with the violations --

DR. IAMS: Yes, that answers my question.

CHAIRMAN BLANCO: Any comments on that?

Anybody want to add anything?

Well, I'll add kind of a summary because

I think it's been said before, but just to make sure

FDA hears it, I think this device is going to need a





fair amount of retraining before it hits the market,

and not after 1600 patients. I mean, I think there is

some education that needs to go with this. It can't

just be sold and expect everybody to use it and know

what they're doing. I think it has some inherent

necessities for a significant amount of training.

There's some precedent for that with other devices.

So I think that we need to recommend that, and I see

some shaking heads saying yes. So I think that's the

feeling of most of the panel.

DR. EGLINTON: Jorge?


DR. EGLINTON: Can I get some retraining?

CHAIRMAN BLANCO: Yes, please do.

DR. EGLINTON: May I ask another question,

please, about the card. I want to know, I have an

intermediary CTG, and I want to know now if I have an

episodic T/QRS rise greater than 0.15, or a baseline

rise greater than 0.10, how do I figure that out?

Looking at the lower scale, the T/QRS scale, that is

rather tight. That's pretty subtle, trying to figure

out or move over one column over to abnormal CTG;





0.05, how am I going to figure that out? Does the

machine tell me that somehow other than just visually?

CHAIRMAN BLANCO: Gary, for the sake of

time and the other questions, and answering some of

the questions that we have asked the sponsor, I think

it's pretty clear, or should be pretty clear, to FDA

and to the sponsor, that that card is confusing and

may not be appropriate, and needs to be worked on

significantly. Maybe we can touch base on the details

at a time when there is more time.

DR. EGLINTON: But this is central. This

is how you make your management decision. I mean, if

it rises, if the baseline rises more than .05 with an

abnormal CTG, that is the reason to intervene. It's

really central.

CHAIRMAN BLANCO: All right, Dr. Rosen?

DR. ROSEN: The computer identifies these

changes, and it will tell you in detail what extent

there is in change, whether it's more than .05 or it's

more than .10, and whether it's episodic of more than

.10 or more than .15, and that's written and it's

flagged on the screen. It is written on the paper.





There is an ST log where all these events are

recorded. That log is available to the operator

throughout the delivery process.

So the issue of interpreting the ST change

is very much a reflection of being capable of reading

the statements made by the computer.

DR. EGLINTON: Is that on the review mode?

Is this illustration, figure 2.2.3, is that what

you're talking about, on the review mode in the upper

right?

CHAIRMAN BLANCO: I'm sorry, Dr. Rosen,

but we kind of need to hear and see what you're saying

for the record. So if you would go ahead and go

back --

DR. ROSEN: So on the user manual there is

a graph showing how the user is informed about a

significant event, where what's called an event log

window is available, where all these events are logged

as well as there is a keyboard, so you can key in

specific information that you tell, "I recognize

this," and so on.

MS. LUCKNER: Dr. Blanco?





behind this to fail because the user would not

understand how to use the equipment and how to

interpret these events. Please remember that those

guidelines you have in front of you, they are like a

pocket, just a quick memory thing. You should, I hope

some of you have been able --

CHAIRMAN BLANCO: Dr. Rosen, I'm sorry to

interrupt you, but you've also got to remember you've

got some fairly, supposedly, bright people up here,

and you know we're frankly confused, okay? So let's

let is loose on the United States, and you're going to

confuse a lot more people. Okay?

DR. ROSEN: Have you consulted the

educational material yourself?

CHAIRMAN BLANCO: Well, no. I mean, I

haven't been educated by what you have, but we don't

have that on here.

DR. ROSEN: Yes, you have.

CHAIRMAN BLANCO: We're just making

suggestions that there is confusion. Okay?

DR. ROSEN: Okay.

CHAIRMAN BLANCO: And there are important





things about how you're labeling that may be

regionally-specific, issues that you need to address.

I think we have made it very clear about the need for

significant education process on there. Okay?

DR. ROSEN: For the record --

CHAIRMAN BLANCO: I'm going to break my

rule and I'm going to recognize Dr. Devoe because I'm

sure that he has something valuable to add at this

point that is short in time, because we are starting

to run a little late.

DR. DEVOE: I'll put on my Yankee hat and

be very brief.

CHAIRMAN BLANCO: Please state your name.

DR. DEVOE: Dr. Lawrence Devoe, Medical

College of Georgia, consultant for Neoventa.

What has probably not been properly

emphasized is that out of the box there is a very,

very specific, detailed, organized, orderly, and

properly-written tutorial that really must be done

before you flop up the first power switch on any of

these devices, and to presume that you can use any

device like we have erroneously done in the fetal





monitoring world for the last 30 years without doing

this is really missing, I think, a very important

concept.

There is a tremendous amount of education

that goes into the use of a device that has this

internal degree of sophistication. It does two

things. It teaches you what this device does that

conventional monitoring doesn't do, and, in turn, as

you have seen by some of the clinical experiences, it

makes the user better at the basics of electronic

fetal monitoring, which is something we have been

derelict in since fetal monitoring was first

perpetrated in the United States.


Gary, any other comments you want to make?

If not, can we move on?

DR. EGLINTON: No, that answers it. Thank

you.

CHAIRMAN BLANCO: All right, let's move

on. Let's try to see if we can do No. 4 before we

take a break.

No. 4: "In addition to a Swedish RCT, the





Gothenburg, again, with experience, or with experience

with this device, it did show reduction in the cases

with metabolic acidosis as well as operative delivery.

DR. RINGEL: It was with the City of

Gothenburg that I raised the question before. Maybe I

am misreading the slide. This is on page 29 of Dr.

Rosen's presentation. That's why I asked the question

before.

Maybe I've got this wrong, but it looks

like, with experience, the obstetricians in Gothenburg

did better with plain CTG than they did with STAN in

detecting metabolic acidosis, with experience. Do I

have that wrong?

CHAIRMAN BLANCO: Dr. Rosen, can you come

up?

DR. RINGEL: The rates of metabolic

acidosis looked much lower than with STAN. In fact,

it's only for the total and for the CTG that there is

a statistical difference demonstrated and none with

the STAN.

CHAIRMAN BLANCO: Anybody?

DR. DEVOE: Devoe again.





One of the things that should be

appreciated is that the selection of cases in the CTG

arm or risk stratification were much less likely to be

high-risk cases than in the STAN arm. In other words,

these weren't cases that were randomly assigned one or

the other in general. One of the obstetricians here

can probably speak to that, if there are further

questions later on.

But the standard CTG arm represented the

lower echelon of risk patients. One would empirically

expect to have a higher rate of complications in the

STAN arm in terms of metabolic acidosis

DR. RINGEL: But you're presenting this

data in support of the efficacy of STAN in an

observational trial, and the rates of metabolic

acidosis in the first half of the trial are

essentially the same, and then they go down

substantially in the CTG arm, but not in the STAN arm.

DR. DEVOE: They declined in both arms,

but also remember that there is also an educational

impact in the area of fetal monitoring in general that

would have affected both arms.





DR. RINGEL: But there's no little

asterisks over the STAN arm to indicate statistical

significance while there are asterisks over the total

in the CTG arm.

DR. DEVOE: Right, because they got

better. They got better as time went on. I mean,

that's part of the educational impact.

DR. RINGEL: But the STAN didn't get

better. So then you could have just educated people,

continued to use CTG, and you would have dropped your

metabolic acidosis rate to .1 percent. Am I reading

this wrong?

CHAIRMAN BLANCO: No, you're reading it

right, except the number you said is not right. I

think these are fractions of a percent. It went from,

in the CTG arm, from 1 percent to .01 percent.

DR. RINGEL: Right.


DR. RINGEL: But the STAN arm didn't

statistically --

CHAIRMAN BLANCO: And the STAN arm went

from a little under 1 percent to about .6 percent.





DR. RINGEL: Yes. So all you had to do

was wait a year and things would get better without

STAN, right?

DR. DEVOE: No.

DR. RINGEL: No?

DR. DEVOE: They're still training on

STAN.

DR. RINGEL: Okay. So it's the paying

attention to fetal ECG that's making the difference

whether it's STAN or not?

CHAIRMAN BLANCO: Go ahead.

DR. ROSEN: Could I address this here? I

think it's one important aspect here, and that is to

say, what happens if you've got obstetricians and

midwives used to having ST information available, and

then there is a group where it is not available?

