U.S. FOOD AND DRUG ADMINISTRATION

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NEUROLOGICAL DEVICES PANEL

OF THE

MEDICAL DEVICES ADVISORY COMMITTEE

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NINETEENTH MEETING

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FRIDAY,

JUNE 17, 2005

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The above‑entitled matter met in Salons A, B, and C of the Hilton
Washington, D.C. North, 620 Perry Parkway, Gaithersburg, Maryland, at
8:30 a.m., Stephen J. Haines, M.D., Chairperson, presiding.

[PRESENT]{.underline}:

STEPHEN J. HAINES, M.D., Chairperson

THOMAS G. BROTT, M.D., Voting Member

JONAS H. ELLENBERG, Ph.D., Voting Member

ANNAPURNI JAYAM-TROUTH, M.D., Voting Member

MARY E. JENSEN, M.D., Voting Member

ROBERT J. COFFEY, M.D., Industry Representative

LEE LEE DOYLE, Consumer Representative

REESE H. CLARK, M.D., Deputized Voting Member

MARK L. HUDAK, M.D., Deputized Voting Member

ROBERT M. NELSON, M.D., Ph.D., Deputized Voting Member

MIRIAM C. PROVOST, Ph.D., Acting Director, Division of

General, Restorative, and Neurological Devices,

ODE

JANET L. SCUDIERO, M.S., Executive Secretary

[FDA PRESENTERS]{.underline}:

SOUSAN S. ALTAIE, Ph.D.

Scientific Policy Advisor, OIVD/CDRH

SUSAN GARDNER, Ph.D.

Director, OSB/CDRH

THEODORE R. STEVENS, M.S.

Chief, Restorative Devices Branch

KRISTEN BOWSHER, Ph.D.

Lead Reviewer/Engineer

SUSAN K. McCUNE, M.D., M.A.Ed.

Neonatologist, Division

JIANXIONG CHU, Ph.D.

Statistician

[SPONSOR PRESENTERS]{.underline}:

EDWARD B. WEILER, Ph.D.

Vice President, Research and Development

JOHN S. WYATT, M.D.

University College Hospital, London, England

PING-YU LIU, Ph.D.

Drug and Device Development Co., Inc., Redmond, WA

[PUBLIC SPEAKERS]{.underline}:

ANNA ROSA, PAMELA DAVIES, and FELICITY KATE

MARK, DEBRA, and SIDNEY GRACE OTTENS

KIMBERLY, ROBERT, and ANTHONY COLAIZZI and ADAM and ROSEMARY MITCHELL

A-G-E-N-D-A

[Olympic Medical Corporation, Olympic Cool-Cap,]{.underline}

[PMA P040025]{.underline}

Call to Order

Conflict of Interest and Deputization to Voting Member Status Statements

Janet L. Scudiero, M.S. . . . . . . . . . 6

Panel Introductions

Stephen J. Haines, M.D. . . . . . . . . . 9

Critical Path Initiative

Sousan S. Altaie, Ph.D. . . . . . . . . . 13

Postmarket Study Design

Susan N. Gardner, Ph.D. . . . . . . . . . 19

Division Update

Theodore R. Stevens, M.S. . . . . . . . . 27

[Open Public Hearing]{.underline}

The Rosa-Davies Family . . . . . . . . . . . . 31

The Ottens Family . . . . . . . . . . . . . . 38

The Colaizzi Family . . . . . . . . . . . . . 46

[Sponsor Presentation]{.underline}

Edward B. Weiler, Ph.D. . . . . . . . . . . . 55

Vice President, Research and Development

Ping-Yu Liu, Ph.D. . . . . . . . . . . . . . . 63

Drug & Device Development Co., Inc., Redmond, WA

John S. Wyatt, M.D. . . . . . . . . . . . . . . 75

University College Hospital, London, England

Panel Questions . . . . . . . . . . . . . . . 101

[FDA Presentation]{.underline}

Kristen A. Bowsher, Ph.D. . . . . . . . . . . . 121

Susan K. McCune, M.D. . . . . . . . . . . . . . 127

Jianxiong Chu, Ph.D. . . . . . . . . . . . . . 152

[Deliberations]{.underline}

Reese M. Clark, M.D. . . . . . . . . . . . . . 169

Question 1 . . . . . . . . . . . . . . . . . . 237

Question 2 . . . . . . . . . . . . . . . . . . 244

Question 3 . . . . . . . . . . . . . . . . . . 249

Question 4 . . . . . . . . . . . . . . . . . . 255

Question 5 . . . . . . . . . . . . . . . . . . 262

Question 6 . . . . . . . . . . . . . . . . . . 263

Question 7 . . . . . . . . . . . . . . . . . . 272

[2nd Open Public Hearing]{.underline} . . . . . . . . . . . . 279

[Panel Vote]{.underline} . . . . . . . . . . . . . . . . . . 280

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

8:30 a.m.

MS. SCUDIERO: Good morning everyone. We\'re ready to begin the
Nineteenth Meeting of the Neurological Devices Panel. I\'m Jan Scudiero,
the executive secretary of this panel, and I\'m a reviewer in the
Division of General Restorative Neurological Devices.

First, there\'s several housekeeping matters. If you haven\'t already
done so, please sign in at the tables outside the doors. Information for
today\'s agenda and panel minutes and transcripts are there at these
tables. Upcoming panel meetings are announced on our advisory panel
website and in the Federal Register. The next tentatively \-- and I
emphasize tentatively because we don\'t know yet \-- meeting for this
panel is December 1 and 2, 2005. I\'d like to welcome our new industry
rep, Dr. Robert Coffey over here. This is his first meeting. He\'s just
joined us. And finally, as a courtesy to the others in the room, if your
cell phones are on, would you please turn them off during the meeting.
Thank you.

Before I turn the meeting over to Dr. Haines, I\'m required to read into
the record three statements. There are two deputization of temporary
voting members, and the conflict of interest statement.

First, pursuant to the authority granted under the Medical Devices
Advisory Committee Charter dated October 27, 1990, and amended on April
20, 1995, I appoint as a voting member of the Neurological Devices Panel
for the duration of this meeting on June 17, 2005, Reese H. Clark, M.D.
For the record, he is a special government employee, and is a consultant
on another panel under the Medical Devices Advisory Committee. He has
undergone the customary conflict of interest review, and has reviewed
the material to be considered at this meeting. This is signed by Dr.
Daniel G. Schultz on June 13 of this year.

And pursuant to the authority granted under the Medical Devices Advisory
Committee Charter of the Center for Devices and Radiological Health
dated October 27, 1990, and amended on April 18, 1999, I appoint the
following as voting members of the Neurological Devices Panel for the
duration of this meeting on June 17, 2005: Mark L. Hudak, M.D. and
Robert M. Nelson, M.D., Ph.D. For the record, Dr. Hudak is a consultant
to the Anti-Infective Drugs Advisory Committee of the Center for Drug
Evaluation and Research, and Dr. Nelson is a member to the
Commissioner\'s Pediatric Advisory Committee. Both are special
government employees, and have undergone the customary conflict of
interest review, and have reviewed the material to be considered at this
meeting. And this is signed by Sheila Dearybury Walcoff, Esquire,
Associate Commissioner for External Relations, on June 13.

The third statement is the conflict of interest statement. The following
announcement addresses conflict of interest issues associated with this
meeting, and is made part of the record to preclude even the appearance
of an impropriety. To determine if any conflict existed, the agency
reviewed the submitted agenda for this meeting and all financial
interests reported by the panel participants. The conflict of interest
statutes prohibit special government employees from participating in
matters that could affect their or their employers\' financial
interests.

However, the agency has determined that the participation of certain
members and consultants, the need for whose services outweighs the
potential conflict of interest involved, is in the best interests of the
government. A waiver has been granted to Dr. Lee Lee Doyle for her
employer\'s interest in the sponsor\'s study. This waiver involved a
grant to her institution for which she had no involvement, and has no
knowledge of the funding. The waiver allows her to participate fully in
today\'s deliberations. Copies of this waiver may be obtained from 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 Drs. Reese Clark and Steven
Haines. Dr. Clark reported his former institution\'s current involvement
with the firm at issue. In the absence of personal financial interest,
the agency has determined that he may participate fully in the panel\'s
deliberations. Dr. Haines reported his institute\'s ongoing involvement
with the firm at issue. Since Dr. Haines is not personally involved, and
there\'s no continuing financial interest, the agency has determined
that he may participate fully in the deliberations.

In the event that the discussions involve any products or firms not
already on the agenda for which an FDA participant has a financial
interest, the participant should excuse himself 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 upon. Thank you. And I now turn over the meeting to Dr.
Haines.

DR. HAINES: Good morning. My name is Steven Haines. I am Professor of
Neurosurgery, Pediatrics, and Otolaryngology at the University of
Minnesota, and head of the Department of Neurosurgery there. I\'m
currently the chairperson of the Neurological Devices Panel. At this
meeting, the panel will be making a recommendation to the Food and Drug
Administration on the approvability of Premarket Approval Application
P040025, for the Olympic Medical Corporation Cool-Cap, intended for use
in infants 36 weeks gestation or older at risk for moderate to severe
hypoxic ischemic encephalopathy, or HIE, to provide selective head
cooling with mild systemic hypothermia to prevent or reduce the severity
of HIE.

Before we begin, I would like our distinguished panel members, who are
generously giving of their time to help the FDA in the matter being
discussed today, and other FDA staff seated at this table to introduce
themselves. I\'d ask each to please state your name, area of expertise,
your position, and your affiliation, and let\'s start with Dr. Coffey.

DR. COFFEY: My name is Robert Coffey. I\'m a neurosurgeon and Medical
Director in the Neurological Division of Medtronic, Incorporated.

DR. DOYLE: My name is Lee Lee Doyle. I\'m a Professor Emeritus of
Obstetrics and Gynecology, and the Assistant Dean for Faculty
Development at the University of Arkansas Medical Sciences College of
Medicine.

DR. HUDAK: My name is Mark Hudak. I\'m a neonatologist and Professor of
Pediatrics at the University of Florida, Jacksonville.

DR. ELLENBERG: Good morning. My name is Jonas Ellenberg. I\'m a
biostatistician and Professor of Biostatistics at the University of
Pennsylvania School of Medicine.

DR. JAYAM-TROUTH: I\'m Annapurni Jayam-Trouth. I\'m Professor and Chair
of the Department of Neurology at Howard University Hospital,
Washington, D.C. I\'m also a pediatric neurologist.

DR. CLARK: I\'m Reese Clark. I\'m a neonatologist. I am the Director of
Research for Pediatrics Medical Group, which runs a large group of
neonatal practices in the United States and Puerto Rico. And my
expertise is in clinical trials. I also have an associate consulting
appointment at Duke University.

DR. BROTT: Thomas Brott, Professor of Neurology at Mayo Clinic School of
Medicine.

DR. JENSEN: Lee Jensen, Professor of Radiology and Neurosurgery at the
University of Virginia, and I am Director of Interventional
Neuroradiology.

DR. NELSON: Robert Nelson, pediatric critical care medicine and
bioethics at Children\'s Hospital of Philadelphia and the University of
Pennsylvania.

DR. PROVOST: I\'m Miriam Provost. I\'m the Acting Director of the
Division of General Restorative and Neurological Devices in the Office
of Device Evaluation, FDA.

DR. HAINES: Thank you. I would like to note for the record that the
voting members present constitute a quorum as required by 21 C.F.R. Part
14.

There will be three brief presentations before the main agenda topic.
The first presenter is Dr. Sousan Altaie \-- and please correct me if
I\'ve mispronounced your name \-- who will speak on the CDRH Critical
Path Initiative.

MS. ALTAIE: Good morning. I\'m the Critical Path Liaison for the Center
for Devices to the agency. And I\'d like to talk to you about the
Critical Path Initiative in the center as it relates to the FDA. First,
I will tell you what the initiative is, and why the FDA is interested in
this initiative. Then I will talk about the Critical Path tools, and the
Medical Devices areas of interest in Critical Path tools. And then I\'ll
actually talk about the Critical Path projects that are going on in
Center for Devices. And then I will ask you to participate in Critical
Path efforts, and I will tell you how.

So to begin, Critical Path is a serious attempt to make product
development more predictable and less costly. Critical Path covers the
journey from medical products from the candidacy to the stage of
actually being developed and approved by FDA. It does not cover the
basic research in the development path. It will only cover the stages of
prototyping, preclinical and clinical development, and then the approval
stages.

So why is the FDA interested? The FDA is interested because there is a
significant benefit of bringing innovative products to the public
faster, and because of our unique perspective on product development, we
see successes and failures and missed opportunities in device
development. And because it will help us to develop guidances and
standards that foster innovation and improved chances of success in
bringing devices to the market.

What do we want to do at the FDA? We really want to work with the
industry, and academia, and patient care advocates to modernize,
develop, and disseminate solutions. And these are tools to address
scientific hurdles impacting industry-wide product developments. The
Critical Path tools are actually methods and techniques used in three
dimensions. These are the safety, efficacy, and industrialization. In
assessment of safety, the tools help predict if a potential product will
be harmful. In proof of efficacy, the tools help determine if a
potential product will have medical benefit. And in industrialization,
the tools help in manufacturing a product at commercial scale with a
consistent quality. So Critical Path tools in our view at the Center for
Devices consist of biomarkers, Bayesian statistics, animal models
biomarkers, and clinical trial design. We also look at computer
simulation, quality assessment of protocols, postmarket reporting, and
whatever else you could tell us that we could look at. We\'re always
open to suggestions of new areas in Critical Path.

Medical device path opportunities are obviously very vast in Center for
Devices because we regulate all sorts of devices, starting from
Band-aids to stethoscopes, scissors, glucose monitors, heart valves, and
MRIs and PET scans. So there is a lot of opportunity in finding tools to
get these devices faster to the market. However, we are different than
the way the drugs are regulated, and look at different issues in
Critical Path. We are different in Critical Path from devices by the
fact that our devices deal with complex components. And we are dealing
with biocompatibility, durable equipment, the lifecycle is not very
short. And we\'re looking at rapid product cycles. They keep updating,
and getting better and better on a daily basis. And we also deal with
device malfunctions and user errors, and we mostly do bench studies,
non-clinical studies to approve these devices. And our regulatory system
is different than the drugs because we work under quality systems regs
and the ISO 9000 instead of the GMPs.

The areas of interest in the Critical Path, what\'s going on in the
CDRH, under the safety tools, we\'re looking at biocompatibility
databases, effect of products on diseases or injured tissues. Under the
effectiveness tools, we\'re looking at surrogate endpoints for
cardiovascular device trials. We\'re also looking on computer simulation
modeling in implanted devices. Under the industrialization tools, we\'re
looking at practice guidelines for follow-up of implanted devices, and
also we\'re looking at validated training tools for devices with known
learning curves.

Now, we actually have several projects going on in the center, and these
are non-funded projects. These are interested individuals outside and
inside the FDA, and working with collaborative efforts to see some of
these projects to fruition. Under the validation biomarkers, we\'re
looking at serum panels to assess sensitivity and specificity. Under
peripheral vascular stents, we\'re looking at computer models of human
physiology to test and predict failure before going into animals or
human studies. This is an effort with Dr. Taylor in Stanford. As far as
the intrapartum diagnosis devices goes, we\'re working with NIH on a
collaborative workshop to determine a regulatory path with a consensus
of the obstetrics community. And under pharmacokinetics and image-guided
innovations, we\'re collaborating with NIH, and the collaboration is in
process.

For new hepatitis assays, there is always a complaint about not having
panels that actually has a clear status. And we\'re working with Johns
Hopkins School, trying to develop \-- and CDC actually \-- trying to
develop these certified panels that have a clear history for developing
hepatitis assays. Under surrogate markers, pathways for statistical
validations are on their way. And for permanently implanted devices,
we\'re working on practice guidelines and appropriate monitoring with
medical specialty organizations. And for neural tissue contacting
materials, we\'re working on extent of neurotoxicity testing in
patients.

Now, if you are interested, and I certainly encourage you to become
interested if you\'re not, you could help with these Critical Path
issues in two ways. There is a white paper put out on the Critical Path.
And there is a docket open for it. You could read it, and I will tell
you where to find it after I give you the references. And send your
comments to this docket and lead us to the better route of getting
devices to the market. And there is also a nationwide opportunity list
for Critical Path devices or drugs \-- of course, the other centers are
involved as well.

So we are compiling that list, and you could take the opportunity to add
to that list what you think is a Critical Path product that needs to be
developed. And this is the address if you\'d like to get involved. You
go to the CDRH webpage, and you will find links to the docket and the
white paper, and you can put in your comments as I mentioned.

Our goal \-- I want to leave you with this thought. Our goal at CDRH is
to ensure the health of the public throughout the total product
lifecycle. And we believe it\'s everybody\'s job. The development of
devices are interrelated because development in one might influence the
other one. Then you look at the cycles being intertwined constantly. So
with that I\'d like to address any questions if you have.

DR. HAINES: Thank you, Dr. Altaie.

MS. ALTAIE: All right, thank you.

DR. HAINES: Next, Dr. Susan Gardner will speak on postmarket study
design.

DR. GARDNER: Good morning. I\'m going to spend a few minutes of your
time telling you about a major programmatic change at CDRH. And the
essence of the change is the move of the condition of approval study
from the Office of Device Evaluation premarket to the postmarket side of
the house, which is primarily OSB.

Although I call it the postmarket side of the house, OSB is actually
involved in both the premarket and postmarket activities. For premarket
review, by virtue of the fact that we have the statisticians in our
office who you hear from at almost every panel meeting, and the
epidemiologists who you will hear from more at panel meetings, we have a
large supporting role in the approval process for the devices. Our
office is also responsible for signal detection by virtue of the fact
that we have the postmarket monitoring tools in the office. The medical
device reporting program and our MedSun program are some of those
postmarket tools. We\'re responsible for risk characterization, that is
through the analysis of incoming adverse event signals, and coordination
of the center response to health care professionals when we\'re dealing
with a postmarket problem. And we\'re responsible for interpretation of
the medical device reporting regulation.

So, for condition of approval studies, the regulation 21 C.F.R. 814,
etcetera, tells us that post-approval requirements can include
continuing evaluation and periodic reporting on the safety,
effectiveness, and reliability of the device for its intended use. The
impetus for the change started a number of years ago when we took an
internal evaluation, an internal look at our condition of approval
program. We did this in about 2002 and 2003. And our epidemiologists
went back and looked at 127 PMAs that had been approved in 1998 through
the year 2000. We found that 45 of those had condition of approval
orders.

And the study actually was started because we wanted to look at the
quality of the condition of approval studies. What we found is that we
couldn\'t complete that task because we had a pretty difficult time
tracking down the condition of approval studies. We found out that we
had limited, and certainly not standardized, procedures for tracking
these studies. And when we then went to the lead reviewers to see if
they had found the studies, we found that, as you might expect in any
organization, people had moved on to different jobs, and these studies,
or the tracking for them, had fallen through the cracks. We also found
that realistically in ODE it\'s very difficult for those folks under the
pressures of premarket approval to continue to track these studies over
time. So we came up with a strategy for change.

The goal of the change obviously is to make sure that the postmarket
information as the device enters the market, that we can continue to
assure the safety and effectiveness of the device in \-- and those
important words are \"in real world use.\" The moment of moving from the
clinical trial into community practice is extremely important, and to
get these studies done, and get the information is really critical. It
gives us the opportunity to better characterize the risk-benefit
profile, and obviously will add to our scientific database, and we can
make better scientific decisions.

So, after a 2-year pilot, actually, on January 1 we transferred the
program from ODE to OSB. We have developed and instituted our automated
tracking system. That is up and working. This will allow us to
acknowledge the receipt of study of reports, which we will do when they
come in, and also to follow up with industry when reports are not
received.

We are adding an epidemiologist to the premarket team when we anticipate
that a condition of approval study might be part of the process. The
epidemiologist is tasked with developing a postmarket monitoring plan
during the premarket process. So where the rest of the team remains
pretty much heads down on the approval process, again, there\'s going to
be somebody sitting on the team that all along is thinking about how
we\'re going to monitor this product if it\'s approved and goes to
market. The epidemiologist will have the lead in developing what would
be a well formulated postmarket question, and the design of the
condition of approval study protocol. They\'ll have the lead in
evaluating the study progress, and the results after approval. And I
want to emphasize, however, this is sort of a shift in lead. The PMA
team will essentially stay intact in doing the evaluation. So when these
studies come in to OSB, we\'ll log them into our tracking system, the
epidemiologist who\'s in the lead will do the evaluation, but also
we\'ll work with their ODE colleagues or other people involved in the
team in looking at the results of the condition of approval studies.

Why do we think this will be better, besides the obvious reason of
tracking and knowing what\'s going on? We\'re going to work really hard
to raise the bar on the postmarket questions that we ask to make sure
that we have really good study designs based on well formulated and
important postmarket questions. I think that will motivate everybody to
continue to be involved. I think the acknowledgement and feedback on the
studies will be important to industry because as anybody, when you do a
task and submit something, and nobody gives you any feedback, it\'s not
particularly motivating.

We also will be posting on our website the status of our condition of
approval studies. And so when they\'re done and done well that will be
posted, and if they\'re not that will also be on the website. And we do
have the ability to mandate a postmarket study if the condition of
approval studies are not done. This is under our Section 522, and that
comes complete with penalties for not having the studies done.

So what does this mean to the advisory panel? We\'re still feeling our
way a little bit as we go along about how much information on postmarket
that we\'ll be sharing with the panel, or what questions we can ask. But
I think at every panel in the natural course of events, questions on
postmarket come up. And in any case when that happens, we ask you to
continue to give us your suggestions, your advice to suggest possible
approaches to consider on the postmarket. That information is extremely
important to us, and is certainly something we will use as we work with
industry after the panel meeting to design a protocol for a condition of
approval study.

The second thing is we\'re going to try and give you better feedback on
these products and the condition of approval studies. So in the future,
either FDA or industry will come update the advisory panel on the
progress and results of the condition of approval studies. Any
questions?

DR. HAINES: Dr. Ellenberg?

DR. ELLENBERG: Dr. Gardner, I would like to say for the record that I
think this is extremely important in terms of how the panel process
works. And I applaud the FDA for taking this on. Can you talk a little
bit about the penalties? It was my understanding, perhaps incorrect,
that FDA did not have regulatory authority to impose penalties for
condition of approval studies if they were not done?

DR. GARDNER: Well, there\'s two pieces, let me separate. First of all,
for condition of approval studies themselves, I think we\'re taking a
very hard look \-- our general counsel right now is taking a very hard
look at what is in the law and what is in the regulation to see that we
can get a clear understanding of this. However, a different regulation
or a different law under Section 522 says that we can mandate postmarket
studies essentially if we have a solid postmarket question and we think
there\'s a risk to public health.

So, if we have a good or well formulated question for condition of
approval, and the study isn\'t done, that should pretty easily translate
into the 522 that we still have an important postmarket question. 522
reg does say that we can levy civil money penalties, and the product can
be labeled as misbranded.

DR. ELLENBERG: Thank you.

DR. HAINES: Any other questions? Thank you Dr. Gardner.

DR. GARDNER: Thanks.

DR. HAINES: Next Mr. Ted Stevens will give us the division update since
the November 2004 panel meeting.

MR. STEVENS: Good morning. I\'m going to tell you about some of the
review status of products that the panel has previously given us input
on. I\'ll also tell you some about reclassifications and other
regulations that the panel would be interested in.

Last year about this time the panel gave us their recommendation for the
Cyberonics Vagus Nerve Stimulator for depression. That file remains
under review, and when a final decision is made on that it\'ll be posted
on the FDA website.

In the most recent panel meeting in November, the panel considered the
Confluent Surgical DuraSeal sealant. That product received approval on
April 7 for adjunctive use in sutured dural repair during cranial
surgery to provide watertight closure. As part of that approval, the
sponsor is required to conduct a post-approval study to further evaluate
complications such as infection and CSF leak.

Another recent approval came under the Humanitarian Device Exemption
regulations. That was for the CoAxia Cathater, which is a balloon-type
device that\'s placed in the aorta to redirect blood flow for the
treatment of cerebral ischemia resulting from vasospasm. In the HDE this
is for populations of fewer than 4,000 patients per year for conditions
for which there\'s not another approved device.

Some other things that are not device approvals per se. The vascular and
neurovascular embolization devices, there was a proposed rule to
reclassify those products. That became final on December 29, 2004. So
those products are now reviewed under the 510(k) premarket notification
provisions. Along with that we published special controls guidance for
industry and reviewers.

As a result of the final rule for good tissue practices and donor
eligibility that was issued in May, Human Dura Mater is no longer
considered a medical device. It\'s now banked human tissue, and is being
considered under those regulations. So there is no longer a premarket
review of Dura Mater.

Another item of interest is that we recently published a public health
notification about adverse events in patients that have spinal cord
stimulators and other implanted stimulators when MRI is used
inappropriately. And that concludes the division update.

DR. HAINES: Thank you. Are there any questions?

DR. JAYAM-TROUTH: Can you please clarify the status of the VNS
stimulator? Because I think it\'s the understanding among many
psychiatrists that it has been approved for depression.

MR. STEVENS: The VNS stimulator for depression, that supplement has not
been approved at this time. And our regulations prohibit us from
disclosing any details about the status of a review until a final
decision is made.

DR. HAINES: Any other questions? Thank you Mr. Stevens. We will now
proceed to the open public hearing portion of the meeting. Prior to the
meeting, three persons asked to speak in open public hearing. They will
speak in the order of their request to speak. We ask you to speak
clearly into the microphone, and you\'re welcome to use either the
podium or the table in front of us. It\'s very important that you speak
into the microphone as the transcriptionist is dependent on this means
of providing an accurate record of the meeting. Please state your name
and the nature of any financial interest you may have in this or any
other medical device company. Ms. Scudiero will now read the open public
hearing statement.

MS. SCUDIERO: Both the FDA and the public believe in a transparent
process for information-gathering and decision-maker. To ensure such
transparency at the open public hearing session of an advisory committee
meeting, FDA believes that it is important to understand the context of
any individual\'s presentation. For this reason, FDA encourages the open
public hearing speakers at the beginning of your written or oral
statement to advise the committee of any financial relationship you may
have with the sponsor, its product, and if known, its direct
competitors. For example, this financial information may include the
sponsor\'s payment of travel, lodging, or other expenses in connection
with your attendance at the meeting. Likewise, FDA encourages you at the
beginning of your statement to advise the committee if you do not have
any such financial relationships. If you choose not to address the issue
of financial relationships at the beginning of your statement, it will
not preclude you from speaking.

DR. HAINES: The first open public hearing presenters are the Rosa-Davies
family from Michigan.

MS. ROSA: Hi, I\'m Ann Rosa and this is Pam Davies and our daughter
Felicity, who just woke up from her nap. Olympic Medical did pay for our
travel out here and the stay in the hotel today.

We want to thank you for the opportunity to speak today and share our
story. We feel so strongly about the impact of the cooling cap on our
daughter\'s life that we have been waiting for this opportunity since
she was discharged from the NICU. We hope that other families will be
provided access to it in appropriate situations as well. I\'d like to
preface our remarks by saying that I am a nurse midwife and my partner
Pam is an obstetrician. We knew all too well throughout much of this
experience the significance of the details of our daughter\'s condition,
and we therefore also feel that we recognize in a special way just how
important this device was in her recovery.

Felicity Kate was born on February 1, 2004. We\'re still not sure what
caused her to be so compromised at birth, but our daughter arrived into
the world with profound metabolic acidosis, respiratory distress, and a
dire prognosis. My pregnancy had been healthy, but the labor was quite
rapid, under two hours in total. We barely made it to the hospital
before she was born, and when we arrived we realized that something was
terribly wrong. Her heart rate was only in the 70s, and we had no idea
how long it had been so low. She was delivered as quickly as possible,
and we had the benefit of being in a hospital where a neonatologist was
present in the delivery room.

Upon birth, Felicity was severely hypoxic, had no spontaneous movement
or respiratory effort, and had a heart rate of around 40 by this time.
She was really quite near death. Her core gases included a pH of 6.85,
indicating severe distress, and later her APGARs would be assigned as 2,
4, and 4. The fact that there was such severe acidosis indicated that
our daughter was at high risk for the worst of the sequelae of oxygen
deprivation, and we knew that many babies with these sorts of \-- do not
survive, and that those who do are at significant risk for severe
neurologic damage. Very quickly, our greatest fear, and to us not an
unfounded one, was that we might not see our daughter survive this. We
were quoted chances of cerebral palsy as high as 90 percent, and even a
50 percent possibility of mortality. Suddenly, within an hour or two, an
uncomplicated pregnancy had produced a critically ill newborn.

In the neonatal intensive care unit, Pam visited our daughter. She was
limp. She had no muscle tone. She did not flinch, move, or grimace while
they performed painful procedures on her. We tried to grasp her hand,
but there was no reflex of grasp, and even her most basic reflexes were
absent, including her gag. Our minds sped ahead to what this picture
meant. Our daughter, if she survived, might require tube feeding. She
could need wheelchairs, special education. What sort of future would we
be able to provide for her?

The neonatologist confirmed our concerns when she indicated that while
Felicity had been stabilized, only the following days would help predict
what her future might be. She then discussed an experimental cooling cap
that was being trialed at the University of Michigan. We trusted the
research team and agreed to enroll Felicity. The randomized study had
been closed by this time, but she was eligible for ongoing use of the
Cool-Cap. Preliminary results were reported to be encouraging, but we
understood that there could be no guarantees. We were dealing with a
very ill child.

She was transferred to the University of Michigan for evaluation and
enrollment in the treatment protocol. The hospital where Felicity was
born is only about five miles from the University of Michigan, and yet
it took about four hours from the time of birth to the application of
the cooling cap, even with such proximity. To this day we are infinitely
grateful for that proximity, and we think often about the children who
have missed out on this technology because the transport time is too
great to meet the enrollment criteria.

She was assessed and enrolled, the cap was applied, and we held vigil at
her bedside. We waited anxiously for 72 hours, and every change in her
course was scrutinized. We were lucky. There didn\'t appear to be any
other endorgan damage, and we hoped that the Cool-Cap could protect her
brain. Her hospital course after removal of the cap was comprised of
minor acts, but to us major milestones. The first time we held her, her
gradual wean from the ventilator, the successful implementation of tube
feedings, the return of her gag, learning to latch onto nurse, and
coordinating her breathing and eating. All of the normal transitions of
a newborn that we often witness in the delivery room in our professional
lives in a matter of minutes were now huge triumphs spanning days of our
daughter\'s life.

Uncertainty for the future remained, despite these steps ahead. Would
she be able to meet her milestones? How would her muscle tone develop?
Would she be able to coordinate movement? Would she have learning
disabilities? We were told that cerebral palsy couldn\'t really be
diagnosed until she was older. Would she need special support measures?

She was discharged to home at 10 days of life, with significantly more
encouraging prognoses, although of course no guarantees. Since then
she\'s grown and flourished. At each developmental checkup she has
passed with flying colors, and we\'re constantly reassured. We still
await her final 18-month evaluation, but as her mothers, we see a child
who achieves developmental milestones ahead of time, who walked at 10
months of age, who has about 20 words now, and who at 16 months knows
her animal signs, some baby sign language, and can kick a ball better
than any of her peers. She\'s an age-appropriate toddler, something we
did not presume to hope for even a year ago, something that seemed
impossible at her birth. We\'ll never know what might have happened
without the cooling cap, and we are thankful for that. There\'s a chance
that our daughter may have been fine, or only minimally compromised, but
as medical providers, we also understand that had we not had access to
this technology, and the exceptional care team at the University of
Michigan through Dr. Barks, our daughter might be very different today.

We are convinced that this device and the careful practitioners
implementing it saved our daughter from adverse outcomes that otherwise
would have been inevitable. We hope that as many children as possible
can have access to this device. Because it is an intervention dependent
on timely implementation, its widespread dissemination seems essential.
We hope that increased accessibility to the cooling cap could provide
other families the opportunity to benefit from this device in time to
help their children too. Thank you for the time, for the opportunity to
share our story, and for the chance to express our profound gratitude
for a device that made the first of February a day we can continue to
celebrate. Thanks.

DR. HAINES: Thank you.

(Applause)

DR. HAINES: Next we have the Ottens family from Texas.

MR. OTTENS: Thank you for allowing us to be here. We did accept travel
and lodging arrangements from Olympus Medical. We do not have any other
financial disclosures.

Please forgive me if my voice wavers. This is an emotional issue for us.
A little over two years ago, my wife and I were very excited to find out
that she was pregnant. It was a miracle for us because we had been
trying for over a year, and had to have fertility drugs, and many visits
to physicians in order to make this happen for us. We were very scared
though, as I had just accepted a job in Dallas, to move from Little
Rock, and we discussed how that was going to affect our lives. My wife
Deb did decide to stay in Little Rock and work for awhile while I went
and set things up in Dallas.

Through the course everything went pretty well, but we did have other
fears. You see, I\'m a registered nurse, and I have extensive background
in critical care emergency medicine and management, and my wife is a
pediatric physical therapist, and she is specialized in children under
three years of age with extreme disabilities. It\'s a great form of
birth control as we do work with people who have experienced the worst
in life, and it did kind of make us wait a little while to have
children.

We did continue. I traveled back and forth from Dallas to Little Rock
many weekends, and we had really considered having the baby in Little
Rock and then moving. We did change our minds near the end and decided
that we had established an OB/GYN in Dallas and we were going to move.
The day before that move was to happen, Deb had an appointment with her
OB in Little Rock and found out that she was diagnosed with intrauterine
growth retardation. She was placed in the hospital at Baptist Health in
Little Rock, and I say that because Dr. Doyle, I know you\'ll know where
I\'m talking about. And I immediately then drove from Dallas back to
Little Rock, met them in the hospital, and she was to be induced the
next morning.

