UNITED STATES OF AMERICA

FOOD AND DRUG ADMINISTRATION

CENTER FOR DEVICES AND RADIOLOGICAL HEALTH

MEDICAL DEVICES ADVISORY COMMITTEE

ANESTHESIOLOGY AND RESPIRATORY THERAPY DEVICES PANEL

MEETING

FRIDAY, May 13, 2005

The meeting came to order at 8:00 a.m. in Salons A and B of the
Gaithersburg, 620 Perry Parkway, Gaithersburg, MD. Dr. Alan Lisbon,
Chair, presiding.

Present:

Alan Lisbon, M.D., Chair

Neel J. Patel, M.Eng., Executive Secretary

Charles J. Cote, M.D., Voting Member

Kenneth Drasner, M.D., Voting Member

Avery Tung, M.D., Voting Member

David J. Birnbach, M.D., Non-voting Consultant

Andrea Kline, R.N., Non-voting Consultant

Jacqueline M. Leung, M.D., M.P.H., Non-voting

Consultant

Robert A. Mueller, M.D., Ph.D., Non-voting Consultant

Babatunde A. Otulana, M.D., Non-voting Member

Carolyn N. Petersen, Non-voting Member

Sousan S. Altaie, Ph.D., FDA

Chiu S. Lin, Ph.D., FDA

Julian M. Goldman, M.D., FDA

Ann A. Graham, CRNA, M.P.H., FDA

Thomas P. Gross, M.D., M.P.H., FDA

Sandy Weininger, Ph.D., FDA

Paul B. Batchelder, LRCP, RRT, Clinimark

Phil Isaacson, Nonin Medical

Paul Mannheimer, Ph.D., Nellcor/Tyco Medical Inc.

Brodie Pedersen, Nonin Medical

Dale Gerstmann, M.D., Utah Valley Regional Medical

Center

[I N D E X]{.underline}

Call to Order 3

Open Session, Welcome and Introductory Remarks,

Dr. Alan Lisbon, Chairman 3

Mr. Neel J. Patel, Executive Secretary 3

The Challenges and Opportunities on the Critical

Path to New Medical Devices, Sousan S.

Altaie, Ph.D. 8

Conditions of Approval Studies: Recent

Changes to CDRH, Thomas P. Gross, M.D.,

M.P.H. 16

Presentation by the FDA:

Introduction and Welcome,

Ann A. Graham, CRNA, MPH 23

Regulation of Pulse Oximeters,

Sandy Weininger, Ph.D. 32

Pulse Oximetry Standards,

Sandy Weininger, Ph.D. 48

Pulse Oximetry: Clinical Considerations,

Julian M. Goldman, M.D. 87

Presentation by the Industry 150

Open Public Hearing 166

Panel Deliberations 194

Open Public Session 276

Panel Recommendations 286

Adjournment

[P R O C E E D I N G S]{.underline}

8:02 A.M.

DR. LISBON: Good morning, welcome to the meeting of the Anesthesiology
and Respiratory Therapy Devices Panel of the CDRH Medical Devices
Advisory Committee.

As I said before, I\'m Alan Lisbon and I\'d like to call this meeting to
order. I\'d now like to have the Executive Secretary make some
introductory remarks.

Neel?

MR. PATEL: Thank you, Chairman Lisbon. My name is Neel Patel, the
Executive Secretary of the Panel.

Allow me to introduce the members of our Panel. Please raise your hand
as I call your name. The Chairman of the Anesthesiology and Respiratory
Devices Panel is Dr. Alan Lisbon. Chairman Lisbon is an anesthesiologist
and is Vice Chair for Critical Care at the Beth Israel Deaconess Medical
Center and Associate Professor of Anesthesia at Harvard Medical School,
both in Boston, Massachusetts.

Joining him are the following panel members: Dr. Charles J. Coté is an
anesthesiologist and is Vice Chairman and Director of Research of the
Department of Pediatric Anesthesiology at Children\'s Memorial Hospital
and Professor of Anesthesiology, Pediatrics at Northwestern University,
both in Chicago, Illinois.

Dr. Kenneth Drasner is an anesthesiologist and Professor of Anesthesia
at the University of California, San Francisco General Hospital in San
Francisco, California.

Dr. Babatunde Otulana is the Industry Representative and is Vice
President of Clinical and Regulatory Affairs for Aerodyne Corporation,
Haywood, California.

Ms. Carolyn Petersen is the Consumer Representative and is a Web
Communications Consultant for the Mayo Clinic in Rochester, Minnesota.

Dr. Avery Tung is an anesthesiologist and Associate Professor int he
Department of Anesthesiology and Critical Care at the University of
Chicago in Chicago, Illinois.

Joining the Panel Members are the following consultants. Dr. David J.
Birnbach is an anesthesiologist and is Professor of Anesthesiology and
Obstetrics and Gynecology at the University of Miami School of Medicine,
Miami, Florida.

Ms. Andrew Kline is a Pediatric Critical Care Nurse and Nurse
Practitioner at Children\'s Memorial Hospital in Chicago, Illinois.

Dr. Jacqueline M. Leung is an anesthesiologist and Professor of
Anesthesiology and Perioperative Care at the University of California,
San Francisco in San Francisco, California.

Dr. Robert A. Mueller is an anesthesiologist and Professor of
Anesthesiology and Pharmacology at the University of North Carolina in
Chapel Hill, North Carolina.

Joining us at the table is Dr. Chiu S. Lin, Director of FDA\'s Division
of Anesthesiology, Infection Control, General Hospital and Dental
Devices.

Next, I\'ll read into the meeting the conflict of interest statement for
this meeting. The following announcement addresses conflict of interest
issues associated with this meeting and it\'s made a part of the record
to include even the appearance of impropriety.

To determine if any conflict existed, the Agency reviewed the submitted
agenda for this meeting and all financial interests reported by the
Committee participants. The conflict of interest statutes prohibit
special Government employees from participating in matters that could
affect their or their employers\' financial interests. However, the
Agency has determined that participation of certain members and
consultants, the need for whose service outweighs the potential conflict
of interest involved is in the best interest of the Government.

A waiver has been granted for Dr. Robert Mueller for his interest in a
firm that could be impacted by the Panel\'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 Doctors Charles Coté and
Jacqueline Leung. Each of these panelists reported current and/or past
interest in the firms at issue, but in matters not related to today\'s
agenda. The Agency has determined therefore, that they may participate
fully in today\'s deliberations.

In the event that these discussions involve any other products or firms
not already on the agenda for which an FDA participant has a financial
interest, the participant should excuse himself or herself from such
involvement and 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.

I would like to request that everyone in attendance at this meeting take
the opportunity to sign the attendance sheet that\'s available at the
door.

Before we begin the meeting, we have two presentations by the FDA, one
on the critical path initiative by Dr. Sousan Altaie, the other on the
condition of previous studies by Dr. Thomas Gross.

Dr. Altaie, please proceed with your presentation.

DR.WEININGER: I\'m having minor computer difficulties at the moment. It
will come up in a minute, I\'m hoping.

(Pause.)

DR. ALTAIE: Good morning. Well, I\'ve never done it without slides, so
I\'ll try to wing it and see how it goes.

I\'ll give you \-- as far as an overview concern, I\'ll give you a brief
history about how the critical path came about at the FDA and then
define some terms in the critical path and then I\'ll give you an
opportunity where devices can play in the critical path and I will give
you some contact information at the end to get involved, actually, and
help the FDA with this initiative.

FDA critical path started with a white paper that was initiated at the
Center for Drugs and the paper analyzes the hurdles of the medical
product development and calls for collaboration between government
research institutions and manufacturers to promote the public health by
getting safe and medical products in the public domain.

Critical path is actually a path where most people refer to as the bench
to bedside and it includes basic research then into prototype designs
and going into preclinical/clinical studies and then finally going
through the FDA review and getting on the market.

Critical path is in the view of FDA, it\'s a critical path rather than a
translational path. And because it\'s critical and not translational
because you think about it if you cannot pursue the path all the way
through, the devices won\'t make it to the market or the medical
products per se don\'t make it to the market.

Critical path is actually a serious attempt to bring attention and focus
to the need for more scientific effort and publicly available
information on evaluative tools. Now we\'re talking only about
evaluating tools in the critical path and these are techniques and
methodologies needed to evaluate the safety, efficacy and quality of
medical devices as they move down the critical path into the market.

There are three areas in the FDA\'s view where critical path research
can impact and if you work in three dimensions, you\'re looking at
safety and you\'re looking at medical utility of medical products and
you also are looking at industrialization of those medical products.

So the safety point of critical path, you\'re looking at material
selection, structure activity relationships and then you go into the in
vitro animal models and then human models and then finally you follow
the safety into the market.

The second dimension that critical path, the tools can influence or
impact the development of medical devices is the medical utility. These
tools can be in vitro and computer models that you can utilize and
simulate physiology in humans and then go into animals and humans and
further down the path.

Also, industrialization impact is doing \-- dealing with the tools that
can participate in physical design of these medical devices. So what
critical path research is is basically studies, the ways \-- critical
path basically studies the ways that medical products\' community can
leverage basic science knowledge and cumulative experience to bring
products to the patients faster without compromising the level of safety
and effectiveness that the public deserves.

So moving on, one might think why FDA is taking the lead on this issue
and trying to identify tools to get devices faster to market. Well, FDA
has a broad perspective of why some products fail and some products do
succeed and get to the market. And companies in this competitive world
and secrecy of proprietary things does not have this ability. And if you
look at academia, centers like NIH and the academics, do not face the
problems of device development and manufacturing. So FDA sounds like a
logical place to pursue these critical path tools.

Since the critical path \-- I\'m on Slide 9 \-- if you can go to that.
Right.

So critical path is different for devices than it is for the drugs and I
said originally that the paper, the white paper was initiated in the
Center for Drugs and it lacks a little bit of modeling for devices and
we are working to include that model for devices in that critical path
white paper. But this is why it\'s different. Device regulations are
totally separate than the drug regulations. We\'re dealing with the
least burdensome provisions of the FDA Modernization Act. We\'re dealing
with quality systems and design controls.

As far as the device innovation process is also different than drugs.
You produce a drug, test it and it\'s on the market forever for its
life. It\'s not an iterative process while the devices are. The devices
are constantly changing and getting better. You have a user learning
curve, how the device is used while it\'s on bedside or by users and
also you have performance and durability issues and biocompatibility
because most of these devices are implanted in humans.

And also device industry is not this conglomerate, huge pharmaceuticals
and they\'re small companies, mom and pop operated. And so the critical
path for device development is certainly different.

Next slide, please.

This is an example of the devices in the Center. We can go anywhere from
a tongue depressor to a contact lens to a CAT scan to a biopsy, so there
is a variety of devices with ways to regulate as far as safety and
efficacy is concerned. So we are different than the drugs.

Next slide, please.

The critical path projects currently being pursued at the Center for
Devices deal with establishing a pedigreed and credentialed serum
samples that could be used for assessing the sensitivity and specificity
of new hepatitis assays. Those panels lack currently in the market and
developing those tools can be getting this in vitro assays quicker to
the market.

Another project we\'re dealing with is to develop computer models of
human physiology that allows testing and predicting failure of
peripheral vascular stents before the animal and human studies.

Also, we\'re working on developing a clear regulatory path with
consensus from obstetric community of intrapartum fetal diagnostic
devices and those devices have been not innovative for a long time. And
we\'re looking as far as reasons why and try to facilitate that
progression.

Next slide, please.

We\'re also looking at establishing agreed ways for statistical
validation of surrogate markers. Surrogate markers can be used in
selection of the patients in clinical trials. You can use them as end
points and so there are quite a number of them in the science arena, but
they are not fairly validated as to how they should be used and that\'s
a huge effort currently in the Center. We\'re working to start with the
cancer markers and also some markers related to stents and peripheral
vasculars.

So working with medical specialty organizations, we also are developing
practice guidelines for appropriate monitoring of permanently
implemented devices, implanted devices.

The last project that we currently are working in the Center for is to
obtain consensus on the extent of neurotoxicity testing for neural
tissue contacting materials.

Next slide, please.

And then these projects are actually quite much more extensive than
this. The reason we are limited to this project at this time is lack of
funding. We were expecting appropriated funds and those funds didn\'t
come in and so now we are dealing with running projects with no funding
and the process is slow, but they\'re all active and alive and kicking.

These are the contact information for you to get involved. If you have
tools in your area of expertise that you think can facilitate putting
material on the market faster, please contact us. You can sent your
comments to the dockets as you see there and add to the white paper and
let us know how you can help to facilitate getting devices faster on the
market.

With that, if there are no questions, I can go on and you can go on with
the rest of the meeting.

MR. PATEL: Thank you, Dr. Altaie.

Dr. Gross?

DR. GROSS: Good morning. I am Tom Gross. I\'m the Director of the
Division of Post-Market Surveillance in the Office of Surveillance and
Biometrics in the Center. And I\'d like to take a few minutes of your
time to talk to you about recent changes in our condition of approval
study program. And before I do that and to put it into context, I\'d
like to tell you a little bit about the functions that the Office of
Surveillance and Biometrics serves for the Center.

Next slide.

The office has several functions, first and foremost is to provide
support for pre-market review. We have a large staff of statisticians
who address statistical aspects of the pre-market submissions, whether
they\'re 510(k)s or PMAs. We have a large staff of epidemiologists who
have been recently incorporated into the pre-market review process to
look at the risk benefit of PMA products and to an eye towards designing
conditional approval studies and I\'ll mention that a bit more in a
minute.

We\'re also responsible for monitoring a nationwide passive adverse
event reporting system, looking for potential public health problems,
signals of potential health problems through out medical device
reporting system or MDR and also a companion system of a nationwide
network of health care facilities all tolled about 350 called MedSun or
the Medical Device Safety Network.

Our epidemiologists also analyze safety issues. They characterize the
risks through literature reviews, design of studies and applied
research. We also coordinate the Center response on important potential
public health issues by convening committees of Center experts to
further investigate these issues, deliberate these issues and then
submit recommendations for actions to our Center senior management.

And lastly, we\'re responsible for interpreting the medical device
reporting regulation. This lays out the mandatory reporting requirements
for manufacturers, user facilities and importers.

Next slide.

Now what about condition of approval studies? As you are well aware,
these studies are ordered as a condition of approval for PMA devices and
the regulations clearly stipulate that post-approval requirements can
include the continuing evaluation and periodic reporting on the safety,
effectiveness and reliability of the device for its intended use. This
gives us our broad authority to levy condition of approval studies.

Next slide.

In 2002, we decided to take a good look at this program. to do that, we
looked at PMAs that were approved between 1998 and 2000. All tolled,
there were 127 PMAs. We focused on those PMAs that had clinical
condition of approval orders. It amounted to 45 PMAs.