Clearly, that group, according to our practice of

using the fetal scalp electrode, would be a low-risk

group, because the high-risk cases, they would have a

scalp electrode applied: those with inductions, those

with augmentation of labor, those with any antenatal

history.





So then you have a remaining group now

being monitored with heart rate only. I believe what

we have seen is the impact of more accurate assessment

of the heart rate trace. We can ask the midwife here

to explain a little bit about the process.

CHAIRMAN BLANCO: Well, but I think that

is what he is saying.

DR. RINGEL: Don't you see what I am

saying --

CHAIRMAN BLANCO: That's what he's saying.

DR. RINGEL: -- is your Gothenburg trial

would suggest that just by educating your care

providers, you can achieve the results you want to

achieve with an expensive apparatus.

DR. ROSEN: On the other hand, this is

done taking the high-risk cases out of the group being

monitored with heart rate only. So, basically, you

would expect a very low incidence of interventions --

CHAIRMAN BLANCO: But there's still a

change, and let's go ahead. I think you have made the

point that there is some data from the Gothenburg

study that shows that there may be a decrease just by





reading the fetal heart rate monitor.

DR. ROSEN: Right. Oh, yes.


MS. TOLEDANO: I just wanted to clarify

some numbers on this same graph. So I'm seeing with

the STAN, in the first half of the graph, an "N" of

668 and approximately 1 percent having the metabolic

acidosis. So that would be seven babies. Then on the

righthand side of the graph, an "N" of 764 with a .6

percent. So that would be about five babies. Is that

what we're looking at, going from seven children to

five children? There is no way you can get

statistical significance there. So that's why there

are no little stars.

CHAIRMAN BLANCO: But I think the point is

still that --

MS. TOLEDANO: They can't.

CHAIRMAN BLANCO: -- in the other arm they

did.

MS. TOLEDANO: Right, in the other arm

they do decrease it by the better education --

CHAIRMAN BLANCO: They do have larger





numbers.

MS. TOLEDANO: And we would benefit from

that.

CHAIRMAN BLANCO: Okay, we're going to

move on, Dr. Rosen. Okay, we're going to move on.

So I think the question was asked,

actually, in a broader issue, which is, is the data of

these other studies that were not specifically aimed

at testing the hypothesis that the sponsor was putting

forth, does it support or not support, and can it be

used in some way to improve our decisionmaking in

terms of approval of the device or lack of approval?

Bring it back to that.

Yes, Ma'am?

MS. BROGDON: Dr. Blanco, I need to point

out that in the written copy of your questions we left

off the Nordic study. It's on the slide up there.


All right, so there is some differences in

the Gothenburg study that may not be supported, is

what you're saying?

DR. RINGEL: That's all I'm suggesting,





yes.

CHAIRMAN BLANCO: Okay. All right, any

other comments on this?

(No response.)

All right, we're going to -- it's 2:22

right now by the official clock. We have a 15-minute

break. So we will start promptly at 2:37. Thank you.


the record at 2:24 p.m. and went back on the record at

2:39 p.m.)


ahead and begin. We're still going through the

discussion process and answering the FDA questions.

We are at Question 5. It's labeling and

training. It's: "The sponsor proposed the following

indication: Use of the STAN system is indicated when

there is a planned vagina delivery and there is a

full-term singleton fetus in a vertex presentation,

and there is a need for close fetal surveillance

during labor, or there are maternal disorders and/or

uteral/placental dysfunction with potential adverse

influence on fetal oxygen and nutritional supply or





there is deviation from the normal course of labor,

including induction, augmentation of labor.

"Does the PMA data support this indication

for use? Do you have any suggestions for

modifications?"

I think, Dr. Ramin, you had some comments?

DR. RAMIN: Yes, I have a comment, and,

again, it is looking at the differences in how we

monitor patients in labor in the United States as

opposed to Sweden. Probably about 90 percent of our

patients, at least at our institution in Houston, get

monitored, whereas I think the number was

significantly less in Sweden. I guess it would be

looking at the indications of kind of narrowing down

specifically which fetuses you're going to use this

device in.

CHAIRMAN BLANCO: Well, would you suggest

that the device be utilized in patients who have a

high-risk condition, so that they are at higher risk

for metabolic acidosis?

DR. RAMIN: I think the device should be

indicated and make it a little bit more tighter in





otherwise -- in a patient's, in a population who has

absolutely no problems or no detectable problems in

labor? That's my first question.

My second question has to do with the

indications here as they are listed. I mean, in this

country, where it says, "There is a need for close

fetal surveillance during labor," I think we are in a

situation from the medical/legal perspective that

every baby needs close fetal surveillance in labor.

So that to me means everybody.

CHAIRMAN BLANCO: Well, but I think that's

Dr. Ramin's point, that that probably is too broad and

that needs to be sharpened up to more high-risk

patients. You would agree with that or not?

DR. O'SULLIVAN: I would agree with that,

but I would also say, is the information out there,

has a study been done to look at women who are

otherwise uncomplicated, and what the impact is in

that population? I would expect it to be excellent,

but, I mean, what I am saying is, are there things

from the perspective of the false positive situation

that we have yet to see?






comments?

(No response.)

Okay, so I guess two issues that were

brought up is that, and I don't know if there is a

consensus from the panel, so I would like a couple

more people to say something, that the indications

need to be tightened to include folks with high-risk

conditions as opposed to the more broader wording that

is currently here?

Then the other issue is concern or at

least some information from the sponsor about in a

low-risk population, if it has been used for that, has

there been some evidence of significant number of

false positives?

Am I paraphrasing you correctly, Dr.

O'Sullivan?

DR. O'SULLIVAN: Yes.

DR. RAMIN: It's kind of the question that

I had asked, and that is, you have normal tracing;

what is the false positive rate in those individuals?






DR. RAMIN: I have another comment just

regarding the deviation from the normal course of

labor, including induction and augmentation of labor.

I can't speak for all institutions in the United

States, but I do know that we don't necessarily have

to do internal monitoring for an induction or

augmentation of labor. We can do external monitoring.

I guess in order to use this device, it

has to be internal monitoring. So my recommendation

would be to have that as an indication.

CHAIRMAN BLANCO: All right.

Jay, you have a question?

DR. IAMS: I just didn't understand the

last part of what Sue said there.

CHAIRMAN BLANCO: Yes, what did you say?

DR. RAMIN: Well, part of the indication

would be deviation from a normal course of labor. So

if you have a woman that you're inducing, that would

mean that you have to insert -- this is an internal

monitor, the scalp electrode. I think there are cases

where you can induce somebody's labor with an adequate

external tracing, not have to do internal monitoring.





CHAIRMAN BLANCO: Well, but wait a minute.

But, Sue, the issue is not that you have to, because

you don't necessarily have to use this technology. I

mean, the question is -- I would phrase it differently

-- is induction of labor sufficient indication to use

the STAN? Is that enough of a condition that makes a

patient non-routine to use the STAN, to justify the

use of a STAN? Not that, okay, I'm inducing somebody,

so I've got to use the STAN. I mean, I think the

question is the other way.

Does that make sense?

DR. RAMIN: That makes sense.

CHAIRMAN BLANCO: Yes. Is induction of

labor, augmentation of labor, enough of an --

DR. RAMIN: Indication.

CHAIRMAN BLANCO: -- indication, a high-

risk condition, it's an indication to insert an

internal and use the STAN monitor? Is that what you

meant? Did that clarify it?

DR. IAMS: Yes.

CHAIRMAN BLANCO: So what do you think?

DR. WOLFSON: Yes.





DR. IAMS: Do I think the labeling, if

modified as described, would be appropriate?

CHAIRMAN BLANCO: Would it be appropriate

to use the STAN monitor in patients just simply

because they're being induced?

DR. IAMS: Oh. No, I wouldn't think that

every patient being induced would need a STAN monitor,

no. Some patients, if -- we all probably have

slightly different indications for use of an internal

fetal monitor, but in recent years the indication for

an internal fetal scalp electrode is often going to be

coincident exactly with the kind of patients that were

studied in this trial. The low-risk patient who is

being watched in order to be careful with every baby

is watched in our unit with an external monitor unless

an adequate tracing can't be obtained.