Everything went pretty well up until we were moved to L&D, and to the
day of delivery when things went suddenly wrong. Her heart rate dropped,
the L&D nurses rushed in, and she was rushed immediately \-- Deb was
rushed for an emergency C-section. We were lucky enough that the OB/GYN
was in the hospital at the time that this happened, and Sydney Grace
could be rapidly born through emergency C-section. We did find out later
that there was a velamentous insertion of the umbilical cord, as well as
a partial abruption, causing Sydney Grace to lose much of her blood
volume. They estimate that she went somewhere between 8 to 10 minutes
with severely decreased oxygenation to no oxygenation at all. I was
informed by one of the nurses that CPR was ongoing on my daughter, and
that she had been taken to the NICU.

On my arrival there, I found her intubated, flaccid, and receiving the
first of two blood transfusions. The neonatologist there at the hospital
informed me that only the day before he had been informed by Dr. Kaiser
of Arkansas Children\'s Hospital of the ongoing study with the Cool-Cap,
and he had already called and spoken to him. I asked a couple of
questions and made a rapid agreement that, yes, I would like her to be
moved to Arkansas Children\'s Hospital to be evaluated for this Cool-Cap
study to see if she would meet the qualifications.

Arkansas Children\'s Hospital is very close to Baptist Health. It
doesn\'t take very long to get there, and we were moved rapidly. I met
them there, met Dr. Kaiser there, and he explained to me what the
Cool-Cap theory was, how it worked. I asked a very few questions, I
asked what were the adverse events, what could I expect. Once he
answered those questions to my satisfaction I told him don\'t waste any
time. She was placed on the Cool-Cap very rapidly after birth, and we
were told that we could expect for her to be in the NICU for
approximately three months.

She did spend the first 72 hours on the Cool-Cap. There were some
difficulties keeping her temperature regulated as she was small and kind
of skinny at the time, but it went very well and she was removed from
the Cool-Cap 72 hours later and had her first MRI, which showed
essentially to be normal. Eight days after being placed in the NICU she
was weaned off the ventilator and we held her for the first time, only
the next morning to be placed back on the ventilator, and for us to
receive a call from the neonatologist telling us that they were pretty
sure she had periventricular leukomalacia. For myself and my wife, this
was a very ominous sign as we knew that the chances of her having
cerebral palsy with this were very high. We were preparing ourselves to
have a child with cerebral palsy, for what that would mean for us and
what kind of a life we could provide. And it was a very difficult
adjustment for us to have to make.

However, she weaned off the ventilator in three days and showed a very
fervent grasp of life and that she wasn\'t going anywhere and she was
going to get better. She began to eat. She began to respond. On our
sixteenth day in the NICU we were moved to a rooming-in room inside the
NICU. The next day we met with the neonatologist and the neurologist
that were seeing her. They told us that they could find absolutely
nothing wrong with her, that she was doing great, that we should treat
her like a normal infant, and that we should go home because there was
no reason to keep her any longer. So on the seventeenth day, much
shorter than the 90 days we had planned on, we were discharged to home.
We spent one night in Arkansas with family, and we made a rapid move to
Texas. From that point on, things only seemed to get better, and I\'ll
let my wife tell you a little bit about that.

MS. OTTENS: When we left the hospital, Sydney Grace was immediately
enrolled in the early intervention program in Texas. The call was made
before we ever left the hospital. They told us even though things looked
really good at the time, that we still had to be very careful and watch
for what things were to come. She also had to go to the pediatrician one
week after, and then two weeks. It was a very monitored process, but our
pediatrician told us without the medical records she would have never
known that she had received such an insult.

At two months she started rolling over and moving. At three months we
went to her neurology appointment which we thought would be the first of
many. The neurologist released us at that appointment, told us to take
her off all medication, and could see that there was nothing wrong. At
this point we began to realize that there was nothing wrong, and we also
began to realize that not only was there nothing wrong, but she began to
be very advanced at her skills. At four months old she could turn pages
in her book and recognize the one she wanted and tell you what she
wanted. At five months old she was sitting. By six months she was
talking. At nine months old she could hold a pen with a pincer grasp and
began to write and draw pictures and tell you what she was drawing. By
12 months old she was walking, talking in three to four words at a time,
sorting her toys by colors and categories, and finishing simple puzzles
all by herself. At 18 months old she could tell us seven of her letters
in the alphabet, count to 10, she did pretend play, and was playing with
children much older than her age. At 21 months old now she feeds herself
with proper utensils, speaks in full sentences, uses pretend play, and
is almost potty-trained. Using the developmental checklist, her
cognitive and speech abilities are that of a 3- to 4-year-old child.

She continues to amaze us every day. When I think back to her birth, we
are blessed that she is even alive. She experienced injuries that at
best should have left her with many physical and mental challenges.
Today Sydney Grace is a happy and thriving toddler, and we truly believe
it is because we were fortunate enough to have been included in the
Cool-Cap study. Where would she be today without the cooling cap? We
thank God that we will never have to find out. We are here today because
we want all infants to have the same advantage that Sydney Grace had.
There are infants born every day with complications or injuries that are
as bad or worse than our daughters. How can we deny them this
opportunity of a normal life? Thank you.

(Applause)

DR. HAINES: Thank you. Next we have the Colaizzi family from Michigan.

MS. COLAIZZI: Good morning. My name is Kimberly Colaizzi, and to start
off by saying Olympic Medical had paid for our travel and lodging. As I
said, my name is Kimberly Colaizzi. I\'m very honored to be here today.
I\'m here today with my husband Robert, my mother Rosemary, my father
Adam, and my beautiful three and a half year old son Anthony, who I\'m
very proud to say is considered not only a University of Michigan
Holding Unit Neonatal graduate, but also a proud wearer of the Cool-Cap.

Anthony was born at full term on December 16, 2001. All appeared well
with the delivery until the last few minutes. As Anthony\'s heart rate
dropped, doctors tried suctioning him out. After many tries the placenta
ripped, and an emergency C-section was done. We are uncertain of the
length of time that Anthony was not breathing. When the trauma took
place, I was wheeled away from my husband and then immediately put to
sleep after feeling the sharp pain of the knife making a C-section
incision. The lab work later showed that the umbilical cord was actually
too short to deliver vaginally, something the doctors were not aware of
during the delivery.

Anthony was flown by helicopter to the University of Michigan by the U
of M flight team. At that time U of M was taking part in something
called a Cool-Cap study, and my little Anthony met the criteria to be in
the study. Since I was at St. Mary\'s Hospital in Livonia with my mom at
my side, my husband, he had to make the most difficult decision of his
entire life. With the support of my father and my brothers by his side,
he had agreed to allow Anthony to be placed in a study. My beautiful son
was going to be part of an experiment. When I awoke I spoke with Dr.
Barks on the phone, who was trying so graciously to explain the study to
me, asking throughout the discussion if I understood what he was telling
me. As I was trying not to faint, I was able to get out the words \"Yes,
I do understand, I teach special education, and I work with cognitively
impaired students every day.\" And then I dropped the phone, and my mom
finished the conversation with him. Anthony spent the next 72 hours
wearing this cap right here, having his family hovering over him every
single second, praying every moment that the study, and the cap, and
this experiment that he was being part of would indeed save our precious
baby\'s brain.

I am here today for many reasons. First to tell you that I believe with
all of my heart and all of my soul that this cap did work and did indeed
help save Anthony\'s brain. Of course, I do believe that the fast-moving
doctors and the outstanding care that he received at U of M kept him
from dying, but the cap, this beautiful shiny cap, saved his mind and I
believe saved his soul. Second, I am here as a special education teacher
who deeply loves her students to ask you to please approve this cap.
Although some of my students have other types of impairments, I have had
many children who definitely would have benefited from wearing this cap.
I fully understand that it may not help every child who experiences this
type of trauma at birth, but please at least give them the same chance
that you gave Anthony and these two other beautiful children that you
saw today. I ask of you to do what I do every day with my students,
which is ask myself \`What would I do if this was Anthony? What would I
do if this was my child?\' Please, be honest with yourselves. Wouldn\'t
you give anything in the entire world to save your child? Which brings
me to the most important reason that I\'m here, and that is to thank
you, those of you who took part in creating this miracle cap. Thank you
for giving my family the precious gift of allowing Anthony to wear it.
What you have done for us is priceless, and I beg those of you voting
today to vote yes to approve this cap, and to allow other babies and
their families the same opportunity to experience a true miracle. Thank
you.

MR. COLAIZZI: I came here today to thank Olympic Medical for giving my
son Anthony a normal, healthy life. I hope the decision will be made to
allow all newborns who experience the same trauma at birth to get a
second chance as my son Anthony did on December 16, 2001, 5:04 p.m.
Thank you.

MR. MITCHELL: Okay. First of all, I would like to thank, and I\'m sure
they\'re probably not in the room, but the person or persons that were
responsible or involved with the invention of this cooling cap. As my
daughter indicated, there\'s no doubts in my mind that this cap had an
awful lot to do with the development of my grandson Anthony. There\'s no
doubts in my mind and heart that because Anthony was given the
opportunity to wear the cooling cap, he was also given the opportunity
to experience a normal and productive life. As you can see, we\'re kind
of an emotional family because of what happened to us, but the end
product that we have sitting here next to me on my left is unbelievable,
and again we feel a miracle, a miracle of life.

He is a child, Anthony, that at birth was deprived of oxygen. He was on
the respirator for three to four days before he could even breathe on
his own. He had a collapsed lung with a chest tube. He drank milk, and
I\'ll never forget this. We were so ecstatic the first time that he had
actually had a couple of drops of milk from an eye dropper. We thought
that was a fantastic accomplishment. And then he graduated from that to
actually a doll-sized baby bottle, which had less than an ounce of milk
in it. And again, we were extremely happy at that point.

All during this time Anthony had a large number of prayers that were
being offered on his behalf. In addition to this, he had one other thing
that most babies with his condition did not have, and that was the
cooling cap. My only regret, as I talked to Dr. Barks that night when he
explained the cooling cap, and what it might be able to do for my
grandson, was the fact that after he gave the explanation he said,
\"Well, now I have to go, and I have to pull a card. And because it\'s
an FDA study, I have to pull a card, and if the card says \`yes\' your
grandson can have it, but if the card says \`no\' he can\'t have it.\"
At that point I turned to my son-in-law Robert and I said, \"Rob, be
ready, because if he walks back, and Dr. Barks tells me my grandson
can\'t have this chance simply because a card was drawn, I\'m probably
going to lose it.\" But thank God that he came back after about 10
minutes and he said, \"Well, everything\'s fine, the cooling cap is on
him, and he\'s going to be part of the cooling cap study.\"

As you can see, Anthony is a healthy, intelligent, talkative, normal
three and a half year old. All indications at birth, if you take a look
at that picture, was that that\'s not what we really expected. As the
other two families indicated, we had also thought about cerebral palsy.
As a matter of fact, the last neurologist that examined Anthony before
she came into the room looked at his file, came in, and became very
emotional. And the reason she said she was very emotional is because
upon looking at his file she thought she was going to come in to see a
child in a wheelchair not being able to talk, or walk, or anything like
that. And here he was running around, talking to her, and having a gay
old time. And she was extremely emotional because of that.

But I do know, and I would like to express, again, exactly how much our
family appreciates the cooling cap and what we think it did for Anthony.
Again, just like my daughter says, I only hope and pray that the panel
finds it within themselves to give the rest of the babies that were or
will be in the same kinds of conditions as Anthony was the opportunity
to have the same effects. Again, you know, there\'s no guarantee. Each
case is different. But again, we\'re just hoping and praying that the
panel sees to it that they allow this cooling cap to become part of the
procedures here in the United States.

(Applause)

MS. MITCHELL: I will be real brief here. I just want to take a moment to
express my gratitude, and thank you for allowing me the opportunity to
speak before you. I want to say that words cannot express all of my
gratitude for having my grandson be a part of this study. And the
extraordinary development is due to wearing the Cool-Cap immediately
after birth. And by approving this for widespread use, you will be
allowing others to experience the same miracle that I feel that my
family have experienced. My gratitude cannot be described in just these
two or three short minutes. I spend every day realizing how fortunate my
grandson and my family were for being a part of this Cool-Cap study, and
I hope and pray that other families whose children have been deprived of
oxygen at birth will have the same medical technology available to them
in their time of crisis that prove to be a miracle for us. And I would
ask you please to approve the Cool-Cap so other families can be as
fortunate. And I thank you so much for this opportunity to speak.

(Applause)

DR. HAINES: Thank you. At this time I would ask if there is anyone else
who wishes to speak in the open public forum this morning. If not, there
will be a second opportunity for an open public forum this afternoon.

We\'ll now proceed to the Olympic Medical presentation for their
Cool-Cap device. Then we\'ll have a short break and proceed with the FDA
presentation. After lunch, the panel will deliberate on the
approvability of the PMA. Before the panel votes on the approvability of
the PMA, there will be another second open public hearing, and FDA and
sponsor summations.

I would like to remind the public observers at this meeting that while
this meeting is open for public observation, public attendees may not
participate except at the specific request of the panel. We\'ll begin
with the sponsor presentation. The first Olympic Medical speaker is Dr.
Edward Weiler, Vice President for Research and Development. He will
introduce the other Olympic Medical presenters. Dr. Weiler?

DR. WEILER: Thank you panel members. Good morning. Thank you for this
opportunity to present our product to you this morning. I am Ted Weiler.
I\'m Vice President of Research and Development for Olympic Medical
Corporation. I am a paid employee of Olympic Medical. And I\'ve served
as Director of the Cool-Cap trial since we began looking into this back
in 1997.

I\'m going to introduce you to the rest of the speakers who may be at
the podium this morning. The other two who will follow me, plus the ones
you may see during the question and answer period, just to give you a
little bit of their background and their affiliations. Following me will
be Dr. P.Y. Liu who\'s a member of the Fred Hutchinson Cancer Research
Center and a consultant for Drug and Device Development of Redmond,
Washington. He served as a Cool-Cap statistician and is a paid
consultant for a living, medical in that capacity. Here to speak on the
clinical results will be Dr. John Wyatt, who\'s a Professor of Neonatal
Pediatrics and a consultant neonatal pediatrician, and also the Director
of the Center for Neonatology at the University College of London. He
served as co-principal investigator of the overall trial with Dr. Peter
Gluckman from the University of Auckland. Netiher Dr. Gluckman nor Dr.
Wyatt received compensation for this service.

Other presenters who may come before you today to answer your questions
will include Dr. Alistair Gunn, who\'s an Associate Professor at the
Department of Physiology and Pediatrics on the Faculty of Medical and
Health Sciences, University of Auckland. He served as both the medical
officer for the Cool-Cap trial and as a scientific advisory committee
scientific officer. Again, he received no compensation for his
participation.

To speak on questions regarding follow-up will be Dr. Roberta Ballard,
who\'s a Professor of Pediatrics and OB/GYN at Children\'s Hospital of
Philadelphia, University of Pennsylvania School of Medicine, and a
member of the Cool-Cap trial scientific advisory committee. Again, no
compensation was received by Dr. Ballard.

And Dr. John Barks, Associate Professor of Pediatrics, University of
Michigan. He was a Cool-Cap trial co-principal investigator at the
University of Michigan at Ann Arbor. And again, he received no
compensation for his participation in the trial. He has probably been
involved in cooling more infants using the Cool-Cap than anyone else in
the world, and is here to provide any input on that experience that you
may want to hear about.

So this morning, I\'m going to start off, give you a background on the
company, on Olympic Medical. I\'ll discuss the clinical need for
hypothermia, and how Cool-Cap meets that need, as well as a description
of the device that we used in the clinical trial. I\'ll be followed by
Dr. Liu, who will give you the clinical trial design and subject
enrollment, and then discuss the safety and efficacy results from a
statistical point of view. He\'ll be followed by Dr. Wyatt, who will
give you some more clinical background, primates and animal research,
and a clinical discussion of the trial data safety and efficacy
findings. He\'ll follow that up with a discussion of the risks and
benefits of the Cool-Cap. I\'ll then return to give you a brief
description of the commercial device that we are asking approval of, and
a summary of our presentation for today.

Olympic Medical. Who are we? We\'re a privately owned company that was
founded in 1959 by Mr. Jay Jones. It is entirely privately held.
There\'s no stock available for anyone outside the company as far as
conflict of interest concerns go. We\'re located in Seattle, Washington.
All employees are based there. And we do about \$12 to \$15 million a
year in sales. We have less than a hundred employees at the site. We
manufacture and sell approximately 20 devices in three areas, including
pediatrics, respiratory therapy, and surgical. It\'s interesting to note
that we actually have a long history in neuroprotective therapy. We were
involved in the introduction of Bili-Lites back in 1969. It was one of
the major products for the company for quite a number of years now, and
those are used for the treatment of hyperbilirubinemia, and protection
from brain damage.

Clinical need for hypothermia. HIE, as we\'ve heard and will hear some
more, happens in about one to three per thousand live births. It\'s an
evolving pathology that starts with a primary injury associated with an
hypoxic ischemic insult. This triggers a biochemical cascade that
produces a secondary energy failure, or secondary cell death. The
secondary cell death usually peaks within about 24 to 36 hours following
the primary injury. And it\'s often more significant than the primary
injury. Animal studies have indicated that there is a window of
opportunity, a therapeutic window of opportunity, during which the
application of hypothermia can disrupt the biochemical cascade,
dramatically reducing or eliminating that secondary cell death. In the
animal studies, maximum neuroprotection was demonstrated when cooling
was started within about six hours of the injury.

So we designed the Cool-Cap system with the help of the folks at
University of Auckland to provide selective head cooling and mild
systemic hypothermia. And this is done by cooling the head, and in fact
cooling the whole body through the head, while the body receives heat
from a radiant warmer. This allows the brain to be colder than the body
and to develop a gradient both across the brain from the cortex to deep
structures as well as between the brain and the core of the body. Dr.
Wyatt will discuss that a little bit further later on. Having the brain
as cool as possible helps to provide the neuroprotection while
maintaining only mild systemic hypothermia reduces the risks of side
effects from hypothermia.

The trial device, as shown here, was designed for research use. It was
not designed for commercial use. It used a circulating water-filled cap,
patented design. The water is circulated using electric pump, and cooled
using thermoelectric cooling device. And the system is a closed system
using a one-liter sterile bag of water to charge the system. The cap
temperature can be adjusted by the operator to +/- 1 degree C accuracy.
And the system provides monitoring of the rectal and other critical
physiologic temperatures, as well as system temperatures, with built-in
alarms for those temperatures, particularly for rectal, to help the user
keep the patient within the target range.

Although hypothermia has been anecdotally reported for over a hundred
years, and there has been animal research going on for over 50 years, we
began investigating doing this randomized controlled trial back in 1997,
and trying to decide on which population to look at. At the end of \'97,
early \'98, we began to develop the protocol, designed the equipment to
be used, and recruited sites to participate in the trial. In 1999, in
January, we submitted our IDE and received approval that spring. July 1
of 1999 we enrolled our first infant at Columbia Presbyterian Hospital
in New York City, and on January 4, 2002, we enrolled Infant Number 235
at the Royal Alexandra Hospital in Edmonton, Alberta. On September 11 of
2003, the last infant enrolled in the main trial had their follow-up
examination at 18 months.

In September of 2003 we enrolled our first child in the continued access
trial. We\'ve seen two of the members of that this morning. At this
point we have 81 infants who\'ve been enrolled in that. That\'s as of
yesterday. We never know what\'s happening out there though. In October
of 2003 we began data analysis on the data from the main trial, and in
May of 2004 submitted our PMA for approval. We had our 100-day meeting
in October of that year with the FDA. In January we responded to their
deficiency letter, and that brings us to today, a short eight years
later, at our panel meeting.

I\'m now going to turn the podium over to Dr. Liu who will go into the
statistical considerations of the clinical data, and we\'ll move on with
the day.

DR. LIU: Good morning. I\'m P.Y. Liu. I am the statistician for this
trial. I will be taking you through the clinical trial design, subject
enrollment, and both safety and efficacy results pretty quickly.

The trial objective for efficacy was to evaluate whether treatment of
moderate or severe HIE in term infants with prolonged head cooling and
mild systemic hypothermia could produce an improvement in their rate of
survival with favorable neurodevelopmental outcome at 18 months of age,
and to evaluate the safety of this treatment approach.

Per protocol, randomization was to occur within six hours of birth,
after which cooling was maintained for those randomized to cooling for
72 hours. During that time, the target temperature for the control group
was 37 degrees C +/- 0.5 degrees, and for the cooled group was 34.5
degrees C +/- 0.5 degree. At Hour 72 re-warming would start at about
half a degree Centigrade per hour for four hours. During the treatment
period, the infant temperature was monitored for rectal, nasopharyngeal,
fontanel, and abdominal areas. Clinical tests for metabolic,
cardiovascular, pulmonary, and coagulation status were also performed.

There was a 6-month follow-up. The primary purpose was to maintain
contact with the family for subject retention. At this visit, the
infant\'s length, weight, and head circumference were measured. The
family was also asked whether infant was participating in any
interventional therapy. I want to make a comment that FDA had a recent
question about the referral pattern. We can address that during the
question and answer period.

At the 18-month visit, the primary study outcome was measured and
recorded. The examiners were masked to the subject\'s original treatment
assignment. The assessments included neurodevelopmental examination for
the GMF instrument, formal psychometric testing with the Bayley
instrument for both mental disability and psychomotor disability
indices. And there were also the ophthalmology and audiology
assessments.

Between 1999 and 2002, 235 subjects were enrolled over two and a half
years. There was one withdrawal by IRB for purportedly inadequate
consent. So the true study size was 234. Nineteen U.S. sites accounted
for 75 percent of the enrollment, and six international sites accounted
for the other 25 percent, including hospitals in the United Kingdom,
Canada, and New Zealand. Here is a patient accounting chart. So, 235
enrolled, one withdrawal, with total of 234 true sample size. One
hundred sixteen were cooled, or randomized for cooling, rather, 118
control. However, among the 116 randomized to cooling, four infants were
not cooled, two due to misread of randomization card, happened earlier
in the trial, one due to equipment malfunction, and one infant died
before cooling could start. So all told, 112 infants were cooled, 122
were not cooled.

On the next slide, I\'ll be showing you the temperature profile for the
112 cooled versus the 122 not cooled. This slide, Time Zero here
represents the time of randomization. The two solid lines represent the
median temperature achieved. As you can see, for both the non-cooled and
the cooled infants, the median lines were right on target, 37 degrees
for the non-cooled and 34.5 for the cooled. For the cooled infants, the
target temperature was achieved within two hours from randomization.
From there on, it was maintained at 34.5 to Hour 72, and then re-warming
started to re-warm the infant back to about 37 degrees. The dotted lines
represent the tenth and the 90th percentile. As you can see, this tenth
through 90th percentile band was pretty close to within about half a
degree from the target. And the width of the band were pretty similar
between those not cooled and cooled, pretty much within half a degree of
the target temperature with occasional flare-ups that goes beyond half a
degree.

Dr. Weiler will comment on the temperature achieved from the clinical
perspective later on. Now, for safety analysis, there were 21 protocol
defined potential adverse events, including four serious ones, two
adverse events potentially related to cooling, and 15 other anticipated
adverse events. The analysis excluded the four infants who were
randomized for cooling but did not receive treatment. Now, for the four,
protocol pre-identified potential serious adverse events. There were no
occurrences of major cardiac arrhythmia. For major venous thrombosis,
there were two cases in the control group, and for severe hypertension
there were three cases each from the cooled and controlled group.
Lastly, there was one report of an unanticipated serious adverse event,
which was described as evidence of skin damage and local hemorrhage
under the cap. This infant also had severe hypertension and coagulation
impairment, and died of complications of severe asphyxia. The medical
officer\'s assessment was that the event was related to the cap, but
infant\'s other clinical problems combined to precipitate local scalp
ischemia and bleeding. Overall, there were no statistically significant
differences among the anticipated serious adverse events between the
cooled and the controlled infants.

For the true protocol identified adverse events potentially related to
cooling, other than the case I just described, there were no occurrences
of skin breakdown to cooling cap pressure. For difficulties in
temperature control, it occurred in both the cooled and the control
groups. The rate was 32 percent in the cooled infants, and 23 percent in
control infants. This difference was not statistically significant.

Among all of the other 15 anticipated adverse events, there were three
statistically significant findings. For elevated liver enzyme levels,
there were actually fewer among the cooled infants compared to the 53
percent \-- 38 percent compared to 53 percent in control. So cooling had
a protective effect for this event. For minor cardiac arrhythmia there
were 9 percent in cooled infants and 1 percent in control. And these
were mainly sinus bradycardia of mild to moderate degree, expected for
hypothermia. Lastly, among the so-called \"Other\" category for adverse
events, 46 percent of the cooled infants reported versus 22 percent of
control. The reason for this difference was scalp edema, 21 percent in
the cooled infants, and 1 percent in control. If scalp edema from this
\"Other\" category, then for the remaining other AEs, the percentages
were not different between the cooled and controlled. And the scalp
edema were mostly of mild to moderate degree severity, and required
little or no intervention. Pretty much all resolved after cooling
stopped. Dr. Wyatt will be commenting on both of these events from a
clinical perspective in his presentation.

To round out our safety picture, here is mortality by 18 months.
Mortality is part of efficacy. Therefore, this is by intent to treat
table. At 18 months, 16 of the 234 infants were lost to follow-up. Among
those with status known, the death rate was 31 percent in the cooled
infants, and 36 percent among the control. This difference was not
statistically significant. And all the deaths were reviewed by the
medical officer and determined to be unrelated to the Cool-Cap or the
trial protocol. Here\'s a closer look at mortality. Most of the deaths
occurred within the first eight calendar days, 53 of 78. For Days 4 and
5, there were 11 deaths in the cooled group, versus two in control. We
postulate this was a possible consequence of the unmasked nature of a
novel therapy trial where life support withdrawal was delayed until
after treatment completion. Both Doctors Wyatt and Barks can comment
more about that from their clinical experience.

So to summarize the safety results, there were no difference for the
serious adverse events between the cooled and the controlled infants, no
differences for the potentially cooling-related AEs pre-identified. For
the other AEs, for enzyme elevation there was a protective effect in
cooled infants, and there were more sinus bradycardia and scalp edema in
the cooled subjects. Both of these were expected. They\'re a mild to
moderate degree of severity, and requiring little or no intervention for
resolution. There is no mortality difference between the cooled and
controlled infants either.

For efficacy, the primary outcome was defined as the combined rate of
mortality and severe neurodevelopmental disability in survivors at 18
months of age. The severe neurodevelopmental disability was defined as
presence of any one of the following three conditions. The first one was
the Bayley MDI, Mental Development Index, less than 70. That\'s two
standard deviations below the mean. The second one was Gross Motor
Function impairment level 3 to 5. Level 3 is for infants who are
non-ambulant, and can sit but with support applied to the lower back.
Levels 4 and 5 were for infants who had limited or no self mobility. The
third condition that qualifies for unfavorable outcome was bilateral
cortical visual impairment.

Here is a patient accounting chart for efficacy. Again, 234 was the
final count, 18 were lost to follow-up, for a 7 percent loss rate. That
leaves us with 218 with 18-month primary outcome data available, 108
cooled versus 110 control. The favorable outcome rate was 45 percent for
the cooled, and 34 percent for the control infants. This is by intent to
treat. So the four infants who were randomized to cooling but were not
cooled were included in the cooled group here, and all four had
unfavorable outcome. For that percentage that I just reported, the
Fisher exact test p-value was 0.10. For the unfavorable outcome rates of
55 percent versus 66 percent, the unadjusted, the relative risk was
0.82. However, more infants randomized to cooling had severely abnormal
aEEG or low APGAR at baseline. Both of these factors were in favor of
the control group. Specifically, for aEEG background, severely abnormal,
there was 37 percent of the cooled infants, versus 28 percent in
control. For APGAR score at five minutes, zero to three, percentage was
78 percent in the cooled group, and 67 percent in the control group.

So, to adjust for baseline imbalances, logistic regression as specified
in the protocol. A pre-specified six-factor logistic regression was
performed. I want to clarify the pre-specified nature of these six
factors. aEEG background and seizure standards, plus aEEG and
randomization, these were specified in the protocol. During the PMA
process, FDA reminded the sponsor that APGAR score, birth weight, and
gender were discussed during protocol development, and they should not
be left out of the logistic regression. Therefore, the definitive
logistic regression included these six factors. And in the result, the
treatment effect was statistically significant with a p-value of 0.042.

I apologize for this busy slide. These are the details of the
regression. For treatment effect, cooled versus control, odds ratio for
unfavorable outcome was 0.53, with a p-value of 0.042. aEEG background
abnormality was a highly predictive baseline factor for unfavorable
outcome, with the severe versus moderate odds ratio about 2.5, p-value
0.01. So was seizure of aEEG odds ratio 1.9. High APGAR score was
favorable, with the odds ratio of 0.85. And high birth weight is
actually unfavorable, with the odds ratio of 1.06.

And some secondary supporting analyses were also performed for the
primary outcome. First, a per-treatment analysis was done, excluding the
four infants who were randomized to cooling but was not cooled. The
treatment effect p-value was 0.02. I need to clarify, the so-called
\"per treatment\" analysis did not move these four infants from the
cooled group to the control group. They were just excluded from the
analysis. And then another analysis added or substituted the aEEG with
baseline Sarnat score, p-value for the treatment effect was unchanged.

Finally, an explanatory subset analysis was done for a pre-defined
subset which encompassed 79 percent of the study subjects who were
infants with both severely abnormal background and seizure on aEEG were
excluded. So this subset represented a somewhat better prognosis group.
Treatment effect p-value was 0.01. So these were secondary supporting
analyses for the primary outcome.

For secondary outcomes, multiple handicaps or Bayley PDI less than 70,
bilateral sensorineural hearing loss, epilepsy, and microcephaly, there
were no statistically significant differences between the cooled and the
control groups. For the first two, multiple handicap and Bayley\'s PDI
less than 70, the actual percentages were about 10 percent lower in the
cooled group compared to the control group. For the other three, the
rates are very similar between the cooled and the control groups.

To summarize efficacy results, there was a statistically significant
treatment effect with odds ratio of 0.53, and these are odds ratio, and
p-value of 0.042 when chance imbalance in the baseline factors were
accounted for by logistic regression. I will now turn the presentation
to Dr. Wyatt.

DR. WYATT: Panel members and members of the public, it\'s my privilege
to address you. My name is John Wyatt. I\'m a Professor of Neonatal
Pediatrics, University College, London, and a clinical neonatologist.
I\'ve been practicing clinical neonatology for over 20 years in London.
I work at a major tertiary center, in fact one of the first neonatal
intensive care centers in the world, created in the \`60s. And I helped
to lead a multidisciplinary research group into mechanisms and
prevention of brain injury, and have been personally involved in both
experimental and clinical studies in the newborn. And I was the
co-principal investigator for the Cool-Cap trial. I\'ve received
financial support for trial costs and travel expenses from Olympic
Medical, but I\'ve had no personal benefit from this involvement in this
trial.

I\'m going to review the issues, the clinical background, the findings
briefly from animal research. I\'m going to discuss the trial data from
a clinical perspective, both safety and the efficacy findings, and
summarize what I see as the benefits and the risks for Cool-Cap.

So I had intended to just try and summarize for you what the clinical
background was, but to be honest I had completely was not prepared for
the very moving accounts that we heard of Felicity, Sydney, and Anthony,
and their dignity and courage as they presented their findings. But I
think this certainly for me, as a clinician working in this area for 20
years, I found it extremely moving to hear their accounts, and I think
it described very clearly my own motivation, my caring for these babies
over 20 years, every time I cared for a baby with profound
encephalopathy, I had a renewed motivation. We must find a way of
helping these babies.

As you\'ve heard, encephalopathy is an infrequent and unexpected
emergency which usually occurs following a normal pregnancy, and occurs
out of the blue. We recognized that to attempt to perform a randomized
clinical trial in this area was going to pose major hurdles. And in
fact, what we were attempting had never before been successfully
achieved in neonatology. This would be the first major clinical
randomized trial of a neuroprotective therapy in the newborn.

The logistical problems in a trial like this is that there would be a
need for very rapid and early identification, and referral to a trial
center. The animal studies showed a relatively short window of
therapeutic opportunity, probably at a maximum six hours, and possibly
less than that. The clinical background meat that there was a challenge
of rapidly communicating complex information to parents during the
informed consent process. As you\'ve heard, extremely emotionally
fraught situation, and the need to communicate information about the
trial. We\'re dealing with extremely sick infants with a very high risk
of complications, of adverse outcome, and of death. And then in addition
to that we had the challenge of achieving high rates of outcome data at
18 months follow-up in a large number of hospitals across the world. So
we recognized that there were major logistical challenges of undertaking
a trial like this.

To summarize the data of animal studies, as you\'ve heard, animal
studies have been going on since the 1950s. An American physiologist
called James Miller started the first evidence. And over the last 50
years, there has accumulated a very powerful and persuasive body of
evidence. And in fact, on our scientific advisory committee, we had
probably a majority of the experimenters and most experienced
investigators in the field of neonatal hypothermia experimental research
actually participating in this trial. So the whole design of the trial
was based on a weight of animal evidence. But to summarize briefly, what
the animal data suggests is that mild hypothermia after hypoxic ischemia
reduces brain cell death, it preserves brain energy metabolism, and
particularly this, it ameliorates the secondary energy failure which
occurs in a period between about 12 and 36 - 48 hours after the insult.
It improves long-term functional outcome, and a number of studies have
been done in the newborn piglet, particularly using the Cool-Cap device.
These have demonstrated that it\'s possible to establish a temperature
gradient using this device both across the brain itself, from
superficial to deep structures. Cooling can be maintained at both deep
and superficial brain structures. And also in the piglet it\'s possible
to obtain a gradient between the brain, which is cooler than the rest of
the body, and that this gradient can be maintained for at least 24
hours.

I\'ll now turn to a clinical discussion of the results of the Cool-Cap
trial which Dr. Liu presented. First of all, from a safety aspect, there
were three findings which were of statistical significance. First was
the elevated liver enzymes, and in fact, as you\'ve heard, there was a
significant decrease in the instance of elevated liver enzymes in the
cooled group. Elevated liver enzymes are a marker of hepatic cell
injury, and we think, and there is experimental evidence to suggest that
cooling can actually have a protective effect directly on the liver.
This probably represents a direct protective effect from the systemic
hypothermia in the Cool-Cap treatment. There was an increased rate of
minor cardiac arrhythmias, 9 percent in the cooled group compared to 1
percent in the control group. And I\'ll discuss those in greater detail.
And there was also an increased rate of scalp edema of 21 percent in the
cooled group.