The bottom line was this, that CDRH had limited procedures for tracking
study results and study progress. Our IT and other systems were found to
be very deficient. There\'s a large turnover of lead reviewers that
resulted in lack of follow up. Forty percent of those individuals that
were lead reviewers at the time the PMA was submitted were no longer the
lead reviewers in 2002, again, stressing the lack of continuity.

The lack of pre-market resources, the pre-market resources were
prioritized elsewhere to analyze pre-market submissions and limited
resources were available to look at these incoming reports.

Next slide.

So we developed a strategy for change, based on some simple goals, to
obtain timely and useful post-market information as the device enters
the post-market period and to get information on real world use, to
better characterize the risk benefit profile of the product, for
instance, it\'s long-term performance and add to our ability to make
sound, scientific decisions increasing the rigor and quality of these
studies.

Next slide.

So what do we do? We transfer the condition of approval study program
from the pre-market side of the house, the Office of Device Evaluation
to the post-market side of the house, the Office of Surveillance in
Biometrics. OSB has the resources and we\'ve got the resident expertise
in terms of a staff of epidemiologists who are expert at designing
observational studies.

We developed and instituted an automatic tracking system for these study
commitments, first and foremost to acknowledge the receipt of study
reports and to follow-up when reports were not received.

Next slide.

I alluded to this before. We added epidemiologists to a PMA review team.
We started this as a pilot two years ago. It was expanded to the rest of
the Center. And the epidemiologists were tasked with several items.
First and foremost was to develop a post-market monitoring plan during
the pre-market review of these products, how best to monitor these
products i the post-market period including CoA studies; second, to take
the lead in developing well-formulated post-market questions, the lead
in the design of these studies because of their expertise and
observational studies, the lead in the evaluation of the study progress
and results, and throughout this process to continue to collaborate with
the lead reviewers, the medical officers, the statisticians as part of
the PMA review team and also to negotiate with the companies.

Next slide.

This speaks to the motivation for good study conduct, not only on our
part but also on industry\'s part. We have to address important
post-market safety questions and those have to be addressed through good
protocol study design. As I stated before we have to be able to track
these studies and give feedback on the interim reports. To be more
transparent, we plan on posting the study status of these results on a
CDRH website. This is currently done at the Center for Drugs and the
Center for Biologics. And lastly, we may have to utilize some
enforcement strategies, if there\'s extreme lack of due diligence in the
conduct of these studies. We can turn to our so-called Section 522
authority, levy a similar study. If that is not done, we can misbrand
the product and it may result in hefty monetary penalties. Again, this
is a last resort. We hope not to have to use this.

Next slide.

What is the impact on the Advisory Panel? We will attempt to lay out the
important post-rule public health questions at the time of panel
presentations and possible approaches for the panel to consider. And
also on a periodic basis, FDA and industry will update the Advisory
Panel on the progress and results of these studies.

That concludes my remarks. Thank you very much. I\'ll entertain any
questions.

MR. PATEL: Thank you, Dr. Gross.

Dr. Lisbon?

DR. LISBON: All right, I note for the record that the voting members
present are constituting a quorum as required by 21 CFR 14.22 Section D
and we\'ll now get started with the agenda.

What we\'re going to start with is four presentations by the FDA. The
first is by Ann A. Graham. I would just ask that everybody identify
yourself for the record, please.

MS. GRAHAM: Good morning, again. I\'m Ann Graham, the Branch Chief in
the Anesthesia and Respiratory Devices Branch. And again, I\'d like to
welcome everyone to this panel meeting this morning.

Before we get started, I would like to introduce the members of the
branch to you. And if you could just raise your hand as I call your
name: Justin Guay, Lisa Lavelle, Mike Husband, Bill Maloney is on
vacation right now and Neel you\'ve met and Dr. Joydeb Roy. Great,
thanks.

We also have three anesthesiologists that we have recently hired through
our Medical Device Fellowship Program, one of whom you will meet later
this morning, Julian Goldman and Bill Norfleet and Eric Pierce were
unable to be here this morning. Bill is an anesthesiologist at Yale and
Eric is 50 percent with FDA and will be soon with Mass. General Hospital
in Boston.

The subject of the meeting this morning is pulse oximeters and I would
just like to briefly go through some of the regulatory aspects related
to pulse oximeters.

As you heard yesterday in your orientation, they are Class 2 devices and
they are subject to 510(k) which is a pre-market notification. The two
classification regulation numbers you see here are the authority under
which we regulate these devices. 2700 regulation is the general category
for oximeters used to transmit radiation at a known wavelength through
the blood and to measure the blood oxygen saturation based on the amount
of reflected or scattered radiation. It may be used alone or in
conjunction with a fiber optic oximeter catheter.

Under Regulation 8702710, we separately regulate the ear oximeter. It\'s
an extravascular device used to transmit light at a known wavelength
through blood in the ear. And again, the amount of reflected or
scattered light, as indicated by the device, is used to measure the
blood oxygen saturation.

The intended use for pulse oximeters is noninvasive, transcutaneous,
continuous or spot checking monitoring of oxygen saturation of
functional arterial hemoglobin and pulse rate. And I\'ve highlighted the
second bullet because it\'s on point to one of the questions that we\'ve
asked you to think about today. They are currently all prescription use
devices for medical indications.

The patient populations are adult, pediatric, infant and neonate for
transmission pulse oximeters. The site of application, depending on the
optical design of the pulse oximeter can be the finger, the earlobe, the
forehead or the back. Those are the four primary locations.

In the environment for use is in the operating room, critical care,
post-anesthesia recovery room and some question of morphing into other
locations, other environments such as home use.

The recommended elements of a 510(k) for a pulse oximeter includes these
four bullets. There\'s obviously much more and these four are
embellished, depending on the complexity of the device. But in general,
the description of the device should include the operating
characteristics, the design, the comparative performance of the subject
device, the device under consideration in the current 510(k), compared
with a legally-marketed predicate. This includes the desaturation
studies that are performed to validate the saturations.

And finally, we look at the subject device and the predicate device
labeling to ensure uniformity.

The accuracy specification of pulse oximeters is somewhat different,
depending on the patient population and the type of oximeter sensor. As
you can see in the chart, for transmittance, wrap and clip, which is the
finger, all patient populations require an accuracy spec of 3 percent or
less. Neonates have 4 percent. There is a 1 percent additional accuracy
degradation added to the allowed spec in adults. This comes from the
Agency\'s agreement to accept adult data for neonatal use and add a 1
percent degradation factor and Sandy and Julian will embellish that
philosophy later in the presentation.

The transmittance earclip has a slightly higher accuracy spec of 3.5
percent and we currently do not have any submissions cleared in the
infant or neonatal population for either the earclip or the reflectant
sensors.

We have been clearing in the last couple of years roughly thirty-five
510(k)s a year, so it\'s a substantial part of our workload. Most are
for transmittance sensors or systems, actually, because the 510(k) not
only includes the sensor, but the oximeter and the patient cable. So
they\'re cleared as a system, unless the 510(k) is just for the sensor
and in that case it must be shown to have been validated with a
previously approved oximeter.

Most are transmittance technology, single use and nonsterile. Last year,
we have several more than our usual number of 510(k)s because we
requested 510(k) submissions from manufacturers who were reprocessing
single use sensors.

And the next slide just shows over the regulatory history of pulse
oximeter at CDRH, you can see before 1985, I think we had five or six
files come in and a big blip from 1986 to 1990 when pulse oximeters
began to morph into clinical practice. And as I mentioned earlier, you
can see in the last five years, we\'ve had a substantial increase in the
number of files for pulse oximeters.

The next two presentations will \-- the first one will be from Dr. Sandy
Weininger, in the Office of Science and Engineering Laboratories. Sandy
is the chair, co-chair of the ISO Committee that has been developing the
standard for pulse oximeters and this standard has recently been
published, I think, in January of 2005.

And Julian Goldman is, as I mentioned earlier, is a medical device
fellow and Julian is going to ask you to think about clinical conditions
for reflectance and transmittance sensors. He\'ll ask you to think about
certain considerations relating to neonatal validation and also to
explore your thoughts and prepare recommendations for over-the-counter
use of pulse oximeters.

We have had in the past two documents that have \-- well, actually one
document that has served the branch as guidance. One is our 1992
guidance document and we realize that this document needs to be amended
and specifically for this panel meeting, we ask that you consider the
questions related to neonatal labeling in OTC use.

The standard that I mentioned, the ISO standard that was published in
January, does not call out a single test method for accuracy, surface
temperature, motion or low perfusion, nor does it distinguish between
reflectance and transmittance technology. So while it is a very good
source document for us, it doesn\'t give FDA all the guidance that we
seek to supplement with your advice today.

With that, I would like to introduce Sandy Weininger.

DR. LISBON: Thank you, Ms. Graham. Can you entertain a few questions
now?

DR. BIRNBACH: I\'d like to know how the FDA is defining neonatal?

MS. GRAHAM: Oh, that\'s a good question.

DR. BIRNBACH: It\'s used pretty often and \--

MS. GRAHAM: Right. We have actually a guidance that I believe is under
30 days and I believe that there is a weight, upper margin, on that as
well, like under 10 kilo.

DR. BIRNBACH: And it excludes fetal use of pulse oximeter?

MS. GRAHAM: Yes, it does. I should have mentioned that. There are two
other oximeter categories that we have at FDA. One is for fetal use and
fetal oximeters are all class 3 devices requiring PMA and the other are
in-dwelling tissue oximeters. The fetal oximeter, I think, is regulated
under a separate classification, but the tissue oximeters are regulated
under the same 870.2700. So we differentiate those when we receive them
from manufacturers with a different product code and they go to a
different group, the cardiovascular group.

Let me get source documentation for you though on your question about
neonates so that I give you the correct answer and I\'ll get that to you
before the end of the day.

Thanks.

DR. LISBON: Dr. Coté.

DR. COTÉ: Dr. Coté. Are we considering fetal oximeters today or just
neonatal use?

MS. GRAHAM: No, neonatal only.

DR. COTÉ: Okay.

DR. LISBON: Avery?

DR. TUNG: Pulse ox. technology is almost 20 years old. I might just,
without knowing anything, expect a machine today to be much, much better
than the ones in 1985 when it was first introduced.

When you say comparative, do you mean compared to a standard, a machine
built in 1985 or do you keep evolving that standard as newer and better
machines come out? Or are they not any better than they were?

MS. GRAHAM: Well, I would like to think that, in general, they are much
better than they were in 1985. It\'s the responsibility of the
manufacturer to identify the comparative oximeter system that FDA would
look at to compare their new device with an existing or a legally
marketed predicate device. So some manufacturers do take a very new
technology to do that comparison. And this is outside of oximeters. This
is in general, some manufacturers take very old predicates and you can
imagine that in 1978 or in 1982, we asked for I think it\'s fair to say
less data than we do today, so the test to meet substantial equivalence
for those older predicate devices is less than it would be in comparing
with a device approved or cleared in 2002, for example.

Does that help? Okay.

DR. LISBON: Do any of the other panelists have questions?

Okay. Thanks, Ms. Graham.

DR. WEININGER: Good morning, Panel Members, my name is Sandy Weininger
from the Office of Science and Engineering Laboratories. And I recently
have come off a detail to the Office of Device Evaluation so I\'m
relatively familiar with how oximeters have been regulated. I\'ve been
following them since roughly about 1990 when we tried to incorporate
them into apnea monitor standard.

Let me briefly address the two questions which was neonatal applications
and how oximeters are regulated. Currently, the manufacturers specify
what they believe to be neonatal and that\'s different than what FDA
considers and so that\'s just a statement of fact, let\'s keep that
clear and that\'s something that needs to be cleared up, obviously.

And oximeters are regulated as Class 2 devices and so the term
substantial equivalence which I\'m sure you heard is what we \-- is how
we regulate them. So if a manufacturer has to demonstrate or if a
manufacturer has to demonstrate that his pulse oximeter system is
substantially equivalent to a legally marketed device, how good or how
bad that device is is up to the predicate that they choose.

And that\'s actually a good segue into the regulation of pulse
oximeters. Next slide. There we go.

In 1992, we came out with the draft guidance document and that was
roughly after about 10 or 15 years of oximeters being on the market. You
have that in your package and you have perhaps had a chance to look
through there. It is 15 years old and I\'ll talk to you about what the
elements of the guidance document are, what are the recommendations and
I\'ll also try to give you an insight into what our current regulatory
policy is because as you know, over the last 15 years, there\'s been a
lot of new scientific and technological developments and our regulatory
policy tried to keep pace with it.

Next, please.

So the obvious things to ask for in a guidance document or from a 510(k)
are what\'s the configuration? We know that pulse oximeters have to have
a probe-monitor combination in order to determine what its accuracy is.
If that probe-monitor combination isn\'t identical to the predicate,
then we ask \-- we typically ask for clinical validation data to
demonstrate accuracy.

We also ask for information about the accessories. For example, extender
cables and some other things. They too have been shown to affect
accuracy and so we want to make sure that the system, the pulse oximeter
system is controlled.

We need to know what the device is so we ask for engineering drawings,
center dimensions. We want to know what the functional elements are,
both electrical and optical, anything that\'s in the signal path from
the probe through to the oximetry. Saturation algorithms we consider to
be essential components and if you make modifications to them we need to
know that it doesn\'t adversely affect the performance of your device.

We obviously want to know about alarms and alarm limits and what
defaults you have. And this information we use and we put into a
comparison table to compare to the predicate. So if you have performance
that\'s commensurate with the predicate device, they\'re deemed to be
substantially equivalent and we do this comparison based on the
features, specifications and accuracy of materials and also we look at
intended use and we look at the indications for use. You\'ve heard Ann
talk about the indications for use; the target population, the use
environment and site of application.

We go through a great deal of evidence or we recommend that you provide
a great deal of \-- manufacturers provide a great deal of evidence to
demonstrate functional verification. We want to know that your box is
going to work and we want to look at the test method to make sure that
the test method is appropriate. We want to look at the acceptance
criteria to make sure that it\'s a reasonable acceptance criteria and we
want to make sure that the results support the conclusions that you\'re
coming to. So we ask for a rationale for the test method and some
others.

So probably the most important piece of information that we get on a
pulse oximeter is the accuracy and as I said, if you make a modification
to any of the components in the optical chain or the signal processing,
we typically ask for laboratory testing based on human subjects. There
are no adequate simulators that can represent the optical
characteristics of the pulse oximeter, and so we need to do human
subjects and these studies require both an IRB approval and informed
consent. They are subject to the IDE, Investigational Device Exemption
regulations but for nonsignificant risk devices.

