us food and drug administration: 3856t1
TRANSCRIPT
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 1/322
UNITED STATES OF AMERICA
FOOD AND DRUG ADMINISTRATION
+ + + + +
CENTER FOR DEVICES AND RADIOLOGICAL HEALTH
+ + + + +
OBSTETRICS AND GYNECOLOGY ADVISORY COMMITTEE
+ + + + +
SIXTY-FIFTH MEETING
+ + + + +
MONDAY
APRIL 22, 2002
+ + + + +
The panel met at 8:00 a.m., in Salons E
and F of the Gaithersburg Marriott Washington Center,
9751 Washingtonian Boulevard, Gaithersburg, Maryland,
at 9:00 a.m., Dr. Jorge D. Blanco, Chairman,
presiding.
PRESENT:
JORGE D. BLANCO, M.D., Chairman
CAROL L. BROWN, M.D., Member
GARY S. EGLINTON, M.D., Temporary Voting Member
JAY D. IAMS, M.D., Temporary Voting Member
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 2/322
PRESENT (continued):
KLEIA R. LUCKNER, J.D., M.S.N, Consumer Representative
MARY LOU MOONEY, R.A.C., Industry Representative
MICHAEL NEUMAN, M.D., Ph.D., Temporary Voting Member
MARY JO O'SULLIVAN, Member
SUSAN M. RAMIN, M.D., Temporary Voting Member
RICHARD E. RINGEL, M.D., Temporary Voting Member
DAVID B. SEIFER, M.D., Member
NANCY C. SHARTS-HOPKO, Ph.D., Member
ALICIA Y. TOLEDANO, Sc.D., Temporary Voting Member
ROBERT N. WOLFSON, M.D., Ph.D., Temporary Voting
Member
JOYCE WHANG, Ph.D., Executive Secretary
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 3/322
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
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 4/322
P-R-O-C-E-E-D-I-N-G-S
8:07 a.m.
CHAIRMAN BLANCO: All right, let's go
ahead and call the meeting to order.
I want to remind everybody that there are
signup sheets outside in the front. Please sign in
and let us know who you are and who you are affiliated
with.
Just a couple of housekeeping matters
before we start: As usual, let's not have any
outbursts from the audience. If you would like to be
recognized, at the appropriate time you will be
recognized; you can come to the podium and speak.
Always identify yourself and identify whether you are
associated with any particular entity, and whether you
have, at least the first time that you come up, you
need to state whether you have any possible conflict
of interest with the issues at hand today. That
includes any type of employee, employer, consultant,
travel, per diem, or any other type of relationship
with any of the companies that might have some
business before the panel.
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 5/322
At this point let's go ahead and have some
introductions of who the panel members are. If we
could start over here, please state your name and
affiliation.
MS. BROGDON: Good morning. I'm Nancy
Brogdon. I have been the Director of the Division of
Reproductive, Abdominal and Radiological Devices, FDA.
CHAIRMAN BLANCO: And next to her will be
Dr. Michael Neuman, who will join us very shortly.
Go ahead.
DR. RINGEL: Yes, I'm Dr. Richard Ringel,
Pediatric Cardiology at Johns Hopkins Hospital.
MS. TOLEDANO: Alicia Toledano, Center for
Statistical Sciences, Brown University.
DR. WOLFSON: Good morning. I'm Robert
Wolfson. I'm an independent maternal fetal medicine
specialist and obstetrician/gynecologist and engineer.
DR. SHARTS-HOPKO: I'm Nancy Sharts-Hopko,
Professor of Nursing, Villanova University.
DR. IAMS: Jay Iams, Professor of
Obstetrics and Gynecology at Ohio State University.
DR. WHANG: I'm Joyce Whang. I'm the
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 6/322
Executive Secretary of this panel.
CHAIRMAN BLANCO: I am Jorge "George"
Blanco. I am a perinatologist in private practice in
Odessa, Texas.
DR. RAMIN: Good morning. I'm Susan
Ramin. I'm a maternal fetal medicine specialist at
the University of Texas, Houston, Medical School.
DR. EGLINTON: Gary Eglinton, maternal
fetal medicine, Cornell and New York Hospital, Queens.
DR. O'SULLIVAN: Mary Jo O'Sullivan,
maternal fetal medicine, University of Miami.
DR. BROWN: Carol Brown, gynecologic
oncologist, Memorial Sloan-Kettering Cancer Center.
DR. SEIFER: David Seifer, reproductive
endocrinologist, UMDNJ, Robert Wood Johnson Medical
School.
MS. MOONEY: I'm Mary Lou Mooney, the Vice
President of Clinical Regulatory and Quality for
SenoRx, and I'm the industry rep. to the panel.
MS. LUCKNER: Kleia Luckner. I'm a
clinical administrator at Toledo Hospital in Women's
Health, and I'm the consumer rep.
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 7/322
CHAIRMAN BLANCO: Thank you very much.
Michael, I introduced you, but please do
the honors for yourself, if you would like.
DR. NEUMAN: I think you did such a good
job, Jorge, I think it's fine. I'm Mike Neuman from
the Memphis Joint Program in Biomedical Engineering of
the University of Tennessee Health Science Center in
the University of Memphis.
CHAIRMAN BLANCO: No, you did much better
than I did. Thank you.
(Laughter.)
DR. NEUMAN: Can't do it in one breath
though.
(Laughter.)
CHAIRMAN BLANCO: We'll have to train you.
We'll have to invite you back more, so we can train
you.
DR. NEUMAN: That's quite all right.
CHAIRMAN BLANCO: All right, at this point
I would like to introduce the FDA press contact, if
she would please stand. The FDA contact for this
particular meeting is Nancy Brogdon, Director,
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 8/322
Division of Reproductive, Abdominal and Radiologic
Devices. Thank you.
All right, at this point I will turn it
over.
DR. WHANG: Good morning. We have two
additional OB/GYN Devices Panel meetings scheduled for
this year. They are July 22nd and 23rd and then
October 21st and 22nd.
Today's panel includes seven temporary
voting members, and I will now read their appointment
to temporary voting status.
"Pursuant to the authority granted under
the Medical Devices Advisory Committee Charter, dated
October 27, 1990, and amended August 18, 1999, I
appoint the following individuals as voting members of
the Obstetrics and Gynecology Devices Panel for this
meeting on April 22nd, 2002:
"Gary S. Eglinton, M.D.; J. D. Iams, M.D.;
Michael Neuman, M.D., Ph.D.; Susan M. Ramin, M.D.;
Richard E. Ringel, M.D.; Alicia Y. Toledano, Sc.D.;
Robert N. Wolfson, M.D., Ph.D.
"For the record, these people are special
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 9/322
government employees and are consultants to this
panel. They have undergone the customary conflict-of-
interest review, and they have reviewed the material
to be considered at this meeting."
This is signed by David W. Feigal, Jr.,
M.D., M.P.H. He is the Director for the Center for
Devices and Radiological Health, and it is dated April
18th, 2002.
Now I will read the conflict-of-interest
in for the record. "The following announcement
addresses conflict-of-interest issues associated with
this meeting and is made a part of the record to
preclude even the appearance of an impropriety.
"To determine if any conflict existed, the
agency reviewed the submitted agenda for this meeting
and all financial interests reported by the Committee
participants. The conflict-of-interest statutes
prohibit special government employees from
participating in matters that could affect their or
their employer's financial interests. However, the
agency has determined that the participation of
certain members and consultants, the need for whose
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 10/322
services outweighs the potential conflict-of-interest
involved, is in the best interest of the government.
"Therefore, a waiver under 18 USC
208(b)(3) has been granted to Dr. Richard Ringel for
his stockholding, between $5,001 to $25,000, in the
parent of a competing technology firm. The waiver
allows this individual to participate fully in today's
deliberations. Copies of this waiver may be obtained
by submitting a written request to the agency's
Freedom of Information Office, Room 12A-15 of the
Parklawn Building.
"We would like to note for the record that
the agency took into consideration certain matters
regarding other panelists. Drs. Gary Eglinton,
Michael Neuman, and Robert Wolfson reported current or
previous interest with firms at issue, but in matters
not related to today's agenda. The agency has
determined, therefore, that they may fully participate
in the panel's deliberations.
"In the event that the discussions involve
any other products or firms not already on the agenda
for which an FDA participant has a financial interest,
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 11/322
the participant should excuse him or herself from such
involvement, and the exclusion will be noted for the
record.
"With respect to all other participants,
we ask in the interest of fairness that all persons
making statements or presentations disclose any
current or previous financial involvement with any
firm whose products they may wish to comment on."
There will be transcripts and videos
available for today's meeting, and if there are any
presenters to the panel who have not already done so,
they should provide FDA with a hard copy of their
remarks, including overheads.
Kathy Daws-Kopp -- would you please stand?
-- will collect these from you at the podium. Thank
you.
CHAIRMAN BLANCO: Thank you.
It's a pleasure for me to introduce Colin
Pollard, Chief of the Obstetrics and Gynecological
Devices Branch, who will make some introductory
remarks.
Colin?
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 12/322
MR. POLLARD: Thank you, Dr. Blanco.
First of all, I want to welcome the panel.
We've got a few new faces, and we really appreciate
the time and trouble you all went to be here, and
especially for the new panel members, the training
that you went through yesterday and this morning.
I would also like to welcome the sponsor,
who has had to travel quite a distance to be here
today.
Before we get into today's agenda, I would
like to go over a few things with you. Since our last
panel meeting, FDA has approved two PMAs. In
September we approved the Novasure Endometrial
Ablation System. This is the fourth such device of
this type. As we get more experience with that, it's
less and less likely that we bring PMAs of this sort
before you, unless it's something new and different, a
new energy mode or some new safety issue, or something
like that.
Just last month, we approved the Lea's
Shield, which is vaginal barrier contraceptive device.
As Joyce just mentioned, we've got two
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 13/322
panel meetings scheduled for the remainder of the
year: July 22nd-23rd and October 21st-22nd. It's
quite possible we will use both of those dates, but
we'll see what the agenda holds for us.
I would like to talk a little bit about
post-approval studies. First of all the purpose of a
post-approval study, it needs to be understood that
there's already, before you even get into the post-
approval study, the determination on the part of FDA
that a reasonable assurance of safety and
effectiveness has already been established. However,
the post-approval studies may address either long-term
events or rare events. If the PMA was based, if the
pivot study supporting the PMA was based on surrogate
endpoints that FDA thought were reasonable, a post-
approval study might be done to validate those
endpoints or a post-approval study might answer
specific panel concerns.
I mention this because at our meeting in
July our Office of Post-Market Surveillance is
planning to give a presentation, and it is going to go
over a number of post-market activities that FDA
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 14/322
engages in, including an update on post-approval
studies.
Today we're going to bring before you a
PMA, which you have had a chance to review already,
for the STAN S21 Fetal Heart Monitor submitted by
Neoventa Medical. I just wanted to give a few remarks
about that.
First of all, this falls generally in the
category of electronic fetal monitors, and I would
just like to highlight that most electronic fetal
monitors are Class II devices and get to the market
through the 510(k) pre-market notification process
where the sponsor would show that they're
substantially equivalent to a monitor that's already
on the market.
However, if there is a new feature for
that fetal monitor, one that we believe has
significant implications, in that case we would
require a PMA. In the case of the PMA before you
today, we felt that the use of the fetal ECG waveform
in this monitor, the special analysis to identify ST
events, and the claims that it would improve
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 15/322
assessment, we felt that, when all taken together,
that this was something that required a PMA.
Just real briefly -- you have this in your
PMA -- the intended use of the STAN monitor is to use
the fetal ECG analysis with the cardiotocography to
obtain information on the impact of labor on the
fetus, and that is intended to improve the assessment
of fetal condition during labor. I'm not going to go
through all the indications for use that are listed in
the PMA, but it represents a fairly broad approach.
It's intended for use on a singleton fetus in the
vertex presentation with greater than or equal to 36
weeks gestation.
Real briefly, I know we went over this
yesterday for the new panel members, and I just remind
the more experienced panel members, the regulatory
framework for PMA reviews. I want to highlight three
elements: valid scientific evidence, safety, and
effectiveness.
With respect to valid scientific evidence,
FDA is given quite a bit of latitude has to what to
recognize for a given product, for a given intended
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 16/322
use, everything from well-controlled clinical studies,
partially-controlled studies, all the way to even
reports of significant human history.
Our assessment of safety -- in fact, this
must be based on valid scientific evidence. In the
case of safety, we must make a determination that the
benefits outweigh the probable risks, and for
effectiveness ultimately that the studies must have
shown a clinically-significant result when used for
the intended population and used the way it is
supposed to be used.
Joyce and Jorge are going to go over this
with you later, but your recommendation, which we
consider very seriously in the context of our making
our decision, should come in the form of a
recommendation, a panel recommendation, that would
take the form of one of those three aspects, either an
approval, a full approval, an approval with
conditions, or not approvable.
So, finally, our agenda, we are going to
hear first from the sponsor. After the open public
hearing, FDA reviewers will present their findings,
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 17/322
and you will have an opportunity to discuss this, hear
more from the sponsor and audience before you engage
in the questions that we've prepared for you.
Thank you, Dr. Blanco.
CHAIRMAN BLANCO: Thank you, Mr. Pollard.
The next item on our agenda is the open
public hearing. We have one speaker signed up to
present before the panel, Dr. Raul Artal, Vice
Chairman, ACOG OB Practice Committee.
Is there anyone, before Dr. Artal
addresses the panel, is there anyone else who would
like to participate in the open public forum at this
time?
(No response.)
All right, thank you.
Dr. Artal?
DR. ARTAL: Good morning. Dr. Blanco,
members of the panel, ladies and gentlemen, thank you
for giving me the opportunity to represent --
CHAIRMAN BLANCO: I'm sorry, Dr. Artel.
Can we start by stating your name, your relationship,
and whether you have any conflict of interest, and
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 18/322
then go ahead with your presentation? I apologize for
interrupting you.
DR. ARTAL: No, thank you. I appreciate
this. Thank you very much.
My name is Raul Artal. I'm currently the
Vice Chair of ACOG's Committee on Obstetric Practice.
I'm also the Professor and Chairman of the Department
of Obstetrics, Gynecology and Women's Health at St.
Louis University. I do not currently have any
conflicts of interest with this device or any current
device that is being considered by this panel.
CHAIRMAN BLANCO: I think you have a
conflict of interest with a computer, though, the way
they're working on them.
(Laughter.)
DR. ARTAL: Yes, well, I'm all prepared,
Mr. Chairman, for this eventuality, too.
(Laughter.)
CHAIRMAN BLANCO: Thank you. Go ahead.
DR. ARTAL: Thank you. Again, thank you
for giving me the opportunity to represent ACOG here
today.
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 19/322
The charge of the ACOG's Committee on
Obstetric Practice is to provide the ACOG membership
with objective, valid, scientific evidence and
guidelines for current practice, as well as existing
and emerging technology.
As to the device that is being considered
today by the panel, we had the opportunity to review
the following documents: The Summary of Safety and
Effectiveness Data of Neoventa Medical, the
publication listed in the summary, the detailed
analysis of the Amer-Wahlin, et al., the Swedish
randomized control trial, as published in the Lancet,
August 2001, and we also had the opportunity to review
a presentation of the lead author, Professor Rosen, at
the International Perinatal Society in Barcelona last
October.
The ACOG Committee on Obstetric Practice
bases its opinions on the fundamental principles of
evidence-based medicine. The extent of the evidence,
the benefits versus risks, patients' inconvenience,
cost, and patients' values.
As to the study presented and the adequacy
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 20/322
of the study design, the experimental study design was
considered to be appropriate for evaluating the
efficacy of cardiotocography plus ST analysis versus
cardiotocography only for intrapartum fetal
monitoring. However, questions remain about the
device's ability to detect either metabolic acidosis
or hypoxia, and certain improvements in future
validation studies will be required.
One concern about the study design is
that, while the main outcome variable was metabolic
acidosis at birth, very few contemporaneous fetal
blood scalp sampling determinations were conducted on
fetuses affected by metabolic acidosis. The overall
rate of fetal acidosis acidemia reported in these
studies was significantly -- significantly -- lower
than the one reported in our country.
In terms of adequacy of the materials,
methods, and procedures, the methods for identifying
eligible study participants, randomizing participants,
training clinicians to use the CTG or CTG plus ST,
gathering baseline, and follow-up measurements, and
analyzing the data are appropriate and clearly
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 21/322
described in the materials submitted.
However, I have to again emphasize the
overall very low incidence or rate of fetal acidemia,
significantly lower than in this country.
No data is provided to determine false
positives and false negatives for the proposed method
to detect metabolic acidosis/hypoxia, such as
physiologic events, environmental factors, fetal
positioning, and so on. None of this has been
reported in the analyses.
ST segment deviations are known to be
caused by the following events: injury to the cardiac
muscle or ischemia, changes in the synchronization of
ventricular muscle depolarization, overload or strain
on ventricular muscle, drug or electrolyte influences,
and certainly could be observed also as a normal
physiological variant. It is this particular thing
that we have not seen any data reported in these
reports. Particularly, it's known that nested segment
deviation can appear as a normal physiological variant
during stressful events. In the studies completed and
data presented, have these factors been considered?
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 22/322
Other things of concern to the ACOG
Practice Committee was that, as reported on page 536
of the Lancet article, second column, first paragraph,
the interim analysis revealed protocol violations in
which the recommendations to intervene were
disregarded, and babies with cord arterial metabolic
acidosis were born. Indeed, the protocol violation
occurred in both arms of the trial, it appears. What
percentage of births were affected in each arm?
In terms of accuracy of interpretation of
the results, the results as presented in the tables
and text material reviewed are presented very clearly.
However, what is the sensitivity and specificity of
the CRT ST for detecting cord artery metabolic
acidosis or hypoxia? And more important, what is the
likelihood ratio?
Nowadays, for an evaluation of a
diagnostic or a screening test, likelihood ratio is
the appropriate effect size to describe the
performance of the test. So what is the likelihood
ratio?
In summary, we urge the panel to clarify
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 23/322
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 24/322
We'll open it up once again, if there's
any other members of the public who would like to
address the panel at this point.
(No response.)
Okay, not seeing anyone, we will move on
to the next item on the agenda. The next item on the
agenda is the presentation by the sponsor, and I
believe Professor Karl Rosen is going to begin the
presentation.
DR. ROSEN: Mr. Chairman, members of the
panel, ladies and gentlemen, my name is Professor Karl
Rosen. I'm a pediatrician/perinatal physiologist. I
am currently Medical Director of Neoventa Medical,
where I hold shares.
What I would like to start is to present
the way we can detect hypoxia during labor, but also
touch on the dissemination of knowledge as we see it
with the research we are doing currently in Europe. I
will be followed by Professor Ingemar Kjellmar, who
will present the current perinatal level of care in
Sweden, and then Professor Karel Marsal will draw
parallel observations with regard to the U.S. and
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 25/322
Swedish obstetric care, and Professor Lawrence Devoe
will follow with comparing or addressing the current
issue in the U.S.
Now to start this, we could look at a case
which is a term delivery where there's been ruptured
membranes for three days, induction. On the upper
part you see the heart rate trace, uterine activity,
and here you have something called the T/QRS ratio.
This is now the height of the T wave related to that
of the QRS. These are ECG complexes recorded from the
fetal scalp electrode. We could have a look at events
as they emerged in the heart rate trace as well as in
the ST with this case.
So we move forward. A baseline heart rate
of roughly 160 beats per minute. The mother has an
increased temperature. She's been given Parasetimol.
Still no ST events, and heart rate now in still first-
stage labor is constant with a tachycardia reactivity.
As we now start to enter the end of first
stage and approaching active pushing in the second
stage, deceleration starts to emerge, and with that we
have a first ST event, which is now the baseline rise
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 26/322
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 27/322
but the outcome seems to be good.
And this you are here to discuss is really
what happens when things like these emerge, and where
we know that there is sometimes some uncertainty about
how to interpret the heart rate rates, and where we
are looking for additional information now contained
in the ST wave form of the fetal ECG. But, at the
same time, to have a system that presents to everyone
what actually is taking place, so that delay factors
are avoided as much as possible.
So what we aim for is to identify fetuses
as risks of an adverse outcome, based on our
understanding of the path of physiology involved. We
know labor is a stress, and we know also that Nature
has provided the fetus with very good resources to
manage labor. Most fetuses are untroubled, although
we may find a lot of heart rate changes. Some are
troubled somewhat but managing and compensating fully,
in no immediate danger. But then there are a few
that's more troubled and forced to utilize key
resources in an attempt to compensate, and some may
not even be able to fully compensate, and we need to
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 28/322
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 29/322
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 30/322
know that the ST interval represents the time of
repolarization of the myocardium. This is now where
energy is required. The ion membrane pumps are
working hard, and metabolic events occur. So in case
of hypoxia, well, this is where we expect changes to
be seen.
Now then we need to quantify these
changes. As you noticed, there were marked peak T
waves. So we could look at the amplitude of the T
wave and relate it to that of the QRS. QRS, well,
that's a passive electrophysiological event, and its
QRS amplitude basically stays the same from the first
through the last heart beat. So by taking the ratio
of T/QRS, in this case in the normal, 5 versus 50, a
ratio of .10; then during hypoxia, 10 versus 50, so
the ratio increases to .20. We have a measure that we
can record and use.
Now the animal work that we have
conducted, starting in the seventies, initially were
observations on hemodynamic cerebral metabolic
function during experimental hypoxia, but also in
spontaneous labor in association with intrauterine
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 31/322
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 32/322
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 33/322
signal, allowing us to assess the specific components
of the fetal ECG.
So then the need for extractive clinical
work. In the eighties, observation started and
technological developments. In the nineties, we saw
the Plymouth randomized trial, fostering further
technological developments, verified in the EU
Observational Multi-Center Study, Nordic Observational
Multi-Center Study, with sensitivity/specificity
figures calculated, and you have then the Swedish
randomized trial, and currently the ongoing EU project
looking at the clinical implementation phase, being
equally important.
So if we look at the Plymouth randomized
trial, that was targeted to show safe reduction in
operative interventions for fetal distress, which was
achieved with almost 50 percent reduction for
operative deliveries for non-reassuring fetal status
with no increase for failure to progress.
If we look at the outcome, comparing the
heart rate only with the heart rate plus ST, meaning
in the STAN, the baby's outcome, whatever parameter we
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 34/322
choose, showed signs of improvements. If you take
metabolic acidosis, this didn't become significant
almost, but there were three cases in the STAN arm.
They had ST events, but they were not recognized. So
we saw the need to refine the technology with further
digital signal processing and automatic ST analysis.
Because we had the basic physiological
findings now verified in a large, randomized,
controlled trial, meaning that an ST rise, that is a
fetus responding to hypoxia, and biphasic ST, meaning
a fetus not fully capable of responding or has not had
the time to respond.
So we didn't want to change this approach
with a standard fetal scalp electrode and maternal
thigh electrode. We wanted to have a clear, nice
signal to work with. So we needed to develop the
computer, the digital signal processing, the software
engineering required, and, in particular, establish
what we call the ST log event log, automatic
identification of ST events, like in this case for its
1 centimeter a minute, but it is the only one showing
that, where you have a heart rate with a varietal
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 35/322
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 36/322
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 37/322
well, you had better be able to trust the data, then
perhaps the computer. So the user is taught how to
use the data also, regardless of what the computer is
saying.
Looking at the specificity issue here, I
want to use different ways to assess that, but the
positive predictive value is sometimes useful. We can
now look at how the STAN versus heart rate performs
with regard to different cutoffs in cord artery pH.
If we take the cutoff of 7.15, well, in 80 percent of
the cases where there are ST indications to intervene,
the cord artery pH was less than 7.15, whereas we had
a heart rate only in 43 percent of the cases. And
there were significant improvements, regardless of
what cutoff you choose. When it comes to sensitivity,
well, if we have metabolic acidosis, in this study of
573 cases, we did identify all of this.
So we take this forward now to the second
randomized trial, this one being multi-center in
Sweden, Gothenburg, Lund, and Malmo. These are all
large maternity unit, university departments with
between 3,000 and 4,000 deliveries. We have among us
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 38/322
here today Hakan Noren, Ingemar Kjellmer, and Karel
Marsal, being part of this study.
As you may notice, perinatal mortality
figures are reasonably low. Obviously, these are
tertiary referral centers, so they would have a little
bit higher perinatal mortality figures. If you look
at Caesarian section rates, you will find those vary,
as they would do between different centers, depending
on the culture of electronic fetal monitoring.
The objective of the study was to show a
reduction in number of newborns born with cord artery
metabolic acidosis by at least 50 percent. We
identified pH of less than 7.05 base deficit,
extracellular fluid greater than 12. Now this is not
a situation where the baby is severely affected.