Looking at the question of the minor cardiac arrhythmias, 8 out of 10
cases in cooled infants were described as mild to moderate sinus
bradycardia. And sinus bradycardia is a recognized physiological
consequence of hypothermia. It was in fact described by James Miller
back in 1950. A very close relationship between body temperature and
heart rate. And the sinus bradycardia resolved through the re-warming.
The remaining two cases had an unspecified cardiac arrhythmias of mild
severity. It\'s important to state that no cooled infants experienced a
major or life-threatening cardiac arrhythmia. That\'s what we were
worried about when we designed the trial, such as ventricular
fibrillation, or ventricular tachycardia. But no infants in fact
experienced such an arrhythmia. And our clinical experience as
neonatologists is that those kind of life-threatening cardiac
arrhythmias are incredibly rare.

There was no increase, also, in hypertension. So the sinus bradycardia
was not associated with hypertension. If anything, there is a trend
towards a slightly increased blood pressure with cooling. So to
summarize, the increase in mild sinus bradycardia is an anticipated
consequence of hypothermic treatment and is not clinically significant.

But with regards to the scalp edema, 20 of 23 cases were described as
mild to moderate. All the cases resolved prior to or shortly after the
end of treatment, except in one case where the infant unfortunately died
as a consequence of the brain injury during the treatment process. No
specific therapy was necessary, although in some cases the cap position
was adjusted. Edema is a direct result of thermal effects on capillary
permeability and possibly mechanical pressure from the cooling cap.
However, of course, transient scalp edema and scalp bruising is common
in all infants delivered vaginally, and we suspect that it may well have
been underreported in the control group because it\'s something that
neonatologists don\'t pay great attention to. And finally, there was no
evidence that scalp edema led to long-term sequelae. In all infants, in
all cases it was transient and resolved. Scalp edema is transient. It
recovers spontaneously and has no long-term sequelae.

Looking at the mortality data, there is overall, as Dr. Liu pointed, no
significant difference in mortality between the two groups, although
there is a trend to reduce mortality in the cooled group. If we see here
in the actual timing at which death occurred, the treatment period
occurs in the first 72 hours and is completed by Day 3, and there did
appear to be an increase in mortality on Days 4 and 5 in the cooled
group, which wasn\'t apparent in the control group. And our impression,
as clinical neonatologists who have been involved in this therapy, is
that because of course this is an unblinded therapy, and therefore all
the clinical staff are well aware of which babies are receiving
treatment, there is a natural tendency that even in cases of babies who
appear to be doing extremely badly, and have a very poor prognosis,
there\'s a natural tendency for the clinical staff to wish to complete
the treatment which is undergoing. They know that it\'s going to last
for 72 hours. To allow the baby to re-warm, and if then it\'s apparent,
the very poor prognosis, to then undertake discussions with parents,
possibly to undertake further investigations such as a further EEG,
which would then lead to a decision to treatment withdrawal. So that the
effect of the cooling therapy may be to concentrate treatment decisions
about withdrawal of therapy in the window of 24 - 48 hours following the
end of the treatment. And of course in the control group, where there is
no specific treatment undergoing, there is simply supported care, this
tendency to focus attention to a period following the end of the
treatment period doesn\'t occur. So it\'s important to state that in no
cases did we think the mortality was directly related to the re-warming
process. The re-warming process itself, if performed according to the
protocol, appears to be safe, but it represents a decision taken by
attending staff independent of the trial, the trial personnel, as to
when treatment withdrawal should be undertaken. We\'d be happy to
discuss that further if it\'s appropriate.

The clinical significance of the fluctuations in temperature control. I
think it\'s true to say that generally neonatologists in the past have
not paid a great deal of attention to the precise temperature control of
babies undergoing intensive care, and we recognize that sick babies may
well have fluctuations around a mean. And as Dr. Liu pointed out, the
data suggests that the temperature fluctuations were no greater in the
cooled group than they were in the control group. So even the babies
just undergoing standard intensive clinical care had quite significant
temperature fluctuations within a range of +/- null-point 5 degrees, and
sometimes greater. There was no evidence that the temperature
fluctuations in the cooled infants had any impact on safety or efficacy.
The degree of fluctuations clearly varied from infant to infant. Some
infants had very marked fluctuations, some very little. Those with large
fluctuations were probably due to the adverse effects of the injury, the
encephalopathy on the thermoregulatory function of the brain stem. And
the design of the commercial configuration of the Cool-Cap is such as to
try and reduce or prevent the phenomenon of temperature chasing, where
the cap temperature is changed too quickly. And all of us who\'ve had
experience of using the Cool-Cap have discovered that there is quite a
lag phase between changing the temperature of the cap and then seeing
the resulting temperature change of the body.

And this illustrates the sort of fluctuations, first of all, that we
sometimes see in a cooled infant. Here is time in hours. Here is the
rectal temperature in degrees Centigrade. The target range was 34 to 35
degrees Centigrade. And it can be seen in this infant there was both a
period where the temperature went above the target range and also went
below the target range. Here is the re-warming period at 72 hours
following initiation.

Here is data from another infant who was in the cooled arm of the trial.
Here is time in hours. The pink data shows the rectal temperature. Here
again is the target zone. And the blue shows the cap temperature. And it
can be seen for instance here that the rectal temperature has gone above
the target range. The cap temperature is being reduced, but there is a
lag phase between the changes being made in the cap temperature and the
rectal temperature. This then leads to an overshoot, and you can see
this oscillation which is occurring. And very often these oscillations
occur particularly in the first 12 - 24 hours of the treatment, before a
more stable period is occurred. And there\'s no doubt that there is \--
with improved experience of using the cooling cap that investigators can
minimize these temperature fluctuations. But I would, again, enforce
that there\'s no \-- reinforce the fact that there\'s no evidence that
these fluctuations are in fact have an adverse effect on the infant,
although we try and minimize them.

In regard to efficacy, the overall unadjusted data show favorable
outcome in 45 percent of cooled subjects compared with 34 percent of
control subjects. And as Dr. Liu showed, after adjusting for the greater
illness severity in the infants enrolled in the treatment group, this is
a statistically significant finding overall. And in particular, one of
our great concerns when we were designing the trial was the possibility
that therapy would lead to a shift in our group of infants who
previously died to those who survived, but with very severe
neurodisability. And there\'s really no evidence in our data of a shift
from death towards severe neurodisability.

If you look at the components of the primary outcome. There are three
components, the Gross Motor Function scale here, neuromotor disability,
the Bayley mental development index, which is a measure of cognitive
development and bilateral cortical visual impairment. And it can be seen
that in each of those three, if we look at this line here, there is a
tendency to reduction of both Gross Motor Function, neuromotor
disability here, of the adverse finding in cognitive impairment here,
and of visual impairment here. So in all three of the primary outcome
components, there is no evidence of increased disability in the cooled
group, and the trend is towards a reduction in all of the three forms of
disability in the primary outcome measures.

So in conclusion, term infants suffering from moderate to severe hypoxic
ischemic encephalopathy, selective head cooling with mild systemic
hypothermia as administered with the Olympic Cool-Cap device according
to the protocol is associated with both a statistically and clinically
significant reduction in the combined rate of death and severe
neurodevelopmental disability.

Some additional clinical questions which have been raised. First of all,
the question of seizures during re-warming. There\'s a total of four
infants who had the phenomenon of seizures during re-warming, one in the
pilot trial, one in the main trial, two in the continued access trial.
Of those four infants, three have survived with good outcomes. So
although seizures may occur during the re-warming period, they are not
associated with a specifically adverse outcome. They are often
relatively mild and can be controlled. Hypothermia in animal evidence
has a suppressive effect on seizures and therefore it\'s understandable
that at the end of the hypothermic treatment, it\'s possible that
seizures may be unmasked, and therefore it\'s an understandable
phenomenon, but one which we don\'t think is of very major clinical
significance. It\'s just something that clinicians need to be aware of
the possibility.

Secondly, the problem going to the QT interval on the EKG. This again is
an entirely physiological effect of cooling, just the effect of cooling
on the conduction system of the heart is to cause elongation of the QT
interval. And there\'s no evidence that this prolongation in itself is
dangerous or leads to an increased incidence of dangerous cardiac
arrhythmias which of course is the concern. It\'s also transient and
goes away with re-warming.

In one infant in our trial there was evidence of a significant increase
in anticonvulsant levels. This again is an anticipated consequence of
hypothermia. It has an effect on the liver to reduce the metabolism of a
range of drugs, including anticonvulsants. And this was referred to in
the study manual, and is just a factor that clinicians using this device
need to be aware of the possibility of increased anticonvulsant levels.

Sclerema neonatorum is a very rare condition, well recognized of the
newborn, which is associated with induration of the subcutaneous tissue.
It has been rarely described in association with hypothermia, although
it can also occur in sick infants, including those with encephalopathy
who are kept at normal temperature. It occurred to one infant in the
continued access trial, but we don\'t believe that the sclerema
neonatorum in itself is a very dangerous condition. It simply reflects
an underlying process, and it\'s the underlying process which is
important.

Finally, in one infant in the continued access, an epidural hematoma was
described. This was in association with a skull fracture from head
trauma during delivery. The epidural hematoma of course is a recognized
complication, as is intracranial bleeding following vaginal delivery.
It\'s frequently not diagnosed. Although there\'s a theoretical
association with cap cooling, or with cooling of the subcutaneous
tissues, in fact in the trial there\'s no evidence that intracranial
hemorrhaging either in this case or in other cases was specifically
related to the cooling therapy.

Just to summarize the clinical need for Cool-Cap. It\'s clear that
neonatal encephalopathy has a devastating outcome. As we\'ve heard, it
often unusually occurs following an uneventful pregnancy. It has
enormous emotional and economic personal cost to families, and to
society as a whole. A very high percentage of infants have adverse
outcome of death or severe neurodevelopmental disability. And this is
the first therapeutic product available for treatment of neonatal
encephalopathy. Currently there is no therapy which has been shown to
improve outcome in encephalopathic infants, and standard care consists
of supportive measures, mechanical ventilation, anticonvulsants, and so
on. So we believe there are very significant benefits. This is an
effective treatment for a devastating condition. There is a trend
towards decreased neurodevelopmental disability in survivors, and no
evidence of a shift from death to disability.

And calculations based on a relative risk calculations are that using
the adjusted figures, for every six to seven treated patients with the
Cool-Cap, improved outcome can be anticipated for one. So a
number-needed-to-treat is between six and seven, based on relative risk
calculations. And it\'s notable that compared with other therapies, well
accepted therapies in neonatal practice, that actually represents a very
good number-needed-to-treat calculation. For instance, if you compare
surfactant therapy in neonatal practice, and with long-term outcome the
numbers needed to treat are in the range of 10 to 20 in infants, and
some other therapies have numbers needed to treat of greater than 20,
that are now standard treatments within neonatal practice. So, we think
that arguably, graded hypothermia is one of the most significant
therapeutic advances in the field of neonatology in the last decade. And
we\'re proud and excited to be associated with it.

And just finally, in terms of minimal risks, there are mild sinus
bradycardia and scalp edema. Neither are life-threatening conditions.
From review of the deaths in our study, no deaths were specifically
related, as far as we were aware, to Cool-Cap treatment, or to being
part of the protocol. And we believe there are minimal risks when
cooling is administered as according to the trial protocol. However, we
recognize that cooling is a major therapeutic intervention undertaken in
very sick infants, and therefore there may be a risk, particularly if
it\'s used in a very uncontrolled manner. But overall, we believe the
benefits clearly outweigh the risks.

And finally, just to try and bring these numbers into a more
comprehensible fashion. If we look at the relative risk calculation \--
if we base our calculation on the intent to treat. This is a six factor
logistic results, regression results which give an alteration of
null-point 53 and we take 100 infants as enrolled in the Cool-Cap trial,
of those 100 infants, if they are within the control group and are
treated by standard care, we would anticipate that 66 infants had an
unfavorable outcome, and 34 infants in the control group would have \--
34 out of 100 would have a favorable outcome. If we took exactly those
same infants and applied the cooling treatment, then based on the
multiple logistic regression calculation we would estimate that 51 of
the infants cooled would have an unfavorable outcome and 49 infants
would have a favorable outcome. In other words, 15 of those 100 infants
would have changed category from the unfavorable to the favorable
outcome.

I\'m now going to hand over to Dr. Weiler who\'s going to conclude.
Thank you very much.

DR. WEILER: I\'m now going to discuss the opportunities for device
improvement that we encountered during the trial. I\'ll discuss the
enhancements that resulted from those that we introduced into the
commercial device, describe the functional equivalence between the trial
device and the commercial device, and then give a summary for our
presentation today. And then make some acknowledgements of the various
people who contributed to making this all happen.

Conducting a trial like this with a research device, we had an
opportunity to hear from our research sites on a number of ways that we
might improve the equipment that they used. Obviously this equipment was
developed very quickly for research purposes, and not for commercial
purposes. It was found to be quite functional, but not particularly
user-friendly. We weren\'t surprised by that finding. It has just a
straight LED temperature display, which provided limited user
information. It in particular did not provide anything other than
current temperature, there was no trending information, requiring the
operator to sort of keep track of trends, and calculate trends in their
head as they worked on the infant. In addition, there was no help built
into this. To carry out the protocol, you required reference to the
paper study manual which was distributed to all the sites in which they
were trained.

So taking those into consideration, we designed a system, basically a
computer-based system with a 10.4-inch color LCD touch-screen display
which has a rectal temperature graph on it. It contains both the current
rectal temperature as well as a temperature graph showing trend displays
of a short time period. So you have a good close-up view of what\'s
happening as well as an extended time period down here which shows the
whole 76 hours of the treatment. In particular, we expect this to have a
significant impact on the temperature chasing we described before.
It\'ll become quite obvious when that\'s happening very early on in the
process, helping the user to recognize that they\'re changing the cap
temperature too soon. We\'ll also have built-in prompts and wizards.
This will basically take the study manual and build it into the system,
along with color photographs showing them how to set up the equipment,
where to place their misters, how to connect the water, and also when to
do things during the treatment, when to adjust the radiant warmer, and
to alert them when they\'re possibly changing the cap temperature too
soon.

This is what the device is going to look like. You\'ll see it\'s very
similar in size and shape to the research device, but it now has a
removable top display control module here which we mounted at bedside,
moving the base away from the crowded cot-side area where there\'s so
much other equipment going on supporting these critically ill infants.

And then the summary, a comparison here between the research and
commercial device. They both use identical thermoelectric cooling
modules. They have identical adaptive cooling algorithm software to
control the temperature of the cap. They both use the exact same
patented cap design, although we\'ve added an additional larger size to
the commercial device as we found that our large size in the clinical
trial was marginal in some larger infants. They both use the same closed
water circulating system that\'s charged with a 1-liter bag of sterile
water, with identical flow rates of approximately one liter per minute.

The major differences come up when you come back to the user interface.
When you get away from those key components that actually affect how
you\'re providing treatment, and now get down to the usability of the
device, that\'s where the major improvements have occurred, going from
the LED temperature display to the color graphic display with the touch
screen, and the built-in help with wizards and protocol prompts.

So in summary, this morning what we\'ve presented is that selective head
cooling using the Cool-Cap may be safely administered to infants who
have been properly selected. It effectively reduces the rate of
unfavorable outcome in term neonates suffering from HIE, provides
treatment for previously untreatable disease. There\'s been nothing else
you can do for these infants before this. The commercial configuration
for the Cool-Cap is functionally equivalent to the trial version. It\'s
user-friendly and conducive to occasional use. Since quite often this
may only be used a few times a year in a lot of facilities having these
sort of built-in wizards and help is going to make it possible for
someone who has received training to walk up to the instrument at three
o\'clock in the morning when they have a significantly ill infant and
not have to worry about trying to remember how to run the machine. It
will tell them what to do. And it\'ll assist the clinicians in
administering then the protocol in a safe and effective fashion.

I want to thank the FDA. The ODE and OCE personnel we\'ve worked with in
this trial have been amazing in their patience in helping us go through
our first PMA process. It\'s been quite an experience and a positive one
overall. Our scientific advisory committee for keeping us on a sound
scientific ground throughout the trial. Data safety monitoring
committee, to make sure that we did no harm while we were testing this
treatment. Our medical and scientific officer who did an amazing amount
of work dealing with all the reports, and helping us with the questions
that come up during a trial like this. Our trial statistician who kept
us on the straight and narrow from a statistical point of view. Site
principal investigators who maintained all the paperwork and kept
everything in order so when the FDA came in to look they found that in
fact we had done a good job with that. The doctors and nurses who cared
for all these babies at these 25 hospitals, sometimes spending long,
long hours at cot-side making sure that these infants were being cooled
properly. And the parents, and the babies.

And I have to agree with John. I was \-- I had not met these families or
heard these stories before, and it\'s very easy sitting back in the
office, or even taking phone calls at three o\'clock in the morning to
answer questions, to get sort of separated from the human portion of
this. But to watch these three families presenting this morning, I know
I was quite moved as obviously John was, and I\'m pretty sure Alistair
\-- Dr. Gunn was as well, to hear these stories and actually see the
effect that this equipment can have. It was quite a shock and a
surprise, and makes it all pretty much worthwhile.

And lastly, I want to acknowledge Tania Gunn. Tania was a pioneer in
this. Her pilot work in infants and development of the protocol that we
used as a basis for our protocol, and also served as a basis for other
protocols being run still today made all this possible. Unfortunately,
Tania passed away a month before we enrolled our first infant, and
didn\'t get to see the trial actually take off. But I know that she
would be very proud and happy, particularly hearing the stories from
these three families this morning, to see how far we\'ve come in the
last eight years. Thank you very much.

(Applause)

DR. HAINES: Thank you, Dr. Weiler. I\'d like to thank the sponsor
representatives for their presentations, for being timely and clear.
I\'d like to give the panel an opportunity at this point to ask any
questions that may have come up. It\'s also a good time if you have a
complicated question that may require the sponsor to do a little leg
work that we can ask that question now and give them time over lunch to
prepare. There will be a second opportunity to ask questions in the
afternoon.

So, just to be sure everyone has a chance, let\'s go around the table.
Dr. Nelson?

DR. NELSON: No specific questions at the moment.

DR. HAINES: Dr. Jensen?

DR. JENSEN: Having the aEEG was obviously very important in not only
determining who could be enrolled but looking at the outcomes. And I
assume that each site had people who were qualified to read the aEEG and
determine what level of abnormality it was. Did you have a core lab that
then went back and looked at all the aEEGs to see if the readings were
correct, or at least consistent, and if not, how do you determine
inter-observer error factors? Because it makes a big difference with the
outcomes. And if you want to answer that later that\'s fine too.

DR. WEILER: Why don\'t we formulate the answer.

DR. JENSEN: Okay.

DR. HAINES: Dr. Brott.

DR. BROTT: I had a few questions of Dr. Wyatt. First of all, I too was
moved by the presentations earlier, and was very much impressed with the
amount of information, and the clarity of the information that we
received in the pamphlet and in the CD. But I was wondering if you could
give me as much detail as you can about that 18-month visit. You know,
where was it carried out, who carried it out, who was present, how long
did each of the tests take, so that we can kind of get a videotape in
our minds of that 18-month visit.

DR. WYATT: I wonder if I could ask \-- should we describe that this
afternoon? We\'d be happy to detail that.

DR. BROTT: Okay, great. The other thing I was wondering about, and
again, these have to do with the endpoints. You know, at zero to seven
days your mortality was 27 and 26, and after seven days you had nine
deaths in one group and 16 deaths in another group. And it was mentioned
that the difference had to do with the developmental disabilities. And
I\'m wondering on those 25 deaths, you can have some detail to assure us
that in fact that\'s the case. And I\'m sure you wouldn\'t have that at
this moment.

DR. WYATT: We could certainly find that.

DR. BROTT: Yes. The other thing that I had, the question about the
difference in deaths at three to four days I think it was.

DR. WYATT: Four to five days.

DR. BROTT: Four to five days. Your hypothesis was very persuasive to me.
With adults in the state that I practice in the ICU, and I\'m there a
lot, we legally have to fill out forms on treatment withdrawal. And so
there\'s a paper trail in our state for adults. I don\'t know how it is
in the other 49 states, in the United States, and of course I don\'t
know about the U.K. and New Zealand, but I would think that there might
be such a thing for neonates, and I\'m wondering if that information
backs up your hypothesis.

DR. WYATT: I wonder, Dr. Barks, would you like to?

DR. BARKS: So I think generally in neonatal practice it would be
customary for the attending neonatologist to write a note describing the
reasons for the withdrawal of support. And I know in our practice, in
our institution there would have been involvement with the pediatric
neurologist in consultation as well. However, at least in Michigan
there\'s no formal process of paperwork that you have to fill out in a
neonate upon withdrawal of support. But good documentation would be
customary.

DR. BROTT: Has that been checked with these \-- because there aren\'t
that many. You know, the difference is not that great. And I would think
there would be, particularly at a place like University of Michigan and
your centers, I would think that there would be a paper trail.

DR. BARKS: There\'s a paper trail to the extent that the FDA when they
came in and reviewed all of our 12 case report forms, had all of the
medical records to go through and verify that what was in the case
report forms was in fact reflected in the medical record.

DR. GUNN: May I briefly? My name is Alistair Gunn, medical and
scientific officer. I\'m from the University of Auckland and Starship
Children\'s Hospital. The only potential conflict of interest is that
Olympic Medical paid my airfare to come here.

I simply want to say I\'ve reviewed all of the cases, all of the death
certificates of all of the babies, including postmortem records when
available. All except five babies who died in the first week of life
died of withdrawal of care.

DR. BROTT: Died with?

DR. GUNN: Of withdrawal of care.

DR. BROTT: Oh, okay. All but how many, did you say?

DR. GUNN: All but five. Including, as you saw, there was one \-- at
least one child who died before we could even start cooling of profound
hypertension.

DR. BROTT: That answers my question satisfactorily. Very briefly, the
gradient that you mentioned Dr. Wyatt. I was wondering what it was in
piglets, and what the evidence is or isn\'t that it is in neonates?

DR. WYATT: Yes, thanks. In piglets, the temperature grade which can be
achieved is of the order \-- I would again just need to check the data,
but it\'s of the order of 5, 6, 7, 8 degrees Centigrade between the
superficial tissue and the center of the brain. Of course, the problems
in translating this data into the human infant are considerable. First
of all, the geometry of the human brain is quite different from the
piglet. The human brain is bigger and has a different configuration. And
secondly, there isn\'t any method of non-invasively measuring brain
temperature in the human infant, effectively, at the moment. It\'s
something that I and other colleagues are actively working on, and we
have now developed a magnetic resonance technique for quantifying brain
temperature, regional brain temperature, which works in piglets, and we
think it will work in babies. But as of now, we do not know what
temperatures are achieved by the Cool-Cap therapy in the human brain. We
can estimate it, but it\'s really quite a vague estimate. My estimate
would be that cortical tissue as applied in the trial, that the cortical
tissue will be of the order of 31 - 32 degrees Centigrade, and that deep
brain will approximate a rectal temperature which is 34.5 degrees
Centigrade during the cooling protocol. But these are just guesses based
on available evidence. And at the moment, it isn\'t possible to actually
know what temperatures are being achieved.

Certainly as we look to the future, there is now accumulating evidence
that the temperature sensitivity of different areas of the brain are
different. We now have piglet data suggesting that the superficial \--
that the optimal protective temperature in the superficial regions are
less than the optimal temperature in the deep brain. We now have a study
suggesting that. So as we look to the future, we think that optimizing
the temperature profile of the brain to provide the best effect, that
that process will continue and may vary from baby to baby. So there\'s a
lot more to learn about temperature, its effect on the brain, and the
best way of applying it. But as applied in the Cool-Cap study, it
appears to be effective.

DR. BROTT: Thank you.

DR. HAINES: Dr. Clark?

DR. CLARK: I had three questions. One I think Dr. Gunn has already
answered. Just to make certain that I heard that correctly, withdrawal
of care was not statistically different. I know the timing may have been
different, but the actual occurrence of that event?

DR. GUNN: That is correct. The early deaths, and numbers of withdrawal
\-- cases of withdrawal of care, absolutely rock solid. There was no
difference.

DR. CLARK: Okay. The second question I had is with regards to the 7
percent loss, I assume that you have outcomes for mortality all the way
up to some point. These outcomes that we have here on mortality
represent all the patients where you had data. The fallout is primarily
in not getting the neurodevelopmental outcome, is that correct?

DR. GUNN: That is correct. It is possible that there may have been some
children who have died after the 6-month follow-up, but I think that\'s
relatively unlikely. The majority are likely to be loss of
neurodevelopmental information.

DR. CLARK: And so your follow-up to six months would have been \-- do
you have an idea for alive, that would be pretty close to 100 percent?

DR. GUNN: I don\'t have an exact figure, but it\'s very close.

DR. CLARK: Yes, okay. I just wanted to make sure, so the mortality
numbers here, we\'re really not missing 7 percent on mortality.

DR. GUNN: No, definitely not. I\'m sure that at most it might be one
infant.

DR. CLARK: All right.

DR. GUNN: I doubt that it\'s more than that.

DR. CLARK: Okay. The \--

DR. GUNN: I would also say it\'s worth \-- mortality after the first
week of life is quite different from mortality during the first week of
life. Essentially the late mortality is a surrogate for profound
handicap. It\'s difficult to tease this out because there are so many
causes of death listed. My best estimate is that virtually all of the
late deaths are infants with profound multiple handicap.

DR. CLARK: And just with regard to that same issue, if you look at it
over time, the numbers of patients who were falling out in the control
is a little bit larger, and that\'s the only reason I brought that up,
is that that would go along with the potential protective effect that
you were discussing.

DR. GUNN: Yes.

DR. CLARK: Okay. I agree. The second question \--

DR. GUNN: It\'s clearly not significant. It\'s 9 versus 16. But the
trend is in the right direction.

DR. CLARK: Right.

DR. HAINES: Dr. Clark, we will have a chance for additional questions.
Just to be sure everyone gets a chance I think we\'ll go around and do
one question at a time, and keep going as long as we have time.

DR. JAYAM-TROUTH: My question is regarding the scalp edema and the
bruising that you had, and the single case of epidural hematoma that you
had. Was there a significant \-- I see there is a difference in the
clotting in the coagulation profile that you have there. You know, did
that play a role in the degree of difference that you had between those
who had bruising, those who had lacerations to the scalp, and those who
had the epidural, and the one that had epidural hematoma?

DR. GUNN: There isn\'t a significant difference in the coagulation
profile, looked at either as incidence of abnormal clotting studies, or
as the actual median biochemical measurements over the whole study. As a
group, there is no question that infants in the study protocol, more
than 80 percent had a significant coagulopathy. The particular infant
who had the scalp damage, and there are two, there was the serious
adverse event who was reported as part of the trial, and the second
infant was reported by Dr. Barks during the continuation trial, clearly
had both biochemical coagulopathy and severe clinical coagulopathy as
shown by evidence of bleeding from multiple sites. I personally do think
that the report of bleeding in the first case, and the report of
bruising in Dr. Barks\' study was at least partly related to the
profound coagulopathy. Whether it would have made a difference if they
had been treated more aggressively, I really can\'t say. It may have, or
it may well have been too late by the time the infant was stabilized
enough to do that.

DR. HAINES: Dr. Ellenberg?

DR. ELLENBERG: This is a single question but it has a Part A and Part B.

(Laughter)

DR. ELLENBERG: I was delighted to see Dr. Liu\'s Slide Number 36 since I
couldn\'t find it in the original material submitted to us. The first
part of the question is in the logistic regression with the six factors
combining the three factors originally proposed in the protocol by the
sponsor, and then the several factors requested to be added by FDA, the
table shows many \-- several either indicator variables that reflect
those factors, or factors themselves, such as gender, that were not
statistically significant. So the Part A question is, is the 0.042
p-value that is quoted as the result for the primary endpoint comparison
based on a logistic model that had deleted those non-significant
factors, or are these factors still in the model when you computed?

DR. LIU: They\'re in the model.

DR. ELLENBERG: They\'re in the model.

DR. LIU: Yes.

DR. ELLENBERG: Do you know what would happen if you deleted these
non-significant factors?

DR. LIU: There would be very little change, hardly any change. But these
were trying to sort of stick with the pre-specified models. So the
non-significant ones were retained.

DR. ELLENBERG: Okay. Then let me move on. In terms of using the Cox
proportional hazards \-- excuse me, hazard survival model, this is a
survival model, and it\'s contrasted in the reports that were submitted
to us, and again today, that the much simpler Fisher exact test, which
looks at 18 months and asks the question is there a difference in the
primary endpoint, which is a combined endpoint. That had a p-value of
0.10, which was not statistically significant based on the protocol
specified value, versus after using the logistic regression it\'s
brought down to 0.042. Now, the survival analysis will not be able to
take account of those subjects that did not survive long enough to have
the 18-month neurodevelopmental examination. And if you look at your
prior slide on death, which is Slide Number 27, you showed 31 percent
versus 35 percent death rates when the two arms are compared, which was
not statistically significant. And then if you look at the combined
endpoint of death plus neurodevelopmental problems, the results
comparing the two arms are 55 percent and 66 percent. The question I
have globally, if in the survival analysis the data that you are
analyzing is now primarily just death, and I\'m obviously not minimizing
death as an outcome, but if those that were not \-- you\'re obviously
not at 18 months when you did this analysis necessarily, but there were
subjects that didn\'t make it. Is it possible that the primary result is
being driven by death alone, and not containing the second part of the
combined endpoint?

And I don\'t necessarily want an answer to that, but this is my thinking
here. I\'m concerned that the primary endpoint which is in a statistical
sense not wildly significant. It\'s got a p-value of 0.42. I\'m
concerned that that is primarily a mortality result, and I want to make
sure that I understand how you\'re thinking about this in terms of the
subjects that were lost to follow-up, and in terms of whether or not the
result itself could be reflecting not necessarily even whether there\'s
a difference in mortality. Because when you looked at that alone there
wasn\'t. But whether the Cox proportional hazard is actually
representing a difference in time to mortality. And this is what is
driving this result. Now, since I saw a lot of this just this morning, I
may not have formulated this in as elegant way as possible, but if we
could discuss that later on in the next round of questioning, and I will
try to formulate it more clearly as I think about it more. Thank you.

DR. LIU: The Cox proportional hazard was for time to death. That part I
can answer. And so that was because initially there was a concern about
potential time to death difference. So that was based on mortality
alone, but considering time to death. And death only.

DR. ELLENBERG: Thank you.

DR. HAINES: Okay. So we\'ll hear more this afternoon. Dr. Hudak?

DR. HUDAK: I guess I have one comment, one short question, and one
longer question. But the comment is, the way that I looked at the data
here of the survivors in the cool group, there\'s a 33 percent incidence
of abnormality, and in the control group there was a 45 percent
incidence of abnormality, if you just look at the survivors, and look at
there what they call a severe abnormality. So maybe that\'s helpful.

The quick question is in terms of blinding the assessment at 18 months,
can you provide some assurance that that was in fact how that was done?
Because if the parents are in the room, I\'m sure that there are I
suppose clues that they might give about whether a child received the
cooling cap or not.

DR. HAINES: Could we perhaps tie that together with the other question
about the 18-month outcome, and get that in one lump this afternoon?

DR. HUDAK: Okay. And the other \-- I have a few questions, but I\'ll
just do one more. The experience that we have as neonatologists is that
there is a window during which withdrawal of support is possible. And
that is that babies, even with severe neurological abnormalities, do
tend to improve. So there may be a time when you can remove the baby
from life support and the baby will expire. If you wait another one day,
two days, three days and try to do that, the baby\'s a survivor. So the
question I have here in reference to this interesting issue of, you
know, the higher mortality in the \-- at four and five days in the
babies who were cooled, because withdrawal of support might have been
deferred through the 72-hour treatment period is what is the possibility
that there may have been some babies in the non-treated group withdrawn
from support who if they had been more aggressively supported for 72
hours might have actually been survivors in the end. And how would that
affect the analysis? Probably something that can\'t be addressed right
now, but something to think about.

DR. HAINES: Would you like to think about? All right. Dr. Doyle?

DR. DOYLE: Just one quick question. Apparently the critical period is
the first six hours. Are there any trends within that 6-hour period that
the earlier in the baby\'s life the cap is applied, the better the
results?

DR. GUNN: That was in fact our original hypothesis. For what it\'s
worth, we compared early life, as in less than four hours, with late,
and there was no significant effect. I believe the primary reason for
that is simply that the group as a whole was recruited so late, that we
had so few babies who were recruited at what I would consider
experimentally to be an early time that we simply don\'t have the power
to address the question.

MR. OTTENS: Thank you. Dr. Coffey?

DR. COFFEY: Just getting back to part of one of the questions that Dr.
Brott had asked earlier about achievable temperature gradients and so
forth. There was mention in some of the documents about nasopharyngeal
temperature being used at one point earlier on during the development,
and that that was difficult for the users. Could you just sort of tell
all of us a little more about that?

DR. WYATT: Yes. In our original design, we attempted to look for
surrogate markers of brain temperature, and we felt the best surrogate
marker was nasopharyngeal temperature. In fact, clinical experience in
the pilot study was that there was a major problem in inaccuracy in
nasopharyngeal temperature monitoring in babies, particularly related to
the babies who were spontaneously breathing. If babies were
spontaneously breathing because they\'re nose-breathers, there\'s a
constant flow of air through the nose, and therefore that affected the
reliability of the measurements. Also, the direct placement of the \--
the positioning of the probe was variable and quite critical. And
experience led us to believe therefore that far and away the most robust
marker of temperature was the rectal temperature, which we could measure
very accurately and reliably. And we decided rather than use a rather
unreliable surrogate marker of brain temperature, we would go for a
reliable monitor of whole body temperature, and use that as our target,
and as a guide for therapy. And I think that was the right decision in
retrospect. And that\'s the way the cooling, we recommend that this
therapy should be used in future.

DR. COFFEY: Has that field been eliminated from the later version, you
know, with the touch screen and so forth?

