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. GROSS
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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 Member JOYCE WHANG, Ph.D., Executive Secretary N. WOLFSON, M.D., Ph.D., Temporary Voting

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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

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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 before we start: a couple As of housekeeping let's not matters have any

usual,

outbursts from the audience. recognized, at the

If you would like to be time you will be

appropriate

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. NEAL R. GROSS
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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: Brogdon. Good morning. I'm Nancy

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: Wolfson. Good morning. I'm Robert

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

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Executive Secretary of this panel. CHAIRMAN Blanco. BLANCO: I am Jorge "George"

I am a perinatologist in private practice in

Odessa, Texas. DR. Ramin. RAMIN: Good morning. I'm Susan

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: President of Clinical I'm Mary Lou Mooney, the Vice 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. NEAL R. GROSS
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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 I'm Mike Neuman from

job, Jorge, I think it's fine.

the Memphis Joint Program in Biomedical Engineering of the University of Tennessee Health Science Center in the University of Memphis. CHAIRMAN BLANCO: than I did. Thank you. (Laughter.) DR. NEUMAN: though. (Laughter.) CHAIRMAN BLANCO: We'll have to train you. Can't do it in one breath No, you did much better

We'll have to invite you back more, so we can train you. DR. NEUMAN: That's quite all right. All right, at this point

CHAIRMAN BLANCO:

I would like to introduce the FDA press contact, if she would please stand. particular meeting is The FDA contact for this Nancy Brogdon, Director,

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Division Devices.

of

Reproductive,

Abdominal

and

Radiologic

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 NEAL R. GROSS
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government panel.

employees

and

are

consultants

to

this

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. prohibit The conflict-of-interest government employees statutes from

special

participating in matters that could affect their or their employer's financial interests. agency has determined that the However, the of

participation

certain members and consultants, the need for whose NEAL R. GROSS
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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. by submitting of Copies of this waiver may be obtained a written request to the 12A-15 agency's of the

Freedom

Information

Office,

Room

Parklawn Building. "We would like to note for the record that the agency took other into consideration Drs. certain Gary matters

regarding

panelists.

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, NEAL R. GROSS
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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 current statements or previous or presentations disclose with any any

financial

involvement

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. you. CHAIRMAN BLANCO: Thank you. Thank

It's a pleasure for me to introduce Colin Pollard, Devices remarks. Colin? NEAL R. GROSS
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Chief Branch,

of

the

Obstetrics will make

and some

Gynecological introductory

who

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. panel meeting, we FDA has approved the Since our last PMAs. In

two

September

approved

Novasure

Endometrial

Ablation System. this type.

This is the fourth such device of

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 NEAL R. GROSS
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panel year:

meetings

scheduled

for

the

remainder

of

the It's

July 22nd-23rd and October 21st-22nd.

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 postapproval 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 postapproval endpoints study or a might be done to study validate might those answer

post-approval

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 NEAL R. GROSS
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activities

that

FDA

engages studies.

in,

including

an

update

on

post-approval

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. 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 I just wanted to give a few remarks

monitors are Class II devices and get to the market through where the the 510(k) sponsor pre-market would notification show that process 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 in that that we believe we has would

significant

implications,

case

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

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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. elements: valid

I want to highlight three evidence, safety, and

scientific

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 NEAL R. GROSS
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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 a panel come in the form that of a

recommendation,

recommendation,

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, NEAL R. GROSS
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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. present before We have one speaker signed up to 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 NEAL R. GROSS
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then go ahead with your presentation? interrupting you. DR. ARTAL: this.

I apologize for

No, thank you.

I appreciate

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: DR. ARTAL: Thank you. Go ahead.

Thank you.

Again, thank you

for giving me the opportunity to represent ACOG here today. NEAL R. GROSS
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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: Effectiveness publication analysis of Data listed the in of the The Summary of Safety and Neoventa summary, et al., Medical, the the the

detailed Swedish

Amer-Wahlin,

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 NEAL R. GROSS
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of the study design, the experimental study design was considered to be appropriate for evaluating the

efficacy of cardiotocography plus ST analysis versus cardiotocography monitoring. only for questions intrapartum remain about fetal the

However,

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. rate of fetal acidosis acidemia The overall in these

reported

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

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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 events, and so acidosis/hypoxia, environmental on. None of such as

physiologic positioning,

factors, this has

fetal 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? NEAL R. GROSS
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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 What

occurred in both arms of the trial, it appears. 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? likelihood ratio? Nowadays,

And more important, what is the

for

an

evaluation

of

a

diagnostic or a screening test, likelihood ratio is the appropriate effect size to describe the

performance of the test. ratio?

So what is the likelihood

In summary, we urge the panel to clarify NEAL R. GROSS
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with the sponsors of the device the following issues: What are the false positives and false negative

results for the proposed method in detecting metabolic acidosis/hypoxia? Do other events influence the ST Clarifications on protocol

waveforms in the fetus? violations. of the CRT

What is the sensitivity and specificity plus ST for detecting fetal metabolic

acidosis/hypoxia?

What is the likelihood ratio?

The ACOG Committee on Obstetric Practice recommendation is that, although this new technology appears required. very promising, additional information is

Currently, the Committee cannot endorse the ACOG is

adoption of this device in clinical practice.

particularly concerned with the introduction of new technology to clinical practice, which could further escalate the cost of medical care without necessarily improving clinical outcome. For example, how does CTG

plus ST analysis improve outcome when compared with a simple and less expensive test like fetal stimulation testing? Thank you very much. CHAIRMAN BLANCO: Thank you, Dr. Artal.

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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. agenda is the presentation by The next item on the 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. am I'm a pediatrician/perinatal physiologist. Medical Director of Neoventa I

currently

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, parallel and then Professor with Karel regard Marsal to the will U.S. draw and

observations

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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 We could have a look at events

fetal scalp electrode.

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 The mother has an

of roughly 160 beats per minute. increased temperature.

She's been given Parasetimol.

Still no ST events, and heart rate now in still firststage 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 NEAL R. GROSS
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of the T/QRS ratio, and there are now more T waves that you can see. Now the midwife in charge, she also

recognizes that heart rate ratio is now becoming what we call abnormal. So there is an indication that this She reports to the clinician.

is ongoing hypoxia.

Over this time period, there are further indications from the STAN monitor that there is an ongoing ST elevation. However, the clinician thinks the heart rate rates may not look that bad. There are signs of

accelerations, and while they are discussing matters, the decision is made to perform a fetal scalp sample, which, as you see, is low, 6.93, and obviously, then, emergency intervention is required. There is failed

vacuum extraction, followed by an emergency Caesarean section and a baby delivered approximately one hour after the onset of hypoxia in second-stage labor. As you may see, the Apgar scores are very low. There is cord vein metabolic acidosis. There

simply wasn't any blood in the artery.

The baby needs

active resuscitation and needs time on the respirator, NEAL R. GROSS
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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 We

understanding of the path of physiology involved.

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 Some are

we may find a lot of heart rate changes.

troubled somewhat but managing and compensating fully, in no immediate danger. that's more troubled and But then there are a few forced to utilize key

resources in an attempt to compensate, and some may not even be able to fully compensate, and we need to NEAL R. GROSS
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identify those. If we look at the history of fetal

monitoring heart rate, clearly, the basis on which we stand for more than 100 years. monitoring was introduced in When electronic fetal the sixties, it was

thought that we needed additional information. pH was introduced already at that point in time.

Scalp The

last couple of years we have seen the introduction of posimetry, and now we have the STAN monitor based on qualified changes. What is, then, the problem? Well, we have assessment of CTG velocity ST waveform

seen the emerging, rising Caesarian section rates, and they vary across the world, with the U.K. and the U.S. running rather high figures, and in Sweden we have somewhat lower figures. You may wonder what the

reason is for this.

Well, one of those is probably

the uncertainty about how we assess the condition of the fetus during the labor, there don't in which is want a to there need see is for

uncertainty. intervention,

Clearly, because we

babies

being affected. NEAL R. GROSS
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So what are the alternatives?

Well, we

have blood-based assessment, oxygen saturation, scalp pH, but maybe could additional be then and more by significant identifying as metabolic

information specific

gained

organ-tissue

functions,

such

acidosis, ST analysis, and also the fetal heart rate. Where I started, well, that was 30 years ago, with a by chance observation, more or less, in the mature guinea pig fetus exposed to hypoxia,

noticing on a strip chart recorder these marked ST events with enormous T wave amplitude changes prior to the bradycardia. had been using Obviously, at that point in time we the electrocardiogram in clinical

medicine, and we know that in a stress test in the adult there are good data to use to assess the

condition of that myocardium we are now looking at, meaning that in case of an ST segment depression or changes in T wave amplitude, that would signify a fetal or a myocardium, rather, not fully compensating, and finding it sometimes hard and sometimes there

would be coronary insufficiency. Why would we see these changes? NEAL R. GROSS
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Well, we

know

that

the

ST

interval

represents

the

time

of

repolarization of the myocardium. energy is required. The ion

This is now where 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 changes. waves. then we need to quantify these

As you noticed, there were marked peak T So we could look at the amplitude of the T QRS, well,

wave and relate it to that of the QRS.

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. can record and use. Now the animal work that we have We have a measure that we

conducted, starting in the seventies, initially were observations function on hemodynamic experimental in cerebral hypoxia, with but metabolic also in

during

spontaneous

labor

association

intrauterine

NEAL R. GROSS
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deaths in predominantly the fetal sheep preparation. We also did studies on myocardium

metabolism, showing that the ST rise was associated with the breakdown of myocardial glycogen, in

particular.

Now this turned out to be regulated by

beta receptors and, in particular, the catecholamine surge that goes with hypoxia. We also studied

gestational age and the impact of growth retardation. In these fetuses emerging we saw biphasic we didn't ST see segment in the

depressions

whereas

appropriately grown fetuses. So, to summarize, the experimental work, the normal ST, anaerobic metabolism, positive energy balance, with hypoxia, we see a rise in T wave

amplitude that is caused by the surge of adrenalin activating glycolysis. potassium beta receptors and then activating

So, with that, we have the liberation of ions, and we the have rate of are know the of close in linear T wave

relationship amplitude glycogen. metabolism, and

between the Thus, which

rise of at

rate we we

breakdown looking from all

myocardial anaerobic

physiological

NEAL R. GROSS
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studies being of the most important defense systems for the fetus exposed to hypoxia. But there are also other fetuses, other signs within the ECG. is now where the ST This we call biphasic ST, which segment is leaning downward,

cutting the baseline.

Grade them, grade 2 and 3 being

those being significant, and where we are now looking at the pumping performance of the myocardium. recognizing a reduction in the ability of So the

myocardium to respond to the stress of labor. We know that prematurity infections will have an impact on that capacity, and we find these associated with biphasic ST events, overall demand. If the heart has to pump beyond its capacity, we will sometimes see biphasicity, rare instances of

myocardial dystrophy, but also chronic hypoxia and in the initial phase of acute hypoxia these changes could emerge. They're not associated with metabolic

acidosis initially, normal acid base, but they signify that the pump is not working at full performance. What are we recording? Thirty beats. Put

them together in an average, thereby getting a better NEAL R. GROSS
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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. the Plymouth randomized

In the nineties, we saw trial, fostering in further the EU

technological

developments,

verified

Observational Multi-Center Study, Nordic Observational Multi-Center figures Study, with and you sensitivity/specificity have then the Swedish

calculated,

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 NEAL R. GROSS
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choose, showed signs of improvements. metabolic acidosis, this didn't become

If you take 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 findings now we had in the a basic large, physiological randomized,

verified

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 So we needed to develop the

signal to work with.

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 NEAL R. GROSS
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deceleration.

Prior to that, there are some biphasic

events now being identified on the log, followed by an episodic rise in T/QRS reaching a level, which means that in this case there is a need to intervene. What this recording is telling us, that in the first stage of labor that fetus could not meet with the challenge of a contraction, so there would be a decrease in fetal placental function, maybe perhaps now metabolic acidosis at that point in time. can show you that that baby entered But I

second-stage

labor, and it developed marked metabolic acidosis and meconium aspiration, and required substantial neonatal care. So the guidelines: heart rate with ST waveform, Well, we are combining recognizing that the

heart rate, when it's normal, is a very good marker of a healthy fetus fully capable of adapting. Then we

have the situation of a pre-terminal heart rate trace, which is a trace They which would shows say, no that variability, is no

reactivity.

sufficient

information, but in between we have a large number of cases where there are non-reassuring fetal heart rate NEAL R. GROSS
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traces and where we now need additional information based on the qualified assessment of ST, meaning

sometimes short-lasting, episodic ST events, sometimes baseline rises lasting more than 10 minutes, and the appearance of biphasic ST. And the computer would

guide where one would be with regard to ST events within these blocks. Then first-stage your side. what to do? Well, if you're time is in on

labor,

obviously,

sometimes

So you can intervene.

But if you are in

second-stage labor, we learned that clearly sometimes there is an urgent need to do something, and with these guidelines, immediate delivery is recommended in second-stage labor. Clearly, when we use a computer, we've got to give it a bit of time to assess the baseline Twenty

because we are largely looking at changes.

minutes is the standard that we have established. But why this is ongoing? The user had

been taught to recognize these dots on the graph, on the screen of the computer, and also in cases when there is somewhat less signal quality, then we say, NEAL R. GROSS
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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. there were significant improvements, regardless And 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. large maternity unit, university

These are all with

departments

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

www.nealrgross.com

here today Hakan Noren, Ingemar Kjellmer, and Karel Marsal, being part of this study. As figures are you may notice, low. perinatal Obviously, mortality these are

reasonably

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 identified acidosis pH of by less at least than 50 percent. base We

7.05

deficit,

extracellular fluid greater than 12. a situation where the baby is

Now this is not affected.

severely

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 NEAL R. GROSS
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for other causes of operative deliveries. Design of the STAN monitor, where

randomization occurred at power on, which allowed us to collect ST information in those cases being

monitored with heart rate only.

So, retrospectively,

we can look back to see what ST might have added. Training period for two months and an

interim analysis of 1800 cases which occurred.

Busy

units, a lot of deliveries, but also in this trial the cases were managed by regular labor ward staff

comprising more than 300 people that had to be trained and meet and understand the clinical protocol. Inclusion criteria: term, active labor,

singleton, cephalic, and the decision to apply a fetal scalp electrode. Clearly, then there was a need for

more continuous detailed information. You see here a sample of a STAN recording with a heart rate showing marked decelerations with contractions. You have a normal ST and a normal

outcome with a normal vagina delivery, whereas this is a case showing ST events in association with this deceleration, initially, followed by baseline rise, NEAL R. GROSS
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forcing an intervention, emergency C-section with a normal outcome. So we look at the clinical management of these. to the The control group, they were managed according 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 preterminal regardless fetal of heart ST; rate, immediate heart delivery rate, no

normal

fetal

intervention regardless of ST. In the interim analysis we found that in the STAN arm there were deviations from the clinical management metabolic guidelines, acidosis with in that STAN six babies and had clear

changes

indications to do something. cases, well, the clinicians

When you discuss these thought perhaps that

wasn't that much of a heart rate change, so they still NEAL R. GROSS
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carried on as they were used to. That training, which focused meant an issue case of repeated

continuing

discussions,

because now we had samples from their own labor ward settings. the ST So we can bring those forward and show how information would affect the clinical

assessment in a neutral fashion. Just to illustrate one of those cases, you have a heart and rate then showing the a somewhat increased but good

baseline,

deceleration,

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. bit, but a lot with The epidural analgesia varies a oxytocin augmentation. So,

clearly, a need for further information during active labor. Now when you develop a technology, you set NEAL R. GROSS
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certain guidelines for how you use it.

You need at In

least 20 minutes in order to obtain information. some cases a recording was less than 20

minutes.

Okay, that was not a recording made according to the specifications of the technology. At the same time as we wanted to assess metabolic acidosis, we said there is a need to have data within 20 minutes of delivery, and also in case one should intervene on the basis of intrapartum So

asphyxia, you need to intervene rather urgently. this was agreed. But also, if he had severe

fetal

malformation, as we know that these cases will have an increased risk of encephalopathy, and so on, so there would be some skewness if they were included. If we look at the inadequately recorded cases, there were no difference between the two arms of the trial. With regard to metabolic acidosis, we

find that in the control arm four cases where the STAN recording was discontinued. That would happen because

of a failure with the printer, for instance, and then the case would still be monitored, but with a standard NEAL R. GROSS
(202) 234-4433 COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 www.nealrgross.com

electronic monitoring device, and the same would go for those cases in the STAN arm. Operative here with the deliveries, well, these or cases

discontinued

recording

shortage

recording, they would have obviously been managed on the standard electronic fetal monitoring procedures, but you may say that, yes, with a short or more than 20 minutes to delivery, clearly, the indications were based on the STAN monitor to intervene. So they

should be still within the group being assessed for reduction in operative interventions. So we look at the primary outcome, what metabolic acidosis, intention-to-treat analysis, a

significant reduction, if we look at it from adequate recording's point of view, then there's further

improvement in the figures. Now before and we can just also compare at the the situation impact of

after,

looking

increased experience, and we find that with regard to metabolic acidosis, there is a reduction, not becoming significant before, but becoming significant after. On the secondary outcome, operative

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

deliveries for non-reassuring fetal status, overall intention-to-treat, significant reduction with no And no

increase in operative intervention indications. if we compared before, after once again, before,

difference,

whereas

retraining

intention-to-

treat analysis, the difference becomes significant. So we can summarize the overall outcome being a 54 percent reduction in metabolic acidosis, 19 percent reduction operative interventions for non-

reassuring fetal status.