Let me give you some elements or some details on the desaturation study.
The desaturation study compares the performance of the pulse oximeter to
the co-oximeter and we typically require a minimum of 10 healthy
subjects that consent to induced hypoxia as part of the experimental
procedure. The subject characteristics should range in age, gender and
skin tone and we report \-- we recommend that the manufacturer report
what\'s called the root mean square error, A~RMS~, and that actually is
defined in the ISO standard which we\'ll get to in the second part of
the presentation.

I\'ll note two of the panel questions deal with comparative, the
comparison between a transmittance and reflectance sensor and if we\'re
looking to see whether I can use a reflectance or transmittance sensor
as a predicate, for comparing substantial equivalency on a transmittance
sensor, perhaps the calibration method is something that needs to be
considered and also for neonatal performance we need to consider what
types of calibration studies can actually be done which brings us to
neonatal use.

The guidance document recommends collecting convenience samples and
recognizes the limitations of doing that. Clearly, you can\'t desaturate
a neonate which leads to all kinds of problems and wider variances,
greater uncertainty in the calibration studies. So our current practice
has been to grade the adult accuracy by 1 percent and our rationale for
doing that is evolved, but it\'s typically spoken about if talking about
the fetal hemoglobins and other error sources which preclude us from
getting those very accurate results as we do with a controlled
desaturation study on an adult. And as I said, certainly the panel
questions can revolve around that.

The data characteristics, we typically require 200 or we recommend that
the manufacturer supply 200 data points over the entire range of 70 to
100 point saturation. These data points are paired observations. That\'s
pulse oximeter and co-oximeter values. They consist of \-- it\'s an
individual pulse oximeter sensor combination with the simultaneous blood
draw. And I\'ll note the asterisk. The standard does not call out \-- it
does not recommend a specific number of data points and we\'ll get into
some of those issues later.

Again, as pointed out, if you use a different pulse oximeter sensor with
a monitor and put them on a different finger for your desaturation study
you\'ve got to demonstrate that the data is poolable, that it comes from
the same type of population because we know oximeter sensors, when you
change them, have different calibration curves. And so that\'s part of
the statistical analysis.s

Next slide, please.

The environmental factors, surface temperature for testing the pulse
oximeter is very important. Oximeters, as you know, take optical energy
and beam it through a finger and you can\'t have optical energy unless
you have heat and the objective is to prevent burns from occurring. So
there\'s a limit of 41 degrees C. which has been around for a long time.
That\'s for the applied part and just as a side note the case also has a
recommended maximum temperature of 50 degrees C. and those are pretty
much recommended or have been identified in the international standards
community as appropriate temperature limits.

Also for environmental factors, electrical safety is very important.
Electromagnetic compatibility, mechanical and environmental testing of
the device are also recommended.

Pulse rate, because it\'s a pulse oximeter, and that\'s one of the
differences between tissue oximeters and tissue oximeters typically
don\'t measure pulsatile blood when look at tissue where as pulse
oximeters measure arterial pulsatile blood, but we allow or we recommend
that manufacturers demonstrate the performance of their pulse rate
detection system using in vitro calibrators. They\'re much more
reproducible to human subjects, but we do ask that the simulator be set
to their lowest values to represent the weakest pulses to make sure that
the oximeters are capable of detecting pulses in weak patients.

A very important part of our review consists of looking at the labeling.
The labeling includes the sensor specification, that\'s the pulse rate
and saturation accuracy claims, what the temperature and humidity
specifications are and importantly, what the pulse oximeter sensor
monitor combination is. And we ask that the patient population be
identified, as well as the indications for use.

An important aspect of labeling is the application time. The 1992
guidance document recommends that the sensor application site be
inspected and repositioned every four hours. I\'ll note that the
standard doesn\'t have that absolute limit, but instead requires
disclosure of the application time and evidence to show that that
application time is appropriate, so it\'s a slightly different approach.

Ann talked about in the intended use continuous versus spot checking.
That needs to be disclosed and if your device is continuous or spot
checking and you \-- if you are \-- for continuous use you need to have
both low and high SpO2 alarms. An interesting note \-- well, not an
interesting note \-- compared that the standard calls out whether \-- or
asks to disclose whether you have a physiologic alarm versus an
equipment alarm as opposed to continuous versus spot checking and it\'s
kind of the flip side of the same coin. If you use a continuous use
device, you have to have a physiological alarm. If you have a
physiological alarm, you must have a low SpO2 alarm. That\'s a slight
variation from what the guidance document calls out.

For reusable probes you must demonstrate that you can clean the probe up
and return it to its normal existing safe conditions and so we ask the
manufacturer to demonstrate how they\'re going to that and to verify
that they can actually get that done.

And we ask them to do that if their probe is going to have a one year
life span or five year life span. We say well, show us some evidence or
show us a test method where you actually do that after 30, 50, 100
cleaning cycles.

Dr. Tung, you raised the specter of oximeters improving and certainly
the first oximeters that came out in the early 1980s, late 1970s, by
today\'s standards had very simple microprocessors. The oximeters that
are coming out today have multiple microprocessors that are extremely
powerful devices. They run multiple algorithms and do a lot of signal
processing which means that they\'re very software intensive.

And so software safety is an issue with pulse oximetry. We ask that
manufacturers demonstrate or use our software safety guidance documents
to demonstrate that their software is safe and effective. Oximeters are
moderate level devices from the perspective of this guidance document.
That means that they are not life-supporting or life-saving, and the
guidance document talks about levels of documentation, types of
documentation. Importantly, software development, as you know, you
can\'t test software to make sure that it works alone. You need to make
sure that the software development process is appropriate, as well as
the outputs of those processes. And that\'s a fairly intensive and
technological review.

Next slide, please.

Oximeters touch tissue and so we need to make sure that their
biocompatibility requirements are there, that the materials used are
biocompatible and so we ask that they list the materials used to
construct the oximeter and demonstrate biocompatibility for all the
materials used. And there\'s various different ways to do that and we
don\'t want to get into that at the moment.

Next, please.

When the guidance document came out in 1992, there were no reprocessed
single use devices. We now have them and they\'re getting to be a larger
part of our review activities. And what does a manufacturer of a single
use device have to \-- a reprocessed single use device have to
demonstrate? They have to demonstrate that their probes are accurate
after the number of use or cleaning cycles. So if they say that their
probe can be reprocessed five times, they have to go through typically,
it\'s a simulated re-use protocol and then demonstrate validity which is
also a human desaturation site.

Importantly, the reprocess probes do not have to show electrical leakage
or electromagnetic interference, susceptibility. They don\'t have to
redemonstrate \-- I\'ll use the term redemonstrate. They don\'t have to
show that they are mechanically safe because the original probe,
original submission 510(k) demonstrated that.

Next, please.

So I\'ve gone through the guidance document and showed you what the
original document was and what some of our updated thinking is. Let me
now take you to the standard. And \--

DR. LISBON: Do you want to take any questions on the first part of your
talk at this point? Are there any questions?

Yes.

DR. COTÉ: How does a manufacturer track how many times a particular
probe has been cleansed? In our practice, we just take them and throw
them in a big box and \--

DR. WEININGER: Are you referring to single use devices that are
reprocessed or are you referring to clam shells that \--

DR. COTÉ: No, single use devices that are reprocessed.

DR. WEININGER: It\'s up to the single use device manufacturer to have a
tracking system in place and we do review that.

DR. COTÉ: So there is a requirement for that?

DR. WEININGER: Yes, I call it a recommendation because it\'s a Class 2
device.

DR. LISBON: Are there any other questions?

DR. TUNG: One more. Because they exist, I\'ve seen them. There are
machines that don\'t have signal sensitivity meters. They just give you
a signal and they don\'t tell you how strong that signal is, nor is
there any requirement that \-- and I\'m just seeing if I get this right,
that there\'s any requirement that the machine be able to sense a
certain amplitude of signal. Is that right?

DR. WEININGER: Correct. The standard used to call out or have a
requirement for a signal amplitude indicator. We\'ve modified that to be
signal adequacy because signal amplitude is very difficult to get from
the box and portray in the front panel and a lot of front panels have
the plethysmogram which you see and which is typically normalized so
that it looks pretty on your display, but might not represent the actual
pulse amplogy.

DR. COTÉ: You said that the 200 samples spread out between paired data
between 70 and 100 percent , how well distributed are those 200 samples.
In other words, it doesn\'t do much good if 190 of them are in the 95 to
100 percent range and only 5 are in the 70 percent range.

DR. WEININGER: The way it\'s stated is that it has to be equally
distributed across the entire range, 70 to 100.

That\'s not a statistically rigorous statement. And we\'re working on
that. The standard and FDA is attempting to make that a more testable
recommendation.

DR. OTULANA: Babatunde Otulana. You said tat the \-- for the neonates,
obviously for ethical reasons studies cannot be done in that population.
Are there other criteria that you use to determine when that application
will be approved for both adults and neonates or just neonates?

DR. WEININGER: That\'s really the subject of the question for
deliberation, for the Panel.

DR. OTULANA: Sure, I\'m asking the current practice.

DR. WEININGER: The current practice \-- I\'ll give you the ideal
practice. The ideal practice would be that a manufacturer demonstrates
that his probe fits on the neonate and it works on the neonate and
demonstrating that it works on the neonate is very difficult because you
can\'t desaturate a neonate like you can do a human. You can convenience
samples and Dr. Goldman is going to get into some of those issues later
on, so let\'s hold off on that discussion, but that is front and center
what I think Question 2 is about.

DR. LISBON: Are there any other questions? Please proceed then.

DR. WEININGER: So let me give you an overview of the pulse oximetry
standard and again I\'ll try to highlight the differences between the
standard and the guidance document. FDA uses standards as much as
possible. We believe they can do multiple different things. The standard
can take the place of just test data as a test method standard. We do,
however, we do also recognize that standards within their scope can
represent safety and effectiveness for particular types of areas, for
example, electrical safety. We typically recommend 601 and so let me get
into this and we\'ll see how that plays out.

Prior to 1992, ASTM built a standard called F1415 which leads to ISO
9919 and the European standard 865 and a high use of acronyms which you
don\'t fully understand \-- please stop me and I\'ll fill them in.

So the history and the reason I\'m bringing this up is that the ASTM
group which is predominantly manufacturers and clinicians and it\'s a
consensus development process puts a standard together and historically
in pulse oximetry, that standard that domestic ASTM \-- American
Standards Testing \-- it\'s a domestic national standards institute.
Typically, that standard has been adopted by the international community
and so it has great weight and now in 1996 with the revision of that
standard from ASTM it got broadened to ISO and then ISO got broadened to
both IEC Joint Working Group and all those acronyms simply mean that it
gets a very wide exposure, large number of clinicians and engineers
participate in the development of the standard. And that\'s good,
because we think that it holds great weight. And as Ann said, it was
completed just in January and FDA is in the process of recognizing.

The title of the standard is particular requirements of the basic safety
and essential performance of pulse oximeter equipment for medical use.
It is a particular standard which is a vertical product standard under
the IEC 60601 family. 60601 is the general requirements for safety. ISO
9919 with the pulse oximeter standard gives specific requirements for
pulse oximeters that expand on the general requirements as well as
requirements that re unique to pulse oximeters.

So let me just compare what the standard talks about which is basic
safety and essential performance to what happens in a 55(k) process.
55(k) process is a process of substantial equivalence so you\'re trying
to show by objective evidence that your device in a 510(k) compares to a
predicate device that has the same performance and safety and
effectiveness as the predicate. The standard calls out, if you will,
absolute requirements for safety and effectiveness. I say those are
absolute requirements. When FDA uses a standard, they are still
recommendations.

If the manufacturer can demonstrate that they have an alternate way of
meeting a recommendation, they can certainly provide that. But it does
give us a consensus opinion about what is basic safety. Basic safety is
protection against direct physical hazards such as shock vibration and
mechanical injury and importantly, essential performance which is
functional safety. And that\'s the performance necessary to achieve
freedom from unacceptable risks. Importantly in pulse oximetry that\'s
the accuracy of the monitor. That\'s an essential performance criteria.

And I\'ll mention the standard talks about equipment when it\'s used
under normal and reasonably foreseeable conditions. I don\'t want to \--
you guys are the experts in figuring out what is an unreasonable use of
a pulse oximeter.

The standard \-- next slide, please.

The scope of the pulse oximeter standard is that it applies to all
original equipment manufacturer probes. It applies to reprocessed probes
and extender cables, so the standard doesn\'t make a distinction between
a reprocessed probe or a brand new probe. They are both new medical
devices and have to be treated as such.

There are extensive requirements for documentation and labeling in the
standard and there are extensive informative annexes that detail the
rationale for each requirement so someone implementing or trying to
declare conformance or use the standard can go to the rationale and
understand what the purpose of that clause is and how the test methods
should work and there is also detailed educational material,
particularly about functional testers because they have a history of
being used as calibrators.

I\'m sure you\'ve all seen in a hospital somebody take their pulse
oximeter and slap it on a functional tester and say I know this device
is working when, in fact, it might work from an electrical perspective,
but that doesn\'t guarantee the 95 percent saturation on your screen is
a 95 percent saturation. We did address that issue.

Next, please.

I said that the guidance document references the standard to call out
what the accuracy specification is. In this case, it\'s a root mean
square error and that\'s the difference between what the pulse oximeter
reads and what the referenced co-oximeter, the blood based co-oximeter.
It has to be defined over the range of 70 to 100. The data must be
evenly distributed and we spoke about this and unfortunately, that\'s
one of the areas of improvement. We have some pictures and I\'ll show
you the pictures in a moment on what that means, but we don\'t have a
recommendation or a requirement to prove, if you will, or a testable
requirement to show that it\'s evenly distributed.

The standard calls out a maximum uncertainty or a maximum accuracy of 4
percent for pulse oximeters. You saw and Ann showed you what the clear
devices are and highest accuracy that we\'ve cleared to date and that\'s
4 percent and that\'s in a neonate. And so the standard attempted to
essentially mirror that and as far as we know there are no unsafe
oximeters on the market, at least due to their accuracy claims and so
the highest accuracy out there must be safe. So that was the upper limit
that was selected.

Next slide, please.

Here\'s a picture of the recommended desaturation profile. The X axis is
time and the Y axis is the co-oximeter saturation. You can see that
there are a number of points taken at each plateau and there are a
number of plateaus that stand the range. Again, the exact number of
plateaus and the number of points for each plateau are not specified.

There are other protocols that have been used in the past, interestingly
enough. There is some evidence that if you use a different protocol you
get a different ARMS and so the standard tried hard to focus or to
select a single protocol. Unfortunately, we didn\'t get there yet and so
this protocol, that\'s why I said it\'s a recommended desaturation
profile. I\'m hoping that in the next version of the standard that it
becomes the desaturation profile.