Eighty percent of those had perfect normal outcome
innately. But this is a marker of an ongoing
anaerobic metabolism, and these are cases that need to
be discussed and identified.
While doing that we did not want to see an
increase in the rate of operative deliveries, but
rather a significant reduction without any increase
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 39/322
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 40/322
forcing an intervention, emergency C-section with a
normal outcome.
So we look at the clinical management of
these. The control group, they were managed according
to the standard practice, FIGO Guidelines for
interpreting the heart rate, allowing for fetal blood
sampling, and that practice varied between the
different centers somewhat. Obviously, if there was a
low cord arterial fetal blood sample, intervention was
required, as recommended.
You've seen the STAN guidelines, and just
to summarize those once again, in a case of pre-
terminal fetal heart rate, immediate delivery
regardless of ST; normal fetal heart rate, no
intervention regardless of ST.
In the interim analysis we found that in
the STAN arm there were deviations from the clinical
management guidelines, in that six babies had
metabolic acidosis with STAN changes and clear
indications to do something. When you discuss these
cases, well, the clinicians thought perhaps that
wasn't that much of a heart rate change, so they still
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 41/322
carried on as they were used to.
That focused an issue of repeated
training, which meant continuing case discussions,
because now we had samples from their own labor ward
settings. So we can bring those forward and show how
the ST information would affect the clinical
assessment in a neutral fashion.
Just to illustrate one of those cases, you
have a heart rate showing a somewhat increased
baseline, and then the deceleration, but good
maintained heart rate variability, and you find an ST
rise with a lot here stating a need for intervention,
but that wasn't a lot for a normal vagina delivery,
and you have a baby born 30 minutes later with a cord
artery metabolic acidosis.
So if we look at the characteristics of
this child, we find that there was more prima gravida,
more post-term cases. The epidural analgesia varies a
bit, but a lot with oxytocin augmentation. So,
clearly, a need for further information during active
labor.
Now when you develop a technology, you set
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 42/322
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 43/322
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 44/322
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 45/322
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. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 46/322
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 47/322
we should look at deficiencies of that technology as
well. Among those 46 cases of metabolic acidosis
there were 15, now also including the control and the
STAN arm, where while there weren't any ST log
statements, 6 of those, yes, there was some reduction
in signal quality, but the ST changes were clearly
visually there. Sometimes they just emerge 10
minutes, 15 minutes, before delivering, in which case
there's not enough time for the computer to tell.
Then there are some in the control arm, in
particular, where there is also poor signal quality
that you couldn't do any ST analysis. But then there
are some where, yes, there are heart rate changes, but
they either regard them as not significant second-
stage events, perfectly healthy, vigorous newborn, and
we say, well, perhaps these are not that significant,
and sometimes you may not have data for the last 10
minutes, for instance, in which case, particularly on
metabolic acidosis, could emerge. But then in one
case, which was a case that died, Streptococci
septicemia, that had a pre-terminal heart rate trace,
and we know that these cases they are rare, but they
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 48/322
will not display ST events.
Another way of analyzing data here,
looking at potential deviations: 5,000 cases managed
by 300 obstetricians/midwives. So there are 46 cases
of metabolic acidosis, 8 in the STAN arm, you might
say potential deviations, 8 in the control arm, and we
can look at these. So we have in the STAN arm cases
where we say, well, in this case no deviations.
Because there were ST events, an action was done,
normal neonatal outcome, a bit of metabolic acidosis,
but that we would expect.
Then there are those where deviations,
probably ST events, no, but at the same time not that
much of a heart rate change, normal neonatal outcome.
But then, clearly, there are those where deviations
occur where we have ST events that were missed, and
these are the ones in the initial phase of the trial,
apart from this last trace that I showed you, the baby
that died with a vacuum and lack of data over the last
24 minutes.
If we look the situation in the control
arm, these are eight cases. There were some cases
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 49/322
where we can say, well, on the basis of heart rate
interpretation, there might not have been any
deviations. There were intermediary fetal heart rate
patterns, but then these got to ST events, and I
believe that is a significant observation, in that if
we add ST, we focus on the heart rate change that
emerged. Then we become more accurate in assessing
the heart rate and reducing the risk of an adverse
outcome. Clearly, there were those where there were
deviations from the standards of clinical practice and
a case, obviously, of no signals, then that's clearly
another cause of deviation.
So we can compare two randomized trials,
the Plymouth, the Swedish, and you'll find
similarities, perhaps a little bit more aggressive on
the reduction of operative deliveries, fetal distress
in the Plymouth trial. But if you look at metabolic
acidosis, the figures look identical.
So what to do next? Well, we have learned
a lot of experience, so we want to disseminate this
knowledge, focusing on education, training, use and
certification, quality control, using cord acid base
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 50/322
as routine, neonatal data, index cases, metabolic
acidosis. Take this up for discussion, provide
feedback, expert assessment.
This is now an EU-supported project,
initially with 10 Centers of Excellence. These are
all academic units across Europe, currently being 22,
who are becoming expert learning their own experience
and providing service to their regions in training,
education, and followup.
The aim is obviously to improve the
understanding during labor and to document consistent
improvements, based on the STAN monitor and a
dedicated teaching/training package. This, I believe,
is important, if we have in our database more than
10,000 cases that we can use in a sort of similar
environment to our STAN use, to our own experience,
before being exposed to real-life cases.
So now we can look at the experience from
STAN being used in routine obstetrics care. This is
now the City of Gothenburg, 16 months' experience. In
September eight STAN monitors were introduced, and
these are the rates of usage per month, covering this
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 51/322
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 52/322
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 53/322
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 54/322
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 55/322
in the national statistics. About 12 percent of the
mothers are immigrant mothers. In the three cities
taking part in the randomized control trial,
Gothenburg, Malmo, and Lund, the immigrant mothers are
around 20 percent, and they come mainly from the
Middle East, from Africa, and from former Yugoslavia.
Since we are talking about fetal
surveillance in term fetuses, the term perinatal
mortality rate, based on the two-year material, is 2.6
per thousand with very low rates of intrapartum death.
We have, since 1972, national guidelines
for resuscitation for asphyxiated babies. This is the
latest pamphlet from 1997 that is widely disseminated
among midwives, obstetricians, neonatalogists.
Now with a country where part is very
sparsely populated, one needs to have a program of
regionalization. This slide I have included to
demonstrate that we do have such a program. The
delivery hospital level refers to the equipment and
the staffing of the hospital. The hospital in the
Category 1 are the very small, rural hospitals with
obstetrics service only, no neonatal service. The
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 56/322
Category 2, the district hospitals with daytime
neonatal service. The Category 4 are the big regional
centers, and the Category 5 are the big university
centers that are fully equipped.
As you see from the first recordings, this
is material covering 12 years of deliveries in the
country, about 1.5 million deliveries, about 9,000
stillborn and neonatally dead babies. You see the
expected progression of the risk for cases accumulated
in the grade 4 and 5 hospitals. These are odds
ratios. You see that this is particularly effective
in cases where you can foresee the events such as
maternal disease and fetal disease, where there is
clear-cut gradient from the poorly equipped to the
very well-equipped hospitals.
But for conditions that are difficult to
foresee, such as obstetrical complications and
asphyxia in labor, the regionalization program
apparently is not enough to rid the smaller hospital
of these problems.
This slide demonstrates one often-
discussed final outcome variable when it comes to
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 57/322
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 58/322
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 59/322
between the use of fetal monitoring in labor in the
United States and in Sweden. I never worked as an
obstetrician in the United States, so I based my
information on the published statements and
recommendations from the American College of
Obstetrics and Gynecology and on my contacts with
American colleagues.
If you look at the staff providing during
labor in the United States, this is done primarily by
obstetricians. In uncomplicated pregnancies and
labors, the midwives are also involved. In Sweden, by
recommendation of the Ministry of Health, the
uncomplicated labors and deliveries are conducted
independently by midwives. It's their task to
recognize deviation from normality and to call upon
obstetricians who in that case will take over
responsibility for these patients. The complicated
pregnancies and the complicated labors and deliveries
are being conducted by obstetricians.
I mentioned the technical bulletin
published by the American College of Obstetricians and
Gynecology, the recommendation on the fetal monitoring
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 60/322
during labor. In Sweden the Swedish National Board of
Health and Welfare published in their database of
medical facts recommendations for the clinical
management of uncomplicated labors. It includes the
use of fetal monitoring. In addition, there are two
reference books which are used by all obstetricians
and midwives in Sweden, and there is rather big
consensus with regard to the use of the fetal
monitoring in labor.
Looking at the definitions of hypoxemia,
hypoxia, and asphyxia, I have found that these are
identical in both countries. The fetal heart rate
evaluation during labor is recommended for all
patients both in the United States and in Sweden.
In pregnancies with absence of risk
factors, auscultation is accepted as the only way of
fetal monitoring both in the United States and Sweden.
However, more and more often the electronic fetal
monitoring is applied also in the low-risk
pregnancies.
In the United States, one-to-one nurse-to-
patient ratio is recommended in the cases of
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 61/322
auscultation. In Sweden the ratio is about one to two
or three patients.
During the active phase of the first
stage, the control of fetal heart rate is recommended
in this stage at least every 30 minutes after a
contraction, and during the second stage at least
every 15 minutes. In cases with risk factors present,
the frequency of recommended controls is higher, risk
control every 15 minutes during the first stage and
every 5 minutes during the second stage.
In Sweden, during the active stage of the
first stage of uncomplicated pregnancy and labor,
auscultation for a minimum of 15 seconds every 15
minutes after a contraction is recommended, and during
the second stage with active pushing after each
contraction.
The electronic fetal heart rate monitoring
is performed using the commercial monitors of similar
makes both in the United States and Sweden. There is
a difference in the speed, which is 3 centimeters per
minute in the United States and 1 centimeter per
minute in Sweden. Also, the heart rate scale differs,
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 62/322
being 30 to 240 beats per minute in the United States
and 50 to 210 beats per minute.
The recommendations for the use of scalp
electrodes as been mentioned in Professor Rosen's
description of the Swedish study, and these
recommendations are practical identical in both
countries. The documentation, either as a paper strip
or electronically, is also similar in both countries.
The absence of risk factors, when using
electronic fetal monitoring, the elevation of the
heart rate is recommended in the United States every
15 minutes during this first stage and every 5 minutes
during the second stage. In Sweden, practically all
pregnant women admitted to the labor ward are using
the admission test, the recording of the heart rate
for 15 to 20 minutes. Afterwards, in those
uncomplicated cases, intermittent recording is done
every two to three hours and, alternately,
auscultation may be used. During the second stage a
continuous recording of the heart rate is recommended
during the pushing stage.
In cases with risk factors present, the
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 63/322
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 64/322
blood sample for the pH, and if indicated, to perform
operative intervention. The operative interventions
used are emergency Caesarian section or the
instrumental vaginal delivery, comprising both forceps
and/or vacuum extraction. These indications are
identical in both countries.
So, to summarize, after looking on these
similarities or differences in the use of fetal
monitoring during labor, I came to the conclusion that
the United States and Swedish national guidelines are
very similar, including even liberal use of electronic
monitoring in normal pregnancies.
Thank you for your attention.
CHAIRMAN BLANCO: Thank you.
DR. DEVOE: By way of introduction, I am
Dr. Lawrence Devoe. I'm Professor and Chairman of
Obstetrics and Gynecology at the Medical College of
Georgia. I'm also a consultant for Neoventa, who paid
for my expenses and travel to attend this meeting.
I would like to kindly thank the panel and
its Chairman for their attention for the remarks that
I am about to make, which deal with the issue of where
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 65/322
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 66/322
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 67/322
nonrandomized trials? The answers to that I think are
very obvious. The early nonrandomized control trials
had less antepartal screening and, consequently, fewer
compromised babies were excluded from labor.
The care in randomized control groups is
very intense, featuring to one-to-one bedside nursing
care, and in turn, during the period in which these
randomized control trials evolved, the neonatal
intensive care unit performance improved.
Consequently, there were fewer neonatal deaths and
much larger groups than those included in almost all
the trials would have been needed.
There are three issues that really affect
the performance of electronic fetal monitoring today
in the United States. These are well-known. They are
the issues of observer reliability and
reproducibility, the issues of fetal heart rate
interpretation per se and its clinical correlates, and
the use of ancillary assessment methods.
As far as the first issue, many studies
have already shown wide ranges of intra- and inter-
observer agreement, and the lack of observer
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 68/322
reliability applies to visual and auditory
identification of fetal heart rate patterns. This is
a summation of best-case studies which is inter-
observer studies simply featuring the same tracings
being presented to individual observers at different
times and showing that cap levels of agreement vary
widely, but definitely fall far short of the gold
standard of 1.0.
Things are clearly much worse when one
gets to the inter-observer agreement, and the
parameters of fetal heart rate baseline, such as rate,
accelerations, decelerations, and variability, all
degrade as more observers are brought into the mix.
The reliability of fetal heart rate
assessment also decreases as you ask the observer to
discriminate more different types of patterns or
categories. In fact, even applying a standard
criteria with standard terminology to visual
inspection may not improve reliability or agreement.
The targets for electronic fetal
monitoring are to make some assessment of fetal
oxygenation and acid-base balance, as well as try to
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 69/322
predict cases in which these are disturbed, and
endpoints have been used such as scalp or cord blood
gases in neonatal outcomes, as you have already heard.
Going back, in fact, as early as the late
1960s, it became very obvious that certain patterns of
fetal heart rate monitoring tended to be more closely
associated with lower pH values, and these
particularly were persistent, severe, variable, or
late decelerations.
But we look at two retrospective studies
which were published in the 1980s. Both of these
identified that the main significant alteration in the
fetal heart rate tracing, when examined visually, was
the occurrence of late decelerations which was
associated with an increased risk for metabolic
acidosis in the study published by Low, and also an
earlier occurrence of decreased fetal pH in a study
published by Fleischer in the same time period.
As far as pathophysiologic correlates of
intrapartal fetal heart rate patterns, there have been
numerous retrospective and few prospective studies
that have ensued in the last 20 years with limited
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 70/322
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 71/322
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 72/322
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 73/322
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 74/322
linkage with adverse CNS outcomes, and to determine
whether the causal relationship between fetal heart
rate outcomes could, in fact, be affected by
interventions using fetal heart rate interpretation as
a clinical guide.
It came to four main conclusions: that no
consensus on strict guidelines for management using
fetal heart rate patterns alone could really be
recommended until evidence-based algorithms could be
developed.
Secondly, that normal fetal heart rate
patterns do exist, that they confer high likelihoods
of well-oxygenated fetuses at the time of observation.
Third, there are several patterns that
predict current or impending fetal asphyxia with
increased risk of injury to the neurologic system or
death.
Fourth, there are many fetuses, possibly
as many as 30 to 40 percent of those being monitored,
that fall between these extremes, and this group would
experience the most benefit from the results of the
recommended research.
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 75/322
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 76/322
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 77/322
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 78/322
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 79/322
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 80/322
Computerized processing of raw fetal heart
rate data might be able to improve point No. 2, but
still by itself gives a limited picture of fetal
adaptation.
And, finally, FECG analysis moves one step
closer to the intrapartum fetal adaptive or
maladaptive responses when hypoxia is present.
Thank you very much.
CHAIRMAN BLANCO: Thank you, Dr. Devoe.
Anything else, Dr. Rosen?
DR. ROSEN: I'm fine with this
presentation, and thank you very much for your
attention. Thank you.
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
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 81/322
go ahead and reconvene?
I think that we will start at this point
with presentation by the FDA, and I believe that Ms.
Daws-Kopp will be starting the presentation.
MS. DAWS-KOPP: Hi. Good morning, ladies
and gentlemen, distinguished panel members, and
guests. I'm Kathy Daws-Kopp, the lead reviewer for
FDA on this PMA, and I'm here to give you a brief
overview of the review process we've gone through on
the PMA.
This is a PMA for a specialized perinatal
monitor that includes a feature for ST analysis of the
fetal ECG.
First, I would like to acknowledge the
review team. As you can see, a number of people have
been involved in the review of this PMA application in
the areas of clinical, statistical, epidemiology,
software, hardware, fire research, monitoring, and
manufacturing.
Before I go over our efforts in review of
this file, I am going to give a brief overview of our
interactions with the company leading up to the PMA
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 82/322
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 83/322
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 84/322
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 85/322
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 86/322
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. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 87/322
guidance on management of data gaps such as advising
the user to reapply the fetal ECG electrode or to do a
manual assessment of the ECG complex, that is, to
estimate the T/QRS ratio by eye. We haven't finished
this review and will work with the sponsor and expect
that we will obtain the descriptive information and
test data we need.
I would also like to mention another
aspect of signal quality because it relates to the
analysis of the data for primary and secondary
endpoints. Analysis II, which Dr. Corrado will
discuss in her talk, excluded cases that did not meet
the sponsor's requirement for adequate recordings.
The database includes reasons why specific cases did
not meet these clinically-based criteria. A large
portion of these excluded cases, about 42 percent,
were to attributable to signal or technical problems.
As mentioned in my last example, our
hardware and software reviews are ongoing. We
currently have some information from the sponsor that
describes the device design requirements and
verification/validation. As I outlined in my previous
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 88/322
slide, we don't have as many details about the design
of components, features, and algorithms for the device
as we would like to answer all of our questions about
how the device works. Likewise, we would like further
information on verification and/or validation testing
that was done to confirm performance issues that may
not come out in the clinical testing. We are still in
the process of describing our needs in this area to
the sponsor.
Bioresearch monitoring and manufacturing
reviews are also still ongoing. The inspections in
Sweden have not yet been scheduled. We will continue
to work with the sponsor on these issues.
Now I will turn the floor over to Julia to
discuss clinical and statistical findings of our
review.
CHAIRMAN BLANCO: Thank you.
DR. CORRADO: Thank you, Kathy. Good
morning, everybody.
As we all know by now, the subject of this
PMA is the STAN fetal ECG monitor, and its use is that
of fetal ECG analysis and that includes standard fetal
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 89/322
heart rate plus ST waveform data to obtain information
on the impact of labor on the fetus, to evaluate the
status of the fetus during labor.
The sponsor's proposed indication for use
is for a term fetus in vertex presentation who is a
singleton, and there are additional criteria, all of
which contribute to an indication for fetal scalp
electrode monitoring.
I'm going to cover the following subjects
during my presentation. I'm going to emphasize the
results of the Swedish randomized controlled trial.
I'm going to talk about clinical issues that arose
during our review of this trial, and then I'm going to
summarize some other clinical experience with the STAN
monitor in European countries, and then try to bring
us to focus on the questions FDA has identified for
the panel.
Very briefly, as Dr. Rosen indicated,
there have been multiple studies of the STAN monitor
in European countries. The Plymouth study was in
England. There was a multi-country trial called the
Fetal ECG Analysis During Labor Trial that was
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 90/322
relatively small. There was then the larger Nordic
Observation Multi-Center Trial. The Swedish RCT is
what we're going to be talking about, and then there
are data from the City of Gothenburg, which she has
summarized and I will summarize very briefly as well.
I am afraid that I accidentally hit the
"end" button. Sorry. I'm sorry. I'll be real
careful not to press that "end" button there.
Finally, I wanted to highlight that
there's an ongoing study that is sponsored the
European Union. It involves obstetrical units in 10
different countries, and the primary focus is the
training and clinical results from a Center of
Excellence and dissemination of knowledge program.
So the point I've just tried to make with
the last couple of slides is, although we're going to
be focusing on the results of the Swedish RCT, there
is a very large body of data from this device that has
been accumulated over the last 10 years, clinical
data.
One of the reasons that we focused on the
Swedish RCT is that we felt that it met the criteria
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 91/322
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 92/322
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 93/322
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 94/322
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 95/322
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 96/322
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 97/322
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 98/322
We don't know the cause of this. We,
nevertheless, thought it was interesting to note that
for some reason that excluded population seemed to
relatively concentrate those subjects who went on to
C-section for fetal distress.
We, at this time, would just like to point
out possible significance of the definition of
metabolic acidosis in this study. The sponsor's
prospectively defined criteria were a pH less than
7.05 and a base deficit of greater than 12. This was
established prior to the carrying out of the study.
So this was an entirely prospective definition.
We thought it would be interesting to
stratify the results for different pH cutoffs, for
example, ACOG in a 1995 technical bulletin described
the pH of less than 7.00 as possibly being significant
with respect to fetal hypoxia. When you look at the
differences between the STAN arm and the control arm
at that pH level, 7.00, you see that the differences
between the two arms are less impressive. For the
7.05 cutoff, it was 15 and 30 versus 31 in the control
arm; for the pH cutoff of 7.00 the numbers were 11 and
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 99/322
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 100/322
most clinically-relevant here. It is very easy to see
that there were no cases of modern encephalopathy in
the STAN arm of the study.
I again want to point out that I'm making
a distinction here between babies who had confirmed
metabolic acidosis and babies who either did not have
metabolic acidosis or the cord blood data just weren't
adequate to confirm metabolic acidosis.
In the control arm there were three
infants who had confirmed metabolic acidosis plus
moderate encephalopathy. There was one additional
infant in the control arm who had modern
encephalopathy, but the cord artery data were not
available. So we don't know whether or not that
encephalopathy occurred in conjunction with metabolic
acidosis. So there is a difference in these two arms
of the study for modern encephalopathy. It was zero
in the STAN arm and 4 in the control arm.
Regarding severe encephalopathy, there
were three cases in the control arm of severe
encephalopathy. There were none in the STAN arm. I
think it's important to note, with regard to severe
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 101/322
encephalopathy, that none of those cases in the
control arm had confirmed metabolic acidosis. As a
matter of fact, two of the cases had evaluable cord
blood and those infants did not have metabolic
acidosis.
One of those infants underwent a mid-
cavity vacuum delivery. This was, I believe, a prima
gravida subject who -- and the baby turned out to be a
little bit over 4,000 grams. Unfortunately, a
shoulder dystocia was encountered, and about 8 to 10
minutes elapsed before delivery of that infant.
In another one of the cases of severe
encephalopathy in the control group the infant also
had an operative vaginal delivery. I believe it was a
vacuum delivery, and there was evidence of trauma,
possible trauma, from that delivery.
The third case is one I believe where the
cord blood data was not available to say whether or
not metabolic acidosis was present.
With regard to intrapartum and perinatal
deaths, there was one perinatal death in the control
arm of the study. Unfortunately, that was a subject
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 102/322
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 103/322
our review, you will find all of you have in your
package today a list of questions that the FDA staff
put together for the panel. One of these is the lack
of automatic ST event signals. The second is
deviations during the Swedish RCT from the patient
management protocol. Another issue has to do with
retraining of clinicians during the trial, and the
last is intercountry differences in clinical practice
between Sweden and the U.S., and whether or not that
has any implications in our review of the PMA.
These are cases where there was not an
automatic ST event signal. Now it's important to note
here that, in all fairness, we only looked at the 46
cases of metabolic acidosis as well as a few other
cases of bad outcomes. We definitely did not look at
every tracing from this study of 4,966. It wasn't
practicable.
So, again, these cases of lack of ST event
signal really only apply to the 46 total cases of
metabolic acidosis in the study. So there's no way we
can draw any conclusion as to whether or not this
occurred in the other 4920-or-so subjects.
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 104/322
There were seven cases in the STAN arm, 7
out of 15, and 8 out of 31 in the control arm. What
you see on the lefthand side of the slide is just
apparent or confirmed reasons why there was no
automatic event signal. In several cases the STAN
monitor hadn't been on for the required 20 minutes.
In other cases poor signal quality probably
contributed to a failure to register an automatic
event.
The last two categories are more difficult
to confirm. Nevertheless, it appears possible that
some sort of acute hypoxic event took place sometime
after the scalp electrode was removed and actual
delivery. We believe that there is one case where
pre-existing severe hypoxia was responsible for
failure to record an automatic ST event because a
myocardium that has been exposed to severe chronic
hypoxia may not respond similarly to hypoxia during
labor, as an infant, a fetus, who is not.
What else did I want to say about this
slide? I think we can go on to the next slide. Oh,
one last thing. I'm sorry.
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 105/322
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 106/322
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 107/322
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 108/322
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
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 109/322
where I believe that patients might have managed
differently in the U.S.
With respect to biostatistical issues,
there are no FDA biostatistical issues regarding the
presentation of the efficacy data for the primary and
secondary endpoints. The numbers and the percentages
and the statistical significance are not being
contested.
As I said earlier, I just wanted to
summarize some outcomes of the other clinical studies
using the STAN monitor, in part to give credit for
what is a vast body of clinical experience with this
device in Europe. The Plymouth study enrolled 2,400
subjects. These were high-risk labors. It was not
designed or powered to evaluate metabolic acidosis.
There was a significant reduction in operative
delivery for fetal distress and Caesarian section for
fetal distress in the arm of the study that used the
STAN device.