This result is largely based

on what was the outcome of the retraining and past experience of the technology and confidence in the technology. Now we are interested in what happens with the neonates. In particular, if you want to sort of

look at the risk here, while you may choose different pH cutoffs -- 7.00, for instance, is one being used -but we know that there is sometimes a problem in obtaining core data, and we wanted to make sure no case was missed. So we took that went into special

care and an experienced neonatalogist went through all these notes -- this is Professor Ingemar Kjellmer -NEAL R. GROSS
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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 NEAL R. GROSS
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tone and metabolic acidosis, low Apgar scores, all in the control arm, or and then we got under some no cases of

jitteriness

irritability

metabolic

acidosis, and there's one in the control and three in the STAN arm before training. These we know are

babies that are not at risk of long-term sequelae. Then you have a group of babies who have metabolic acidosis and predominantly respiratory

symptoms requiring special neonatal care, and in this case we had one in the second stage of the trial, which was a case requiring three hours in special care for observation after delivery, followed the mother, but later on developed signs. So we saw a significant reduction in the second phase of the trial of the number of babies having regard an to adverse cases, outcome, but to we also severe saw, with

moderate

neonatal

encephalopathy, increased neuromuscular tone, innate diseases, a reduction with an incidence in the control arm of 3.3 per thousand to .4 per thousand in the STAN arm of the trial. Clearly, when we look at a new technology, NEAL R. GROSS
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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 secondstage 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. case, which was a case that But then in one died, Streptococci

septicemia, that had a pre-terminal heart rate trace, and we know that these cases they are rare, but they NEAL R. GROSS
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will not display ST events. Another way of analyzing data here,

looking at potential deviations: by 300 obstetricians/midwives.

5,000 cases managed 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. where we say, So we have in the STAN arm cases in this case no deviations.

well,

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

NEAL R. GROSS
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where we can say, well, on the basis of heart rate interpretation, deviations. there might not have been any

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 NEAL R. GROSS
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as

routine,

neonatal Take this

data, up

index for

cases,

metabolic provide

acidosis.

discussion,

feedback, expert assessment. This is now an EU-supported project, These are

initially with 10 Centers of Excellence.

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 In and

now the City of Gothenburg, 16 months' experience. September eight STAN monitors were introduced,

these are the rates of usage per month, covering this NEAL R. GROSS
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16-month period, finishing January this year.

You

will see initial rise and then a continuing rise here, approaching more than 30 percent of all term

deliveries and active labor being monitored with STAN. So let's look at the outcome. compare the initial four months period, Now we can where the

technology was reasonably new, with one year later, October-January, more than 2,000 deliveries over both periods. delivery We see significant improvements in operative for fetal distress, in the reduction in

Caesarian sections, reduction in cord artery metabolic acidosis, coming down to very low levels, and also with neonates having moderate-severe encephalopathy, over the last 2,256 cases, only one baby that had short-lasting neonatal seizures. What we also noticed, that in the STAN, in the CTG arm, where heart rate monitoring is taking place, we see extraordinary improvements. this is not that surprising. I think

If you focus on the

monitoring issue, if you bring physiology into this, you improve also We the no understanding risk, in of heart rate

reactions.

see

fact

considerable

NEAL R. GROSS
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improvements,

in

those

cases

where

heart

rate

monitoring is applied; as you remember, 34 percent being monitored on the STAN. We encephalopathy, can summarize that in on the issue of

finding

the

CTG-monitored

group over this time period of 11,000 cases with term deliveries, eight cases, three perinatal deaths, all post-term severe emergency and C-section the with for fetal dying, and distress, three two of

asphyxia

baby

intrapartum natally.

hypoxia

acidosis,

post-

In the STAN arm there are two cases of hypoxia, one that died two hours after birth,

associated with an E. coli septicemia, another case with listeriosis. Yes, there is one case where still

ST events were missed and second-stage hypoxia and then natal seizures, and then post-natal, and then some cases with a more unclear origin. So we can summarize now where we start with experimental work, engineering developments,

clinical research.

Guidelines were developed, tested Then we learned

in randomized, controlled trials. NEAL R. GROSS
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www.nealrgross.com

clinical experience, and the need for expert system support, the Swedish randomized trial, and now we can verify in routine clinical care the situation of

improved fetal monitoring. Intended use. Well, if approved, the

assessment of fetal condition in labor.

Is it a

singleton fetus, vertex, at term, and the indication. Well, as you noticed, though, the indication in the Swedish randomized trial was based on the need for close surveillance, the need for more accurate

assessment.

I believe this is what we're trying to

bring forward. Thank you very much for your attention. CHAIRMAN Rosen. BLANCO: Thank you, Professor

I think you have several other individuals who

will be presenting? DR. ROSEN: Ingemar Kjellmar. CHAIRMAN BLANCO: Please, for the record, We will start with Professor

remember to introduce yourself, your affiliation, and any conflict of interest. DR. KJELLMAR: Thank you, Mr. Chairman,

NEAL R. GROSS
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members Ingemar

of

the

panel, I

ladies

and

gentlemen. stepped down at

I'm as the

Kjellmar. of

recently

Professor

Pediatrics,

Neonatology,

University of Gothenburg, Sweden.

I've been involved I'm acting Neoventa

in the ST development for very many years. as a non-paid scientific consultant

for

Medical.

They have paid my fare and my accommodation

here, but I have no economic interest. I briefly reviewed some quality markers of perinatal care in Sweden. First, just to give you an

idea of the country we are talking about, I have on the scale included Scandinavian peninsula, Sweden in yellow, in comparison to the United States. You see

areawise Sweden is not a very small country, but it is sparsely populated, particularly in the northern part of the country. We have only 8.5 million inhabitants.

We have roughly 100,000 births a year. It's not only the rate of the cord

acidemia that is lower in our birth population; it's also the prematurity rate, about 5 percent, and the perinatal mortality rate, that is close to 5 to 1,000; the infant mortality rate, that is below 5 per 1,000 NEAL R. GROSS
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in the national statistics.

About 12 percent of the In the three cities control trial,

mothers are immigrant mothers. taking part in the

randomized

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 surveillance in we term are talking the about term fetal

fetuses,

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 The

demonstrate that we do have such a program.

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. NEAL R. GROSS
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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, asphyxia such in as labor, obstetrical the complications and

regionalization

program

apparently is not enough to rid the smaller hospital of these problems. This discussed final slide outcome demonstrates variable when one it oftencomes to

NEAL R. GROSS
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intrapartum demonstrates population cohorts,

asphyxia, the of rate

namely, of

cerebral

palsy. in

It the

cerebral following 1954 up

palsy in to

west the

Sweden from

four-year 1994, and

all

way

followed, moreover, by the same team of investigators. As you see, there is a rather big

fluctuation in the total incidence of cerebral palsy with a very promising decline during the years when perinatal care was first instituted in my country, but then a gradual increase that took place from the

middle of the sixties up to the mid-eighties, and after that at least a tendency toward a drop. If this material is split crudely into term and pre-term deliveries, and both of them are counted on the basis of the total population, so these are not gestation age-specific incidence rates, you see that most of the fluctuations are explained by changes in the pre-term population, which is not very surprising. This is what has been demonstrated from

many other countries. But the CP incidence in term babies stays, has very little changes over this 40-year period.

NEAL R. GROSS
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Mind you, this is the period when electronic fetal monitoring was introduced during the seventies in west Sweden, where modern neonatology gradually was

introduced from the beginning of the sixties.

We have

been, like many others, quite successful in effecting the outcome rates in the premature baby, but when it comes to the term baby, very little has been achieved. The imaging is latest cohort, where brain neuro28

available,

demonstrates

that

about

percent of all the term babies with cerebral palsy might be ascribed to intrapartum asphyxia. Thank you. CHAIRMAN BLANCO: DR. MARSAL: Thank you very much.

Mr. Chairman, members of the

panel, ladies and gentlemen, my name is Karel Marsal. I am Professor and Chairman of the Department of

Obstetrics and Gynecology, the University of Lund, in Sweden. Medical, I am an unpaid scientific advisor of Neoventa and the company covers my travel and

accommodation expenses. In the next few minutes I would like to address the question of similarities and differences NEAL R. GROSS
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between the use of fetal monitoring in labor in the United States and in Sweden. obstetrician information in on the United I never worked as an States, so I based my and of with

the from

published the

statements College contacts

recommendations Obstetrics and

American and on my

Gynecology

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. recommendation uncomplicated independently of labors by the and Ministry of

In Sweden, by Health, are the

deliveries It's

conducted task to

midwives.

their

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 NEAL R. GROSS
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during labor. Health medical and

In Sweden the Swedish National Board of published in their for database of

Welfare

facts

recommendations

the

clinical

management of uncomplicated labors. use of fetal monitoring.

It includes the

In addition, there are two

reference books which are used by all obstetricians and midwives in Sweden, regard to and there use is of rather the big

consensus

with

the

fetal

monitoring in labor. Looking at the definitions of hypoxemia, hypoxia, and asphyxia, I have found that these are identical in both countries. evaluation during labor is The fetal heart rate 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 is and more often also the in electronic the fetal

monitoring pregnancies.

applied

low-risk

In the United States, one-to-one nurse-topatient ratio is recommended NEAL R. GROSS
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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 during every the 30 minutes stage after at a

contraction,

and

second

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, NEAL R. GROSS

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www.nealrgross.com

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 description as been mentioned Swedish practical in Professor and in Rosen's these both

of

the are

study, identical

recommendations 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 NEAL R. GROSS
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recommendation to use the electronic fetal heart rate monitoring is identical, either continuously or

intermittently, depending on the degree of risk, and this is up to the obstetrician to decide. Looking at the definition of the fetal heart rate patterns with regard and in to the baseline these The

variability definitions

accelerations are identical

decelerations, both countries.

overall definition of the fetal heart rate patterns is in the United States, according to the guidelines of American College of Obstetrics and Gynecology, divided into reassuring In or non-reassuring we are the fetal using records heart the into rate fetal four

patterns.

Sweden

classification, classes: abnormal

classifying

the normal one, suspect, pathological or one, and pre-terminal. These -three would -be

suspect,

pathological,

pre-terminal

classified as non-reassuring in the United States. The management of such non-reassuring

patterns is very similar in both countries four steps recommended to find the etiology of the abnormality, attempt to correct the pattern, to analyze the fetal NEAL R. GROSS
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blood sample for the pH, and if indicated, to perform operative intervention. used are emergency The operative interventions 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. CHAIRMAN BLANCO: DR. DEVOE: Dr. Lawrence Devoe. Thank you.

By way of introduction, I am 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 NEAL R. GROSS
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we are with intrapartum fetal monitoring in the United States at the present time and the case for new

technologies such as the STAN S21 system. My objectives are to give you a snapshot of the current situation of affairs with monitoring the U.S., where the current problems and limitation are, and possibly where the STAN system might fit in to be a useful adjunct. As we know, back in the 1960s, when fetal monitoring first arrived on the scene, it had some very discrete and laudable goals. That was to screen

for intrapartum fetal asphyxia, to detect fetuses at risk or in early stages of compromise, to prevent fetal neurologic injury or death without, on the other hand, an excessive maternal risk from obstetric

interventions. But this is a summation of about 90,000 patients that were collected in in the the first U.S.

observational,

nonrandomized

reports

literature that emanated from the late seventies and early eighties. Looking at these, at that point in

time, painted a rather sanguine picture for the use of NEAL R. GROSS
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electronic fetal monitoring with substantial reduction in intrapartal stillbirths and neonatal deaths

compared to the lack of monitoring or auscultation. As recently as 2002, going to the Cochrane Library, Thacker has updated the meta-analysis of the randomized control trials, which currently number 13, that met their criteria and assume about 60,000

pregnancies comparing electronic monitoring with or without scalp sampling for pH with auscultation.

Looking at the outcomes, both maternal interventions and infant outcomes of Apgar -NIC admissions,

seizures, and death -- to cut to the chase, this metaanalysis direction hasn't changed very much since it was first published in 1995 and suggests that the use of electronic monitoring is associated with a higher rate of Caesarian and operative deliveries, similar perinatal death rates, and the only group in which there apparently was benefit and reduction of neonatal seizures was a group in which EFM was backed up with fetal scalp sampling. The question one might ask is, why were the randomized control trials not as good as the early NEAL R. GROSS
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nonrandomized trials? very obvious.

The answers to that I think are

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 intensive Consequently, control care there trials unit were evolved, the neonatal improved. deaths and

performance fewer neonatal

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. the issues of the These are well-known. observer issues of They are and rate

reliability fetal heart

reproducibility,

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 interobserver agreement, and the lack of observer

NEAL R. GROSS
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reliability

applies

to

visual

and

auditory This is inter-

identification of fetal heart rate patterns. a summation of best-case studies which is

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 categories. criteria with more In different fact, standard even types of patterns a to or

applying

standard visual

terminology

inspection may not improve reliability or agreement. The monitoring are targets to make for some electronic assessment of fetal fetal

oxygenation and acid-base balance, as well as try to NEAL R. GROSS
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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 particularly with were lower pH values, severe, and these or

persistent,

variable,

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 with of an late decelerations risk for which was

associated

increased

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 NEAL R. GROSS
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sample sizes.

In the main, the fetal heart rate There have been

pattern assessment has been visual.

various studied conditions as well as interpretative criteria, and few fetal heart rate features

specifically stand out, that is, late decelerations and the absence of variability, that correlate well with current fetal acid-based status. There are current standards of care that have been published, and you have already heard some of these bulletins referred to, both in the United States and elsewhere. I want to call your attention

to what we currently refer to in the ACOG Technical Publication of 1995, and specifically direct your

attention to the issue at hand of the management of persistent non-reassuring fetal heart rate patterns. Professor Marsal has already indicated the four-step algorithm for attempting to determine the etiology of the pattern, to attempt to correct the conditions that produce this pattern, and if this fails, consideration of a fetal scalp blood pH, and finally to determine if and how urgently operative intervention is needed. If the fetal heart rate pattern persists, NEAL R. GROSS
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intervention depends on the clinician's assessment of the likelihood of severe hypoxia and metabolic

acidosis, as well as the estimated time to spontaneous delivery. Now late, or severe we have accepted that persistent, with and absent require

variable are

decelerations non-reassuring

variability

always

prompt intervention unless they spontaneously resolve or are rapidly corrected. Spontaneous accelerations

virtually assure the absence of fetal acidosis. Ancillary stimulation or vibrio methods, acoustic such as fetal scalp can be

stimulation,

used to induce accelerations, and also, when positive, indicate the absence of acidosis, but in nonresponsive fetuses, assessment of scalp blood pH may be used to clarify acid-based status. Frankly, this technique,

while occasionally helpful, is used uncommonly in most current obstetric units, including tertiary centers. When fetal heart rate patterns are

persistently non-reassuring and acidosis is present or, as importantly, cannot be ruled out, the fetus should be prompt delivered by the most expeditious NEAL R. GROSS
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route.

This

current

status

I

believe

places

clinicians in a dilemma. heart rate patterns lack

Most non-reassuring fetal precise correlation with

current fetal status or prognosis. Secondly, there are limited adjunctive

tools to evaluate such patterns, not all of which are either practicable or available. Third, the fetal heart rate feature best correlated ultimately, with local myocardial is the hypoxia and, of

metabolic

acidosis

evolution

repetitive late decelerations. The intervention width this of the window that for optimal late

for

pattern,

is,

decelerations, may be unclear in any given fetus. Fifth, the education and experience of

bedside caregivers on fetal heart rate interpretation, technology, and intrapartum management of abnormal

fetal heart rate patterns varies widely across this country. Sixth, the clinician is left to determine the best management with limited supportive data, and supported by better analyses, these results in a

NEAL R. GROSS
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probable

excess

of

risky

obstetric

interventions

without demonstrable perinatal benefits. I was privileged to be part of an NIH research planning workshop which was conducted between the years 1995 and 1996. The thing that spurred this

workshop on ostensibly was the lack of consensus on definitions monitoring, and but nomenclature really behind of electronic this was fetal the

all

knowledge that the meta-analysis and the results of the randomized control trials were disappointing to those of us that had been proponents of electronic monitoring for two decades. This experts and workshop half put a together 22 of clinical clinical

about

millennium

experience in electronic fetal monitoring, and arrived at standardized unambiguous definitions for visual

interpretation of fetal heart rate. recommendations for further research.

It also made

The study areas that came out of this were to address these very issues of reliability of visual interpretation of fetal heart rate pattern, the

validity of pattern interpretation when viewed in its NEAL R. GROSS
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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, predict current there are several fetal patterns asphyxia that with

or

impending

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. NEAL R. GROSS
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So that brings us to what I think we have to look at to improve the status of electronic

monitoring today in the United States.