So if tracing is then normal, I wouldn't

think you would need the STAN, but if you have any

abnormality of the tracing or any abnormality of the

course of labor, or the antepartum conditions there

were mentioned, then I think you would have an

indication for a STAN.





CHAIRMAN BLANCO: Dr. Wolfson, I heard you

say "yes." So would you like to comment?

DR. WOLFSON: Well, I agree with what Jay

just said. I think that most inductions can be done

without the need for internal monitoring, if not

probably nearly all of them. I just wouldn't want to

-- let me back up.

I believe the evidence that was presented

suggested that one of the greatest, one of the

complications of induction, which is hypertonus, will

probably be detected through the STAN. So if it is

missed from clinical assessment, the system might

alert the person. So I a value of utilizing it in

patients who are under induction.

CHAIRMAN BLANCO: All right, anyone else

care to comment?

(No response.)

I take it from the silence on the other

issues, most panel members are in agreement that

tighter indications to make it more clear that this is

to be used in high-risk conditions until there is more

information at least, until there is more information





controlling how the product is labeled, how the

indications for the product are made. If somebody

from the FDA wants to contradict me, feel free, but in

my experience it is the province to say, "This is a

problem." Say, "This is a terrific device. We think

it ought to come on the market," whatever, "but it can

be misused if people don't understand, or used

inappropriately" -- that may be a better terminology

-- "used inappropriately without the appropriate

educational level, labeling, and indications," and

then it is up to us, if that is the issue, to suggest

not in crossing the "T's" and dotting the "I's"

detail, but in some general detail, what types of

education, labeling, and indications need to be put on

the device in order to market it safely in the United

States.

So I would say that is the only thing I

disagree with. I think we can do that, if that's what

you want.

DR. IAMS: Well, that's good to hear.

What I meant was I didn't think the FDA could really

mandate that stuff.





Dr. Wolfson, I think I saw your hand up?

DR. WOLFSON: Yes, I was just going to

comment. I like the Fetal Surveillance Manual. I

read it cover to cover. I found it -- I loved the

diagrams and I loved the choice in the terminology,

and I think this is a wonderful educational tool for

anybody in obstetrics and gynecology, whether they're

in nursing or whether they are physicians or midwives.

I, unfortunately, did not have the

experience in being able to open their educational

tool on my machine. My machine kept bombing. It just

wouldn't let it open.

So I think that education is a key point

is this particular product, and I don't feel that I am

sufficiently expert in their educational process to

say that what they have is currently insufficient to

train someone who is not knowledgeable in this

technology to become knowledgeable in this technology.

One of my original questions was, what is

the endpoint when you know that someone is adequately

trained? Is the software built in such a way where

you have to demonstrate a specific number of cases





the use of the device to ensure that it is used

appropriately.

Yes?

DR. O'SULLIVAN: The one thing I would

also suggest in this manual, which I am sure both Mike

and Gary have pointed out, and I suspect Dr. Rosen

knows, is that the teaching tools using the fetal

monitor tracings in here are the European as

contrasted to our 3 centimeters a minute.

Fortunately, I am familiar with that, so it was not

difficult, but for students it will be difficult.

CHAIRMAN BLANCO: Well, I think that goes

under what we said of a little bit of Americanization

for the American market will probably be very helpful

to their product.

All right, any other comments on No. 6?

Anything else that anyone would like to say?

(No response.)

All right, let's move on to No. 7. "If

the panel votes to recommend approval of the STAN

monitor, is there a need for post-approval studies,

and if so, what is the purpose of such studies and





what are the key elements of the study design?"

Who would like to begin that discussion?

Gary, I haven't heard from you in a while.

DR. EGLINTON: I think this question, I

don't need to get to this question.


DR. EGLINTON: I stop short of this

question.

CHAIRMAN BLANCO: All right. Well, then,

let's move on to someone else and see if they have

something to the question. Dr. O'Sullivan?

DR. O'SULLIVAN: I feel the same way Gary

does.


DR. O'SULLIVAN: I would rather know what

we're going to do before I answer this question.

CHAIRMAN BLANCO: All right, well, then,

unless someone else feels strongly -- Jay?

DR. IAMS: I'll try to bail you out,

Jorge.

CHAIRMAN BLANCO: Thanks. I appreciate

it.





DR. IAMS: I think the gold standard for

tests is the Papanicolaou smear. It ought to be

possible to have post-marketing studies for

obstetrical interventions or screening tests that do

pretty much what the last 50 years have done for the

Pap smear. You ought to be able to see, and the

Gothenburg study may be the beginning of such an

event, that the introduction of a technology into

practice results in appropriate screening and

intervention that results in a real clinically-

important outcome.

So I think this is a device which pretty

much automatically should qualify, if approved,

whenever it is approved, for that sort of post-

marketing surveillance.

CHAIRMAN BLANCO: Thank you. Anyone else?

Go ahead.

DR. WOLFSON: I wanted to second what Jay

said. I think that, clearly, the experience that

occurs in the United States has to be monitored and it

has to be reported because, again, of the diversity

that we are going to expect to see from country to





country. Without the European Union information, we

don't really know even the initial diversity over

there. So I would suggest that there, indeed, be

post-marketing studies.

DR. SHARTS-HOPKO: I have a question for

Jay. Would the outcome of a post-marketing study

still be metabolic acidosis or would you like to carry

that forward to be neurological outcomes?

DR. IAMS: Well, of course, you would like

to see both. I don't think it is the company's

responsibility to follow every patient that uses their

device forever and ever, but I think it would be their

responsibility to participate actively in that sort of

effort over time with whoever wants to follow that

sort of thing. That's a bigger issue than just for

one individual company within an industry to do, but

it ought to be the kind of thing we look forward, and

that the company fosters and doesn't impede.

We have had examples of that in other

technologies where that doesn't happen. Technologies

have been approved, and then when they're not

successful in influencing the ultimate outcome,





there's a tremendous literature in obstetrics dating

back 50-plus years about why it didn't exactly do the

way it was supposed to do, but it is because the

population got riskier, or all those cocaine babies,

or whatever. We've heard all that stuff before. I

don't think we should accept that anymore.


comments?

(No response.)

All right, that ends the section on the

questions that the FDA posed to the panel. What I

would like to go through is I would like to go through

with the different questions that were asked, and a

lot of the questions that were asked of the company,

the sponsor, have already been addressed, but maybe,

Dr. Rosen, if you could come up and we can go through.

Please forgive me; I have "X'ed" some of these out.

Yes, sir? One more question? You mean a

new question of Dr. Rosen?

DR. RINGEL: Right.

CHAIRMAN BLANCO: Okay. Why don't we go

through what I have here. Yes, sir, you can certainly





DR. ROSEN: Well, unfortunately, we don't

have that many cases in the Swedish randomized trial.

As far as I remember, there were actually two or three

cases that showed ST events as well.

It is the issue of a fetus that is exposed

to the stress of labor, regardless of race, would

respond, according to what we know, in a similar

fashion.

CHAIRMAN BLANCO: Okay. So for IUGR you

don't have that --

DR. ROSEN: We don't have the numbers

required.

CHAIRMAN BLANCO: All right, the other one

was, how as the management schema arrived at?

DR. ROSEN: This is very much part of the

whole development process of the STAN device, starting

with the experimental work, technological development,

and then followed by observational studies in the

clinical sense.

Obviously, you're observing these cases of

metabolic acidosis as they emerge and recognizing

events that we previously saw in the animal setup,





where we had structured settings with well-defined

hypoxia.

Then obviously there is the issue of the

technology, to what extent we can detect significant

events, given the source of information, the

electrocardiogram. In the Plymouth randomized trial

we used sort of an old technology, analog signal

processing. There was a scatter of data presented,

but we also looked for trends.

Today the database in the ECG quality is

so much different and so much improved that we can

look for more detailed ST events emerging, thereby --

CHAIRMAN BLANCO: Actually, I think the

question was really more addressing the issue that we

may have brought up already in terms of, when you put

down the way to use this device, you know, are you

going to say, you look at the fetal heart rate

monitoring and you only use it when the fetal heart

rate monitoring is not reassuring. Then you look at

whether you've got ST events, and you add that

component to make your decision. That's what they --

DR. ROSEN: That is basically the way it





should be used, according to the instructions.

CHAIRMAN BLANCO: Okay. All right. Dr.