At that time -- that was in the early
1990s -- there were some differences between the
device used then and the one used in the Swedish RCT;
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 110/322
for example, in automatically identifying biphasic
events. There was also in that study a trend toward
reduction of metabolic acidosis in the STAN arm, but
that was not statistically-significant. As you see,
the cases of asphyxia were approximately the same in
each arm.
The European multi-center trial was a
relatively small trial which, as I understand,
prospectively recruited subjects. However, the ST
data was blinded, and the subjects, the tracings were
evaluated retrospectively. Eleven out of 12 of those
cases with evidence of hypoxia or asphyxia did have ST
changes when the tracing was unblinded for that data.
The Nordic observational study was larger
than the EC multi-center study. Management was based
only on the fetal heart rate data, although ST data
was available, and the results showed that following a
retrospective evaluation, the tracings blinded to
clinical outcome of 100 percent sensitivity for the
STAN guidelines to recommend intervention for cases
with neurological symptoms and/or metabolic acidosis.
The City of Gothenburg experience was what
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 111/322
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 112/322
tracings of some cases using the STAN monitor. The
first three cases I would like to show, for those of
you who might not have gotten your disks working,
actually, they're from a training CD, a collection of
cases that are used to train clinicians using the STAN
monitor. The purpose of showing these case studies is
just to illustrate different aspects of the STAN
monitor, but it is not to comment on management per
se.
The first case that I'm going to show you
isa VBEC patient at 41 weeks -- I'm sorry, 42 weeks,
one day, who was dilated 5 centimeters at the time
that the monitor was applied.
These tracings go relatively quickly. So
I'm just going to back up very briefly.
Again, what you see on the bottom of the
screen is the T/QRS data here. So this is the line
that we would be looking at during cases recorded with
the STAN monitor. For those of you in the audience
who might not be obstetricians, this line up here is
the fetal heart rate, and this line down here reflects
the uterine contraction pattern.
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 113/322
So what I'm going to ask you to do is
mentally be evaluating how you think the fetal heart
rate tracing is going, and bear in mind what's going
on in the bottom of the screen, where we are getting
our T/QRS data.
I'll try to speed this up to what I think
is the punch line.
There's reasonable variability here with
some reactivity, and then we're going to evolve into a
slightly different pattern.
So what we had here -- I'm just going to
back that up for a second -- drop in baseline, and
again some drops in baseline that look to be -- it's
difficult to evaluate the fetal contraction pattern.
We're losing some variability. We're
losing reactivity.
And what I am looking for here is an ST
signal event marker.
(Member of the audience begins to speak.)
CHAIRMAN BLANCO: I'm sorry, please, no
comments from the audience. If you need to make a
comment, you need to identify yourself, okay?
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 114/322
DR. CORRADO: What might be happening here
is that the point that I was trying to illustrate from
this case is that there was an ST event, an automatic
ST event, that occurred approximately 40 minutes prior
to delivery. It would have signaled an intervention.
The infant was born with Apgars of 1-5-5 and a cord
arterial pH of 6.82 and a base deficit of 17.
The reason I selected this case was to
illustrate that if the ST event data had been
available and the case intervened according to the
STAN monitor, we very likely would have gotten a
better outcome.
Can I just interrupt this for a second,
please, and ask if maybe the sponsor can tell me, are
we not going to see the actual ST event automatic
signals here? Because that was what I was trying to
illustrate.
(Sponsor representative speaks privately
to Dr. Corrado.)
Well, given that I need a slightly
different directory, what I will do here is, regarding
these training cases, what I would like to do is just
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 115/322
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 116/322
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 117/322
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 118/322
definition of metabolic acidosis as prospectively
identified by the sponsor clinically meaningful?
Question No. 2 has to do with the outcomes
in the study. I showed a couple of slides just
presenting the outcomes. We would ask the panel to
discuss the clinical significance of these results,
first for the intent-to-treat group -- that was
Analysis I -- and then for the adequate recordings
group.
As I just summarized -- I apologize, this
is very difficult to see on the screen. It's
virtually impossible to see. So I just, again, point
out for everybody that you've got these questions in
the handout for the meeting.
This is panel Question 3, and we would
like the panel to discuss the implications of a number
of issues in relation to the clinical significance of
the results that were described under Question 2.
First, deviations from the patient
management protocol. Second, no registration of an
automatic ST event in certain cases. Third,
exclusions of subjects in the study based on
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 119/322
inadequate recordings. Fourth, intercountry
population and management differences. Then, lastly,
whether or not there's any significance to the
retraining that occurred in the middle of the study.
We would like the panel to weigh the other
body, the large body of clinical data outside of the
Swedish RCT and determine to what extent do the
results from those studies support the safety and the
efficacy of the monitor.
We haven't said much about labeling and
training, but it's one of the most important things
that we do here at FDA. We would like the panel to
comment on the appropriateness of the indication and
whether or not the PMA data support this indication
for use, and whether or not the professional labeling
and training materials are sufficient to ensure
appropriate use of the STAN monitor.
If the panel votes to recommend approval
of the monitor, we would like the panel to comment on
whether or not there's a need for post-approval
studies.
With that, I'm going to retire here,
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 120/322
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 already read the discussion
questions, and, Panel Members, they are in your
handout folder, so you can look at that.
What I would like to begin with, and we
started doing this, is we would like to try to address
if the panel members have any questions of fact that
they might like for the company, the sponsor, or FDA
to address, if we could bring those up during the time
that we have before lunch, so that would give them
some time over lunch and prior to the last open public
hearing portion to try to address those specific
issues. Is that kind of clear with everybody?
All right, I'm going to ask Dr. Ramin, as
the lead reviewer, to go ahead and start us off on the
discussion.
DR. RAMIN: I'm Susan Ramin. I'm the lead
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 121/322
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 122/322
umbilical cord occlusions, trying to simulate the
dynamic changes that occurred during labor.
What the authors concluded is that
monitoring must include the T/QRS height as well as
the waveform analysis. I was wondering if you could
clarify, does the STAN monitor evaluate the height of
the T/QRS as well as the waveform analysis?
There were also approximately 14 percent
of the cases, roughly about 600 cases, where there was
no cord gas data available. I know that part of the
trial requirement was to have both an artery and a
venous sampling. I was wondering if you have the
numbers of how many cases had just an arterial sample
and how many cases had a venous sample, and whether or
not there were any cases of metabolic acidosis based
on one artery or venous sample.
I was wondering if the sponsors could
provide their definition of mid-pelvic operative
delivery, and whether or not -- what is utilized for
that definition in Sweden and what was utilized for
the trial.
CHAIRMAN BLANCO: Your implication there
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 123/322
being a comparison to what may be the definition in
the United States, correct?
DR. RAMIN: Correct.
There were the 46 cases of metabolic
acidosis out of the entire population. In the
randomized clinical trial, as was brought out by the
FDA, the STAN monitor did not register an ST event in
7 of the 15 cases in the STAN arm and in 8 of the 31
cases from the control arm. My question would be,
what is the sensitivity and specificity of this device
in detecting metabolic acidosis and hypoxia?
Likewise, in the randomized controlled
trial, there were inadequate tracings or inadequate
recordings in almost 12 percent of the cases. My
question is, is the 11.6 percent inadequate recording
rate satisfactory?
In the United States there is a tendency
toward less operative vaginal deliveries, marked
increase in Caesarian delivery rates, and there's a
limited use of fetal scalp blood pH. Given the lower
Caesarian delivery rate in Sweden, roughly 13 to 15
percent, compared to the United States, which is over
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 124/322
20 percent, is there any evidence that the use of the
information from the ST event or the ST waveform
analysis during the second stage of labor would result
in obstetricians not to intervene when it's
appropriate?
CHAIRMAN BLANCO: I'm sorry, could you
clarify that a little bit more?
DR. RAMIN: Sure.
CHAIRMAN BLANCO: Because I'm not sure I
understood that one.
DR. RAMIN: You gave the example of that
recording where there was good variability, beat
variability in the fetal heart rate tracings, but
there was also an ST event, and a Caesarian delivery
was performed. The cord gas was normal, and thus
intervention was done based on the ST event recording.
And the question is, how many times did that occur
where an intervention was done based on ST events even
though the fetal heart rate tracing was reassuring and
the cord gas status was normal?
Yes, you have a question?
DR. ROSEN: Could I ask for clarification?
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 125/322
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 126/322
I understand that it's observational, but I was, I
guess, curious about whether these were commercially-
acquired devices by the hospitals that then did the
study or were they provided by the company? What was
the training like? How much was this like a study as
opposed to how much was this like clinical practice?
Because I think that has a lot of implications for how
the device would be used once sold in the United
States.
And I don't think it was reviewed in his
presentation by Dr. Rosen, but I was curious about the
results in the Gothenburg trials. It appeared that
the decrease in metabolic acidosis was not as good in
the STAN group as in the CTG group in the latter half
of the trial, October to January, 2001 to 2002. So it
appeared as if the greater improvement was in the
patients monitored by traditional technique rather
than by the STAN, I think.
Then my final question was regarding
alarms. Does the system come with any alarms? Are
there alarms that can be set, or is it all totally
dependent on observation of the treating physician or
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 127/322
nurse?
CHAIRMAN BLANCO: Thank you.
MS. TOLEDANO: Alicia Toledano from Brown.
I had the same question about audible
alarms, and I had a question about how much experience
you have with breach presentation.
My main question is, how much do you think
you would have an effect on labor management if you
just retrained people on the current -- you know what
I'm trying to say. If you retrained people on using
the current fetal monitoring techniques, would you be
able to effect the same change as retraining them
including the STAN?
I'm done.
CHAIRMAN BLANCO: Okay, thank you.
DR. WOLFSON: I'm Bob Wolfson.
My question is actually a couple of
questions. One, why the 20-minute interval? What is
the statistical basis of that? I presume it has to do
with signal-to-noise ratio, but could you please
explain why that was derived?
Also, the issue of mid-forceps, my
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 128/322
impression is that is a relatively rare event in the
United States. Therefore, one could at least crudely
move the mid-forceps rate either by vacuum or by
forceps formally that's reported in the Swedish study
into the Caesarian section column for assessment in
the U.S.
I'm interested if you have any specific
information on IUGR. The low birth weight rate
clearly in the United States is substantially higher.
Granted, a significant portion of that is due to pre-
term births because our pre-term birth rate obviously
is approximately twice that of Sweden, typically
running around 10 percent.
But, specifically, because IUGR represents
a fetus at risk for metabolic acidosis, and you've
demonstrated, at least my understanding of the
physiology, you're reporting that this is specifically
an area in which the biphasic T wave is important. I
would like to know if you can tell us a little bit
more about the predictive value specifically in IUGR,
since I think that's a major impact in the population
differences.
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 129/322
Oh, and could you please clarify for me, I
still remain confused as to which is the primary drive
in this study or in the way of using this device.
When you're monitoring an individual, are you using
the electronic fetal monitoring information that would
be, I'll say, conventional information as your primary
tool, where the ST segment information now becomes
secondary in making a decision? Or are you really
utilizing the ST segment information, and when that is
of question, you then look to the electronic monitor?
So which is the primary tool here?
CHAIRMAN BLANCO: But what you're asking,
by primary tool, you mean, what was supposed to be the
trigger that caused, that would have caused an
intervention in the patient? Is that what you mean?
DR. WOLFSON: Well, Jorge, it's not just
the intervention. The thing that I find myself doing,
and just in looking at the images that were put up on
the screen, my mind always looks for more information.
I found myself rapidly watching the T wave
information, and when I saw the segment rise or become
biphasic, I merely looked to the EFM part of it, the
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 130/322
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 131/322
traffic signal with a green light and a red light
that's made by a decision in the machine some way or
another. I'm not sure I understand what that decision
is, and it worries me a bit.
So I would like to ask the proposers and
the FDA if they could comment a little more about
that, particularly the issue that Dr. Wolfson brought
up, namely, about the 20-minute period where we don't
know what's going on. Yet, in one of the
presentations the mention was made that 30 cardiac
cycles were averaged to do the analysis, and I get
that to be about 15 seconds or so. So I'm wondering,
what else is going on?
The second thing is the robustness of the
analysis routine in terms of signal distortions,
either arising from the electrode itself or from some
of the technical issues in terms of signal matching,
which I don't think we should get into here. But at
least we should hear a little more about how robust it
is and what constitutes the gaps in the data that we
see. What does the monitor decide as non-analyzable
data?
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 132/322
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: Thank you.
Dr. Sharts-Hopko?
DR. SHARTS-HOPKO: Okay, Nancy Sharts-
Hopko.
I was also concerned about lead placement
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 133/322
and diagnostic tracings. So thank you.
I am also concerned about the
comparability of how women are attended during labor
in Sweden versus the United States. We can typically
two registered nurses to six laboring women, thanks to
central monitoring. So there has to be a person there
watching for these ST events, so that intervention can
happen within 20 minutes, and I'm pretty worried about
that.
I am also concerned about in Book 1,
Section 2, page S-4, we have a list of complaints from
people who purchased 96 units. There were 57
complaints. I am interested to know how those have
been addressed, and I'm assuming that these complaints
the data that we've been given.
Thank you.
CHAIRMAN BLANCO: Thank you.
Jay?
DR. IAMS: Jay Iams, Ohio State.
I have a couple of study questions that
can probably be best found by looking at Dr. Corrado's
presentation on pages 8 and 9 regarding infants who
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 134/322
were excluded in Analysis II. Is there any reason to
think that infants who were excluded due to inadequate
cord blood might have a different incidence of
metabolic acidosis than infants who remained in the
study? Were they so profoundly depressed and had such
poor cardiac output that the cord samples
preferentially perhaps would have revealed babies who
were sicker? And if so, or regardless, do you have
any data on those babies regarding their Apgars
scores?
The next one was on the next page, Dr.
Corrado's slide No. 17, on page 9. The percent of
removals, she listed them as removals according to
what percentage of removals were 1.3 percent, 37
percent. Those are percentages of the removals. I
was wondering more about in each group, the STAN
versus the CTG alone, if those percentages within each
group were approximately the same.
Let's see, we also learned that the STAN
is not completely sensitive in detecting pre-terminal
or being coincident or in agreement with pre-terminal
tracings. What is the degree of concordance when
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 135/322
there's a pre-terminal tracing? Does the STAN
virtually find that always?
And then the last question is regarding --
it's somewhat theoretical. When you're looking at
myocardial hypoxia, myocardial acidosis, how
reflective of that, in animal studies perhaps, how
much does that reflect hypoxia and acidosis elsewhere?
Is it so sensitive to the heart that, in fact, it's
not necessarily applicable to the systemic
circulation?
CHAIRMAN BLANCO: Thank you.
Gary?
DR. EGLINTON: I'm still thinking about
mid-pelvic operative deliveries and wondering about
the definitional difference. It's probably in here
and I just can't remember it. I would like to know
what the frequency of mid-pelvic operative delivery is
in this sequence of studies, if it's relatively
uniform in all these studies or especially in the
Swedish RCT.
Since I've been a chairman for three years
and been looking at credentials packages, a third of
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 136/322
my staff that has joined my staff in the last three
years, almost none of them apply for privileges for
mid-pelvic operative delivery. They just skip that
box on the credentials sheet. I think there's
probably a major cultural difference here between the
European Union and the U.S.
Thank you.
DR. O'SULLIVAN: Mary Jo O'Sullivan,
Miami.
I have a question regarding the
training/retraining. I would like to know (a) what
were the differences between the initial training and,
after the first interim analysis, the retraining, if
there were any differences at all and how that
training was done, other than I realize that
individual hospital cases were used for the retraining
purposes, and they were, therefore, retrained on their
cases. Was that the only difference that occurred in
the whole retraining process? If it was not, then
what were the characteristics of the original versus
the retraining? I ask that because of the differences
between the interim analysis and the subsequent
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 137/322
analysis.
DR. BROWN: Carol Brown, New York. I have
a couple of questions.
One was about the correlation between
cardiac ischemia and specifically the effects on the
central nervous system. Is that a correlation, again,
in an animal model, specifically to metabolic acidosis
and encephalopathy, any type of fetal model?
Another question about the
training/retraining: Was there any assessment of the
baseline experience and familiarity with using CTG at
your centers? In Sweden I obviously you have, I would
assume, a much higher proportion of nurse midwives for
managing most labors. Was there an assessment of what
their baseline experience and interpretation of CTG
was before retraining, before training and retraining?
And specific numbers in terms of the percentages of
these traces that were managed by nurse midwives
versus OB/GYNs, proportionately, because I would
suspect there would be a big difference in the United
States in terms of the number of nurse midwives
proportionately who would be managing these cases.
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 138/322
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: Thank you.
DR. SEIFER: David Seifer, New Jersey.
Two questions: One is the inadequate
recordings of 12 percent, is a number that one would
expect with a new technology, looking at these
endpoints? Also, so would one in actual practice, as
opposed to a study, expect to see 12 percent
inadequate recordings?
I would imagine that part of the answer to
that question might include what clinical information
investigators have to understand if this greater than
50 percent of greater than 20 minutes between the
device and delivery, if we have an explanation of why
that might have occurred and whether or not that would
be preventable in a clinical setting? Also, with
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 139/322
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 140/322
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
encourage the sponsor and FDA to be very brief. Most
of these are actually addressed to the sponsor. Be
concise and to the point because we need to not be
spending all the time listening to the answers. We
need to discuss what we think. So we would like
clarifications, and many of the questions are similar,
so you might want to join them together on there.
DR. WOLFSON: Jorge?
CHAIRMAN BLANCO: Yes, go ahead.
DR. WOLFSON: Can I add an additional
question?
CHAIRMAN BLANCO: Sure.
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 141/322
DR. WOLFSON: Could you clarify the basis
by which the actual management guidelines were
derived? There were specific differences in the rise
of the ST segment based on the CTG information. It
wasn't clear to me, though I think you had one slide
that suggested, but I didn't understand the
differences as to why in one case it's greater than .1
where in the other case it's greater than .15. Is
there actually specific statistical information that
demonstrates the value of those specific thresholds or
was this based on clinical grounds and then simply
prospectively moved forward?
The other question that occurred to me in
the midst of the discussion was, could you clarify
again the use of fetal monitoring in Sweden compared
to the U.S.? My impression certainly in my own venue
is that electronic fetal monitoring will be used
somewhere in 80 to 90 percent of labors. Granted,
typically, this is external monitoring through the
bulk of the labor and not an internal monitoring?
My impression was that your data suggests
that the internal monitoring takes place in about 40
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 142/322
percent of your labor. So you have different
criterias. I would just appreciate a clarification.
Thank you.
CHAIRMAN BLANCO: All right, so let's be
concise, and let's try to put some of the questions
that are fairly similar together, so that we can get
some discussion of the questions that FDA would like
for us to address.
The other thing that we're doing, I think
we only have 30 minutes under the current agenda. I'm
going to take the Chairman's prerogative and go ahead
and close the meeting now for lunch and reconvene a
bit early, so that we don't have to break the
discussion up into a small amount of time, if that's
all right with the panel. Okay?
So it is right now, by the official clock,
11:30. We would reconvene at 12:30 and begin the
discussions at that point. Thank you very much.
(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.)
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 143/322
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
ahead and see if we can get started, please. All
right, let's go ahead and begin the afternoon session.
The way that we're going to try to do this
is we would like to, first of all, address the
discussion questions that the FDA has posed to the
panel. Panel Members, you should have a copy of these
in your panel booklet.
If some of the questions that were asked
by the panelists of the sponsor are included in this
particular questions for the FDA, then we'll ask them
to come up and answer it at that time, but if not,
then we will wait until the time that we have allotted
for the open public hearing later this afternoon
again, and at that time we'll bring up the company,
the sponsor, to answer some of the questions that the
panelists posed.
All right, well, let's go ahead and begin
then. Let me just read the first question, and it's
also up on the screen for everyone.
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 144/322
Discussion question, safety and
effectiveness. No. 1: "The pivotal clinical study
supporting this PMA is a large multi-center randomized
controlled trial conducted in Sweden. The Swedish RCT
was designed to compare several fetal and maternal
outcome measures between women managed with STAN
monitor technology and women managed by conventional
monitoring technology."
A: "The primary endpoint for the study is
metabolic acidosis. Is this endpoint appropriate?"
And I guess I'll go ahead and turn to Dr.
Ramin to start off the discussion on 1A.
DR. RAMIN: I think the primary endpoint
using metabolic acidosis is appropriate and reasonable
to utilize, given the pathophysiology behind this
device.
CHAIRMAN BLANCO: Okay. Any other
comments? Anybody else want to address the issue of
the metabolic acidosis?
DR. IAMS: I'll just make one comment. It
has to be recognized; it's the best surrogate endpoint
you can use, but metabolic acidosis is not, in and of
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 145/322
itself, an endpoint. It's a marker for the ultimate
endpoint, which is neurologic injury, presumably. We
all know the difficulties inherent in using that as an
endpoint. So it's an appropriate choice for a
surrogate endpoint.
CHAIRMAN BLANCO: Well, let me throw out
some things on this. I mean, they may be an
appropriate endpoint as surrogate, but in looking at
how it was defined in this particular study, there
seems to be a significant number of neonates that,
although had the definition, really didn't have very
much of a significant, were not affected in any way
that was reported. So I don't know if part of that
might have been what FDA had in mind, but to me I had
some concern about whether the definition of that
really reflects, and is a good surrogate for,
something bad happening in the fetus and neonate.
DR. RINGEL: Our markers of a bad outcome,
if you just look at the neonate, are perhaps weak. So
that stress that occurred during delivery might not
show up for a year, two years, five years. So that
you have to use some marker; otherwise, the studies
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 146/322
would never get completed. Then you won't even be
able to link it to later events, learning
disabilities, and so forth. So I think that metabolic
acidosis is a reasonable marker.
DR. IAMS: I would just add I think the
best marker, and I certainly defer to the pediatric
colleagues around the table, but the best clinical
actual marker of long-term performance that's
measurable in the neonatal period is seizures. If you
have seizures in the newborn period, I think that's
still the best clinical marker, not laboratory marker.
CHAIRMAN BLANCO: I'm sorry, was there a
comment over here?
DR. O'SULLIVAN: Yes, I was just going to
say, a lot of kids with seizures, Jay, don't have any
problems at all.
DR. IAMS: Well, true, they don't, but if
you're looking for a marker that's not a laboratory
event, subject to the vagaries of where you set the
threshold, et cetera, seizures I think are the one
that's been used in most trials trying to predict
who's going to have neurologic injury. That's not
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 147/322
perfect by a long shot, I agree, but I think that's
the one that's in most common use.
DR. RAMIN: I have a comment just about
your statement about metabolic acidosis and a fair
number of these babies didn't have any adverse
outcome. We have seen that in a lot of studies where
two-thirds of babies with metabolic acidosis go to the
newborn nursery and do perfectly fine. But I think we
have to have some endpoint in this study, and it would
be an immediate marker. I mean, ultimately, what we
need is long-term neurological outcome, but that's not
the purpose of this study.
CHAIRMAN BLANCO: Gary, you had a comment?
DR. EGLINTON: That's okay.
DR. O'SULLIVAN: Maybe the difference
should be in terms of what is metabolic acidosis.
CHAIRMAN BLANCO: Well, that's part of the
next question, so that's why I was leaving for that.
I just wanted to make sure. I think it's important to
point it out, as Jay did, that it is a surrogate
endpoint for what you eventually want to do.
DR. WOLFSON: My only comment was that I
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 148/322
think that we all would agree that metabolic acidosis
is not a natural state and, therefore, it's a state of
physiology that we want to avoid. While we may not
have all the information on its actual impact, both
short-term and long-term, on an individual, I think
it's still a worthwhile endpoint to choose in a study
of this nature because it's a space we don't want to
be in for a fetus or, for that matter, the mother.
CHAIRMAN BLANCO: All right. Any other
comments on 1A?
(No response.)
All right, well, let's move on to 1B,
brought up as well by Dr. O'Sullivan. "The definition
of metabolic acidosis in this study was an umbilical
cord arterial pH less than 7.05 and a base deficit
greater than 12 millimeters per liter. Is this
definition of metabolic acidosis clinically
meaningful?"
Would you like to go ahead and start, Dr.
O'Sullivan?
DR. O'SULLIVAN: I think that the data
that was pointed out by the FDA showing the
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 149/322
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 150/322
think it may be appropriate at this point maybe to
have Dr. Rosen, whoever is going to answer the
question about, why was the definition of 7.05
utilized, if somebody could come up and address that?
Maybe to the podium might be better.
DR. ROSS: I'm Michael Ross, Professor of
OB/GYN at Harbor UCLA, and I'm a consultant to the
sponsor. My travel has been reimbursed for today.