With very few

exceptions, the kind of research to move the subject along has been lacking since the 1980s. In fact,

there have been new technologies that have arrived. We obviously used from time to time vibrio acoustic stimulation, but this particular intervention is not useful if the fetus fails to respond. Biophysical profile is cumbersome and has not been shown to be helpful during labor. has simply been inadequately evaluated in Doppler labor.

There have been three more recent approaches using computerization of fetal heart rate, fetal oximetry, and ECG-waveform analysis. Going to computerized online evaluation of fetal heart rate, there have been a number of studies that have been published in the last decade. have all been somewhat limited in number. These

Although

computerization may yield a more reliable and precise analysis of fetal heart rate compared to visual

assessment, thus taking the observer problem out of NEAL R. GROSS
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the equation, it has not been shown to improve the detection of acidemia or fetal compromise. Fetal oximetry has also recently appeared. The FDA trial, for did as you are well aware, reduced rate

intervention cases, section but

non-reassuring not There reduce are the still

fetal

heart

overall

Caesarian signal

rate.

documented

capture failures.

The best targeted use for this The cost-

technology has not been fully identified.

benefit ratio was unclear, and products are in play now that are adaptable to current electronic

monitoring systems. I summarize the ACOG Committee opinion on oximetry simply in this single paragraph and emphasize the points that the Dr. Artal already that articulated heard in

reference morning.

to

material

you've

this

What monitoring?

is

the

target

for

electronic

I think it is really unrealistic to think

that a single tool, unaided, is going to make any difference encephalopathy in or eliminating cerebral hypoxia This ischemic is still,

palsy.

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fortunately, a rather infrequent event, and the sample sizes to really clarify this need to be humongous. The reduction in profound acidemia or

asphyxia with a pH falling below 7.10 or 7.05, we don't know how often this occurs in the United States, but this reflects a 2.5 percentile of births,

somewhere between 10,000 and 100,000 births per year. This was achieved in the Swedish STAN trial. reduction surrogate in for newborn later seizures, performance a in rather The

limited and

neonatal

childhood outcome.

Again, this was the only group

that was shown to be affected when using electronic monitoring backed up with some ancillary adjunctive guide. Fourth, intervention, the avoidance deliveries of or unnecessary operative

Caesarian

deliveries, and this was also achieved in this latest STAN trial. STAN S21 addresses the problem areas I think of acidosis and OB interventions. It has

soundly founded in a scientific basis which has been established for higher-level FECG analysis. NEAL R. GROSS
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There now

is

real-world

experience

and

high-quality

clinical

obstetric units that show that this technology mated, importantly, with responsible oversight and education, is applicable and practical. Other advantages is that it comes into an arena where there is always already some familiarity, that is, using a standard fetal heart rate monitoring device and using signals that are inherent in the fetal ECG with a familiar probe. display with real-time in events, time It to is There is concurrent making change alerting the to

clinicians history of

possible a

natural It is

labor.

objective.

reproducible data display which deals with a thorny and still unresolved issue of observer problems,

resulting in visual estimation alone. It is an adjunct for problematic fetal heart rate patterns, which is a most desirable target and goal. by It reflect myocardial and and events that It a is are a

affected

hypoxia system,

acidosis. that is,

conservative

conservative

system in computer terms requires both good input and requires some time. Both of these are important

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prerequisites. The educational context which embraces

this system is added valued.

I think as you saw from

the Gothenburg study, in a real-world situation in a busy clinical unit, users got better at doing

monitoring overall, whether they used the STAN system or conventional monitoring, largely I think boosted by the education process that is required for the use of this system. As importantly in busy obstetric units,

it is adaptable to labor units with different provider levels of expertise and experience. I just want to conclude by making four statements: Auscultation, I think we really have to bite the bullet and accept the fact that it is an impractical approach in today's environment. labor-intensive. It requires one-to-one It is nursing.

This is a level that is hard to achieve in almost any obstetric unit in the United States today. I have alluded to, and I'll iterate, that unaided visual assessment of fetal heart rate tracings remains problematic for a variety of variance issues. NEAL R. GROSS
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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. presentation, attention. and ROSEN: thank I'm you fine much with for this your

very

Thank you. CHAIRMAN BLANCO: Thank you very much.

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

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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: and gentlemen, Hi. Good morning, ladies panel members, and

distinguished

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, fire statistical, research, epidemiology, and

software,

hardware,

monitoring,

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 NEAL R. GROSS
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submission.

We met with the company in 1999, when

they briefed us on the Plymouth trial and the Swedish randomized controlled clinical trial. At that time

the Plymouth trial was completed, and the Swedish RCT was ongoing. In December of 1999, the sponsor submitted a plan to start a modular PMA review where the company is allowed to submit portions of the PMA information early in an attempt to address some requirements of PMA submission prior to submission of clinical data. In this slide you will notice that one modular for general information is closed, a term we use with modular submissions to indicate that the

issues addressed within the module have been addressed to our satisfaction. and device However, description the prior clinical

studies

and

non-clinical

testing were not closed, and those reviews were rolled into the PMA review. I'm going to give a brief overview of the device design, and I'll discuss what we have looked at in the course of our review. I will finish with an

outline of ongoing issues that we're still working NEAL R. GROSS
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with the company to resolve. For design, I'm going to talk about both the components of the device and the mechanism of action. As previously mentioned, this device is a It

perinatal monitor with ST analysis capabilities. has many of the features of a typical

perinatal

monitor.

The STAN system is made up of the following base unit, monitor, software, and

basic components: sensors.

The base unit has as a main electrical component that serves as a conduit for input and

output connections such as those for data storage or access and accessories to the device, including the sensors. The monitor is the display. Software

includes all the software for the standard monitoring functions as well as the ST analysis features. The next slide I will address the sensors. Spiral electrode is used for the ST analysis feature and for the fetal heart rate. The STAN system does

not have external fetal heart rate doppler ultrasound capabilities. This device does have the capability NEAL R. GROSS
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for

both

internal

and

external

uterine

activity

monitoring.

The event marker is used by the patient

to mark fetal movement. As previously mentioned, the device uses the fetal spiral electrode to obtain a fetal ECG

signal.

This signal is an analog electrical signal The ST

that is converted to digital by the device.

analysis software manipulates the signal to create a smooth wave form. The software evaluates this wave

form for the three types of events the device is looking for: episodic T/QRS rise, baseline T/QRS

rise, and biphasic ST. As you have seen, the device displays the T/QRS ratio with "X's" below the uterine activity on the strip chart, with events annotated next to the "X's." The smooth ECG complex is also displayed. It

should be noted that the device will not identify an event in the first 20 minutes of operation, so that the device can set baseline. This slide lists the things that we look at during our review. For software and hardware, we Examples of safety

look at safety and effectiveness. NEAL R. GROSS
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www.nealrgross.com

issues

for

software

and

hardware

include

electric Examples

shock, EMI shielding, and explosion hazard.

of effectiveness are adequate identification of the ECG waveform and ST events and poor signal quality. We specifically look at requirements in testing. We check to see that the device is designed

to do what the sponsor and manufacturer says it will do, and we look to see that the tests check to see that the device works the way it is supposed to. We also look at biocompatibility and

sterilization or disinfection of the materials that contact the patient. look at study consent we For bioresearch monitoring, we including et recordkeeping, cetera. with For design

execution,

informed

administration, look at

manufacturing, controls.

compliance

Both include an inspection. Bioresearch monitoring inspects clinical

sites as well as any records related to the conduct of the trial at the sponsor's facility. Manufacturing A for

conducts an inspection at manufacturing facilities. bioresearch monitoring inspection is common

clinical trials supporting the PMA. NEAL R. GROSS
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www.nealrgross.com

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

NEAL R. GROSS
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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 endpoints. of the data for II, primary which Dr. and secondary will

Analysis

Corrado

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 hardware and mentioned software in my last are example, ongoing. our We

reviews

currently have some information from the sponsor that describes the device design requirements and

verification/validation.

As I outlined in my previous

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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 The inspections in We will continue

reviews are also still ongoing.

Sweden have not yet been scheduled.

to work with the sponsor on these issues. Now I will turn the floor over to Julia to discuss review. CHAIRMAN BLANCO: DR. CORRADO: Thank you. Thank you, Kathy. Good clinical and statistical findings of our

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 NEAL R. GROSS
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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. England. Fetal ECG The Plymouth study was in

There was a multi-country trial called the Analysis During Labor Trial that was

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relatively small.

There was then the larger Nordic The Swedish RCT is

Observation Multi-Center Trial.

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, there's an ongoing I wanted that to is highlight sponsored that the

study

European Union. different training

It involves obstetrical units in 10 and the primary from focus a is the of

countries, and

clinical

results

Center

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 data. One of the reasons that we focused on the Swedish RCT is that we felt that it met the criteria NEAL R. GROSS
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accumulated

over

the

last

10

years,

clinical

that we look for in establishing relatively more value to certain types of clinical studies. This was the

prospect of randomized multi-center controlled study. It December 1998 took place during of a time period of

through

June

2000.

Forty-nine

hundred and sixty-six subjects were enrolled at three university hospitals, relatively equally throughout

those three centers.

It involved a comparison of the

STAN monitor, which, again, includes both fetal heart rate plus the analysis of the fetal ECG versus fetal heart rate only data. I would like to point out, though, that in the control arm the STAN monitor was used. It is just

that the ECG data was not available to the clinician while they were taking care of the patient. So they

just had essentially fetal heart rate plus uterine contraction pattern. The reduce perinatal objectives morbidity of as that study were by to cord

identified

artery metabolic acidosis; secondarily, to evaluate the use of STAN protocols and clinical guidelines in practice. That will be the focus of several of our NEAL R. GROSS
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slides that we will get to. operative interventions.

Then, finally, to reduce

The endpoints, slightly different from the objectives, were several. The study endpoints that

I'm going to focus on are the primary outcome for the study, which was metabolic acidosis. It is important

to keep in mind that that was defined by a cord artery pH of less than 7.05 with a base deficit of greater than 12. In order to calculate and analyze this data,

both cord arterial and venous samples were required to ensure that the data, the arterial and data, frequency were of

reliable.

Neonatal

morbidity

operative interventions, including Caesarian sections, were also evaluated. I would like to just give an overview in terms of safety. FDA looks at safety and efficacy, as In terms of safety, I wanted to

everyone here knows.

make a couple of kind of broad statements. The safety of the device with respect to the specific components actually did not bring up any new issues because these components are already in use in other devices. However, the safety implications of NEAL R. GROSS
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interpretation of the STAN data and resulting clinical management are part of our safety evaluation of this device. For efficacy, the sponsor did two

analyses, referred to as Analysis I. intent-to-treat analysis.

That was an

They also did an Analysis

II in which they only looked at what they considered to be adequate recordings. I will take us through a

patient tree and, hopefully, make it clear to you all what these two analyses, what patients these two

analyses involved. This intent-to-treat is the Analysis I. This is the and

analysis.

Forty-nine

hundred

sixty-six subjects were enrolled and randomized more or less equally to the two study arms that I describe. As you see, 2,519 were enrolled in the STAN arm, 2,447 in the control arm. For the primary endpoint, which was

metabolic acidosis, it is important to keep in mind that around 700 subjects total could not be evaluated, and the reason was that the cord blood sample, for some reason, was considered inadequate in some way for NEAL R. GROSS
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analysis.

Again, recall that you had to have both

umbilical cord artery plus umbilical cord vein blood, and they had to meet certain criteria for

acceptability.

Therefore, for the primary endpoint of

metabolic acidosis, somewhat fewer than the enrolled numbers were actually evaluated: arm and 2,079 in the control arm. This is just a quick slide that shows the Analysis I. This is an important slide because this 2,159 in the STAN

is essentially the primary endpoint, the results of the analysis for the primary endpoint for the study. As you see, for metabolic acidosis, for the intent-totreat population minus those whose blood samples were considered inadequate, 15 out of 2,159 subjects in the STAN arm met the definition that was prospectively identified as constituting metabolic acidosis, whereas 31 of 2,079 in the control arm did. This boiled down

to 0.7 percent in the STAN arm and 1.5 percent in the control arm, and this did meet the test for

statistical significance. As we move down the list and we look at operative deliveries for fetal distress, now that

NEAL R. GROSS
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includes

vacuum,

forceps,

as

well

as

C-section

deliveries, and you can take a look at the numbers there. There was a reduction in numbers of operative

deliveries for fetal distress in the STAN arm of the study, and that also met statistical significance for the intent-to-treat population. We looked at Caesarian sections for fetal distress for the intent-to-treat population, and

although there were fewer relative numbers in the STAN group, this did not meet statistical significance for the intent-to-treat analysis. I would like to return to the patient

tree, and moving through, I would like to just point out that sort of the lower half, the middle and lower half of the diagram represents Analysis II, and that was the analysis that was done for what were

considered adequate recordings. As you can see, approximately the same number of subjects were excluded in each arm of the study. I will go into the reasons for that in a

subsequent slide. The point here is that, for Analysis II NEAL R. GROSS
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adequate records, the numbers of subjects evaluated are less by around 280 or 290 in each group,

approximately, again, the same numbers on both sides of the study. The reasons for inadequate recordings were as follows, and we've given percentages, so you get an idea, of those subjects who were excluded, about what percent fell into different categories of

explanations.

A very, very small number of congenital Thirty-seven and a

malformations, only 1.3 percent.

half percent were excluded because the tracing, the labor didn't meet the requirement for at least 20 minutes on the STAN monitor. More, a larger percentage, 56 percent,

were excluded because more than 20 minutes had elapsed between removal of the scalp electrode and delivery. Then there was a small category of other reasons for excluding cases for inadequate recordings. So these are the results. with this. These were the primary We're familiar and secondary

endpoints that were looked at.

Metabolic acidosis

became even more statistically significant after the NEAL R. GROSS
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subjects

were

excluded.

The

P

value

decreased.

Operative deliveries for fetal distress also improved in statistical significance. For Analysis II there

was a statistically-significant reduction in Caesarian sections for fetal distress in the STAN group. I guess what I would like to do right now is very briefly -- the sponsor didn't speak to this issue of Caesarian section for fetal distress. We did

an analysis of this because we were very interested in why that became statistically significant after cases were excluded. Very briefly, on this slide what you see is that although for fetal and the total numbers in the of Caesarian

sections

distress after

intent-to-treat inadequate

population,

even

excluding

recordings, was relatively small and uniform across both arms of the study. of patients who were However, among the population excluded due to inadequate

recordings, that population seemed to be enriched in subjects who ultimately went on to Caesarian section for fetal distress, and there were more in the STAN arm, which might help explain the outcome. NEAL R. GROSS
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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 in this of the definition The of

metabolic

acidosis

study.

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 NEAL R. GROSS
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15. Let me also add that, in all fairness, the Swedish RCT was not powered to detect the statistical difference between the two groups at a pH cutoff of 7.00. So in some ways it is unfair to apply such a Nevertheless, we think it's just

criterion.

worthwhile noting. With study, there respect 29 to adverse events in the this

were

adverse

outcomes.

Now

excludes one death in each arm in fetuses who had severe anomalies. Therefore, excluding those two

cases, there were three deaths in the study, either intrapartum or early perinatal deaths. There were 11

babies with mild, moderate, or severe encephalopathy. Now that includes the babies with and without

metabolic acidosis, and I'll talk about that a little bit more as I go on. Fifteen other babies were

admitted to the Sick Care Baby Unit with metabolic acidosis and other symptoms. I'm just going to focus on moderate and severe encephalopathy because I think that those are probably, I believe that those are the ones that are NEAL R. GROSS
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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 infants moderate infant who the control arm there were three plus

had

confirmed

metabolic There arm was who

acidosis one

encephalopathy. in the but control the

additional modern were not

had data

encephalopathy, available.

cord

artery

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 It was zero

of the study for modern encephalopathy. in the STAN arm and 4 in the control arm. Regarding were three cases in severe the

encephalopathy, control arm of

there severe I

encephalopathy.

There were none in the STAN arm.

think it's important to note, with regard to severe NEAL R. GROSS
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encephalopathy,

that

none

of

those

cases

in

the As a

control arm had confirmed metabolic acidosis.

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 NEAL R. GROSS
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for whom about only 20 minutes of the tracing is available. The STAN monitor was disconnected from the

fetus around two-and-a-half hours prior to delivery. So we don't have data to know how that labor really -what took place during that labor and what the

tracing looked like. conclusions as to the

Therefore, we can't make any cause or the circumstances

surrounding that perinatal death. We have more information on the two deaths in the STAN arm. One occurred before retraining and One is described in

one occurred after retraining.

the PMA as an intrapartum death, one as a perinatal death. I've included them both under intrapartum.

The reason being is that both of them had Apgars of 0-0-0 at 1, 5, and 10 minutes. One of these infants

was resuscitated approximately 12 minutes after birth, placed on life support, and then expired or had life support removed at approximately 36 hours of age.

Because of the Apgars at 1, 5, and 10 minutes, I included those under intrapartum death, although that might be controversial. Some of the other issues that arose out of NEAL R. GROSS
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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. of automatic ST event One of these is the lack The second is

signals.