Neuman asked about lead configuration, T wave

configuration, from spiral electrode, lead vector

changes as labor progresses and fetus moves. Have you

looked at that at all?

DR. ROSEN: Oh, yes, very much so. That's

the reason why we have the unipolar electrode

configuration, thereby creating an opportunity to have

a consistent ST wave form displayed throughout labor,

regardless of how the fetus rotates, but also

identifying what's called the "Y" lead in the

longitudinal plane of the fetus; that is where the T

vector is represented. So that is the way to secure

that we will pick up T wave ST events throughout

labor. There is literature on this and papers

published on this issue of lead configuration.

So, as I said, to record the ST, it's

completely different from just one heart rate being

displayed.

CHAIRMAN BLANCO: All right. Another

question was brought up about, what were the





complaints of the purchased units?

DR. ROSEN: These were related to failures

of the printer, technical failures that were easily

sorted.

CHAIRMAN BLANCO: Technical failures of

the printer or of the machine?

DR. ROSEN: There was nothing on the

safety aspect.

CHAIRMAN BLANCO: The concordance of the

STAN results with pre-terminal tracings?

DR. ROSEN: Well, we have pre-terminal

tracings as part of the guidelines. As you noticed,

there was one case that has been displayed here where

they didn't follow the protocol.

The physiology behind this is that, when a

fetus is exposed, if you go beyond the point where the

fetus is responding, and the heart rate performance or

cardiovascular performance starts to decrease, you

will not see a further rise in the ST.

On the issue of when we use the technology

and where there is a risk, could we identify cases

prior to the onset of labor, if we look at the data





in that case because I am not quite sure I got that

out of the instructions. Is that pretty clear in the

instructions, that you do not --

DR. ROSEN: Yes.

DR. IAMS: I noticed that there were

different criteria or that you had to be careful

during pushing, but I didn't get the idea that you

really shouldn't add this to someone's labor at the

point where she's already pushing.

DR. ROSEN: That is what is told and what

is very much part of the education process.

CHAIRMAN BLANCO: But is it just when

you're pushing or is it when you already have a fetus

that has had some myocardial decompensation?

DR. ROSEN: The reason we're doing this is

that what we found in the study is that this period

when you go from early stage to active pushing in

second-stage, that is where we find that the fetus is

exposed to hypoxia.

CHAIRMAN BLANCO: Okay. I know, but there

are going to be some patients, if this gets used in

the United States, that will already have some level





of hypoxia at the time that patients come in. A lot

of our patients come in late in labor. They've got

severe complications that create a problem, and the

fetus may already be hypoxic.

I think Dr. Iams' question is, if you

already have hypoxia, myocardial deterioration, and

you put the STAN monitor on, does it show you that

that is occurring, or because there are already ST

changes, the program will not recognize it?

DR. ROSEN: Well, this is obviously a

somewhat difficult question to answer. Depending on

where you are, if you are in the pre-terminal phase,

you have to rely on the heart rate trace, showing no

variability, no reactivity, but if you've got

reactivity, if you've got a fetal heart capable of

responding, then you will also see ST events,

regardless of what degree of metabolic acidosis you're

at.

CHAIRMAN BLANCO: So the answer is really

yes?

DR. ROSEN: Yes.

CHAIRMAN BLANCO: If you've already got





significant myocardial effects, the STAN monitor will

not show you anything?

DR. ROSEN: Well, it depends on where you

are. You may still have a heart which is exposed to

hypoxia where you will find marked ST events

associated with that. But if you take it through the

next step, where the cardiovascular system is failing,

where the fetus has decreased blood pressure, then you

will have the pre-terminal heart rate trace, and don't

expect ST events to go with that.

CHAIRMAN BLANCO: Okay. Jay, are you

satisfied?

DR. IAMS: Yes, I think so. Just let me

say it back to you again. If I have a patient with

the appropriate risk factors, my good care of this

patient would be maximized by having a STAN electrode,

rather than a regular electrode, inserted by the time

the time the patient reaches 6 or 7 centimeters,

because if I don't do it then, I might end up failing

to use the device in its most appropriate fashion?

DR. ROSEN: That would be according to the

recommendations of use of the device.





DR. IAMS: Right.


Did I get everybody's questions that were

not answered? Yes?

DR. WOLFSON: I just wanted to just

clarify what I thought I heard you say, Dr. Rosen. On

the STAN criteria or the algorithm for intervention,

the different levels of the .1, .15, and .05 are based

on clinical review and interpretation of the large

database that you have, and are not necessarily based

specifically, for example, on receiver operating

characteristic analyses per se?

DR. ROSEN: You are correct.

DR. WOLFSON: Is that correct?


Anything else? Go ahead, Gary.

DR. EGLINTON: Do you practice intrapartum

fetal stimulation in Sweden, vibrio acoustic

stimulation or LS clamp provocation of the fetus,

looking for accelerations?

DR. ROSEN: Varying between different

centers. We do have the fetal blood sampling in





Gothenburg, for instance, where in Lund there would be

more vibrio acoustic stimulation, and so on. So this

varies depending on where you would look.

DR. O'SULLIVAN: Let me ask you a question

regarding pushing, because this was something that I

was impressed about. In terms of at least in those

tracings that you showed us where the baby developed

or showed significant metabolic acidosis, while it

wasn't present in all of them, it seemed that the

tracings, at least as you looked at them, showed some

degree of abnormality, which got worse with pushing.

Was there any attempt to stop the pushing,

to allow the baby to recover? Or even to stop

contractions to allow the baby to recover, before the

baby developed some other abnormality?

DR. ROSEN: Well, once there's been a

significant event, according to the clinical

management protocol, obviously, we recommend immediate

delivery under those circumstances. According to the

data we have, we want that baby out as soon as

possible.

To try to stop pushing, to try to give





drugs, I mean if you obviously stop pushing and if you

give tributalin, for instance, stopping contractions,

okay, if contractions are the cause of hypoxia and

active pushing, you would expect there to be less

hypoxia, clearly. But how to institute that, I'm not

sure it would be practical and what we are

recommending is simply take the baby out, please.


questions from the panel members? Anything else they

would like to bring up?

(No response.)

Okay, let's move on. Open public hearing

again. At this point, what we would like to have is

not questions or interaction, but just basically if

anyone has any short comment from the audience, from

the FDA, or the sponsor. We will take them in that

order. Is there anyone in the audience not affiliated

with the sponsor or with FDA that would like to make

some final comments before the panel begins its

deliberation and votes?

(No response.)

Okay, next would be from anyone from the





FDA that would like to make any additional comments at

this point.

(No response.)

Nope? All right, then we go to the

sponsor. Anyone from the sponsor that would like to

make any additional comments at this point?

Okay, please identify yourself and your

relationship.

DR. NOREN: My name is Hakan Noren. I am

a consultant obstetrician in the University Hospital,

Gothenburg. I have no economic contract with

Neoventa, but they have paid my trip here and my stay

here.


DR. NOREN: I would comment on the

Gothenburg study. You must realize this is a clinical

situation. This is not a randomized trial. So don't

look at them in a STAN group or a CTG group. Look at

them together to see what is the number of metabolic

acidosis is. We are now down to .48 percent from

October to January.

So it is two quite different groups: the





high-risk group, the STAN group, and the low-risk

group. This is dependent on the midwives an

obstetricians getting better all the time to recognize

that there is something wrong with the CTG, and they

are immediately going over to the STAN group. So you

can't compare them. Look at them as one unit.

DR. RINGEL: May I ask a question?

CHAIRMAN BLANCO: Please, go ahead.

DR. RINGEL: You presented, you, the

sponsors, presented the data for us to interpret. I

understand what you're saying, but without knowing the

historical controls for your bad outcomes, without

knowing any comparison, without knowing what just

education of your midwives and your obstetricians

would produce, how am I to interpret the data?

For all I know, it could just be the

education process that has created such a tremendous

statistical improvement in your outcomes. For all I

know, you may have a very low rate of bad outcomes in

Gothenburg in general.

So how am I to interpret the data

regarding this machine?





DR. NOREN: You must realize that the

knowledge in the CTG interpretation before the

randomized trial wasn't that good, and a lot of

midwives, and even doctors, we looked at CTG in

different ways. Doctor, this study, when we started

with the STAN machine, we were forced to speak the

same language. This was the first thing.