The issue of the 7.05 and the base excess
is a great question. Firstly, although, Dr. Neuman,
as you suggested, pH and base excess are continuous
variables, it appears from really the best literature,
and that's largely derived from the extensive work of
Jim Low in Canada, indicates that really there are
threshold levels, and that base excess is probably the
best single individual level to assess the risk of
newborn neurologic disease.
So I would argue that, rather than looking
at either pH or base excess as a continuum, it appears
that babies have a minimal to negligible risk of
neurologic disease from an acute event unless their
base deficit is 12 or greater. And at that point
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 151/322
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 152/322
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 153/322
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 154/322
the harvested umbilical cord?
DR. O'SULLIVAN: They're taken from the
umbilical cord --
DR. RINGEL: But the CO2 is changing then?
DR. O'SULLIVAN: Hum?
DR. RINGEL: The CO2 is changing as --
DR. O'SULLIVAN: Not significantly.
DR. RINGEL: Not significantly?
DR. O'SULLIVAN: No.
DR. RINGEL: Because it's clamped on
either end.
DR. RAMIN: There have been studies that
have shown that it doesn't change dramatically.
DR. RINGEL: Thank you.
DR. ROSS: Right. So I think that the
minor differences in procedures or rapidity of doing
samples are not going to change the value
significantly.
CHAIRMAN BLANCO: All right, thank you.
All right, any other comments on the
definition, and we do we think the definition is
clinically meaningful?
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 155/322
(No response.)
I guess there is no comment on that.
DR. EGLINTON: Jorge? Jorge, let me be
the naysayer then. I mean, everybody is familiar with
probably 25 publications by Dr. Low on base deficit.
That's fairly straightforward, fairly clean. I don't
think anybody, answering Michael's original question,
I don't think anybody has performed a receiver
operator characteristic curve analysis of pH, which is
probably what we would like to see. But I think that,
based on clinical outcomes, a bunch of the things that
have been published, and a lot of it by Larry
Gilstrap, has focused on a pH under 7 as being more
clinically important in terms of longer-term outcome.
If we look at the slide that Dr. Corrado
provided for us, slide 21, at a pH of less than 7,
there was no difference between the STAN and control
arms. They're really identical proportions.
So it seems subtle, 7.0 versus 7.05, but
it may actually be clinically important. The 7.05 may
not front-load the population with enough risk to be
clinically useful. It may require a pH lower than
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 156/322
that in order to have enough risk in the resultant
population, enough risk of long-term injury.
CHAIRMAN BLANCO: Well, I think it goes
back to the original issue of, is the definition --
you know, we said metabolic acidosis as a term is a
good surrogate endpoint for damage, but, yet, you
know, that's part of the problem: Is 7.05 enough of a
definition that it a surrogate marker or should a
lower number have been used to have been a better
marker of actual damage to the neonate or the fetus or
neonate? I think that's the question that needs to be
addressed.
Dr. Wolfson?
DR. WOLFSON: Two things: One, if we're
looking back at other studies, we've got to be
consistent in terms of what the outcome is. What's
the gold standard here that the pH is being compared
to, and what level of damage are you requiring in
those studies? We also know that many of those older
studies didn't take into account that a lot of the
damage that was observed was not based on metabolic
issues. It was anatomic disorders in the individual.
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 157/322
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 158/322
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 159/322
to show?
MS. TOLEDANO: Let me focus for a second
on damage to a neonate and what's clinically
significant. We have on Dr. Corrado's slides on page
12, her slides 23 and 24, and those show us the babies
with moderate and severe encephalopathy. There are
seven of those babies. What was their core blood pH?
Was it all less than 7 or were there some of them that
fell between the 7.0 and the 7.05 that within the
United States we would not have considered to have
metabolic acidosis?
So maybe if people are interested to find
that out, how many of those babies fell below 7.0
versus within 7.0 and 7.05 --
CHAIRMAN BLANCO: Well, why don't we see
if they're able to address that. I think along with
that, Dr. Ramin had asked a question about the 46
cases that were defined as having metabolic acidosis
and what was the sensitivity and specificity of this
device in identifying those particular cases. Maybe
we can have someone from the sponsor try to address
those two questions at this point.
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 160/322
Dr. Rosen, come to the podium, please.
DR. ROSEN: So the issue is very much,
what babies are affected by the process of being born?
And we did an attempt in analyzing those cases by
using the neonatal records, looking at what happened.
Did they have increased neuromuscular tone? Did they
have neonatal seizures? What we found was that some
of them had metabolic acidosis and others were exposed
to the forces of labor applied by vacuum/forceps
deliveries.
I think the issue is very much on how we
manage, learn to manage labor more appropriately. As
Dr. Corrado demonstrated, there were no cases in the
STAN arm that suffered severe or moderate
encephalopathy, whereas there were seven cases in the
control arm that did this. I believe that monitoring
is very much a managerial issue and how you relate to
the changes.
To what extent there were metabolic
acidosis of greater than 7, I have to look at the
data. You have all the data presented to you in your
folder. We have a detailed analysis of all these
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 161/322
cases.
CHAIRMAN BLANCO: Well, that's why I would
ask you if you could have someone maybe in the next 30
minutes or so -- I mean the seven cases with
encephalopathy were either moderate or severe, and see
what their pHs were.
DR. ROSEN: Well, I know that in some of
these the pH was quite reasonable.
CHAIRMAN BLANCO: Well, let's see if we
can figure that one out.
DR. ROSEN: Yes.
CHAIRMAN BLANCO: Okay? And then how
about the issue of the sensitivity and specificity in
the 46 cases?
DR. ROSEN: Well, we haven't done that
analysis simply because in those 46 cases we
intervened, obviously. We did sensitivity/specificity
analysis on the Nordic observational data, where no
intervention was done, according to the STAN protocol.
So, clearly, whether one should go for
automatic ST assessment or whether we should use what
the educational program says, and the way the user is
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 162/322
taught to handle the information by visual analysis as
well -- and as I showed you, yes, there were cases
where metabolic acidosis did emerge with no ST events,
in one case with a pre-terminal heart rates where the
guidelines said there was a need to do something, but
there will be the occasional case where there may not
be that dominant heart rate change and there will be
no ST, or there may be a period of time, of 10
minutes, where we don't have data available to us.
CHAIRMAN BLANCO: All right, well, thank
you for your answer. I think we ought to add the
question of, if you could see if you can have your
data and have someone look to see what the pH of the
seven cases with encephalopathy were. We would
appreciate it.
All right, any other comments on 1B? No
other comments? Dr. Wolfson?
DR. WOLFSON: Just one more question: If
part of the outcome issue is neonatal outcome with
respect to neonatal encephalopathy, then can we not
consider that the outcome that was created, since
that's the long-term outcome, was one that was
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 163/322
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 164/322
Okay, well, let's move on to Question 2
then: "List the outcomes from the Swedish randomized
control trial. Please discuss the clinical
significance of these results, essentially looking at
the primary endpoint as metabolic acidosis. In the
Analysis I, which is the intent-to-treat group, you
have a significant difference from 0.69 percent to 1.5
percent with a P value of 0.02, and in the Analysis
II, the adequate recording group, you have a 0.57
percent versus a 1.4 percent with a P value of 0.01."
Any comments on those results and the
clinical significance?
I think it's kind of what we've been
discussing, which is the definition, whether you
accept the definition of metabolic acidosis, as was
done in the study, and then show the difference.
Anybody else want to say anything else?
Jay, do you want to add something?
DR. IAMS: I was thinking of something
else when you were asking that question, but the
bottom line comes down to the number of individuals
with an adverse event. Although the almost 5,000
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 165/322
patients is a lot, by the time you get down to the
final endpoint, you're dealing with numbers that, for
other tests, other populations, would perhaps be
considered simply not enough.
That's a concern I think that I have about
the -- I'm not sure what the right word is, but the
durability of these relationships is evident. As Bob
said, the P values are fine. The design of the study
was appropriate. I don't disagree with the choice of
endpoints. I think the response that Dr. Ross gave
was appropriate. But when you get all finished with
that, you end up with not very many patients in those
cells, which is troubling. If you add to that other
issues that we'll talk about regarding trans-Atlantic
transplantation, it just gets a little concerning.
So it's hard to say I'm really concerned
about this question or this question so much, but in
the end the number of babies who had problems is a
genuine concern.
CHAIRMAN BLANCO: I thank you.
Gary?
DR. EGLINTON: I wanted to talk just a
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 166/322
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 167/322
wouldn't come out of this trial, the RCT.
CHAIRMAN BLANCO: Any other comments from
any panel member?
DR. BROWN: Yes, I just had kind of an
informational question for the maternal/fetal medicine
people around the table in terms of translating this
data. Someone made the comment earlier that the
incidence of metabolic acidosis, I guess you all were
saying, defined as less than 7.0, is much higher in
the United States.
Can you comment on that in terms of the
numbers, if you were to sort of extrapolate this data,
in terms of the numbers of patients you would expect
to see if you were using this intervention in the U.S.
population? Or if you're going to use the cutoff of
7.05, which is what the indication is, do you have any
sense or can you give us a sense of what comparable
expectations of percentage of babies born, say, at
Jackson Memorial who have less than 7.05 and base
excess of greater than 12 are?
DR. O'SULLIVAN: Very low. Very low.
DR. BROWN: So it's still very low?
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 168/322
DR. O'SULLIVAN: Uh-hum.
CHAIRMAN BLANCO: Any other comments?
MS. TOLEDANO: I've got my hand up, as
usual.
CHAIRMAN BLANCO: Any other comments?
MS. TOLEDANO: I've got my hand up.
I'm used to a screening setting in
radiology usually where we look at very rare outcomes.
When I sit here, I see us talking about, are there too
few of these babies? Is this too rare of an outcome
to really worry about?
I think the decision has already been made
by clinical practice where we are worried about that
outcome because we go after operative deliveries and
any indication of fetal distress to try to avoid the
metabolic acidosis, to try to avoid the neurological
damage. So every single one of those 45 babies or 50
babies or 90 babies in the United States that could be
saved by this, I think it's worth considering. And,
yes, it's a low number, but it's an important number.
That's just my personal opinion.
CHAIRMAN BLANCO: Dr. Ross, do you have
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 169/322
the pH use? Is that what you've got? All right, come
on up and let us know.
DR. ROSS: My appreciation to Dr. Corrado
for helping me with these cases here. Again, there
were three cases in the moderate encephalopathy group,
all of whom were from the control arm. Their values
were 6.78 with a base deficit of 12.8, 6.73 with a
base deficit of 21.8, and 6.87 with a base deficit of
16.9. Clearly, those three cases would meet anyone's
definition.
In the severe group there were two cases,
again severe encephalopathy, again two cases, both
from the control group, and those both have a little
interesting twist. One was born and a cord gas
obtained only from one vessel, and it's not noted
which vessel. That baby was born after 8 to 10
minutes of a shoulder dystocia. You're aware that
that sort of marks your point in time and then you
have 10 more minutes of now acidosis. So that baby's
single cord value was 7.17 with a base deficit of 3.7.
However, the immediate newborn blood, which was done
at 13 minutes of age, essentially just following the
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 170/322
shoulder dystocia, was 6.79 with a base deficit of
16.5, consistent with encephalopathy.
Then the final case speaks to this issue
of the importance of base deficit rather than pH, and
that is the severe encephalopathy case, the second one
from the control group, had a pH at birth of 7.1 but a
base deficit of 13.7. That likely was possibly due to
some loss of carbon dioxide in the sample or some
absence of respiratory acidosis. But, again, it
speaks to the base deficit being the key issue.
So I don't think there's any real
difference in this prediction whether you use 7.05 or
7.0. Thank you.
CHAIRMAN BLANCO: Thank you. All right,
how about the secondary endpoints and other measures
in the intent-to-treat group? We haven't addressed
the issue of operative intervention and C-section.
We've been mainly on the metabolic acidosis. Anyone
care to make some comments on the data for the
secondary endpoints and other measures?
(No response.)
Not particularly overwhelmed by the
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 171/322
panel's response here.
(Laughter.)
DR. SEIFER: Only to reiterate Dr. Iams'
concern about the small margin of difference here.
It's even slimmer, and it becomes more of an issue
when we get to the next question.
DR. O'SULLIVAN: I think that the only
thing I would add here is that, since mid-cavity
delivery is whether they're forceps or vertex -- I'm
sorry, forceps or ventouse -- are extremely rare in
this country. Now it's not that they don't happen,
but it is extremely rare.
CHAIRMAN BLANCO: It's extremely rare, so
you think it's not that applicable to the United
States situation? Is that what you're saying?
DR. O'SULLIVAN: Yes.
MS. TOLEDANO: But what would have
happened to them? Would they have ended up being
operative abdominal?
DR. O'SULLIVAN: They would have fallen
into the all operative interventions, which includes
Caesarian section.
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 172/322
MS. TOLEDANO: Okay, so they still would
have been C-section?
DR. O'SULLIVAN: Right.
CHAIRMAN BLANCO: So I guess the question
is, you know, later on to think about in the vote, so
I'll go ahead and bring it up, eventually, if the
device is approved, the company will have indications
for which the device has been proven to be clinically
useful. Does the fact that P value is somewhat small,
and you have the issue of the difference in operative
delivery rates in terms of vaginal versus Caesarian
section in Europe versus in the United States, do you
think that that makes any difference? Would someone
like to make a comment about the validity of operative
intervention differences for this particular device?
DR. RINGEL: Just before we get to the
issue of how they're delivered, I'm just thinking this
through. The STAN doesn't fix anything. All it does
is indicate that you've got to get the baby out
sooner. So in a certain group of patients that the
STAN identifies as being at risk, you will increase
the number of C-sections, or whatever, you know,
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 173/322
operative interventions.
So if we have accepted the metabolic
acidosis as the endpoint, the small difference in
operative interventions shouldn't bother us because,
hopefully, the ones that are being intervened on are
more appropriate candidates, so that we are swapping.
We are taking jeopardized or at-risk babies and doing
operative intervention, and taking healthy babies out
of that group. So we wouldn't expect a huge
difference in C-section rate, just in the metabolic
acidosis rate.
CHAIRMAN BLANCO: Well, actually, I was
going in a totally different area. I was going
exactly the opposite. One of the things that's always
of interest is being able to say that you've got a
fetal heart rate monitoring tracing that may look non-
reassuring, but you have a STAN tracing, if you will,
that is reassuring, so you can keep going and maybe
end up with a non-intervention vaginal delivery.
If you look at the numbers down here in
the first part, in the bottom part of the first page,
the rate of operative delivery was actually lower in
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 174/322
the STAN group.
DR. RINGEL: Right, I agree, yes.
CHAIRMAN BLANCO: What I was really
addressing was just exactly the opposite of what you
said, which is, you know, if the company is interested
in saying that they can lower Caesarian section rates
by identifying the non-reassuring fetal heart rate
tracings, that the STAN monitor says it's okay to keep
watching. Is that data that we have before sufficient
to be able to allow that statement to be made. That's
what I was trying to get at. Okay? Do you
understand?
DR. RINGEL: Yes.
CHAIRMAN BLANCO: Okay. Anybody want to
address that?
DR. BROWN: Well, I just think it's
problematic because, although you would have to then
make the assumption that all the patients that had
mid-forceps in Sweden would be patients who would have
C-sections here, is that really a valid assumption
without actually knowing? I mean, you're making a
jump in the data to make that statement. So I would
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 175/322
personally have some concerns about making that
statement, because you don't actually have the data in
the labor management culture that you're saying the
indication would apply for.
DR. IAMS: That's a reasonably comfortable
jump, I think, for most of us doing obstetrics in the
United States. We don't do mid-forceps very often, as
has been discussed. So that's a concern -- I mean
that is not as much a concern for me as the issue of
we operate with nearly almost twice the rate of
Caesarian sections in the first place, many of which
are done for presumed fetal compromise when, in fact,
no such thing exists.
So in this marketplace that's a very
appealing endpoint. It wasn't the primary endpoint in
this trial, but it is a very appealing endpoint
because we know we do more Caesareans than we would
like to do. So that's a concern. Our culture takes
devices like this, and it's on the next page, I guess,
as questions, and we do have a hard time using
information like this to reduce the Caesarian section
rate.
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 176/322
I think culturally caregivers in this
country are more likely to look at this as another way
to find babies, especially given the primary endpoint
of the study, babies who wouldn't be identified with
traditional cardiotocography. It might further raise
our C-section rate, maybe appropriately, as you said,
but we already have a perhaps even bigger problem with
injury to many mothers and complications with many
mothers. So we really are in a very different
cultural environment to use this technology than what
was done, I think, in Sweden.
CHAIRMAN BLANCO: Jay, I've got to kind of
call you a little bit on that because you started out
sort of saying you were comfortable with the fact that
there's a difference in Caesarian section rates in the
United States and Sweden, but you kind of ended with
sort of implying, or at least to me making me think
that you're really not comfortable with trading the
data to necessarily have that indication.
DR. IAMS: Let me see if I can say it
quickly and clearly again. The simple issue of the
data in this study using operative delivery as a
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 177/322
descriptive term for operative vaginal and operative
abdominal deliveries, that doesn't bother me. That's
nice. So end of comment.
I guess the second point was what I was
trying to say, maybe not clearly, is that in our
culture, marketed and promoted for its primary
indication, this device has some significant potential
to increase the Caesarian section rate, looking for
babies who have got problems. So we may decrease it;
we may increase it, but we're more likely perhaps in
this culture to increase it.
CHAIRMAN BLANCO: All right. Any comments
from anyone else?
DR. O'SULLIVAN: I think it's kind of
interesting that we are talking about, on the one
hand, decreasing the Caesarian section rate and, on
the other hand, now people can come in and ask for a
Caesarian section for any reason they want.
CHAIRMAN BLANCO: Yes?
DR. WOLFSON: I don't think we have the
data, but I think that we have to be very careful in
making the comparisons to look at, again, obstetrical
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 178/322
management because, as I recall in some of the early
work that was done on one of the NIH panels, one of
the principal reasons or one of the areas of concern
was that Caesarian section rates were increasing
because of, for example, breach delivery.
I don't know -- when we're looking here,
we're looking specifically at delivery for fetal
distress. I don't have a way of comparing raw
Caesarian section data or operative delivery data
between the two. My anticipation is that the overall
incidence of Caesarian delivery for fetal distress is
going to probably be uniform among most populations,
given that the individuals come relatively healthy
into the laboring process.
We talk about the translation between
countries. That may be the key point, that in many of
our academic centers, many of our urban facilities,
that the individual coming in in terms of the level of
pre-natal care, the knowledge of what's going on with
the infant, or I should say the fetus, are not going
to be comparable to the Swedish system, where they may
have much more information and have their patients
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 179/322
better defined than we do.
So I think that for fetal distress I think
we're okay. I don't think that the differences in
section rates is going to make a big difference.
CHAIRMAN BLANCO: Let me bring it back,
because I really started this as an adjunct to, in
other words, what the sponsor and company can claim
that their product does. Let me get not necessarily
the definition, but if you're comfortable with the
lumping together and if you're comfortable with the
differences between Sweden and the United States in
terms of operative deliveries, is this level of data,
this level of significance sufficient to make the
panel comfortable that they can make a claim that
they've lowered the rate of operative interventions
for fetal distress?
Did I make that specific and clear?
DR. RAMIN: It's only 1.6 percent
difference.
Can you hear me?
CHAIRMAN BLANCO: No.
DR. RAMIN: When you look at it, it's only
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 180/322
about 1.6 percent difference. So it's questionable if
it really ultimately decreases, at least clinically
significant.
DR. WOLFSON: Okay, but you have to look
at it from a proportional standpoint. It's 1.6
percent out of 7.7. So, proportionately speaking,
it's a relatively large number if you then project it
into a general population. I know we're sort of maybe
splitting hairs here, but even though it looks like a
small number, the fact that it's statistically-
significant says that you should be able to expand it
to a larger portion.
CHAIRMAN BLANCO: All right. If there are
no other comments, I think we probably beat that one
to death. So let's move on.
Let's go on to No. 3. Hang on, we're
going to No. 3.
"Several issues identified in the FDA
review may affect the results. Please discuss the
implication of each issue in relation to the
clinically significance of the results presented in
Question 2."
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 181/322
You can see that there are five items, so
let's go ahead and take it with the first side of 2A,
deviations from the randomized clinical trial patient
management protocol. Anybody want to start the
discussion? Maybe Dr. Ramin?
DR. RAMIN: Right.
CHAIRMAN BLANCO: Do you think that the
fact that there were deviations once patients were
identified as having an event, but yet the management
protocol was not followed, does that create a problem
in your understanding or support of the data? Or do
you understand what I'm getting at?
DR. RAMIN: My opinion would be that, yes,
there would be a significance clinically in the fact
that there was deviation in the clinical management
protocol, in defining an ST event but not intervening,
especially in cases of non-reassuring fetal heart rate
tracing, and you take the opposite approach as well.
So I think there are implications.
CHAIRMAN BLANCO: Okay. Anyone else want
to make a comment on that? Agree or disagree?
DR. EGLINTON: Yes.
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 182/322
CHAIRMAN BLANCO: Gary?
DR. EGLINTON: I would like to
congratulate the sponsors on in one case at least a
30-year career working on this and translating some
basic science research. This is translational
research here now, bringing this into the delivery
room.
But I'm worried about a second
translation. These are services that are very tightly
controlled, very high-level excellent care, people who
are very bright, coached by zealots who are also very
bright, and now we're talking about trying to
translate this across an ocean.
When we have some people who really have a
lot of trouble understanding basic fetal heart rate
patterns at this point, I don't see this as a question
on piece of paper here, but it is a question -- maybe
this is it; this is the best place for it, deviations.
I mean, they had deviations from their management
protocol. I'm just trying to imagine the deviations
from this management protocol in my own labor and
delivery unit, if I'm trying to introduce this
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 183/322
technology. I don't see that this is going to
translate.
We don't have any evidence that this
management protocol is doable in the United States,
that this can be implemented in the United States.
CHAIRMAN BLANCO: Yes, Dr. O'Sullivan?
DR. O'SULLIVAN: Well, I think there are
two issues. First, I think that the investigators
pointed out, and they have to answer this question for
me, what were the differences in education before and
after? I mean prior to the protocol violations, when
they first got started, versus after the protocol
violations.
I would hope that eventually, with the
right education, and starting out from ground zero,
that we could teach our people in this country to
perform adequately. I think that it will be
difficult, but I think it can be done.
I think the big issue here is, what was
the difference in the educational process as it was
introduced versus after the first 1600 patients were
done and the interim analysis were looked at that made
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 184/322
the difference here? How come there was such a
difference? Or how come it appears there as such a
difference?
MS. TOLEDANO: I want to be devil's
advocate for a moment and just to notice that when we
evaluate safety and effectiveness as members of an FDA
panel, it's for the device used in accordance with its
indications. While looking at the way the device
would be used in our culture is certainly very
important to all of us, that is not necessarily what
we are supposed to be looking at when we are
determining whether the device is safe and effective.
DR. RINGEL: Just to comment on the
deviations question that you're asking us to comment
on, I thought the deviations were equal in the control
group and the STAN group, so I actually think it's a
moot point. People deviate from protocols, people
deviate from accepted medical practice. They were
just showing that the deviations were equal in the two
groups. It may be a high number of deviations, but
they were equal. So I think it's a wash.
CHAIRMAN BLANCO: Yes, I think the
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 185/322
question was really aimed, and it's because of what
you said, in terms of how the FDA has to evaluate
things. The question was more, does the fact that
there were so many deviations invalidate the results?
Your point is they were probably randomly in both
groups, or maybe not randomly, but at least they were
the same numbers. So probably it didn't affect it one
way or another. Correct?
DR. RINGEL: That's the way I look at it.
CHAIRMAN BLANCO: Okay. Any other
comments? Anyone else want to say something?
DR. SHARTS-HOPKO: Well, I have to recall
that we've had experience in this panel with devices
that were not used according to the written
instructions and with adequate training. The chicken
came here home to roost. So I think that is something
that we have to be concerned about, and I'm concerned
about that.
CHAIRMAN BLANCO: Okay. Any other
comments?
(No response.)
All right, what about B, no registration
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 186/322
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 187/322
go and look for the ST event marker and it's not
there. So where does that leave you?
DR. RAMIN: Which one do you rely on?
DR. IAMS: Yes, and that gets back to one
of the questions we asked before the break, about the
number of pre-terminal tracings that were also marked
as being abnormal by the STAN.
DR. RINGEL: But, in fairness to the
company, they very clearly, even in their brief
summary, state that a pre-terminal ECG, you don't look
at the ST analysis.
DR. IAMS: Right, that assumes that pr-
terminals are all that easy to identify, which is one
of the tracings that we were shown this morning
reminds me of, sometimes they look pretty good. It
depends on where in the process you come into it, I
guess. If you come in at the end, it can get
confused. So we're just looking to see if there is a
correlation there, and then what degree of
correlation.