And again, the \-- one last bullet on the last one. The important thing
about having a single desaturation protocol and I\'m doing these ideal
human desaturation studies is so we can compare Monitor X to Monitor Y.
If everyone is using a different desaturation protocol, then we have no
objective way to compare it and since \-- particularly in a substantial
equivalency determination where you\'re looking at comparison to a
predicate, you need to have your test method, you need to have a single
test method to support that comparison.

Next, please.

The standards body spend a great deal of time trying to understand what
the shocking vibration environment is, particularly for home and
hospital. But you can see we also went into vehicles. There\'s four
different standardized types of tests for shock and vibration and
there\'s shock, vibration. There\'s drop testing and bump testing and
you can conceive of in your hospital, your home where you\'re hitting
steps or dropping monitors, these are the different types of tests that
is out there.

The original guidance document had similar types of testing levels, but
used what I\'ll call nonstandard tests. And there\'s nothing wrong with
using nonstandard tests, except that most of the testing industry has
centered on using what I\'ll call standard test levels and so the
standard attempted to update those, one, to make them more realistic and
relevant to what the perceived environments are and two, to make them
standardized levels so that they can get done in a practical and
efficient manner.

Next, please.

Alarms and indicators, clearly that\'s an important part of pulse
oximeters and as I said before the standard calls out or requires that
if you have physiologic alarms that you must have a low SpO2 alarm
present. The original 1992 versions of the standard called out a low
SpO2 limit of 80 percent saturation. That was the default and you, as
the operator, can apply a higher limit, but the default was 80. That\'s
been raised to 85. There are all kinds of arguments around false alarm
rates which we can discuss later. And I\'ll compare that again to the
guidance document which calls out continuous versus spot checking and
has requirements for both or recommendations for both a high and low
SpO2 alarm limit.

And again, here\'s the disclosure for the description of the signal
adequacy indicator. It used to be called signal strength, but many of
the boxes these days it\'s more than signal strength. It\'s actually a
quality indicator and it does morphology checking to make sure that the
pulse actually looks like a pulse, because there\'s lots of different
noise and motion artifact and electromagnetic interference and those
typically make the pulse not look like a pulse. And if your oximeter can
detect that because it\'s got plenty of processing power, that\'s
important information that the clinician should know.

And so the important message here is that the standard calls for a
description of that so that you, the clinician, when you\'re purchasing
the oximeter, can make an informed decision, based on your particular
application.

Next slide, please.

Patient characteristics. The patient population, age, weight and the
application area of the body, the types of tissue you\'re going to apply
it to and the environment, frequency of use and location all have to be
called out.

Next slide, please.

Both use and human factors are certainly important. The recommended
maximum application time has to be disclosed as well as rationale on the
manufacturer\'s part on why they chose that limit and evidence to
support that. There is also from a human factors perspective a
requirement for a variable pitch tone. Most of the oximeters out there
when saturation decreases you can hear the pitch go down. It would be
bad if half the oximeters, the pitch went up. It would be counter
intuitive and present a real patient safety issue and so the standard
addresses this by having a requirement. Compared to the 1992 guidance
document, it doesn\'t address this at all because in 1992, things were
just getting started and everybody did it their own way.

Next slide, please.

I mentioned safe surface temperature in the guidance document. I talked
about the applied part which is the probe and I talked about the monitor
itself. I want to give you just a five second history of where that
comes from and talk about what the updated version of the standard talks
about. The general standard, 60601, the third edition is about to come
out this year or next year. It raises the limit, decreases the safety
margin from 41 degree C. to 43 C. It does, however, require a risk
analysis to demonstrate that that\'s still a safe surface temperature.

The ISO or the ASTM and the ISO Committee actually had a large amount of
input into that decision. We were the driving force and did extensive
literature and there\'s actually some experimental studies to show that
43 C. is relatively safe. Interestingly enough though the pulse oximeter
standard adds further constraints. It only allows 43 C. for four hours.
It allows 42 C. for eight hours and it allows 41 C. essentially for the
maximum exposure time, but that\'s in adults. For neonates, children,
pediatrics, you have to stick with 41.

Also, the standard requires that there be an automatic setback. If the
clinician decides that they need the higher temperature and I\'ll state
the obvious. The reason they need the higher temperature is to get more
light because they\'re not getting good signal. They\'re not getting
good signal adequacy and they want to \-- they need to get the
saturation on those types of patients. But they set it at 43 C. and they
walk away. The standard requires that the monitor automatically be set
back to a safe limit, 41 C. after four hours. And I\'ll note here that
there\'s been lots of, if you will, burns reported in the literature.
Many of those burns are actually pressure contusions. The pulse oximeter
can be off and you can still see the same type of injury, so even though
you\'re not delivering any heat, the mere fact that you\'re taping
something and constricting the perfusion and the flow and some oximeters
I\'ve seen get taped on with many layers of tape and they\'re actually
squeezed on pretty tightly to try to get a good signal.

Next, please.

Oximeters in the early days were primarily trend devices and their
response time, if you wanted to see what your oximeter is doing you
could set \-- if you wanted to get rid of some of the noise in the
oximeter, you could actually raise the averaging time or the number of
beats that the oximeter averaged over and over the last few years people
have discovered \-- that\'s not quite the right word, but there\'s been
new clinical applications, for example, some sleep studies where
there\'s been evidence of a very rapid desaturations and resaturations
and we heard testimony from many clinicians that that\'s an important
performance aspect of pulse oximeters.

So the standard body sat down and we said well, what\'s the best way to
talk about that to the manufacturers and the clinicians? And we came up
with a disclosure requirement of response time and you can see on the
curve that percent saturation is on the Y axis and the X axis is time.
The very pretty idealized desaturation profile is the solid line and you
typically do that with the simulator, but you can see there\'s some
delay and the dotted line is the oximeter response, the displayed
oximeter response. And so there is some delay as to when the oximeter
determines that the saturation is falling and there\'s also some
infidelity in the depth of the trough that the oximeter picks up.

All this goes to show that the oximeter needs to disclose how it
performs, so that clinicians can select the best monitor for their
particular application.

Next, please.

In a similar vein, the alarm system also has delays in its response time
and so you can see in this type of curve, there\'s an alarm condition
threshold. And we use again, the standard recommends the use of a
simulator input because you\'re not interested in the patient
variability here, you\'re interested in characterizing the performance
of this particular signal processing device and there are many delays
and the standard goes into great detail about the sources of the delays
in the hopes that the person using the box, clinicians, can adequately
understand how their device is going to work and select the best monitor
for their particular task at hand.

Next, please.

I mentioned that the standard has several informative annexes. It goes
to a tremendous amount of rationale, particularly for safe surface
temperature and for the shock and vibration, but each of the test
methods and each of the requirements has a rationale. There\'s
informative annexes that talk about how to determine the accuracy of the
pulse oximeter or techniques to do that and it talks about how to
calibrate them and what the desaturation profile should look like and
how to set up the desaturation profile. And importantly, Annex FF talks
about simulators, calibrators and functional testers and what those are
appropriate to be used for.

In the early days, we had several oximeters that \-- or manufacturers
made 510(k)s where they tried to demonstrate or clear their devices
based on the response to the simulator and we said that well, the
simulator can demonstrate or verify a particular calibration curve, but
it is not an independent assessment of accuracy.

Also, because this is an international standard, well, so Annex GG, we
get into, the concepts of equipment response time and the alarms which I
just showed you the pictures. Annex HH is a reference to the essential
principles. That\'s the European Union has I think it\'s 53 essential
requirements which lay out in an objective fashion what they consider to
be safe. And because this is an international standard, it cross
references the requirements to that and also it has environmental
aspects of pulse oximeter, what

you\'re supposed to do with it when you\'re done with your oximeter,
should you just throw it in the garbage or should you attempt to
reprocess it?

Next slide please.

So, let me touch base for a minute on what\'s not in the standard. The
standard does not have specific validation or I\'ll call them
qualification requirements for neonates, that\'s clearly question number
two on your list of questions. It doesn\'t have a requirement for
disclosure of possibly poor performance on neonates. You saw that the
guidance document talks about the degradation factor, the 1 percent
degradation factor. The standard is mute on that subject. There is no
requirement for, or a test method for motion artifact or low perfusion.
I\'m sure you\'ve all heard about motion artifact in pulse oximeters as
the hot topic of the late 90\'s and the early 2000\'s.

The standard talks about disclosure of your performance on motion as
well as the guidance document also talks about that. But there isn\'t a
test method for that.

The standard also talks about, or the standard has a recommended
desaturation profile, but it\'s not a requirement and that\'s from a
standard\'s perspective. So the next generation asks for the assessment
of accuracy or calibration. And, so as I said, if would be nice if the
standard, and the standard will address that in the next go-around.

The standard also has two test methods for, two recommended test methods
for assessing safe surface temperature. One is a human body model, one
is actually a piece of plastic which is calibrated or represents the
human, so it would be nice if the standard had a single test method so
that everybody could agree upon the one way to do it. But we took the
approach of let\'s get it in the standard this time and the next
go-around, which should occur in five years or less, will hopefully
adopt one of those test methods.

Next slide please.

Let me say a few words about laboratory-idealized human subject studies
versus clinical performance or clinical assessment on patients. It\'s a
very important distinction between doing your laboratory, your accuracy
assessment on a human subject versus a patient. And the importance of
this is we need, we want to compare apples to apples, so when
manufacturers report their performance on oximeters, we want the test
method to be as similar as possible, so that it\'s the performance of
the oximeter and the saturation algorithms and the probe configuration
that is contributing to that accuracy as opposed to the types of
subjects that were used or the experimental set-up.

And so I\'ll just run through some of the things that are very well
controlled in an idealized laboratory study, which you can infer are not
very well controlled in an actual clinical performance assessment.

So, clearly in an idealized laboratory study, they\'re performed on
healthy adult subjects. There is typically no motion or electromagnetic
compatibility. And I use the word compatibility because not only are we
interested in making sure that the pulse oximeter itself is not
interfered with, but there\'s also very sensitive measure equipment
going on in your laboratory suite which could be interfered with and so
you want to make sure that the electromagnetic compatibility is broad
and across all your electronic devices.

The room temperature and the subject temperature a very stable and so if
you will, hopefully perfusion is relatively constant. The treatment of
the blood sample and the co-oximeter is very well controlled. You get
the blood out as soon as you can and you zip it over to the co-oximeter
and in fact, you might have multiple co-oximeters and take averages or
have some other statistical scheme for making sure that the results that
you\'re getting from your co-oximeter are as accurate as possible.
There\'s been some studies to show that under poorly controlled
conditions, co-oximeters can have differences in bias of up to 4 percent
which completely swamps out the accuracy of your pulse oximeter that
you\'re trying to measure.

The probe is typically held on and they\'re brand new probes and
they\'re taped up very well and they\'re glued on and their attachment
is assured and you\'re getting good signal strength and you\'re making
sure that the pulse oximeter is in its optimal state and if you\'re a
manufacturer you can know that because you\'ve got your vision into the
inside of the box as well as just what\'s displayed \-- when I say
inside the box \-- you have vision or you can get vision into what the
oximeter is doing as well as just to what it\'s displaying.

When you do a controlled desaturation study, you\'re able to calibrate
or at least to identify what the transport delay is. If you\'re taking a
blood sample from up top of the arm and you\'re looking at pulse
oximeters down at the fingers and I\'m an engineer, so I\'ve now
exhausted my clinical knowledge. But you can calibrate that transport
delay whereas in a patient all bets are off. You\'re not really sure
what the transport delays are. There might be some abnormalities going
on and so you need to know those things.

And finally, particularly for low saturations, the saturation jumps all
over the place in the desaturation profile and in a controlled subject,
you are able to do some averaging and to try to figure out what the real
value of the saturation is whereas in the clinic, it\'s much more
difficult to get that value.

I\'ve already alluded to most of the future work of the Committee. You
can tell where the weaknesses are and those are issues that the pulse
oximeter standards committees are actively working on. A selection of a
single desaturation protocol and treatment of co-oximeter accuracy and
statistics are front and center, more rigorous treatment of statistical
power. The number of subjects is important and the number of sample
points is important, but there shouldn\'t necessarily be a fixed number
for that if you have a higher quality process and you get tighter
variances, then you should need fewer data points.

And that\'s the ethical thing to do is take as few samples as you can.
The statistics to support convenience samples has to be worked out,
particularly in the neonatal setting and that\'s question 2 on your list
of panel questions.

Building a test method promotion which we\'re working on, having a
single test method for calibration and temperature and trying to figure
out how to define low perfusion and assess that are important. And
language to disclose that the accuracy under actual clinical use will be
different from the ideal clinical accuracy which you measure in a
laboratory.

Next, please.

And so we\'ve gone through the guidance document and shown that with \--
that we\'re actually keeping \-- the guidance document lays out the
basis for recommendations for substantial equivalence as they were put
out in 1992 as well as our current thinking to bring the guidance
document up to date. And I\'ve gone through the standard to show that
it\'s a reasonably comprehensive treatment of safety and essential
performance. It needs some improvement and those things are being worked
on, but I think it\'s a valuable tool that the FDA will leverage in the
future to support some of our substantial equivalency determinations.

Are there any questions on that?

DR. LISBON: Charles.

DR. COTÉ: I had one question on the tone of the oximeter pari parsu with
saturation. And apparently, there\'s no requirement that a pulse
oximeter change tone as the saturation drops which means to me that
those oximeters that are not configured that way, there\'s a delay in
response time for the clinician to realize something is developing. And
I could just go by my own experiences of a pediatric anesthesiologist.
Years ago, when we used to use \-- do bronchoscopies in babies, we had
to wait until the heart rate dropped to 60 and then the surgeon would
stop their bronchoscopy and we\'d ventilate the patient and get them
pink again and the heart rate up. But as soon as oximetry became
available, as soon as that oximeter went doot, doot, doot, is everything
okay up there? And we no longer had these arguments or discussions in
the operating room.

So it seems to me it makes no sense to have an oximeter that doesn\'t
take advantage of that wonderful monitor that tells you something is
developing and you don\'t have to be looking at it.

DR. WEININGER: The standard currently has a requirement for that, for
the variable pitched tone.

DR. COTÉ: But only going up.

DR. WEININGER: And going down, yes.

DR. COTÉ: It doesn\'t have one for going down. There are oximeters out
there that don\'t have that change in tone.

DR. WEININGER: Conformance with the standard is voluntary, so what I
would say is that those manufacturers that make that product are not
producing a quote standard oximeter. So there\'s no legal requirement
that a manufacturer conform to the ISO standard. And there\'s currently
no recommendation in the 1992 guidance document to address that.

DR. COTÉ: Is that something we should be considering today or is that a
separate issue?

DR. WEININGER: The ISO standard does address that. It does have a
requirement for that tone and in fact, now that the Nellcor patent has
expired, the actual frequencies can be put into the standard which
they\'ve agreed to, but if you think that that\'s important that the FDA
consider that in its guidance document, you can make that
recommendation.