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 It wasn't

every tracing from this study of 4,966. 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. NEAL R. GROSS
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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 to a poor failure signal to quality an probably automatic

contributed event.

register

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 severe hypoxia was responsible for

pre-existing

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. I'm sorry. NEAL R. GROSS
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Oh,

one last thing.

There's one other point that I wanted to make. That is that the fact that there was no

automatic ST event signal doesn't mean that you can't figure out whether there was an episodic or a baseline or a biphasic change. That is a skill that is

intended as part of the training for use of this device, but it's important to understand that there is a difference between registering an automatic signal that's very obvious to the clinician and the need for the clinician to look closely and try to look for ST events that might not be registering automatically. Now I would like to just talk about

deviations from the patient management protocol during the Swedish randomized fall when under it is trial. a Primarily of by the these of

deviations intervention

category

lack

indicated

patient

guidelines, and there are different combinations of situations of intermediate, abnormal fetal heart rate combined with different ST T/QRS changes or ST segment changes that, taken together, lead the clinician to intervene. different So, without going into specific cases of combinations, nevertheless, I can again

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summarize

and

say

that

these

deviations

from

the

clinical management protocol primarily involve failure to intervene. I included a category for the STAN

subjects in one case of failure to replace the scalp electrode. the Although this was not explicitly stated in clinical guidelines, it was in the

simplified

protocol for the study that in the second stage that, if the signal quality was poor, the clinician was supposed to replace it, and in at least one -- well, in a number of cases this didn't happen. But that is

a protocol deviation that doesn't satisfy the strict definition that you see on the slide, which is the Swedish RCT clinical patient management guidelines. For the control arm, similarly, lack of intervention constituted the general category of

protocol deviations.

We're only talking again about

the patients who fell into that metabolic acidosis group. That was only 46 out of 4,966. So we can't

make any generalizations regarding frequency or rates of protocol deviations across the entire study. One observation I would just like to make NEAL R. GROSS
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at this time is that, with respect to deviations from clinical management guidelines, we looked at the

numbers of deviations in the two arms before and after retraining. It was interesting to note that, of the

protocol deviations that we have come to agreement with with the sponsor, that in the STAN arm four occurred before retraining; only two occurred after retraining. In the control arm all of the protocol

deviations occurred after retraining. The purpose of this slide is just to

summarize or highlight some differences in clinical practice between Sweden and the U.S., and our guests here have done a very thorough job of this already. So I'm not going to belabor it. There are some subtle differences between FIGO and ACOG terminology and definitions. Certainly

there is a difference in rates of Caesarian delivery between Sweden and the U.S. The average rates at the

three centers in the Swedish RCT were, I believe, around 11 and 12 percent, whereas our national rate in the U.S., I believe, is somewhere between 20 and 22 percent. NEAL R. GROSS
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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

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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. and the statistical The numbers and the percentages 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. subjects. The Plymouth study enrolled 2,400 It was not

These were high-risk labors.

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; NEAL R. GROSS
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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 relatively European trial multi-center which, subjects. as I trial was a

small

understand, the ST

prospectively

recruited

However,

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 NEAL R. GROSS
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we would term an observational study. at some of those data. the improvement that

We have looked

Primarily, we have looked at occurred from the first four

months of the study to the last four-month interval of the study and the labors monitored with the STAN

device.

We would note that this, as an observational

study, one of the sites I believe was a participant in the Swedish RCT. experience other two. study, we and So that site probably had greater with the device than the

expertise

If we were designing an observational might have tried to include sites with

similar levels of experience. Currently, sponsoring a large the of European 10 Union is

study

different

sites,

evaluating the dissemination of knowledge and training in the use of the STAN monitor, and this is

significant because there is clinical outcome data for part of the study, and the sponsor would plan to establish a similar Centers of Excellence program in the United States for this device. At this time, if you'll just bear with me briefly, I'm going to try to show you some examples of NEAL R. GROSS
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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. just to The purpose of showing these case studies is 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. 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 So

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. NEAL R. GROSS
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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 reactivity. And what I am looking for here is an ST signal event marker. (Member of the audience begins to speak.) CHAIRMAN BLANCO: comments from the audience. I'm sorry, please, no If you need to make a losing some variability. We're

comment, you need to identify yourself, okay? NEAL R. GROSS
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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? illustrate. (Sponsor representative speaks privately to Dr. Corrado.) Well, given that I need a slightly Because that was what I was trying to

different directory, what I will do here is, regarding these training cases, what I would like to do is just NEAL R. GROSS
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tell

the

panel

that

that

is

a

case

where

there

actually was an automatic ST signal.

There were a

couple of other cases where there were no automatic ST events, and I think that, because there are no

automatic ST events, I'm going to go ahead and look at those. So, again, we're getting into an area here where there's relatively little variability, extremely low variability, really a poor tracing. It's hard to

tell whether these decels, the pattern of the decels here. Okay, follows: heart rate the lesson in this case is as

We saw there was a non-reassuring fetal during this tracing. There were no

automatic ST events recorded, however.

This baby was

born with Apgars of 9-10-10, and the point here is that this was a case where we could have relied on the STAN monitor the and not intervened and essentially heart rate.

tolerated

non-reassuring

fetal

Because this baby had a normal vaginal delivery and was in very good shape. Okay, third case, we want to talk about, NEAL R. GROSS
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again, this is a case where there was no ST event, but I would like you all to think about, looking at this case, whether or not you would have intervened. try to slow down just a little bit. So, again, the exercise is to think what might I have done here. Okay, no automatic ST events. normal vaginal delivery. There was a I'll

In this case the baby was I think that this is

born with Apgars of 7-10-10.

illustrative of the importance of the training because I think that that time of tracing, given the clinical guidelines, will require a lot of training and

experience for us to manage a case like that according to the STAN guidelines. The last case that I would like to show is a case that occurred in the RCT, the Swedish RCT. This was a case of an infant whose mother had a fever of 39.3 degrees C., was on antibiotics. This is an I

infant who died, who was born with Apgars of 0-0-0.

believe this is the case Dr. Rosen referred to as the cervix having been colonized with Group B strep.

Let's just take a look at this case. NEAL R. GROSS
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We have a relatively short record on the STAN monitor from this case. slow this down. This I'm just going to try to

Extremely almost absent variability. recording takes place after a

prolonged rupture of membranes. antibiotics. pre-terminal guidelines, intervened guidelines.

The patient is on

So, again, this would have constituted a tracing, and in is a according case that to would to the have the STAN been STAN

earlier

according

The point here, though, is, again, this is a case of a stillbirth, and there was no automatic ST event signal. ST event So sometimes when there's no automatic everything turns out great, and

signal,

sometimes it doesn't. I'm going to just conclude now with a

wrapup of FDA's review to date that focuses on the panel questions. Everybody has a copy of the

questions that we posed to the panel. Question 1 has to do with the study design and the endpoints. endpoint appropriate? Question 1A is, was the study And Question 1B was, was the

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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, management protocol. automatic exclusions ST of event deviations from the patient

Second, no registration of an in certain in the cases. study Third, based on

subjects

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inadequate

recordings.

Fourth,

intercountry Then, lastly, to the

population and management differences. whether or not there's any

significance

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 studies. With that, I'm going to retire here, or not there's a need for post-approval

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unless there are any questions for me specifically regarding the FDA review, and let the panel begin its deliberation. CHAIRMAN BLANCO: Thank you very much.

We'll go ahead and begin the deliberation portion of the meeting. We've questions, and, already Panel read the they are discussion in your

Members,

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 issues. portion to try to address those specific

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

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reviewer of this PMA. I have a question to begin with, and that is, looking at the Plymouth study, the intervention there was that it should be performed, to be done, if the T/QRS ratio rise exceeded a certain value or a certain level, whereas in the Swedish randomized

clinical trial the intervention should be if there is a non-reassuring fetal heart rate tracing and if there is a rise in the T/QRS ratio that occurred. I was

wondering if we could have clarification regarding the use of a certain value for the rise in the T/QRS ratio versus the occurrence of a rise in the T/QRS ratio. CHAIRMAN BLANCO: the questions. Go ahead. Keep on with

What we would like to do, give them a

chance to write them down, think about it, and then come back later on in the afternoon, so that they don't have to do immediately. So let's just keep

going if you have other questions for them. DR. RAMIN: Certainly. In the report

published in the American Journal of OB/GYN in 2001 by Westgate, they looked at near-term fetal sheep,

looking at ST waveforms that occurred during repeated NEAL R. GROSS
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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 provide their was wondering if the sponsors could

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

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being a comparison to what may be the definition in the United States, correct? DR. RAMIN: There acidosis out of were the Correct. the entire 46 cases of metabolic In the

population.

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 NEAL R. GROSS
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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: clarify that a little bit more? DR. RAMIN: Sure. Because I'm not sure I I'm sorry, could you

CHAIRMAN BLANCO: understood that one. DR. RAMIN: recording variability where in there the

You gave the example of that was good variability, rate tracings, beat but

fetal

heart

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?

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CHAIRMAN BLANCO:

I'm sorry, are you going

to ask her to clarify the question, so you understand how to approach it? first, please. DR. ROSEN: sponsor team. So you are looking for cases where Karl Rosen, a member of the Yes, go ahead. Identify yourself

intervention was made on the basis of ST information only -DR. RAMIN: DR. ROSEN: rate -DR. RAMIN: -- fetal heart rate tracing. Any other questions? Correct. -- with reassuring fetal heart

CHAIRMAN BLANCO: (No response.)

All right, does anybody else on the panel have some questions? end. DR. cardiology. I had questions or clarifications, or I would like a clarification on the Gothenburg reports. NEAL R. GROSS
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Well, let's just start from this

RINGEL:

Richard

Ringel,

pediatric

I understand that it's observational, but I was, I guess, curious about whether these were commerciallyacquired devices by the hospitals that then did the study or were they provided by the company? the training like? What was

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 alarms. my final question was regarding Are

Does the system come with any alarms?

there alarms that can be set, or is it all totally dependent on observation of the treating physician or NEAL R. GROSS
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nurse? CHAIRMAN BLANCO: MS. TOLEDANO: I had the Thank you.

Alicia Toledano from Brown. question about audible

same

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: DR. WOLFSON: My questions. question Okay, thank you.

I'm Bob Wolfson. is actually a couple of

One, why the 20-minute interval?

What is

the statistical basis of that? with signal-to-noise ratio,

I presume it has to do but could you please

explain why that was derived? Also, the issue of mid-forceps, my

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impression is that is a relatively rare event in the United States. move the Therefore, one could at least crudely rate either by vacuum or by

mid-forceps

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 preterm 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. NEAL R. GROSS
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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? DR. WOLFSON: the intervention.

Is that what you mean?

Well, Jorge, it's not just

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 NEAL R. GROSS
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electronic fetal monitoring part. So I'm wondering, in the actual clinical practice, where is the emphasis in making the decision to intervene? originally tool. what Because my impression was that this was as an electronic fetal monitoring Yes, that's ST segment So

done

That's what drives the decision. drives the decision, and the

information is the secondary piece of information.

that if it's reassuring, you're cool; if it's not, you move toward delivery. And, therefore, in a non-

reassuring electronic fetal monitoring tracing, the ST segment information is the tie-breaker as to whether you're going to intervene or whether you're not. that the correct impression? CHAIRMAN BLANCO: DR. WOLFSON: Anything else? Thank you. Is

That's it.

CHAIRMAN BLANCO: to Dr. Neuman over here. DR. NEUMAN: I

We're going to go back

have

several

questions

related to the technology, and let me begin these questions with a clinical issue; namely, the machine is essentially, if we put it in very simple terms, a NEAL R. GROSS
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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. what else is going on? The second thing is the robustness of the analysis routine in terms of signal distortions, So I'm wondering,

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. data? NEAL R. GROSS
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What does the monitor decide as non-analyzable

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? CHAIRMAN BLANCO: Dr. Sharts-Hopko? DR. Hopko. I was also concerned about lead placement NEAL R. GROSS
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Thank you.

SHARTS-HOPKO:

Okay,

Nancy

Sharts-

and diagnostic tracings. I am

So thank you. concerned about the

also

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. CHAIRMAN BLANCO: Jay? DR. IAMS: Jay Iams, Ohio State. Thank you.

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 NEAL R. GROSS
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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? poor Were they so profoundly depressed and had such cardiac output that the cord samples

preferentially perhaps would have revealed babies who were sicker? any data on And if so, or regardless, do you have 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 I

percent. was

Those are percentages of the removals. more about in each group, the

wondering

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 NEAL R. GROSS
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there's

a

pre-terminal

tracing?

Does

the

STAN

virtually find that always? And then the last question is regarding -it's somewhat theoretical. myocardial hypoxia, When you're looking at acidosis, how

myocardial

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? CHAIRMAN BLANCO: Gary? DR. EGLINTON: I'm still thinking about Thank you.

mid-pelvic operative deliveries and wondering about the definitional difference. and I just can't remember it. It's probably in here 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 NEAL R. GROSS
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my staff that has joined my staff in the last three years, almost none of them apply for privileges for mid-pelvic operative delivery. box on the credentials sheet. They just skip that I think there's

probably a major cultural difference here between the European Union and the U.S. Thank you. DR. Miami. I have a question regarding the O'SULLIVAN: Mary Jo O'Sullivan,

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 other at than all I and how that that

training

was

done,

realize

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 If it was not, then

the whole retraining process?

what were the characteristics of the original versus the retraining? between the I ask that because of the differences analysis and the subsequent

interim

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analysis. DR. BROWN: a couple of questions. One was about the correlation between Carol Brown, New York. I have

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 training/retraining: question about the

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 versus traces that were managed by nurse midwives I would

OB/GYNs,

proportionately,

because

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. NEAL R. GROSS
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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? CHAIRMAN BLANCO: DR. SEIFER: Two Thank you.

David Seifer, New Jersey. One is the inadequate

questions:

recordings of 12 percent, is a number that one would expect with a new technology, looking at these

endpoints? opposed to

Also, so would one in actual practice, as 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? NEAL R. GROSS
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Also, with

regard to the greater than 35 percent with the less than 20 minutes of recording, again, is that something that is preventable? My second question has to do with just basic statistics with regard to positive and negative predictive value of the control group versus the STAN group with respect to metabolic acidosis and Caesarian section rates. MS. MOONEY: I have no questions. Thank you. Kleia

CHAIRMAN BLANCO: MS. LUCKNER: Luckner, Toledo, Ohio.

I've just got one.

We've had some discussion here about the comparability of the labor management between Sweden and the United States. My question is, specifically,

in Sweden is the nurse midwife physically present in the labor suite, for the Swedish colleagues? And then Where mean

ACOG or FDA have any data on the United States? labor is managed by obstetricians, does that

physical presence at the labor suite, since most of us around the table know that that's not what happens? CHAIRMAN BLANCO: Anything else?

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MS. LUCKNER:

Thank you.

That's it.

CHAIRMAN BLANCO:

Thank you.

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 Most Be

encourage the sponsor and FDA to be very brief. of these are actually addressed to the sponsor.

concise and to the point because we need to not be spending all the time listening to the answers. need to discuss what we think. We

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? Yes, go ahead. Can I add an additional

CHAIRMAN BLANCO: DR. question? CHAIRMAN BLANCO: WOLFSON:

Sure.

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DR. WOLFSON: by which the actual

Could you clarify the basis management guidelines were

derived?

There were specific differences in the rise It

of the ST segment based on the CTG information.

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.? is that My impression certainly in my own venue fetal monitoring will be used

electronic

somewhere in 80 to 90 percent of labors. typically, this is external monitoring

Granted, the

through

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 NEAL R. GROSS
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percent

of

your

labor.

So

you

have

different

criterias. Thank you.

I would just appreciate a clarification.

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 Thank you very much.

discussions at that point.

(Whereupon, the foregoing matter went off the record at 11:31 a.m. for lunch and went back on the record at 10:54 a.m.)

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

S-E-S-S-I-O-N 12:34 p.m.

CHAIRMAN

BLANCO:

All

right,

let's

go All

ahead and see if we can get started, please.

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. NEAL R. GROSS
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Discussion effectiveness. No. 1:

question,

safety

and

"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 Is this endpoint appropriate?"

metabolic acidosis.

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 comments? BLANCO: Okay. Any other

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 NEAL R. GROSS
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itself, an endpoint.

It's a marker for the ultimate We

endpoint, which is neurologic injury, presumably.

all know the difficulties inherent in using that as an endpoint. So it's an appropriate choice for a

surrogate endpoint. CHAIRMAN BLANCO: some things on this. I Well, let me throw out 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 and is the a definition of that for,

really

reflects,

good

surrogate

something bad happening in the fetus and neonate. DR. RINGEL: Our markers of a bad outcome, So

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

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 NEAL R. GROSS
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would never get completed. able to link it to

Then you won't even be 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 If you

measurable in the neonatal period is seizures.

have seizures in the newborn period, I think that's still the best clinical marker, not laboratory marker. CHAIRMAN BLANCO: comment over here? DR. O'SULLIVAN: Yes, I was just going to I'm sorry, was there a

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. NEAL R. GROSS
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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 outcome. of these babies didn't have any adverse

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: DR. EGLINTON: DR. Gary, you had a comment?