CHAIRMAN BLANCO: Well, yes, I think
that's a very important point. I think we ought to
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 188/322
spend a little bit more time on it, because I think
this is an issue with some other things that have come
before this panel as well.
You wonder, going back to A, if you'll
allow me, how many of the deviations went, because it
wasn't clear in terms of the indications, if you look
at the little box thing where you act on it, I mean it
wasn't totally clear to me, you know, exactly where
you needed to go.
I wonder if some of the deviations might
have been the STAN monitor was identifying an
abnormality or an event, but, oh, hey, the tracing
looks great, so I'm just going to keep on trucking and
keep laboring the baby, even though I should be
delivering it, according to the protocol.
So I think this is an important point in
trying to give some guidance to the sponsor as to how
they need to specifically word the actions. I mean,
what are we trying to do here? Are we saying that
this particular monitor is going to be useful when you
have a non-reassuring fetal heart rate pattern, and
then you use the fact that you have an ST event as
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 189/322
your point at which you say, well, this baby's in
trouble, so we've got to deliver this baby pretty much
immediately, or are we going to say, or is the sponsor
going to say, well, you know, I've got a reassuring
fetal heart rate pattern, but we know that may not
mean that much, so you've got an event, an ST event,
being flashed by the STAN monitor; you still need to
deliver that baby?
Some comments on that?
DR. IAMS: Well, let me follow up on that
comment I made about Dr. Wolfson's comment before and
guess what the answer will be from the sponsors about
the question of which one goes first.
My sense is you will probably answer that
by, with experience, you integrate the two of them
together. I don't know, maybe that's the answer.
CHAIRMAN BLANCO: Well, I don't know that
that gives them a lot of guidance, Jay, but --
DR. IAMS: I'm not asking for guidance or
trying to give them guidance. I really would like to
know the answer to that question before we deliberate
a whole lot further, I guess.
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 190/322
CHAIRMAN BLANCO: All right, well, Dr.
Rosen? All right, Dr. Ross?
DR. ROSS: Michael Ross again.
That's not the answer, Jay. It is really
a sequence of looking first at the fetal heart rate
tracing and, secondarily, at the STAN. As indicated
on the little package insert, if the tracing is
entirely reactive and reassuring, there is no need,
nor request, to look at the STAN. If the tracing is
pre-terminal, then one has to act upon that. In fact,
because of the physiology of T/QRS in a pre-terminal
baby, the T/QRS actually decreasing with ultimate
hypotension just prior to cardiovascular collapse, you
may not see it. Again, of course, that's assuming
that you start at the STAN relatively late in the
process, which was the case in the examples shown.
For all other heart rate tracings, those
that are non-reassuring in our terminology or,
according to the FIGO terminology, somewhat the
different levels of concern, then the STAN becomes the
secondary level.
DR. WOLFSON: Dr. Ross, then explain to
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 191/322
me: So if you have a reassuring electronic fetal
monitoring tracing, and because the display shows you
your ST segment, and you're seeing either ST event,
because I'm still not sure which one to focus on more,
the rising or the biphasic. The biphasic certainly
sounds more ominous.
So if you see an ST event, you're going to
tell me you're going to ignore the ST event because
the electronic fetal monitoring tracing is
reassuring --
DR. ROSS: That's correct, and, in fact,
it may be an episodic rise. I mean, let's assume that
we have a completely reactive, reassuring tracing. In
looking at hundreds of these tracings, one may have an
occasional deceleration with an episodic rise that
does or doesn't meet criteria for what would be an
abnormal tracing, as indicated on here. Those would
be ignored and viewed as a short-term event.
So you're correct, look first at the
tracing; ignore some short-term events in the ST, if
they occur, which is infrequent at best.
CHAIRMAN BLANCO: Any other comments from
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 192/322
the panel? Go ahead, Gary. Go ahead.
DR. EGLINTON: I wanted to ask about this
card. The system, I may not understand it.
Obviously, I don't understand it well enough, but it
appears on the surface of it to be impossibly complex,
because there's an algorithm on this side where
there's a normal CTG, an intermediary which is other
places labeled suspicious, an abnormal CTG, which
other places is labeled pathological, and then pre-
terminal.
So there are six boxes in here that
require a great deal of interpretation along the
horizontal axis with intermediary and abnormal. Once
one pigeonholes the strip into one of these four
lines, then one turns this over here and watches each
individual EKG complex that shows up on the right side
of the screen, or at least that's what I was trying to
do, watching the strips, because you either have a
biphasic ST for continuous for greater than five
minutes or more than two episodes of coupled BP2 or
BP3 in the case of an intermediary CTG, but it also
could be an episodic T/QRS rise of greater than .15 or
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 193/322
a baseline T/QRS rise greater than .1.
Is the computer doing this in real-time
continuously, and that's what puts the little ST event
marker down on the bottom channel?
DR. ROSS: That is. You do not look at
the ST waveform. That's in fact just displayed on the
computer. It's not displayed on the monitor paper.
So the computer will integrate that.
I could see at first glance that this
looks confusing, the grids on both sides, which speaks
in part to the need for an education program, but it
actually is not that dissimilar from what we use. We
could all agree on a normal definition of CTG, pretty
much can agree on pre-terminal CTGs. What this is
attempting to do is define in fairly objective
criteria what is the intermediary and the abnormal.
So it is really breaking our suspicious tracing into
two categories, one being suspicious or intermediary
and one being abnormal. But the computer does the
rest of that calculation.
CHAIRMAN BLANCO: I'm glad that Gary found
it confusing because I'm always happy when I find
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 194/322
something confusing that I'm not the only one. I find
it's very confusing, and I don't think it was clear at
all, the episode or the sequence of events that should
occur in terms of the assessment, what you've
clarified for us at this point.
I think you need to, I guess addressing
the sponsor, I think you need to do a lot of work on
clarifying it. I guess if you forgive my being --
well, anyway, if you just forgive me --
DR. EGLINTON: Being from east Texas? Is
that what you're trying to say, Jorge, from east
Texas?
CHAIRMAN BLANCO: Yes, from west Texas.
(Laughter.)
But you've got to Americanize it. This
isn't very Americanized, and it's not very much the
way practice is done in the U.S. This is going to be
confusing. This is confusing.
Thank you, Dr. Ross.
Any other comments?
DR. WOLFSON: Jorge?
CHAIRMAN BLANCO: Yes?
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 195/322
DR. WOLFSON: I just want to get one thing
that still isn't clear to me, going back to this.
What does the machine actually show us? In other
words, just the basic question, when there is an ST
event, does an alarm go off audible, visible? Do we
know so that it at least alerts the attendant to the
patient to look at the tracing, if nothing else?
DR. ROSEN: Karl Rosen.
The attempt that we are doing is to verify
when the fetus is forced to respond to the stress of
labor. We're utilizing the ST and we're asking the
computer to verify when there is a change from the
situation that occurred prior to this event, and, in
particular, with contractions, obviously, coupled
contractions with illustration of where you then would
see an episodic rise which is identified, and it has
strict rules in the software to tell what type of
change is required to achieve an episodic as well as a
baseline change, as well as a set of biphasic STs.
CHAIRMAN BLANCO: I'm sorry, Dr. Rosen, I
don't think his question was addressing that. I think
his question was addressing, you've got some bells and
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 196/322
whistles when this bad thing happens --
DR. ROSEN: All right, yes.
CHAIRMAN BLANCO: -- bells and whistles to
call somebody to look at this. Is that right, Dr.
Wolfson?
DR. WOLFSON: Yes, that was question one.
Just does it go off?
DR. ROSEN: It doesn't go off. It's
there. It's written. There is a flag raised on the
screen, and you would have to go and verify that, sort
of recognize that, that that is a possibility. We
have not included bells and whistles.
We try to bring knowledge more, but, I
mean, it might a cultural thing here that you like
bells and whistles, in which case it will have it.
DR. RINGEL: We would like a sign that
flashes, "C-section now!"
(Laughter.)
That would be good. That would be good.
CHAIRMAN BLANCO: All right, thank you,
Dr. Rosen.
DR. WOLFSON: I would just like to go back
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 197/322
to the other questions. Why 20 minutes? What is
the -- do you want to wait for that?
CHAIRMAN BLANCO: I'll tell you what, I
think that's maybe not necessarily in here. That's
one of the questions that you asked that we said we
were going to handle later on.
DR. WOLFSON: Okay.
CHAIRMAN BLANCO: So I don't see the exact
applicability to the issue. So let's make sure we
finish with these before we go into the others. We'll
get to that one, I promise.
DR. WOLFSON: Well, I asked the question
relative to how it made the decisions it did, but I
will be glad to wait.
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. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 198/322
And there was a significant number, or maybe not
significant, but there were large numbers of folks who
had exclusions based on inadequate recordings.
Yes, sir?
DR. WOLFSON: I was going to ask a
question of my colleagues, since I haven't been in the
delivering process for many years. What actually is
the incidence of failure of standard electronic fetal
monitoring, of getting an inadequate signal?
CHAIRMAN BLANCO: A scalp electrode?
DR. WOLFSON: In other words, in a scalp
electrode, what proportion of the time does it
actually fail when you're just doing regular
monitoring?
CHAIRMAN BLANCO: I think I'm hearing from
my left very low.
DR. WOLFSON: Because in this group it
would be about 5 percent, if you look at it from a
purely technical perspective. Only 5 percent of
failures of where it would have been replaced. I
don't know what it is in the U.S. history.
CHAIRMAN BLANCO: Was it 5 percent? I
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 199/322
thought it was more.
DR. WOLFSON: It is. The total number is
about 11 percent, but when you actually look at the
technical issues of poor signal where the system
couldn't operate, that's only about half that. So
it's about 5 percent. It's around 5 percent.
DR. SEIFER: On slide 17 she says less
than 20 minutes on the STAN monitor. Of that, less
than 12 percent, 37 percent, and greater than 20
minutes removal of device and delivery at 56 percent.
CHAIRMAN BLANCO: Congratulations on
getting the 20 minutes back into the discussion.
(Laughter.)
Dr. Wolfson?
DR. WOLFSON: That was not intended,
Jorge.
CHAIRMAN BLANCO: That's okay. We're
going to talk about it now. We're going to deal with
it. So be prepared.
All right, so the issue is it is overall
12 percent, but then if you break it down, what
percentage --
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 200/322
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 201/322
required for the computer to do automatic analysis,
and you need a baseline consisting of approximately 10
minutes to verify where you are to start with, and
then you start to look for a change. Obviously, you
do a minute-by-minute basis, but after an additional
10 minutes, calculating the median value change. Then
you are significant and you can demonstrate
automatically by mathematics.
DR. WOLFSON: So it needs about 1400
samples or 1200 samples?
DR. ROSEN: Well, in this process we
require 10 T/QRS data for a median to be calculated.
DR. WOLFSON: Okay.
DR. ROSEN: So you could do that in a
shorter space of time tentatively, but to be able to
secure the accuracy of this data, according to the
software mathematics that the machine is using, there
is this 20-minute guidelines to secure.
It is also a function of how the electrode
stabilizes, because sometimes a few minutes are
required for this calculator to just settle down and
provide us with a clean signal.
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 202/322
Now on the issue of exclusions --
CHAIRMAN BLANCO: Before you go onto that,
because I'm still not clear, I mean do you have data
that you looked at that said that 20 minutes was what
you needed for the mathematical model? I'm
remembering Dr. Neuman's comment, and somewhere in the
presentation, somewhere in the data it was that you
needed 30 QRS complexes, and then you've got some
information.
DR. ROSEN: But --
CHAIRMAN BLANCO: Wait a minute. Wait a
minute. Let me finish.
Then that 30 QRS complex in a fetus is a
fraction, a fraction of a minute. So could you
elaborate a little bit more on the 20 minutes?
DR. ROSEN: I mean the 30 beats, now we've
got to separate the beats from QRS data.
CHAIRMAN BLANCO: Okay.
DR. ROSEN: So 30 beats, high-quality
beats, are required, and the system looks for that
high quality. So it will disregard those that are
poor quality. Then we say we need at least 50 percent
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 203/322
of the time covered with acceptable half-beats to say
this is a reasonable quality recording.
Because the thing I don't want to see is
erroneous data being entered into the T/QRS plot. So
our software is very much focused on avoiding that
issue and using modern digital signal processing to
sort of take noise out of this problem.
I think from the traces you have seen you
might have recognized the quality of the ECGs has
actually been displayed, where you can identify a P
wave, a QRS, and a T wave very accurately.
Then we have T/QRS ratios that in a normal
case -- and now I'm talking about 90 percent of all
recordings, where we have a continuous; that means up
to four QRS data plots per minute, and that is the
norm. We may address that now looking at the
Gothenburg experience, where, according to the
information I had here, it's only 1 percent now of the
cases where we don't obtain an ECG. It is obviously a
reflection of the motivation of the staff to apply the
scalp electrode correctly, but also the software
engineering is continuing, and we learn and we improve
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 204/322
the technology. It is part of the process.
CHAIRMAN BLANCO: Dr. Wolfson, have you
gotten your questions on the 20 minutes answered by
that?
DR. WOLFSON: I think so, yes.
CHAIRMAN BLANCO: Now several people
brought up the 20 minutes. So does anybody else have
any comments on the 20-minute window?
DR. NEUMAN: I still have a question
regarding the fact that you used 30 good QRS
complexes. Is there a maximum number of bad QRS
complexes in between? If I can be a bit sarcastic,
you wouldn't want to choose just 30 QRS complexes over
the entire 20 minutes.
DR. ROSEN: Sure. There are also are
rules that in that case would turn the system on. I
mean we have set strict rules, and I don't have those
in my pocket today to show you, but they are part of
the software engineering, the quality control, the
safety aspects. We have spent 15 years of software
engineering time to develop, having had access to the
ECG. As you can imagine, it is a bit of a challenge
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 205/322
to record an ECG where you have a reference electrode
placed on the maternal thigh. This is required to
obtain the vector to identify the T wave, which is
different from the standard ECG monitoring procedure,
where we don't need ST; we only rely on QRS. It's
very simple to measure that, but with ST it is
becoming more of a challenge.
So we need a unipolarity configuration.
We need the maternal thigh. The mother is moving.
That creates a problem. We've got to spend a lot of
energy and time and skills in developing the software.
Today, with the latest software there is, it appears
there's only 1 percent of the cases we obtain a
signal.
You should also remember in the Gothenburg
database, that's all intention-to-treat. The only
guidelines have been 20 minutes of recording, and it's
all intention-to-treat. There are no cases taken out
of that. So that really shows how the current
technology works in clinical practice.
CHAIRMAN BLANCO: All right, thank you.
Go ahead, Mike.
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 206/322
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? Go ahead.
MS. BROGDON: Dr. Blanco, Dr. Corrado has
tallied some data that may help to answer some of your
questions.
CHAIRMAN BLANCO: Please, Dr. Corrado.
DR. CORRADO: We used the spreadsheet of
the results from the entire study that the sponsor
provided us, and we tried to evaluate what the precise
causes for recordings of less than 20 minutes on the
monitor, categories of deliveries that occurred more
than 20 minutes after disconnection, and I'll
certainly defer to the sponsor, but I will share the
information with you that we have been working from.
For recordings that were excluded,
patients who were excluded because the STAN was on for
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 207/322
less than 20 minutes, we counted about 111 in the STAN
arm and 105 in the control arm. Of those, 94 in the
STAN arm and 76 in the control arm were identified
with the word "partus," P-A-R-T-U-S, which we
interpreted to mean perhaps the patient had delivered.
Is that -- that is the case?
So for the STAN arm, out of 111, 94
weren't included because they delivered sooner than 20
minutes, and then 76 out of 105 in the other group.
There was something called signal, which was
identified as a problem in 14 of the STAN patients and
21 in the control arm.
Technical problem, question mark, "TOCO"
occurred in four patients in the CTG arm. The rest of
the numbers are very small. They're less than three
or four. So the overwhelming majority of the category
of STAN on for less than 20 minutes was due to
delivery.
CHAIRMAN BLANCO: So, basically, 60
percent, I mean roughly -- I don't know the exact, but
70 or 80 out of the 100, a little over 100, were
because they delivered before the 20-minute window was
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 208/322
up?
DR. CORRADO: Correct.
CHAIRMAN BLANCO: Okay. So I think that,
I don't know, to me at least it sort of puts an end to
the exclusions based on inadequate recordings issue.
DR. CORRADO: Well, that is just for less
than 20 minutes. There were also a bunch of cases,
133 in the STAN arm, 130 in the control arm, that were
excluded because, for some reason, the monitor was
disconnected, and more than 20 minutes elapsed between
the time it was disconnected and delivery.
I will just quickly summarize those
numbers for you. Our analysis showed that there was
apparently a signal problem in 80 out of 133 in the
STAN arm and 85 out of 130 in the control arm. There
was a category identified as technical that included
20 patients out of 133 in the STAN, 15 out of 130 in
the control.
There is a category that "user error," six
and seven, respectively, in the STAN and the control
arms, and a category that was just labeled "unknown."
I'm not sure if that is our label or the sponsor's.
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 209/322
There were 19 of those out of 133 in the STAN arm and
16 in the control arm. So in that category, that is,
it was disconnected more than 20 minutes before
delivery, the overwhelming majority comes under a
category of signal problems.
CHAIRMAN BLANCO: Okay.
DR. CORRADO: I hope that helps.
CHAIRMAN BLANCO: Yes. Thank you very
much.
Yes, go ahead.
MS. TOLEDANO: Just a point of
clarification: Were the signal problems at all
correlated with the removal of the electrode to do
forceps or ventouse deliveries?
CHAIRMAN BLANCO: Go ahead, Dr. Rosen.
DR. ROSEN: That was not the common
situation. The more common situation was that they
would then would not reapply the scalp electrode and
they would switch to a standard electronic fetal
monitoring device.
CHAIRMAN BLANCO: Thank you.
All right, any other comments? Questions?
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 210/322
Issues on 3C?
DR. IAMS: Jorge, is this a good place to
ask about the exclusions based on cord blood?
CHAIRMAN BLANCO: Okay, go ahead.
DR. IAMS: Because you're talking about
exclusions.
CHAIRMAN BLANCO: We're talking about
exclusions, so go ahead.
DR. IAMS: That was a lunchtime question.
Is there any additional data about that?
CHAIRMAN BLANCO: This is a question where
you did not have both the arterial and venous cord
blood or didn't have, or you didn't have any on some.
Dr. Rosen?
DR. ROSEN: I did a quick look at these
data where there was the cord artery sample and then
there were in the STAN arm about 170, and 190 in the
control arm, where there were additional cord vein
samples. In the STAN arm there was no case with
metabolic acidosis or cord artery pH of less than
7.05, whereas in the control arm there are two cases,
a cord vein, metabolic acidosis, and where the cord
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 211/322
vein pH are less than 7.00.
DR. IAMS: Okay, my concern before was
that babies with metabolic acidosis might have been
particularly difficult to sample for some reason. So
it sounds like that was not the case.
DR. ROSEN: Well, it's probably true.
There were two cases in the control arm where they
couldn't obtain a cord artery sample. So they were
actually excluded from the cord metabolic acidosis
group. They obviously are included, because they had
the clinical symptoms, so they are included in the
adverse outcome cases, one of those, and the other one
is not included. So you have those represented in the
material, in the neonatal outcome of the study.
DR. IAMS: Thank you.
CHAIRMAN BLANCO: Thank you. Any other
comments on the exclusions?
(No response.)
All right, let's move onto 3D then, and
this has somewhat been alluded to, but maybe we can
spend a little bit more time. 3D, "The intercountry
population and management differences." Anybody want
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 212/322
to make a statement about that?
DR. O'SULLIVAN: I think that, depending
upon the facility on the labor floors as to whether
there is central monitoring, one, and, two, that
somebody actually looks at a central monitor, which is
not common, and, three, if there are alarms and the
alarms go off and everybody is still sitting at the
desk. All of these are issues when we talk about
bells and whistles. The whole idea of bells and
whistles, and whatever you can do, red lights, et
cetera, is to get the staff to pay attention to them,
but the answer is usually, "It's not my patient."
I have grave concerns where you have
individual labor rooms with individual delivery room,
labor and delivery suites, with a nurse usually taking
care of anywhere from four to six, although the floor
will tell you it's one to two. When you actually look
at it, between lunch breaks, coffee breaks, union
breaks, all kinds of breaks, it's one nurse to four to
six patients. So I have a lot of concerns about it
from that perspective in terms of practicality.
Yet, I also wonder if the educational
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 213/322
process somehow or another will make a difference,
since there was such a difference in what you all
showed before with your education. I come back to
that. I keep coming back to that because of the
importance that I think it has in introducing this in
the United States at all. It's going to be a major
educational process, and it's going to be
desensitization with resensitization.
CHAIRMAN BLANCO: Well, let me play a
little devil's advocate. I mean, I totally understand
what you're saying in terms of you have a concern.
You know, you've got a 1-to-4, 1-to-6 ratio, and
whether somebody's going to pay attention to this, but
that's really not a problem with the device.
DR. O'SULLIVAN: No.
CHAIRMAN BLANCO: That's really a problem
with our system, and actually you might be better, you
know, if you've got something that records, so that
when they do come around and pay attention to the
patient, that they will notice that this event
occurred. They may not have gotten to it on a timely
basis, but the other option is simply to central
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 214/322
monitor and not showing that.
I'm not sure that that necessarily to me
makes me against the device.
DR. O'SULLIVAN: No, but I think in terms
of, when you're talking about marketing it in this
country, and its useful utilization in this country,
to do what it did in Sweden, for example, it is going
to be important. Otherwise, it won't do what it is
supposed to do. It's subsequent failure.
DR. IAMS: Jorge, my concerns about
transportability don't reflect very well on this
country. I was struck by one of the comments Dr.
Rosen made in this beginning of his discussion, that
there is a general consensus in Sweden about the
interpretation of cardiotocography and some other
issues about management.
I'm not so sure that you could make that
statement about any manner of fetal surveillance in
labor in this country. It varies tremendously;
interpretation varies tremendously.
The natural inclination of even the least
technological American obstetrician, most of us as we
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 215/322
talked about this, did you look at these tracings?
We're all looking at that little EKG thing over there.
We're not supposed to look at that, but that's what
American obstetricians do. We're looking -- I didn't
see the ST wave go up or down. If I were going to
redesign the equipment for an American user, I would
take out everything except the ST event marker. Why
do I need the rest of it? Because we will want to
analyze and argue with the computer. That's what we
do.
CHAIRMAN BLANCO: Don't forget the light
and the bells and whistles.
DR. IAMS: Well, I don't need a bell and
whistle. Maybe a little bell, but really take out the
data that supports when the ST monitor goes off,
because the nature of the American physician -- I
won't necessarily just indict obstetricians -- is to
argue with, well, I didn't see anything go on there.
I'm sure I am right, and the computer algorithm that's
taken you 15 years to develop is wrong. That might be
a reason maybe in Sweden why you had to re-educate
people. I don't know. But in this country it would
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 216/322
be a big problem, I think, something you could easily
fix.
CHAIRMAN BLANCO: Well, let me pin you
down a little bit, and Dr. O'Sullivan as well. Is
that an issue that's sufficient enough that you are
concerned about the introduction of this device into
this country?
DR. O'SULLIVAN: Absolutely.
CHAIRMAN BLANCO: Really?
DR. O'SULLIVAN: Because, again, if the
device is introduced into this country without that
whatever it is secret he has about education, and that
education is not done universally, widespread, it is
doomed to failure.
CHAIRMAN BLANCO: Jay?
DR. IAMS: The second issue I brought up
about changing what is displayed, I think you could
change that fairly easily. The larger issue is trying
to get American physicians to buy into (a) there's a
problem with our current system and (b) this is the
answer. I think, unfortunately for you guys, after
all your fine work, the answer to that is probably
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 217/322
going to be an American study.
MS. TOLEDANO: The No. 2 question on my
page, from reviewing all these materials last night,
was, how will the knowledge be disseminated in the
United States? Because I definitely agree with the
importance of the question, but, if I recall
correctly, Ms. Daws-Kopp was telling us that the
sponsor is prepared to set up a program similar to the
Centers of Excellence that they have in Europe, so
that they would be coming into harvest, disseminating
the knowledge, doing the educational program,
reviewing cases, and monitoring the way that this
technology is marketed and distributed in the United
States. So, to me, that alleviates some of the
concern.
DR. SHARTS-HOPKO: I share the issues that
Dr. O'Sullivan raised, and we mentioned earlier a
concern about, how are women attended? When a woman
is attended by a midwife in the United States,
typically, that person stays with her pretty
constantly throughout the labor and the delivery.
That's only 1 percent of our births that are midwife
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 218/322
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 219/322
happen agree and I feel very uncomfortable with any
piece of medical equipment that does not have
appropriate alarms, so that when it is reading a value
that they consider out of bounds, the fact that there
is no alarm I think makes it personally unmarketable
in this country, because you can't have a piece of
medical equipment attached to a patient without alarm
parameters. So in that way I agree.