Secondly, the midwives were forced to

identify what kind of CTG pattern it was in a much

more detailed way than they had done before. It has

been an ongoing education all the time, especially

after the relearning period, because we actually took

those cases where something has happened and discussed

them, and also pinpointed, say, to the doctor who had

made violations against a protocol and tell them,

"This is why there is a protocol." That's why,

obviously, this fetus has metabolic acidosis.

So by doing this all week, all months,

let's say, we have forced cooperation, to speak the

same language, and also to be aware of the situation.

Of course, many times the clinical situation it sounds

scientific here today, but many times you have a non-





reassuring CTG, and we are more or less waiting for

that ST event. When that happens, everyone is ready

to do the C-section. Of course, the time between

event and actually the C-section or vacuum extraction,

what we do is decreasing. That is one of the reasons

why we are better all the time, but it has continued

to be better.

CHAIRMAN BLANCO: Okay, unless you have

something else different, let's go ahead and bring it

to a close, that you would like to say, okay? All

right, thank you.

Okay, anything else the panel wants to

bring up? Questions or comments before we start?

(No response.)

All right, if not, Dr. Whang is going to

address the issue of the recommendations, options,

that we have available to us. I will go over a little

bit about how we're going to do the voting.

DR. WHANG: The panel will now be voting

to determination its recommendation to the FDA. Its

recommendation can be one of the following:

approval, approvable with conditions, or not





approvable.

Approval means there are no attached

conditions.

Approvable with conditions means there are

specific conditions which are discussed by the panel

and listed by the panel Chair. Conditions could be

labeling changes such as a revised indication,

contraindication, warnings or precautions, or a

condition could be a post-approval study or a

reanalysis of the data that have been presented.

Not approvable can be recommended for one

or more of the following reasons: (A) There is a lack

of showing of reasonable assurance that the device is

safe under the conditions of use prescribed,

recommended, or suggested in the proposed labeling.

(B) There is a lack of showing of reasonable assurance

that the device is effective under the conditions of

use prescribed, recommended, or suggested in the

proposed labeling. Or (C), based on a fair evaluation

of all material facts, the proposed labeling is false

or misleading.

If the panel votes not approvable, the





panel members will be asked to indicate why they think

it is not approvable and what is needed to make it

approvable; for example, additional clinical studies.

CHAIRMAN BLANCO: Thank you, Dr. Whang.

So, basically, what we have before us is

that we need to take a fairly complicated vote, and

I'll try to make it simple. Essentially, what we are

going to do is we are going to see if anybody is

interested in putting forth a motion and has a second

that would approve the PMA without any conditions,

just simply it's approved, done with, that's it. I

guess that will be the start.

Does anyone have an interest in making a

motion to approval without any condition at this

point?

(No response.)

Okay, not hearing or seeing anyone who is

interested in full approval, the next step is to see

whether there are members who want to propose and

second a motion that the PMA is not approvable. Is

there anyone who would like to make a motion, second,

that the PMA is not approvable?





DR. IAMS: I'll make that motion.

CHAIRMAN BLANCO: Okay, there is a motion

on the floor that the PMA is not approvable. Is there

a second?

DR. EGLINTON: Second.

CHAIRMAN BLANCO: There is a second on the

floor. Therefore, we are going to discuss this, and

then take a vote.

Jay, why do you think that it is not

approvable?

DR. IAMS: Well, I would like to

congratulate the authors on all their work. I don't

mean for this motion to be taken as a critical comment

on all that they have done.

I need to preface my remarks by -- I think

I can speak for lots of people, myself perhaps

specifically, in learning some lessons from the past

about more data not necessarily leading to better

outcomes. My presence on this panel may have

something to do with my involvement in studies of

uterine contraction frequency, where more data did not

lead has not led to better outcomes, and yet it was





much more data. That caused me to look back into

history and see if other examples might exist, and

they do, back to x-ray pelvimetry, for one, once used

rather routinely, now used hardly at all.

Electronic fetal monitoring as standardly

practiced is probably the best example. We have used

it progressively and often, and we haven't

accomplished, as Dr. Devoe pointed, the goals that we

had set for ourselves.

The second lesson of the past is that what

works in one place may not work someplace else. Baby

aspirin in this country in large populations of people

at risk didn't seem to do nearly as well as it did in

other studies.

So, with those concerns in mind, I'm

concerned about transportability and I'm concerned

that more data may not lead to better outcome. I am

hopeful that this will be an exception to both of

those historical lessons, because, I confess, I was

impressed with the information presented, but I don't

think it is yet time to approve.

I think that the reason for that would be





Item B. I'm not certain that it is going to be

effective in the United States population. I do not

have concerns about its safety in general. I think

I'm more concerned about whether it would do here what

it so clearly seems to have done in Sweden.

CHAIRMAN BLANCO: Let me put you on the

spot again. What would the sponsor have to do to

satisfy your concerns and be able to achieve an

approvable result?

DR. IAMS: Well, I think their EU study

will, in part, perhaps address the concern about

transportability from one place to another. An

American study would be another avenue to that.


DR. IAMS: So that's it.

CHAIRMAN BLANCO: Does anyone want to

speak to Dr. Iams' concerns or shall we move on to Dr.

Eglinton and see his concerns?

(No response.)

All right, Gary?

DR. EGLINTON: I also want to congratulate

Dr. Rosen and all of his co-workers for the years of





work. I learned a lot reading this. I look forward

to reading a lot more and learning much more in the

coming years.

I am very excited about this concept. I

am very excited about this technology, and I hope it

works. I hope that it improves where we are with

fetal heart rate monitoring in this country.

But I am not persuaded by what I have read

that this will improve clinical practice in this

country. I hope that there will be a study performed

in this country that will have very clear results and

will convince me and others that this is a wonderful

technology for us to use in this country.

CHAIRMAN BLANCO: And the same question to

you, and I think I know the answer, but just so that

it goes straight on the record: What would the

sponsor have to do to be able to satisfy your

concerns, to make the PMA approval?

DR. EGLINTON: I think it is going to have

to be done in this country.

CHAIRMAN BLANCO: All right. Let me just,

before we open the discussion to the other panel





members, make note that the PMA review is independent

of cost, previous regulatory difficulties, clinical

data submitted in other PMAs, and the medical/legal

climate and its effect on the standard of care.

Having said that, does anyone else care to

make any comments, either in favor or against the

current motion and the comments about what has been

said by Dr. Iams and Dr. Eglinton.

DR. EGLINTON: Can I just add one more

phrase?

CHAIRMAN BLANCO: Sure.

DR. EGLINTON: I think it needs to be done

in this country because of differences in the style of

practice. The way obstetrics is practiced in this

country is dramatically different from the way

obstetrics is practiced in Scandinavia, and probably

many other places in the world.


Any comments? Michael?

DR. NEUMAN: Mr. Chairman, I'm just

curious what the difference is between not approvable

and suggested things to do and approvable with





conditions, with the condition being a study in the

United States.

CHAIRMAN BLANCO: Well, I would appreciate

any help from the FDA, if I say it incorrectly, but if

you're requesting another total study before it is

approved, you're basically not approving it. You're

making the requirement that they have to have a total

new study to come forward before the FDA and before

the panel.

As part of a condition, you can get post-

market surveillance or another post-market approval

study, but it will already have been on the market

during that time. So if it is approved with

conditions, and the condition is that you do another

study, then it is a post-market approval of study, and

it is marketable at that point.

Am I correct on that? I would appreciate

some help from members of the FDA.

MS. BROGDON: I think that's a semantics

problem. If you recommend that it's approvable, but

one of the conditions is a whole new study be done, we

would essentially take that as a not approvable





recommendation because the sponsor would have to

essentially start over with their clinical study. If

you mean a post-approval study, you should say that

clearly.

CHAIRMAN BLANCO: That would be a

condition then. That's what I was trying to explain.

Mr. Pollard?

MR. POLLARD: Right, and I would just like

to --

CHAIRMAN BLANCO: Would you identify

yourself, please?

MR. POLLARD: Thank you. Colin Pollard

with the Center for Devices and Radiological Health,

FDA.

I just wanted to remind the panel, from

some comments that I made at the beginning of the day,

just some basic definitions of safety and

effectiveness. With safety, basically, you -- FDA,

actually, ultimately, and you in your recommendation

-- have found that the probable benefits outweigh the

risks of the device. To find it effective, the

studies that support that PMA have shown a clinically-





significant result. That is basically the threshold

for an approval.