That's okay. Maybe the difference

O'SULLIVAN:

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

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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: comments on 1A? (No response.) All right, well, let's move on to 1B, All right. Any other

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 of millimeters metabolic per liter. Is this

definition meaningful?"

acidosis

clinically

Would you like to go ahead and start, Dr. O'Sullivan? DR. O'SULLIVAN: that was pointed out by I think that the data the FDA showing the

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differences between the 7.05 versus the 7.00, and the equivalent base deficits, is a little bit more

convincing in some ways; plus, it's also what we use in this country, which I think is much more what we're used to. That would be my only point. CHAIRMAN BLANCO: DR. comment that it NEUMAN: seems Any other comments? like to just looking make at a a

I'd to me

we're

continuous variable and trying to make it a categoric variable. Perhaps there should be some way of

analyzing this data where severity enters in rather than just yes or no. CHAIRMAN BLANCO: So what you're saying is

some sort of analysis where you're looking not just at a cutoff 7.05, but you're looking at, you know, how well did it perform as the pH was lower? you're saying? DR. NEUMAN: Yes, and, of course, base Is that what

deficit as well, but I think the data from the FDA demonstrated that, depending on where you take your cut point, you can get different results. CHAIRMAN BLANCO: All right. Well, I

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think it may be appropriate at this point maybe to have Dr. Rosen, about, whoever why was is the going to answer of the 7.05

question

definition

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. NEAL R. GROSS
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And at that point

still, Dr. Ramin, as you say, two-thirds of those babies will do well, but up to a third will have a significant neurologic deficit, again depending upon the degree. CHAIRMAN BLANCO: So what you're saying is

that the base excess of 12 was utilized on the basis of the study that you quoted with having correlation with neurological sequelae? DR. ROSS: That study as well as really

the extensive human literature largely produced by Dr. Low. So the key issue in this, rather than being a

pH, which is both a log function and has its problems, and a mixture of respiratory and metabolic issues, is the base deficit. That is the key number. Yes, but, nevertheless,

CHAIRMAN BLANCO:

the study was designed and the PMA is being produced utilizing both of those numbers. DR. ROSS: Right, and both of those are

important, if I may, because a base deficit of 12 is associated with a pH of 7.05, if the PCO2 is less than 60. If you get above a 60 value with the same pH, We felt that

then your base deficit is going to drop. NEAL R. GROSS
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www.nealrgross.com

invariably these babies have some mixture of metabolic and respiratory acidosis. One could move to a value of 7.1 and then you only require a PCO2 of 50. your base deficit is less. Anything above that,

So this, in fact, is a

really stringent requirement of both the pH and the base deficit -CHAIRMAN BLANCO: Well, you haven't

addressed, or at least I'm sorry if I missed it, but you haven't addressed how you came up with 7.05. DR. ROSS: 7.05 is based on the issue that

if the base deficit, being the primary issue, being 12 or greater, that denotes a high-risk infant. If the

PCO2 is less than or equal to 60, then the pH will be less than or equal to 7.05. So it's a mixture,

plugging in the CO2 value.

If you raise the pH -- or

lower the pH threshold to 7.0, you may turn out to have largely just a component of respiratory acidosis in that. DR. RINGEL: question? Can I ask, it's almost a lay

Does everyone obtain the umbilical cord Are we talking about

arterial sample the same way? NEAL R. GROSS
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the same thing here?

I really don't know.

I mean the

OBs in the room would be able to tell me. DR. O'SULLIVAN: Well, they had a

specified way of doing it in their studies. DR. RINGEL: here? DR. O'SULLIVAN: DR. RINGEL: DR. WOLFSON: DR. RINGEL: No.

They did.

And is it done the same way

Oh, okay. It's not? How's it done here? Well, first of all, I

DR. O'SULLIVAN:

mean I can talk about one place, and perhaps Susan will talk about another. But the cord is doubleThe specimens are not kept valid at room 60

clamped and cut for one thing. sent right away and because

they're to be

temperature minutes.

they're

felt

for

Here they were much more rigid about that.

Then if we decide to send them off, we collect them and send them off. We usually collect them with the We do not ice

heparinized needle, as they suggested. them at all. DR. RINGEL:

And they're taken, then, from

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the harvested umbilical cord? DR. O'SULLIVAN: umbilical cord -DR. RINGEL: But the CO2 is changing then? Hum? They're taken from the

DR. O'SULLIVAN: DR. RINGEL:

The CO2 is changing as -Not significantly.

DR. O'SULLIVAN: DR. RINGEL:

Not significantly? No. Because it's clamped on

DR. O'SULLIVAN: DR. either end. DR. RAMIN: RINGEL:

There have been studies that

have shown that it doesn't change dramatically. DR. RINGEL: DR. ROSS: Thank you. 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 definition, and right, we do any we All right, thank you. other think comments the on the is

definition

clinically meaningful? NEAL R. GROSS
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(No response.) I guess there is no comment on that. DR. EGLINTON: the naysayer then. Jorge? Jorge, let me be

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 NEAL R. GROSS
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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? addressed. Dr. Wolfson? DR. WOLFSON: looking back at other Two things: studies, One, if we're got to be I think that's the question that needs to be

we've

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. NEAL R. GROSS
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So I don't think that you can -- I'm not sure how to use that information. depend on what your endpoint It is all going to what your gold

is,

standard is, as people say. Second of all, I think we have to be very careful. This study was not designed -- we cannot go back and expect a different As the

retrospectively analysis.

The power was not designed on that.

FDA pointed out to us, we have to be very careful in saying that, gee, it out to be a 7.0 based on some of the information that was presented. If the study had

been designed based on a 7.0, the study would probably have been larger and it would have been different, and maybe the same outcomes would occur, but we don't know that. So I think we have to accept what we've got as a good measure of metabolic acidosis that is reasonable in its calculation, as I understand the response, and its resource, and go with it. CHAIRMAN BLANCO: Well, let me play

devil's advocate a little bit and say, well, you know, I recognize what you're saying, that when you design a NEAL R. GROSS
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study, you use a certain number, and that's really what you're trying to achieve, and that you can't change the numbers after the fact to fit what you would like to see. But, at the same time, the issue, as we have already as said, a is that we're what to using metabolic really and

acidosis interested neonate.

surrogate which is

for damage

you're the

in,

fetus

Okay? DR. WOLFSON: Right. So the question that I

CHAIRMAN BLANCO:

was asking was not, let's change the definition and, oh, it doesn't work at 7.0, so that invalidates it. It goes back to the issue of, with the numbers used, they show difference, but was the definition stringent enough to have and that difference for the be clinically of

meaningful

significant

application

other patients that this is going to be applied to, if it's approved? the That's the or question. changing was the It's not

changing It's, is

statistics

analysis. definition

that

definition,

that

appropriate to show what this surrogate endpoint needs NEAL R. GROSS
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to show? MS. TOLEDANO: on damage to a neonate Let me focus for a second 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. seven of those babies. There are

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 I think along with

if they're able to address that.

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. NEAL R. GROSS
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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? have neonatal seizures? Did they

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. folder. You have all the data presented to you in your We have a detailed analysis of all these NEAL R. GROSS
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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: can figure that one out. DR. ROSEN: CHAIRMAN Yes. Okay? And then how Well, let's see if we

BLANCO:

about the issue of the sensitivity and specificity in the 46 cases? DR. ROSEN: analysis simply because Well, we haven't done that 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 NEAL R. GROSS
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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: you for your answer. All right, well, thank

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? other comments? Dr. Wolfson? Just one more question: If No

DR. WOLFSON:

part of the outcome issue is neonatal outcome with respect to neonatal encephalopathy, then can we not consider that's that the the outcome that was was created, one that since was

long-term

outcome,

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statistically-significant,

and

therefore,

it

correlates with the definition of acid-base? In other words, what I am really saying is that we just said that the metabolic status is a surrogate marker for neonatal outcome. We have

neonatal data across both the two groups and the total analysis that demonstrates the statistical level of .02. That's on page 15 of the original book that we So it seems to me that the endpoint we just

received.

said is statistically-significant in and of itself. MS. something TOLEDANO: I just wanted to say

about

sensitivity

and

specificity

calculations.

We need to make sure that when you're

calculating your sensitivity, it's for the protocol guidelines. Because, for instance, when you have a

pre-terminal CTG trace, independent of whether or not there's an ST event, you would still catch it because that's your guidelines. people realize that. CHAIRMAN BLANCO: this issue? (No response.) NEAL R. GROSS
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So I want to make sure that

Any other comments on

Okay, well, let's move on to Question 2 then: control "List the outcomes from the Swedish randomized 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 discussing, think it's the kind of what we've whether been you

which

is

definition,

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: else when you were I was thinking of something asking that question, but the

bottom line comes down to the number of individuals with an adverse event. Although the almost 5,000

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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. said, the P values are fine. was appropriate. endpoints. As Bob

The design of the study

I don't disagree with the choice of

I think the response that Dr. Ross gave But when you get all finished with

was appropriate.

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: Gary? DR. EGLINTON: I wanted to talk just a I thank you.

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little

bit

more and

about

people's I

concerns think is what

about we're an

sensitivity talking

specificity. here with the

about

RCT

really

interventional trial.

So we're not really interested We're interested in the an outcome outcome reduced of of the

in sensitivity and specificity. whether interest, interest the and intervention it did.

reduced There was

prospectively

assigned;

it

outcome of interest. In terms of sensitivity and specificity, we really shouldn't talk about that. We should talk

-- if you want to talk about that concept, what you really want to talk about is likelihood ratio. This

is a screening test, and in that regard, then, you would get that information from the multi-center trial and the Nordic Observational Trial, where it's not really an interventional trial. That will tell you, based on these 11 or 12 cases with evidence of hypoxia or asphyxia in the multi-center trial, and in looking at the Nordic

Observational Trial, how good was the test, and the measure of that is the likelihood ratio, but it

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wouldn't come out of this trial, the RCT. CHAIRMAN BLANCO: any panel member? DR. BROWN: Yes, I just had kind of an Any other comments from

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: DR. BROWN: Very low. Very low.

So it's still very low?

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DR. O'SULLIVAN: CHAIRMAN BLANCO: MS. TOLEDANO: usual. CHAIRMAN BLANCO: MS. TOLEDANO: I'm used to

Uh-hum. Any other comments? I've got my hand up, as

Any other comments?

I've got my hand up. 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? 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 Is this too rare of an outcome

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

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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 Again, there

for helping me with these cases here.

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 NEAL R. GROSS
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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? the issue of operative We haven't addressed and C-section. Anyone for the

intervention

We've been mainly on the metabolic acidosis. care to make some comments on the data

secondary endpoints and other measures? (No response.) Not particularly overwhelmed by the

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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: thing I would add here is I think that the only 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: you think it's not that It's extremely rare, so to the United

applicable

States situation?

Is that what you're saying? Yes. But what would have

DR. O'SULLIVAN: MS. TOLEDANO:

happened to them? operative abdominal?

Would they have ended up being

DR. O'SULLIVAN:

They would have fallen

into the all operative interventions, which includes Caesarian section. NEAL R. GROSS
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MS. TOLEDANO: have been C-section? DR. O'SULLIVAN:

Okay, so they still would

Right. So I guess the question

CHAIRMAN BLANCO:

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. is The STAN doesn't fix anything. that you've got to get All it does baby out

indicate

the

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,

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operative interventions. So acidosis as if we have accepted the small the metabolic in

the

endpoint,

difference

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: going in a totally different Well, actually, I was 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 nonreassuring, 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 NEAL R. GROSS
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the STAN group. DR. RINGEL: CHAIRMAN Right, I agree, yes. What I was really

BLANCO:

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 That's Do you

to be able to allow that statement to be made. what I was trying to get at. Okay?

understand? DR. RINGEL: Yes. Okay. Anybody want to

CHAIRMAN BLANCO: 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 So I would

jump in the data to make that statement. NEAL R. GROSS
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www.nealrgross.com

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 So that's a concern -- I mean

has been discussed.

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. this trial, but it

It wasn't the primary endpoint in 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. NEAL R. GROSS
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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 The simple issue of the operative delivery as a

quickly and clearly again. data in this study using

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descriptive term for operative vaginal and operative abdominal deliveries, that doesn't bother me. 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 That's

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: from anyone else? DR. O'SULLIVAN: I think it's kind of All right. Any comments

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: DR. WOLFSON: Yes?

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 NEAL R. GROSS
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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 I specifically don't have or a at delivery of for fetal raw data

distress. Caesarian

way

comparing delivery

section

data

operative

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 countries. talk about the translation between

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 NEAL R. GROSS
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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. difference. Can you hear me? CHAIRMAN BLANCO: DR. RAMIN: No. RAMIN: It's only 1.6 percent

When you look at it, it's only

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about 1.6 percent difference.

So it's questionable if

it really ultimately decreases, at least clinically significant. DR. WOLFSON: at it from a Okay, but you have to look standpoint. It's 1.6

proportional

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. going to No. 3. "Several issues identified in the FDA Hang on, we're

review may affect the results. implication of each issue in

Please discuss the relation to the

clinically significance of the results presented in Question 2." NEAL R. GROSS
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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 discussion? protocol. Anybody want to start the

Maybe Dr. Ramin? DR. RAMIN: Right. Do you think that the

CHAIRMAN BLANCO:

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? you understand what I'm getting at? DR. RAMIN: My opinion would be that, yes, Or do

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: to make a comment on that? DR. EGLINTON: Okay. Anyone else want

Agree or disagree? Yes.

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CHAIRMAN BLANCO: DR. EGLINTON:

Gary? 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 translation. I'm worried about a second

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

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technology. translate. We

I

don't

see

that

this

is

going

to

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: DR. O'SULLIVAN: two issues. Yes, Dr. O'Sullivan? Well, I think there are

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? they I mean prior to the protocol violations, when got started, versus after the protocol

first

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 NEAL R. GROSS
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the

difference

here?

How

come

there

was

such

a

difference? difference?

Or how come it appears there as such a

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. would be used While looking at the way the device 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 They were

deviate from accepted medical practice.

just showing that the deviations were equal in the two groups. It may be a high number of deviations, but So I think it's a wash. BLANCO: Yes, I think the

they were equal.

CHAIRMAN

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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. way or another. So probably it didn't affect it one

Correct? That's the way I look at it. Okay. Any other

DR. RINGEL: CHAIRMAN comments?

BLANCO:

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. came here home to roost.

The chicken

So I think that is something

that we have to be concerned about, and I'm concerned about that. CHAIRMAN comments? (No response.) All right, what about B, no registration NEAL R. GROSS
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BLANCO:

Okay.

Any

other

of an automatic ST event? brought that up.

I think, Dr. Ramin, you

What you meant by this -- let's try

to get clarification -- was that there was obviously an ST event, but that the machine did not record it, or that there was some event happening with the fetus and it wasn't recognized as an ST event? DR. RAMIN: Like, for instance, there was

an example of an ominous or pre-terminal tracing where subsequently the infant died or had Apgars of 0-0-0. So it was an intrapartum death, but there was not registration of an ST event. CHAIRMAN BLANCO: So what you're saying,

the machine may not have been accurate enough in the identification that fetus? DR. RAMIN: about that. DR. IAMS: That gets back to what Dr. Right. I have some concerns of metabolic acidosis or hypoxia in

Wolfson said a little bit ago, what is the primary piece of the information displayed that is going to be the action item? Is it going to be the tracing, which And the you

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go and look for the ST event marker and it's not there. So where does that leave you? DR. RAMIN: DR. IAMS: Which one do you rely on? 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. company, they RINGEL: very But, in even fairness in their to the

clearly,

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 It

reminds me of, sometimes they look pretty good.

depends on where in the process you come into it, I guess. confused. correlation correlation. CHAIRMAN BLANCO: Well, yes, I think If you come in at the end, it can get

So we're just looking to see if there is a there, and then what degree of

that's a very important point. NEAL R. GROSS
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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. what are we trying to do here? I mean,

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 NEAL R. GROSS
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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 I really would like to

trying to give them guidance.

know the answer to that question before we deliberate a whole lot further, I guess. NEAL R. GROSS
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CHAIRMAN BLANCO: Rosen? All right, Dr. Ross? DR. ROSS:

All right, well, Dr.

Michael Ross again. It is really

That's not the answer, Jay.

a sequence of looking first at the fetal heart rate tracing and, secondarily, at the STAN. on the little package insert, if the As indicated tracing is

entirely reactive and reassuring, there is no need, nor request, to look at the STAN. If the tracing is In fact,

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

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 to the FIGO in our terminology somewhat or, the

according

terminology,

different levels of concern, then the STAN becomes the secondary level. DR. WOLFSON: Dr. Ross, then explain to

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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. 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 The biphasic certainly

reassuring -DR. ROSS: That's correct, and, in fact, I mean, let's assume that In

it may be an episodic rise.

we have a completely reactive, reassuring tracing.

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

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the panel?

Go ahead, Gary. DR. EGLINTON:

Go ahead. I wanted to ask about this may not understand it.

card.