DR. WOLFSON: Yes, but a lot of our fetal
monitors, you can have recurrent late decelerations;
nothing goes off. You're supposed to look at it.
DR. RINGEL: Ah, but that's an
interpretation. I'm being told that people interpret
this differently. They are specifying an out-of-
bounds value for their ST or T waves -- excuse me --
for their T wave QRS ratio. That is part of their
premise. They have an out-of-bounds ratio, and that
they have an automatic detection. So if we don't want
the alarms, then we go back to displaying just the QRS
pattern and, like any electrocardiogram, where we
would then interpret it ourselves, or if you're going
to say there's automatic detection and you set
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 220/322
boundaries, and they have set boundaries, then I think
you have to have an alarm.
DR. WOLFSON: I would agree. I would like
to see some type of alarm because part of what I see
the power of this tool is, is that it's another factor
that's going to come back and alert people to go back
and re-evaluate the status of the patient, the status
of the tracing in the context of interpreting it.
Because the other feature relative to
outcome is, what's the time to delivery? If the time
to delivery is felt to be under 5 to 10 minutes, or
even some people might even argue as far as 30
minutes, then, clearly, you're going to go for a
vaginal delivery, and the patient is not going to fall
into an operative category. Otherwise, you're going
to go in the other direction.
CHAIRMAN BLANCO: I think we have sort of
gotten off 3D here and we're going back to the fact
that, again, and the word I was looking for before was
to be so provincial, but I think you need to
Americanize the device a little bit as to what the
practice here is.
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 221/322
But let's try to go back into 3D and 3E.
In a way, we've also talked about retraining. I think
training is coming out as an extremely important
adjunct to this particular device.
But, Nancy, go ahead.
DR. SHARTS-HOPKO: Thank you. I
remembered my point.
The Swedish study looked at applying the
device to women that had some risk indicator, and we
monitor everybody pretty much here. So we don't know
what kind of false findings we're going to find in a
normal population, a general population. I'm
concerned about that.
DR. BROWN: Another point is we don't
know, in terms of comparing the populations, the
incidence of pre-existing conditions that might be
undiagnosed or unknown or even that are known.
Someone mentioned the contrast in prenatal care. Was
there a comparable rate of women with diabetes, IUGR,
pregnancy-induced hypertension, smoking, drug use,
whatever, in this population? I mean, I have some
concerns about that.
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 222/322
Then I think, getting back to Dr. Iams'
point, if you're talking now about the management
differences, I think the question about, can this be
marketed to reduce the operative rate is a valid
point, because if the indication of this is that your
company wants to market as a way to avoid operative
deliveries by letting you use this for that gray area
of fetal heart rate tracing, and sit on that patient,
that needs to be very clear. Because to me, just
reading it, not having done obstetrics in a long time,
it is a little confusing.
Is that really the primary point of this
device, to allow you to sit on the questionable
tracing, if there is not an ST flag on the screen or
an alarm?
CHAIRMAN BLANCO: I think that was sort of
what was addressed, that that's one of the ways that
the fetal heart monitoring is not reassuring, is non-
reassuring; you then look at the ST events or ST
changes.
DR. BROWN: Because that will require a
whole complete change of culture and education.
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 223/322
CHAIRMAN BLANCO: Well, I think some
people think so.
The other issue that you brought up, and I
think it's important to bring up, because it's been
talked about immeasurably, is when it applies to
Caesarean section rates in terms of comparing, say,
Ireland versus the United States, the United States is
a very heterogeneous population. I'm sorry I've never
been to Sweden, but my understanding is that it is a
very homogeneous population, very much like Ireland.
So other than your percentage -- and I
don't have my hands on it right now -- of folks that
were from the Middle East and Africa and former
Yugoslavia, and most everybody else is pretty
homogeneous, and that percentage was 20 percent --
DR. O'SULLIVAN: Twelve percent.
CHAIRMAN BLANCO: -- 12 percent. So I
think that that is a concern in trying to extrapolate
the data from Sweden into the United States. I think
there really are different populations.
DR. O'SULLIVAN: But the other thing to
keep in mind, too, when you're looking at that, at
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 224/322
least based on our own experience in this country, is
the initial immigrant who comes in is generally the
healthier individual. That's why they're here. And
they generally do better than our own U.S.-born
individuals do.
CHAIRMAN BLANCO: I'm sorry, but I don't
understand your point.
DR. O'SULLIVAN: I was just saying that
because somebody is an immigrant into the country
doesn't mean that they are going to perform more, that
something's going to happen that's going to be more
complicated in terms of the obstetrical outcome for
that index pregnancy.
CHAIRMAN BLANCO: Okay, so what you're
saying is that, even though they have a 12 percent
population that is not what would be classified as
homogeneous, they may not be as homogeneous as some of
the population in the United States?
DR. O'SULLIVAN: Oh, absolutely.
CHAIRMAN BLANCO: Okay. Any other
comments? Yes, Ma'am?
MS. MOONEY: I think one of the things we
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 225/322
should keep in mind with this particular area question
is that, if we think the data we have in hand
essentially supports the safety and effectiveness,
answering these types of questions may be the things
we talk about in the post-approval study area. So to
keep cognizant of the fact that we can separate out
the inherent safety and effectiveness in the data we
have and make that judgment call versus what we could
look at entertaining the post-market study.
CHAIRMAN BLANCO: While I don't disagree
that you may need to look at it in a post-market
study, I'm not sure -- I think the point is that there
is some concern that the difference in populations may
mean that the safety and effectiveness may not be the
same. We're not talking about something that's
showing an 80-versus-20 percent difference. We're
talking about something that shows a very small
difference, significant but very small. So I think it
may still be applicable, an applicable point.
DR. WOLFSON: Jorge?
CHAIRMAN BLANCO: Yes, sir?
DR. WOLFSON: Going back to the
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 226/322
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. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 227/322
what is being seen on the strip. So the nursing staff
is making the decision, and they are generally going
to utilize external monitoring. When internal
monitoring is required, then they're going to call the
obstetrician in.
So I think that the difference in makeup
of the populations relative to whether it is the
heterogeneity of the American population, that as long
as we are using it where we think there is a specific
need for this additional information, it's not going
to differ from population to population.
CHAIRMAN BLANCO: All right, let's move on
to 3E, retraining during the Swedish randomized
controlled trial. I think we've kind of addressed
that. Does anybody want to summarize it or say
something?
DR. IAMS: I don't want to summarize it.
I have one question about it.
It's this sort of event that made me
wonder why the investigators did not decide, since we
didn't execute the interventions according to our
original plan, why didn't you restart the study
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 228/322
basically and then get your end from that point on?
It's powerful actually that you were able to achieve
the P values you got when the first, what, third of
the study was not totally compliant with the original
protocol. So why not repower it at that point? There
must have been some thinking along those lines at some
point.
CHAIRMAN BLANCO: I think there is some
disagreement with you on that. Do you want to make a
comment? I saw you shaking your head.
MS. TOLEDANO: You can't do that. You now
have to turn --
DR. IAMS: Yes, you can. You can do what
is basically a run --
CHAIRMAN BLANCO: Wait a minute. Let her
have a chance to finish. Go ahead.
MS. TOLEDANO: That would be so sorely
frowned upon, because basically you would have to
report the first study, that you terminated it early
for the protocol deviations. Protocol deviations
happen in all sorts of studies that are used by any
governing body in this country and in the European
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 229/322
Union and other areas as well.
As far as it is ingrained into me with
that all the ethics training that we are required to
take during studies and holding NIH grants, you can't
just stop a study because you don't like the protocol
deviations that people make. If there are protocol
deviations, you do your interim look. You can try to
fix it, but you finish up the study. You don't just
stop the study.
DR. IAMS: I don't disagree with that, but
all I can say is that you can, because we do it all
the time in NICHD-funded trials --
MS. TOLEDANO: Well, we don't do it in
cancer --
DR. IAMS: -- look at the performance and
then decide that you do not have enough in that has
followed the protocol. You just continue for longer;
that's all. You don't really deny the existence of
the first 1600.
MS. TOLEDANO: Right.
DR. IAMS: You report them. You're
completely honest, but you say, "We haven't achieved
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 230/322
our end, and so we're going to have to continue this
study in order to make sure that we have the results."
MS. TOLEDANO: They did that actually.
They recalculated the total sample size. It wasn't
based on protocol deviation. It was based on the
baseline rate of metabolic acidosis. So they did go
at the 1600 and calculate that they needed more than
the original 3200.
DR. IAMS: Okay, I missed that part,
but --
MS. TOLEDANO: Yes.
CHAIRMAN BLANCO: And the other point is
they showed more of the difference now. So I think
they showed that, with the retraining and re-
education, they actually did better off than without
it, before with the violations --
DR. IAMS: Yes, that answers my question.
CHAIRMAN BLANCO: Any comments on that?
Anybody want to add anything?
Well, I'll add kind of a summary because
I think it's been said before, but just to make sure
FDA hears it, I think this device is going to need a
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 231/322
fair amount of retraining before it hits the market,
and not after 1600 patients. I mean, I think there is
some education that needs to go with this. It can't
just be sold and expect everybody to use it and know
what they're doing. I think it has some inherent
necessities for a significant amount of training.
There's some precedent for that with other devices.
So I think that we need to recommend that, and I see
some shaking heads saying yes. So I think that's the
feeling of most of the panel.
DR. EGLINTON: Jorge?
CHAIRMAN BLANCO: Yes?
DR. EGLINTON: Can I get some retraining?
CHAIRMAN BLANCO: Yes, please do.
DR. EGLINTON: May I ask another question,
please, about the card. I want to know, I have an
intermediary CTG, and I want to know now if I have an
episodic T/QRS rise greater than 0.15, or a baseline
rise greater than 0.10, how do I figure that out?
Looking at the lower scale, the T/QRS scale, that is
rather tight. That's pretty subtle, trying to figure
out or move over one column over to abnormal CTG;
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 232/322
0.05, how am I going to figure that out? Does the
machine tell me that somehow other than just visually?
CHAIRMAN BLANCO: Gary, for the sake of
time and the other questions, and answering some of
the questions that we have asked the sponsor, I think
it's pretty clear, or should be pretty clear, to FDA
and to the sponsor, that that card is confusing and
may not be appropriate, and needs to be worked on
significantly. Maybe we can touch base on the details
at a time when there is more time.
DR. EGLINTON: But this is central. This
is how you make your management decision. I mean, if
it rises, if the baseline rises more than .05 with an
abnormal CTG, that is the reason to intervene. It's
really central.
CHAIRMAN BLANCO: All right, Dr. Rosen?
DR. ROSEN: The computer identifies these
changes, and it will tell you in detail what extent
there is in change, whether it's more than .05 or it's
more than .10, and whether it's episodic of more than
.10 or more than .15, and that's written and it's
flagged on the screen. It is written on the paper.
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 233/322
There is an ST log where all these events are
recorded. That log is available to the operator
throughout the delivery process.
So the issue of interpreting the ST change
is very much a reflection of being capable of reading
the statements made by the computer.
DR. EGLINTON: Is that on the review mode?
Is this illustration, figure 2.2.3, is that what
you're talking about, on the review mode in the upper
right?
CHAIRMAN BLANCO: I'm sorry, Dr. Rosen,
but we kind of need to hear and see what you're saying
for the record. So if you would go ahead and go
back --
DR. ROSEN: So on the user manual there is
a graph showing how the user is informed about a
significant event, where what's called an event log
window is available, where all these events are logged
as well as there is a keyboard, so you can key in
specific information that you tell, "I recognize
this," and so on.
MS. LUCKNER: Dr. Blanco?
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 234/322
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 235/322
behind this to fail because the user would not
understand how to use the equipment and how to
interpret these events. Please remember that those
guidelines you have in front of you, they are like a
pocket, just a quick memory thing. You should, I hope
some of you have been able --
CHAIRMAN BLANCO: Dr. Rosen, I'm sorry to
interrupt you, but you've also got to remember you've
got some fairly, supposedly, bright people up here,
and you know we're frankly confused, okay? So let's
let is loose on the United States, and you're going to
confuse a lot more people. Okay?
DR. ROSEN: Have you consulted the
educational material yourself?
CHAIRMAN BLANCO: Well, no. I mean, I
haven't been educated by what you have, but we don't
have that on here.
DR. ROSEN: Yes, you have.
CHAIRMAN BLANCO: We're just making
suggestions that there is confusion. Okay?
DR. ROSEN: Okay.
CHAIRMAN BLANCO: And there are important
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 236/322
things about how you're labeling that may be
regionally-specific, issues that you need to address.
I think we have made it very clear about the need for
significant education process on there. Okay?
DR. ROSEN: For the record --
CHAIRMAN BLANCO: I'm going to break my
rule and I'm going to recognize Dr. Devoe because I'm
sure that he has something valuable to add at this
point that is short in time, because we are starting
to run a little late.
DR. DEVOE: I'll put on my Yankee hat and
be very brief.
CHAIRMAN BLANCO: Please state your name.
DR. DEVOE: Dr. Lawrence Devoe, Medical
College of Georgia, consultant for Neoventa.
What has probably not been properly
emphasized is that out of the box there is a very,
very specific, detailed, organized, orderly, and
properly-written tutorial that really must be done
before you flop up the first power switch on any of
these devices, and to presume that you can use any
device like we have erroneously done in the fetal
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 237/322
monitoring world for the last 30 years without doing
this is really missing, I think, a very important
concept.
There is a tremendous amount of education
that goes into the use of a device that has this
internal degree of sophistication. It does two
things. It teaches you what this device does that
conventional monitoring doesn't do, and, in turn, as
you have seen by some of the clinical experiences, it
makes the user better at the basics of electronic
fetal monitoring, which is something we have been
derelict in since fetal monitoring was first
perpetrated in the United States.
CHAIRMAN BLANCO: Thank you.
Gary, any other comments you want to make?
If not, can we move on?
DR. EGLINTON: No, that answers it. Thank
you.
CHAIRMAN BLANCO: All right, let's move
on. Let's try to see if we can do No. 4 before we
take a break.
No. 4: "In addition to a Swedish RCT, the
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 238/322
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 239/322
Gothenburg, again, with experience, or with experience
with this device, it did show reduction in the cases
with metabolic acidosis as well as operative delivery.
DR. RINGEL: It was with the City of
Gothenburg that I raised the question before. Maybe I
am misreading the slide. This is on page 29 of Dr.
Rosen's presentation. That's why I asked the question
before.
Maybe I've got this wrong, but it looks
like, with experience, the obstetricians in Gothenburg
did better with plain CTG than they did with STAN in
detecting metabolic acidosis, with experience. Do I
have that wrong?
CHAIRMAN BLANCO: Dr. Rosen, can you come
up?
DR. RINGEL: The rates of metabolic
acidosis looked much lower than with STAN. In fact,
it's only for the total and for the CTG that there is
a statistical difference demonstrated and none with
the STAN.
CHAIRMAN BLANCO: Anybody?
DR. DEVOE: Devoe again.
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 240/322
One of the things that should be
appreciated is that the selection of cases in the CTG
arm or risk stratification were much less likely to be
high-risk cases than in the STAN arm. In other words,
these weren't cases that were randomly assigned one or
the other in general. One of the obstetricians here
can probably speak to that, if there are further
questions later on.
But the standard CTG arm represented the
lower echelon of risk patients. One would empirically
expect to have a higher rate of complications in the
STAN arm in terms of metabolic acidosis
DR. RINGEL: But you're presenting this
data in support of the efficacy of STAN in an
observational trial, and the rates of metabolic
acidosis in the first half of the trial are
essentially the same, and then they go down
substantially in the CTG arm, but not in the STAN arm.
DR. DEVOE: They declined in both arms,
but also remember that there is also an educational
impact in the area of fetal monitoring in general that
would have affected both arms.
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 241/322
DR. RINGEL: But there's no little
asterisks over the STAN arm to indicate statistical
significance while there are asterisks over the total
in the CTG arm.
DR. DEVOE: Right, because they got
better. They got better as time went on. I mean,
that's part of the educational impact.
DR. RINGEL: But the STAN didn't get
better. So then you could have just educated people,
continued to use CTG, and you would have dropped your
metabolic acidosis rate to .1 percent. Am I reading
this wrong?
CHAIRMAN BLANCO: No, you're reading it
right, except the number you said is not right. I
think these are fractions of a percent. It went from,
in the CTG arm, from 1 percent to .01 percent.
DR. RINGEL: Right.
CHAIRMAN BLANCO: Okay.
DR. RINGEL: But the STAN arm didn't
statistically --
CHAIRMAN BLANCO: And the STAN arm went
from a little under 1 percent to about .6 percent.
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 242/322
DR. RINGEL: Yes. So all you had to do
was wait a year and things would get better without
STAN, right?
DR. DEVOE: No.
DR. RINGEL: No?
DR. DEVOE: They're still training on
STAN.
DR. RINGEL: Okay. So it's the paying
attention to fetal ECG that's making the difference
whether it's STAN or not?
CHAIRMAN BLANCO: Go ahead.
DR. ROSEN: Could I address this here? I
think it's one important aspect here, and that is to
say, what happens if you've got obstetricians and
midwives used to having ST information available, and
then there is a group where it is not available?
Clearly, that group, according to our practice of
using the fetal scalp electrode, would be a low-risk
group, because the high-risk cases, they would have a
scalp electrode applied: those with inductions, those
with augmentation of labor, those with any antenatal
history.
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 243/322
So then you have a remaining group now
being monitored with heart rate only. I believe what
we have seen is the impact of more accurate assessment
of the heart rate trace. We can ask the midwife here
to explain a little bit about the process.
CHAIRMAN BLANCO: Well, but I think that
is what he is saying.
DR. RINGEL: Don't you see what I am
saying --
CHAIRMAN BLANCO: That's what he's saying.
DR. RINGEL: -- is your Gothenburg trial
would suggest that just by educating your care
providers, you can achieve the results you want to
achieve with an expensive apparatus.
DR. ROSEN: On the other hand, this is
done taking the high-risk cases out of the group being
monitored with heart rate only. So, basically, you
would expect a very low incidence of interventions --
CHAIRMAN BLANCO: But there's still a
change, and let's go ahead. I think you have made the
point that there is some data from the Gothenburg
study that shows that there may be a decrease just by
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 244/322
reading the fetal heart rate monitor.
DR. ROSEN: Right. Oh, yes.
CHAIRMAN BLANCO: Okay, thank you.
MS. TOLEDANO: I just wanted to clarify
some numbers on this same graph. So I'm seeing with
the STAN, in the first half of the graph, an "N" of
668 and approximately 1 percent having the metabolic
acidosis. So that would be seven babies. Then on the
righthand side of the graph, an "N" of 764 with a .6
percent. So that would be about five babies. Is that
what we're looking at, going from seven children to
five children? There is no way you can get
statistical significance there. So that's why there
are no little stars.
CHAIRMAN BLANCO: But I think the point is
still that --
MS. TOLEDANO: They can't.
CHAIRMAN BLANCO: -- in the other arm they
did.
MS. TOLEDANO: Right, in the other arm
they do decrease it by the better education --
CHAIRMAN BLANCO: They do have larger
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 245/322
numbers.
MS. TOLEDANO: And we would benefit from
that.
CHAIRMAN BLANCO: Okay, we're going to
move on, Dr. Rosen. Okay, we're going to move on.
So I think the question was asked,
actually, in a broader issue, which is, is the data of
these other studies that were not specifically aimed
at testing the hypothesis that the sponsor was putting
forth, does it support or not support, and can it be
used in some way to improve our decisionmaking in
terms of approval of the device or lack of approval?
Bring it back to that.
Yes, Ma'am?
MS. BROGDON: Dr. Blanco, I need to point
out that in the written copy of your questions we left
off the Nordic study. It's on the slide up there.
CHAIRMAN BLANCO: Okay, thank you.
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,
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 246/322
yes.
CHAIRMAN BLANCO: Okay. All right, any
other comments on this?
(No response.)
All right, we're going to -- it's 2:22
right now by the official clock. We have a 15-minute
break. So we will start promptly at 2:37. Thank you.
(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 BLANCO: All right, let's go
ahead and begin. We're still going through the
discussion process and answering the FDA questions.
We are at Question 5. It's labeling and
training. It's: "The sponsor proposed the following
indication: Use of the STAN system is indicated when
there is a planned vagina delivery and there is a
full-term singleton fetus in a vertex presentation,
and there is a need for close fetal surveillance
during labor, or there are maternal disorders and/or
uteral/placental dysfunction with potential adverse
influence on fetal oxygen and nutritional supply or
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 247/322
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. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 248/322
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 249/322
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. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 250/322
CHAIRMAN BLANCO: Okay. Any other
comments?
(No response.)
Okay, so I guess two issues that were
brought up is that, and I don't know if there is a
consensus from the panel, so I would like a couple
more people to say something, that the indications
need to be tightened to include folks with high-risk
conditions as opposed to the more broader wording that
is currently here?
Then the other issue is concern or at
least some information from the sponsor about in a
low-risk population, if it has been used for that, has
there been some evidence of significant number of
false positives?
Am I paraphrasing you correctly, Dr.
O'Sullivan?
DR. O'SULLIVAN: Yes.
DR. RAMIN: It's kind of the question that
I had asked, and that is, you have normal tracing;
what is the false positive rate in those individuals?
CHAIRMAN BLANCO: Okay.
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 251/322
DR. RAMIN: I have another comment just
regarding the deviation from the normal course of
labor, including induction and augmentation of labor.
I can't speak for all institutions in the United
States, but I do know that we don't necessarily have
to do internal monitoring for an induction or
augmentation of labor. We can do external monitoring.
I guess in order to use this device, it
has to be internal monitoring. So my recommendation
would be to have that as an indication.
CHAIRMAN BLANCO: All right.
Jay, you have a question?
DR. IAMS: I just didn't understand the
last part of what Sue said there.
CHAIRMAN BLANCO: Yes, what did you say?
DR. RAMIN: Well, part of the indication
would be deviation from a normal course of labor. So
if you have a woman that you're inducing, that would
mean that you have to insert -- this is an internal
monitor, the scalp electrode. I think there are cases
where you can induce somebody's labor with an adequate
external tracing, not have to do internal monitoring.
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 252/322
CHAIRMAN BLANCO: Well, but wait a minute.
But, Sue, the issue is not that you have to, because
you don't necessarily have to use this technology. I
mean, the question is -- I would phrase it differently
-- is induction of labor sufficient indication to use
the STAN? Is that enough of a condition that makes a
patient non-routine to use the STAN, to justify the
use of a STAN? Not that, okay, I'm inducing somebody,
so I've got to use the STAN. I mean, I think the
question is the other way.
Does that make sense?
DR. RAMIN: That makes sense.
CHAIRMAN BLANCO: Yes. Is induction of
labor, augmentation of labor, enough of an --
DR. RAMIN: Indication.
CHAIRMAN BLANCO: -- indication, a high-
risk condition, it's an indication to insert an
internal and use the STAN monitor? Is that what you
meant? Did that clarify it?
DR. IAMS: Yes.
CHAIRMAN BLANCO: So what do you think?
DR. WOLFSON: Yes.
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 253/322
DR. IAMS: Do I think the labeling, if
modified as described, would be appropriate?
CHAIRMAN BLANCO: Would it be appropriate
to use the STAN monitor in patients just simply
because they're being induced?
DR. IAMS: Oh. No, I wouldn't think that
every patient being induced would need a STAN monitor,
no. Some patients, if -- we all probably have
slightly different indications for use of an internal
fetal monitor, but in recent years the indication for
an internal fetal scalp electrode is often going to be
coincident exactly with the kind of patients that were
studied in this trial. The low-risk patient who is
being watched in order to be careful with every baby
is watched in our unit with an external monitor unless
an adequate tracing can't be obtained.
So if tracing is then normal, I wouldn't
think you would need the STAN, but if you have any
abnormality of the tracing or any abnormality of the
course of labor, or the antepartum conditions there
were mentioned, then I think you would have an
indication for a STAN.
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 254/322
CHAIRMAN BLANCO: Dr. Wolfson, I heard you
say "yes." So would you like to comment?
DR. WOLFSON: Well, I agree with what Jay
just said. I think that most inductions can be done
without the need for internal monitoring, if not
probably nearly all of them. I just wouldn't want to
-- let me back up.
I believe the evidence that was presented
suggested that one of the greatest, one of the
complications of induction, which is hypertonus, will
probably be detected through the STAN. So if it is
missed from clinical assessment, the system might
alert the person. So I a value of utilizing it in
patients who are under induction.
CHAIRMAN BLANCO: All right, anyone else
care to comment?
(No response.)