DR. COTÉ: I think it\'s very important justin looking at demographics of
accidents that occur outside of the operating room. There are a lot of
these oximeters out there that don\'t change the tone and there\'s a
delay in response that something is occurring.

DR. WEININGER: I think that\'s a very good question to address to Dr.
Goldman. He\'s been dealing with alarms in the Patient Safety Foundation
and Anesthesia Patient Safety Foundation and his presentation, you can
ask him that question and he can give you a very good clinical
perspective on that.

DR. COTÉ: Another question I had for you is this temperature, surface
temperature being based on adult data. Obviously, the skin of an
premature baby and a term infant is very fragile, very thin. I guess I
don\'t know enough about that to see if this 43 or 41 even would be
harmful to a baby that size.

DR. WEININGER: In considering an appropriate maximum safe surface
temperature, the ISO and the ASTM Standards Committee tried to identify
the worse case situation and we believe or the standards body that that
was a neonate in an incubator which has the highest ambient temperature
that the incubator can be set to which is roughly 35 or 37 and we said
all right, we don\'t want the probe to go above 41 in that particular
case. There\'s been some work in the \'50s and the \'60s and granted, it
was done on adults and some others, but the evidence to date has shown
that 41 is pretty safe.

DR. LISBON: Are there other questions? Yes.

DR. DRASNER: I\'m a bit confused on one point. Does approval rest not
just on establishing substantial equivalence, but also meeting the
standards that have been set for these devices now?

DR. WEININGER: From an FDA perspective, and this is semantics, but
we\'re talking about clearance as opposed to approval. Approval has to
have objective evidence of safety and effectiveness, substantial
equivalence is a comparison to a legally marketed predicate.

DR. DRASNER: Okay, clearance then.

DR. WEININGER: The way the regulatory policy unfolds is that we can use
the standard in our decision as to whether a device is substantially
equivalent. It\'s not a requirement.

DR. DRASNER: But when you set a standard that now is higher than what
existed for a predicate device, what happens to that predicate device?
Does that still exist?

DR. WEININGER: Yes. Once cleared, unless you can identify a safety
hazard with devices that are currently on the market, those devices stay
on the market.

DR. DRASNER: So can you still get clearance by establishing substantial
equivalence to a predicate device even though you don\'t meet these new
standards that have been set by the FDA?

DR. WEININGER: Yes. But the flip side is again that if there\'s an
obvious safety risk, I mean latex is a perfect example. Until we figured
out the latex, that there were very serious latex allergies, there\'s
all kinds of products on the market with latex and then once you
determine that latex is a safety hazard, you can say well, those
products have to be pulled from the market.

DR. TUNG: How do you seek and process the clinical feedback on the
standards that you\'ve set?

DR. WEININGER: I\'m sorry?

DR. TUNG: How do you seek and process the clinical feedback on the
standards that you set? Is there a \--how does that \--

DR. WEININGER: From a standards perspective, clinicians have a seat at
the table. The standards bodies, particularly ASTM require a balanced
committee of clinicians, manufacturers and others to sit at the table
and determine consensus standards.

DR. TUNG: And when you sat down in \'96 to revise this, was there a
pattern to the clinical commentary?

DR. WEININGER: I\'m not sure I understand.

DR. TUNG: Consistent in the kinds of comments that you were getting
back, the kind of clinical feedback or not really any pattern that you
could identify. Say everybody was asking for a tone or something like
that.

DR. WEININGER: I\'m sorry?

DR. TUNG: For example, everybody was asking for a tone or everybody
wanted this or that. Was there any kind of pattern to the clinical
feedback or not really?

DR. WEININGER: Not that I can immediately recall, but I have to think
about that for a while. I mean clearly the clinicians and I\'ll say FDA,
their primary concern is patient safety. So in that sense their pattern
is the requirements that have to be set have to support patient safety.

And I guess I would even emphasize that they were very adamant about
patient safety, particularly when it comes to safe surface temperature
and some of the other disclosure requirements.

DR. LISBON: Are there other questions?

DR. BIRNBACH: It may be semantics, going back to what Charlie had asked
before, I\'m a little confused about what you can require versus
recommend. You made a distinction that seems to exist.

DR. WEININGER: Now you\'ve eclipsed my pay grade.

(Laughter.)

I\'m going to let the Branch Chief address the differences between
requirements and recommendations.

MS. GRAHAM: In a 510(k), we make recommendations. We recognize certain
voluntary consensus standards. We give guidance to industry and to FDA
staff. When we recognize certain standards, if we recognize the entire
standard or certain parts of the standard and we state in that
recognition whether we adopt, recognize it in its entirety or not. If we
have exceptions, we state them and we may point you to additional
guidance on those standards.

There are requirements, regulatory requirements in a 510(k) that are set
out in the CFR. But those are \-- there are some exceptions, but in
general, it\'s a broad list of requirements for any 510(k). It has to be
labeling and manufacturer\'s \-- certain manufacturer disclosures,
etcetera. So were you thinking of something in particular?

DR. BIRNBACH: How about we go back to the alarms. Some of these are not
requirements per se.

MS. GRAHAM: Right, right.

DR. BIRNBACH: Even though the expectation is that they will be present,
is that correct?

MS. GRAHAM: That\'s correct. It has evolved over time as the indication
for us has changed. In the beginning, and this is my understanding, I
wasn\'t in the branch in 1978 when they first started to be submitted,
but when we first received 510(k) files, they were for spot checking.

And because there was not a great reliance, minute by minute, on these
devices, the necessity for an alarm was not felt to be there. But these
devices have become primary clinical decision making tools, certainly
within the last 10 or 15 years. They are now continuously being used.

And so in 1992 we added or developed our original guidance document to
include in vitro validation of the pulse rate, for example, and other
aspects that we expect the manufacturer to submit to us. Again, that\'s
a guidance document and it\'s a recommendation. It\'s not a requirement.

So in theory, a manufacturer may choose to submit a 510(k) to us without
any of the requirements, recommendations in their 510(k). As a practical
matter, FDA would be hard pressed to fine that device substantially
equivalent to a predicate, particularly if it\'s a newer predicate.

DR. BIRNBACH: But they can intentionally use an older predicate?

MS. GRAHAM: Yes, they can. Yes, they can.

And that\'s one of the difficulties when are faced with a new
application that points to an older device where there has been little
or no performance data provided, no alarms, the labeling is cryptic and
these present challenges to us. And that\'s where we very often enter
into a lengthy dialogue with the manufacturer.

DR. LISBON: Are there other questions?

DR. DRASNER: Another question. Isn\'t there a mechanism to impose
standards?

MS. GRAHAM: Impose standards?

DR. DRASNER: I mean when you set these standards that would supersede
this idea that you can go and go against an early predicated device, can
you set standards that all devices must meet?

MS. GRAHAM: Well, when we develop a guidance document and we have two
different levels of guidance documents, level 1 and level 2. A level 1
guidance document basically tells the world we\'re changing the way we
think about a particular device or a particular regulatory decision
making paradigm. And we will recognize that there are predicate devices
already on the market, but from the effective date of that guidance
document that would serve as a special control for manufacturers, this
is the way we\'re going to do business. But in the absence of that,
Sandy is going to embellish my remarks, and correct me \-- but in the
absence of that we do have to acknowledge that previously cleared
predicate.

DR. WEININGER: Let me try to put this in some historical perspective. In
\'76, when the medical device amendments were written, Congress said to
FDA thou shall develop mandatory performance standards for all class 2
medical devices, pulse oximeters.

Safe Medical Device Act of 1990 and 1992 recognize that that was an
impossibly difficult task and relaxed the requirement to allow us to use
special control guidance documents, that\'s one big word which are
recommendations for what \-- I don\'t want to say constitute safety and
effectiveness, but what shows is substantially equivalent to a safe
device already, as well as recognizing the use of voluntary consensus
standards. So FDA over the last 5 to 10 years has invested a great deal
of resources in upgrading and participating in the development of these
voluntary consensus standards so that we can use them in our regulatory
process. They serve several things. There are test method standards
which you say all right, here\'s a test method and everybody is using
the same standard so we can get some idea that these apples are \-- the
results of comparable.

There are other standards like, as I said, 601, which talk about
electrical safety and FDA has recognized 601 that if you conform with
601, then your device is electrically safe. So standards have a lot of
different uses. They can substitute for pieces of the substantial
equivalency determination. They don\'t \-- if you look at the Venn
diagrams, they don\'t cover the entire sphere because there\'s lots of
other things in a 510(k) which the standards don\'t address, but for the
pieces that are appropriate from the scope of the standard, we can use
those standards in our regulatory decisions.

I sense that there was some confusion about the requirements of a
standard. Those are not, if you will, imposed \-- FDA cannot require
those types of tests or requirements. FDA has recommendations.

Is that clear as mud yet?

DR. LISBON: Are there other questions for our previous two speakers?

Dr. Weininger, can you just give me a little background on where this 1
percent degradation for the neonates came from?

DR. WEININGER: Yes, I can give you a little background. It\'s not well
captured, if you will, in FDA policy as to where that 1 percent comes
from. So to the best of my ability to cipher this out, in the mid \'90s,
there was some question as to what the influence of fetal hemoglobin was
on actually the co-oximeter. There were some studies shown that the
co-oximeter is inaccurate, particularly at low saturations with a large
percentage of fetal hemoglobin. Of course now we have to ask the
question of what\'s the percentage of fetal hemoglobin in neonates and
then you have to ask how quickly it clears and how quickly, what
patients were actually applying these to, so you go through all those
reps. But that was kind of the basis of them.

On the flip side in roughly \'89, I believe, NIH had a consensus panel
which talked about the influence of fetal hemoglobin and they said yeah,
there\'s clearly an influence, but we don\'t think it\'s clinically
significant. And so we\'ve got several articles that show it is
significant and some articles that show that it isn\'t significant and
so the middle of the road compromise was to allow this 1 percent
degradation and recognizing that you can\'t do a desaturation study in a
neonate and that the convenience samples you typically get only at
higher saturation values and Dr. Goldman is going to address many of
these issues shortly.

DR. LISBON: Are there any other questions? Yes?

MS. GRAHAM: I would like to clarify the neonatal question earlier. May
14, 2004, FDA published a document with a catchy tune of FDA Guidance
for Industry and FDA Staff, Pre-market Assessment of Pediatric Medical
Devices. And in that document, we defined neonates as from birth to one
month; infants from greater than one month to two years; children from
greater than two years to 12 years; and adolescence from 12 to 21 years.

DR. COTÉ: And is that required of industry to follow that?

MS. GRAHAM: It\'s a recommendation.

DR. LISBON: In the interest of keeping things moving, I\'d like to move
on to our next speaker, Dr. Goldman.

DR. WEININGER: Let me just give you a brief introduction for Dr.
Goldman. Dr. Goldman, I think is uniquely qualified to talk about the
clinical aspects of the three questions in your panel because he\'s been
on both sides of the fence. You can see now he\'s with Mass. Gen and
Harvard. He was previously \-- he worked for one of the manufacturers as
their medical officer. And so I think he\'s going to give you good
aspect. He is a Visiting Scholar under FDA\'s Medical Devices Fellowship
Program.

So I will turn it over to Dr. Goldman.

DR. GOLDMAN: Thank you, Sandy. Good morning. I\'d like to clarify
something before we move into here. I know that some of this is
confusing to everyone because it\'s a complicated topic and it asks and
invokes for concepts in the standards world which uses one set of
terminology and the FDA regulatory world which uses another set of
terminology sometimes. But I know that it\'s a hot topic right now, the
issue of pulse oximetry variable saturation tone because of some of the
discussions that are recurring within the world of the Anesthesia
Patient Safety Foundation and the ASA. And so I\'d like to clarify
something that Sandy said and that is the standards that are published,
the standards, that is, the ASTM and the ISO standards, do not require
the use of the variable saturation tone. What they state that if
present, the pitch of the tone should increase as the saturation
increases and should decrease as it decreases, because obviously it
would be terrible if some manufacturers decreased the tone when the
saturation went up and others did it the other way. So that\'s what
it\'s about. That\'s one important point.

And the other is that question about alarms and things like that and we
have to keep in mind that some pulse oximeters are designed for what you
could call spot checking and don\'t have a need for physiological
alarms, it wouldn\'t make sense. It would add to the cost and others, if
necessary.

And another principle that is int he standards world is typically that
of minimum safety and performance; to leave room for differences in
features and models and costs, but to make sure that at a minimum there
is something that\'s safe. So I\'d rather not spend more time on that,
since that was someone else\'s material.

So I have \-- I will try and cover some highlights, some key issues with
that address specifically the questions that you\'ve been asked to
ponder today.

The first concept I\'d like to comment on is the importance of
understanding the underlying model of pulse oximetry. There\'s a model
that encompasses assumptions about the physics and the physiology of
pulse oximeter and some or, in fact, much of the improvement in pulse
oximetry over the last decade or two decades is related to improving the
\-- is deeper understanding of the model and then the ability to design
and manufacture an instrument that could accommodate for the variability
in that in clinical conditions.

One of the important assumptions in the model we can show graphically
and that is that the thing that we care about in pulse oximetry is the
change in finger blood volume over time and that change in finger blood
volume over time is changing the incident light on the photo detector
and the light decreases as the blood volume increases.

That\'s the signal that we are attempting to measure i pulse oximetry
and sometimes it\'s successful and sometimes it isn\'t and any other
signals that are produced for any other reason are things that probably
confuse the picture and fortunately there have been great strides in
that area.

So let\'s \-- so in thinking about the model, we should keep in mind
that the clinical use of the pulse oximeter will be most successful if
the use conditions match the model assumptions. We should also keep in
mind that calibration is out of necessity performed on healthy adults
under laboratory conditions and not on sick patients under clinical
conditions. And again, the model is an ideal model usually, although
that\'s changing.

Now the problems creep in in terms of clinical performance when there\'s
divergence of clinical conditions from the ideal lab conditions and that
may contribute to inaccuracy. Examples would include dyshemoglobinemias,
that is higher than the minimum amount that would be present in the
laboratory condition. Venous congestion, pulsatile venous blood because
the model assumed that primarily it\'s the arterial blood pulsation
that\'s being detected by the photo detector most of the time. And
extreme vasoconstriction, probably for complex reasons.

In the clinical setting, just a quick list to help jog the memory and
expand the picture, in no specific order a list of errors in the
clinical setting may be due to device failure and typically high
readings in pulse oximetry are not infrequently due to a problem with a
sensor or the cable, more so than a physiological statement.

Motion conditions, very low profusion with poor signals and noise ratio.
The presence of pulsatile absorbers that are not the arterial signal
that we care about. That would include venous pulsation from a wide open
tricuspid valve, severe tricuspid valvular regurgitation, particularly
when measurements are being made on the head and the venous pulsation is
transmitted in a strong manner right to the measurement site.