The

system,

I

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 preterminal. So require a there deal are of six boxes in here along that the Once four

great

interpretation

horizontal axis with intermediary and abnormal. one pigeonholes the strip into one of these

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 NEAL R. GROSS
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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: the ST waveform. computer. That is. You do not look at

That's in fact just displayed on the

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. attempting to do is define in What this is objective

fairly

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. rest of that calculation. CHAIRMAN BLANCO: I'm glad that Gary found But the computer does the

it confusing because I'm always happy when I find NEAL R. GROSS
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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: that what you're trying Being from east Texas? to say, Jorge, from Is east

Texas? CHAIRMAN BLANCO: (Laughter.) But you've got to Americanize it. This Yes, from west Texas.

isn't very Americanized, and it's not very much the way practice is done in the U.S. confusing. This is confusing. Thank you, Dr. Ross. Any other comments? DR. WOLFSON: Jorge? Yes? This is going to be

CHAIRMAN BLANCO:

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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 I think

don't think his question was addressing that.

his question was addressing, you've got some bells and NEAL R. GROSS
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whistles when this bad thing happens -DR. ROSEN: All right, yes. -- bells and whistles to Is that right, Dr.

CHAIRMAN BLANCO:

call somebody to look at this. Wolfson? DR. WOLFSON: Just does it go off? DR. there. ROSEN: It

Yes, that was question one.

doesn't

go

off.

It's

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. 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: flashes, "C-section now!" (Laughter.) That would be good. CHAIRMAN BLANCO: Dr. Rosen. DR. WOLFSON: I would just like to go back That would be good. All right, thank you, We would like a sign that We

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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 That's

think that's maybe not necessarily in here.

one of the questions that you asked that we said we were going to handle later on. DR. WOLFSON: Okay. So I don't see the exact So let's make sure we We'll

CHAIRMAN BLANCO: applicability to the issue.

finish with these before we go into the others. 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. CHAIRMAN BLANCO: Okay, thank you.

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. NEAL R. GROSS
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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: DR. WOLFSON: electrode, actually what fail A scalp electrode?

In other words, in a scalp of the just time doing does it

proportion when you're

regular

monitoring? CHAIRMAN BLANCO: my left very low. DR. WOLFSON: Because in this group it I think I'm hearing from

would be about 5 percent, if you look at it from a purely technical perspective. Only 5 percent of I

failures of where it would have been replaced. don't know what it is in the U.S. history. CHAIRMAN BLANCO: Was it 5 percent?

I

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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 So

couldn't operate, that's only about half that. it's about 5 percent. It's around 5 percent.

DR. SEIFER:

On slide 17 she says less Of that, less than 20

than 20 minutes on the STAN monitor. than 12 percent, 37 percent, and

greater

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. Jorge. CHAIRMAN BLANCO: That's okay. We're WOLFSON: That was not intended,

going to talk about it now. it. So be prepared.

We're going to deal with

All right, so the issue is it is overall 12 percent, but then if you break it down, what

percentage -NEAL R. GROSS
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DR. SEIFER:

Thirty-seven percent or -Thirty-seven were due to

CHAIRMAN BLANCO: less than 20. DR. SEIFER: Yes.

CHAIRMAN BLANCO:

And then 56 percent were

greater than 20 minutes between removal of the device and delivery. Maybe we do need to address the 20

minutes and see what that is. DR. SEIFER: But if anyone has any greater

clarification or definition of those cases in those two categories that aren't congenital malformations or other, what that's about, why that occurs, under what circumstances, because it accounts for more than 315 patients? CHAIRMAN BLANCO: I think this is probably

the appropriate time to talk about why the 20 minutes, what that has to do about, and then the overall 12 percent that. Dr. Rosen, it looks like you're coming up. DR. ROSEN: Karl Rosen. inadequate tracings, and how you think of

These 20 minutes, that is what the time NEAL R. GROSS
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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. you are significant and you can Then

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: DR. ROSEN: Okay. 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. NEAL R. GROSS
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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 -Wait a minute. Wait a

CHAIRMAN BLANCO: 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: DR. ROSEN: So Okay. 30 beats, high-quality

beats, are required, and the system looks for that high quality. poor quality. So it will disregard those that are Then we say we need at least 50 percent NEAL R. GROSS
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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 where, now looking at to the the

Gothenburg

experience,

according

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 NEAL R. GROSS
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the technology.

It is part of the process. Dr. Wolfson, have you

CHAIRMAN BLANCO:

gotten your questions on the 20 minutes answered by that? DR. WOLFSON: CHAIRMAN I think so, yes. Now several people

BLANCO:

brought up the 20 minutes.

So does anybody else have

any comments on the 20-minute window? DR. regarding complexes. the NEUMAN: fact that I still you have 30 a question good QRS

used

Is there a maximum number of bad QRS If I can be a bit sarcastic,

complexes in between?

you wouldn't want to choose just 30 QRS complexes over the entire 20 minutes. DR. ROSEN: Sure. There are also are I

rules that in that case would turn the system on.

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 NEAL R. GROSS
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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. very simple to measure that, but with ST It's it is

becoming more of a challenge. So we need a unipolarity configuration. We need the maternal thigh. That creates a problem. The mother is moving.

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 signal. You should also remember in the Gothenburg database, that's all intention-to-treat. The only only 1 percent of the cases we obtain a

guidelines have been 20 minutes of recording, and it's all intention-to-treat. of that. So that There are no cases taken out shows how the current

really

technology works in clinical practice. CHAIRMAN BLANCO: Go ahead, Mike. NEAL R. GROSS
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All right, thank you.

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. CHAIRMAN BLANCO: All right, thank you.

Any other comments, going back, now that we have the 20-minutes issue? MS. BROGDON: Go ahead.

Dr. Blanco, Dr. Corrado has

tallied some data that may help to answer some of your questions. CHAIRMAN BLANCO: DR. CORRADO: Please, 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 NEAL R. GROSS
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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 numbers are very small. or four. of STAN The rest of

They're less than three

So the overwhelming majority of the category 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 NEAL R. GROSS
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up? DR. CORRADO: Correct. Okay. So I think that,

CHAIRMAN BLANCO:

I don't know, to me at least it sort of puts an end to the exclusions based on inadequate recordings issue. DR. CORRADO: than 20 minutes. Well, that is just for less

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. NEAL R. GROSS
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There were 19 of those out of 133 in the STAN arm and 16 in the control arm. it was disconnected the So in that category, that is, more than 20 minutes comes before under a

delivery,

overwhelming

majority

category of signal problems. CHAIRMAN BLANCO: DR. CORRADO: Okay.

I hope that helps. Yes. Thank you very

CHAIRMAN BLANCO: much. Yes, go ahead. MS. clarification: TOLEDANO: Were the

Just signal

a

point at

of all

problems

correlated with the removal of the electrode to do forceps or ventouse deliveries? CHAIRMAN BLANCO: DR. situation. ROSEN: Go ahead, Dr. Rosen. was not the common

That

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. CHAIRMAN BLANCO: Thank you. Questions?

All right, any other comments? NEAL R. GROSS
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Issues on 3C? DR. IAMS: Jorge, is this a good place to

ask about the exclusions based on cord blood? CHAIRMAN BLANCO: DR. IAMS: exclusions. CHAIRMAN BLANCO: We're talking about Okay, go ahead.

Because you'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 NEAL R. GROSS
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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. it sounds like that was not the case. DR. ROSEN: Well, it's probably true. So

There were two cases in the control arm where they couldn't obtain a cord artery sample. actually group. excluded from the cord So they were acidosis

metabolic

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. Thank you. Any other

CHAIRMAN BLANCO: 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 Anybody want

population and management differences." NEAL R. GROSS
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www.nealrgross.com

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 The whole idea of bells and

bells and whistles.

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. at it, between lunch breaks, When you actually look 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

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process somehow or another will make a difference, since there was such a difference in what you all showed before with your education. that. I come back to

I keep coming back to that because of the

importance that I think it has in introducing this in the United States at all. educational process, and It's going to be a major 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: CHAIRMAN BLANCO: No. 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, occurred. basis, but that they will notice that this event

They may not have gotten to it on a timely the other option is simply to central

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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. supposed to do. DR. transportability country. Otherwise, it won't do what it is It's subsequent failure. IAMS: don't Jorge, reflect my very concerns well on about this

I was struck by one of the comments Dr.

Rosen made in this beginning of his discussion, that there is a general of consensus in Sweden and about some the

interpretation

cardiotocography

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 NEAL R. GROSS
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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 If I were going to

see the ST wave go up or down.

redesign the equipment for an American user, I would take out everything except the ST event marker. do I need the rest of it? Why

Because we will want to That's what we

analyze and argue with the computer. do. CHAIRMAN BLANCO: and the bells and whistles. DR. IAMS: whistle. data that

Don't forget the light

Well, I don't need a bell and

Maybe a little bell, but really take out the 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

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be a big problem, I think, something you could easily fix. CHAIRMAN BLANCO: Well, let me pin you Is

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

that an issue that's sufficient enough that you are concerned about the introduction of this device into this country? DR. O'SULLIVAN: CHAIRMAN BLANCO: DR. O'SULLIVAN: Absolutely. Really? 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: DR. IAMS: Jay?

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 NEAL R. GROSS
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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? importance correctly, of Ms. Because I definitely agree with the the question, was but, telling if us I recall the

Daws-Kopp

that

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, cases, doing and the educational the way program, that this

reviewing

monitoring

technology is marketed and distributed in the United States. concern. DR. SHARTS-HOPKO: Dr. O'Sullivan raised, and I share the issues that we mentioned earlier a So, to me, that alleviates some of the

concern about, how are women attended? is attended by that a midwife person the in the

When a woman United her the States, pretty

typically, constantly

stays labor

with and

throughout

delivery.

That's only 1 percent of our births that are midwife NEAL R. GROSS
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attended. situation.

I don't know if it is similar in your

The other -- I just forgot the other issue that I was going to raise. DR. RINGEL: It will come back later. I

Just a couple of comments:

agree with a lot of what has been said there, but I think we are being a little bit harsh on all of our colleagues around the country on their adaptability to use computers. You guys accept that heart rate

printout where it shows you a line that's the heart rate. As a cardiologist, that's anathema to me. I

want to see the QRSs.

I don't want to see something I want

that tells me the heart rate is actually 110.

to measure it myself, but you have learned to accept something that tells you the heart rate is 110. So my guess is that the younger people coming out would learn how to accept the ST or the T wave QRS ratio is actually what the computer says it is, as we all get more comfortable with computers. So

I'm not sure that that's -- you know, to say that we're so stuck in our ways in this country that we couldn't accept that, that that's really valid -- I do NEAL R. GROSS
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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. DR. interpretation. this You're supposed to look at it. RINGEL: Ah, but that's an

I'm being told that people interpret They are specifying an out-of-

differently.

bounds value for their ST or T waves -- excuse me -for their T wave QRS ratio. premise. That is part of their

They have an out-of-bounds ratio, and that So if we don't want

they have an automatic detection.

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

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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 you're argue going as to far go as for 30 a

minutes,

then,

clearly,

vaginal delivery, and the patient is not going to fall into an operative category. to go in the other direction. CHAIRMAN BLANCO: I think we have sort of Otherwise, you're going

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. NEAL R. GROSS
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But let's try to go back into 3D and 3E. In a way, we've also talked about retraining. training is coming out as an extremely I think 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. know, in terms of BROWN: of Another point is we don't the be

comparing

the

populations, that might

incidence

pre-existing or unknown

conditions or even

undiagnosed

that

are

known. Was

Someone mentioned the contrast in prenatal care.

there a comparable rate of women with diabetes, IUGR, pregnancy-induced hypertension, smoking, drug use,

whatever, in this population? concerns about that. NEAL R. GROSS
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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 nonreassuring; you then look at the ST events or ST changes. DR. BROWN: Because that will require a

whole complete change of culture and education. NEAL R. GROSS
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CHAIRMAN people think so.

BLANCO:

Well,

I

think

some

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 and Middle most East and Africa else and is former pretty

Yugoslavia,

everybody

homogeneous, and that percentage was 20 percent -DR. O'SULLIVAN: CHAIRMAN BLANCO: Twelve percent. -- 12 percent. So I

think that that is a concern in trying to extrapolate the data from Sweden into the United States. there really are different populations. DR. O'SULLIVAN: But the other thing to I think

keep in mind, too, when you're looking at that, at NEAL R. GROSS
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least based on our own experience in this country, is the initial immigrant who comes in is generally the healthier individual. they generally do That's why they're here. than our own And

better

U.S.-born

individuals do. CHAIRMAN BLANCO: understand your point. DR. O'SULLIVAN: because somebody is an I was just saying that into the country I'm sorry, but I don't

immigrant

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: CHAIRMAN comments? Yes, Ma'am? MS. MOONEY: I think one of the things we Oh, absolutely. Okay. Any other

BLANCO:

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should keep in mind with this particular area question is that, if we think the data we and have in hand

essentially

supports

the

safety

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. showing talking We're an not talking about something that's We're small

80-versus-20 something

percent that

difference. shows a very

about

difference, significant but very small.

So I think it

may still be applicable, an applicable point. DR. WOLFSON: Jorge? Yes, sir? Going back to the

CHAIRMAN BLANCO: DR. WOLFSON:

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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 NEAL R. GROSS
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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: to 3E, retraining during All right, let's move on the Swedish randomized

controlled trial. that. Does

I think we've kind of addressed want to summarize it or say

anybody

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 plan, the why interventions didn't you according restart the to our

original

study

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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: disagreement with you on that. comment? I think there is some Do you want to make a

I saw you shaking your head. MS. TOLEDANO: You can't do that. You now

have to turn -DR. IAMS: is basically a run -CHAIRMAN BLANCO: have a chance to finish. MS. TOLEDANO: frowned upon, because Wait a minute. Let her Yes, you can. You can do what

Go ahead. That would be so sorely you would have to

basically

report the first study, that you terminated it early for the protocol deviations. Protocol deviations

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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 You can try to You don't just

deviations, you do your interim look. fix it, but you finish up the study. 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: cancer -DR. IAMS: -- look at the performance and Well, we don't do it in

then decide that you do not have enough in that has followed the protocol. that's all. You just continue for longer;

You don't really deny the existence of

the first 1600. MS. TOLEDANO: DR. IAMS: Right. You report them. You're

completely honest, but you say, "We haven't achieved NEAL R. GROSS
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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. It wasn't

They recalculated the total sample size. based on protocol deviation.

It was based on the So they did go

baseline rate of metabolic acidosis.

at the 1600 and calculate that they needed more than the original 3200. DR. but -MS. TOLEDANO: Yes. And the other point is So I think and reIAMS: Okay, I missed that part,

CHAIRMAN BLANCO:

they showed more of the difference now. they showed that, with the retraining

education, they actually did better off than without it, before with the violations -DR. IAMS: Yes, that answers my question. Any comments on that?

CHAIRMAN BLANCO: 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 NEAL R. GROSS
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fair amount of retraining before it hits the market, and not after 1600 patients. I mean, I think there is It can't

some education that needs to go with this.

just be sold and expect everybody to use it and know what they're doing. necessities for a I think it has some inherent 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. feeling of most of the panel. DR. EGLINTON: Jorge? Yes? So I think that's the

CHAIRMAN BLANCO: DR. EGLINTON:

Can I get some retraining? Yes, please do.

CHAIRMAN BLANCO: DR. EGLINTON: please, about the card.

May I ask another question, 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; NEAL R. GROSS
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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. really central. CHAIRMAN BLANCO: DR. ROSEN: All right, Dr. Rosen? It's

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.

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There

is

an

ST

log log

where is

all

these to

events the

are

recorded.

That

available

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 this illustration, Is that on the review mode? 2.2.3, is that what

figure

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. back -DR. ROSEN: So on the user manual there is So if you would go ahead and go

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?

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CHAIRMAN BLANCO: MS. LUCKNER:

Please. At least four times the

question has been raised that the panel participants are unaware of what the machine does automatically versus what the individual practitioner must do

observing it.

So my recommendation put on the FDA

record is that part of that must be more clearly specified. I mean, I read several times, just trying to figure out, do I have to do it or does the machine do it? I thought that was just me in Toledo, Ohio,

and now I'm very comforted to hear that the rest of my panelists have the same questions. CHAIRMAN BLANCO: say something? DR. ROSEN: It is very important that the Okay. You would like to

user is fully informed about how the system operates. I can tell you there has been quite a lot of resources in the education package. You should remember that we

have a certification process which takes the users through all these aspects. This is very essential.

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behind

this

to

fail to use

because the

the

user

would how

not to

understand

how

equipment

and

interpret these events.

Please remember that those

guidelines you have in front of you, they are like a pocket, just a quick memory thing. some of you have been able -CHAIRMAN BLANCO: Dr. Rosen, I'm sorry to You should, I hope

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. DR. ROSEN: Okay? 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: CHAIRMAN Yes, you have. BLANCO: We're just making

suggestions that there is confusion. DR. ROSEN: Okay.

Okay?

CHAIRMAN BLANCO:

And there are important

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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. DR. ROSEN: Okay?

For the record -I'm going to break my

CHAIRMAN BLANCO:

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: be very brief. CHAIRMAN BLANCO: DR. DEVOE: Please state your name. I'll put on my Yankee hat and

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, tutorial organized, that really orderly, must be and done

properly-written

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 NEAL R. GROSS
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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 things. degree of sophistication. It does two

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, in which is something we have was been first

derelict

since

fetal

monitoring

perpetrated in the United States. CHAIRMAN BLANCO: Thank you.