DR. WEILER: Yes.

DR. HAINES: Thank you. We\'ll now take a short break, five minutes, and
when we return we\'ll have the FDA presentation. All right, 10 minutes.

(Whereupon, the foregoing matter went off the record at 11:00 a.m. and
went back on the record at 11:15 a.m.).

DR. HAINES: It\'s now 11:15 and I would like to call the meeting back to
order. We will now have the FDA presentation on this PMA. The first FDA
presenter is Dr. Kristen Bowsher, the review team leader for this PMA.
She will introduce the other FDA speakers.

DR. BOWSHER: Okay. I\'m Kristen Bowsher, and I\'m going to start off the
FDA presentation of the Olympic Medical Cool-Cap PMA. I\'d first like to
introduce our FDA review team. I\'m Kristen Bowsher. I was the lead
reviewer, and I am a biomedical engineer. The statistician on the review
team was Dr. Chu. We also had a clinical epidemiologist, that would be
Dr. Cope. Dr. Susan McCune was a neonatologist and a pediatrician who
will be giving the clinical presentation today. And Dr. Joy Samuels-Reid
who is also a pediatrician.

The proposed indications for use for this device are for use in infants
greater than or equal to 36 weeks gestation at risk for moderate to
severe HIE to provide selective head cooling with mild systemic
hypothermia to prevent or reduce the severity of HIE.

And Olympic Medical went through the history already so I\'ll be brief
on this slide. The IDE was submitted, approved, and the first patient
was enrolled in 1999. The final 18-month exam was completed in September
of 2003. FDA approved the continued access trial in April of 2003. The
PMA was submitted in May of 2004, and here we are today with the
presentation of the results to the panel.

I\'ll now present the engineering section. And Olympic Medical went
through much of this information, so I\'ll try and be brief with my
slides. The device components again, the main component consist of a
cap, a cooling unit, a control unit, and temperature sensors. I think
this is a nice diagram that gives a good depiction of how the components
interact with each other as a system. The control unit sits on top of
the cooling unit. The target cap temperature is then entered into the
control unit, and the cooling unit then makes adjustments to maintain
the target temperature. The cooling unit pumps water through a cap which
is in contact with the patient. Temperature probes from the patient are
connected to the temperature sensor module, which is connected to the
control unit for display. Although not part of the Cool-Cap system, it
is important to point out that a radiant warmer is also necessary to
help maintain the target rectal temperature.

And here is a picture of the actual cap. On the left is the water-filled
polyurethane cap. In the middle is a spandex retainer that goes on top
of the water-filled cap to hold it into place. And on the far right
you\'ll see the polyester fleece insulated cap which will provide
insulation from the radiant warmer. And there is another picture of the
control unit.

The user interface, some of the key components are a touch screen.
It\'ll display the rectal temperature, which is recorded to an accuracy
of +/- 0.1 degree Celsius. It also can display and record the scalp,
skin, and cap temperature at the same accuracy. An added feature is it
will display a numeric rate of temperature change. It also has alarms
that will signal when it\'s out of temperature range. It also consists
of wizard screens to help with setup, re-warming, and shutdown of the
system.

The sponsor provided device testing. It met electrical safety standards
in accordance with appropriate IEC standards. Biocompatibility met
appropriate AAMI/ANSI/ISO standards. ENC testing met appropriate IEC
standards, and the packaging met the appropriate ASTM standards.

Olympic Medical went into a discussion of the differences between the
trial and the proposed commercial system. And I\'d like to point out
that the key difference is the software control system. And the new
system includes a touch screen, a built-in study manual, and more data
is displayed, including the rate of change of the temperature.

Since the proposed commercial system has many updates as compared to the
trial system, the sponsor performed usability testing to help
demonstrate the updates should not adversely affect treatment use,
especially since treatment use may be infrequent in hospitals. Usability
testing took place in three phases, assessment testing, followed by
preliminary validation testing, and finally the final validation
testing.

The assessment testing was to test the graphical user interface software
controls and software-based wizards. Five NICU personnel underwent
realistic representative tasks. These personnel were users with prior
direct experience using or coordinating use of the clinical trial
configuration. After performing the tasks, they completed an 8-page
questionnaire, and all test participants concluded that the commercial
device is easier to use than the clinical trial device.

The next phase of testing was the preliminary validation testing. This
testing was on the user interface of the new configuration, and again,
realistic representative tasks were performed. Seven subjects
participated. Again they were users with prior direct experience using
or coordinating use of the clinical trial configurations. Two subjects
completed the operator manual validation, and five completed the
labeling validation. Overall, the participants responded favorably to
the device, and some device modifications were made as a result of the
testing.

The final validation testing was performed on a production unit of the
commercial configuration. Three NICU nurses with no prior experience
this time with the Cool-Cap took place in the test. It consisted of user
testing, questionnaires, and observation by trained personnel. The test
environment was a conference room at Olympic Medical made to mimic the
NICU environment. Overall, again the participants responded favorably to
the device, and some additional device modifications were made.

Now I\'ll turn it over to Dr. McCune who will do the clinical
presentation.

DR. McCUNE: Thank you Dr. Bowsher. Ladies and gentlemen of the panel,
guests, I apologize for turning my back on you. My name is Susan McCune.
I\'m a neonatologist and a Medical Officer in the Division of Pediatric
Drug Development, and I\'m going to present the clinical review on
behalf of the clinical review team. Much of the data you\'re going to
have the opportunity to review as it\'s been previously presented by
Drs. Weiler, Liu, and Wyatt.

In terms of background information, hypoxic ischemic encephalopathy, or
HIE, is a frequent cause of neurodevelopmental disability in full-term
infants, occurring in approximately 1 to 4 per 1,000 live births. Severe
HIE is a devastating condition as we\'ve heard of this morning, with
death in 15 to 20 percent of infants, and permanent neurologic deficits
in an additional 25 percent. In terms of the pathophysiology of hypoxic
ischemic encephalopathy, the neuronal injury is multifaceted. It
includes a number of factors, including circulatory factors, metabolic
factors, and biochemical factors.

I\'d like to just go through this diagram with you briefly. This is
modified from Dr. Ferriero who gave a recent talk at the Pediatric
Academic Society\'s meeting entitled Neonatal Neuroprotection: Cocktails
and Ice. And I want to draw your attention here to the timeline of
injury. In the first few hours of injury you have oxidative stress and
excitotoxicity. This is then followed by a period of inflammation over
the course of hours to days, and subsequently over the course of days to
weeks you have a repair process that is ongoing. I want you also to note
that at the time of the initial phase of injury that cell death is
occurring in, that cell death probably continues to occur throughout the
course of hours, and potentially days and weeks.

Another way to look at this pathologic process, because we\'ve heard a
lot about secondary energy failure this morning, is that the initial
insult, whether it be asphyxia or empiric profusion, can lead to primary
neuronal death. It can also lead to cytotoxic mechanisms that then lead
to delayed neuronal death. And it is during this period where these
cytotoxic mechanisms occur that there are opportunities for potential
neuronal rescue.

In terms of the current treatment of hypoxic ischemic encephalopathy,
this is all supportive care. Ideally we would like to prevent
intrauterine asphyxia, but we\'re really left with supportive treatment
that includes maintaining adequate ventilation, adequate profusion,
monitoring fluid balance and electrolytes, maintaining adequate blood
glucose levels, and then treating the complications of HIE which
primarily involve treating seizures.

As you\'ve heard before, the proposed indications for use for the
Olympic Cool-Cap is for infants greater than or equal to 36 weeks
gestation who are at risk for moderate to severe encephalopathy to
provide selective head cooling with mild systemic hypothermia to prevent
or to reduce the severity of HIE. In terms of the mechanism of action of
hypothermia, it\'s believed that hypothermia provides neuroprotection by
suppressing a number of the steps in that biochemical pathway that I
spoke of earlier, leading to apoptotic cell death. It\'s also postulated
that there is that window of opportunity where there is that cytotoxic
injury to intervene with patients with HIE before that secondary phase
of brain injury.

Now I\'m going to present the results of the Cool-Cap trial. In terms of
study design this was an international, multi-center, prospective,
randomized study that involved a total of 25 sites that enrolled 235
patients. One patient was withdrawn due to inadequate consent, leaving a
total of 234 patients. A data safety monitoring committee was in place
and reviewed the data periodically. The study objectives were to
determine whether treatment of moderate to severe HIE in term infants
with head cooling and mild systemic hypothermia can produce meaningful
improvements in neurodevelopmental outcome and survival rates at 18
months of age, and to confirm the safety of prolonged head cooling with
mild systemic hypothermia in term newborns with moderate to severe HIE.
The primary outcome measures, as you\'ve previously heard of, were
mortality prior to 18 months of age, and severe neurodevelopmental
disability in the survivors, as defined by either Gross Motor Function
impairment at the level of 3 to 5, or a Bayley Mental Development Index
of less than 70, or bilateral cortical visual impairment. In terms of
secondary outcome measures, these included length of NICU
hospitalization in those surviving to discharge, multi-organ dysfunction
in the neonatal period involving three or more organ systems, rate of
multiple handicaps in survivors, Bayley PDI score of less than 70,
sensorineural hearing loss less than 40 decibels, epilepsy, and
microcephaly.

In terms of the study design, after meeting entry criteria, which I will
go into in just a few moments, the infants were randomized to receive
either 72 hours of head cooling plus mild systemic hypothermia with a
goal rectal temperature of 34.5 degrees +/- 0.5 degree Centigrade, or 72
hours of non-cooled control with a target temperature of 37 degrees +/-
1 degree. The study was unmasked because of the potential increase in
head temperature for control infants who would have a cap placed on
their head. After 72 hours of cooling, the temperature was then allowed
to rise by no more than 0.5 degrees Centigrade per hour, to a goal
temperature of 37 degrees +/- 0.2 degrees Centigrade. This was followed
then by a 6-month evaluation by the pediatrician. The primary reason for
this 6-month evaluation was cohort retention. At that time what was
recorded was length, weight, and head circumference, as well as referral
to therapy. It is important to note that there were no systematic
neurologic evaluations done at that time, there were no guidelines for
referral for therapy, and there was no consistent plan for therapy. And
it is not known how many of the patients actually received therapy, and
what therapy they actually received. The 18-month neurodevelopmental
evaluation involved Gross Motor Function, the Bayley II, ophthalmologic
evaluation, and auditory assessment.

In terms of inclusion criteria, these infants needed to be greater than
or equal to 36 weeks gestation with one of the following: an APGAR score
of less than 5 at 10 minutes after birth; continued need for
resuscitation, either endotracheal or mask ventilation at 10 minutes
after birth; acidosis involving an umbilical cord or arterial pH of less
than 7.0 within 60 minutes of birth, or a base deficit of less than or
equal to 16 millimols per liter in umbilical cord or any blood sample
within 60 minutes of birth. Additionally, once those patients met those
criteria they were assessed for neurologic abnormality. Those patients
with moderate to severe encephalopathy with altered state of
consciousness and at least one of the following were then further
evaluated. The patients needed to have at least one of lethargy, stupor
or coma, hypotonia, abnormal reflexes including oculomotor, or pupillary
abnormalities, absent or weak suck, or clinical seizures. Once the
patients met those criteria they were then assessed by amplitude
integrated EEG that was 20 minutes in duration that was performed
between one and five and a half hours of age, and was not performed
within 30 minutes of receiving IV anticonvulsant therapy. Patients that
were identified with abnormal background activity or seizures could then
be randomized to participate in the trial.

I just want to briefly go over the aEEG criteria in case there are
questions about this later in the day. Normal was defined as a lower
margin of activity above 7.5 microvolts with a present sleep/wake cycle.
Mildly abnormal was a lower margin of activity above 5 microvolts, but
sleep/wake cycle absent. Moderately abnormal was an upper margin of
activity above 10 microvolts, and a lower margin below 5 microvolts.
Severely abnormal had an upper margin of activity below 10 microvolts,
and a lower margin below 5 microvolts. And seizures were defined as a
sudden increase in voltage, with narrowing of the aEEG band followed by
a brief period of suppression. And just to give you an idea, these
tracings, it\'s a little hard to see, but you can see that these
tracings are in the 5 to 10 \-- actually 10 to 25 range here. You\'re
dropping below in the moderately abnormal aEEG tracing, below 5
microvolts. And in the severely abnormal aEEG you\'re dropping both
below 10 microvolts for the top border and 5 for the lower border, and
then you have a burst of what appears to be seizure activity.

The exclusion criteria were infants who were expected to be more than
five and a half hours of age at the time of randomization, those who had
received prophylactic administration of high-dose anticonvulsants,
patients with major congenital anomalies, patients with imperforate anus
because you cannot record rectal temperature, evidence of head trauma or
skull fracture, infants less than 1800 grams birth weight, a head
circumference below two standard deviations below the mean for gestation
if the birth weight and length were within two standard deviations,
infants in extremis or who were requiring resuscitation or in the
process of dying. Unavailability of the essential equipment, concurrent
participation in other experimental trials, and additional
contraindications were proven sepsis and hemorrhagic diatheses.

I have busy slides, but I would like to at least point out some of
these. Up here in the purple you will see these are the U.S. sites that
enrolled in the trial. There were 25 sites total that enrolled, 19 of
them were in the United States. And of these, 10 sites enrolled 10 or
more patients each. In terms of the international sites, there were
three international sites that enrolled more than 10 patients, one in
England, one in Canada, and one in New Zealand.

Now I\'m going to just show you the infant baseline characteristics. And
I wanted to highlight those factors that have been brought up before in
terms of being involved in the logistic regression, and potentially
reflecting severity of injury in terms of a higher number of male
patients, 55 percent in the cooled group compared to 49 percent in the
control group. A higher number of patients with APGAR scores of zero to
three, 77 percent in the cooled group compared to 68 percent in the
control group. A higher percentage of patients with the severely
abnormal aEEG background at pre-randomization, 36 percent in the cooled
group and 27 percent in the control group. I also want to point out that
the majority of patients here, 74 percent and 78 percent, were enrolled
within that 4- to 6-hour window for randomization.

In terms of entry criteria violations, there were a total of 27
violations, 14 in the cooled group and 13 in the control group. The
majority of these violations were related to randomization at more than
five and a half hours of age, less than 20 minutes of aEEG recording, or
a combination of the two.

In terms of general information about the continued access trial, I\'ll
discuss some of the safety information in subsequent slides. On April
26, 2003, the FDA granted approval for up to 100 patients in the
continued access trial. And as of January 24, 2005, 55 infants have been
enrolled, 16 at Children\'s Hospital of Denver, 13 at Arkansas, 12 at
University of Michigan, 5 Vanderbilt, 5 Schneider Children\'s Hospital,
3 Children\'s Memorial Hospital of Chicago, and 1 at Thomas Jefferson.

Now I\'m going to present the primary safety information. And you have
seen this slide before. In terms of the overall mortality at 18 months,
31 percent in the cooled group, 36 percent in the control group, with a
total of 33 percent. And in terms of early mortality during that first
week of life, and to note that for Day Zero to 5, there were 26 cooled
babies and 21 control babies who died, but when you look more
specifically at Days 4 to 5 there were 11 in the cooled group compared
to two in the control group. And as Dr. Wyatt discussed, this may
reflect the fact that these babies were given the opportunity to
complete cooling therapy to give them the best chance for better
outcome.

In terms of the major adverse events that have already been presented
both by Dr. Liu and Dr. Wyatt. There were four adverse events that were
looked at, major cardiac arrhythmias including ventricular tachycardia,
ventricular fibrillation, and acquired conduction block. There were no
patients in either group that had any of those adverse events. In terms
of major venous thrombosis there were two patients in the control group.
There were three patients in each group that had severe hypotension
despite full support. And there was one patient here in the cooled group
that had an unanticipated serious adverse event. And as you\'ve already
heard, that was a cooled infant with bruising and superficial skin
necrosis on the scalp after cap removal.

In terms of looking at the other adverse events, the cardiac arrhythmias
that did not reach that previous code, there were 10 patients in the
cooled group, and I\'ll go through those in a little bit more detail in
a minute, which were 9 percent of the group compared to 1 percent of the
control group. There were no statistically significant differences
between the two groups in either hypotension that did not reach the
original code, coagulopathy, prolonged coagulation times, abnormal renal
function, hyponatremia, or hypokalemia. In terms of \-- and no
differences in bone marrow depression, metabolic acidosis, respiratory
distress, systemic infection, hemoconcentration, or hypoglycemia. As has
already been presented, elevated liver enzymes were actually improved in
the cooled group compared to the control group. There were no
differences between the two groups in hypocalcemia, skin breakdown due
to cap pressure, or difficulties in temperature control. As was already
stated, there were significant differences in the other group that were
primarily attributable to 23 of the 51 cooled infants having
cooling-related head or scalp edema.

Okay. Just to go back to those 10 patients that I pointed out in terms
of the cardiovascular events. Of those 10 patients, eight had mild to
moderate bradycardia. There was one case of mild cardiac arrhythmia with
normal 12 lead EKG, and one case of dysrhythmia. There were 13 cooled
and no control infants with prolonged QT interval. It was noted that
there was normalization of the QT that was documented in seven of the
patients, although one of those patients had a QT interval increase
again after therapy was completed.

In terms of the scalp edema and injury, I showed you those 51 cases of
other adverse events in cooled patients, that 23 of them had
cooling-related head or scalp edema. All but three of the cases were
mild to moderate in severity and resolved prior to or after completion
of cooling with either no action, massage, changing position, or cap
adjustment. There was one patient with severe scalp, facial, and neck
edema that resolved with no action taken. There was one patient with
severe head edema that lasted until the death of that patient at 24
hours after cooling completion. And there was one case of severe, quote,
\"cerebral edema,\" which resolved after head elevation upon completion
of re-warming. And there was one control infant that was noted with
moderate scalp edema.

Although there were no statistically significant differences between the
two patients in terms of being able to maintain target temperature, it
was important to look at what target temperatures were achieved, and
also to look at the lowest temperatures from a safety perspective. There
were 23 cooled patients with a rectal temperature of either less than 33
degrees, or greater than 38 degrees or both, of which there were 12
patients less than 33 degrees, nine patients greater than 38 degrees,
and two that had both. Twenty-nine control patients had a rectal
temperature of greater than 38 degrees. Of note, only 14 infants, six
cooled and eight control, had no temperature deviations. And by that,
that\'s not the adverse event definition of temperature deviation. This
was a very narrow range between 34 and 35 degrees Centigrade for the
cooled babies, and 36 to 38 degrees Centigrade for the control babies.
And you\'ve already seen this slide, in terms of trying to chase cap
temperatures and rectal temperatures, and the lag time between those
two.

In terms of seizures on re-warming, one patient was noted to have severe
seizures that were exacerbated with re-warming. This was a patient who
while being cooled was \-- prior to being cooled was on a benzodiazepine
infusion. While being cooled that infusion was stopped because the
seizures appeared to be controlled. The seizures then recurred after \--
they recurred several hours after the immediate re-warming phase. This
patient had severe neurodevelopmental disability and death at 19 months
of age. Based on this report, Olympic went back to the sites to examine
whether or not there were additional patients who had seizures on
re-warming, and there was only one report of two patients in the
continued access trial who either had the onset of or an increase in
seizures after re-warming. And it was suggested by these patients that
the head cooling suppressed the seizures, and that both infants survived
with good neurologic outcome.

In addition, one cooled patient with intractable seizures had elevated
clonazepam levels. That patient died after withdrawal of care due to
severe hypoxic ischemic encephalopathy. It\'s known in the literature,
and as was previously pointed out by Dr. Wyatt, that hypothermia can
alter drug kinetics, and the precaution that hypothermia can inhibit the
metabolism and clearance of many anticonvulsants, including
Phenobarbital, phenytoin, lidocaine, and the benzodiazepines has been
added to the manual.

In terms of safety in the continued access trial, from April of 2003
through January of 2005 there have been 55 patients. Ten of those
patients, or 18 percent, died during treatment. There were no
anticipated serious adverse events. There were three unanticipated
serious adverse events. The first was an epidural hematoma that needed
to be evacuated surgically, and was included because the severity was
unexpected. The patient with sclerema neonatorum, and a patient with
respiratory distress following attempted elective extubation reported
because it was a potentially life-threatening event.

I just \-- for people who are not neonatologists and have not seen
sclerema neonatorum because it\'s a fairly rare occurrence, I just
wanted to describe this for you. It\'s a disorder of the subcutaneous
tissue that actually was first described in 1784 as skinbound disease.
Actually the term \"sclerema\" was coined in 1817 based on the Greek
term skleros, which is hard. And what it is, is a hardening of the
subcutaneous tissue, and it can be seen particularly in babies who have
overwhelming illness, particularly shock and sepsis, but can be seen
with hypothermia. And the reason why is because babies have an increased
amount of saturated to unsaturated fatty acids in their lipocytes. And
that higher amount of saturated fatty acid actually has a higher melting
point. And so in babies, particularly when they\'re stressed, there\'s
the potential for the crystallization of these saturated fatty acids in
the lipocytes that form the hardening of the skin. And as Dr. Wyatt
previously said, it\'s a manifestation of serious underlying illness,
not a disease in and of itself. And that if the underlying illness can
be reversed, that the skin process reverses as well. Unfortunately, many
of these babies have such overwhelming underlying disease that they do
not survive, but not because of the skin disorder.

So in summary of the safety information, and this will be discussed in
Panel Questions 1, 3, and 5, there were no differences in the major
adverse events seen between the two groups. The other adverse events
that were increased in the cooled patients included the cardiovascular
adverse events that were bradycardia and prolonged QT interval, the
scalp edema and injury. While it was not increased in cooled patients,
the ability to maintain target temperature is important because these
are the patients that are being cooled. Seizures on re-warming,
increased serum levels of anticonvulsants, and sclerema neonatorum in a
patient in the continued access trial.

Now I\'m going to go through the primary effectiveness information. In
terms of treatment completion, 86 percent of patients in the cooled
group completed the treatment as planned, 81 percent in the control
group completed treatment as planned. There were 16 patients in the
cooled group and 22 patients in the control group that discontinued with
less than 72 hours \-- at a time less than 72 hours post randomization.
The majority of those patients, the discontinuation of treatment was due
to death or in extremis in both groups. In terms of major treatment
deviations, in the cooled group there were four infants not cooled,
there were six infants who had cooling started greater than six hours of
age, and one patient who received steroids. In the cooled group, one
baby had \-- the father washed them with cold water, and another baby
was actually placed in another trial.

In terms of the information about the patients who were lost to
follow-up. There were 16 patients lost to follow-up, eight in the cooled
group and eight in the control group. Six in each group were seen at six
months, two in each group were referred for therapy at six months. In
terms of the demographic and baseline characteristics of the lost to
follow-up patients compared to the whole cohort group, there was a
borderline difference in head circumference, with a slightly smaller
head circumference in those patients who were lost to follow-up, and
there was a statistically significant difference in maternal age in
patients who were lost to follow-up, with the mothers being younger in
that group.

In terms of primary effectiveness, you\'ve seen this slide before. There
were 235 patients who were enrolled. That one was canceled because of
inadequate informed consent. There were a final count of 234 patients,
of which 16 had unavailable 18-month outcome data. The 18-month outcome
data were available for 218 patients, or 93 percent of the cohort, of
which 50 percent were in the cooled group, and 50 percent in the control
group. There was a 45 percent favorable outcome compared to a 55 percent
unfavorable outcome in the cooled group, and a 34 percent favorable
outcome compared to a 66 percent unfavorable outcome in the control
group. The analysis, not including those patients lost to follow-up, was
a Fisher\'s exact test for primary outcome, with a p-value of 0.10. The
logistic regression analysis, adjusting for those clinical factors that
have previously been discussed, including aEEG background seizure
status, APGAR score, birth weight, gender, and age at randomization
yielded a p-value of 0.042.

I wanted to briefly talk about the subpopulation analysis because it was
brought up in the original PMA application, but also because it was
included in the Lancet article that was published in February of this
year. This was an analysis that actually looked at removing the worst
prognosis group. That was a group that had severe aEEG background and
seizure, and then looking at the subpopulation that was left, including
those in the best prognostic and the intermediate prognostic groups, of
which there were 84 patients in the cooled group and 88 patients in the
control group. Favorable outcome in 44 patients versus 40 patients in
the cooled group, and favorable outcome in 30 versus 58 in the control
group. And the Fisher\'s exact test for that primary outcome, excluding
the worst prognostic patients, and excluding those lost to follow-up was
a p-value of 0.21.

The effort here was to try to define those patients in the worst
prognostic group who would potentially not be able to respond to
therapy. And the question is whether that\'s a population which reflects
severity of disease, or reflects timing in terms of being able to
respond to the hypothermia treatment. So in looking at the severity of
disease, a Sarnat score is a clinical score \-- encephalopathy score
that includes clinical factors, including level of consciousness and
reflexes, as well as seizures, Stage 1 being mild encephalopathy, Stage
2 moderate, and Stage 3 severe encephalopathy. Of note in Stage 1,
patients, most of them are hyper-alert. In Stage 2, they have decreased
level of consciousness, but are arousable. In Stage 3, which actually
the parents of the patients who came and spoke very eloquently this
morning, they gave you an excellent description of patients that would
be in Stage 3 Sarnat. And of note, seizures are very common in patients
with Stage 2 encephalopathy, but actually are not necessarily common in
patients with Stage 3 encephalopathy.

So, just in looking at severity of illness and whether or not cooled
patients with the most severe illness would be able to respond, 70
percent of those Sarnat Stage 3 patients in the cooled group had an
unfavorable prognosis, compared to 91 percent in the control group,
suggesting that this population might be able to still respond to
hypothermia treatment.

In terms of the question of seizure status, of the 234 patients in the
trial, there were 143 who had aEEG seizures. There were 188 with
clinical seizures. Twelve patients in the trial with aEEG seizures had
no clinical seizures. And there\'s a significant debate in the
literature about what this means in terms of patients with aEEG seizures
and no clinical seizures. There were 55 patients with no aEEG seizures
who had clinical seizures, and that is probably reflective of the
snapshot in time that the aEEG has, and not the overall clinical
progress of the patient. And in terms of the deaths, it was important to
note that 35 percent had severe aEEG background, and 33 percent had no
seizures.

In terms of potential trial issues, in terms of overall issues, the
inability to blind treatment because of not being able to put the cap on
the head I think is something that\'s already been brought up in the
questions. In terms of the effective referral to therapy on the 18-month
neurodevelopmental evaluation is another issue. In terms of the
subpopulation, it\'s not clear whether the ability of the EEG is to
predict the severity of injury, or ability to respond to secondary
energy failure. And there were no centralized readings of the aEEG for
the subpopulation analysis.

So in summary, in terms of the safety review, there were no increases in
major adverse events seen in cooled patients. Other adverse events to
monitor include bradycardia and prolonged QT interval, scalp edema and
injury, temperature control, seizures on re-warming, anticonvulsant
levels, and sclerema neonatorum.

In terms of effectiveness, just to reiterate that severe HIE is a
devastating disease with no currently available therapy other than
supportive care. The Cool-Cap study showed a p-value of 0.10 for the
primary outcome. However, statistical significance was demonstrated with
a p-value of 0.042 after adjusting for baseline aEEG background, seizure
status, APGAR score, birth weight, gender, and age at randomization.

I\'m now going to turn the podium over to Dr. Chu who\'s going to
present the statistical analysis.

DR. CHU: My statistical talk will focus on three issues: the potential
impact of missing data on the primary effectiveness analysis. As you
have heard several times, there are 16 so-called lost to follow-up
patients. And also I will discuss briefly on the six months follow-up
data regarding the referral for additional therapy. And finally, I will
briefly discuss the sponsor\'s original subgroup analysis.

In the next three slides I would like to briefly go through the study,
the background key information which refers to the statistics. So the
study was a prospective, multi-center, randomized, concurrently
controlled. It\'s an open-label study. Both investigators and patient\'s
parents cannot be masked. And the patients with encephalopathy of
abnormal aEEG background, or aEEG seizure status would be randomized in
equal ratio to the cooling treatment for 72 hours, or to the non-cooled
control group. There\'s two follow-ups, six months mainly was conducted
by the pediatricians. The protocol states the main purpose is to retain
cohort for 18 months evaluation. And the other purpose, as protocol
states, is to identify infants with neurosensor problems, and
microcephaly, potentially could be called for additional therapy as
referred by pediatricians. At 18 months, the evaluation was conducted by
masked evaluator for the neural outcome measures.

The study was a fixed sample size design, at sample size 235 patients.
The study was powered at 80 percent power to detect a significant
difference of expected treatment difference of 21 percent in terms of
the expected proportion of failure. Controlling the false positive
finding rate, 5 percent.

Unfavorable outcome is a composite endpoint, either death in the first
18 months of life, or severe neurological developmental disability among
survivors at 18 months evaluation. And there\'s three components for the
NDD \-- from now on, I will refer severe neurodevelopmental disability
as NDD. As long as one of the three components failed, then it\'s
defined as NDD at 18 months. The three components is NDI score less than
70, or Gross Motor Function impairment level beyond 3, or visual
impairment. And the null hypothesis for the study is there\'s no
significant difference in terms of proportional failure in the cooled
group compared to the control. An alternative hypothesis is there\'s
some difference. Alternatively, we can use odds ratio. If odds ratio
equals 1, there\'s no difference. And the study will try to collect
enough evidence to reject null hypothesis to see whether or not the
cooling treatment is effective.

And the planned analysis, the sponsor in the protocol used both Fisher
exact tests without any covariate adjustment, or logistic regression
adjusting for three protocol pre-specified covariates, aEEG background,
aEEG seizure, and age at randomization. Please be aware, according to
the protocol, the intent to treat principle will be adhered to. That
means all randomized patients will be included in the primary effective
analysis. Also note there\'s no subgroup analysis was planned in the
original protocol. But three subgroups were postulated as sponsor
states, prior to unlocking data, based on two baseline covariates, aEEG
background, and aEEG seizure status, best, intermediate and worst
prognostic subgroup.

This slide shows the results for the primary endpoint. Again, this is a
composite endpoint, survival status, and also the three components of
the NDD. Almost the same number of patients were randomized to receive
cooling treatment or the control treatment, 116 in cooled group versus
118 in the control. At 18 months evaluation, the failure rate for the
cooled group is 55 percent versus 66 percent in the control group. So we
observe 11 percent difference in terms of the proportion failure. Among
those failures, 36 died before 18 months evaluation in the cooled group.
Six more babies in the control, 46 died before 18 months evaluation.
Again, please be aware that those numbers do not include those 16
so-called lost to follow-up patients, LTF, eight in each group. And the
sponsor\'s analysis excludes those 16 LTF show marginal significance by
logistic regression, near borderline significant at 0.05 using
pre-specified three covariates in the protocol, aEEG background, aEEG
seizure status, and age at randomization. As I will show later in
detail, actually in the control group there was three lost to follow-up
patients, actually were partially evaluated at 18 months.

So based on the protocol-specified principle, ITT analysis should be
used. FDA recommends all randomized patients should be included in the
primary analysis. They recommend sponsor to retrieve mortality
information for those 16 lost to follow-up patients. Please note that
all these 16 lost to follow-up patients occurred in U.S. site. And also,
FDA recommends sensitivity analysis for potential impact of those lost
to follow-up patients on the primary endpoint analysis result.

Since during the IDE discussion stage, and also at PMA stage, our
clinical officers in addition to aEEG background, aEEG seizure status,
and age at randomization, patients\' gender, APGAR score, and birth
weight are important covariates for predicting the clinical outcome. So
from now, all my analysis will include not only the protocol-specified
three covariates, but also the three additional covariates in the model.

This slide shows some detailed information about those 16 lost to
follow-up patients. As I have mentioned, actually this was three
controlled so-called lost to follow-up patients actually were partially
evaluated. The reason for missing outcome is because some of the
components missing. Among those three, two were evaluated for GMF, and
visual impairment, and one was evaluated for MDI. And four in the
control group was unable to locate, six in cooled was unable to locate.
With regard to parental refusal, equally we had one in each group.

At six months follow-up, the missing pattern looks identical. There\'s
one in each group was lost to follow-up at six months, and two were
referred for additional therapy by pediatricians, and five were not
referred in both groups. A majority of the baseline covariates looks
very similar between these two groups and to the missing population. The
only exception is a lot more cooled babies actually have much lower
birth weight, five had birth weight less than first quartile, compared
to only one in control.

Before I present the study results using sensitivity analysis, I\'d like
to clarify several different scenarios. First, as a reference, complete
case as analysis, excluding those 16 lost to follow-up patients. And all
failure, we assume all failures for those lost to follow-up patients.
And all success assume all success. There\'s two extreme case, best case
and a worst case. In a best case scenario, we assume all control lost to
follow-up as failure, but success with cooled. And then in worst case
scenario, against the cooling treatment arm, we assume all success for
the control but failures for the cooled.

Instead of filling in the single value, multiple imputation is an
attractive approach to taking into account the uncertainty of filling
missing values. We could replace each missing value with a set of
possible values. Here, because the outcome is binary theory on success.
So basically the approach of multiple imputation is to random draw
several values in terms of probability of success, and then replace the
missing values several times based on the predicted distribution of the
primary outcome as viewed from observed data.

So here is the result of the FDA\'s sensitivity analysis with regard to
the potential impact of those lost to follow-up patients on primary
outcome failure at 18 months. As has been shown before by the sponsor,
the complete case analysis shows near borderline significance with
p-value 0.04. And 95 percent confidence interval odds ratio of the
failure of cooled versus control, the upper bound is below 1.0. Shows
some marginal significant treatment effect. Because the complete case is
only near borderline significant, so the overall analysis, including all
the randomized patients, appears to be sensitive to the lost to
follow-up patients. Actually, a couple of patients switched among those
lost to follow-up patients may change the p-value from 0.05 to not
significant. As extreme case here, in worst case scenario, the p-value
is 0.36, and only in the best case scenario, all failure or all success,
and all multiple imputations results show similar results compared to
the complete case. Again, this is the logistic regression analysis. The
covariates, including the model, including not only the
protocol-specified three covariates, but also the additional covariates,
gender, APGAR score, birth weight, and also the site, foreign versus
U.S.