Large artery pulsations. It has been written in some places that you
should put the pulse oximeter over an artery, let\'s say it\'s on a
neonate and if someone is having trouble getting a signal, people have
erroneously instructed in the literature to put it over an artery. Well,
the artery \-- the reason it\'s called a pulse oximeter, as you well
know, if you put it over an artery you end with bad data. The light
cannot penetrate a larger artery. And so you\'re not actually measuring
the blood in the artery. But that happens. And some people are
misinformed and actually do that.

Any other conditions that are different from that lab ideal calibration
setting, that venous congestion and also poor sensor fit would fit under
the category. And then there are the environmental conditions which
produce those conditions that are listed above and you can \-- some
people think of challenging states and describe environmental conditions
instead.

So let\'s go to Question 1 and what I\'d like to do is go through the
Questions 1, 2 and 3 without spending time on the questions because you
already know the questions, but maybe talk a little about some of the
issues that will affect how you think about the answers.

So Question 1, in general, we are addressing the differences between
transmission and reflectance pulse oximetry and technology. Well, the
first thing is to recognize that reflectance pulse oximetry and
transmission are based on the same model and the same assumptions about
light absorption and the signal that we\'re interested in.

But once you get beyond that point, there are other effects that may be
different. For example, with reflectance pulse oximetry, one may have to
consider reflection from underlying structures such as underlying bone
which could overwhelm the photo detector if there\'s a light
reflectance.

Another factor would be venous pooling. Now we know venous pooling can
be a problem with transmission pulse oximetry. With reflectance pulse
oximetry, it may occur under different conditions. For example, if the
sensor is placed on the head and the patient is tilted in
Trendelenburg\'s position and that\'s why we typically see the
application of pressure over the reflectance measurement site.

In addition, transmission pulse oximetry probe design constrains
placement and may reduce application error. A finger sensor has been
carefully designed to fit a finger. So it\'s less likely for that sensor
to be put intentionally to be put on incorrectly, such as sideways,
whereas a reflectance sensor, if it\'s a flat sensor, could be put in
the wrong place. It could be moved a few inches to the right or to the
left which may be an incorrect measuring site. And that\'s another thing
that we should consider and what should we do perhaps to minimize the
likelihood of that type of use error.

Continuation of the issues related to Question 1, do reflectance sensors
need better instructions for use or operator feedback from the
instrument itself? In the example, for example, with the placement, when
one is using a forehead sensor, it\'s designed for use on a specific
area of the forehead. That area does not include the temple where it
would be placed over an artery that\'s pulsating and introduce the
problem that we mentioned.

So what do we do about that? How can that be addressed? How can we
minimize the likelihood that clinicians will make that error? We know
how hard it is to train clinicians, all clinicians in all environments.
It\'s absolutely impossible. So what we can do from the design or the
educational perspective?

Another example is that some recommendations are made both by
manufacturers and in the literature by clinicians that one can use a
signal strength or what is sometimes called the perfusion index to
select an optimal measuring site. So perhaps a finger probe is put on a
finger and the signal is poor and the reading isn\'t very good or stable
and one sees a low signal strength, so one can move into another digit
and perhaps get a stronger signal and may get a more reliable
measurement.

But if you use that same knowledge, that same trouble shooting and
clinical diagnostic knowledge and apply that to a reflectance sensor,
and move it around until you get the best signal, that may be the wrong
place to make the measurement. It may perhaps be over an artery with a
great signal, but it\'s not giving the right data.

So again, the question continues, how do we transfer that knowledge, how
do we educate, perhaps with the instruments. Do they need to be designed
to provide more information? Is that even possible.

A related question to these issues in Question 1 is should reflectance
probes be specified for use only on sites that have been validated? So
let\'s take again the example of the forehead probe. Normally what would
be done is the forehead probe would be calibrated on adult laboratory
volunteers under ideal conditions and then if it was used, if the probe
was used on a neonate, specified for use on a neonate, we would expect
to add that one percent and the technical term for that one percent is
the fudge factor. And that\'s the way it would be used. And that would
be the typical state today.

So one question that we would ask, if you asked about the use of the
sites is would a convenience sample, would samples that could be
obtained in the neonatal population on a convenience basis in a clinical
environment, would it help validate that that concept was right?

Similarly, we would ask, if there a significant difference between the
same site in adults and neonates? Is the neonatal forehead essentially
the same as the adult forehead? Is it appropriate to make this transfer
of the technology of the measurement and just perform that with that one
percent fudge factor or are there anatomical or physiological
differences between the adult and the neonate that would lead us to be
concerned about just transferring that measurement?

One possibility, for example, and I think the data \-- I don\'t know how
much data there is in this area is that it has been mentioned that in
children with cyanotic heart disease, there may be a higher peripheral
venous pressure and we know that if there is an increase in peripheral
blood volume, that may affect measurement accuracy and perhaps that
would be the case as well in these patients. And if so, should there be
data collected on those patients to validate the concept that you could
transfer the adult data to the neonatal setting?

Another question is is it clinically acceptable to specify use of probes
for other sites? For example, if we have adult laboratory validation
data, if we have the adult forehead and if we\'ve agreed that it\'s
acceptable to then use that probe on the neonatal forehead, is it also
okay to use the probe on other areas of the neonatal body, such as the
abdomen or the back. Currently, the FDA would expect that there would be
some validation data for the site for which it would be used. But there
are people who do use clinically and report it and there\'s data in the
literature to \-- for use of probes on other sites. And we should at
least think about is that acceptable practice or not, how would one
approach that.

Question 2 relates to the use of that 1 percent accuracy reduction
factor. I really want to say fudge factor, but it may be more
appropriate. Accuracy reduction factor, is that clinically appropriate?
And as Dr. Weininger said, he talked a bit about the history which is a
bit nebulous, but the current practice to add 1 percent to the specified
accuracy from the adult laboratory setting to estimate performance in
neonates under ideal lab conditions. So keep that in mind. That 1
percent would be, would express the expected performance on neonates if
they were in that same setting which is the ideal laboratory conditions.

So as Sandy said, the rationale is confusing, but it looks like the
clinical accuracy data that does exist in the literature now in numerous
studies of the devices under clinical use does seem to suggest that the
current approach when reflecting on that, does make sense and that it is
an appropriate approach, it seems to be the case.

So let\'s ask some other questions. Would post-market convenience
samples be useful to support the clinical assumptions?

Should there be a need? Should there be thinking of collecting neonatal
clinical data, but doing that under a post-market setting, after FDA
regulatory approval and clearance of the device?

Why would that \-- what would the value be? Well, current regulatory
practice as has been discussed at some length, does not require testing
on neonates for neonatal probes. Although it may be a commonly performed
practice, so at most and potentially possibly all manufacturers may test
neonatal probes in some way. They have to make sure that it fits
correctly or they should make sure that it fits correctly, that if it\'s
an adhesive it sticks in place. If there\'s a wrap type sensor that
it\'s comfortable and so forth.

A lot of that is being done currently, it appears and one should ask
should there be a requirement for that? What is the expectation
clinically? When a clinician opens a package and applies a probe to a
patient, are they assuming that there has been clinical testing or not?
And if not, is that an issue of education or should there be a change in
the requirements?

The other interesting thing is that manufacturers are ideally suited to
perform some testing and they can and generally do a much better job
than the clinician who has access to clinical material and may have
excellent clinical knowledge, but doesn\'t have access to the underlying
engineering information about the instrument or the data collection
tools. Manufacturers can collect data that would include data about the
amplifier settings in the instrument and the emitter settings and so
forth.

Question 3 is with regard to over-the-counter use of pulse oximetry. Now
if pulse oximeters were cleared for over-the-counter use, it would
require pre-market submission and an assessment of the instructions for
use for lay people. One of the key parts to the decision has to be can a
lay person go to the drug store, by a pulse oximeter and use it safely
and appropriately?

Well, let\'s look at some of the concerns. One of the obvious concerns
would be if there\'s incorrect application of the device leading to bad
data, could that result in bad outcome? Well, that\'s reasonable. Kind
of self evident. How about errors in interpreting and using the data? Is
it possible that someone will see a low saturation value, 50 percent and
think that that\'s normal? Maybe, who knows. Maybe they\'ll see it in
the 70s and think it\'s a passing grade. It\'s probably a letter C grade
and the patient is okay.

How will they interpret the information? And will having a device like
that provide a false sense of security? Okay, reasonable questions, I
think, for you to consider.

Let\'s look at the mitigating factors that would mitigate those
concerns. What if there are use errors in the pulse oximeter? Well, as
we know, based upon the historical use of pulse oximetry, most errors
produce erroneously low saturations which would produce false positive
results. Therefore, to be a false positive detection of hypoxemia, not a
false negative and it\'s more likely that the consumer will see the
value and especially with the instructions for use are clear, would call
a clinician for advice, just because of the nature of the technology.
It\'s less likely that they will see a falsely high value and then
ignore a problem. So I think that\'s one of the mitigating factors that
we should think about.

Now let\'s think of the benefits. If pulse oximetry becomes available to
the population at large in their local drug store, the benefit would be
empowerment of patients to detect potentially seriously medical
problems. So when their neighbor is complaining that they\'re short of
breath and they call their friend who has a pulse oximeter who has a low
saturation, perhaps they\'ll seek medical attention much sooner than
they would have otherwise. That might be a good thing.

It also starts to prepare for innovation in health care in this country
in terms of moving measurement ability into the home and in our
institution and Partners Healthcare, we are seeing development of things
which are occurring elsewhere in the country like the ambulatory
practice of the future which are ways of disseminating, distributing
medical devices of some type to patients at home, finding ways of
acquiring the data and interpreting it remotely and so forth. This is
the movement int he country. And so as we start to think about
over-the-counter use of these devices, it\'s probably an important
question in terms of public health and safety in that we may be
empowering people to take better care of themselves.

And probably more applications will develop as we start to deploy
technology like this nationally. For example, there\'s clearly a need
for easy and safe titration for patients who are home oxygen. And
they\'re generally very knowledgeable consumers and they may use
technology for things that we never considered once it out there in the
home such as biofeedback, assessment to athletic conditioning and things
of that sort.

So finally, just some other validation issues to think about. Should
probes be tested in ill patients prior to marketing? Right now, as has
been discussed at length, that isn\'t a requirement.

On the one hand, from a clinical perspective, from a clinician\'s
perspective, one would say of course I want these devices tested on sick
patients before I buy it. I want to know that it works on ill patients.
But although that sounds reasonable, it\'s very simplistic and probably
things to consider is the variability in illness, the implications for
the stability of measurement data, what metrics would be used, how many
convenience samples might be required, could those patients be found,
would they be in the target saturation range of interest? So important
questions and ones that have really challenged people for a while.

Next question. Would post-market convenience sampling provide a needed
reality check? Post-market samples may be easier to obtain due to less
stringent IRB requirements because if the device has been cleared and
it\'s available for sale in the country, that alters some of the way
that\'s handled through the IRB. So would it be reasonable to start
collecting and expecting a report from manufacturers of the performance
of the instrument after it\'s released for marketing and sale. Would
that help with the reality check on the design and on the use of the
instrument that it censor?

And finally, the question that we alluded before and this gets to the
issue of how does one get good convenience samples and in which
populations. It\'s very tempting to go to the low saturation range of
children with cyanotic heart disease. But there is an interesting issue
with those children and we probably need more information about the
nature of their peripheral circulation. Do they represent the ideal
patients for which to get low saturation data or are they somehow
different than other children who are experiencing a transient event
such as a respiratory event and a transient desaturation? For those
children, they probably don\'t have the same peripheral circulation or
may not have. A question for you to consider and perhaps you have the
expertise among you to think about that.

And finally, I think we have to recognize and we all know that the
knowledge, the clinical knowledge of the average and potentially even
expert clinician about the correct and ideal use of pulse oximetry,
it\'s strengths and weaknesses and interpretation of the data is
probably inadequate. And perhaps it would be reasonable to talk about,
think about, what can be done to support effective clinical use, perhaps
education or what other things might really help.

I\'d be happy to answer questions.

DR. LISBON: We\'ve got about five or so minutes for questions.

Dr. Birnbach.

DR. BIRNBACH: I\'ll make it quick. Two questions about your mitigating
factors in no particular order. While I understand that it might be nice
for someone on home oxygen to also have a pulse oximeter, isn\'t home
oxygen based only on a prescription and you need to be followed? It\'s
not like I can say I want to use home oxygen today.

DR. GOLDMAN: Well, in reality, the patients remove and apply their
oxygen and they\'re instructed to, frequently, based upon how they feel.
And so they come back to the office and the clinician has essentially no
data, no objective data. They have the patient\'s report on how they
felt, but wouldn\'t be helpful to know that when they felt bad their
saturation was low and \-- or maybe their saturation wasn\'t low and
they felt bad for other reasons. It\'s another area where we don\'t have
all the information.

DR. BIRNBACH: And right now, can a physician prescribed a pulse
oximeter, for example, purchase one and give it to a patient?

DR. GOLDMAN: To the best of my knowledge, yes. I believe they certainly
can.

So it gets to the area of the cost and the distribution of tools to the
population, more so than the core ability of being able to get to that
measurement. Absolutely, you\'re right. You can get the data if you want
it today.

DR. BIRNBACH: And the second question is is regards to device failure.
Did you suggest early on that a device, if it failed, was more likely to
give you a high pulse oximeter reading?

DR. GOLDMAN: What I said was or what I intended to say was that a high,
an erroneously high reading is more likely due to a device failure, that
is, equipment failure, as opposed to a physiological reason for that.

DR. BIRNBACH: And do we have data about device failures and how often
that gives you a falsely high reading?

DR. GOLDMAN: I wish I had that data.

DR. BIRNBACH: Because if you are describing mitigating factors, and
suggesting that anybody can carry around their own pulse oximeter, they
might not have the clinical basis to say this reading doesn\'t make
sense.

DR. GOLDMAN: That\'s a very good point and perhaps that should be in the
consideration for OTC use, what is the likelihood of reaching \-- of
having values that are erroneously high in patients who have a
physiological low saturation.

DR. LISBON: Dr. Otulana?

DR. OTULANA: Let me just answer one of the questions you raised about
use of home oxygen. Yes, we do give, we do prescribe pulse oximeters,
pulmonologists do that \-- for these patients to have spot checking of
their SpO2 at home, so that is done often.

The question I have, you showed a number of factors that would affect
the accuracy of the pulse oximeters at home. This is an interesting
question in terms of the extrapolation from adults, healthy adults to
sick adults on one hand and extrapolation from healthy adults to sick
neonates on the other.

Do you, just your own estimate, do you think the extrapolation from
healthy adults to sick adults is the same level of risk when we
extrapolate from healthy adults to sick neonates or have I confused you?