Gary, any other comments you want to make? If not, can we move on? DR. EGLINTON: you. CHAIRMAN BLANCO: on. All right, let's move No, that answers it. Thank

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 NEAL R. GROSS
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sponsor has conducted the following clinical studies using the STAN monitor. To what extent do results

from these studies support the safety and efficacy of the STAN monitor? trial, the EC The Plymouth randomized controlled and the City of Gothenburg

study,

Observational Study?" Anybody want to take a stab at that to start off with? Go ahead. Dr. Ramin?

DR. RAMIN:

With the Plymouth randomized

clinical trial, it was not designed or powered to look at the primary endpoint that was used in the Swedish randomized control trial, that being metabolic

acidosis, but it did show, at least in that trial, a reduction in operative delivery, both vaginal delivery and Caesarean delivery for fetal distress. For the EC study, here there were in that trial 12 cases, 11 of whom had evidence of hypoxia or asphyxia associated with an ST change. There was one

case out of the 12 that had low Apgars scores and encephalopathy and cerebral palsy, that had a normal fetal heart rate tracing and a normal ST waveform. The Observational Study for the City of NEAL R. GROSS
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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. am misreading the slide. Rosen's presentation. before.

Maybe I

This is on page 29 of Dr.

That's why I asked the question

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. have that wrong? CHAIRMAN BLANCO: up? DR. RINGEL: The rates of metabolic In fact, Dr. Rosen, can you come Do I

acidosis looked much lower than with STAN.

it's only for the total and for the CTG that there is a statistical difference demonstrated and none with the STAN. CHAIRMAN BLANCO: DR. DEVOE: Anybody?

Devoe again.

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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. can probably speak to One of the obstetricians here 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: data in support of the and But you're presenting this efficacy the half and of STAN of in an

observational acidosis in

trial, the the

rates of then

metabolic trial go are down

first same,

the they

essentially

substantially in the CTG arm, but not in the STAN arm. DR. DEVOE: They declined in both arms,

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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. better. DEVOE: Right, because they got

They got better as time went on.

I mean,

that's part of the educational impact. DR. better. RINGEL: But the STAN didn't get

So then you could have just educated people,

continued to use CTG, and you would have dropped your metabolic acidosis rate to .1 percent. this wrong? CHAIRMAN BLANCO: No, you're reading it I Am I reading

right, except the number you said is not right. think these are fractions of a percent.

It went from,

in the CTG arm, from 1 percent to .01 percent. DR. RINGEL: Right. Okay. the STAN arm didn't

CHAIRMAN BLANCO: DR. statistically -CHAIRMAN BLANCO: RINGEL:

But

And the STAN arm went

from a little under 1 percent to about .6 percent. NEAL R. GROSS
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DR. RINGEL:

Yes.

So all you had to do

was wait a year and things would get better without STAN, right? DR. DEVOE: DR. RINGEL: DR. STAN. DR. RINGEL: Okay. So it's the paying DEVOE: No. No? They're still training on

attention to fetal ECG that's making the difference whether it's STAN or not? CHAIRMAN BLANCO: DR. ROSEN: Go ahead. I

Could I address this here?

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. NEAL R. GROSS
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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: is what he is saying. DR. saying -CHAIRMAN BLANCO: DR. RINGEL: would suggest that That's what he's saying. RINGEL: Don't you see what I am Well, but I think that

-- is your Gothenburg trial by educating your care

just

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 NEAL R. GROSS
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reading the fetal heart rate monitor. DR. ROSEN: Right. Oh, yes.

CHAIRMAN BLANCO: MS. TOLEDANO:

Okay, thank you. I just wanted to clarify So I'm seeing with

some numbers on this same graph.

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. are no little stars. CHAIRMAN BLANCO: still that -MS. TOLEDANO:

So that's why there

But I think the point is

They can't. -- in the other arm they

CHAIRMAN BLANCO: did. MS. TOLEDANO:

Right, in the other arm

they do decrease it by the better education -CHAIRMAN BLANCO: They do have larger

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numbers. MS. TOLEDANO: that. CHAIRMAN BLANCO: move on, Dr. Rosen. So I Okay, we're going to And we would benefit from

Okay, we're going to move on. 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. Okay, thank you.

CHAIRMAN BLANCO:

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,

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yes. CHAIRMAN BLANCO: other comments on this? (No response.) All right, we're going to -- it's 2:22 right now by the official clock. break. We have a 15-minute Thank you. Okay. All right, any

So we will start promptly at 2:37.

(Whereupon, the foregoing matter went off the record at 2:24 p.m. and went back on the record at 2:39 p.m.) CHAIRMAN ahead and begin. BLANCO: We're All right, let's go the

still

going

through

discussion process and answering the FDA questions. We are at Question 5. training. indication: It's: It's labeling and

"The sponsor proposed the following

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

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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 NEAL R. GROSS
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using

it

in for

the

high-risk

pregnancy, that

perhaps have a

IUGR non-

fetuses,

example;

patients

reassuring fetal heart rate, for instance. There was a question raised about whether or not it could be utilized -- I think one of the other panel members brought up about breeches. So

this is for vertex presentation, but I don't know if it is applicable to perform a breech presentation. DR. RINGEL: that. actually If you look at I was going to comment on their for usual using manual, it in they

give

instructions

breech

presentations.

So I didn't understand, if it's not

applicable, why it is in the manual. CHAIRMAN BLANCO: Okay. Any comments from Any agreement or

any of the other panel members?

disagreement with, that because of the changes, the differences in populations, that maybe a stronger

indication, looking at high-risk conditions, needs to be utilized, rather than a somewhat broader wording, as it is now? DR. O'SULLIVAN: No. 1, do we know anything I have two questions. about its use in an

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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? NEAL R. GROSS
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CHAIRMAN comments?

BLANCO:

Okay.

Any

other

(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 O'Sullivan? DR. O'SULLIVAN: DR. RAMIN: Yes. I paraphrasing you correctly, Dr.

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? CHAIRMAN BLANCO: Okay.

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DR. RAMIN: regarding the deviation

I have another comment just 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: DR. RAMIN: Yes, what did you say?

Well, part of the indication So

would be deviation from a normal course of labor.

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. NEAL R. GROSS
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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, I mean, I think the

so I've got to use the STAN. question is the other way. Does that make sense? DR. RAMIN:

That makes sense. Yes. Is induction of

CHAIRMAN BLANCO:

labor, augmentation of labor, enough of an -DR. RAMIN: Indication. -- indication, a highto insert an

CHAIRMAN BLANCO: risk condition, it's an

indication

internal and use the STAN monitor? meant? Did that clarify it? DR. IAMS: Yes.

Is that what you

CHAIRMAN BLANCO: DR. WOLFSON:

So what do you think?

Yes.

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DR. IAMS:

Do I think the labeling, if

modified as described, would be appropriate? CHAIRMAN BLANCO: to use the STAN monitor in Would it be appropriate 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. NEAL R. GROSS
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CHAIRMAN BLANCO: say "yes."

Dr. Wolfson, I heard you

So would you like to comment? DR. WOLFSON: Well, I agree with what Jay

just said. without the

I think that most inductions can be done need for internal monitoring, if not

probably nearly all of them. -- let me back up.

I just wouldn't want to

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. missed from clinical assessment, the So if it is system might

alert the person.

So I a value of utilizing it in

patients who are under induction. CHAIRMAN BLANCO: care to comment? (No response.) I take it from the silence on the other issues, most panel members are in agreement that All right, anyone else

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 NEAL R. GROSS
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on its use in low-risk patients, would be the way that the panel would see it, would suggest to FDA that they label the use of the product. Anybody want to disagree with that? (No response.) No? then? (No response.) All right, having no other comments on No. 5, we'll move on to No. 6. "Are the professional Okay. Any other comments on No. 5

labeling, users' manual, and the training materials, Section 1A of the panel package, provided by the

sponsor sufficient to ensure appropriate use of the STAN system?" Anybody care to open that up? DR. IAMS: that. States. your Jorge, I'll take a dive into

I think that's a big problem in the United You just saw the panel members up here read information, put our disks into our

written

computers, and think we're following things. sense your disappointment that we didn't

I can quite

appreciate your product the way it perhaps deserves to NEAL R. GROSS
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be appreciated.

And we've had not just a day or two

to do it, but we've had weeks, months, even to do it. So training I'm not are sure that the I labeling think and this

materials

sufficient.

really isn't the province of the FDA, but it's a concern to imagine intrapartum fetal monitoring data entering the current United States atmosphere, with all of its legal concerns and all of our arguments with each other. I don't mean to suggest that we're We simply don't agree, and the

resistant to change.

young colleagues don't agree with each other; they don't agree with the old ones. We simply don't have

an homogeneous approach across the country or even in the same department to how tracings ought to be

interpreted. So I'm not clearly quite sure what to tell the sponsor of this product how to prepare the

marketplace, but there needs to be some preparation of the marketplace for this product. CHAIRMAN BLANCO: Jay, the only thing that

I disagree with you is that it's not the province of the FDA. It is actually the province of the FDA, by NEAL R. GROSS
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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 level, without and the appropriate and

educational

labeling,

indications,"

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. you want. DR. IAMS: Well, that's good to hear. I think we can do that, if that's what

What I meant was I didn't think the FDA could really mandate that stuff. NEAL R. GROSS
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I guess the other comment I would make along those lines is that the only time obstetricians in America line up and behave in a fairly uniform fashion is when ACOG says something: done. This is how it's

So you can't really -- I don't know if we can

mandate that or not, either, but -CHAIRMAN BLANCO: can mandate that. (Laughter.) DR. IAMS: But getting input from ACOG No, I don't think they

would be a major step in the direction of preparing the population for following the rules, because as long as they're not inside that process, you'll either get no use or inappropriate use. CHAIRMAN BLANCO: comments? DR. RINGEL: Just, again, the issue of All right, any other

breech, I was surprised to see that they tell you how to use it for breech cases. CHAIRMAN BLANCO: Okay. Obviously, with

the current indication of vertex, that shouldn't be in there. NEAL R. GROSS
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Dr. Wolfson, I think I saw your hand up? DR. WOLFSON: comment. Yes, I was just going to I

I like the Fetal Surveillance Manual.

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. 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 My machine kept bombing. It just

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 NEAL R. GROSS
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where you have properly interpreted them, and whether those are randomized and blinded to the individual? If that is not the case, that would be one of my recommendations, because I think we have to have on an individual basis, if you're doing this -- physicians do what they feel most comfortable with, and the best outcomes occur when there is consistency, which we all know. Access will come and utilization will come with that comfort level. What is paramount here is

creating that comfort level, and I think that is going to come through the educational process. CHAIRMAN BLANCO: Well, I think they

obviously re-educated their personnel when they were doing the study. From what we have heard, I think the

sponsor certainly has a commitment to education -DR. WOLFSON: Yes. -- and to making sure So I think the

CHAIRMAN BLANCO:

their product is used appropriately.

issue is, to again reiterate, and I think we have said it multiple times today, that there needs to be some significant educational component that goes along with NEAL R. GROSS
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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 to in our here 3 are the European a as

contrasted

centimeters

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 NEAL R. GROSS
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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. CHAIRMAN BLANCO: DR. question. CHAIRMAN BLANCO: All right. Well, then, EGLINTON: Okay. I stop short of this

let's move on to someone else and see if they have something to the question. DR. O'SULLIVAN: does. CHAIRMAN BLANCO: DR. O'SULLIVAN: Okay. I would rather know what Dr. O'Sullivan? I feel the same way Gary

we're going to do before I answer this question. CHAIRMAN BLANCO: All right, well, then,

unless someone else feels strongly -- Jay? DR. Jorge. CHAIRMAN BLANCO: it. NEAL R. GROSS
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IAMS:

I'll

try

to

bail

you

out,

Thanks.

I appreciate

DR. IAMS:

I think the gold standard for It ought to be studies for

tests is the Papanicolaou smear. possible to have post-marketing

obstetrical interventions or screening tests that do pretty much what the last 50 years have done for the Pap smear. Gothenburg event, that You ought to be able to see, and the study the may be the beginning of a of such an

introduction in

technology screening real

into and

practice

results that

appropriate in a

intervention

results

clinically-

important outcome. So I think this is a device which pretty much automatically it is should qualify, for that if sort approved, of post-

whenever

approved,

marketing surveillance. CHAIRMAN BLANCO: Go ahead. DR. WOLFSON: said. I wanted to second what Jay Thank you. Anyone else?

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 NEAL R. GROSS
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country. don't there.

Without the European Union information, we know even the initial diversity over

really

So I would suggest that there, indeed, be

post-marketing studies. DR. SHARTS-HOPKO: Jay. I have a question for

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: to see both. I Well, of course, you would like think it is the company's

don't

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. have been approved, in and then the when

Technologies they're not

successful

influencing

ultimate

outcome,

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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. CHAIRMAN comments? (No response.) All right, that ends the section on the questions that the FDA posed to the panel. What I BLANCO: Okay. Any other

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. Okay. Why don't we go

CHAIRMAN BLANCO: through what I have here.

Yes, sir, you can certainly

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ask a new one. Dr. Ramin, did you feel like most of your questions were addressed or did you have any questions that you wanted to bring forth at this point, from what we asked earlier on? DR. RAMIN: CHAIRMAN I think they were addressed. BLANCO: Okay, so you're

satisfied that they have addressed the questions that you had. All right. Dr. Ringel, you had asked about the

decrease in metabolic acidosis that looked more in the control. already. I think we had kind of addressed that

Were there any other questions? DR. RINGEL: In the Gothenburg trial. Yes, in the Gothenburg

CHAIRMAN BLANCO: trial.

So you've got that done. Any of the others? I thought the others

were probably addressed.

All right.

Let's see, Dr. Wolfson, you questioned, and Dr. Ramin also brought up, about, did they have any data on IUGR fetuses that were included in the study. NEAL R. GROSS
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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, fashion. CHAIRMAN BLANCO: don't have that -DR. required. CHAIRMAN BLANCO: All right, the other one ROSEN: We don't have the numbers Okay. So for IUGR you according to what we know, in a similar

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, NEAL R. GROSS
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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. we used sort of

In the Plymouth randomized trial 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. whether you've got ST events, Then you look at and you add that

component to make your decision. DR. ROSEN:

That's what they --

That is basically the way it

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should be used, according to the instructions. CHAIRMAN BLANCO: Neuman asked about from lead spiral Okay. All right. T Dr. wave vector Have you

configuration, electrode, lead

configuration,

changes as labor progresses and fetus moves. looked at that at all? DR. ROSEN: the reason why we

Oh, yes, very much so. have the unipolar

That's

electrode

configuration, thereby creating an opportunity to have a consistent ST wave form displayed throughout labor, regardless identifying of how the fetus the rotates, "Y" lead but in also the

what's

called

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 question was BLANCO: up All about, right. what Another were the

brought

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complaints of the purchased units? DR. ROSEN: These were related to failures

of the printer, technical failures that were easily sorted. CHAIRMAN BLANCO: the printer or of the machine? DR. safety aspect. CHAIRMAN BLANCO: The concordance of the ROSEN: There was nothing on the Technical failures of

STAN results with pre-terminal tracings? DR. ROSEN: Well, we have pre-terminal As you noticed,

tracings as part of the guidelines.

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 NEAL R. GROSS
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presented to you, there are very few cases of an adverse outcome, where they actually annotate

complications, and, in particular, active pushing in second-stage labor, that's where things start to go wrong, when they do go wrong. The reason why we put forward the

indications being a bit wide is to not miss out. Clearly, there was the requirement for a scalp With

electrode, and that is not standard procedure.

us, roughly 30, 40 percent of all term pregnancies in active labor obtain a scalp electrode. CHAIRMAN BLANCO: has sort of addressed that, Well, I think the panel that they think that

rather than reaching out, we need to tighten up. DR. IAMS: Can I follow up on that? Yes, sure.

CHAIRMAN BLANCO: DR. IAMS:

I'm a little confused by that I thought I

answer about the pre-terminal tracings.

was on the same page as you, in that by the time you get to a pre-terminal tracing that should have been recognized technology before, at that the point introduction may not of the STAN it as

recognize

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abnormal because there is no further change? DR. changes. DR. IAMS: Would that translate, if you ROSEN: There will be no further

back that process up a little bit, to whatever is right between pretty bad and pre-terminal? Is there

an opportunity for the delayed application of the STAN technology to fail to recognize, so if you wait too long it doesn't help you? Is that the message that

we're to take from this, is that we should -DR. ROSEN: Well, if you look at the

indications that we have been using in the Swedish randomized trial, then that's now used in labor ward settings where the STAN is utilized, that is that you don't start a STAN recording in active pushing secondstage labor. recording. You have to start prior, at least 30 That is not the case where you start a

minutes; you attempt to do that. the fact that we need a

That is to recognize where we have a

period

baseline. DR. IAMS: Right. Well, refresh me then

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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: DR. different IAMS: or Yes. I that noticed you that to there be were

criteria

had

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 NEAL R. GROSS
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of hypoxia at the time that patients come in. of our patients come in late in labor.