Now for a post-approval study, for

instance, you need to meet that threshold, and then

that post-approval study would be looking at, you

know, things beyond that threshold, either rare events

or long-term results or fairly focused questions or

validating a surrogate endpoint, that sort of thing.


The floor is open for comments from the

panel members.

DR. O'SULLIVAN: I really do believe that

a study should be conducted in this country. I think

I say this because I think even the Scandinavians have

shown that introducing it initially, followed by their

interim analysis, re-education, and so on, shows that

there is a great deal of learning that needs to go on

in understanding how to use this and how to properly

interpret it. That's No. 1.

No. 2, in contrast to Scandinavia and in

contrast to what we would even say as far as product

labeling is concerned, if this device is in a





hospital, it will be like the pulse oximeter; they

will use it routinely, and it won't matter.

I think that the additional factor

regarding its success would be that if we don't do

this thing and were to otherwise approve it, that

getting it off the ground and getting it working and

getting everybody educated would take forever, would

not be successful, not as successful, because of the

thinking processes of physicians, nurses, and nurse

midwives in this country.

So if this was going to be at all

successful in the United States, then I think that

there's only one way to go, and that's a randomized

controlled trial.

CHAIRMAN BLANCO: In the United States?

DR. O'SULLIVAN: In the United States.

CHAIRMAN BLANCO: Okay. Let me just point

out, in all fairness to the sponsor and the FDA, that

the issue of non-approved use, unfortunately, is not

the purview of the FDA. They have to approve for the

indications, but they don't and can't control how

physicians in the United States then use the devices





that are out on the market and available, just for the

record, so everyone is aware of that.

Okay? Any other comments? Dr. Wolfson, I

think I see your hand.

DR. WOLFSON: A question for Dr. Pollard

and then some thoughts.

Colin, can you clarify again that what we

are looking at when we are approving the PMA is that

the investigations that have been accepted by FDA

demonstrate statistical significance, and that the

device is considered to not put increased risk of

patients at jeopardy?

CHAIRMAN BLANCO: Let me just point out,

we're not approving. We're talking a motion for non-

approval of the device. Okay? Just so we're clear.

Mr. Pollard?

MR. POLLARD: Right, and your question is

about to approve the PMA. Basically, there's three

elements that we talked about this morning. One is

that it is based on valid scientific evidence, and we

talked about what that means, the different types of

studies that any sponsor can submit.





Based on valid scientific evidence, the

PMA would need to show that it is both safe and

effective, and sort of the operative words with safety

is that the probable benefits outweigh the probable

risks when it is used as it is intended to be used in

the labeling that is given in the application.

Secondly, for effectiveness, that that sum total of

the valid scientific evidence in the application shows

when the device is used as it is intended to be used,

that it produces a clinically-significant result.

CHAIRMAN BLANCO: Now let me just add, if

you read it in your package, there should be the

definitions, and there are issues of target

population. Maybe it would be worthwhile to read the

definition of effectiveness for the panel. The

definition is: "There is reasonable assurance that a

device is effective when it can be determined, based

upon valid scientific evidence, that in a significant

portion of the target population, the use of the

device for its intended uses and conditions of use,

when accompanied by adequate direction for use and

warnings against unsafe use, will provide clinically-





significant results."

I believe that what Dr. Iams and what Dr.

Eglinton and Dr. O'Sullivan have been brought forth is

concerns about the significance of it in the target

population, and also the uses, the intended uses and

conditions of use, by the physicians who would use it,

if I could paraphrase that. Is that all right, Dr.

Iams?

DR. IAMS: That's fine with me. I think,

to say it differently, if I were a Swedish panel

member in Sweden, I would easily vote yes. I would

vote it to be approved with some of the minor

considerations we have talked about, but the issue is

the target population.

CHAIRMAN BLANCO: All right, any other

comments here? Yes?

MS. MOONEY: Yes. In light of the fact

that we have two randomized controlled trials,

acknowledging the fact that we have had that done

outside the U.S., both showing significant improvement

and meeting the study objectives, I wonder if perhaps

the better course here would be to entertain more





narrow indications in approvable status, where we

target the highest-risk patients, if that would not

tip the risk-benefit in a more favorable light, and

then again come back to a post-approval status as far

as determining whether any of our concerns with the

U.S. population are valid; also, in light of the fact

that the sponsor has indicated a willingness and

commitment to put together an extensive training

program, and at least in the Swedish situation has

shown that that training commitment and executing that

did, in fact, improve the use of the device.

CHAIRMAN BLANCO: Any comments? Dr.

Wolfson?

DR. WOLFSON: Jorge, yes, I'm really going

to speak against not approving. I guess that means

I'm speaking toward approval, but I'm not sure, based

on these definitions.

I share my colleagues' concerns relative

to effectiveness, but I would like to back up for the

record and make a couple of points.

I think it is clear to all of us in the

obstetrical realm that one of our principal goals is





to improve neurologic outcome. For decades, we have

looked at various tools to achieve that. This is the

first tool that has come along with demonstrable

scientific evidence that it has improved neurologic

outcome, period. It's demonstrated in the UK. It's

been demonstrated in Scandinavia. So I think the

validity is there, and I think we don't want to lose

track of that.

Two, I would like to point out that we are

looking at a paradigm shift, in my opinion, with

respect to the use of fetal monitoring. For one of

the first times, we are now taking a signal, as crude

as it is -- all of us understand that; we always are

amazed that we can tell anything about a fetus by

heart rate because you can't do that with anybody

else, but the idea is we are now analyzing that

signal, looking for information that has specific

correlates with respect to outcome. I believe the

authors have done decades of work demonstrating the

efficacy of this particular technique, and we're not

to lose sight of the value of that.

I think that an offshoot of this process





that's been addressed by my colleagues is the fact

that there is a great deal of variance or diversity in

the interpretation of electronic fetal monitoring in

the United States. This is a concern. It's an

educational issue. There's no doubt about that.

I think clearly the same issue was true in

the institutions that were part of the Swedish RCT,

because we saw that from the beginning to the end,

that as they received more training, their outcomes

became better.

I believe that a most important --

important, important -- offshoot of this particular

tool, this particular product, is that it is going to

take the American population of obstetrical providers,

whatever be their ilk, and bring them back to

restudying what is the electronic surveillance that we

utilize for the intrapartum patient. So that we will

become better as a nation and as providers in

interpreting the electronic fetal monitor, and with

the proper interpretation of the ST segment, produce

better outcomes and duplicate, in my opinion, the

findings that were seen within the Swedish and U.K.





studies.

I have no evidence that this particular

device creates harm when applied in an effective

manner. I would agree with my colleague who said that

what would be preferable here, in my mind, is perhaps

tightening up the indications of where it is utilized,

rather than voting for non-approval, and therefore,

obstructing access of obstetrical providers to this

device for an undetermined period of time.

We all know for them to mount a randomized

controlled trial, even through the maternal-fetal

network of the NIH, and bring it back to this

institution is going to take perhaps anywhere from two

to even as long as maybe four years.

So I would share the concern of my

colleagues with respect to effectiveness in an

American population, and I am still, in my own mind,

working through whether that requires non-approval or

whether it requires approval with post-market study.

Thank you.

CHAIRMAN BLANCO: Thank you for your very

thoughtful statements, Dr. Wolfson.





Anyone else who would care to address an

issue? Yes, Doctor?

DR. BROWN: I just have a point of

clarification with something that Dr. Wolfson said.

He made the statement that the studies clearly showed

an improvement in neurological outcome. By that, do

you mean they clearly showed a surrogate endpoint of

neurological, improvement in the surrogate endpoint,

meaning acidosis?

DR. WOLFSON: No, I was referring --

DR. BROWN: Because it wasn't my

understanding that they were really powered to detect

the neurologic outcome differences -- could you

clarify that? -- on a statistical basis?

DR. WOLFSON: I was looking purely at the

information that was provided in a Swedish randomized

trial on neurologic outcomes.

DR. BROWN: But that was not one of the

endpoints of the study or the objectives, right?