DR. GOLDMAN: No, no. I think your question is a good question. I think
that\'s frankly one of the questions that is being presented to the
panel to consider today is those clinical issues.

DR. OTULANA: Right.

DR. GOLDMAN: And I think the answer to that will \-- what will influence
that to some degree is the kind of illness, the kind of conditions
we\'re talking about.

DR. OTULANA: Right.

DR. GOLDMAN: And how it affects the peripheral circulation and the
stability of the values.

I think that one of the \-- a few of the really interesting problems
here are we all have a clinical sense of the performance of pulse
oximetry. With just three years of use, we think we understand it and we
think we understand when the values are right. But how do we know? How
do we get that information, that clinical sense? We\'re getting it from
the pulse oximeter itself and we don\'t have, for example, another gold
standard that we can use. The only gold standard we have is co-oximetry
and that doesn\'t provide continuous data. It doesn\'t even provide real
time data.

So one of the core problems with understanding pulse oximetry and it\'s
true performance in those challenging populations is that we don\'t have
a gold standard to use and that\'s why this is, I think, an unusual
monitor in a particularly challenging setting.

If we had a \$50,000 instrument that could provide continuous reliable
co-oximetry data, then at least it could be used for research purposes
and we would know what the performance of pulse oximeters was.

DR. LISBON: Dr. Leung and then we\'ll break.

DR. LEUNG: I have a question which could be brought up again during the
discussion later with the Panel. My question is what would be the real
advantage of recommending post-marketing measurement versus
pre-marketing measurement. And I\'m thinking of the equivalent in the
drug. You\'re requesting only Phase 1 data currently for marketing and
we\'re not looking at Phase 2 or Phase 3 data.

The question is is there really and obviously to the manufacturers it\'s
advantageous, but in terms of public health concerns and a false sense
of security to the users and for pulse oximeter it will be clinicians
and nurses that is FDA approved. And the liability, so I think that
might be something to consider.

DR. GOLDMAN: I can give a quick answer although I\'ll be going out on a
limb here. I think the answer relates to the fact that we have a few
decades of historical use of performance of pulse oximetry. Generally
speaking, the instruments seem to work. They seem to have saved many
more lives than they put at risk. The approaches that the manufacturers
are using seem to be generally okay, although there\'s room for
improvement. And I suppose if we were all here today discussing a new
instrument that no one ever heard of before and wanted to use called a
pulse oximeter, that probably would be exactly what we would be talking
about I would think is getting the data in that manner.

So I think that analysis is being colored by the historical use that we
have and then the question is is it worth the additional cost, expense
and delay to market given that history. Those are the questions. And the
answer is, I think, subjective.

DR. LISBON: We will have time for questions as we go further on during
the day. I have about 10:17. We\'ll reconvene at 10:30. It\'s time for a
short morning break.

DR. GOLDMAN: Thank you.

(Off the record.)

DR. LISBON: All right, if I could get started again. Next on our agenda
are presentations by our industry stakeholders. There will be four
presenters, actually three presentations. However, I would ask that the
presenters limit themselves to 15 minutes with five minutes for
questions, please, and please identify yourself for the record.

I believe that we\'re going to start with Dr. Paul Batchelder from
Clinimark and I apologize if I\'ve mispronounced your name.

MR. BATCHELDER: No, that was exactly right, Paul Batchelder.

Thank you for allowing the time for me and my colleagues to speak. I am
the \-- I\'m with Clinimark. As you had mentioned, we are an independent
physiological monitoring and research facility with one of the few
desaturation or hypoxia laboratories in operation today.

We recently separated our labs from G.E. Healthcare, but for the last 14
years have been the head of Omeda Clinical Research in G.E. Health care.

The important piece there, the reason I tell you that is that Omeda with
Nellcor were one of the two pulse oximetry developers that started out
in the early \'80s, \'82, \'81. And so we\'ve got a lot of experience
validating and testing these devices. The desaturation laboratories,
they do desaturation studies that you\'ve been hearing about this
morning. They were instituted and developed in our types of laboratories
way back in the 1980s.

The question that we\'re going to deal with today, that you\'re dealing
with is how can pulse oximetry be effectively evaluated in neonates.
What we\'ve done is we\'ve evaluated around 43 published peer-reviewed
journals, papers, over the years that dealt with accuracy of pulse
oximetry in the clinical environment in adults and neonates. I believe
that you received a copy of the letter that we sent to Neel earlier
today. Is that true? Does everybody have a copy? Yeah, yeah.

Unfortunately, you won\'t have time to read that and digest all of the
information during my talk. I\'ll talk to that and refer to various
sections there.

The papers that we evaluated, we evaluated the ones that reported bias
in precision in such a way that we could calculate the ARMS accuracy of
the pulse oximeter. Now the ARMS accuracy is similar to a standard
deviation. It\'s what accuracy specification is published in the pulse
oximeter manual and it\'s what is submitted to the FDA for regulatory
concerns.

Now Ann\'s table, Ann Graham, that mentioned, she mentioned earlier
about the \-- that she displayed, that had accuracy of less than or
equal to 3 percent for adults and I think the greatest inaccuracy of
acceptable was less than 4 percent, those are the maximum acceptable
limits. Generally, pulse oximetry that you use today has an accuracy
specification that was developed on healthy adult humans in the
desaturation laboratory of plus or minus 2 percent.

And then you\'ve heard about the 1 percent fudge factor. I\'ll use that
technical term that has been applied to the values from the adult
laboratory to claim accuracy for the neonatal environment. The key
points that I\'m going to go over today are the fact that we believe,
the literature suggests the accuracy of pulse oximetry in the
hospitalized population is not dissimilar between adults and neonates.
We\'ll talk about that in a little bit more detail in a moment.

The theoretical and published influence of fetal hemoglobin is
clinically insignificant and the 1 percent adder, is based on anecdotal
evidence and is incorrect. It took quite a bit of work with our \-- the
best retrospectroscope that we have to look back and try to determine
where that adder came form. I\'ll talk about that a little bit.

Then we surveyed the neonatologists. That survey is not in your \-- in
the letter that we sent to get a spot check, a sanity check on some of
the questions and to try to determine, well, how can we validate
accuracy in the neonates or verify the accuracy as the case may be? And
all of the feedback that we got from our neonatologists on both
seaboards and in the middle of the United States was pretty much
unanimous. They said collecting a statistically meaningful number of
simultaneous SpO2 from the pulse oximeter and SaO2 from the co-oximeter
over the full range is unfeasible. But there is hope. There is a
feasible approach to effectively evaluate pulse oximetry in neonates and
provide that recommendation also.

Now what we\'re dealing with here is accuracy in various areas of this
matrix. Currently accuracy specifications are determined and developed
in the adult laboratory and the 1992 review of guidance document states
that we can use the data on adults to make claims in pediatrics, but not
neonates.

Then the question that we\'re going to talk about today is well, how
does the accuracy in the hospital environment relate to that laboratory
determination? We will not be talking about neonatal desaturation in
laboratory because that\'s unethical and for other reasons that\'s not
available at all.

So our question is how does the neonate in the hospital environment,
accuracy of a pulse oximetry look. How does the adult accuracy look? And
how do both of those compare to the adult accuracy in the laboratory?

Let me just run over quickly, this is a picture from a laboratory before
our study was started, many years ago back in the early 1990s. They\'ve
improved quite a bit since then, but the point here is is that we use
consented healthy adults and our purpose is to provide reproducible
results.

In the controlled laboratory setting, we screened for interferences like
total hemoglobin, high blood pressure, dyshemoglobins, perfusion
instabilities and that\'s a very important piece and the purpose of all
of this is to establish a stable plateau to provide stability in the
arterial tree, to reduce lag time because we sample at one point of the
co-oximeter value and we measure the pulse oximeter values at another
point. In addition to that, the co-oximeter is a point in time
measurement as pulse oximeters are real time continuous measurement.

Now the way we do attempt to maintain stability in the laboratory is by
controlling the title volume of the subject, the respiratory rate
movement and dynamically control the inspired gases. We actually have a
computer-controlled gas mixing system that allows us to fly the subject
saturation to appropriate levels, remembering that the purpose of the
physiology of the human is to maintain homeostasis and that is not
homeostasis at a low saturation. The body is always trying to pull the
saturation up. So it\'s quite a feat, even in healthy, stable
volunteers, to maintain a stable saturation.

So laboratory to clinical. The clinical is subject to inherent noise,
the saturation differences between the A line and the pulse oximeter due
to hemodynamic instabilities and the unstable oxygen saturation.

Now there are other sources of clinical inaccuracy also, but the biggest
difference can be created quickly by hemodynamic instability.

So the actual saturations at the arterial sample site and the pulse
oximeter site are often not precisely the same due to time lag,
fluctuation in the saturations, differences between the reading types.
One is a static point in time reading and the other is a dynamic
reading. Oftentimes, the blood that bathes the arterial catheter is not
the same saturation as the blood that\'s bathing the pulse oximetry
sensor site and therein lies the rub.

If your ruler is bounding around, you cannot measure the length of your
device very well. If you co-oximeter says it\'s 12 inches and exactly at
that moment the co-oximeter sees the 12-inch or a saturation of 85
percent, but the pulse oximeter is still being bathed in blood that is
of a higher saturation, then it\'s going to give a wrong reading.

In other words, to kind of put a point to it, the arterial catheter in
adults is usually placed in the radial artery and the \-- and in
infants, in the neonates, the arterial sample site is usually the
umbilical artery and then the sensor site of the pulse oximeter is
placed on a finger in the neonate. Most often, it\'s on the foot,
depending on the type of sensor, of course.

And as the blood oxygen level changes, it doesn\'t reach both sites at
the same time. And as a matter of fact, there are several studies
recently showing that the delay in time from the arterial sample site to
the finger site can be as much as three minutes in some cases.
Oftentimes, low perfusion will cause shunting of the blood and the
actual highly perfuse or a change in the saturation blood reaching the
sensor site will be several seconds or minutes later.

They\'re both, the co-oximeter and the pulse oximeter could both be
reading correctly, but until they both are bathed in the same saturation
of blood, they\'re going to give inaccurate results.

So, what did we do? We reviewed the papers on adults that evaluated the
accuracy of pulse oximetry in the clinical environment and we evaluated
papers that did the same in neonates. Twenty-eight papers in adults and
28 papers in neonates and I see one of the authors of some of the
neonatal papers is here.

What we found after calculating from the bias and precision ARMS of all
of the papers, was that in the adults we see about 3.26 percent plus or
minus accuracy in the hospital; when compared to the laboratory, very
carefully controlled stable values. And interestingly enough, this is
the important piece here.

The neonates showed a 3.44 percent. Very similar data. And when we
overlaid the data, looked at the distributions and the T tests and F
tests, we could not show that they were different. What we think this
means and these data, this particular slide is not in your \-- not in
the paper, but both of the graphs that make up this, the red for
neonates and the blue for adults are in your handouts and in the letter.

The bottom line here is what this means is that the laboratory is a very
good place to measure things. It\'s a stable ruler, but the hospital,
remembering back to the distribution here. We have a fairly large
distribution in the hospital which might indicate that it\'s much harder
to maintain a stable saturation that is bathing both the arterial
catheter sample site and the pulse oximetry sample site at the same
time.

What this means is that the hospital environment, in the hospital, the
adults and the neonates show about the same accuracy precision and the
laboratory though is much tighter. So maybe the 1 percent adder that
I\'m going to talk about next, more reflects the laboratory to hospital
difference than neonates to adult difference.

Well, where did the 1 percent adder come from? We started searching back
and looking at when it first showed up in the accuracy specifications
and I think it\'s associated, we think it\'s associated with the time
when the Nellcor N 100 was evaluated.

Jennis, his work is in your letter that you just recently received. On
page 20, there is a graph, graph number 23, or paper number 23, that
shows a bias and since we at that point in time we did not have the
wealth of experience that we have now in pulse oximetry and a large
number of clinical papers, to be safe, we thought it might make sense to
add a 1 percent inaccuracy adder, just so that we didn\'t provide the
clinician with inaccurate information.

Now Jennis showed though that the accuracy in his study was 2.6 percent
which is pretty close to the 2 percent that we see in the laboratory.
The bias, however, was correlated with fetal hemoglobin, but their
literature review concluded that the fetal hemoglobin should not be a
factor.

Then another paper looking at the effect of total hemoglobin, showed
that the error was not related to fetal hemoglobin and in their study
they\'ve shown that fetal hemoglobin levels did not have significant
effect on accuracy.

Pologe and Raley, one of whom is my colleague at Clinimark took data
from Dr. Ziltra who lysed adult and fetal red blood cells and measured
the extinction coefficient of the hemoglobin of both adult and fetal
hemoglobin over the range in which pulse oximetry works, about 660 and
940.

And the thickness of this line actually depicts the difference of the
pulse oximetry of error that could possibly be resultant from adult and
fetal hemoglobin. So basically, interpolating from the data, the
inaccuracy would go from laboratory 2.0 to 2.1 or a one-tenth increase
with fetal hemoglobin.

Why not go to the ICU, collect data to support accuracy claims in the
neonates? We\'ve all heard I\'ve got lots of kids with low sats. Use
data from blue babies. This is our starting point. This is what we
required in adults. The neonatologists that we spoke with were all very
animated and very unanimous in \-- and we also checked with some data
collection nurses. Basically, the kids with cyanotic hearts usually do
not have A lines. They\'re usually larger kids and they often are
hypertensive with high venous pressures.

The reason for the A lines, they\'re unstable. Things change quickly.
And most lower sats are transitory. The low sats the clinicians are
talking about is below 90, not where we need.

So I\'ll just jump through this since we\'ve got to move on, but the
limited availability of neonates with A lines who are within the lower
saturation range and inability to obtain data under stable, controlled
conditions makes collecting data in those kids unfeasible.

Well, what can we do? The most common saturation range of the kids is 85
to 95. It\'s up to 100 percent in the older kids, but of course they
don\'t have A lines. That doesn\'t help us. The vast majority are being
kept between 85 and 89, and 95 percent of all the patients in ICU C
range is between is 80 and 98 percent.

So what do we do? These are the recommendations. I\'d be happy to
entertain questions about these or we can talk about it further later.
But to continue to use the best router we have to determine pulse
oximetry accuracy in the adult laboratory and then add, which we do not
have at this point in time, physical testing on the intended population
for form, fit and function testing of the sensor design to demonstrate
that it\'s the right thing for these neonates, to evaluate the adhesive
and so forth and then do convenience samples and discontinue use of the
adder and clarify clinical performance in labeling.

DR. LISBON: Thank you, Mr. Batchelder. WE do not have time for
questions. I am going to keep on a pretty tight schedule so that the
next speaker is Mr. Paul Mannheimer from Nellcore and Tyco Healthcare. I
would recommend, so that we do have time for questions, that you keep
your presentation to 15 minutes so that people can have a chance to ask
you questions.