I take it from the silence on the other
issues, most panel members are in agreement that
tighter indications to make it more clear that this is
to be used in high-risk conditions until there is more
information at least, until there is more information
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 255/322
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 256/322
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 257/322
controlling how the product is labeled, how the
indications for the product are made. If somebody
from the FDA wants to contradict me, feel free, but in
my experience it is the province to say, "This is a
problem." Say, "This is a terrific device. We think
it ought to come on the market," whatever, "but it can
be misused if people don't understand, or used
inappropriately" -- that may be a better terminology
-- "used inappropriately without the appropriate
educational level, labeling, and indications," and
then it is up to us, if that is the issue, to suggest
not in crossing the "T's" and dotting the "I's"
detail, but in some general detail, what types of
education, labeling, and indications need to be put on
the device in order to market it safely in the United
States.
So I would say that is the only thing I
disagree with. I think we can do that, if that's what
you want.
DR. IAMS: Well, that's good to hear.
What I meant was I didn't think the FDA could really
mandate that stuff.
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 258/322
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 259/322
Dr. Wolfson, I think I saw your hand up?
DR. WOLFSON: Yes, I was just going to
comment. I like the Fetal Surveillance Manual. I
read it cover to cover. I found it -- I loved the
diagrams and I loved the choice in the terminology,
and I think this is a wonderful educational tool for
anybody in obstetrics and gynecology, whether they're
in nursing or whether they are physicians or midwives.
I, unfortunately, did not have the
experience in being able to open their educational
tool on my machine. My machine kept bombing. It just
wouldn't let it open.
So I think that education is a key point
is this particular product, and I don't feel that I am
sufficiently expert in their educational process to
say that what they have is currently insufficient to
train someone who is not knowledgeable in this
technology to become knowledgeable in this technology.
One of my original questions was, what is
the endpoint when you know that someone is adequately
trained? Is the software built in such a way where
you have to demonstrate a specific number of cases
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 260/322
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 261/322
the use of the device to ensure that it is used
appropriately.
Yes?
DR. O'SULLIVAN: The one thing I would
also suggest in this manual, which I am sure both Mike
and Gary have pointed out, and I suspect Dr. Rosen
knows, is that the teaching tools using the fetal
monitor tracings in here are the European as
contrasted to our 3 centimeters a minute.
Fortunately, I am familiar with that, so it was not
difficult, but for students it will be difficult.
CHAIRMAN BLANCO: Well, I think that goes
under what we said of a little bit of Americanization
for the American market will probably be very helpful
to their product.
All right, any other comments on No. 6?
Anything else that anyone would like to say?
(No response.)
All right, let's move on to No. 7. "If
the panel votes to recommend approval of the STAN
monitor, is there a need for post-approval studies,
and if so, what is the purpose of such studies and
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 262/322
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: Okay.
DR. EGLINTON: I stop short of this
question.
CHAIRMAN BLANCO: All right. Well, then,
let's move on to someone else and see if they have
something to the question. Dr. O'Sullivan?
DR. O'SULLIVAN: I feel the same way Gary
does.
CHAIRMAN BLANCO: Okay.
DR. O'SULLIVAN: I would rather know what
we're going to do before I answer this question.
CHAIRMAN BLANCO: All right, well, then,
unless someone else feels strongly -- Jay?
DR. IAMS: I'll try to bail you out,
Jorge.
CHAIRMAN BLANCO: Thanks. I appreciate
it.
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 263/322
DR. IAMS: I think the gold standard for
tests is the Papanicolaou smear. It ought to be
possible to have post-marketing studies for
obstetrical interventions or screening tests that do
pretty much what the last 50 years have done for the
Pap smear. You ought to be able to see, and the
Gothenburg study may be the beginning of such an
event, that the introduction of a technology into
practice results in appropriate screening and
intervention that results in a real clinically-
important outcome.
So I think this is a device which pretty
much automatically should qualify, if approved,
whenever it is approved, for that sort of post-
marketing surveillance.
CHAIRMAN BLANCO: Thank you. Anyone else?
Go ahead.
DR. WOLFSON: I wanted to second what Jay
said. I think that, clearly, the experience that
occurs in the United States has to be monitored and it
has to be reported because, again, of the diversity
that we are going to expect to see from country to
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 264/322
country. Without the European Union information, we
don't really know even the initial diversity over
there. So I would suggest that there, indeed, be
post-marketing studies.
DR. SHARTS-HOPKO: I have a question for
Jay. Would the outcome of a post-marketing study
still be metabolic acidosis or would you like to carry
that forward to be neurological outcomes?
DR. IAMS: Well, of course, you would like
to see both. I don't think it is the company's
responsibility to follow every patient that uses their
device forever and ever, but I think it would be their
responsibility to participate actively in that sort of
effort over time with whoever wants to follow that
sort of thing. That's a bigger issue than just for
one individual company within an industry to do, but
it ought to be the kind of thing we look forward, and
that the company fosters and doesn't impede.
We have had examples of that in other
technologies where that doesn't happen. Technologies
have been approved, and then when they're not
successful in influencing the ultimate outcome,
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 265/322
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 BLANCO: Okay. Any other
comments?
(No response.)
All right, that ends the section on the
questions that the FDA posed to the panel. What I
would like to go through is I would like to go through
with the different questions that were asked, and a
lot of the questions that were asked of the company,
the sponsor, have already been addressed, but maybe,
Dr. Rosen, if you could come up and we can go through.
Please forgive me; I have "X'ed" some of these out.
Yes, sir? One more question? You mean a
new question of Dr. Rosen?
DR. RINGEL: Right.
CHAIRMAN BLANCO: Okay. Why don't we go
through what I have here. Yes, sir, you can certainly
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 266/322
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 267/322
DR. ROSEN: Well, unfortunately, we don't
have that many cases in the Swedish randomized trial.
As far as I remember, there were actually two or three
cases that showed ST events as well.
It is the issue of a fetus that is exposed
to the stress of labor, regardless of race, would
respond, according to what we know, in a similar
fashion.
CHAIRMAN BLANCO: Okay. So for IUGR you
don't have that --
DR. ROSEN: We don't have the numbers
required.
CHAIRMAN BLANCO: All right, the other one
was, how as the management schema arrived at?
DR. ROSEN: This is very much part of the
whole development process of the STAN device, starting
with the experimental work, technological development,
and then followed by observational studies in the
clinical sense.
Obviously, you're observing these cases of
metabolic acidosis as they emerge and recognizing
events that we previously saw in the animal setup,
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 268/322
where we had structured settings with well-defined
hypoxia.
Then obviously there is the issue of the
technology, to what extent we can detect significant
events, given the source of information, the
electrocardiogram. In the Plymouth randomized trial
we used sort of an old technology, analog signal
processing. There was a scatter of data presented,
but we also looked for trends.
Today the database in the ECG quality is
so much different and so much improved that we can
look for more detailed ST events emerging, thereby --
CHAIRMAN BLANCO: Actually, I think the
question was really more addressing the issue that we
may have brought up already in terms of, when you put
down the way to use this device, you know, are you
going to say, you look at the fetal heart rate
monitoring and you only use it when the fetal heart
rate monitoring is not reassuring. Then you look at
whether you've got ST events, and you add that
component to make your decision. That's what they --
DR. ROSEN: That is basically the way it
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 269/322
should be used, according to the instructions.
CHAIRMAN BLANCO: Okay. All right. Dr.
Neuman asked about lead configuration, T wave
configuration, from spiral electrode, lead vector
changes as labor progresses and fetus moves. Have you
looked at that at all?
DR. ROSEN: Oh, yes, very much so. That's
the reason why we have the unipolar electrode
configuration, thereby creating an opportunity to have
a consistent ST wave form displayed throughout labor,
regardless of how the fetus rotates, but also
identifying what's called the "Y" lead in the
longitudinal plane of the fetus; that is where the T
vector is represented. So that is the way to secure
that we will pick up T wave ST events throughout
labor. There is literature on this and papers
published on this issue of lead configuration.
So, as I said, to record the ST, it's
completely different from just one heart rate being
displayed.
CHAIRMAN BLANCO: All right. Another
question was brought up about, what were the
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 270/322
complaints of the purchased units?
DR. ROSEN: These were related to failures
of the printer, technical failures that were easily
sorted.
CHAIRMAN BLANCO: Technical failures of
the printer or of the machine?
DR. ROSEN: There was nothing on the
safety aspect.
CHAIRMAN BLANCO: The concordance of the
STAN results with pre-terminal tracings?
DR. ROSEN: Well, we have pre-terminal
tracings as part of the guidelines. As you noticed,
there was one case that has been displayed here where
they didn't follow the protocol.
The physiology behind this is that, when a
fetus is exposed, if you go beyond the point where the
fetus is responding, and the heart rate performance or
cardiovascular performance starts to decrease, you
will not see a further rise in the ST.
On the issue of when we use the technology
and where there is a risk, could we identify cases
prior to the onset of labor, if we look at the data
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 271/322
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 272/322
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 273/322
in that case because I am not quite sure I got that
out of the instructions. Is that pretty clear in the
instructions, that you do not --
DR. ROSEN: Yes.
DR. IAMS: I noticed that there were
different criteria or that you had to be careful
during pushing, but I didn't get the idea that you
really shouldn't add this to someone's labor at the
point where she's already pushing.
DR. ROSEN: That is what is told and what
is very much part of the education process.
CHAIRMAN BLANCO: But is it just when
you're pushing or is it when you already have a fetus
that has had some myocardial decompensation?
DR. ROSEN: The reason we're doing this is
that what we found in the study is that this period
when you go from early stage to active pushing in
second-stage, that is where we find that the fetus is
exposed to hypoxia.
CHAIRMAN BLANCO: Okay. I know, but there
are going to be some patients, if this gets used in
the United States, that will already have some level
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 274/322
of hypoxia at the time that patients come in. A lot
of our patients come in late in labor. They've got
severe complications that create a problem, and the
fetus may already be hypoxic.
I think Dr. Iams' question is, if you
already have hypoxia, myocardial deterioration, and
you put the STAN monitor on, does it show you that
that is occurring, or because there are already ST
changes, the program will not recognize it?
DR. ROSEN: Well, this is obviously a
somewhat difficult question to answer. Depending on
where you are, if you are in the pre-terminal phase,
you have to rely on the heart rate trace, showing no
variability, no reactivity, but if you've got
reactivity, if you've got a fetal heart capable of
responding, then you will also see ST events,
regardless of what degree of metabolic acidosis you're
at.
CHAIRMAN BLANCO: So the answer is really
yes?
DR. ROSEN: Yes.
CHAIRMAN BLANCO: If you've already got
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 275/322
significant myocardial effects, the STAN monitor will
not show you anything?
DR. ROSEN: Well, it depends on where you
are. You may still have a heart which is exposed to
hypoxia where you will find marked ST events
associated with that. But if you take it through the
next step, where the cardiovascular system is failing,
where the fetus has decreased blood pressure, then you
will have the pre-terminal heart rate trace, and don't
expect ST events to go with that.
CHAIRMAN BLANCO: Okay. Jay, are you
satisfied?
DR. IAMS: Yes, I think so. Just let me
say it back to you again. If I have a patient with
the appropriate risk factors, my good care of this
patient would be maximized by having a STAN electrode,
rather than a regular electrode, inserted by the time
the time the patient reaches 6 or 7 centimeters,
because if I don't do it then, I might end up failing
to use the device in its most appropriate fashion?
DR. ROSEN: That would be according to the
recommendations of use of the device.
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 276/322
DR. IAMS: Right.
CHAIRMAN BLANCO: Thank you.
Did I get everybody's questions that were
not answered? Yes?
DR. WOLFSON: I just wanted to just
clarify what I thought I heard you say, Dr. Rosen. On
the STAN criteria or the algorithm for intervention,
the different levels of the .1, .15, and .05 are based
on clinical review and interpretation of the large
database that you have, and are not necessarily based
specifically, for example, on receiver operating
characteristic analyses per se?
DR. ROSEN: You are correct.
DR. WOLFSON: Is that correct?
CHAIRMAN BLANCO: All right, thank you.
Anything else? Go ahead, Gary.
DR. EGLINTON: Do you practice intrapartum
fetal stimulation in Sweden, vibrio acoustic
stimulation or LS clamp provocation of the fetus,
looking for accelerations?
DR. ROSEN: Varying between different
centers. We do have the fetal blood sampling in
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 277/322
Gothenburg, for instance, where in Lund there would be
more vibrio acoustic stimulation, and so on. So this
varies depending on where you would look.
DR. O'SULLIVAN: Let me ask you a question
regarding pushing, because this was something that I
was impressed about. In terms of at least in those
tracings that you showed us where the baby developed
or showed significant metabolic acidosis, while it
wasn't present in all of them, it seemed that the
tracings, at least as you looked at them, showed some
degree of abnormality, which got worse with pushing.
Was there any attempt to stop the pushing,
to allow the baby to recover? Or even to stop
contractions to allow the baby to recover, before the
baby developed some other abnormality?
DR. ROSEN: Well, once there's been a
significant event, according to the clinical
management protocol, obviously, we recommend immediate
delivery under those circumstances. According to the
data we have, we want that baby out as soon as
possible.
To try to stop pushing, to try to give
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 278/322
drugs, I mean if you obviously stop pushing and if you
give tributalin, for instance, stopping contractions,
okay, if contractions are the cause of hypoxia and
active pushing, you would expect there to be less
hypoxia, clearly. But how to institute that, I'm not
sure it would be practical and what we are
recommending is simply take the baby out, please.
CHAIRMAN BLANCO: Okay. Any other
questions from the panel members? Anything else they
would like to bring up?
(No response.)
Okay, let's move on. Open public hearing
again. At this point, what we would like to have is
not questions or interaction, but just basically if
anyone has any short comment from the audience, from
the FDA, or the sponsor. We will take them in that
order. Is there anyone in the audience not affiliated
with the sponsor or with FDA that would like to make
some final comments before the panel begins its
deliberation and votes?
(No response.)
Okay, next would be from anyone from the
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 279/322
FDA that would like to make any additional comments at
this point.
(No response.)
Nope? All right, then we go to the
sponsor. Anyone from the sponsor that would like to
make any additional comments at this point?
Okay, please identify yourself and your
relationship.
DR. NOREN: My name is Hakan Noren. I am
a consultant obstetrician in the University Hospital,
Gothenburg. I have no economic contract with
Neoventa, but they have paid my trip here and my stay
here.
CHAIRMAN BLANCO: Thank you.
DR. NOREN: I would comment on the
Gothenburg study. You must realize this is a clinical
situation. This is not a randomized trial. So don't
look at them in a STAN group or a CTG group. Look at
them together to see what is the number of metabolic
acidosis is. We are now down to .48 percent from
October to January.
So it is two quite different groups: the
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 280/322
high-risk group, the STAN group, and the low-risk
group. This is dependent on the midwives an
obstetricians getting better all the time to recognize
that there is something wrong with the CTG, and they
are immediately going over to the STAN group. So you
can't compare them. Look at them as one unit.
DR. RINGEL: May I ask a question?
CHAIRMAN BLANCO: Please, go ahead.
DR. RINGEL: You presented, you, the
sponsors, presented the data for us to interpret. I
understand what you're saying, but without knowing the
historical controls for your bad outcomes, without
knowing any comparison, without knowing what just
education of your midwives and your obstetricians
would produce, how am I to interpret the data?
For all I know, it could just be the
education process that has created such a tremendous
statistical improvement in your outcomes. For all I
know, you may have a very low rate of bad outcomes in
Gothenburg in general.
So how am I to interpret the data
regarding this machine?
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 281/322
DR. NOREN: You must realize that the
knowledge in the CTG interpretation before the
randomized trial wasn't that good, and a lot of
midwives, and even doctors, we looked at CTG in
different ways. Doctor, this study, when we started
with the STAN machine, we were forced to speak the
same language. This was the first thing.
Secondly, the midwives were forced to
identify what kind of CTG pattern it was in a much
more detailed way than they had done before. It has
been an ongoing education all the time, especially
after the relearning period, because we actually took
those cases where something has happened and discussed
them, and also pinpointed, say, to the doctor who had
made violations against a protocol and tell them,
"This is why there is a protocol." That's why,
obviously, this fetus has metabolic acidosis.
So by doing this all week, all months,
let's say, we have forced cooperation, to speak the
same language, and also to be aware of the situation.
Of course, many times the clinical situation it sounds
scientific here today, but many times you have a non-
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 282/322
reassuring CTG, and we are more or less waiting for
that ST event. When that happens, everyone is ready
to do the C-section. Of course, the time between
event and actually the C-section or vacuum extraction,
what we do is decreasing. That is one of the reasons
why we are better all the time, but it has continued
to be better.
CHAIRMAN BLANCO: Okay, unless you have
something else different, let's go ahead and bring it
to a close, that you would like to say, okay? All
right, thank you.
Okay, anything else the panel wants to
bring up? Questions or comments before we start?
(No response.)
All right, if not, Dr. Whang is going to
address the issue of the recommendations, options,
that we have available to us. I will go over a little
bit about how we're going to do the voting.
DR. WHANG: The panel will now be voting
to determination its recommendation to the FDA. Its
recommendation can be one of the following:
approval, approvable with conditions, or not
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 283/322
approvable.
Approval means there are no attached
conditions.
Approvable with conditions means there are
specific conditions which are discussed by the panel
and listed by the panel Chair. Conditions could be
labeling changes such as a revised indication,
contraindication, warnings or precautions, or a
condition could be a post-approval study or a
reanalysis of the data that have been presented.
Not approvable can be recommended for one
or more of the following reasons: (A) There is a lack
of showing of reasonable assurance that the device is
safe under the conditions of use prescribed,
recommended, or suggested in the proposed labeling.
(B) There is a lack of showing of reasonable assurance
that the device is effective under the conditions of
use prescribed, recommended, or suggested in the
proposed labeling. Or (C), based on a fair evaluation
of all material facts, the proposed labeling is false
or misleading.
If the panel votes not approvable, the
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 284/322
panel members will be asked to indicate why they think
it is not approvable and what is needed to make it
approvable; for example, additional clinical studies.
CHAIRMAN BLANCO: Thank you, Dr. Whang.
So, basically, what we have before us is
that we need to take a fairly complicated vote, and
I'll try to make it simple. Essentially, what we are
going to do is we are going to see if anybody is
interested in putting forth a motion and has a second
that would approve the PMA without any conditions,
just simply it's approved, done with, that's it. I
guess that will be the start.
Does anyone have an interest in making a
motion to approval without any condition at this
point?
(No response.)
Okay, not hearing or seeing anyone who is
interested in full approval, the next step is to see
whether there are members who want to propose and
second a motion that the PMA is not approvable. Is
there anyone who would like to make a motion, second,
that the PMA is not approvable?
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 285/322
DR. IAMS: I'll make that motion.
CHAIRMAN BLANCO: Okay, there is a motion
on the floor that the PMA is not approvable. Is there
a second?
DR. EGLINTON: Second.
CHAIRMAN BLANCO: There is a second on the
floor. Therefore, we are going to discuss this, and
then take a vote.
Jay, why do you think that it is not
approvable?
DR. IAMS: Well, I would like to
congratulate the authors on all their work. I don't
mean for this motion to be taken as a critical comment
on all that they have done.
I need to preface my remarks by -- I think
I can speak for lots of people, myself perhaps
specifically, in learning some lessons from the past
about more data not necessarily leading to better
outcomes. My presence on this panel may have
something to do with my involvement in studies of
uterine contraction frequency, where more data did not
lead has not led to better outcomes, and yet it was
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 286/322
much more data. That caused me to look back into
history and see if other examples might exist, and
they do, back to x-ray pelvimetry, for one, once used
rather routinely, now used hardly at all.
Electronic fetal monitoring as standardly
practiced is probably the best example. We have used
it progressively and often, and we haven't
accomplished, as Dr. Devoe pointed, the goals that we
had set for ourselves.
The second lesson of the past is that what
works in one place may not work someplace else. Baby
aspirin in this country in large populations of people
at risk didn't seem to do nearly as well as it did in
other studies.
So, with those concerns in mind, I'm
concerned about transportability and I'm concerned
that more data may not lead to better outcome. I am
hopeful that this will be an exception to both of
those historical lessons, because, I confess, I was
impressed with the information presented, but I don't
think it is yet time to approve.
I think that the reason for that would be
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 287/322
Item B. I'm not certain that it is going to be
effective in the United States population. I do not
have concerns about its safety in general. I think
I'm more concerned about whether it would do here what
it so clearly seems to have done in Sweden.
CHAIRMAN BLANCO: Let me put you on the
spot again. What would the sponsor have to do to
satisfy your concerns and be able to achieve an
approvable result?
DR. IAMS: Well, I think their EU study
will, in part, perhaps address the concern about
transportability from one place to another. An
American study would be another avenue to that.
CHAIRMAN BLANCO: Okay.
DR. IAMS: So that's it.
CHAIRMAN BLANCO: Does anyone want to
speak to Dr. Iams' concerns or shall we move on to Dr.
Eglinton and see his concerns?
(No response.)
All right, Gary?
DR. EGLINTON: I also want to congratulate
Dr. Rosen and all of his co-workers for the years of
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 288/322
work. I learned a lot reading this. I look forward
to reading a lot more and learning much more in the
coming years.
I am very excited about this concept. I
am very excited about this technology, and I hope it
works. I hope that it improves where we are with
fetal heart rate monitoring in this country.
But I am not persuaded by what I have read
that this will improve clinical practice in this
country. I hope that there will be a study performed
in this country that will have very clear results and
will convince me and others that this is a wonderful
technology for us to use in this country.
CHAIRMAN BLANCO: And the same question to
you, and I think I know the answer, but just so that
it goes straight on the record: What would the
sponsor have to do to be able to satisfy your
concerns, to make the PMA approval?
DR. EGLINTON: I think it is going to have
to be done in this country.
CHAIRMAN BLANCO: All right. Let me just,
before we open the discussion to the other panel
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 289/322
members, make note that the PMA review is independent
of cost, previous regulatory difficulties, clinical
data submitted in other PMAs, and the medical/legal
climate and its effect on the standard of care.
Having said that, does anyone else care to
make any comments, either in favor or against the
current motion and the comments about what has been
said by Dr. Iams and Dr. Eglinton.
DR. EGLINTON: Can I just add one more
phrase?
CHAIRMAN BLANCO: Sure.
DR. EGLINTON: I think it needs to be done
in this country because of differences in the style of
practice. The way obstetrics is practiced in this
country is dramatically different from the way
obstetrics is practiced in Scandinavia, and probably
many other places in the world.
CHAIRMAN BLANCO: Thank you.
Any comments? Michael?
DR. NEUMAN: Mr. Chairman, I'm just
curious what the difference is between not approvable
and suggested things to do and approvable with
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 290/322
conditions, with the condition being a study in the
United States.
CHAIRMAN BLANCO: Well, I would appreciate
any help from the FDA, if I say it incorrectly, but if
you're requesting another total study before it is
approved, you're basically not approving it. You're
making the requirement that they have to have a total
new study to come forward before the FDA and before
the panel.
As part of a condition, you can get post-
market surveillance or another post-market approval
study, but it will already have been on the market
during that time. So if it is approved with
conditions, and the condition is that you do another
study, then it is a post-market approval of study, and
it is marketable at that point.
Am I correct on that? I would appreciate
some help from members of the FDA.
MS. BROGDON: I think that's a semantics
problem. If you recommend that it's approvable, but
one of the conditions is a whole new study be done, we
would essentially take that as a not approvable
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 291/322
recommendation because the sponsor would have to
essentially start over with their clinical study. If
you mean a post-approval study, you should say that
clearly.
CHAIRMAN BLANCO: That would be a
condition then. That's what I was trying to explain.
Mr. Pollard?
MR. POLLARD: Right, and I would just like
to --
CHAIRMAN BLANCO: Would you identify
yourself, please?
MR. POLLARD: Thank you. Colin Pollard
with the Center for Devices and Radiological Health,
FDA.
I just wanted to remind the panel, from
some comments that I made at the beginning of the day,
just some basic definitions of safety and
effectiveness. With safety, basically, you -- FDA,
actually, ultimately, and you in your recommendation
-- have found that the probable benefits outweigh the
risks of the device. To find it effective, the
studies that support that PMA have shown a clinically-
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 292/322
significant result. That is basically the threshold
for an approval.
Now for a post-approval study, for
instance, you need to meet that threshold, and then
that post-approval study would be looking at, you
know, things beyond that threshold, either rare events
or long-term results or fairly focused questions or
validating a surrogate endpoint, that sort of thing.
CHAIRMAN BLANCO: Thank you.
The floor is open for comments from the
panel members.
DR. O'SULLIVAN: I really do believe that
a study should be conducted in this country. I think
I say this because I think even the Scandinavians have
shown that introducing it initially, followed by their
interim analysis, re-education, and so on, shows that
there is a great deal of learning that needs to go on
in understanding how to use this and how to properly
interpret it. That's No. 1.