With regard to the six months follow-up data, we do find some
interesting things, that a high proportion of cooled infants were
referred for additional therapy at six months, but it is difficult to
assess the potential effect of additional therapy on the final 18 months
outcome evaluation. Because we don\'t know whether or not the referral
to therapy was actually received, or what type, and the frequency.

In terms of the sponsor subgroup analysis, as shown in this slide, I
include all randomized patients, 234 was classified into three subgroups
based on aEEG background rating and aEEG seizure status. The sponsor\'s
logistic regression analysis, including treatment by subgroup
interaction terms in the model show there was no statistical
significance in terms of the treatment effect comparing best versus
intermediate. And p-value for the comparison of worst versus
intermediate is 0.07. Based on this, the sponsor pooled best and
intermediate subgroup to create the subpopulation. Out of this 186
subpopulation patients, 90 in the cooled, 96 in the control, and at 18
months, we observe 40 failure in the cooled versus 58 failure in the
control. And by excluding those lost to follow-up patients, six in the
cooled, eight in control, the percentage of failure rate in the cooled
is 48 percent versus a larger percentage of failure, 66 percent in the
control group. So we observe a larger difference her compared to
original whole population analysis. Here we\'re talking about 18 percent
difference. And the Fisher exact test showed p-values of 0.02, logistic
regression analysis adjusting for those covariates, 0.01. But again, 14
lost to follow-up patients were excluded. And also, those p-values were
not adjusted for multiplicity.

If you look into details about what happened to those babies in the
worst subgroup, it turns out in the cooled group they observed much
higher failure rate, even higher than the control group in the
subpopulation, 79 percent. But approximately similar number of failures
observed in the control among the worst subgroup compared to what we
observe in subpopulation, 68 percent versus 66 percent. So in the worst
subgroup analysis, it looks like the trend is in the opposite direction
compared to the subpopulation. And actually, the majority of failure for
the cooled group is 30 deaths, nine cooled babies did not survive up to
five days, compared to only two in the worst subgroup.

So, to summarize, there\'s no predefined plan for subgroup analysis. And
also, the randomization was not stratified by the subgrouping criteria,
aEEG background, and aEEG seizure status. Especially important, we see
an overall treatment effect was marginally significant. Under these
circumstances, if you do further unplanned subgroup analysis, the chance
of making false positive finding among subgroup will be inflated. FDA\'s
likelihood interaction test actually show the overall treatment by three
subgroup interaction effect was not statistically significant at the
level of 0.05. And also, I want to emphasize a large percentage of most
severely affected infants in the cooled group, in terms of Sarnat Stage
3 and early deaths, were excluded from the pooled subpopulation
analysis. So the question is selection bias could be introduced.

To summarize my statistical discussion, the selective head cooling
treatment with Cool-Cap may reduce the combined rate of deaths and
survival with severe neurodevelopmental disability at 18 months, as
shown by the logistic regression ITT analysis strategy, with multiple
imputations. P-value 0.04. But because of this small sample size study,
and the treatment effect of confidence interval in terms of 95 percent
confidence interval of odds ratio range from 0.28 up to 0.96. That means
that cooling treatment may reduce the odds of failure by 72 percent, or
only 4 percent. Again, a higher percentage of infants in the cooled
group was referred for additional therapy at six months follow-up. But
it is difficult to assess the effect of any potential difference in
additional therapy between the two groups. With regard to the subgroup
analysis, the trial was not designed to demonstrate statistically
significant treatment effect. In these circumstances, any subgroup
finding should be hypothesis generating, not as conclusive analysis.
Thank you very much for your attention.

DR. HAINES: Thank you. At this time I would ask if anyone on the panel
has any important questions to ask of the FDA at this time. There will
be an opportunity to ask questions after lunch. Dr. Ellenberg?

DR. ELLENBERG: I wonder if someone from the FDA could comment on the
issue of the protocol hypotheses to be tested, and the list of
covariates in the protocol itself, and the issue of post hoc addition of
covariates by the FDA, and how that plays out in terms of one being
allowed to be able to change the covariates after the study design was
begun.

DR. McCUNE: I can address that maybe a little. I\'m not sure if I\'m
getting totally to your question. There were a number of discussions at
the IDE phase that were prior to my involvement with this, but from what
I understand all of these covariates were discussed at that time as
being potentially important to be in the protocol. What ultimately was
defined in the protocol were aEEG background, seizure, and age at
randomization. And it was felt that those other additional clinical
variables had been discussed previously that they were clinically very
relevant, and would be important in the analysis.

DR. ELLENBERG: But they were added after the clinical trial was begun?

DR. McCUNE: They were discussed before the trial was begun. They were
not specifically stated, written in the protocol.

DR. HAINES: Any other questions?

DR. JENSEN: I have one question for Dr. McCune. In terms of the aEEG,
you noted that there was no core lab that looked at the aEEG. But I
don\'t have any experience with reading them. It looked like the
criteria were relatively straightforward and simple, and it either is or
isn\'t between 5 and 10, or you know, above 10, or below 5, or whatever.
In evaluating the data, do you have any idea of who was making the
determinations as to what level the aEEG was? Was it a resident? Was it
an attending? Do you know? And do you feel that this was a relatively
easy \-- you don\'t know. Okay. And do you feel this is something
that\'s pretty straightforward, it\'s kind of hard to put an infant in a
wrong category?

DR. McCUNE: There are a couple of issues there. I don\'t have the
information about exactly who was reading it. I know that the people
that were reading the aEEGs were trained to read them. I think that the
physicians from Olympic could probably answer that a little bit better
this afternoon. In terms of the specifics, I do know that they were
trained and evaluated.

In terms of aEEG, there\'s much discussion in the literature about the
optimal way to use this as a tool to evaluate patients. And it is a
snapshot in time. There is some literature to look at how the aEEG
evolves over time with the clinical evolution of the patients, and
patients that have one aEEG reading at one time within a few hours can
have a different aEEG reading.

There\'s also what you see here in terms of this reading you\'re
absolutely correct is that it\'s easy to classify above or below for
most of the patients, but there is more information that\'s buried
within that in terms of the type of background. And so there are some
articles in the literature that discuss actually a more in-depth
approach to looking at the aEEG, as opposed to just kind of these very
standard criteria. It is something that is relatively easy to do using
these criteria, and that was the reason why this was developed in terms
of entry criteria for these patients, because it was something that had
to be done within a limited time frame in order to get these patients
randomized within that window of opportunity. In terms of then using
that as a tool to identify a subpopulation, it\'s not clear based on the
literature whether this would be the ideal tool in terms of how the
aEEGs were classified, and then once again, the fact that they were not
evaluated by a centralized center.

DR. HAINES: Thank you. We\'ll now break for lunch, and reconvene in this
room in 45 minutes.

(Whereupon, the foregoing matter went off the record at 12:15 p.m. and
went back on the record at 1:03 p.m.).

DR. HAINES: We will now resume the panel discussion. Dr. Reese Clark
will open this part of the meeting with his remarks to help focus our
deliberations. The panel will then deliberate on the information in the
PMA, and on the information the sponsor and FDA presented this morning.
The panel can ask sponsor and FDA questions at any time. After a general
discussion, the panel will address the specific FDA questions. And there
will be a second open public hearing, and FDA and sponsor summaries.
Then the panel will conclude their deliberations by voting on their
recommendation to FDA regarding this PMA. Dr. Clark will now give us his
remarks.

DR. CLARK: Okay. Well, neonatal encephalopathy is a clinical diagnosis
based on the findings of abnormal consciousness, altered tone, abnormal
reflexes, poor feeding, irregular respirations, and the occurrence of
seizures. It\'s estimated about 70 percent of the encephalopathy we see
in neonates occurs secondary to event. 70 percent of the neonatal
encephalopathy is due to events outside of the perinatal period, and
that\'s from the ACOG statement, the Neonatal Encephalopathy and
Cerebral Palsy that was put out several years ago.

The overall incidence of neonatal encephalopathy attributable to
intrapartum events is about 1.6 per 10,000. It\'s interesting, we\'ve
heard 1 to 3 per 1,000. That probably represents perinatal depression.
When we look at the occurrence of the diagnosis of actually hypoxic
ischemic encephalopathy as a cause for cerebral palsy, that event rate
is a much lower event rate.

The term most commonly used to describe infants with a diagnosis of
encephalopathy felt due to intrapartum events is hypoxic ischemic
encephalopathy. And the American College of Obstetricians and Gynecology
in this particular document have been very careful to outline the
features of that diagnosis, most importantly, to exclude other things
that might cause the problem, for example, infection, anomalies, inborn
errors of metabolism, and genetic abnormalities, all of which were
screened for in the primary study that we\'ve heard reported here today.

I originally had in my comments a review of the study, but I feel like
that we\'ve had that review both by the FDA and the sponsor. So I\'m
going to kind of skip down to the meat of the issue. In the concluding
remarks that were in the paper that was published in the Lancet, the
investigators concluded that these data suggest that although induced
head cooling is not protective in a mixed population of infants with
encephalopathy, it could safely improve survival without severe
neurodevelopmental disability in infants with less severe aEEG changes.
And I think we\'ve heard this morning both from the FDA and from the
sponsor the issues that bring that conclusion to bear, that if we look
at the overall, the p-value is 0.1. If we begin to look at subgroups,
there appears to be a subgroup that may benefit, and that\'s in part our
charge here today, is to understand whether it\'s safe and effective
therapy.

The FDA in the materials they sent to us, and as in their presentation,
have presented several questions, and I will address them very briefly
here. The first is do we believe that the current data suggests the
device is safe. The second is who should we offer the therapy to, and I
think we\'ve heard a lot of discussion this morning that brings us to
the issue of how do we select patients. We know in neonatal medicine
that a therapy targeted to a very narrow population will expand and be
used off label, and part of our charge here today is to try to define a
label which will guide physicians to use the therapy in the safest way
if we should decide that therapy is approvable.

Can a safe therapeutic temperature be maintained consistently, and
we\'ve heard some issues, and I would like to hear more from the sponsor
about feedback mechanisms that might make the device safer, which allow
the device to turn off automatically when out of bounds temperatures are
read.

Is the label appropriately written, and how would it change. I think one
of the comments that we need to address is the use of the term \"hypoxic
ischemic encephalopathy\" is a very emotional term. It leads to lots of
different lawsuits in this country, and we need to make sure that if
that term is used, that it\'s carefully defined, and that we understand
that the use of this therapy will indicate that that specific event has
occurred, and may imply some liability to the folks that are providing
care to the patient.

Are safety and efficacy related, and if so, do we know enough about each
of those to say that this therapy should be approved? And finally, what
postmarketing study should be done to establish efficacy and safety of
this device if any are needed. That will conclude my summary remarks,
and I think that addresses the questions that I had from this morning.
I\'ll throw it back to you.

DR. HAINES: Thank you, Dr. Clark. Does anyone on the panel have a
question for Dr. Clark? Okay. Then we will begin the general panel
discussion. The format will be an opportunity to make general comments
on what has been heard. This is also an opportunity to ask specific
questions of the sponsor and/or the FDA. What I would ask is that we go
around \-- we\'ll go around the table to be sure everyone has an
opportunity to make their comments and ask questions. I would ask that
we try to limit to one question, and we\'ll continue to go around as
long as there are questions to ask. This is an opportunity to get the
response to the questions that were asked this morning, and that the
sponsor has had a chance to collect their information and thoughts. So
let\'s begin with Dr. Jayam-Trouth and proceed.

DR. JAYAM-TROUTH: Okay. I have a few questions too. For the inclusion
criteria, you know you use patients, and you label them as those having
loss of consciousness or altered state of consciousness, plus \-- and
lethargy, somnolence, stupor, coma, and the other probabilities. Now, to
me altered state of consciousness is lethargy, stupor, coma. So I\'m not
really sure \-- it\'s not well clarified. Did you have altered mental
state and lethargy/coma? I mean, that itself is lethargy/coma as part of
altered mental state. So how was this inclusion criteria actually, you
know, how were the patients included?

DR. HAINES: I assume that\'s a question addressed to the sponsors.

DR. JAYAM-TROUTH: To the sponsors, right.

DR. BARKS: I\'m John Barks. I\'m a neonatologist from the University of
Michigan. And by way of disclosure, Olympic paid my travel expenses to
get here, and also paid my travel expenses as one of those validity
testers back in last September.

I agree that all of those things would constitute definitions of altered
level of consciousness. And the way that I applied, and speaking from my
own practice, the way that I applied the entry criteria was that
lethargy, stupor, or coma were included in my perception of altered
level of consciousness. And then on top of that were the other things,
like the abnormal reflexes, absent suck, clinical seizures.

DR. JAYAM-TROUTH: So it wasn\'t that and, you know. Because there were
two criteria. They said they should have altered mental state and. And
included in the \"and\" group was the stupor, coma, lethargy, aEEGs, the
specific criteria, etcetera.

DR. BARKS: Right.

DR. JAYAM-TROUTH: If you look at the inclusion criteria.

DR. BARKS: In my own practice those were included in altered level of
consciousness. And the other abnormal reflexes were above and beyond
that.

DR. JAYAM-TROUTH: So they had to have plus something else.

DR. BARKS: In my mind yes. I can\'t speak for the multiple investigators
at 25 other sites around the world, but that\'s how I interpreted it,
and my co-investigator Dr. Dunn, that\'s how we interpreted it.

DR. GUNN: Alistair Gunn again. Just to say, I suspect what we\'re
dealing with here is corrupted wording.

MS. SCUDIERO: Would you speak more into the mic?

DR. GUNN: That what we\'re dealing with here is corrupted wording. It
was meant to be, as I remember writing it, altered state of
consciousness as shown by and including the additional findings. You\'re
quite right, it was just \-- the wording got corrupted as it moved down.

DR. JAYAM-TROUTH: Okay. There\'s one more question. Oh, I\'m sorry.
That\'s my question?

DR. HAINES: We\'ll come back.

DR. JAYAM-TROUTH: Okay.

DR. HAINES: Do you have any general comments at this stage?

DR. JAYAM-TROUTH: Well, at this stage I mean I have one more
clarification that I need done. The Sarnat score, you know I think the
FDA did that analysis there. And according to them if I look at it, if
you take Stage 1. You know, Stage 1 Sarnat score did much worse in the
cooled category. You know, you talk about 60 percent favorable, 100
percent in the control category. So should we then be looking at
different stages, and look at perhaps that Stage 1 should not be a stage
where we should be using the Cool-Cap, you know, whereas we should be
considering Stage 2 or Stage 3, because those two show favorable rates.
So that was one of my.

DR. GUNN: I think it\'s fair to say that there are extremely few Stage 1
patients. You simply can\'t take anything from that at all on that
number. Even the Stage 2, I would like to emphasize, the key reason for
having the aEEG was indeed to enrich the population. And I believe
compared with published results, the published outcome of Stage 2, that
we are significantly more severe than would be expected. And that\'s a
result of enriching the population, if you like, favoring the Stage
2-pluses rather than the borderline Stage 1 to Stage 2. So this is not a
pure clinical Grade 2. This is Grade 2 with the milder cases taken out.

DR. McCUNE: I just wanted to make one comment about the Sarnat analysis.
As we were looking at the subpopulation analysis that Dr. Clark
mentioned, the question was whether or not the severe aEEG background
and seizure truly represented a population that was unable to respond
either based on severity of injury or length of time between the insult
and the Cool-Cap in terms of being in that secondary phase of energy
failure. And so in looking at the Sarnat score in those patients was an
attempt to try to get yet another handle on the severity of illness, to
see if whether truly those patients who were the most severe in terms of
Sarnat Stage 3 would be that class of patients that wouldn\'t be able to
respond. And yet what appears is that Sarnat Stage 3 patients do respond
to cooling, as opposed to the severe aEEG background and seizure
population. So the question is what is that test defining? What
population is that test defining? And I\'m not sure yet that we truly
know exactly what that population is defining. It may be those patients
who are so far along from a time perspective that they\'re into
secondary energy failure and not able to respond. But I\'m not sure that
the severity \-- that it truly represents severity based on looking at
the Sarnat scores.

DR. JAYAM-TROUTH: Okay. The base excess too. Was there any reason why
the base deficit greater than 16 was excluded?

DR. BARKS: To clarify, that was one of the inclusion criteria.

DR. JAYAM-TROUTH: Yes but it states here that a base deficit greater or
equal to 16 was excluded in Size Number 30 of the FDA.

DR. BARKS: Then the slide would be \--

DR. JAYAM-TROUTH: Less than. I\'m sorry, base deficit only less than or
equal to 16 was included.

DR. McCUNE: I\'m sorry. That should be a -16.

DR. HAINES: Dr. Ellenberg?

DR. ELLENBERG: I would just like to clarify one question that I thought
I heard answered differently. In terms of the primary analysis for the
logistic regression, was the endpoint used in the logistic regression
just mortality, or was it the combined endpoint of mortality and/or
neurologic development?

DR. LIU: It\'s not just mortality.

DR. ELLENBERG: Okay, thank you. I\'ll pass.

DR. HAINES: Would you like to summarize your question from the morning
and have that response?

DR. ELLENBERG: In terms of how you would assess essentially what\'s
going on here, if I\'ve read everything and heard everything correctly,
currently we\'re looking at no difference in the total mortality between
the two arms, and then we\'re looking at a p-value of 0.042 for the
adjusted difference between the arms for the combined endpoint of
mortality and developmental disability. I might take from that that the
driving force in this result is the developmental disability. That is,
the surviving children are doing better in the cooling arm than in the
non-cooling arm. And I would like a comment on whether my assessment or
reading of that is correct, at this stage. And I\'ll have further
questions later, but that\'s a very important issue I think, at least
for me, at this stage.

DR. WYATT: Could I answer that from a clinical perspective and not as a
statistician? But my understanding of the data is that there is a
contribution of both factors to the eventual outcome, that there is both
a trend to reduction in death, and a trend to reduction in disability,
and that when they are combined together in a combined outcome measure,
that reaches statistical significance. In terms of our clinical
understanding, we think that this is a neuroprotective therapy which is
working on brain cells, and it is likely, therefore, and certainly in
consistent with the animal \-- there\'s a body of experimental evidence
to show that it will improve brain function, and that is likely to be
revealed in an increase in the number of survivors who are healthy, of
babies who survive without either dying or having severe disability. And
that\'s indeed what our data suggests. And that\'s the reason why we
took a combined outcome measure of death plus severe disability as \--
that that reflected what our primary hypothesis, that this treatment
would protect brain cells, and would lead to a greater number of
children surviving without disability.

Our great concern was that the effect of this therapy would be marginal,
and therefore that it would simply transfer babies who were going to die
because of profound brain injury into those who would survive, but
survive with very severe disability. But our data does not, we believe,
show any evidence of that phenomenon, that there is a trend towards
reduction of both death and disability, and that both of those
contribute to our final outcome marker.

DR. ELLENBERG: Well, it\'s not clear how death is contributing to the
\-- in a preferential way towards the cooling if when you just look at
death it doesn\'t appear to be contributing. If you look at the
preliminary analyses where Cox proportional hazards, and the
Kaplan-Meier techniques were both used in your presentation. Actually,
it\'s in the \-- I\'m sorry, it\'s in the clinical reviewer\'s summary.
There seems to be no difference. But you have answered my question in
terms of the other outcome. I can pass and then come back.

DR. HAINES: Dr. Hudak?

DR. HUDAK: The couple of questions I had asked before, I was wondering
if there had been any response? One was the issue of how you ensured
masking at the 18-month neurodevelopmental examination, and the second
was the \-- what the thoughts were about the potential impact of \-- in
the control group of perhaps having an earlier tendency to withdraw
support on the final outcomes.

DR. BALLARD: Okay. I\'m Dr. Roberta Ballard, and I\'m a Professor of
Pediatrics and a neonatologist at Children\'s Hospital of Philadelphia
and University of Pennsylvania. And I was asked to join the scientific
advisory committee of this study because of my experience with
randomized multi-center clinical trials, which had in general been
focused on the lung, but I was able to recognize that the brain was
important.

(Laughter)

DR. BALLARD: And I have been honored to be a part of this process
because as a neonatologist, I have known how many times no matter what
we can do for the lung, we can\'t do anything for the brain. I went into
this believing, as the ACOG does, and as Reese brought up, that we
probably weren\'t going to make any much difference to most of the kids,
and actually have been quite surprised and pleased that it does appear
that we are making a difference. I have received no compensation from
Olympic Medical, except for my travel expenses to this meeting. And I
think you need to know that the group of people involved in this on the
scientific advisory committee have done this for love, and commitment,
and an opportunity to be part of something important.

I was also asked because I have had some experience in neonatal
follow-up, and because I see that as a tremendously crucial part of any
intervention we do in the newborn, to know what happens to the babies. I
was asked to be involved in addressing some of these issues.

And I\'d like to first just comment on the question that\'s been raised,
which was pointed out to us, actually, that there seemed to be an
increased number of babies who had been referred for therapy. The
question of what happened with the 6-month follow-up and the number
referred for therapy. And the question was asked about what happened.
And on the form, as has been pointed out, that exam was done just to try
to keep track of the families. And the form is a one-page form, and on
it the families are asked whether or not they have been referred for
therapy, or whether they have received any kind of therapy. So it was
not \-- no referral was necessarily made at that time, and what we found
was that there are some sites, as I think many of you know, where all
babies who had this history are always referred for some kind of therapy
at the time of discharge. And that happened in certain states, in
certain circumstances, particularly if there were the resources
available to do that. Also it turned out that three of the children who
had had referrals had been marked down because they\'d been sent for
vision or hearing testing, which should in general be automatic in this
group of children. So although the observers at that time might or might
not have known what the status was, we did not tell them not to reveal
it. At the 18-month follow-up, instructions to the families, and to
everyone else were that there should be no unmasking of the treatment
group.

Just to point out, we did look at this, and we found, as you\'ll see
here, that if you look at the outcome of the subjects who were referred
for therapy, if you were looking at favorable outcome, the cooled
infants who were referred had a better outcome than the controls who
were referred. Then if you look at the children who were not referred
for therapy, you\'ll find out that the outcome for those who were not
was probably generally because they didn\'t need it. So we do not think
that this was a confounder. It was an interesting post hoc observation
that falls, I believe, under the category if you torture the data long
enough it will confess. But I don\'t think there was a real effect,
certainly not one that we could look at intentionally.

DR. BROTT: Could you go back to that slide? Because it looks like the
p-values were better for subgroups than they are for the study as a
whole. And I find that confusing.

DR. BALLARD: In this we\'re just looking at \--

DR. BROTT: I know, but there\'s \-- and I guess I\'d ask Dr. Ellenberg
on this. We\'ve got p-values down there that are the lowest ones we\'ve
seen, and they\'re on smaller groups of the study. But they seem to
cover all the patients.

DR. BALLARD: Probably therapy made no difference. So this is, again, you
know.

DR. BROTT: Do you know what I\'m getting at? You\'ve got all the
patients there, don\'t you? Or is it just the \--

DR. BALLARD: No. This is not all the patients. This is just looking at
those who were referred for therapy.

DR. BROTT: You\'ve got 69 patients, and your p-values are very low.

DR. BALLARD: All we\'re trying to show here is \--

DR. BROTT: No, I\'m wondering about the arithmetic. Because you have 60
out of 234 patients, and you\'re coming up with some very impressive
p-values.

DR. LIU: That depends upon the actual magnitude of difference. So here,
this slide is simply showing that for the control infants referred to
therapy, they did not do very well at all. And for reasons we\'re not
clear, that the cooled infants referred to therapy seems to have fared
better. So, and like Roberta was commenting, I mean, my clinical
colleagues can certainly comment on why there\'s this pattern.

DR. HAINES: Thank you. Dr. Hudak?

DR. HUDAK: I agree with Roberta. This is just an accident. I mean, at
the 6-month visit you\'d expect that in each group there would be an
equal number \-- percent of babies who had unfavorable outcomes because
that is what motivates the referral. And it\'s not true. So I think any
conclusions from this are \-- you can\'t draw any conclusions at all.

DR. HAINES: So, have you had a response to your question?

DR. BALLARD: I think he still wants to know 18-month. And I\'m actually
answering some others that were asked earlier, so I hope I\'m saving
some other time.

The 18-month follow-up, there was a request for masking, and the exams
were done, and Dr. Barks can describe how that happened at his
institution. However, I want to point out that after all of that, the
forms contained the information that described what the child could and
could not do. That\'s what happened in terms of what went on at those
exams. The Bayley exam was done in a standard fashion, the Gross Motor
examination was also done, and the information was entered in the forms.

Subsequently, two very experienced members of our scientific advisory
group, Charlene Robertson from Edmonton who\'s done more than 20 years
of neonatal follow-up, and Dr. Donna Ferriero who\'s a neuroscientist a
UC-San Francisco, reviewed every single one of the follow-up forms
blinded. This was before the \-- so they had no idea. And they went
through each of them as is appropriate to do in a clinical trial,
reviewed all of them for accuracy of the final outcome diagnosis. So if
there was any question about there being a problem with blinding early
on, we put a second level of blinding into this before we broke the
code. I\'ll let Dr. Barks address that.

DR. BARKS: So, I can address how we handled the 18-month developmental
follow-up at our particular institution only. But we had the physician
portion of the exam was done by a developmental pediatrician, and our
developmental pediatricians aren\'t involved in the NICU. The Bayley was
done by a pediatric psychologist Ph.D., and they\'re not involved in the
NICU. The patients\' medical records, I asked our nurse coordinator for
the follow-up clinic do not have the hospital charts of the previous
admission show up in the follow-up clinic like they usually would. I
emphasized to the patients early on that it was important that they not
tell people what happened to their baby when they came back for the
final visit. And I asked Ann, who was our clinic coordinator, to make
the same point to the patients when they came to clinic. I explained to
them how important it was that the evaluation be unbiased, and the
person doing that be unaware of the treatment assignment of the baby.
So, that\'s how we handle it. And incidentally, believe it or not, there
were some parents who actually didn\'t remember which treatment group
their baby was in. Obviously not the ones who are here today, but there
were some who actually didn\'t remember. But we always made an effort to
emphasize the importance of them not discussing that in that 18-month
clinic visit.

DR. WEILER: And just one other final comment on that. The procedures
that Dr. Barks followed in instructing the parents not to disclose their
follow-up, and ideas of not having previous records included. Those were
instructions that were given to all the sites during their training for
the trial as ways to avoid having any problems with blinding at 18
months.

DR. HAINES: Yes?

DR. JAYAM-TROUTH: Pertinent to that 18-month visit, how many of those
patients who came at 18 months had been referred for therapy? Do you
have any numbers on that? How many had received therapy in the interim
period when they came at 18 months in the favorable and the unfavorable
groups?

DR. BARKS: That wasn\'t a question that we gathered at the 18-month
visit. So we don\'t have the answer to that.

DR. JAYAM-TROUTH: I think that\'s very important, though. Because
basically, even any patient who has a neurological problem, if you put
them on therapy, most of them early in therapy seems to \-- it\'s
interventional. And it seems to help quite a bit.

DR. BALLARD: I don\'t think there\'s good evidence that for children who
have this kind of severe outcome there\'s evidence that you can change
the category by any type of therapy or I think we would have been doing
that for these children all along. It falls in the category of no, we
really don\'t have any intervention we can do. So I am unaware of any
information that would suggest that we could have made a major
difference.

DR. HAINES: Thank you. This was a question that Dr. Brott had also
asked, so do you have any follow-up?

DR. BROTT: Yes. Well, this is helpful so far. I just want to go through,
and this is all one question. The Bayley. How long does it take, and is
it purely an examination, or is there any information that\'s gathered
from anyone but the child?

DR. BALLARD: The Bayley is an examination of the child to assess both
the mental abilities and the physical abilities. It\'s a highly
standardized test. It\'s not perfect, as nothing is in this field, but
it is the only really standardized way we have of looking at outcome in
children this young.

DR. BROTT: And who carried it out?

DR. BALLARD: And in most \-- it would variability a little bit from site
to site, but ordinarily it would be a psychologist. They are trained to
do this, and it is a standard part of neonatal units to have a follow-up
team with someone who has been certified in doing Bayley examinations.

DR. BROTT: And how long does it take?

DR. BALLARD: You know, you\'re embarrassing me now.

DR. BROTT: Does it take five minutes, or an hour?

DR. BALLARD: Oh no, no. This takes about 45 minutes to 60 minutes to do.

DR. BROTT: Okay. What if the child\'s in a bad mood? I\'m a parent, and
you know, we saw some variability here today.

DR. BALLARD: That happens.

DR. BROTT: What do you do?

DR. BALLARD: What happens is you end up having to say that you cannot do
a full assessment if the child is severely damaged.

DR. BROTT: And how \-- I didn\'t see that.

DR. BALLARD: I don\'t do the exam.

DR. BROTT: I saw that in three cases, you know, where they didn\'t have
a full assessment. But how frequent was the absence of a full assessment
with the Bayley?

DR. BALLARD: I don\'t know that I know that answer.

DR. BROTT: Okay.

DR. BALLARD: I do know that one of the reasons for having two other
folks look at all of these was to satisfy ourselves that it was done in
a proper fashion.

DR. BROTT: And I\'ll try to be quick. The Gross Motor Function. Is that
purely an examination, or if the child can\'t do it do you ask somebody
with the child?

DR. BALLARD: No, that\'s purely an examination.

DR. BALLARD: And that\'s what any of us can do.

DR. BROTT: And how long does that take?

DR. BALLARD: And I don\'t think I put the slide up. That doesn\'t take
long because you just look and you can see. And a zero means that \-- do
we have it?

DR. BROTT: I don\'t need to see the whole exam, but you know.

DR. BALLARD: It won\'t take \--

DR. BROTT: Okay.

DR. BALLARD: A zero means the kid is cruising around like children that
you\'ve seen today. Okay? And it\'s been developed in order to have a
way of functionally looking at children. So a Level Zero means that the
child is doing what you expect them to do, they\'re moving about, and
it\'s been zeroed in for what we\'d expect at this age.

A Level 1 means that the child, these kids are just a little bit older
and they should be doing a little bit more than this, but they are most
likely going to be okay. So they move in and out of sitting, and crawl
on hands and knees, they pull to stand, and so forth. Okay? So we
generally think that a Zero and a 1 at 18 months are really going to be
fine.

And the Level 2, the infant can sit on the floor but may need to use
hands or feet, or his hands to support, to maintain balance. He can
creep on his stomach. But these are things that are clearly a little
suspect for an 18-month old. And a Level 3, the infant can only sit if
the back is supported. The infant can roll and creep forward. So we
would all know. Again, this is something that you and I can do.

DR. BROTT: Okay. I just \-- I guess my question here, and I\'m trying to
be quick, what\'s the inter-rater reliability? Do you know?

DR. BALLARD: I don\'t know that \-- we haven\'t tested that. But if you
look at this, you know, by Level 4 you can see \--

DR. BROTT: No, I\'m not wondering about. I\'m wondering splitting in the
categories. You know, how reliable that is.

DR. BALLARD: We said just 3 to 5 was a bad thing.

DR. BROTT: Okay.

DR. BALLARD: So our outcome is just taking these two, 3 to 5, and
that\'s where we had, again, Dr. Ferriero and Dr. Robertson go back, go
through the exam that was done and recorded, and make sure they agreed
on this level.

DR. BROTT: Now how did they \-- they didn\'t see the children?

DR. BALLARD: No, they didn\'t see the children, they read the form.

DR. BROTT: How did \-- what did they do?

DR. BALLARD: They read all the forms.

DR. BROTT: But I mean, so they\'ve got the forms. How did they change
the forms?

DR. BALLARD: No, they blindedly read to see if they agreed with the way
in which the observer who did the study had called a favorable versus
unfavorable.

DR. BROTT: That\'s what I\'m wondering. Just logistically, what did they
do? They\'ve got the forms. The forms have the numbers.

DR. BALLARD: The forms will have a description of what the child\'s
doing. So the form might say child was \-- okay, all right.

MS. MULLANE: Hi, my name is Judy Mullane. I work for Olympic Medical.
I\'m an employee. And I was the study monitor for the study. And as far
as the determination of the Gross Motor Function classification, the
infants or the children would be examined by the follow-up clinic. And
what happened was that they had a 5-page form as part of the
neurodevelopmental exam. And as part of that, they saw the physician,
and they were assessed physically for physical motor function, and also
for functionality. So there was a physical assessment and then a
functional assessment. And as part of the five pages there was muscle
tone assessed, their access function, and reflexes. What else. Yes, like
pincer grasp, you know, gross grasp, all those kinds of things that go
into the neurodevelopmental exam at 18 months. And then from those five
forms, the blinded review, they were given the results of those five
forms. And they made sure that they were in line and made sense as far
as what the Gross Motor Function classification outcome was.

DR. BROTT: So they didn\'t use these forms? Your two experts abstracted
these forms from another form? Is that correct?

MS. MULLANE: No.

DR. BROTT: No, no, I understand. But did they have \-- and I\'m sorry to
be such a nitpicker on this, but with our stroke studies, you know,
we\'ve got Measure A, Measure B, Measure C, you know, what\'s the
inter-rater reliability, what\'s the validity. And we\'ve got the forms,
and the forms tell you exactly how to do it so that everybody does it
the same way. And I guess, was this form that we see right here, was
this used at the time of the examination, or was it abstracted from a
general form?

MS. MULLANE: It was a portion of those forms. It was half a page that
listed the categories of Gross Motor Function. It was half a page of a
5-page form. And so the person who actually assessed the child did have
to choose what level of Gross Motor Function the child had.

DR. BROTT: Okay. That\'s what I wanted to find out. And finally, and
I\'m sorry to take so long, the bilateral cortical visual, how was that
done? Who did it? How long did it take?

MS. MULLANE: It varied from site to site. And some sites decided to send
the child to an ophthalmologist and have a formal ophthalmology exam
performed. But, and I\'m not a physician so I\'m not sure how this is
done, but there is a way to test for bilateral cortical visual
impairment.

DR. BROTT: And how is it done?

DR. BALLARD: Basically just seeing whether you could get the child to
fix and follow. There was nothing more. If it needed something more
complex than that, then as I understand it \--

DR. BROTT: Maybe you should put down \"fix and follow.\" Because that
tells you what you\'re doing. That\'s \--

DR. BALLARD: And blink. And then you would send the kid to the
ophthalmologist. It\'s not so easy to do visual assessments on these
kids.