DR. WOLFSON: No, I know it's not one of

the endpoints of the study. I'm simply pointing out

to everyone that, in my mind, it may be the most





important aspect. It may not have been specifically

what they were after. They were after reducing the

risk of, or the likelihood of, metabolic acidosis, and

they were after the idea of demonstrating that you

could do it without increasing the Caesarean section

rate, because that's been the principal criticism of

all these new technologies we bring online, that it

becomes nothing more than another indication to

deliver somebody abdominally or operatively.

What I said is that I guess, in my mind,

the icing on the cake, the thing I've been grasping

for for 25 years of practice is to have a tool that I

can tell a patient that, because I am utilizing this,

I have the opportunity to perhaps improve the

neurologic outcome for your child. This is part of

the data that came out of that.

So, yes, it is not one of the endpoints,

but it is, to me, the most valuable aspect of it.

DR. BROWN: Well, let me be specific. Was

that -- and I'll ask the statistician -- was that a

statistically-significant finding?

DR. WOLFSON: Yes, it was.





MS. TOLEDANO: The probability of having

seven out of seven babies -- we had seven babies who

had moderate or severe encephalopathy. The

probability of having all seven of those babies in one

group is less than 2 percent. So that is "P" less

than .02. That is a two-sided P value.

DR. WOLFSON: In both analyses, the

intent-to-study as well as the revised, there was a

statistically-significant difference. It is in Volume

1, and God knows what page it is on because I didn't

memorize it, but it was one of those things that, when

I was going through the data and I was looking at

focusing on all this stuff, and all of a sudden it hit

me. It's the detail on the Swedish RCT. It's those

tables that are printed out in landscape in your

guide.

DR. IAMS: Page 15.

DR. RINGEL: Is it in 2, page 16? Is that

what you're referring to? I'm not sure if that's what

you were referring to or not.

DR. WOLFSON: I don't now.

DR. IAMS: I think it is the page before,





page 15, but the first box, "intention-to-treat

total." That's eight versus one.

DR. WOLFSON: Yes, neonatal outcome. The

intention-to-treat total, moderate to severe, neonatal

encephalopathy, it was 4 in the CTG group, 1 in the

STAN group, statistically-significant, a .02 level.

Then when you took those neonatal outcomes and looked

at them in -- what is interesting is -- where is it?

Well, anyway --

DR. IAMS: Go back a page to 15. You're

on 16.

DR. WOLFSON: No, I've got 15. What I was

looking for is that, when you then go into where you

take out the adequate recordings, that moderate to

severe neonatal encephalopathy becomes seven up

against zero in the STAN group, giving a statistically

significance of --

CHAIRMAN BLANCO: What page are you on?

DR. WOLFSON: Oh, I'm now on page 22. It

is the upper table.

MS. TOLEDANO: Yes, that's a one-sided P

value.





DR. WOLFSON: It's the fifth line down.

Now you are at a P level of .007.

MS. TOLEDANO: That's a one-sided P value.

That's just for -- all right, you guys know what's a

one-sided versus a two-sided.

CHAIRMAN BLANCO: Any other questions or

anything else you want to elaborate on?

DR. O'SULLIVAN: I would just like to say

I didn't follow him at all because I haven't figured

out where he was.

CHAIRMAN BLANCO: Okay, well, let's make

sure that you do. Let's start off --

DR. WOLFSON: We're in Volume 2.

CHAIRMAN BLANCO: Volume 2.

DR. WOLFSON: Page 15.

CHAIRMAN BLANCO: Page 15.

DR. WOLFSON: Go to page 15, the upper

part of the table where it says, "intention-to-treat

total," within the box it's the fifth line down.

DR. O'SULLIVAN: Yes, I can see where it

says, "Moderate to severe encephalopathy," there's a

.02 P value.





DR. WOLFSON: Right. Then on page 22,

they now have taken out the -- page 22 includes the

adequate recordings. So they have removed the - what

is it? -- 300-plus cases, or whatever it is, where the

recordings weren't adequate. Then the similar

analysis now is seven against zero. So we have

eliminated one. So now it is at .007.

DR. O'SULLIVAN: Yes, but where is the

long-term neurologic outcome?

DR. WOLFSON: That's it.

DR. O'SULLIVAN: It's short-term, though.

DR. WOLFSON: Oh, I'm sorry, no, there is

no long-term because that wasn't the purpose. I'm

just looking at this from the standpoint that what

happened in the nursery and the diagnosis that was

made acutely, it disappeared.

MS. TOLEDANO: Somewhere there was long-

term.

DR. WOLFSON: Was there long-term?

MS. TOLEDANO: Somewhere there was a table

of long-term.

DR. WOLFSON: I don't remember the long-





term.

DR. O'SULLIVAN: There was one thing where

they did -- I think Dr. Wolfson would know this, but

they did 18 months of followup or 16 months.

CHAIRMAN BLANCO: Please come.

DR. O'SULLIVAN: But I don't remember

where it is.

CHAIRMAN BLANCO: Identify yourself.

DR. KJELLMAR: Ingemar Kjellmar, Professor

of Pediatrics and Neonatology.

I had included in the material that was

distributed to you in my presentation on perinatal

markers of quality in Sweden a few slides dealing with

an old material of cases that I have resuscitated in

the 1970s, and where we could provide real long-term

follow-up studies. They were about 25 years of age.

In that material there is a table on the

assessment at 18 months of age. Out of the 74

resuscitated babies, we had 14 cases who became

disabled.

The point with the table that I have

included, the points are actually two. The first one





is to demonstrate that there are recognizable patterns

of cerebral palsy that dominate the outcome. These

are either dystonic cerebral palsy or tetraplegic or

hemiplegic cerebral palsy.

The second point is that those will be

recognized at a very early stage, and already when the

babies are 18 months of age, you recognize that they

have poor motor performance and that they have a

neurologic disability, although you are probably not

able at 18 months of age to definitely tell which type

of cerebral palsy this patient will have.

CHAIRMAN BLANCO: All right, let me

interrupt you for a minute. These 14, those were part

of this study?

DR. KJELLMAR: No, no.

CHAIRMAN BLANCO: I wanted to make sure

that was clear.

DR. KJELLMAR: Absolutely not. They were

all born in the 1970s. So that is the reason why I

did not --

CHAIRMAN BLANCO: So you don't have 18-

month data for these babies. You just have the acute





data?

MS. TOLEDANO: That was my question

actually. Are we allowed to ask them directly or do I

ask you?

CHAIRMAN BLANCO: Either way.

MS. TOLEDANO: I can ask him directly?

Do you have any followup, 18-months'

followup, one-year followup of the babies who were in

your special care?

DR. KJELLMAR: Not yet.

(Laughter.)

CHAIRMAN BLANCO: The answer, for the

record, was "not yet" from Dr. Kjellmar. Thank you.

All right, any other comments concerning

the motion on the flow?

DR. RINGEL: I would like to say, not in

response to Dr. Wolfson, but after you mentioned these

things, I went to look at it again. I'm a technology

junkie basically, but my problem here is that there

are basically three studies we have been presented

with.

The Plymouth study does not show any





difference in neurologic outcome and just barely shows

a difference in the acidosis outcome, and that's why

they felt they needed to go further and to use the

automatic detection. Okay, so the Plymouth study

doesn't really help us.

The Gothenburg study, I know I keep

harping on it, but as best as I can tell, the

Gothenburg study does not tell us anything about the

device itself, only about the possibilities of

training and expertise and learning. Maybe all this

is about learning how to read the standard traces

better.

So we are left with one study where the

data is a bit questionable because of the re-training

that happened in the middle of the study, and because

there are some questions about how significant the

changes are. For that reason, I pretty much agree

with my colleagues who say that there needs to be

another study done in the United States where there

are comparable patients.

I notice jitteriness is an outcome;

irritability it an outcome. There are some nurseries





in the innercities where all the patients come out

jittery and irritable. We don't have to get into why,

but I happen to know that is true because I have

worked in the innercity my entire professional career.

So I have to say that while, yes, we would

love to believe that we can start preventing or

decreasing the amount of cerebral palsy we see, the

amount of learning disorders we see that may be

related to asphyxiated deliveries, I'm not sure we

have the proof yet.

CHAIRMAN BLANCO: All right, any other

comments? Dr. Toledano?

MS. TOLEDANO: I have to agree with Ms.

Mooney and with Dr. Wolfson. I would much rather see

this going to a setting of approval with conditions.