No. 2, in contrast to Scandinavia and in
contrast to what we would even say as far as product
labeling is concerned, if this device is in a
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 293/322
hospital, it will be like the pulse oximeter; they
will use it routinely, and it won't matter.
I think that the additional factor
regarding its success would be that if we don't do
this thing and were to otherwise approve it, that
getting it off the ground and getting it working and
getting everybody educated would take forever, would
not be successful, not as successful, because of the
thinking processes of physicians, nurses, and nurse
midwives in this country.
So if this was going to be at all
successful in the United States, then I think that
there's only one way to go, and that's a randomized
controlled trial.
CHAIRMAN BLANCO: In the United States?
DR. O'SULLIVAN: In the United States.
CHAIRMAN BLANCO: Okay. Let me just point
out, in all fairness to the sponsor and the FDA, that
the issue of non-approved use, unfortunately, is not
the purview of the FDA. They have to approve for the
indications, but they don't and can't control how
physicians in the United States then use the devices
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 294/322
that are out on the market and available, just for the
record, so everyone is aware of that.
Okay? Any other comments? Dr. Wolfson, I
think I see your hand.
DR. WOLFSON: A question for Dr. Pollard
and then some thoughts.
Colin, can you clarify again that what we
are looking at when we are approving the PMA is that
the investigations that have been accepted by FDA
demonstrate statistical significance, and that the
device is considered to not put increased risk of
patients at jeopardy?
CHAIRMAN BLANCO: Let me just point out,
we're not approving. We're talking a motion for non-
approval of the device. Okay? Just so we're clear.
Mr. Pollard?
MR. POLLARD: Right, and your question is
about to approve the PMA. Basically, there's three
elements that we talked about this morning. One is
that it is based on valid scientific evidence, and we
talked about what that means, the different types of
studies that any sponsor can submit.
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 295/322
Based on valid scientific evidence, the
PMA would need to show that it is both safe and
effective, and sort of the operative words with safety
is that the probable benefits outweigh the probable
risks when it is used as it is intended to be used in
the labeling that is given in the application.
Secondly, for effectiveness, that that sum total of
the valid scientific evidence in the application shows
when the device is used as it is intended to be used,
that it produces a clinically-significant result.
CHAIRMAN BLANCO: Now let me just add, if
you read it in your package, there should be the
definitions, and there are issues of target
population. Maybe it would be worthwhile to read the
definition of effectiveness for the panel. The
definition is: "There is reasonable assurance that a
device is effective when it can be determined, based
upon valid scientific evidence, that in a significant
portion of the target population, the use of the
device for its intended uses and conditions of use,
when accompanied by adequate direction for use and
warnings against unsafe use, will provide clinically-
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 296/322
significant results."
I believe that what Dr. Iams and what Dr.
Eglinton and Dr. O'Sullivan have been brought forth is
concerns about the significance of it in the target
population, and also the uses, the intended uses and
conditions of use, by the physicians who would use it,
if I could paraphrase that. Is that all right, Dr.
Iams?
DR. IAMS: That's fine with me. I think,
to say it differently, if I were a Swedish panel
member in Sweden, I would easily vote yes. I would
vote it to be approved with some of the minor
considerations we have talked about, but the issue is
the target population.
CHAIRMAN BLANCO: All right, any other
comments here? Yes?
MS. MOONEY: Yes. In light of the fact
that we have two randomized controlled trials,
acknowledging the fact that we have had that done
outside the U.S., both showing significant improvement
and meeting the study objectives, I wonder if perhaps
the better course here would be to entertain more
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 297/322
narrow indications in approvable status, where we
target the highest-risk patients, if that would not
tip the risk-benefit in a more favorable light, and
then again come back to a post-approval status as far
as determining whether any of our concerns with the
U.S. population are valid; also, in light of the fact
that the sponsor has indicated a willingness and
commitment to put together an extensive training
program, and at least in the Swedish situation has
shown that that training commitment and executing that
did, in fact, improve the use of the device.
CHAIRMAN BLANCO: Any comments? Dr.
Wolfson?
DR. WOLFSON: Jorge, yes, I'm really going
to speak against not approving. I guess that means
I'm speaking toward approval, but I'm not sure, based
on these definitions.
I share my colleagues' concerns relative
to effectiveness, but I would like to back up for the
record and make a couple of points.
I think it is clear to all of us in the
obstetrical realm that one of our principal goals is
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 298/322
to improve neurologic outcome. For decades, we have
looked at various tools to achieve that. This is the
first tool that has come along with demonstrable
scientific evidence that it has improved neurologic
outcome, period. It's demonstrated in the UK. It's
been demonstrated in Scandinavia. So I think the
validity is there, and I think we don't want to lose
track of that.
Two, I would like to point out that we are
looking at a paradigm shift, in my opinion, with
respect to the use of fetal monitoring. For one of
the first times, we are now taking a signal, as crude
as it is -- all of us understand that; we always are
amazed that we can tell anything about a fetus by
heart rate because you can't do that with anybody
else, but the idea is we are now analyzing that
signal, looking for information that has specific
correlates with respect to outcome. I believe the
authors have done decades of work demonstrating the
efficacy of this particular technique, and we're not
to lose sight of the value of that.
I think that an offshoot of this process
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 299/322
that's been addressed by my colleagues is the fact
that there is a great deal of variance or diversity in
the interpretation of electronic fetal monitoring in
the United States. This is a concern. It's an
educational issue. There's no doubt about that.
I think clearly the same issue was true in
the institutions that were part of the Swedish RCT,
because we saw that from the beginning to the end,
that as they received more training, their outcomes
became better.
I believe that a most important --
important, important -- offshoot of this particular
tool, this particular product, is that it is going to
take the American population of obstetrical providers,
whatever be their ilk, and bring them back to
restudying what is the electronic surveillance that we
utilize for the intrapartum patient. So that we will
become better as a nation and as providers in
interpreting the electronic fetal monitor, and with
the proper interpretation of the ST segment, produce
better outcomes and duplicate, in my opinion, the
findings that were seen within the Swedish and U.K.
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 300/322
studies.
I have no evidence that this particular
device creates harm when applied in an effective
manner. I would agree with my colleague who said that
what would be preferable here, in my mind, is perhaps
tightening up the indications of where it is utilized,
rather than voting for non-approval, and therefore,
obstructing access of obstetrical providers to this
device for an undetermined period of time.
We all know for them to mount a randomized
controlled trial, even through the maternal-fetal
network of the NIH, and bring it back to this
institution is going to take perhaps anywhere from two
to even as long as maybe four years.
So I would share the concern of my
colleagues with respect to effectiveness in an
American population, and I am still, in my own mind,
working through whether that requires non-approval or
whether it requires approval with post-market study.
Thank you.
CHAIRMAN BLANCO: Thank you for your very
thoughtful statements, Dr. Wolfson.
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 301/322
Anyone else who would care to address an
issue? Yes, Doctor?
DR. BROWN: I just have a point of
clarification with something that Dr. Wolfson said.
He made the statement that the studies clearly showed
an improvement in neurological outcome. By that, do
you mean they clearly showed a surrogate endpoint of
neurological, improvement in the surrogate endpoint,
meaning acidosis?
DR. WOLFSON: No, I was referring --
DR. BROWN: Because it wasn't my
understanding that they were really powered to detect
the neurologic outcome differences -- could you
clarify that? -- on a statistical basis?
DR. WOLFSON: I was looking purely at the
information that was provided in a Swedish randomized
trial on neurologic outcomes.
DR. BROWN: But that was not one of the
endpoints of the study or the objectives, right?
DR. WOLFSON: No, I know it's not one of
the endpoints of the study. I'm simply pointing out
to everyone that, in my mind, it may be the most
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 302/322
important aspect. It may not have been specifically
what they were after. They were after reducing the
risk of, or the likelihood of, metabolic acidosis, and
they were after the idea of demonstrating that you
could do it without increasing the Caesarean section
rate, because that's been the principal criticism of
all these new technologies we bring online, that it
becomes nothing more than another indication to
deliver somebody abdominally or operatively.
What I said is that I guess, in my mind,
the icing on the cake, the thing I've been grasping
for for 25 years of practice is to have a tool that I
can tell a patient that, because I am utilizing this,
I have the opportunity to perhaps improve the
neurologic outcome for your child. This is part of
the data that came out of that.
So, yes, it is not one of the endpoints,
but it is, to me, the most valuable aspect of it.
DR. BROWN: Well, let me be specific. Was
that -- and I'll ask the statistician -- was that a
statistically-significant finding?
DR. WOLFSON: Yes, it was.
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 303/322
MS. TOLEDANO: The probability of having
seven out of seven babies -- we had seven babies who
had moderate or severe encephalopathy. The
probability of having all seven of those babies in one
group is less than 2 percent. So that is "P" less
than .02. That is a two-sided P value.
DR. WOLFSON: In both analyses, the
intent-to-study as well as the revised, there was a
statistically-significant difference. It is in Volume
1, and God knows what page it is on because I didn't
memorize it, but it was one of those things that, when
I was going through the data and I was looking at
focusing on all this stuff, and all of a sudden it hit
me. It's the detail on the Swedish RCT. It's those
tables that are printed out in landscape in your
guide.
DR. IAMS: Page 15.
DR. RINGEL: Is it in 2, page 16? Is that
what you're referring to? I'm not sure if that's what
you were referring to or not.
DR. WOLFSON: I don't now.
DR. IAMS: I think it is the page before,
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 304/322
page 15, but the first box, "intention-to-treat
total." That's eight versus one.
DR. WOLFSON: Yes, neonatal outcome. The
intention-to-treat total, moderate to severe, neonatal
encephalopathy, it was 4 in the CTG group, 1 in the
STAN group, statistically-significant, a .02 level.
Then when you took those neonatal outcomes and looked
at them in -- what is interesting is -- where is it?
Well, anyway --
DR. IAMS: Go back a page to 15. You're
on 16.
DR. WOLFSON: No, I've got 15. What I was
looking for is that, when you then go into where you
take out the adequate recordings, that moderate to
severe neonatal encephalopathy becomes seven up
against zero in the STAN group, giving a statistically
significance of --
CHAIRMAN BLANCO: What page are you on?
DR. WOLFSON: Oh, I'm now on page 22. It
is the upper table.
MS. TOLEDANO: Yes, that's a one-sided P
value.
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 305/322
DR. WOLFSON: It's the fifth line down.
Now you are at a P level of .007.
MS. TOLEDANO: That's a one-sided P value.
That's just for -- all right, you guys know what's a
one-sided versus a two-sided.
CHAIRMAN BLANCO: Any other questions or
anything else you want to elaborate on?
DR. O'SULLIVAN: I would just like to say
I didn't follow him at all because I haven't figured
out where he was.
CHAIRMAN BLANCO: Okay, well, let's make
sure that you do. Let's start off --
DR. WOLFSON: We're in Volume 2.
CHAIRMAN BLANCO: Volume 2.
DR. WOLFSON: Page 15.
CHAIRMAN BLANCO: Page 15.
DR. WOLFSON: Go to page 15, the upper
part of the table where it says, "intention-to-treat
total," within the box it's the fifth line down.
DR. O'SULLIVAN: Yes, I can see where it
says, "Moderate to severe encephalopathy," there's a
.02 P value.
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 306/322
DR. WOLFSON: Right. Then on page 22,
they now have taken out the -- page 22 includes the
adequate recordings. So they have removed the - what
is it? -- 300-plus cases, or whatever it is, where the
recordings weren't adequate. Then the similar
analysis now is seven against zero. So we have
eliminated one. So now it is at .007.
DR. O'SULLIVAN: Yes, but where is the
long-term neurologic outcome?
DR. WOLFSON: That's it.
DR. O'SULLIVAN: It's short-term, though.
DR. WOLFSON: Oh, I'm sorry, no, there is
no long-term because that wasn't the purpose. I'm
just looking at this from the standpoint that what
happened in the nursery and the diagnosis that was
made acutely, it disappeared.
MS. TOLEDANO: Somewhere there was long-
term.
DR. WOLFSON: Was there long-term?
MS. TOLEDANO: Somewhere there was a table
of long-term.
DR. WOLFSON: I don't remember the long-
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 307/322
term.
DR. O'SULLIVAN: There was one thing where
they did -- I think Dr. Wolfson would know this, but
they did 18 months of followup or 16 months.
CHAIRMAN BLANCO: Please come.
DR. O'SULLIVAN: But I don't remember
where it is.
CHAIRMAN BLANCO: Identify yourself.
DR. KJELLMAR: Ingemar Kjellmar, Professor
of Pediatrics and Neonatology.
I had included in the material that was
distributed to you in my presentation on perinatal
markers of quality in Sweden a few slides dealing with
an old material of cases that I have resuscitated in
the 1970s, and where we could provide real long-term
follow-up studies. They were about 25 years of age.
In that material there is a table on the
assessment at 18 months of age. Out of the 74
resuscitated babies, we had 14 cases who became
disabled.
The point with the table that I have
included, the points are actually two. The first one
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 308/322
is to demonstrate that there are recognizable patterns
of cerebral palsy that dominate the outcome. These
are either dystonic cerebral palsy or tetraplegic or
hemiplegic cerebral palsy.
The second point is that those will be
recognized at a very early stage, and already when the
babies are 18 months of age, you recognize that they
have poor motor performance and that they have a
neurologic disability, although you are probably not
able at 18 months of age to definitely tell which type
of cerebral palsy this patient will have.
CHAIRMAN BLANCO: All right, let me
interrupt you for a minute. These 14, those were part
of this study?
DR. KJELLMAR: No, no.
CHAIRMAN BLANCO: I wanted to make sure
that was clear.
DR. KJELLMAR: Absolutely not. They were
all born in the 1970s. So that is the reason why I
did not --
CHAIRMAN BLANCO: So you don't have 18-
month data for these babies. You just have the acute
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 309/322
data?
MS. TOLEDANO: That was my question
actually. Are we allowed to ask them directly or do I
ask you?
CHAIRMAN BLANCO: Either way.
MS. TOLEDANO: I can ask him directly?
Do you have any followup, 18-months'
followup, one-year followup of the babies who were in
your special care?
DR. KJELLMAR: Not yet.
(Laughter.)
CHAIRMAN BLANCO: The answer, for the
record, was "not yet" from Dr. Kjellmar. Thank you.
All right, any other comments concerning
the motion on the flow?
DR. RINGEL: I would like to say, not in
response to Dr. Wolfson, but after you mentioned these
things, I went to look at it again. I'm a technology
junkie basically, but my problem here is that there
are basically three studies we have been presented
with.
The Plymouth study does not show any
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 310/322
difference in neurologic outcome and just barely shows
a difference in the acidosis outcome, and that's why
they felt they needed to go further and to use the
automatic detection. Okay, so the Plymouth study
doesn't really help us.
The Gothenburg study, I know I keep
harping on it, but as best as I can tell, the
Gothenburg study does not tell us anything about the
device itself, only about the possibilities of
training and expertise and learning. Maybe all this
is about learning how to read the standard traces
better.
So we are left with one study where the
data is a bit questionable because of the re-training
that happened in the middle of the study, and because
there are some questions about how significant the
changes are. For that reason, I pretty much agree
with my colleagues who say that there needs to be
another study done in the United States where there
are comparable patients.
I notice jitteriness is an outcome;
irritability it an outcome. There are some nurseries
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 311/322
in the innercities where all the patients come out
jittery and irritable. We don't have to get into why,
but I happen to know that is true because I have
worked in the innercity my entire professional career.
So I have to say that while, yes, we would
love to believe that we can start preventing or
decreasing the amount of cerebral palsy we see, the
amount of learning disorders we see that may be
related to asphyxiated deliveries, I'm not sure we
have the proof yet.
CHAIRMAN BLANCO: All right, any other
comments? Dr. Toledano?
MS. TOLEDANO: I have to agree with Ms.
Mooney and with Dr. Wolfson. I would much rather see
this going to a setting of approval with conditions.
If we are talking about being able to learn how to
read tracings, these are the people and they have the
materials to teach us how to read the tracings better.
I think we need to have access to that in this country
in a more timely manner.
CHAIRMAN BLANCO: Thank you. Any other
comments?
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 312/322
MS. MOONEY: Just one final remark: I
think that, obviously, if we think we need a U.S.
trial before the device can come here, then that's
what needs to be done, but we should recognize that
there is the potential that the cost associated with
this trial would preclude the sponsor going forward
with the study. So this sort of decision could
actually be a decision to not make the devise
available at all.
CHAIRMAN BLANCO: Unfortunately, I must
remind the panel that cost is not one of the things
that we are able to consider here.
All right, unless there is something
different, we're going to go take a vote. Do we have
something different, Dr. Wolfson?
DR. WOLFSON: No, I was just going to
address the type of trials. Thank you.
CHAIRMAN BLANCO: Okay. Well, I think we
can do that depending on what the outcome of the vote
is. Unfortunately, there's no way to hide here. So
we're just going to go down the side. Michael, Dr.
Neuman, you've been here a long time, so I'm going to
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 313/322
start on your side, so you'll be the first one.
Now let's remember that the motion is for
non-approval. So that a yea vote on the motion is a
motion to not approve the PMA.
Your vote, Dr. Neuman?
DR. NEUMAN: Yes, I vote not to approve
the motion.
DR. RINGEL: Yea.
CHAIRMAN BLANCO: Dr. Ringel?
DR. RINGEL: Yes.
CHAIRMAN BLANCO: Not to approve?
DR. RINGEL: Not to approve.
CHAIRMAN BLANCO: Dr. Toledano?
DR. IAMS: No, no, no. He got that wrong.
CHAIRMAN BLANCO: He said "yea."
DR. RINGEL: I said "yea" three times.
CHAIRMAN BLANCO: Yes, "yea," not to
approve the motion, correct?
DR. RINGEL: Yes.
CHAIRMAN BLANCO: Not to approve --
DR. RINGEL: I'm the one that messed it
up. I'm sorry. Not to approve the PMA. I apologize.
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 314/322
I'm the one for non-approval.
CHAIRMAN BLANCO: Yea or no?
MS. TOLEDANO: No, I do not approve the
motion.
CHAIRMAN BLANCO: Okay, so you vote for
some other --
MS. TOLEDANO: That is correct.
CHAIRMAN BLANCO: We would like
confirmation of Dr. Neuman's [sic] vote. You voted
"yea" for the motion to not approve the PMA?
DR. RINGEL: No. I voted not to approve
the motion to not approve --
(Laughter.)
CHAIRMAN BLANCO: We've got too many noes
there.
DR. BROWN: It might be better if we said
for or against the motion, for or against it.
CHAIRMAN BLANCO: Why don't we just say do
not approve of the PMA. Let's just say, not approve
of the PMA --
DR. SHARTS-HOPKO: No, no, you can't do
that.
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 315/322
CHAIRMAN BLANCO: -- to make sure that we
don't get into any difference, and let's start all
over again.
DR. O'SULLIVAN: That violates
parliamentary procedure.
DR. BROWN: For or against the motion.
MS. TOLEDANO: The motion is to not
approve. Are you for the motion or against?
CHAIRMAN BLANCO: All right. Dr. Neuman,
are you for the motion or against?
DR. NEUMAN: I am against the motion to
not approve.
CHAIRMAN BLANCO: Thank you.
DR. RINGEL: For.
MS. TOLEDANO: Against.
CHAIRMAN BLANCO: Against.
DR. WOLFSON: Against.
DR. SHARTS-HOPKO: Against.
DR. IAMS: For.
DR. RAMIN: For.
DR. EGLINTON: For the motion.
DR. O'SULLIVAN: For the motion.
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 316/322
DR. BROWN: For the motion.
CHAIRMAN BLANCO: Wait, wait, not so fast.
(Laughter.)
Dr. O'Sullivan, for the motion.
Dr. Brown?
DR. BROWN: For the motion.
CHAIRMAN BLANCO: Dr. Seifer?
DR. SEIFER: Against.
CHAIRMAN BLANCO: Against.
The motion carries 6 to 5. The motion is
approved. The PMA is not approved.
We now need to go around and explain why
we voted in a brief way. I think we have already said
most of the things that needed to be said in terms of
what the sponsor will need to do to be able to bring
forth an approval PMA.
Dr. Neuman?
DR. NEUMAN: While I agree with the
concerns about the different patient population in
North America compared to Sweden and the U.K., I feel
there is compelling evidence that looking at the
configuration of the electrocardiogram is providing
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 317/322
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: Thank you.
DR. RINGEL: I don't think there's
reasonable assurance that the device is effective.
CHAIRMAN BLANCO: Thank you.
MS. TOLEDANO: I agree with Dr. Neuman.
CHAIRMAN BLANCO: Thank you.
DR. WOLFSON: I think I have expressed my
concerns.
CHAIRMAN BLANCO: Thank you.
DR. SHARTS-HOPKO: I agree with Dr.
Neuman, and I didn't want to close the door against
continued development of the product.
CHAIRMAN BLANCO: Thank you.
DR. IAMS: I think I've already stated my
rationale.
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 318/322
CHAIRMAN BLANCO: Thank you.
DR. RAMIN: I, too, have concerns about
the effectiveness or efficacy, and I think just a
randomized clinical trial in the U.S. population is
what is needed.
CHAIRMAN BLANCO: Dr. Eglinton?
DR. EGLINTON: I have the same concerns.
I think we'll see clinical use in Europe and it will
spread, and it will spread around the world, and maybe
someday in the future it will spread far enough that
we'll be happy with it here. But I think at this
point it is still a research tool, the way we are
looking at it. I think it's an exciting research
tool, but I think it's still a research tool at this
point.
CHAIRMAN BLANCO: Dr. O'Sullivan?
Thank you, Dr. Eglinton.
DR. O'SULLIVAN: There's really nothing I
can add to that.
CHAIRMAN BLANCO: Thank you.
DR. BROWN: I specifically have concerns
that I did not believe there was enough proof of
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 319/322
clinical significance, although there was statistical
significance of the endpoints.
CHAIRMAN BLANCO: Thank you.
DR. SEIFER: I agreed with Dr. Neuman's
points.
CHAIRMAN BLANCO: Thank you.
I would like to thank all the panel
members.
I would like to see if the FDA, Dr.
Pollard, do you have anything to say?
MR. POLLARD: Yes, I just wanted to get a
little bit of clarification. I mean, I did hear the
panel ask for a randomized clinical trial to be
conducted in the U.S. It might be helpful to have a
little better sense of just what kind of trial are you
talking about. You know, specifically, what kinds of
endpoints would a trial like that require?
DR. IAMS: I think a trial very much
similar to the one they have proposed, powered to look
at metabolic acidosis, powered, if possible -- you
have to look at the numbers to look at markers,
clinical markers, of newborn encephalopathy, seizures
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 320/322
and some of the markers you've already used in your
current trial. That may not be possible. Metabolic
acidosis is fine. I have no problem with that.
CHAIRMAN BLANCO: Dr. Iams and Dr.
Eglinton and Dr. O'Sullivan, and the others, anyone
else, can you specify a little further? I mean, it
wasn't the issue of the endpoints. So that this helps
the sponsor and the FDA. I don't think it was the
issue of the endpoints as much as the issue of the
population in terms of the patient population and the
issue of the management in terms of what occurs in
this country as opposed to what might occur in other
countries.
Am I --
DR. IAMS: That's correct.
CHAIRMAN BLANCO: -- paraphrasing it for
you all appropriately?
DR. O'SULLIVAN: The only thing that I
think would be of benefit, although, again, I think it
would be very expensive, you can't certainly do a two-
year followup. So from that perspective, I think
cost-effective-wise that would be ridiculous. But
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 321/322
there are now currently emerging imaging studies that
one might think about tagging on here, at least before
the baby is discharged or at some point after
discharge, but, ideally, during the hospital course of
the baby because that's when the baby is a captive. I
think those could be looked into, and certainly I'm
not expert in those.
CHAIRMAN BLANCO: Any other points?
DR. WOLFSON: Can I make one?
CHAIRMAN BLANCO: Yes, sir.
DR. WOLFSON: I would encourage that the
studies be done not solely in academic centers. Most
centers tend to be urban, low-income, minority, and
the majority of births that are affected -- well, I
should say they just simply take place within the
United States are clearly occurring in what are
principally Caucasian, non-urban environments. So it
is important from that standpoint, though, granted, if
you demonstrated in an urban environment, then you'll
demonstrate it anywhere.
CHAIRMAN BLANCO: Thank you.
If there are no other comments, I would
NEAL R. GROSSCOURT REPORTERS AND TRANSCRIBERS
1323 RHODE ISLAND AVE., N.W.(202) 234-4433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com
8/14/2019 US Food and Drug Administration: 3856T1
http://slidepdf.com/reader/full/us-food-and-drug-administration-3856t1 322/322