DR. BROTT: No, that\'s why I asked.

DR. BALLARD: You\'re correct about that.

DR. HAINES: Back to Dr. Hudak. How are we doing on your question?

DR. HUDAK: I think we got the one. We didn\'t get the other, about the
control group.

DR. HAINES: Could you rephrase the question succinctly for us?

DR. HUDAK: Okay. The question was that from what we\'ve heard is that
there might have been a greater facility in offering parents withdrawal
support at an earlier time in the babies who did not receive the
Cool-Cap therapy. And we all know that some babies at an early time if
you withdraw support the babies die, whereas if you wait a longer period
of time the babies recover spontaneous respiratory activity and whatnot,
and will not expire if life support is removed. And how would that
impact?

DR. GUNN: I can\'t fully answer the question, and neither can anybody.
Obviously, in the sense that we can\'t say what would have happened
differently in any particular baby. However, I think we can look at the
pattern of timing of death. And I think what we see very clearly is the
time of death has been shifted in the cooled group compared with the
control group. But only the time of death. The actual number of deaths
in the first week of life has not changed. So I think that\'s really the
primary answer, that yes there\'s a difference between the first three
days during the cooling protocol compared with the second four-plus
days. Although it\'s not a significant difference, but there\'s a clear
trend there. But the overall number at the end of the first week is
exactly the same. That I think is the key one.

The second is if we explore what would we expect to happen if death was
delayed. The concern right from the beginning was that, okay, perhaps by
delaying withdrawal of care, that we will enable babies to survive who
might otherwise have died. That is a real possibility, and it was the
single biggest issue that everybody raised with me when we were
proposing the trial. If that was the case, you would expect either more
infants with profound handicap who would then die in the first 18
months, or else more infants surviving for 18 months and having more
disability in the cooled group compared with the control group. In fact,
we find the reverse. We find fewer infants with severe multiple handicap
dying in the first 18 months of life, and we find fewer infants with
multiple disabilities as measured either with the functional GMF scale,
or with the standardized BSID score. So I believe from that deduction it
is unlikely that there was a significant effect.

DR. HUDAK: Thank you. I guess I can ask my real question this time, with
your permission.

DR. HAINES: Sure.

DR. HUDAK: I think there are obviously lots of different ways to look at
the results here that people have sort of struggled with in terms of
doing the analysis, and looking at subpopulations. But bottom line is, I
think that what we look at, or one of the things we look at that people
have emphasized is that the percentage or the number of babies who
survive with severe disability is reduced. I mean, that\'s what we\'d
like to see as one of the outcomes. And the combined outcome of death
and/or a disability is an integration of death and that, so that that
disguises what happens just in terms of surviving babies, with or
without disability.

But I\'m trying to struggle with the numbers here. And if I\'ve got
these correct, with the analysis of 108 cooled infants, and 110 control
infants, there were 36 deaths in the cooled, 42 deaths in the control,
leaving 72 surviving cooled babies, and 68 surviving control babies. The
number of babies with a disability, one of those disabilities was 23 out
of the 72 in the cooled group for 32 percent disability rate, and in the
control group it was 31 surviving with disability out of 68, which by my
long division is about 46 percent. So in fact there does appear to be a
reduction in disability, which is good. That\'s probably not significant
if you do a Fisher test on it.

The other question I did have, though, about trying to get a better
picture of the differences between these two groups. It\'s very
difficult because there are so many things that can potentially be
problems, but I noticed that there was no \-- we basically looked at the
GMF, which is something new for me in a way. But we\'ve shied away from
looking at calling things cerebral palsy or not, I take it. We don\'t
have the information on percent cerebral palsy, or if we do it\'d be
nice to see that.

And the other thing is the other outcomes are, like for instance the
Bayleys, they\'re categorical. There are you 70 or better, or are you
less than 70. And that is a yes or no response, and we don\'t have
information looking at the distributions and comparing the
distributions. And that would be helpful to sort of look at, or
integrate the effect of the Cool-Cap therapy.

DR. GUNN: For what it\'s worth, if I could just stick with the BSID
score issue. We did look at the continuous score, and the distribution
within that. To my surprise, in fact, there\'s almost no intermediate
babies. If we call babies with BSID score between 70 and 85 as moderate
disability, they represent less than 15 percent of the total surviving
population. So whether we stuck to the categorical severe, or moderate
to sever, we got exactly the same binary outcome.

We also looked at it as a continuous variable. It showed the same
overall trend towards a favorable outcome as the binary outcome did, but
as an individual variable not quite reaching significance.

DR. HUDAK: Thank you.

DR. WYATT: I wonder if I could just make a comment, because I think, for
those who aren\'t neonatologists, I think this is perhaps a helpful
thing to say. And that is the clinical experience of following babies
who\'ve had severe encephalopathy, and many of us have had that clinical
experience, is that by and large, and this fits exactly with what
Alistair has just said, the children fit into two categories. They\'re
either normal, completely normal or relatively normal as the sort of
children we\'ve seen today, or else they are profoundly handicapped.
They have profound motor disability, they frequently have profound
intellectual disability as well. And it is a bimodal distribution. There
are a few children, inevitably, who fit into a gray zone between the
two. But in principal, the vast majority of children fit clearly into
one category or another, so much so that any member of the panel could
decide just by looking at a child in the vast majority of cases, without
going through these very sophisticated standard assessments of which
category a child comes into. So that was the reason that we went for,
apart from the statistical reasons, why a categorical binary outcome
fits exactly with both the experimental evidence and the clinical
evidence. And I think that that\'s just an important background concept
to help the panel understand the disease we\'re dealing with.

DR. HAINES: Thank you. Dr. Doyle, any comments or questions?

DR. DOYLE: Given the level of the sophistication of the previous
questions, I\'m almost afraid to ask mine it\'s so simple-minded. But
why did you decide to do the second evaluation at 18 months? I noticed
the Bayley score had 18 months in it. Was this \-- or what drove either
not 12 months or 24. Why 18?

DR. WYATT: There was quite a lot of discussion at protocol development
about which was the best age. And the advice we had in the discussion
was that the earliest possible age at which adverse outcome can be
reliably detected is 12 months. The best possible age in terms of
getting the most information is 24 months. And 18 months to be honest is
a compromise figure which many other groups have also come down on as
being an age which gives you \-- where if significant problems are going
to develop, they will have already developed, certainly in terms of
major motor, or profound learning disability problems. And so it
represented a compromise, but it\'s one that many other studies have now
chosen, that this 18-month outcome has been selected as generally agreed
as a good compromise age.

DR. HAINES: Thank you. Dr. Coffey?

DR. COFFEY: Yes, I don\'t have any questions, but I\'d just like to
restate a couple of things, and clarify basically three issues. The
referral for therapy, physical therapy, rehabilitative therapy, and so
forth. I think it\'s important to raise that it was probably the
patients with the most severe disabilities who would have been referred.
And although it\'s purely guesswork, and purely conjecture, one might
therefore assume that the patients, given the data in this trial, that
the patients who were referred for therapy may have actually had worse
scoring at 18 months than the patients who were \-- you know, that
argument could become circular, but I think it just needs to be clear to
all of us.

DR. GUNN: This is in fact correct. The children are referred, in both
groups, both the cooled group and the control group, that are
significantly worse at 18 months than those. There\'s no question that
you\'re correct.

DR. COFFEY: Yes. And so that\'s not a reason not to refer, but it\'s,
you know, it\'s just the cold, hard facts. I did happen to remember, you
know, regarding Dr. Brott\'s question about cortical blindness and so
forth, and how that was determined. I couldn\'t find it today, but I
remember reading it recently in the protocol, and in the responses to
letters. And it was actually fairly well defined during the examinations
just the way we would in adult neurology, in that they made sure that
the baby had intact extra-ocular motions, you know, vestibulo-ocular
reflexes, and pupillary responses, and then presented stimuli in the
visual fields. And so that\'s how they defined a unilateral, or a
bilateral cortical visual deficit. And I don\'t believe there were any
unilateral cortical visual deficits, at least detected at 18 months in
this study.

DR. BROTT: You\'re probably right, because in their manuscript, they\'ve
only got 11 with bilateral cortical.

DR. COFFEY: Okay. And that there was one patient that I remember reading
about that because of the length of times of these various evaluations
that, you know, that we were talking about previously, had all except
maybe either the visual or the hearing test, or something. So there was
that one missing data point. But it seemed to me that it was a sensible
way of assessing cortical visual function as being intact or not intact
by looking at retinal, and brain stem, and visual pathway function
first.

The other thing is regarding the business of, you know, at the risk of
beating Dr. Hudak\'s question and Dr. Ellenberg\'s questions to death,
the business of are these results \-- is this p-value, P of 0.4, driven
by deaths, or driven by disability. And is it possible to sort that out.

The number of deaths, just the N number in each group, was nearly
identical in the first seven days of life, and please correct me if I\'m
wrong. It was 27 in the cooled group and 26 in the control group. And at
the end, as you just mentioned, there were 36 deaths in the cooled
group, and a higher number of deaths, slightly number of higher, 42 in
the control group at 18 months. But the N number of cases with late
death or disability, in other words beyond seven days is in Table 32,
Page 44 our of 202 in Document 9. That\'s the response to the FDA
letter. And I only found that by doing a word search on disability in
the PDF document. Believe me, no one could remember something like that.
But we saw a chart similar to that in which late death or disability in
the cooled group was 32 patients, and in the control group was 47
patients. So either a lot of people died after seven days and there was
some difference in the deaths after seven days, but there was still
excess disability in just raw N numbers beyond the N numbers of death.
So I don\'t want to reduce that to be too simple-minded. So to me it
doesn\'t suggest that deaths are completely driving the statistical
significance. It\'s not an out of the park home run, but it doesn\'t
appear to be entirely driven by deaths.

DR. HAINES: Thank you. Dr. Nelson?

DR. NELSON: Well, this has been a fascinating discussion to listen to,
and I guess your comments answered a large part of what I was interested
in hearing about, which is the statistics. Let me ask one question, and
that\'s what one would anticipate based on experience. And so I assume
this would be directed mainly to our neonatology colleagues, of the
durability of an 18-month follow-up going forward. What would one
expect? What I was taught was that you really don\'t know until you get
out into the school-age years about what you\'ve really gotten. So what
would one expect about the durability of these particular findings past
18 months?

DR. BALLARD: We are obviously concerned about that issue, but did not
feel in the beginning that it would be appropriate to wait till they
were seven or eight years old to find out the answer to that. We believe
that there are data from other earlier studies suggesting that certainly
in terms of \-- we don\'t expect to see P to develop, but certainly in
terms of cognitive outcomes, there could be concerns raised. And so for
that reason, myself along with Donna Ferriero, Andy Whitelaw, and
Alistair Gunn are currently in the process of applying for funding from
March of Dimes and NIH to try to do follow-up at age 7 to 10, including
some MRI studies on these infants, which will require some significant
sleuthing, but we share that concern and are very interested in knowing
about that. And we\'ll see if we can get further answers.

DR. NELSON: Just as a follow-up. I mean, looking at the non-death,
you\'ve got the three. I mean, my take on the cortical impairment is
either you see or you don\'t see. The Gross Motor Function, it looks
like you walk or you don\'t walk. The Bayley, I\'m not so sure. So in
terms of the durability, I would anticipate that the Bayley might be a
little hard to predict what\'ll happen there, but that\'s mainly
cognitive. But in terms of the motor and visual, would you expect there
to be really any shifting between those categories going forward?

DR. WYATT: No, I think you\'re exactly right. I think the motor function
is stable pretty well in the vast majority of infants. If you\'ve got
normal motor development like the children that we\'ve just seen, it\'s
extremely unlikely that at seven years of age you\'re going to develop
significant motor disability. But what is clear is that as you go
towards \-- so the motor side is relatively fixed, and relatively
predictable at 18 months. What is clear is as you go to school age, more
problems may emerge, particularly specific learning disorders, such as
difficulties with maths, or with attention deficit, or so on. And all
the data suggests that one can\'t reliably predict those at 18 months of
age. So having said that, we believe that one of the advantages of the
Cool-Cap therapy is that it preferentially cools the cortical and
subcortical regions compared to the deep structures which control
movement. And therefore, we hope, and also on the basis of experimental
evidence that in fact we have got good cortical protection, and
therefore that we will continue to see on into school age and beyond
that this therapy does provide significant protection in cortical
function and learning processes.

DR. NELSON: I think that may be true, but just to point out in the
uncombined data, actually the one with the strongest trend, just a
trend, was the motor.

DR. WYATT: That\'s right, and I think that there\'s no doubt that the
dominant way in which hypoxic ischemic injury affects the developing
brain is in the motor areas, which is why motor impairment cerebral
palsy is such a major feature of infants who had problems at birth. And
we are very encouraged to see that strong trend in protection of the
motor.

DR. HAINES: Thank you. Dr. Jensen?

DR. JENSEN: So, back to my question about the aEEGs. And the only reason
I\'m sort of honing in on this is because this particular diagnostic
test was used not only to allow patients to be eligible, but also
because it affects, I think, your outcome evaluation. And I find it
curious that you had experts reviewing case report forms, but you
didn\'t have anybody reviewing the EEG data to ensure that the correct
categorization was being made. And if the test is really as simple to
read as the one slide that Dr. McCune showed is, then why were there
five patients who had an unclassifiable EEG? And I think this is
important because as we move forward if we get to the point where we\'re
looking at labeling there\'s going to need to be some sort of guidelines
on that. And so, just some specific questions would be could you
describe who was eligible to read a study, what the training program was
for them in order to be able to read the study, what sort of examination
did they have to take to pass reading the study. And this is all based
upon a lot of the stroke trials that we do where everybody has to know
how to use an NIH stroke scale score, etcetera. And was there anybody
doing over-reads once that individual was deemed to be an examiner?

DR. WEILER: Yes. I\'ll sort of work my way through the questions. I\'ll
give you a little bit of background first. When we initially were
designing the protocol, and looking at how to put this trial together,
we received strong input from the FDA and our scientific advisory
committee to be cautious that we didn\'t end up cooling infants who
didn\'t need to be cooled, who were going to go ahead and do well. The
physiologic criteria for evaluating an infant for HIE are notoriously
not that great at actually predicting outcome.

Adding a strong European component to this, co-PI\'s from Auckland, New
Zealand, and London, it was brought to our attention there was a device
that had been used in Europe for over 20 years that had been shown in
multiple trials to have a strong positive predictive value for HIE
outcome. And it was suggested that we use that to enrich our population
to make sure that we were only cooling infants who should be cooled as
much as was possible with the knowledge at that time. The equipment
available at that time was originally developed and designed in 1983 and
has some limitations to it. It\'s since been replaced with newer
equipment. But at that time that\'s what was available, and we brought
that into the country, and specifically got 510(k) approval for it to
use it for this trial. It had not been used in the U.S. before. So
that\'s sort of how CFM came into the trial, a little bit of that
background.

As far as training goes, the training for the use of this device was
developed by Dr. Dennis Azzopardi at Hammersmith Hospital in London. He
is a very experienced user of CFM, had done some trials himself on its
use as a predictive tool for outcome in HIE, and had a strong interest
in training and use of it, had done some inter-observer variability
testing, and that sort of thing with it, using the protocol that\'s been
described to you, the 10 microvolt/5 microvolt level test.

Also in use in Europe is a different classification which is
considerably more subjective. It requires deciding whether something is
a continuous normal voltage, or a discontinuous normal voltage. And
there are five different levels there. But on discussion between Dr.
Azzopardi and the other folks who use the other method, they found that
actually they agree quite well in classifying these infants, that they
were reasonably interchangeable. It was very attractive to us because it
being a new technology not in use in the U.S. we needed to train each
site on something that they hadn\'t used before to select these infants.
They would generally be doing this at three o\'clock in the morning and
under a fair amount of pressure because of all the circumstances which
we\'ve discussed earlier today.

So Dr. Azzopardi put together this training manual. I can\'t remember
how long it was, but it took about an hour to work your way through the
training manual, teaching you how to recognize normal versus abnormal,
and grade them as a 1, 2, 3, or give them an S for the presence of
seizures. Following that they were then given a test which consisted of
52 traces which they had to then grade as a 1, 2, 3, or assign a seizure
to it. And then we graded those tests separately. They had to mail them
in, and they were graded by Drug and Device Development, who was our
data center at the time. And they were given a score based on their
ability to correctly enroll infants in the trial. And they had to
achieve a 90 percent score on that test to be then qualified to read a
CFM for the trial. This was limited only to MDs. Nurses, although they
could be trained and take the test, they were not allowed to certify a
CFM for the trial. At some sites this was limited to the PI, or possibly
co-PIs at the sites where there would be one or two people, and if there
was an infant to enroll they were called in, and they\'d have to come in
and read the CFM. Other sites would certify 10 or 15 people who would be
able to read it. It simply depended on their particular method of
operation at that hospital. So everyone was certified. Everyone had to
pass this test and go through the training. It was, as you described, a
very simple, straightforward, and easy to apply rule.

Now you asked about the records that were unclassifiable. The equipment
that was used during the clinical trial was a two-channel hot pen
recorder that was recording this trace on a 100-millimeter wide paper.
And it\'s an EEG technique which is notoriously \-- EEG, you have to be
very careful about noise, as you are well aware. And so in some
circumstances, due to the other activity going on with the infant, or
other conditions, the trace would be very difficult to classify. And I
can\'t address those five specifically, I don\'t have them in front of
me, but I would assume that it would have been something along those
lines, that there was either external noise, or muscle artifact, or some
other artifact that was interfering with the recording and their ability
to classify it. But the other thing that could allow an infant to be
enrolled under those circumstances was the presence of seizures. And I
believe that was the case in most of those, if not all of them. In all
of them, yes. It was the presence of seizures that allowed them to go
ahead and be enrolled, even though they couldn\'t be classified as a 1,
2, or 3.

You had another question. Oh, central reading, and why we didn\'t do
central reading. Again, this was originally envisioned as a tool for
enriching our protocol. And it was set up to be used that way. It was
not looked at as a primary sort of outcome criteria the way the Bayley
and neurologic exam was, which is obviously the key to our outcome. And
so, while we certainly paid significant attention to that, and went to a
lot of trouble to make sure that that was centrally read, we did not do
that with the CFM. They certainly could not have been checked at the
time of enrollment as we were under the 6-hour time limit, and being
able to find somebody who was going to be awake in the right time zone
to read it, and then it would have to be faxed which is notoriously low
quality on a paper trace to begin with. It was not felt to be feasible
to do that reading at the time. And at that time, in hindsight, we all
wish we had done more reading of those. But at the time we did not feel
that it would be appropriate to try and do central reading. Does that
address?

DR. JENSEN: It addresses it. You know, just to use a similar trial, like
the ProAg trial, where patients had to have CT scans done prior to being
treated, those CT scans were not looked at by a core lab immediately at
the time, but they were looked at afterwards, and there were CT\'s that
were misread, that when you took them out of the group changed the
outcomes. So I guess my next question would be does the company have any
intention of collecting these EEGs to ensure that the data that\'s
presented here is true and correct by trying to eliminate inter-observer
error. That\'s just one thought.

DR. WEILER: And we have made some attempts to do that. Again,
unfortunately this is a thermal paper, and on going back we found that
some of the records had not been stored in such a way that they were
usable any longer, and so we have not been able to complete that.

DR. HAINES: Thank you. Yes, Dr. Nelson?

DR. GUNN: I just want to make one follow-up. In terms of interpreting
the results, as a backup in the absence of being able to re-interpret
the EEG, we have also done a secondary analysis, which I say definitely
secondary, but it was at the top of my list of things I wanted done
after the primary analysis, which is to replace the EEG criteria simply
with the Sarnat score. And a logistic model with only treatment and
Sarnat score will get essentially the same result as with the 6-factor
regression.

DR. JENSEN: So would it be the intention that if the product were to be
approved, that having the EEG will not be an enrollment criteria?

DR. GUNN: That is correct. We would \-- we clinically would recommend
using either the aEEG or something similar in order to gain experience,
because it does provide potentially an objective record, particularly
now with the electronic data capture that I personally believe very
strongly we should be able to capture much more information from the
EEG, and thereby improve recruitment and identification of treatable and
untreatable groups in the future. But at this time we\'re not in a
position to say definitively what should be done.

DR. HAINES: Dr. Hudak?

DR. HUDAK: With respect to the enrichment issue, do you have information
on the babies who were screened because of meeting one of the four
functional criteria, and then the sort of neurological examination
criteria? How many of those babies who might have been screened who were
Sarnat Stage 2 or 3 had normal aEEGs or did not have seizures? I mean,
how was your population enriched?

DR. BARKS: Well, I\'ll try to address that for University of Michigan.
So, we were required to keep a log of all patients that we evaluated for
the trial. And I would say that we probably did not enroll somewhere
between two to three patients for every patient that we enrolled. And
those were babies who were Sarnat Stage 2 whose amplitude integrated EEG
we interpreted as not meeting the criteria of abnormality. Now, I will
say with the benefit of hindsight, knowing as I do now a lot more about
amplitude EEG than I did at the time that I started, it\'s possible
there may have been some artifacts there that confounded, and that there
were children who were not included. But mostly it was kids who had
Sarnat Stage 2 who had a non-qualifying amplitude EEG, and who did fine
in the NICU. So yes, that\'s our own experience. I can\'t tell you about
the other centers.

DR. HUDAK: Okay, thank you.

DR. HAINES: We\'re really \--

DR. JAYAM-TROUTH: Can I ask?

DR. HAINES: We\'re really running into some time problems. We have to go
over all the FDA questions. So if it\'s essential to the decision-maker
that we\'re going to have to make, yes.

DR. JAYAM-TROUTH: Well, one more thing about the EEG. I need to make
some clarifications too. Okay, one is for the cortical \--

DR. HAINES: We\'re coming back. You\'ll have another chance.

DR. JAYAM-TROUTH: For the aEEG then, how do they differentiate between
Level 1 and Level 2? Sleep/wake cycles present and not present.

DR. WEILER: There were three levels that were identified for the trial.
There was Level 1 where you had a lower margin above 5 microvolts, an
upper margin above 10 microvolts. There was no reference to sleep/wake
cycling in that. And that was considered to be normal whether sleep/wake
cycling was present or not. A Level 2 was when the lower margin dropped
below 5 microvolts, and the upper margin was still above 10 microvolts.
And then Level 3 was if the upper margin dropped below 10 microvolts,
and then it didn\'t matter what the lower margin was. That was
considered a severe Level 3.

DR. JAYAM-TROUTH: Okay. So you didn\'t use the sleep/wake cycles that
you described in here?

DR. WEILER: No. That\'s a subdivision up in normal and very mild. It was
not part of the trial.

DR. HAINES: Thank you. Dr. Jensen.

DR. JENSEN: One other quick question. I know that the babies had 72
hours of cooling, and I assume that comes from the animal data. But you
know that when things get out into the real world, you know, if 72 hours
is good, 96 hours may be better. Is there a way that \-- first of all,
is there any data to support or not support that 96 hours may be better
or worse, and is it possible to make the equipment such that the cooling
is terminated at 72 hours and cannot go further?

DR. GUNN: Starting with the scientific question, it is unfortunately an
easy question to answer. Nobody has ever done a study like that. I\'m
certain from my own data, from published data, that 24 hours is less
good than 48 hours-plus. We get very impressive rebound, cytotoxic
edema, rebound seizures, rebound deterioration if we stop earlier than
that. It is possible that 96 hours is better than 72. I don\'t know.
John has recently suggested that perhaps in fact this might even be an
individual thing. It is certainly clear that the optimal duration
depends on the severity of the initial insult. The more severe the
initial insult, the later you start, the harder you have to cool, and
the longer. So it\'s possible that there may be a subpopulation on whom
96 hours, 120 hours might be better. I don\'t know, and we would not
recommend it at present.

DR. HAINES: Thank you. Dr. Brott.

DR. BROTT: Actually this is not a question. Does anybody have this
5-page CRF on a computer that I could look at from the 180 \-- you know,
the 18-month visit?

DR. HAINES: Okay. We\'ll \-- our remaining task in the next hour is to
go through the FDA\'s seven questions which will focus our discussion.
However, I did promise that we\'d come around again. So please limit
your questions now to things that are essential to answering the
questions and arriving at a conclusion at the end of the day.

DR. CLARK: Are they going to put the questions up?

DR. HAINES: We\'re doing another round of questions prior to doing the
FDA questions. They\'re getting ready.

DR. CLARK: Okay. Very simple question. I think in your original
manuscript you had site in the logistic model. I know that site had
small numbers, but in the big sites where you had lots of enrollment,
was the outcome consistent across those large sites, or was there
heterogeneity in that?

DR. GUNN: Basically yes. There was no effect between large and small
sites. There was no apparent effect on the Bayley \-- those scores,
across the larger sites either.

DR. HAINES: Yes, Dr. Jayam-Trouth. Passes to Dr. Ellenberg, but will
pass back.

DR. ELLENBERG: Now that I fully understand the analytic approach, I
would like to address the issue of multiple testing. As I understand it,
the first submission by the sponsor was sent to FDA with the logistic
regression as the primary analytic approach using three of the
covariates. And the p-value for that particular regression was 0.053.
Then I take it FDA asked that the covariates be added to, so that there
would be six covariates in the model. And then we got the answer 0.042
for the logistic regression. Further, for reasons that I don\'t fully
understand, the Fisher exact test was used in addition to the logistic
regression, which is another test of essentially the same hypothesis. So
what we have here is a marginal significance level of P = 0.042, and we
have three tests done for the same endpoint. So my question is should
not we be penalizing this result, or requiring a higher level of
p-value, or alpha, because we did these three tests, rather than just
one test?

DR. LIU: My understanding of the multiple testing is typically you would
be either testing it in different subsets, or looking actually for
different endpoints. And this is the, as you said, for the same
endpoint, analyzed in three different ways. I believe the Fisher\'s
exact was for so-called the unadjusted analysis, not adjusting for
baseline imbalance. So that\'s the Fisher\'s exact result. As presented
that there were some baseline imbalance, and some key factors.

And the second three-factor logistic regression in our mind is a
misunderstanding that FDA didn\'t think that was a valid model, that
actually three other factors should be added to the model. And that was
not based on having looked at the data, but was based on external input
from FDA saying that the full model should have these six factors. So
that was the one that\'s regarded as the definitive logistic regression.
So basically there are really two approaches. One is the Fisher\'s
exact, and the second one was the six-factor logistic regression. The
difference between the two was that the Fisher\'s exact did not account
for baseline imbalance, whereas the six-factor logistic regression did.

DR. HAINES: I\'d like the FDA response to the same question.

DR. CHU: Basically I agree with Dr. Liu\'s opinion about this. It\'s not
kind of data judging here, trying to pick the covariates they like or
not. And actually, also \-- logistic regression the sponsor did, just,
result in additional three covariates there. If I just put Sarnat score,
multiple imputations result is consistent with what the pre-specified
covariates in the implementation model. So, according to my multiple
imputations model, looks like just no difference whether or not you have
pre-specified covariates, or you just use Sarnat score.

So I tend to believe in if it\'s clinically important, I believe more in
the logistic regression model rather than Fisher\'s exact test because
this is \-- although it\'s a randomized trial, but imbalance in some
covariates, important covariates, occur by chance. This is a small size
study, so to me I agree with sponsor\'s additions.

DR. HAINES: The issue of the pre-specified test. I mean, the protocol
clearly specifies the three-factor logistic regression. And the result
was provided. And then the six-factor logistic regression was done. So,
I mean I don\'t see how it can be said that the data wasn\'t looked at,
or that it was a pre-specified test.

DR. CHU: What I say is the three additional covariates is suggest, and
as discussed at IDE stage. So, and \-- what you said is right. By
looking at the covariate distribution, you observe additional three
important covariates, looks like they\'re imbalanced there. So based on
that, so we suggest the six-factor model for the sponsors. Rather than
\-- instead of looking further for evidence trying to identify subgroup
analysis. So basically what I suggest at time, I model the whole
population analysis. And whether or not you put additional covariates
there, to me the difference is not so much. 0.05 versus 0.04, to me as a
statistician, I don\'t see the big difference.

DR. HAINES: Thank you. Dr. Jayam-Trouth.

DR. JAYAM-TROUTH: Okay. I have some comments. First of all for the
visual \-- cortical visual deficit. The best test is the visual evoked
response. And that is really much more finite than the gross testing of
whether the pupillary responses are present, whether the child fixates
or the child follows. So I think that we could use better tests to
identify that.

Secondly, learning disability cannot be determined until the child is at
least about five years of age. And this \-- we cannot tell whether or if
the child will or will not have learning disability.

Thirdly, the most common problem that you see with hypoxic ischemic
encephalopathy is PVL, periventricular leukomalacia. There\'s really no
imaging study at all at any point to show whether or not there was a
difference, and whether there were greater numbers of PVLs present or
not present in these patients.

And there is no question in my mind that if you intervene early, the
brain is plastic. The younger the brain, the more plastic it is. If you
intervene early, you can modify results. Maybe not in the very severe
forms of HIEs, but certainly there is a difference when intervention is
carried out.

DR. HAINES: Thank you.

DR. BARKS: Can we respond?

DR. HAINES: I didn\'t actually hear a question, but yes, you may.

DR. BARKS: Okay. If you don\'t want a response \-- no. The
periventricular leukomalacia is predominantly a neuropathology of the
premature infant, although it can also be seen in term infants,
particularly term infants with cyanotic congenital heart disease. So it
is not the predominant neuropathology, and it\'s not predominantly
what\'s found in neuroimaging in infants with \-- in term or near-term
infants with hypoxic ischemic encephalopathy. We see either global
injury, or we see cortical, subcortical, predominantly either widespread
or in a bilateral watershed distribution, or we see a predominantly
basal ganglia pattern. And so PVL would not be an issue in these
infants.

Routine neuroimaging was not specified as part of the protocol. Many
neonatologists in this trial undoubtedly did neuroimaging because
that\'s part of our practice, I think Dr. Clark would agree, in infants
with hypoxic ischemic encephalopathy. Generally we do neuroimaging as a
way of helping us to make prognostic statements to families. And that
was the case in the majority of patients in our center. But PVL is not
the predominant pathology here. And do you want to address the
developmental intervention issue any further, Roberta? No, we don\'t
want to address. We feel we\'ve already responded to that concern once.

DR. HAINES: Thank you. Is there any other member of the panel who has a
burning question before we move on to the discussion of the FDA
questions? Thank you. Dr. Bowsher?

MR. STEVENS: I\'m just going to put the question up because it\'s
lengthy and you\'ve got it in front of you. Unless you\'d particularly
like me to read it.

DR. HAINES: If you\'d like to briefly summarize the question to start us
off, that would be.

MR. STEVENS: Well, why don\'t I read the full question then. Because I
don\'t want to have you misinterpret anything. So the question is that
there was a statistically significant difference between the cooled and
control groups for minor cardiac arrhythmias, 9 percent for cooled
versus 1 percent for controls, and other adverse events, primarily head
and scalp edema or injury, 46 percent for cooled versus 22 percent for
controls. Additionally, although not statistically significant there
were more deaths in cooled infants than controls for four or five days
after birth, 11 cooled versus two controls, and one patient in this
investigation and two patients in the continued access trial that had
onset of seizures after re-warming. And we\'d like you to discuss the
safety of the device in view of these findings.

DR. HAINES: Why don\'t we start with Dr. Brott.

DR. BROTT: With regard to Question 1, and the safety of the device in
view of these findings, I was not particularly concerned about this
being a major safety issue, given how sick these patients were, and
basically the other issues that were involved. And that\'s all I would
have to say.

DR. HAINES: Thank you. Dr. Jensen?

DR. JENSEN: There were no serious adverse events, and the adverse events
that are described in this question are to be expected with the therapy.
So I agree with Dr. Brott.

DR. HAINES: Dr. Nelson?

DR. NELSON: I agree with what\'s been said.

DR. HAINES: Dr. Coffey?

DR. COFFEY: I believe that all of these have been addressed already. So
I have no further question.

DR. HAINES: Dr. Doyle?

DR. DOYLE: I\'m comfortable with the coverage.

DR. HAINES: Dr. Ellenberg?

DR. ELLENBERG: No additional comments.

DR. HAINES: Dr. Jayam?

DR. JAYAM-TROUTH: I agree. I don\'t think there\'s a safety issue there.
I think they have been explained.

DR. HAINES: Dr. Clark?

DR. CLARK: I agree. I just want to make the comment that as this
technology is applied, these deaths and the withdrawal of care is an
extraordinarily important issue in terms of selection. And this was
discussed in great detail at an NIH consensus conference recently, and
it\'s very important for that piece to be a part of the label as we move
forward.

DR. HAINES: Thank you. I would summarize the panel\'s response as not
having significant concerns about safety with respect to this question.

DR. BOWSHER: FDA\'s second question is logistic regression analysis
adjusting for baseline EEG background, seizure status, APGAR score,
birth weight, gender, and age at randomization indicated a treatment
effect of statistical significance of P = 0.042. Additionally, the
sponsor performed an analysis in which they excluded patients with a
severe aEEG background in seizures from the analysis. Based on the study
results, please discuss whether the use of the device should be limited
to a particular subset of the HIE population. For example, gestational
age, weight, size, aEEG, etcetera.

DR. HAINES: Let\'s start with Dr. Clark.

DR. CLARK: Okay. I do think there need to be limitations. They\'ve
already outlined the gestational age limitation. In general, my opinion
is that the label should reflect the clinical trial in detail. I think
we\'ve heard lots of concerns about the use of the aEEG, and there needs
to be consideration for the Sarnat score as an alternate way of
identifying this. And I\'d very much like to hear from my obstetrical
colleague about how this is going to be coordinated between perinatal
and neonatal medicine because I think many of the events that we end up
treating are not acute perinatal events. And I think that the label
should reflect some way of identifying the sentinel event going forward.

DR. HAINES: Dr. Jayam-Trouth?

DR. JAYAM-TROUTH: I agree with Dr. Clark. There has to be certain
limitations. Label should contain that.