If we are talking about being able to learn how to

read tracings, these are the people and they have the

materials to teach us how to read the tracings better.

I think we need to have access to that in this country

in a more timely manner.

CHAIRMAN BLANCO: Thank you. Any other

comments?





MS. MOONEY: Just one final remark: I

think that, obviously, if we think we need a U.S.

trial before the device can come here, then that's

what needs to be done, but we should recognize that

there is the potential that the cost associated with

this trial would preclude the sponsor going forward

with the study. So this sort of decision could

actually be a decision to not make the devise

available at all.

CHAIRMAN BLANCO: Unfortunately, I must

remind the panel that cost is not one of the things

that we are able to consider here.

All right, unless there is something

different, we're going to go take a vote. Do we have

something different, Dr. Wolfson?

DR. WOLFSON: No, I was just going to

address the type of trials. Thank you.

CHAIRMAN BLANCO: Okay. Well, I think we

can do that depending on what the outcome of the vote

is. Unfortunately, there's no way to hide here. So

we're just going to go down the side. Michael, Dr.

Neuman, you've been here a long time, so I'm going to





start on your side, so you'll be the first one.

Now let's remember that the motion is for

non-approval. So that a yea vote on the motion is a

motion to not approve the PMA.

Your vote, Dr. Neuman?

DR. NEUMAN: Yes, I vote not to approve

the motion.

DR. RINGEL: Yea.

CHAIRMAN BLANCO: Dr. Ringel?

DR. RINGEL: Yes.

CHAIRMAN BLANCO: Not to approve?

DR. RINGEL: Not to approve.

CHAIRMAN BLANCO: Dr. Toledano?

DR. IAMS: No, no, no. He got that wrong.

CHAIRMAN BLANCO: He said "yea."

DR. RINGEL: I said "yea" three times.

CHAIRMAN BLANCO: Yes, "yea," not to

approve the motion, correct?

DR. RINGEL: Yes.

CHAIRMAN BLANCO: Not to approve --

DR. RINGEL: I'm the one that messed it

up. I'm sorry. Not to approve the PMA. I apologize.





I'm the one for non-approval.

CHAIRMAN BLANCO: Yea or no?

MS. TOLEDANO: No, I do not approve the

motion.

CHAIRMAN BLANCO: Okay, so you vote for

some other --

MS. TOLEDANO: That is correct.

CHAIRMAN BLANCO: We would like

confirmation of Dr. Neuman's [sic] vote. You voted

"yea" for the motion to not approve the PMA?

DR. RINGEL: No. I voted not to approve

the motion to not approve --

(Laughter.)

CHAIRMAN BLANCO: We've got too many noes

there.

DR. BROWN: It might be better if we said

for or against the motion, for or against it.

CHAIRMAN BLANCO: Why don't we just say do

not approve of the PMA. Let's just say, not approve

of the PMA --

DR. SHARTS-HOPKO: No, no, you can't do

that.





CHAIRMAN BLANCO: -- to make sure that we

don't get into any difference, and let's start all

over again.

DR. O'SULLIVAN: That violates

parliamentary procedure.

DR. BROWN: For or against the motion.

MS. TOLEDANO: The motion is to not

approve. Are you for the motion or against?

CHAIRMAN BLANCO: All right. Dr. Neuman,

are you for the motion or against?

DR. NEUMAN: I am against the motion to

not approve.


DR. RINGEL: For.

MS. TOLEDANO: Against.

CHAIRMAN BLANCO: Against.

DR. WOLFSON: Against.

DR. SHARTS-HOPKO: Against.

DR. IAMS: For.

DR. RAMIN: For.

DR. EGLINTON: For the motion.

DR. O'SULLIVAN: For the motion.





DR. BROWN: For the motion.

CHAIRMAN BLANCO: Wait, wait, not so fast.

(Laughter.)

Dr. O'Sullivan, for the motion.

Dr. Brown?

DR. BROWN: For the motion.

CHAIRMAN BLANCO: Dr. Seifer?

DR. SEIFER: Against.

CHAIRMAN BLANCO: Against.

The motion carries 6 to 5. The motion is

approved. The PMA is not approved.

We now need to go around and explain why

we voted in a brief way. I think we have already said

most of the things that needed to be said in terms of

what the sponsor will need to do to be able to bring

forth an approval PMA.

Dr. Neuman?

DR. NEUMAN: While I agree with the

concerns about the different patient population in

North America compared to Sweden and the U.K., I feel

there is compelling evidence that looking at the

configuration of the electrocardiogram is providing





additional information that we currently are not

using, and that the studies that have been done up

until now certainly have concerns. Nevertheless, I

think that, provided that additional post-marketing

studies are done in the states to make sure that these

concerns of the panel are not as significant as some

members feel they are, would be sufficient.


DR. RINGEL: I don't think there's

reasonable assurance that the device is effective.


MS. TOLEDANO: I agree with Dr. Neuman.


DR. WOLFSON: I think I have expressed my

concerns.


DR. SHARTS-HOPKO: I agree with Dr.

Neuman, and I didn't want to close the door against

continued development of the product.


DR. IAMS: I think I've already stated my

rationale.






DR. RAMIN: I, too, have concerns about

the effectiveness or efficacy, and I think just a

randomized clinical trial in the U.S. population is

what is needed.

CHAIRMAN BLANCO: Dr. Eglinton?

DR. EGLINTON: I have the same concerns.

I think we'll see clinical use in Europe and it will

spread, and it will spread around the world, and maybe

someday in the future it will spread far enough that

we'll be happy with it here. But I think at this

point it is still a research tool, the way we are

looking at it. I think it's an exciting research

tool, but I think it's still a research tool at this

point.

CHAIRMAN BLANCO: Dr. O'Sullivan?

Thank you, Dr. Eglinton.

DR. O'SULLIVAN: There's really nothing I

can add to that.


DR. BROWN: I specifically have concerns

that I did not believe there was enough proof of





clinical significance, although there was statistical

significance of the endpoints.


DR. SEIFER: I agreed with Dr. Neuman's

points.


I would like to thank all the panel

members.

I would like to see if the FDA, Dr.

Pollard, do you have anything to say?

MR. POLLARD: Yes, I just wanted to get a

little bit of clarification. I mean, I did hear the

panel ask for a randomized clinical trial to be

conducted in the U.S. It might be helpful to have a

little better sense of just what kind of trial are you

talking about. You know, specifically, what kinds of

endpoints would a trial like that require?

DR. IAMS: I think a trial very much

similar to the one they have proposed, powered to look

at metabolic acidosis, powered, if possible -- you

have to look at the numbers to look at markers,

clinical markers, of newborn encephalopathy, seizures





and some of the markers you've already used in your

current trial. That may not be possible. Metabolic

acidosis is fine. I have no problem with that.

CHAIRMAN BLANCO: Dr. Iams and Dr.

Eglinton and Dr. O'Sullivan, and the others, anyone

else, can you specify a little further? I mean, it

wasn't the issue of the endpoints. So that this helps

the sponsor and the FDA. I don't think it was the

issue of the endpoints as much as the issue of the

population in terms of the patient population and the

issue of the management in terms of what occurs in

this country as opposed to what might occur in other

countries.

Am I --

DR. IAMS: That's correct.

CHAIRMAN BLANCO: -- paraphrasing it for

you all appropriately?

DR. O'SULLIVAN: The only thing that I

think would be of benefit, although, again, I think it

would be very expensive, you can't certainly do a two-

year followup. So from that perspective, I think

cost-effective-wise that would be ridiculous. But





there are now currently emerging imaging studies that

one might think about tagging on here, at least before

the baby is discharged or at some point after

discharge, but, ideally, during the hospital course of

the baby because that's when the baby is a captive. I

think those could be looked into, and certainly I'm

not expert in those.

CHAIRMAN BLANCO: Any other points?

DR. WOLFSON: Can I make one?

CHAIRMAN BLANCO: Yes, sir.

DR. WOLFSON: I would encourage that the

studies be done not solely in academic centers. Most

centers tend to be urban, low-income, minority, and

the majority of births that are affected -- well, I

should say they just simply take place within the

United States are clearly occurring in what are

principally Caucasian, non-urban environments. So it

is important from that standpoint, though, granted, if

you demonstrated in an urban environment, then you'll

demonstrate it anywhere.


If there are no other comments, I would



us food and drug administration: 3856t1

Documents