A lot

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: yes? DR. ROSEN: Yes. If you've already got So the answer is really

CHAIRMAN BLANCO:

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significant myocardial effects, the STAN monitor will not show you anything? DR. ROSEN: are. Well, it depends on where you

You may still have a heart which is exposed to where you will find marked ST events

hypoxia

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 satisfied? DR. IAMS: Yes, I think so. Just let me BLANCO: Okay. Jay, are you

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. NEAL R. GROSS
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DR. IAMS:

Right. Thank you.

CHAIRMAN BLANCO:

Did I get everybody's questions that were not answered? Yes? WOLFSON: I just wanted to just On

DR.

clarify what I thought I heard you say, Dr. Rosen.

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. Is that correct? All right, thank you.

DR. WOLFSON:

CHAIRMAN BLANCO: Anything else? DR. EGLINTON: fetal stimulation or LS in clamp

Go ahead, Gary. Do you practice intrapartum Sweden, vibrio of acoustic the fetus,

stimulation

provocation

looking for accelerations? DR. centers. ROSEN: Varying between different

We do have the fetal blood sampling in NEAL R. GROSS

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Gothenburg, for instance, where in Lund there would be more vibrio acoustic stimulation, and so on. varies depending on where you would look. DR. O'SULLIVAN: Let me ask you a question So this

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. significant ROSEN: Well, according once to there's the been a

event,

clinical

management protocol, obviously, we recommend immediate delivery under those circumstances. data we have, we want that baby According to the out as soon as

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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. sure it would But how to institute that, I'm not be practical and what we are

recommending is simply take the baby out, please. CHAIRMAN BLANCO: Okay. Any other

questions from the panel members? would like to bring up? (No response.) Okay, let's move on. again.

Anything else they

Open public hearing

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. order. We will take them in that

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 NEAL R. GROSS
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FDA that would like to make any additional comments at this point. (No response.) Nope? sponsor. All right, then we go to the

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. CHAIRMAN BLANCO: DR. Gothenburg study. situation. NOREN: I Thank you. would comment on the

You must realize this is a clinical So don't Look at

This is not a randomized trial.

look at them in a STAN group or a CTG group.

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: NEAL R. GROSS
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the

high-risk group.

group, This

the is

STAN

group, on

and the

the

low-risk an

dependent

midwives

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. can't compare them. Look at them as one unit. May I ask a question? Please, go ahead. You presented, you, the I So you

DR. RINGEL:

CHAIRMAN BLANCO: DR. RINGEL:

sponsors, presented the data for us to interpret.

understand what you're saying, but without knowing the historical knowing controls for your bad outcomes, knowing your without just

any of

comparison, your

without and

what

education

midwives

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? NEAL R. GROSS
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DR. knowledge randomized midwives, in

NOREN: the CTG wasn't

You

must

realize

that

the the of in

interpretation that good, we and

before a at lot CTG

trial and

even

doctors,

looked

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. the midwives were forced to

Secondly,

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 "This violations is why against is a a protocol and tell That's them, why,

there

protocol."

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 nonNEAL R. GROSS
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reassuring CTG, and we are more or less waiting for that ST event. When that happens, everyone is ready Of course, the time between

to do the C-section.

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? 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, All

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 Its

to determination its recommendation to the FDA. recommendation approval, can be one with of the

following: or not

approvable

conditions,

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approvable. Approval conditions. Approvable with conditions means there are specific conditions which are discussed by the panel and listed by the panel Chair. labeling changes such as a or Conditions could be revised indication, or or a a means there are no attached

contraindication, condition could

warnings be a

precautions, study

post-approval

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 NEAL R. GROSS
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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. guess that will be the start. Does anyone have an interest in making a motion 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 to approval without any condition at this I

there anyone who would like to make a motion, second, that the PMA is not approvable? NEAL R. GROSS
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DR. IAMS:

I'll make that motion. Okay, there is a motion Is there

CHAIRMAN BLANCO:

on the floor that the PMA is not approvable. a second? DR. EGLINTON: Second.

CHAIRMAN BLANCO: floor.

There is a second on the

Therefore, we are going to discuss this, and

then take a vote. Jay, approvable? DR. IAMS: Well, I would like to why do you think that it is not

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 My not necessarily on leading panel to may better have

outcomes.

presence

this

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 NEAL R. GROSS
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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. it progressively and often, and We have used 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, concerned about with those concerns and in I'm mind, I'm

transportability

concerned I am

that more data may not lead to better outcome.

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 NEAL R. GROSS
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Item B.

I'm not certain that it is going to be I do not I think

effective in the United States population. have concerns about its safety in general.

I'm more concerned about whether it would do here what it so clearly seems to have done in Sweden. CHAIRMAN BLANCO: spot again. satisfy your Let me put you on the

What would the sponsor have to do to concerns and be able to achieve an

approvable result? DR. IAMS: will, in part, Well, I think their EU study address place the to concern another. about An

perhaps from

transportability

one

American study would be another avenue to that. CHAIRMAN BLANCO: DR. IAMS: CHAIRMAN Okay.

So that's it. 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 NEAL R. GROSS
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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 have to on do the to record: be able What to would the your

sponsor

satisfy

concerns, to make the PMA approval? DR. EGLINTON: to be done in this country. CHAIRMAN BLANCO: before we open the All right. to the Let me just, other panel I think it is going to have

discussion

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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: phrase? CHAIRMAN BLANCO: DR. EGLINTON: Sure. Can I just add one more

I think it needs to be done

in this country because of differences in the style of practice. country is The way obstetrics is practiced in this dramatically different from the way

obstetrics is practiced in Scandinavia, and probably many other places in the world. CHAIRMAN BLANCO: Any comments? DR. NEUMAN: Thank you.

Michael? Mr. Chairman, I'm just

curious what the difference is between not approvable and suggested things to do and approvable with

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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 postmarket 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? some help from members of the FDA. MS. BROGDON: problem. I think that's a semantics I would appreciate

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

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recommendation

because

the

sponsor

would

have

to If

essentially start over with their clinical study.

you mean a post-approval study, you should say that clearly. CHAIRMAN condition then. BLANCO: That would be a

That's what I was trying to explain.

Mr. Pollard? MR. POLLARD: to -CHAIRMAN yourself, please? MR. POLLARD: Thank you. Colin Pollard BLANCO: Would you identify Right, and I would just like

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 clinicallyNEAL R. GROSS
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significant result. for an approval. Now for

That is basically the threshold

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. CHAIRMAN BLANCO: Thank you.

The floor is open for comments from the panel members. DR. O'SULLIVAN: I really do believe that I think

a study should be conducted in this country.

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

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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: DR. O'SULLIVAN: CHAIRMAN BLANCO: In the United States? In the United States. 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. indications, but they They have to approve for the don't and can't control how

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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: 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 and by FDA the A question for Dr. Pollard

demonstrate

statistical

significance,

that

device is considered to not put increased risk of patients at jeopardy? CHAIRMAN BLANCO: we're not approving. Let me just point out,

We're talking a motion for nonOkay? Just so we're clear.

approval of the device. Mr. Pollard? MR. POLLARD:

Right, and your question is Basically, there's three One is

about to approve the PMA.

elements that we talked about this morning.

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. NEAL R. GROSS
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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, population. definition and there are issues of target

Maybe it would be worthwhile to read the 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 clinicallyNEAL R. GROSS
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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. Iams? DR. IAMS: That's fine with me. I think, Is that all right, Dr.

to say it differently, if I were a Swedish panel member in Sweden, I would easily vote yes. vote it to be approved with some of I would minor

the

considerations we have talked about, but the issue is the target population. CHAIRMAN BLANCO: comments here? Yes? Yes. In light of the fact controlled trials, All right, any other

MS. MOONEY: that we have two

randomized

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 NEAL R. GROSS
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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 to put has indicated an a willingness and

commitment

together

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 Wolfson? DR. WOLFSON: Jorge, yes, I'm really going I guess that means BLANCO: Any comments? Dr.

to speak against not approving.

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 NEAL R. GROSS
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to improve neurologic outcome.

For decades, we have This is the demonstrable

looked at various tools to achieve that. first tool that has come along with

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 for is we are now analyzing has that

signal,

looking

information

that

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 NEAL R. GROSS
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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. become better as a nation and So that we will 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

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studies. I have no evidence that this particular device manner. creates harm when applied in an effective

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 network of trial, the even NIH, through bring the it maternal-fetal back to this

and

institution is going to take perhaps anywhere from two to even as long as maybe four years. So colleagues with I would respect share to the concern of in my an

effectiveness

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. NEAL R. GROSS
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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: DR. BROWN: No, I was referring -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 I'm simply pointing out

the endpoints of the study.

to everyone that, in my mind, it may be the most NEAL R. GROSS
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important aspect.

It may not have been specifically They were after reducing the

what they were after.

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. the data that came out of that.

This is part of

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.

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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. than .02. So that is "P" less

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. that are printed out in It's those in your

tables guide.

landscape

DR. IAMS:

Page 15. Is it in 2, page 16? Is that

DR. RINGEL: what you're referring to?

I'm not sure if that's what

you were referring to or not. DR. WOLFSON: DR. IAMS: I don't now.

I think it is the page before,

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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: on 16. DR. WOLFSON: No, I've got 15. What I was Go back a page to 15. You're

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: DR. WOLFSON: is the upper table. MS. TOLEDANO: value. NEAL R. GROSS
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What page are you on? It

Oh, I'm now on page 22.

Yes, that's a one-sided P

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: sure that you do. Okay, well, let's make

Let's start off -We're in Volume 2. Volume 2.

DR. WOLFSON:

CHAIRMAN BLANCO: DR. WOLFSON:

Page 15. Page 15.

CHAIRMAN BLANCO: 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. NEAL R. GROSS
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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 analysis weren't is adequate. against Then zero. the So similar we have

now

seven

eliminated one.

So now it is at .007. Yes, but where is the

DR. O'SULLIVAN: long-term neurologic outcome? DR. WOLFSON:

That's it. It's short-term, though.

DR. O'SULLIVAN: DR. WOLFSON:

Oh, I'm sorry, no, there is I'm

no long-term because that wasn't the purpose.

just looking at this from the standpoint that what happened in the nursery and the diagnosis that was made acutely, it disappeared. MS. TOLEDANO: term. DR. WOLFSON: MS. TOLEDANO: of long-term. DR. WOLFSON: I don't remember the longWas there long-term? Somewhere there was a table Somewhere there was long-

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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: DR. where it is. CHAIRMAN BLANCO: DR. KJELLMAR: Identify yourself. O'SULLIVAN: Please come. But I don't remember

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 we of had age. 14 Out cases of who the 74

resuscitated disabled.

babies,

became

The

point

with

the

table

that

I

have

included, the points are actually two. NEAL R. GROSS
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The first one

www.nealrgross.com

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. of this study? DR. KJELLMAR:

These 14, those were part

No, no. I wanted to make sure

CHAIRMAN BLANCO: that was clear. DR. KJELLMAR: all born in the 1970s. did not -CHAIRMAN BLANCO: month data for these babies.

Absolutely not.

They were

So that is the reason why I

So you don't have 18You just have the acute

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data? MS. actually. ask you? CHAIRMAN BLANCO: MS. TOLEDANO: Do you have Either way. TOLEDANO: That was my question

Are we allowed to ask them directly or do I

I can ask him directly? any followup, 18-months'

followup, one-year followup of the babies who were in your special care? DR. KJELLMAR: (Laughter.) CHAIRMAN BLANCO: The answer, for the Not yet.

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

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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 harping on it, Gothenburg but as study, as I I know can I keep the

best

tell,

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

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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: comments? Dr. Toledano? MS. TOLEDANO: I have to agree with Ms. I would much rather see All right, any other

Mooney and with Dr. Wolfson.

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: comments? NEAL R. GROSS
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Thank you.

Any other

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. be a So this to sort not of decision the could devise

actually

decision

make

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 Do we have

different, we're going to go take a vote. something different, Dr. Wolfson? DR. WOLFSON: address the type of trials. CHAIRMAN BLANCO:

No, I was just going to Thank you. 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 NEAL R. GROSS
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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: the motion. DR. RINGEL: Yea. Dr. Ringel? Yes, I vote not to approve

CHAIRMAN BLANCO: DR. RINGEL: Yes.

CHAIRMAN BLANCO: DR. RINGEL:

Not to approve?

Not to approve. Dr. Toledano? He got that wrong.

CHAIRMAN BLANCO: DR. IAMS:

No, no, no.

CHAIRMAN BLANCO: DR. RINGEL: CHAIRMAN

He said "yea."

I said "yea" three times. Yes, "yea," not to

BLANCO:

approve the motion, correct? DR. RINGEL: Yes. Not to approve --

CHAIRMAN BLANCO: DR. RINGEL: up. I'm sorry.

I'm the one that messed it I apologize.

Not to approve the PMA. NEAL R. GROSS

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I'm the one for non-approval. CHAIRMAN BLANCO: MS. TOLEDANO: motion. CHAIRMAN BLANCO: some other -MS. TOLEDANO: CHAIRMAN That is correct. We would like Okay, so you vote for Yea or no? No, I do not approve the

BLANCO:

confirmation of Dr. Neuman's [sic] vote. "yea" for the motion to not approve the PMA? DR. RINGEL: No.

You voted

I voted not to approve

the motion to not approve -(Laughter.) CHAIRMAN BLANCO: there. DR. BROWN: It might be better if we said We've got too many noes

for or against the motion, for or against it. CHAIRMAN BLANCO: not approve of the PMA. of the PMA -DR. SHARTS-HOPKO: that. NEAL R. GROSS
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Why don't we just say do

Let's just say, not approve

No, no, you can't do

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: MS. approve. For or against the motion. The motion is to not

TOLEDANO:

Are you for the motion or against? CHAIRMAN BLANCO: All right. Dr. Neuman,

are you for the motion or against? DR. NEUMAN: not approve. CHAIRMAN BLANCO: DR. RINGEL: For. Against. Against. Thank you. I am against the motion to

MS. TOLEDANO:

CHAIRMAN BLANCO: DR. WOLFSON:

Against. Against.

DR. SHARTS-HOPKO: DR. IAMS: DR. RAMIN: For. For.

DR. EGLINTON:

For the motion. For the motion.

DR. O'SULLIVAN:

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DR. BROWN:

For the motion. Wait, wait, not so fast.

CHAIRMAN BLANCO: (Laughter.)

Dr. O'Sullivan, for the motion. Dr. Brown? DR. BROWN: For the motion. Dr. Seifer?

CHAIRMAN BLANCO: DR. SEIFER:

Against. Against. The motion is

CHAIRMAN BLANCO:

The motion carries 6 to 5. 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. concerns about NEUMAN: the While I agree with the in

different

patient

population

North America compared to Sweden and the U.K., I feel there is compelling evidence that looking at the

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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. CHAIRMAN BLANCO: DR. RINGEL: Thank you. I don't think there's

reasonable assurance that the device is effective. CHAIRMAN BLANCO: MS. TOLEDANO: Thank you.

I agree with Dr. Neuman. Thank you.

CHAIRMAN BLANCO: DR. WOLFSON: concerns. CHAIRMAN BLANCO: DR.

I think I have expressed my

Thank you. I agree with Dr.

SHARTS-HOPKO:

Neuman, and I didn't want to close the door against continued development of the product. CHAIRMAN BLANCO: DR. IAMS: rationale. NEAL R. GROSS
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Thank you.

I think I've already stated my

CHAIRMAN BLANCO: DR. RAMIN:

Thank you.

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: can add to that. CHAIRMAN BLANCO: DR. BROWN: Thank you. There's really nothing I

I specifically have concerns

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clinical significance, although there was statistical significance of the endpoints. CHAIRMAN BLANCO: DR. SEIFER: points. CHAIRMAN BLANCO: I members. I would like to see if the FDA, Dr. would like Thank you. to thank all the panel Thank you.

I agreed with Dr. Neuman's

Pollard, do you have anything to say? MR. POLLARD: Yes, I just wanted to get a I mean, I did hear the clinical trial to be

little bit of clarification. panel ask for a randomized

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,

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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. BLANCO: Dr. Iams and Dr.

CHAIRMAN

Eglinton and Dr. O'Sullivan, and the others, anyone else, can you specify a little further? wasn't the issue of the endpoints. the sponsor and the FDA. I mean, it

So that this helps

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. -- paraphrasing it for

CHAIRMAN BLANCO: 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 twoyear followup. So from that perspective, I think that would be ridiculous. But

cost-effective-wise

NEAL R. GROSS
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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: DR. WOLFSON: Any other points?

Can I make one? Yes, sir.

CHAIRMAN BLANCO: DR. WOLFSON:

I would encourage that the Most

studies be done not solely in academic centers.

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. CHAIRMAN BLANCO: Thank you.

If there are no other comments, I would NEAL R. GROSS
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like to thank the sponsors for their presentation, their patience, and their information. I would like to thank the FDA for their presentations and their assistance. I would like to thank each and all of the panel members for their very erudite comments and

their involvement. And almost all the members who have been to other hotels, I would like to thank the FDA for having it at this hotel as opposed to the one that we shall not mention, but you're well aware of that none of us like. (Laughter.) Thank you all very much. adjourned. (Whereupon, matter was concluded.) 3:58 p.m., the foregoing This meeting is

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