DR. HAINES: Dr. Ellenberg?

DR. ELLENBERG: I\'m not sure we\'re being responsive to this question
exactly. Can I be refreshed for a moment? Was this sub-analysis, did it
show the difference as statistically significant when the subgroup was
looked at between the control arm and the cooling arm?

DR. CLARK: Yes. In the subgroup, the original subgroup analysis where
you pulled out the aEEG severe patients, not by Fisher exact, but by
logistic regression.

DR. ELLENBERG: Then the cooling versus the non-cooled? There was a
beneficial?

DR. CLARK: Is that right?

DR. HAINES: There was a stronger relationship.

DR. ELLENBERG: But it was statistically significant?

DR. HAINES: Statistically significant. Into the microphone, please.

DR. CHU: According to the likelihood ratio test, to assess whether or
not treatment effect differed across the three subgroups, the overall
test, the p-value is 0.10 by logistic regression.

DR. ELLENBERG: Okay. But what about the individual comparison?

DR. CHU: If you look at separate for the pooled population, and also
separate for the worst, in the pooled one you have a large sample size,
about almost 80 percent total patients. For that pooled best
intermediate subpopulation, without any adjustment for multiplicity, the
Fisher test I remember is 0.02, and the logistic regression is 0.01. But
my point here, because overall treatment effect and interaction effect,
treatment by subgroup does not give us enough evidence to do further
analysis among each individual subgroup. So I would \-- statistically, I
would not agree with the subgroup findings as conclusive here.

If you look at the worst subgroup between the cooled and the control,
the direction of the treatment effect is in opposite, compared to the
subpopulation. And if you look into the details, in the worst prognosis
subgroup, actually you have a much higher percentage of failure in the
cooled treatment compared to the control. So I don\'t see why we have
opposite direction. So that\'s kind of a warning sign about subgroup
analysis.

DR. ELLENBERG: Then let me respond personally to this question by
saying, in general, we don\'t like to see subgroup analysis, post hoc
analysis, thought about after the design of the trial drive
recommendations. However, that\'s not to say that panels before us and
panels after us might not see something in the data, with or without
statistical analysis that makes it concerned and would want to pose a
limit.

So my problem is the first part of the question does not lead to the \--
I\'m sorry, the first statement on Question 2 does not immediately lead
into the right question. If we strike the first part of the question, my
response would be that based on what we\'ve seen, I don\'t see as FDA
has responded, any evidence that this particular subgroup should be
broken out in the labeling. But that\'s a statistical issue. We\'re into
subgroup analysis, and this may not be dispositive.

DR. HAINES: Okay. Dr. Hudak?

DR. HUDAK: I guess I\'m having a little problem with this question too,
because I think it\'s worded in such a way that it presupposes that
we\'ve established efficacy. And that\'s Question 5 or 6. I\'ll take a
slightly different tack here. I guess I have some \-- let\'s presume
efficacy. Let\'s presume safety. And now we\'re looking at this issue,
which is really a labeling issue. The question of which babies this
would be used in, or how the label would be written, I\'m sort of
hearing that it\'s going to be written to be based upon the Sarnat
scores, because truly, very few institutions have the ability to do
aEEGs, especially since most of these cases would be occurring in Level
2 or Level 1 nurseries. And the importance of trying to get these babies
started on therapy early would be an issue. But then I\'ve heard two
things. One is that for every baby who is enrolled in this study through
enrichment, there were two or three babies at least in Michigan that
were Sarnat Level 2 that did not have abnormal aEEGs or seizures who
were not studied. So that if you go by the Sarnat, potentially you\'re
going to be enrolling three to four times as many babies as had actually
met study criteria. And that may be an issue for a post approval type of
recommendation for a study.

I don\'t know what happens to normal babies who if you cool their heads,
whether they\'d have better or worse outcomes. I don\'t know if we have
any animal information on that or not. It\'s sort of hard to do a Bayley
on an animal. But nonetheless, I think there are very few numbers in the
Sarnat 1 group, and I agree we can\'t draw any conclusions there, but
one can\'t be 100 percent assured that using this therapy in that group
of patients is going to be completely harmless either. So I think \--
you know, the issue here I\'m struggling with is I think that the
analysis as it came out initially was a P = 0.01. That\'s just the gross
analysis without any corrections for any of these factors.

I have issues with the aEEG, because we don\'t have a standardized
assessment put into the model for the analysis for the logistic
regression. As I understand it\'s just from the sites. There might be
differences if it were centralized. I have an issue with using APGAR
scores in analysis, because APGAR scores are not linear, and I\'m not
sure how the logistic regression corrected for that. So in other words,
I think there\'s a difference between a baby who has an APGAR of 3
versus 5. That difference is clinically different than the difference
between a baby who is a zero versus a 2. So, you know, a difference of 2
in the APGAR doesn\'t correspond to the same delta and clinical
severity, if you will.

So I think, you know, we\'ve got this six model analysis, which shows
0.042, which I think has some issues. We have an initial analysis of
0.1. We\'ve got other analyses with the initial three of 0.053, which I
think is \-- can be questioned on the basis of the standardization of
the aEEGs. That\'s not to say that I think we need to hold this therapy
to a P = 0.05 for efficacy. But I think it does raise some issues.

DR. HAINES: Thank you. Dr. Doyle?

DR. DOYLE: I guess thinking as a consumer rather than as a scientist,
everything I\'ve heard today makes me think that the overall
risk/benefit is far in favor of the risk and the lower benefit. And
we\'re torturing it, as I think Dr. Ballard said, with statistics down
to nitpicking. And I think from a consumer point of view, that goes
beyond what we are supposedly being asked to decide in the panel.

DR. HAINES: Dr. Coffey?

DR. COFFEY: Yes, I don\'t have much to add other than what\'s already
been said on this topic. I think it\'s been studied in a certain
population according to gestational age and weight, and it was discussed
that low birth weight babies might speculatively be already somehow
immunized or resistant to HIE. So I think labeling should reflect the
study population.

DR. HAINES: Thank you. Dr. Nelson?

DR. NELSON: I agree with what both the previous three speakers have
said.

DR. HAINES: Thank you. Dr. Jensen?

DR. JENSEN: I just point out that in the response to one of the FDA
questions, the company said in addition there seemed to be no effect or
possible worse effect in patients with Sarnat 1 who were treated. So I
agree with the previous four speakers that essentially who you need to
treat are the people that you studied.

And in terms of Dr. Doyle\'s question, or remarks, I think that it
sounds like this EEG device is something that could be made readily
available, and if it is as simple to interpret the study, if there are
places that have nurses actually interpreting the data, this is
something that can easily be done even at community-level hospitals.

DR. HAINES: Thank you. Dr. Brott?

DR. BROTT: I agree with everything except that last couple of
statements. I think EEG in newborns, it\'s very difficult, very
difficult. And it\'s not there already, and I don\'t think you\'re going
to sell community hospitals on an EEG system. Time is brain. It was very
impressive to hear today how these families got in so quickly. And I
think to give residents in the middle of night, or nurses reading a new
EEG method, in fact trying to tease out the best patients is going to be
tough. And for clinical reasons therefore I wouldn\'t limit it. And
we\'ve heard the warning signs from Dr. Chu and Dr. Ellenberg with
regard to limiting it on the basis of statistics. So I would not limit
it.

DR. HAINES: Thank you. I would summarize the panel\'s discussion as
saying that there is no evidence that makes the panel believe that there
should be further limitations placed on the target population, and that
the labeling should reflect the patients who were actually studied in
the study.

DR. BOWSHER: FDA Question Number 3. It was noted during the trial that
due to several reasons, one being the patient population being treated,
it was difficult to maintain the target temperature range specified in
the study protocol. That is, 34.5 degrees Celsius +/- 0.5 degrees
Celsius for the cooled group, and 37 degrees Celsius +/- 1 degree
Celsius for the control group for the complete treatment duration of 72
hours. Please discuss any potential safety and/or effectiveness concerns
raised by these findings, and whether the instructions for use should be
modified to include more detailed guidance for maintaining proper
temperature.

DR. HAINES: Thank you. Let\'s start with Dr. Nelson.

DR. NELSON: My impression is, at least from the graphs that were shown,
based on the research system, which my understanding is that the
commercial system is designed in a way that provides trending such that
the graphs that were shown of wide fluctuations hopefully could be
anticipated that a trained and hopefully skilled clinician ought to be
able to use the temperature control in a way to prevent those
fluctuations, or at least mitigate them.

DR. HAINES: Thank you. Dr. Jensen?

DR. JENSEN: I agree.

DR. BROTT: I agree.

DR. CLARK: Those graphs scared me. I\'d like to see graphs that show
that you can get those things in order. I also would be interested in
why there\'s not a feedback system that shuts off when it gets too low.
There ought to be some system, and going back up may be just as bad. So
I\'d like to hear a comment on that.

DR. WEILER: The system is designed to provide significant audible and
visual alarms when you go outside the range of the +/- 0.5 degree C.
That would be similar to other NICU alarms, and so the clinicians can be
quite aware that they\'re out of range. It\'s a significant alarm. But
it will not shut down the system in that way. The only things that will
shut down the system would be a system failure of some sort.

DR. HAINES: Thank you.

DR. WEILER: Yes, I\'m sorry. The temperature is always controlled by the
clinician. We can\'t control the radiant warmer, so we have no close
control of the system. So it\'s always under the clinician\'s control.

DR. JAYAM-TROUTH: From that point of view I think that couldn\'t the
machine nowadays with so much computerization, couldn\'t the machine
read the temperature, cool temperature, and automatically adjust, and
then make sure that you don\'t fluctuate too much? Because from what I
see, it\'s the first 24 hours that there\'s a lot of fluctuations
that\'s occurring, and then the control system seems to work better.

DR. WEILER: The system isn\'t the only thing that\'s affecting the
patient\'s temperature. It\'s a delicate balance between the radiant
warmer input to the patient, and the system\'s cooling. And in order to
do a complete closed loop servo control of that we would need to have
control of the radiant warmer.

DR. BARKS: I think those of us who are clinicians who\'ve had to manage
babies in this system would add that there are patient variables
independent of either the radiant warmer or the cool care system
themselves that can have a major impact on thermoregulation, such as
whether the baby\'s having subclinical seizures, whether you just gave
them \-- or clinical seizure \-- whether you just gave them
Phenobarbital, which apparently may decrease brain metabolism, lead to
drops in temperature. So there are other things contributing that are
outside of the control of the feedback systems, that you could deal with
with a servo controller.

DR. JAYAM-TROUTH: Well, I see that this is a problem from my point of
view in the sense that it\'s not really being regulated well. And if you
really say you\'re going to go +/- 0.5, you know, that\'s a fluctuation
that you\'re allowing, then in that case I think the device falls short
of that. And I think that the manufacturer should possibly look into,
you know, into making the device better so that these fluctuations can
be addressed.

DR. WEILER: Yes, and that\'s what we\'ve tried to do with the displays,
and the additional alarms, and the user input and feedback, so that if
they go outside the alarms, they are given recommendations on what to do
to overcome those. But we\'ll continue.

DR. HAINES: Dr. Ellenberg?

DR. ELLENBERG: No further comments.

DR. HAINES: Dr. Hudak?

DR. HUDAK: Is it fair to say that if this goes forward that there will
be some sort of a partial closed loop system developed to facilitate
better temperature control, number one. And number two, I find it as it
is pretty acceptable. I mean, I think that our ability to regulate with
our current servo control systems babies\' skin temperatures within the
prescribed range is subject to as much variability at times. And the
third thing I point out is that bottom line is the outcome in the cooled
group was superior to that in the non-cooled group, and that\'s really
the bottom story.

DR. HAINES: Dr. Doyle?

DR. DOYLE: I have nothing to add.

DR. HAINES: Dr. Coffey?

DR. COFFEY: Yes, I have nothing unique to say other than that these were
addressed in more than 25 pages in Attachment 9 in response to FDA
letter. So this has been done to death, I think, the issue of
temperature control.

DR. HAINES: Thank you. I would summarize the panel\'s discussion as
suggesting that the system as it performed in the study seemed
reasonably safe in that there are not strong concerns. However, there
appears to be room for improvement, and some interest in the possibility
of more automated temperature control.

DR. BOWSHER: The fourth FDA question. The sponsor has provided draft
labeling for the device which includes indications for use,
contraindications, warnings, precautions, and instructions for using the
device. Please discuss whether the device should be further limited in
its use. For example, time of cooling start, duration of cooling, degree
of cooling, and whether any additional information should be included in
the labeling.

DR. HAINES: Let\'s start with Dr. Coffey.

DR. COFFEY: For me this is almost \-- or very similar to the kind of
question as Question 2. It\'s been studied in a certain population over
a certain time period, and I think we should stick to that.

DR. DOYLE: I agree. I think it should be noted that there is no data
available for use after 72 hours that substantiates it should be used
beyond the 72 hours.

DR. HUDAK: I agree. I think the labeling should reflect this, and
clearly if this is approved there will be all sorts of studies done to
optimize all of those variables.

DR. ELLENBERG: No further comment.

DR. JAYAM-TROUTH: I agree.

DR. CLARK: No further comment.

DR. BROTT: I was wondering if I might be able to persuade the panel that
on this particular point to consider a statement if this device is
approved, and there is a label, that we mention either before or after
the time threshold that while such and such is the time that you can do
it, every minute counts for the brain, and you should do it as quickly
as possible. And we could word it some way like that.

With TPA, you know, the label said three hours. And everybody waits to
give it until three hours. And frankly I\'d like to get it, particularly
if you know, maybe I can get Dr. Jensen over there right away. But
certainly I think she would agree in our experience with the brain in
adults is that every minute counts. And I think that that deserves to be
on the label. It\'s not supported by the data that we have. The study
wasn\'t addressed to look at time. But I would like the members of the
panel to \-- or try to persuade you to include such a statement if it\'s
approved.

DR. HAINES: Dr. Jensen?

DR. JENSEN: Dr. Brott are you suggesting that IATPA before three hours
is appropriate therapy?

DR. BROTT: I knew you would read the tea leaves.

DR. JENSEN: I agree that the labeling should reflect the patient
population. I think a statement is fine, but I really don\'t know that
it needs to be in the labeling. I think that\'s going to be something
that hopefully we\'ll discuss a training course at some point in time
here, that will be hammered home in the training course for the users of
the device.

DR. HAINES: Dr. Nelson?

DR. CLARK: Just as a quick comment from the neonatology side. Our
problem is just the opposite. We tend to adopt and use it more
indiscriminately than what the label says. And that\'s just the nature
of neonatology. I don\'t know that you need to encourage \--

DR. BROTT: Oh, I just meant the sooner the better.

DR. CLARK: Right.

DR. BROTT: That\'s all I wanted to.

DR. NELSON: If I could ask just a quick question of clarification first.
Are we referring to the operator\'s manual as the label in this case?
Because \-- yes? Well, I\'ll point out the operator\'s manual has
absolutely nothing in it that we\'ve been talking about as far as
specifying things like Sarnat scores. I mean, the indications for use is
basically a very general sentence about at risk for. And unless there\'s
a lot more clarity and specification of that, this will get applied to
anyone with APGAR score of less than 6. I think that everything we\'ve
said I agree with, but I see nothing in the current labeling that says
anything at all about what we\'ve been talking about. All of it\'s about
how to use the machine and use it safely on anybody, except for that
general statement.

And if I can then \-- there\'s no question here that pertains to the
brochure that\'s for advertising. And I\'m of the bias that physicians
will read the brochure and not the label, necessarily. So may I have
permission to make a couple of comments about the brochure? It\'s not
clear to me that the phrase \"prevent or reduce\" is really accurate.
It\'s not clear the data suggest prevention, given the variability of
this condition. And as I read this brochure, it sounds like this is a
miracle cure, as opposed to something that\'s basically we\'re debating
a 0.043 between 46 percent versus 38 percent. And I also would take
issue with this notion, and I hope most neonatologists would, with the
implication that everything we\'ve been doing up till now has not made a
difference. Because I suspect if we didn\'t have a ventilator, didn\'t
have dopamine, dobutamine, or whatever, in fact these patients, many of
them would have died. So I think the brochure is misleading, and will
propagate inappropriate use. Just to put that on the record.

DR. HAINES: Dr. Coffey?

DR. COFFEY: Yes, I don\'t believe the advertising or marketing brochure,
or the operator\'s manual really are anything that resembles labeling.
But there are sections in the SSE that look like indications for use,
contraindications, warnings, precautions. And so maybe if those of us on
the panel look in those pages, the SSE starting on Page 2 through Page 5
maybe.

DR. WEILER: And those would be included in the operator\'s manual, the
indications for use, contraindications.

DR. PROVOST: Dr. Haines? Miriam Provost with FDA. I just want to explain
that obviously this labeling, we\'re coming to you with the labeling as
presented by the sponsor. And as part of our process with any
application, if we\'re moving towards approval we will work very
interactively with the sponsor to write a labeling that includes a
summary of the clinical trial results. And I guess what we\'re trying to
ask in this question, are there any particular warnings,
contraindications, things that you believe based on your review of the
data you think should be included in the label. And I guess that\'s kind
of what we would like with this question, not so much a critique of the
labeling as presented by the sponsor.

DR. HAINES: All right. With that clarification, does anyone on the panel
have additional comments they\'d like to make on this question? Then I
would summarize the panel\'s responses as suggesting that the final
labeling should clearly indicate the indications and contraindications
as they were applied in the study, and that there was a specific concern
expressed about emphasizing that the lack of information about cooling
for longer than 72 hours.

DR. PROVOST: Thank you.

DR. BOWSHER: FDA\'s fifth question. 21 C.F.R. 860.7(d)(1) states that
there is a reasonable assurance that a device is safe when it can be
determined that the probable benefits to health from use of the device
for its intended uses, when accompanied by adequate instructions for use
and warnings against unsafe use, outweigh any probable risks. Please
discuss whether the data in the PMA provide a reasonable assurance of
safety.

DR. HAINES: Dr. Hudak?

DR. HUDAK: Yes.

DR. HAINES: Dr. Ellenberg?

DR. ELLENBERG: Yes.

DR. JAYAM-TROUTH: Yes.

DR. CLARK: Agree.

DR. BROTT: Agree.

DR. JENSEN: Yes.

DR. NELSON: Yes.

DR. HAINES: I would summarize the panel\'s discussion as yes.

(Laughter)

DR. BOWSHER: FDA\'s Question Number 6. 21 C.F.R. 860.7(e)(1) states that
there is a reasonable assurance that a device is effective when it can
be determined based upon valid scientific evidence that a significant
portion of the target population through use of the device for its
intended uses and conditions of use, when accompanied by adequate
directions for use and warning against unsafe use, will provide
clinically significant results. Please discuss whether the data in the
PMA provide a reasonable assurance of effectiveness.

DR. HAINES: Dr. Jayam-Trouth, would you like to start?

DR. JAYAM-TROUTH: Okay. I guess I\'ll take a swing at it. Well, to me I
would say that maybe our data showed that clinically significant
results, I\'ll say clinically promising results. And I\'d say based on
that, yes, there\'s enough evidence that there is some promise in the
device, and therefore I\'d say, you know, I\'d agree with the statement
that there is a reasonable assurance.

DR. HAINES: Thank you. Dr. Clark?

DR. CLARK: Based on my experience with drugs, I would say that the trial
as designed did not show efficacy. And the investigators clearly state
that in their results of their paper. The subgroup analysis as suggested
is promising, and I\'d be interested in the other people\'s opinion.

DR. HAINES: Dr. Brott?

DR. BROTT: I was concerned that at seven days the two populations were
identical, and that the differences were driven by what happened after
that. I\'m reassured that mortality is a hard endpoint, and it\'s tragic
when death occurs at any time, whether it\'s before or after seven days.
However, we saw today, this morning, the passion of parents when
involved in a trial such as this one. And it\'s understandable,
certainly as a physician and as a parent. And therefore, at 18 months I
think that it\'s necessary to take every precaution with regard to the
tools that are used to eliminate the possibility of assessment bias. A
2-page questionnaire was taken from the parent at the time that the
assessment was taken out. I did look at the CRFs. And by what I was told
today, I\'m not persuaded that bias was minimized at the 18-month
assessment. And I would agree with the comment that was made about the
Lancet publication, and the conclusion by the investigators. And
therefore I further agree that the results are clinically promising, but
I\'m not persuaded they are clinically significant, and am also
concerned with some of the biostatistical comments made by Drs.
Ellenberg and Chu.

DR. HAINES: Dr. Jensen?

DR. JENSEN: I agree with the previous comments, and I would just add
that since it seems to be most promising again in the subgroup analysis,
that those should be the patients that are included.

DR. HAINES: Dr. Nelson?

DR. NELSON: My take on the discussion of p-values was that basically,
looked simplistically, it was P = 0.1. And then in a more sophisticated
analysis, which struck me that both the sponsor and the FDA agreed that
that was appropriate, brought it down to 0.043. My own view is that the
choice of p-value is as much a moral question as it is a statistical
one. And it needs to be placed in the context of the availability of
options, and of the impact of that on that population. And I guess at
the end of the day I am persuaded that there is an effect to treat, and
whether we put it at 1 out of 7, or 1 out of 12, I\'m persuaded even
absent death that there is probably is an effect to treat.

I am worried at the two margins about the temptation to treat kids that
are severely affected too long, and what that might do about issues of
appropriate decisions about ongoing treatment, or those who are less
severely affected getting treated and therefore being harmed. But that
gets into the accuracy of labeling, and then professional responsibility
in the use of the device, which admittedly the profession is not very
good at. Which I don\'t see as our purview. So \-- at least that\'s my
take on some of these questions.

DR. HAINES: Thank you. Dr. Coffey?

DR. COFFEY: I believe that the sponsors did everything that the FDA
asked in terms of their protocol and analysis. The 18-month endpoint was
agreed upon, there were not supposed to be any endpoints involving
imaging, or advanced electrophysiological tests. The six-factor logistic
regression was actually put upon the sponsors by the agency. There\'s no
suggestion that this device caused any deaths or disabilities. The
mortality time shift within the first week may be a good thing in that
we don\'t have a therapy that appears to increase survivors with severe
disability. So admittedly, although not a home run, this is a
non-invasive, non-surgically implanted device, a physical modality, and
I believe the sponsors have shown that it\'s effective. They followed
the rules.

DR. HAINES: Thank you. Dr. Doyle?

DR. DOYLE: I guess going back to the last one. If we were willing to
take the definition of \"safety\" as being a benefits over risk, I\'m
willing to take \"effectiveness\" in the same way. And I think that they
have shown that, even though it may be a trend that suggests it will
come to significance, even though it isn\'t. I think that the benefits
are substantial.

DR. HAINES: Dr. Hudak?

DR. HUDAK: One of the things we learned last night at our orientation
session for devices as opposed to drugs is that clinically significant
is different than statistically significant. And I agree. I think that
there has been demonstrated a treatment effect for a condition that is
extremely bad prognosis, can\'t communicate how devastated families
become if they have babies with severe disability. It breaks families
apart, may require lifelong therapies and care for the child. So I think
anything we can do that will minimize that cumulative societal burden is
helpful. And my real issues here are going to be identifying the target
population, and identifying what further studies might be requested
after a PMA.

DR. HAINES: Dr. Ellenberg?

DR. ELLENBERG: I would add to Dr. Nelson\'s comments that a p-value has
to be netted out in the light of the disease or disorder that one is
dealing with, and the risk of the treatment. But I would also add to
that that the clinical impact has to be considered in this equation when
you\'re looking at a p-value. So if we were looking at a p-value now of
0.042, and we all believe that that was the case, versus a p-value of
0.053 as originally submitted, if the clinical evidence, if the
difference in the Cool-Cap versus the control was dramatic in terms of
saving lives, or saving debilitation, we might be much more flexible in
the nature of how big a risk we would wish to take that this device
would be ineffective. And that\'s what the p-value is.

Sponsor presented a number of 1 in 7 as the number of patients we would
have to treat, seven patients to save one patient from this endpoint.
That in statistical jargon was a point estimate. That is, the 1 in 7 was
simply an observed rate, without putting any confidence interval on
that. I certainly don\'t know what that confidence interval would be,
but rather than us thinking that you sort of have a 14 percent hit rate,
if that\'s what 1 out of 7 is, it might be a range of anywhere from 1
percent to 87 percent. So the risk ratio is very important here. I think
the general tendency is to look at the magic p-value of 0.05 as
something that has become the standard, but one has to be flexible. And
I think we\'ve all talked about that in one degree or another. However,
it is important that we not sway from that in a way that becomes
arbitrary and capricious. And in the way that these p-values were
presented to us today, I\'m simply not convinced that we know what the
true p-value is. For example, if I argued that the first p-value we saw
was 0.10, the second p-value that we saw was 0.53, although that wasn\'t
really presented to us head on, and the third value we saw was 0.042,
and we really should have adjusted for that fact that we were looking at
this same answer three times. And FDA and the sponsor disagree with me
on this point. But if in fact that were the case, then the equivalent P
= 0.05 might be something like we would need a 0.01 to be statistically
significant because we\'ve looked at this three times. I don\'t know
what the exact value is, but it\'s going to be lower than 0.05. In that
case, 0.42 simply does not come near what we might want to accept as the
appropriate p-value, or the risk of making a mistake in putting this out
there. So I still need to conclude that we, for this particular
question, that we have not seen an appropriate evidence of efficacy.

DR. HAINES: I\'m going to add my own comments, which are sort of a blend
of Dr. Ellenberg\'s and Dr. Nelson\'s. I don\'t think that we have seen
a demonstration that stands up to acute statistical inquiry that there
is a very low risk of making an error of concluding that there is
efficacy here for the reasons that Dr. Ellenberg stated. On the other
hand, we\'re dancing around a level of assurance that I believe is
adequate to meet the criterion of clinical significance as opposed to
statistical significance, given the high degree of safety that\'s been
demonstrated with the device.

I would summarize the panel\'s discussion by saying that there is a
predominance of opinion that clinical significance has been
demonstrated, although the magnitude of that impact, and many of the
subtleties and finer issues around it have not been clarified.

DR. BOWSHER: FDA Question Number 7. A reasonable assurance of safety and
effectiveness as defined in Questions 5 and 6 must be demonstrated for
device approval. If you believe the data in the PMA demonstrate a
reasonable assurance of safety and effectiveness, but think there are
specific focused questions regarding this device that still remain and
can be addressed in a post-approval study, please identify those
questions.

DR. HAINES: Let\'s start with Dr. Jensen.

DR. JENSEN: I believe that we have a reasonable assurance of safety and
effectiveness. In terms of specific focused question, the one that I
would want to see identified is that if it ends up that patients are
selected based upon some other criteria besides that that was used in
the trial, that there has to be some way to assure that we are not
including or excluding appropriate candidates. For example, if you
choose to go with the Sarnat score as opposed to the aEEG, that there
will not be patients that will be placed at risk, or patients that may
end up being excluded who would otherwise have been treated if the
criteria outlined in the trial are not used.

DR. HAINES: Dr. Brott?

DR. BROTT: I was very impressed with the study on durability that is
being pursued. I think that\'s a great idea. Of course, the problem is
retention, finding the patients from this study, and in any further
study retention. I\'m not convinced that things are quite so simple with
the brain as being bimodal was just \-- you know, they\'re either this
way or that way. I think the brain\'s a little bit more complicated than
that, and hopefully you could find that out in others.

The other is my big problem with this was what happened after one week.
And bias, and you know, ascertainment. It\'s tough to look at these
patients, and of course, now we\'re in a new century, and we\'ve got
wonderful tools to look at the brain. And you know, if you \-- and we
couldn\'t anticipate it for this study, but for the future, if one were
able to come up with some modern imaging correlates to what you\'re
finding in a 5-page questionnaire, you know, wouldn\'t that be nice for
all of us to make our job so much easier, and to learn more about this
condition, which again I think is much more complicated than the
submission would indicate, but you know, that\'s where we are with the
data. So I think that\'s one very wide open area for research, and I
think that the NIH would be receptive to creative proposals along that
line.

DR. HAINES: Dr. Clark?

DR. CLARK: I think in the materials that were sent to us there was a
discussion about Vermont Oxford considering setting up a registry of
information about these infants as they\'re treated. I would suggest
that the sponsor look very carefully among the sites for sure that have
been enrolling in their own trial, and establish some type of \-- as you
have the continuance study. You have 55 patients within that study, and
the mortality in that group is 18 percent, if I read that number
correctly. And so you\'re already beginning to see that just based on
that kind of gross measure of severity of illness, you\'re using the
device in those centers, that patients who don\'t have the same
mortality rate as you\'ve studied. And so understanding those outcomes
and looking at factors that influence those outcomes is going to be
essential. Coming up with better definitions about who benefits from
this therapy. That would be the only question that I would encourage you
to do.

DR. JAYAM-TROUTH: Yes, I think there is a reasonable assurance of safety
and effectiveness, but I think it has been shown in a subset in the
population. And I think that at this time you have to be able to do
subset populations in which the device is being used, and we should
probably standardize how it\'s going to be used, which infants will be
selected, the basis for selection. And I think long-term outcomes should
be followed through. We\'ve got to study the population more. We have to
analyze this and see which subpopulation probably would most benefit
from this, and not have every neonatal baby with an APGAR of 6 end up
with a Cool-Cap.

DR. HAINES: Dr. Ellenberg?

DR. ELLENBERG: No comment.

DR. HAINES: Dr. Hudak?

DR. HUDAK: Well, I find I can\'t answer this question unless I know
exactly how the label is going to be written in terms of which babies
are eligible for this therapy. So until we have that identified, I
can\'t answer the question. If we\'re talking about babies who Sarnat 2
or Sarnat 3, and that\'s going to go on the label, as opposed to aEEG
sort of enrichment of Sarnat 2 and 3, then I think it\'s mandatory in a
post-study approval that there be a randomized control trial of babies
with Sarnat 2 or 3 who have normal aEEG findings, and no seizures, who
are the unenriched babies, if you will, and see what their outcomes are
with or without this therapy. Because I think that\'s a significant
number of babies from the Michigan experience, and those babies weren\'t
studied in this particular protocol.

If it\'s going to be a label that says you have to have exactly the
entry criteria, and the enrichment sort of factors that were used to
identify these babies, the real world is that basically clinicians are
going to look at Sarnat 2 and 3 and treat those babies without doing
aEEGs. And I think the same question, the same study, needs to be done.
There may be others, but I think that\'s certainly a need.

DR. HAINES: Thank you. Dr. Doyle?

DR. DOYLE: Nothing to add.

DR. HAINES: Dr. Coffey?

DR. COFFEY: I can\'t think of any specific questions that I would want
to ask. I would like to say that the risk of failure of this therapy is
very different than an actual risk to the patient. And that the only
reason that we\'re at panel and treating this as a Class 3 device is
sort of a coincidence of the regulations and history. So I wouldn\'t
push for a post-approval trial.

DR. HAINES: Thank you. Dr. Nelson?

DR. NELSON: Because I share Dr. Hudak\'s concerns for the infants who
may not be severely affected then receiving this therapy, but I also
realistically know that once this \-- assuming it is out there being
used, it will be used, and the feasibility then of doing a randomized
trial to where someone who has a low APGAR score and a Sarnat 2 or 3,
even with a normal \-- with the other testing being normal, there would
be a lot of pressure to use it outside of the trial. So I think some
thought would have to be given for more of a dose response type trial,
even if you\'re actually having 24-hour treatment as one of the doses,
which admittedly may well be just effectively a placebo if it was a drug
trial, because there would be a lot of pressure to do something, even
for infants that are mildly affected. So it would be unreasonable to
require a company to do something that\'s in fact not doable just based
on professional practice and public demand. So some creative trial
design may have to be done.

DR. HAINES: Thank you. I would summarize the discussion as indicating
that the panel believes that serious consideration should be given to
continuing study of the durability of the response, that any indications
that were not indications for inclusion in this trial should be studied,
and that further work on clarifying the subgroups who may benefit and
may not benefit is important as well.

Have we addressed the questions satisfactorily?

DR. PROVOST: Yes, thank you.

DR. HAINES: Now that the panel has responded to the FDA questions, we
will have the second open public hearing of this meeting. Does anyone
here wish to address the panel now from the public? If so, please come
forward to the podium and state your name, affiliation, financial
interests, if any, in the device being discussed today, or any other
device. Seeing no one, we\'ll take a 10-minute break and reconvene.

(Whereupon, the foregoing matter went off the record at 3:23 p.m. and
went back on the record at 3:39 p.m.).

DR. HAINES: Well, it\'s 3:40, and I think everyone\'s here so we\'ll
resume the meeting. We next have an opportunity for summary statements
from the FDA and sponsor. Is there any further comment or clarification
from the FDA?

DR. PROVOST: No, we have no further comments.

DR. HAINES: Thank you. Is there any further comment or clarification
from the sponsor?

DR. WEILER: Just to thank the panel. We have no further comments.

DR. HAINES: Thank you. We\'re now ready to vote on the panel\'s
recommendation to FDA for this PMA. Ms. Scudiero will now read the panel
recommendation options for premarket approval applications.

MS. SCUDIERO: The Medical Device Amendments to the Federal Food, Drug,
and Cosmetic Act as amended by the Safe Medical Devices Act of 1990
allows the Food and Drug Administration to obtain a recommendation from
an expert advisory panel on designated medical device premarket approval
applications (PMAs) that are filed with the agency. The PMA must stand
on its own merits, and your recommendation must be supported by the
safety and effectiveness data in the application, or by applicable
publicly available information.

\"Safety\" is defined in the Act as reasonable assurance based on valid
scientific evidence that the probable benefits to health under the
conditions of intended use outweigh any probable risks.
\"Effectiveness\" is defined as reasonable assurance that in a
significant portion of the population the use of the device for its
intended use and conditions of use when labeled will provide clinically
significant results.

Your recommendation for the vote are as follows. Approval if there are
no conditions attached. Approvable with conditions. The panel may
recommend that the PMA be found approvable subject to specified
condition, such as physician or patient labeling, education, further
analysis of existing data. Prior to voting, all the conditions should be
discussed by the panel. Not approvable. The panel may recommend that the
PMA is not approvable if the data do not provide reasonable assurance
that the device is safe, or the data do not provide reasonable assurance
that the device is effective under the conditions recommended or
suggested in the proposed labeling.

Following the voting, the chair will ask each panel member to present a
brief statement outlining the reasons for his or her vote. This was
revised December 10, 2004.

DR. HAINES: Are there any questions from anyone on the panel about these
voting options before I ask for a main motion on the approvability of
this PMA?

DR. BROTT: Yes, I have a question.

DR. HAINES: Dr. Brott.

DR. BROTT: Are the voting options yes/no, or yes/no/abstain?

MS. SCUDIERO: Yes, those options are \-- on any given vote you may vote
yes, no, or abstain.

DR. HAINES: Any other questions? Is there a main motion for either
approvability, approval with conditions, or disapproval from the panel?
Dr. Nelson.

DR. NELSON: I\'ll stick my neck out. Come on you guys, cowards. I would
make a motion for approvable with conditions.

DR. HAINES: Is there a second?

DR. JAYAM-TROUTH: Second.

DR. HUDAK: Second.

DR. HAINES: There\'s a motion for approvable with conditions that has
been seconded. To move this process along, I will now entertain an
amendment of the main motion for the first condition of approvability.

DR. NELSON: The first condition I would like to address specifically the
concerns of the application of this technology outside of what would
hopefully be labeled indications restricted to the population in the
clinical trial, which would be in two directions: those who are less
severely affected, and those who are more severely affected. And
specifically, to request or require, depending on the FDA\'s legal
authority to do either, dose response studies of cooling for those two
populations.

DR. HAINES: So there is a motion \-- correct me if I restate it
incorrectly. A motion for a condition of approvability study of the
duration of pooling, period?

DR. NELSON: Well, I don\'t want to specify period to that level, but for
those that are less severely affected, reference previous discussion of
Sarnat scores, and the EEG. And those who are more severely affected
reference their own sub-analysis that had excluded that group. It may be
that they don\'t respond, or it may be that they need 96 or whatever.
They may need more.

DR. HAINES: So a condition of approvability study on the duration of
cooling for children treated outside of the indications in the pivotal
study?

DR. NELSON: Yes.

DR. DOYLE: Can I have a point of clarification? Can you ask for a study
of off-label use?

DR. PROVOST: Yes, this is Miriam Provost. That wouldn\'t be a
post-approval study because it would be outside the indication. So that
would be an additional IDE-type study. So a post-approval study would be
a study of the indicated population, or if you wanted to do a
registry-type study, that may mean collecting data sort of as it\'s used
clinically, not pre-specifying that you are to enroll patients outside
of the indication.

DR. HAINES: I just want to make it clear, we\'re just trying to get the
motion in order. We haven\'t \-- we\'re not really discussing it yet.

DR. NELSON: I guess I\'m applying the drug world to the device world, so
forgive me. I guess then in terms of a pre-approval requirement, then at
the very least a registry that would look at things. Because I realize
that you can\'t require studies that are off label because that puts you
in an uncomfortable legal position as requiring the company to support
off-label use, which I accept as a criticism. So let me revise it to say
a registry approach to those infants that are receiving it, and I would
certainly hope that then there would be studies done at the discretion
of the sponsor, that these populations would be discussed. But at the
very least, a registry so the FDA can in fact know who\'s getting this,
and then can do appropriate assessment of adverse effects, etcetera,
which is post-marketing assessment which is a difficult area. So I\'ll
revise my.

DR. HAINES: Okay. There\'s a motion for a condition of approvability
registry that \-- there\'s a motion for a registry of all patients
treated to track adverse outcomes, and to track adverse and positive
outcomes. Track outcomes. Is there a second?

DR. CLARK: I would second that motion.

DR. HAINES: And now you can discuss it.

DR. CLARK: In defining the registry, not only would I want to see
adverse outcomes, I would want to see how the technology is actually
applied. Because I don\'t know if there will be internal experiments
that will get at this dosing issue because people will use it outside of
the context of the label. And from that data, there should be useful
information. In particular I would like to see information on
temperature control, and out of bounds measurement, which would again
get back to the usability of the product. In other words, I don\'t know
that I would revise the motion. I would just try to make sure that
we\'re inclusive in that motion.

DR. HAINES: Yes.

DR. JAYAM-TROUTH: I think that as part of the motion, basically we are
limiting its use to the population that has been studied, I presume? In
the motion?

DR. HUDAK: I have a question. In general I support the motion, with the
caveat that registries may get you information on safety and adverse
events. They don\'t get information on efficacy. And as a question I was
wondering whether or not it would be appropriate \-- it would sort of be
useful if we knew from several of the larger centers if it were possible
to go back and identify those children who were screened but not
enrolled because they didn\'t have abnormal aEEGs or seizures, to see
what they\'re neurodevelopmental status is at this point. The reason
being that if, you know, 90 percent of those kids are normal, that\'s a
large population that I think one would have difficulty treating en
masse. And that seems like that would be a population that is three to
four times larger than the population that was studied.

DR. HAINES: I think the question would lead to a second condition of
approval, which we can investigate.

DR. HUDAK: That\'s what I\'m asking.

DR. HAINES: But yes, I think we \--

DR. HUDAK: If that\'s feasible or not.

DR. HAINES: We can come back to that as a motion for a second condition
of approval.

DR. CLARK: Mark, just as a point, I\'ll say I don\'t think so, just
based on our experience with nitric oxide in other therapies. It\'s very
hard to keep up with the patients who were in this study. Trying to go
back and identify the patients who were screened, especially in the era
of HIPAA, for example in the last study we just did we had to take all
the names off even the logs, and they were just counts. It becomes very
difficult. So while I agree with you scientifically, I don\'t think
it\'s practical to try to do.

DR. HAINES: Okay. Back to the motion for a registry as a condition of
approval. Any other discussion or comments?

DR. BROTT: I would just make the comment that the registry, it was
mentioned would primarily get at safety. And I think we already know
it\'s pretty safe. So while I\'m ambivalent on some issues, I\'m just
wondering if we should make that a condition of approval.

DR. NELSON: What the registry would give you, though, is information
about diagnostic use outside of the labeled indications. It\'s an
indirect way of getting at the issue of if it\'s being used
appropriately or not, and allow you to assess that over time. And if you
saw a burgeoning off-label use, then there might be strategies that one
could evaluate for possibly addressing that, at least based on my
experience in the pediatric drug area. I mean, it just provides a signal
that you then say, well, what do we do now. Yes, it\'ll give you safety
data, but it\'ll also tell you, you know, and I agree. The use in the
diagnostic indications, you should know who is it being used on as well.

DR. BROTT: Just practically how do you \-- I haven\'t done a registry
like that before. What do you do \-- the family comes in and you say
that you want to use it, and they have to be in the registry to get it?

DR. NELSON: Yes, there would be a registry form, and then they, you
know, you get into issues about if they say no, I don\'t want to be in
the registry. I mean, you\'d probably give it to them anyway, but most
of them you then have basically a case report form that would be filled
out and sent in to the sponsor, and then you just keep a track of that.
Growth hormone\'s had a registry, there\'s been \-- now if you ask the
drug people, they don\'t think they\'re very effective. But that\'s a
whole different discussion.

DR. BROTT: Who pays for it? It\'s not reimbursed?

DR. NELSON: It would be considered part of the overhead costs, I assume.
I mean, use of the device would be reimbursed, and therefore it would be
part of the overhead costs of the use of the device.

DR. CLARK: There are several volunteer registries that are maintained.
The one that\'s probably the most prominent in neonatology is the Extra
Life Support organization that\'s run out of the University of Michigan.
It\'s a registry of patients who are treated with ECMO. And as
described, it\'s a voluntary system. The member organizations actually
pay for it. It can be supported by sponsor. At Duke there was a nitric
oxide registry. The most valuable piece of it is just to get a sense of
what\'s happening post-market in as scientifically as careful a fashion
as you can.

DR. HAINES: I need to point out that cost is not an issue that we\'re
\-- take on.

DR. BROTT: I understand, but IRBs, does it go through the IRB, and the
reason I ask is if it goes through the IBR there are certain IRB
regulations in terms of how the study is run.

DR. HAINES: I think also the matter of detail of implementation, and
exact content is not something we are supposed to resolve here today.

DR. DOYLE: Again, I come back to the thing. I think what Dr. Nelson\'s
saying is \-- what he\'s basically trying to get at is again off-label
use. And I don\'t think that should be the responsibility of the
manufacturer to keep track of what\'s happening to people whose
physicians are essentially doing off-label use.

DR. CLARK: I would argue that it is to a certain extent, and the reason
is in the pediatric population in particular, there is a tremendous
effort from the government standpoint to try \-- the Best Pharmaceutical
Practice Act is to get at how are drugs being used in children. Now,
this is a particularly neonatal topic, and it does come to the table
with a randomized clinical trial. Unfortunately, it will expand, and I
believe that it\'s all of our obligations, not just the investigators,
but the sponsor, to support ongoing science to make sure that the
technology is used in a reasonable and responsible way. Though they
don\'t control that, understanding that is a valuable piece. And so I
would beg to differ on that, I think.

DR. HAINES: Dr. Coffey?

DR. COFFEY: I think it might be a very different animal, recommending a
post-approval trial versus a registry. Because a post-approval trial is,
you know, we learned yesterday afternoon, is going to be mandatory, and
let\'s say policed a lot more thoroughly than in the past. Registry,
it\'s tough to mandate voluntary participation in a registry, just like
it\'s tough to mandate voluntary reporting from the field of adverse
events in the post-approval setting. So I would just urge caution about
what we\'re recommending to the agency here.

DR. HAINES: Yes.

DR. PROVOST: Could I just make one more clarification? I just want to
explain that with regard to this registry concept, I mean this has been
used before, and the idea is that we\'re not asking the sponsor to
collect data on off-label use per se. We would be doing that if we made
them do a post-approval study on an off-label use with a protocol that
said this is the population to study. I think what I hear being
discussed is the concept of trying to capture information on the device
use in a real world scenario, and an effort to try to understand when a
device is used in a real world clinical setting, does it have the same
safety and effectiveness profile as we\'ve seen in the clinical study.
And that is something that, you know, from the FDA perspective is
appropriate.

DR. HAINES: Dr. Nelson?

DR. NELSON: It occurred to me, just one question for the FDA. Does the
provisions for extension of exclusivity that\'s available in drugs apply
to devices?

DR. PROVOST: No.

DR. NELSON: No.

DR. HAINES: Okay. I would add my own part of the discussion that there
are many good reasons for the registry for on-label use as was pointed
out. And in addition, we in our previous discussion have identified a
degree of discomfort with the magnitude of the therapeutic benefit, and
some of the details. And with release into common use, tracking whether
that changes or not when it\'s in actual use rather than in a trial may
be a valuable effort.

So, in the absence of other discussion we\'re ready to vote on the first
condition, which is as a condition of approval that a registry of all
patients treated with the cooling cap device be maintained. The voting
procedure will be to ask the voting members in response to raise their
hands and hold them up long enough so that we can keep track of who\'s
voted. So all in favor of this amendment, please raise your hand.

(Hands raised)

DR. HAINES: Thank you. All opposed? Abstention?

(Hands raised)

DR. HAINES: The motion passes. With a vote of 6 and 1 abstention. Is
there a second motion for a second condition of approval? Dr. Jensen.

DR. JENSEN: I believe that there should be a formal training program for
the use of this device that all users will be required to go through
this training program, that it include a didactic portion where it\'s
clearly outlined what the indications and contraindications are, the
enrollment criteria, etcetera, that all users also have to undergo an
equipment competency test and show that they can use the equipment
appropriately, and that there be some sort of recertification, or
re-credentialing criteria to ensure that users remain competent in the
use of the equipment.

DR. JAYAM-TROUTH: Second.

DR. HAINES: Second? Any discussion?

DR. BROTT: I think that\'s an outstanding idea, and the company already
has groundwork for carrying this out.

DR. HAINES: Dr. Ellenberg?

DR. ELLENBERG: Do you want to define user? Or leave it at that for FDA?

DR. JENSEN: A user would be any medical personnel who would be involved
in the use of this device at any level with the patient. So that could
include nurses, physicians, nurse\'s assistants, whoever.

DR. HAINES: Any other discussion? Then the motion for second condition
of approval is that there be a formal training program for use of the
device for all users of the device, including a didactic component, a
technical equipment management component, and a recertification
component. All in favor of this motion raise your hands.

(Hands raised)

DR. HAINES: All opposed? Abstentions?

(Hands raised)

DR. HAINES: The motion passes, 6 in favor, one abstention. I\'ll
entertain a motion for a third condition of approval.

DR. JAYAM-TROUTH: Can I ask a question? Is there any reason why there
are only two sizes for the caps? You know, my feeling is that some heads
are big, some heads are small, and some of the heads were getting
squeezed because the caps maybe were too small. And I\'m just wondering
whether the company will reconsider having several sizes of caps so that
they would fit the patients, and if there\'s any changes in the device,
and as new things come on they would update the devices that have been
in use.

DR. HAINES: I\'ve been asked to update the record with the names of the
voters on the two conditions. They are actually identical. And the yes
votes are Dr. Nelson, Jensen, Brott, Clark, Jayam-Trouth, and Hudak. And
Dr. Ellenberg abstained. I\'m sorry.

DR. JAYAM-TROUTH: I had posed a question as a possible condition. You
know, as to why there are no \-- in different sizes for the heads of
babies, they have only two standard sizes that they\'re using, and the
heads actually vary from child to child.

DR. HAINES: I think that the sponsor may be able to clarify that issue
easily.

DR. WEILER: Yes, there are actually three sizes in the commercial
device. There were only two sizes in the clinical trial. We\'ve added an
extra large size to the commercial version, to address exactly the issue
you brought up.

DR. HAINES: Thank you.

DR. JAYAM-TROUTH: One more question. Any changes that you modify in the
software, anything, that will be passed on to the devices that are
bought by people who are using it? Would that be made available, or do
they have to repurchase this again?

DR. WEILER: No, the updates to the equipment, standard updates. If
there\'s a major change in the equipment, but if it\'s a standard update
just to keep it current those are distributed to current users, and
it\'s a simple process of putting a CD in and it updates the system.

DR. HAINES: I would then ask the committee. There were two issues that
were brought up during discussion, one having to do with labeling
issues, and one having to do with studies of durability of the effect.
And I would just ask if anyone wants to consider a condition related to
either of those. Dr. Nelson?

DR. NELSON: I guess a clarification. I\'m assuming based on the
discussion of my rapidly revised initial condition, that if the label
says 72 hours, which I gather we decided earlier, or recommended
earlier, and is limited to the study population that was in fact
enrolled, we cannot recommend as a condition other than encourage the
sponsor to do studies looking at either duration, or even the
durability, to follow up on that population, or other requirements. I
mean, if we can, we could pile on a lot of things, probably. But I took
away from that discussion that we\'re limited in our ability to do that.
And so I would guess if we\'re not \-- I\'d just ask for some
clarification about that. There are a lot of issues we raised about
future studies that I\'m sure everyone else is thinking of, but as a
condition of approval it wasn\'t clear we could do that.

DR. HAINES: Dr. Provost, could you clarify?

DR. PROVOST: Yes, that\'s correct. I believe you were asking about
durability with regard to the patients already in the clinical trial,
whether the panel wanted that as a post-approval condition.

DR. HAINES: That\'s correct.

DR. PROVOST: And I think with regard to labeling it was, you know,
oftentimes in panel meetings panel members will recommend to FDA that a
condition be that certain statements are in the labeling, or certain
restrictions are made to the indication for use that are perhaps more
restrictive than what was in the PMA. So I would say if any member has a
condition of that nature that they would like to make then that\'s what
I think we would like to hear right now.

DR. HAINES: Dr. Hudak.

DR. HUDAK: Can I then \-- we\'ve heard different things, but the actual
labeling that every committee member here anticipates going forward may
be different. My understanding is that the labeling would be exactly the
inclusion criteria in the study. And I\'ve heard a couple of people say,
well, we need to limit it to the subgroup, take out the severely
affected infants. Personally I don\'t find that that\'s appropriate.

DR. CLARK: But I think people did agree to that, right? Didn\'t we say
that it should be just as the study population suggested? That\'s what I
heard.

DR. HUDAK: Okay. Good.

DR. PROVOST: You can make that a condition if you like. I mean, that\'s
often what FDA does, but if you \-- it\'s not always what we do, so if
you would like the labeling indication to be limited to the patients
studied, then you can make that as a condition if you like.

DR. HUDAK: I\'ll make that motion then.

DR. CLARK: And I\'ll second.

DR. HAINES: The motion on the table for condition of approvability, that
the labeling reflect the inclusion and exclusion criteria of the
clinical trial. Dr. Nelson?

DR. NELSON: I guess discussion on that. The discussion about the
difficulties of the use of the integrated EEG tracing versus Sarnat, and
clinical scores, and that sort of thing. What I heard was, (a) everybody
doesn\'t have that technology, (b) it\'s not going to be in the small
Level 1 - Level 2 nurseries, since this has to happen often before
you\'ve got transport to a tertiary facility, etcetera, etcetera. So I
guess my question is on that one point, what would be the
recommendation? Because I didn\'t hear us coming away saying that that
machine would have to be used as the third screen under all
circumstances.

DR. HUDAK: I think that\'s not within the committee\'s purview to
regulate practice at other hospitals. And \--

DR. CLARK: He\'s asking specifically with regards to the labels. Should
aEEG be in the label.

DR. NELSON: So I guess would you label it with aEEG in it, and then
everything else is off-label if they don\'t have the machine? Is that
what you would \-- the way you would go?

DR. HUDAK: That\'s what I would recommend. Anticipating that there would
be from the get-go significant off-label use.

DR. JENSEN: That\'s in the inclusion criteria.

DR. BROTT: What page? Oh here we go, 17.

DR. JAYAM-TROUTH: The inclusion criteria actually is not correctly
written then. It should be properly modified to indicate it\'s altered
mental status manifested as stupor, coma, drowsiness, lethargy, and one
of the other criteria. I think that should be modified then, the
inclusion criteria.

DR. HUDAK: I just don\'t see how this committee can extrapolate data to
another population of babies that wasn\'t studied.

DR. BROTT: Could I just ask a question as an adult neurologist? Is there
information either from our neonatal specialists or from the sponsor
with regard to use of the aEEG on an urgent basis within three hours of
birth? In the United States. In hospitals, children\'s hospitals.

DR. CLARK: It\'s certainly not a standard of care, by any stretch.

DR. WEILER: I can certainly comment if you\'d like. The current device
which is available on the market as a replacement of the one that was
used in the trial, and which has been tested to be shown to provide
identical output except it\'s in a digital storage format so there\'s a
lot more you can do with it, such as look at the underlying EEG from the
CFM.

That product is designed to be used at three o\'clock in the morning
when they\'ve just dropped off a floppy baby, and you need to get it on
quickly, and it\'s you put on three electrodes and push one button.
It\'s a very simple and easy-to-use device designed for use by NICU
nurses and neonatologists in the middle of the night. So it\'s \--
that\'s exactly what its application is and what it has been in Europe.
And it has gained wider acceptance in the U.S., obviously that\'s a
whole another device, and whole another discussion. But I can assure you
that it is designed for that.

DR. CLARK: And I would argue that it serves the purpose of putting a
safety on the trigger, that it adds another element. I\'m specifically
thinking about my obstetrical colleagues now trying to realize that each
time this device is used, the assumption now on the label is this is for
hypoxic ischemic encephalopathy, which is directed, as you probably know
better than me, is going to be assigned to the obstetrician for not
delivering the baby quickly enough, or some other event which it often
is. And so, by having another objective measure between the patient and
the treatment, it should narrow the use rather than expand the use.

DR. HAINES: Any other comments or discussion? Dr. Ellenberg?

DR. CLARK: Just one other comment. And I don\'t think there\'s any way
to get around this, but I\'m just going to put it on the public record.
The term \"hypoxic ischemic encephalopathy\" has very specific
connotations in the legal arena, and I\'d love to hear what your
perspective is on this, you know, should we be using instead of hypoxic
ischemic encephalopathy, just encephalopathy?

And I realize that that\'s a broader term that\'s less directive, but it
does give some wiggle room when you\'re trying to defend a case and say,
no, this child was placed on this therapy with all good intent. After
the therapy was started it became clear that the child had Group B strep
meningitis, and the cause for his encephalopathy had nothing to do with
the perinatal events. What\'s your thoughts? You\'re the obstetrician,
right?

DR. JENSEN: I\'m a neuroradiologist.

DR. CLARK: We don\'t have any obstetricians. Oh, okay.

DR. NELSON: I would agree as a non-obstetrician.

DR. CLARK: Sorry. My bad.

DR. JAYAM-TROUTH: Well, I don\'t know that we should put a broad
encephalopathy there. Then any child who is a little drowsy, maybe
exposed to cocaine, maybe exposed to some intrauterine drug will come
into that same category. I think we should be specific, that it is
hypoxic related, and that the APGARs and the other inclusion criteria
that are used be applied to the patients. I don\'t think we should say
encephalopathy from any origin.

DR. JENSEN: And just one other thing. I do think that, being a
radiologist, what you\'ll probably find is that these infants are going
to get imaged, and so if they did have a Group B streptococcus
meningitis, that would ultimately end up being imaged and discovered,
either that way or by lumbar puncture.

DR. HAINES: Dr. Nelson?

DR. NELSON: And in listening to the discussion and response, my first
query about the EEG, I am compelled that if you have all those criteria
in, and they had in fact not been met, and it\'s been used off-label,
that there\'s enough wiggle room there that if in fact the diagnosis is
other than hypoxic ischemic encephalopathy, then that should hopefully
all work its way out in the course of our due process system. That may
be naïve, but hopefully.

DR. BROTT: Can I make a comment? I\'m a little concerned because I think
I heard earlier you said something that, you know, I read just in
passing, that perinatal or postpartum encephalopathy has X, but half of
X occurred well before the delivery process, correct? Of this patient
population, what do our neonatologists believe the fraction of this
patient population of the critical events actually predated birth and
delivery?

DR. CLARK: Well, I think in the context of these studies, they were, you
know, you heard that it was 1 in 3. So that\'s \-- the number that the
ACOG document on this says is 70 percent of the encephalopathy we see in
nurseries is related to events that are outside of a sentinel event like
the ones we heard this morning, the three events this morning. They
occurred right at the time of delivery, there was some marker.

And the diagnosis of hypoxic ischemic encephalopathy has within it that
connotation, in other words that the patient, in order to have that
diagnosis assigned, must have had an event in proximity to delivery. And
obviously, one of the biggest problems with any of these therapies, and
Dr. Gunn spoke to it in his talk, is we sometimes don\'t know when the
event occurred. The baby comes out completely floppy. Again, the numbers
on that for at least 50 percent of the babies who come through our
nurseries, we don\'t know what happened, and those babies we\'re not
supposed to use the term HIE because we don\'t have a sentinel event to
assign that diagnosis. Does that make sense?

DR. BROTT: Yes. What\'s your estimate of the 234 patients? How many of
them, because you\'ve been over at your neonatologist. Are we talking
about 5 percent could have been before birth? In this study.

DR. CLARK: In this study I would assume by the way they included
patients that almost 90 percent of them had HIE, they had a sentinel
event because of their APGAR scores.

DR. BROTT: That was my question.

DR. HAINES: Dr. Coffey?

DR. COFFEY: Yes, I was just afraid that you were answering a different
question than the one that was asked. My impression is the same as yours
that these patients had placental abnormalities, umbilical cord
abnormalities, shortening, knots, and so forth, so that it was well
documented that they did actually study what they intended to study. But
the other deal of using HIE imprecisely and the pejorative and
medical/legal connotations of that is a whole other thing.

DR. HAINES: Okay, good. Then we have a motion on the table that labeling
be limited to the inclusion and exclusion criteria of the clinical
trial, with corrections in those that have been indicated in the prior
discussion. Dr. Ellenberg?

DR. ELLENBERG: I\'m sorry, I simply don\'t understand. We\'ve already
heard the sponsor talk about using the Sarnat as a surrogate for one or
all of these things, certainly the aEEG. We\'ve already heard that the
aEEG is not available outside of the urban areas. Are we restricting
this use to the presence of an aEEG machine? And do we mean that?

DR. NELSON: I think that was back to my \-- I asked that question
originally, maybe not as clearly. But what I heard was yes. It\'ll force
people without it to do it off-label. That might be good because it
gives wiggle room for our obstetrical colleagues. And the machine to use
is easy to use. I don\'t know how much it costs, but that\'s not our
purview. So if people did want to get it, they could get it. So my take
on it is yes, it would limit it to that, and then what happens happens
out in the real world.

DR. JAYAM-TROUTH: Question. Did I hear that this machine had the ability
to have the sensors to get EEG rapidly? It is already built-in to the
machine?

DR. WEILER: Not into the cooling device, no. It is a separate device to
do that measurement.

DR. JAYAM-TROUTH: Okay, so if there\'s a different machine and they have
to learn how to do that. And they have to be credentialed then, right?
To use it.

DR. WEILER: They would have to be trained to use it. There is not an
organization for credentialing on that at this time, although one
appears to be forming.

DR. CLARK: It is an approved device that\'s currently used clinically.
Your concern is exactly correct, and the answer to your question is yes,
we do want that to try to drive the patients. Because one of the biggest
issues here that was raised even this morning is it may be the site
where the care is provided may be just as important as the device
itself. And we don\'t have enough numbers in these sites to make any
sense of site effect. But as we\'ve heard, these are expert physicians
that have provided expert care in a specific area that have done
research. We have no clue how this will perform when it disseminates.
And based on previous experience in neonatal medicine, it will
disseminate. And if we can put, you know, specific criteria to try to
get the patient treated as much as possible the same way they were
treated within the context of this study, we should promote a safer
application of the technology, rather than a less safe application.
Although it will impose a barrier to an extent to some patients.

DR. ELLENBERG: Two points. Let me raise a point that\'s already been
raised. I think it would be somewhat naïve to consider registry as a
Phase 4 measure of efficacy. And second, I don\'t think it would \--
well, I guess it would. Are we saying that it will be off-label use if
you don\'t have the aEEG machine to put a patient on?

DR. CLARK: Yes.

DR. ELLENBERG: Because you can\'t determine the eligibility criteria?

DR. CLARK: Well, in the eligibility criteria \--

DR. ELLENBERG: Was it everything, or?

DR. CLARK: I think it was an \"or\". Maybe I\'m blocking on this.
Alistair? What was the criteria? Were they \"or\"? Go through those
again for us real quick.

DR. BARKS: I have the original card. So Step A was as presented by the
FDA earlier, the step that involved APGAR scores, or base deficits, or
continued need for resuscitation. They were all \"or\'s\" one out of
those. The B step was the \-- if the patient meets A, then assess for B,
which is the encephalopathy as re-written the way Alistair intended it
to be originally written: altered level of consciousness plus at least
one or more of ?. And then if the infant meets criteria A and B, then
assess by amplitude EEG.

DR. ELLENBERG: So that\'s required.

DR. BARKS: Yes.

DR. ELLENBERG: Okay.

DR. HAINES: Dr. Coffey?

DR. COFFEY: But patients were allowed in if they had clinical seizures.
And even if there was some technical problem, or the aEEG was a little
too short. And that wasn\'t thought to be a problem in the study, or the
analysis.

DR. GUNN: Clinical seizures were considered to be a strong sign of Stage
2 encephalopathy. So basically it was an automatic in. And many of those
had such movement to that effect that the aEEG could not be interpreted.

DR. BARKS: I think we could also add, I think it\'s correct that nobody
was admitted to the trial without an amplitude EEG being done. And
remember that the way \-- well, maybe you didn\'t hear this, but the way
we were taught to interpret the amplitude EEG is if some part of that
20-minute tracing met the abnormality criteria, then they qualified. So
if the patient got 15 minutes instead of 20 minutes, even if you\'d left
it on for another five minutes, the first 15 minutes still would have
qualified that patient in the final study.

DR. COFFEY: Absolutely.

DR. JAYAM-TROUTH: Maybe we shouldn\'t hold the aEEG as part of the
criteria for inclusion for one reason, and that is that if you have an
obvious seizure, I mean there\'s really \-- aEEG is not as good as
having a seizure. And if you have a regular EEG, you don\'t need an
aEEG. So I\'m not really sure that we should stick with the aEEG as a
definitive necessity.

DR. HUDAK: It\'s not. It\'s an abnormal aEEG and/or clinical seizure.

DR. JAYAM-TROUTH: Say that again?

DR. HUDAK: It\'s an abnormal aEEG and/or clinical seizure. That\'s the
study design.

DR. JAYAM-TROUTH: Oh, okay.

DR. HAINES: Then I think we are ready to vote on the third condition of
approval. All in favor please raise your hands. Dr. Hudak, Dr.
Jayam-Trouth, Dr. Clark, Dr. Brott, Dr. Jensen, Dr. Nelson. All opposed?
None. Abstentions? Dr. Ellenberg. The motion passes. Are there any other
conditions of approval? Motions for conditions of approval?

Seeing none, we will vote on the primary motion. That motion is that the
Olympic Medical PMA Application P040025 be conditionally approved with
the conditions of approval the panel has just voted on. All in favor of
the main motion with the identified conditions of approval, please raise
your hand. Dr. Hudak, Dr. Jayam-Trouth, Dr. Clark, Dr. Jensen, Dr.
Nelson. All opposed, please raise your hand. Dr. Ellenberg. Abstentions?
Dr. Brott. The motion passes, 5 to 1, with 1 abstention.

(Applause)

DR. HAINES: It is the recommendation of the panel to the FDA that the
Olympic Medical PMA Application P040025 for the Cool-Cap be
conditionally approved with the previously voted upon conditions. I
would now like to ask each voting member of the panel to briefly state
their reasons for their vote. Let\'s start with Dr. Nelson.

DR. NELSON: I guess I\'m compelled that the treatment effect that we saw
is real for a small group in a condition for which there is little other
available treatments apart from supportive care, and that the safety of
the device as demonstrated is sufficiently good to justify being a
little bit more relaxed on the statistical criteria to reach the
clinical significance requirement.

DR. HAINES: Dr. Jensen?

DR. JENSEN: I agree with Dr. Nelson. I think the company has shown a
reasonable assurance of safety and clinical effectiveness in the patient
population that we have circumscribed for the company, and I look
forward to finding further evidence that this is an effective treatment
in this group of patients.

DR. HAINES: Dr. Brott?

DR. BROTT: I don\'t \-- I\'m very impressed that there\'s a great need
for treatment of this condition. I\'m very impressed with the very large
randomized control trial that was carried out by the sponsor, and which
was very admirable. However, I\'m concerned about whether or not it
works. I\'m just not sure. From the clinical point of view I think
there\'s room for bias with regard to the assessments at 18 months. And
I agree with Dr. Ellenberg\'s comments that we need to be very careful
before we reject our conventional use of biostatistics. They\'re there
to protect us. Therefore I\'m kind of in the middle which is why I
abstained.

DR. HAINES: Dr. Clark?

DR. CLARK: I agree with Dr. Nelson. I think that the safety piece is
what\'s compelling me to actually kind of change my perspective on this
over the course of the day in listening to the evidence. The other
reason that I would point to is I don\'t believe we\'ll have more
evidence in this arena on this specific device because of the time and
nature of these kinds of studies. And so we\'re left today with making a
decision that\'s based on the best current evidence.

These investigators are to be applauded for their careful design of this
study, and the long-term follow-up that they\'ve achieved in this. I
would remind them that they do need to continue to show the durability
that has been suggested here, and is critically important to knowing
that this is truly a safe device and doesn\'t hurt anyone. And I would
also encourage them to continue in their research efforts because the
failure rate in this study was still quite large, and there were a
number of infants that we did not hear from today that are devastated,
and their families are devastated. And I applaud those families that
showed up today, but we need to remember the other families that we did
not hear from today. And I thank you for the willingness to share
honestly and openly with your data. Thank you.

DR. JAYAM-TROUTH: I agree that the company has shown that the device is
effective and that it is relatively safe. And for this given population
we have very little to offer, and I see the outcome, you know, every
time as a neurologist. And certainly I think anything that would benefit
this group I think is a welcome addition to the therapeutic
armamentarium.

DR. ELLENBERG: I agree with all the panelists who have spoken so far,
that this study is exemplary. The international nature, the number of
centers, the difficulty of carrying this out in such a timely fashion
\-- I\'m sorry, what I meant is the six-hour stretch was extraordinary.
But the data is what they are as I see it, and therefore I would not
repeat what Dr. Brott has said, but I\'m basically on the same
wavelength, and that\'s why I unfortunately had to vote no.

DR. HUDAK: I think I concur with the other panelists who voted for
approval. I think that there is in my mind sufficient efficacy for this
very difficult problem. Caveats are that the therapy clearly needs to be
optimized. I think there is room for a lot of research, which I think
will happen with or without company support. The one thing we haven\'t
mentioned, of course, in this hearing is there are other methods of
hypothermia. This in fact, I could be persuaded this might be a superior
method, but that will be studied eventually. And the one thing I\'m \--
it would be nice to have data on some of the patients who weren\'t
studied, but that\'s not something we can do about in terms of approving
or disapproving at this point. Thank you.

DR. HAINES: I would like to thank all the members of the panel. Would
Dr. Doyle or Dr. Coffey like to make any additional comments at this
point?

DR. DOYLE: I would have voted in favor because I felt that the risks
were minimal, and the benefits while not what we would have hoped, at
least there were benefits.

DR. COFFEY: I think the safety was the most compelling thing, you know,
for me as it was for others. I would have gone on the side of approval.

DR. HAINES: Thank you. So I would like to thank the panel for taking the
time, and being so diligent and careful in their work. Dr. Provost, do
you have any final comments?

DR. PROVOST: No. I\'d just like to thank the panel on behalf of FDA for
your very thoughtful deliberations and recommendations today. I\'d also
like to thank the members of the public who took the time and effort to
come here and to tell us and give us their input on this application.

DR. HAINES: Thank you. The Nineteenth Meeting of the Neurological
Devices Panel is now adjourned.

(Applause)

(Whereupon, the foregoing matter was concluded at 4:31 p.m.).