DR. MANNHEIMER: Thank you. I want to address the issue of reflectance
pulse oximetry and I essentially want to cover three important points as
I step through this. One, I\'d like to demonstrate to you that
reflectance and transmission oximetry really ought to be treated
equivalently. There is some misconception on what reflectance oximetry
is. I\'d like to address that.

I think there\'s value in our ability as manufacturers to provide
products to clinicians, whether it\'s reflectance or transmission
geometries and I\'ll talk a little bit about what additional value might
be afforded by having access to reflectance sensors.

And ultimately, I think the appropriate path is to treat reflectance
oximetry just like Mr. Batchelder described, to test it in the
laboratory, validate it in the laboratory and do the verification
testing of its appropriateness on neonates in the clinic to demonstrate
safety, appropriateness and do some sampling versus blood.

First of all, let\'s talk about pulse oximetry, in general. This first
bullet point that I grabbed, actually lifted from ISO 9919, although I
paraphrased to fit within the confines of a slide. It\'s noninvasive
estimate of SaO2 from light signals. It interacts with tissue using the
time-dependent changes in tissue, optical properties that occur with the
pulse of a blood flow. I think Julian did a nice job of describing where
that\'s coming from.

That statement is not specific to transmission or reflectance. It\'s
based on the principles of the modified Lambert-Beer Law, light diffuses
through tissues, true for both reflectance and transmission. The
detected signals travel through about a centimeter of tissue. I\'ll show
you that in a minute. And it\'s empirically calibrated or validated on
signals from human tissues compared to co-oximetry.

All of these principles are independent of where the emitter in the
detector are located.

Let\'s take a look at the most conventional transmission design. It\'s
intended to go across the fingertip or other opposable tissue surface
that in all intents and purposes, the only reason we limit ourselves to
the fingers, the toes, the foot or the earlobe and the nose, those sites
are thin enough where we can get enough light through the tissue bed to
detect and run into the pulse oximeter. We would do transmission
oximetry across the head, if we could get enough light through, but most
people, that doesn\'t work.

(Laughter.)

The photograph at the bottom is intended to show you and I\'m sorry when
I took this, I didn\'t preview that there was a wire running back behind
here. This is the emitter of a pulse oximetry probe sitting on the pad
of the finger. I\'ve over-exposed it a little just so that you can see
the light coming out.

This is the red light from the pulse oximetry probe. Typically, we would
place the detector on the opposing surface, but note that whether
you\'re driving a light from the end or the side or even on the pad, all
of that light is scattered through the tissue.

It doesn\'t really matter. All of the information that the pulse
oximeter is seeing to calculate a saturation exists in every photon
that\'s coming out of there. The one that counts is where the photon
detector is located.

Let\'s take a look a reflectance probe and I would like to shoot the
person that coined the phrase reflectance and we were talking about this
at breakfast this morning. I\'m not sure where it came from because I
think there\'s a lot of misconception of what that means. There\'s been
some discussion, I think in some of your handout that reflectance probe
requires some surface to bounce off of and that\'s incorrect.

I like to think of reflectance probe as a transmission probe, only it\'s
sideways. So whether you\'re going north and south or east and west,
we\'re transmitting light through a bulk of tissue.

An example of this, I have my handy demo here, if I shine my laser
pointer into a glass of water which has just a little bit of creamer in
it, we see that the light is scattering back, scattering sideways. If we
were to collect the light that is over here, it hasn\'t reflected off of
any surface. It\'s scattered through this bulk scattering media.
Scattering length of light and tissue is about one millimeter. So as
long as the emitter and detector are located along a surface, more than
a couple of millimeters apart, you\'re measuring the transmission of
light through that bulk surface. Had we put the detector directly over
or right immediately, adjacent to the emitter, within a scattering
length, that might be considered reflectance, but even then it\'s a bulk
scattering through a depth of tissue. It doesn\'t require a mirror on
the other side to reflect that light back.

How do we know this? Well, I\'m going to refer to some modeling work
that I have done and published in the past where I\'ve used a random
walk model through a homogeneous tissue bed in this example. A slab of
tissue, about 12 scattering lengths thick, that\'s comparable to about
12 or 13 millimeters thick, but the light emitted at the surface and
collected at the bottom. These gradations here are depicting where the
photons had the highest visitation probability.

So the region where the photons traveled the most is up and down through
this middle. But there is still a lot of scattering signal that\'s
coming from the periphery, so this cigar shape, if you will, is
describing the tissues that would influence the readings of the pulse
oximeter.

In a reflectance mode, I\'ll continue to use that bad word, but really
what I\'m referring to is a transmission east and west. Once again, the
light is traveling primarily through this region a few millimeters deep
within the tissue. Very little is traveling along the surface. The light
that scatters here tends to escape. It doesn\'t contribute. Photons that
travel very deep into the tissue or in this case on the transmission
case very wide, they have a greater likelihood of being absorbed and not
being detected. Photons that aren\'t detected don\'t matter very much.
They\'re not going to affect what the pulse oximeter reads.

Is the calibration the same for reflectance and transmittance? We can
use this type of modeling to characterize what the signal of the
probability of collecting a photon if the detector is at a systolic and
a diastolic equivalent absorption in a tissue bed and from that generate
a correlation between modulation ratio, the pulse oximeter measures and
the SAT and we see that a reflectance probe and a transmission probe
behave generally the same, but their calibration may be slightly
different from one another. That\'s not a limitation, if we\'re
designing our pulse oximeter system to behave as a system to work with
the reflectance probe or work with the transmission probe. We simply
need to build that calibration curve into the monitor, into the design.
And virtually every manufacturer I\'m aware of, does something along
those lines.

I went back and looked through the FDA website of cleared pulse oximetry
systems that specific a reflectance probe and I came across 11 510(k)s.
There\'s 10 listed here and one PMA and Sandy, correct me if I\'m wrong,
there may be others that I missed, but reflectance oximetry has been
available since the mid-1980s. There were a number of products cleared
through the early 1990s. There\'s been a recent flurry of new products
cleared. All of these in blue are designed and intended for use on
adults. As has bene mentioned earlier, the only clearance for 510(k)
products, pictures of them is shown at the top.

One product that I want to include here is the Nellcor fetal oximeter
system. It was a PMA and I do want to share a little bit of insight with
you from our experience developing that product.

One of the things I just want to mention because I\'ll get to it, this
flurry of recent activity is coming about because I think there\'s a
renewed interest in reflectance oximetry from what\'s been available in
the past, one of the things I\'ll show in a later slide.

The monitors that were cleared through the early 1990s, I think it was
alluded to a little bit earlier, were older generation devices. They
couldn\'t tolerate the very small pulses. They might be a little bit
more sensitive to movement and other artifacts. We\'ve learned a lot in
the intervening 15 years. Reflectance sensors aren\'t inherently low
signal products, but they\'re placed in locations in the body where
signals are generally weaker. The strongest signals that we typically
see are on finger tips in a warm, well perfused patient. We try to place
the sensor on the chest or the arm or the forehead, it\'s usually a
substantially weaker pulse.

Monitors today are one or two orders of magnitude more sensitive in
picking up those weaker pulses, so the performance we saw in the past,
maybe we need to revisit today because we can do better with our
monitors.

I\'ll talk about that a little bit more in a minute.

This is data we collected for the Nellcor fetal oximeter system back in
the late \'90s and it\'s not to say that manufacturers can\'t go out and
gather this data. We can collect data on neonates, although when we
started to target the true neonatal population, we do become challenged.

This is data to validate the accuracy or the performance of a Nellcor
system. It\'s a reflectance probe designed for use in fetuses, but since
we couldn\'t take blood draws from fetuses any more readily than we can
do bleed downs on neonates, we had to go to the closest model we could
find. We found 27 cyanotic infants and children. Only a few of them
would fit this definition of a neonate. Many of these kids were outside
the scope of less than 30 days. We were able to gather 72 observations
over a sat range of 41 to 93. In fetal oximetry, we\'re really very
interested in determining what the accuracy is down in this 30 to 50
percent range, less so at the upper end. We place the sensors by hand or
with a head band on the cheek, temple or forehead. Some of those
locations we now \-- actually, we knew then, are not ideal from the
standpoint of pulse oximetry, but for the fetal environment where you
don\'t know precisely where the sensor is located, we want to make sure
we included those less than ideal sites as well.

And we used arterial samples that were taken from the same circulation
that was feeding sensor site, particularly in these cyanotic kids or
shunting kids, the feet and the hands and the head may be very
different.

Just to point out, the study took us more than a year to accumulate
these 72 observations using three sites and a full-time research nurse
on call to get on an airplane and go to the facility that had the
patient that met our criteria. It\'s possible to do these things, but
it\'s very time consuming and expensive to do so and as Mr. Batchelder
presented to you, the value of the results that we get don\'t seem to
add a lot to the equation.

Let\'s take a look at the vulnerabilities of transmission reflectance
oximetry because ultimately what I\'m trying to demonstrate to you is
that there\'s really no practical difference between reflectance and
transmission.

One of the things that can occur with transmission sensors and I\'ll
grab another one of my samples here, is something that was coined \-- I
hadn\'t heard this phrase other than reading in Kelleher\'s paper on
penumbra. We all refer to it as shunting. But a sensor properly applied
to a fingertip places the emitter and detector so that the light that\'s
detected necessarily has gone through good blood perfused tissues. If
the sensor is malpositioned so that some of the light can bypass the
tissue, it disrupts the pulse amplitudes that we measure and will give
us an erroneous reading.

So a sensor that\'s improperly applied, it may be applied sideways and I
think Julian referred to this or on the neonate\'s foot improperly could
potentially shunt and this does occur today. Every one of your
institutions, I\'m sure there are a number of subjects or patients being
monitored where the sensor has slid off a little bit or it wasn\'t
properly applied to begin with.

Sensors can be applied too tightly. Particularly wrap style sensors, it
can be wrapped very snugly, use additional tape. Sandy referred to
earlier. The consequences to that is it diminishes the pulse amplitude.
It does affect and can affect accuracy, generally not greatly, but it
does have some impact. The comment about burns usually being some form
of necrosis, a sensor that\'s applied too tightly, especially with the
lumpy emitter and detector components in there can occlude blood flow to
that local tissue and over many hour period of time the tissue can be
damaged.

Venous pulsation can occur in a transmission probe as well as
reflectance. If the sensor is placed too tightly, that can capture some
venous blood at the distal end of the fingertip, for example and cause
some venous pulsations.

And sensors can be improperly located. I think in the handout that you
received, I\'m not going to show this slide, I did a study of what
happens if you take a digit probe that\'s designed for transmission
across the fingertip and place it in transmission across an earlobe, you
get a very different answer and it\'s not accurate. But sometimes when
patients are peripherally shut down, clinicians will move the sensor to
some site where you can get a pulse. If we\'ve not validated it for that
location and have not labeled it that for location, I can\'t, as a
manufacturer, tell you that it will work properly.

If we move on and say what are \-- well, how do we mitigate all of those
vulnerabilities? Obviously, we\'d like to make our products foolproof.
To the extent we can, we will. We also want to make them easy to use.
And so to the extent that we can balance those two, and I don\'t have
answers for foolproofness, we have to mitigate that with labeling and
education. And Julian raised the issue of how do we better educate the
clinicians that re using the product. I\'m on the same bandwagon as
Julian. Whatever we can do to educate the users is going to go to great
lengths. It\'s going to be quite beneficial. So we deal with these
issues, these limitations, vulnerabilities with labeling and education.

Well, there\'s almost a one to one correspondence although the details
may vary just slightly when we talk about reflectance technology. We get
shunting if the emitter and detector aren\'t cleanly placed against the
tissue. The sensor could be applied too tightly, particularly if you\'re
using a band to hold it in place with similar consequences that you get
with transmission. You can properly locate a sensor, as Julian pointed
out, over larger vessels and that\'s not good, placing a reflectance
probe on the temple is not an appropriate place to put it.

And we can get venous pulsations, I think it was discussed in
Trendelenburg positions where the head is below the heard. We\'ve got a
continuous fluid column between the right side of the heart and the
pulse oximeter site. Venous pulsations will cause the pulse oximeter to
read low.

We deal with all of these things, once again, with labeling and
education. For example, the Trendelenburg effect or the Trendelenburg
position is contraindicated with some of our products at least.

So the bottom line here is that the light is transmitting through the
tissues, not necessarily north and south, but perhaps it\'s east and
west and there\'s an equivalence between reflectance and transmittance.
It works on adults and kids. All of these vulnerabilities are present in
both. It\'s not foolproof. Both are similar, however and any
differences, I didn\'t really touch upon this, any differences that we
might be concerned of between adult and neonatal tissues might not
affect pulse oximetry is true whether we\'re shining a light through a
tissue bed vertically or horizontally. All of those tissue differences
are present.

So is there value in reflectance sensors? Why should we be interested in
thinking about this problem? And I\'d like to equate pulse oximetry to
real estate. It\'s all about location, location, location.

What we\'re looking for is a site to place the probe where we\'ve got a
strong pulse. Ideally, we\'re also measuring a core circulation and what
reflectance probes give us is additional access to some of the sites.
One of the things we\'ve learned is that the forehead, for example, is a
site absent vasoconstrictor response, so that the pulsable signal levels
are fairly consistent, even if you\'re peripherally shut down. And
circulation lag time. I\'m going to address these two issues in a
second.

And in the neonates, we also have an additional site for pre-ductile
circulation on the right hand. It can be placed on a flat body part. We
have access to non-hand and non-feet sites. These are things that we
hear from clinicians who are looking for help in their sensor designs.

Let\'s take a look at what the vasoconstrictor response is all about.
These are signal amplitudes. It\'s the pulse amplitude of the wiggle
size that the oximeter is tracking and healthy adult volunteers, the red
bars represent what the pulse size is from a finger and ear and a
forehead sensor. And the finger is clearly the strongest pulse.

The gray region in the bottom half is what I call weak pulses. And this
is the size signal that the 1990 era technology struggled with, signals
weaker than this were hard to monitor, although some could do it, they
didn\'t do it gracefully.

When we take these same subjects and cool them off so that they\'re \--
they\'ve been exposed to a cold room environment for 45 minutes, they
peripherally basoconstrict. And the pulse amplitude that was on the
order of 5 percent drops down to about a half a percent. Ear sensors, we
found, dropped from a little under 1 percent to about a half of that.
But the forehead lacks the vasoconstrictor response and its pulse
amplitude was unaffected.

Another advantage of monitoring a core circulation site and this is an
example on the head. This is the circulation lag time slide that I\'ve
taken from the MacLeod group at Duke, where they\'ve desaturated a
healthy volunteer that\'s been exposed to a cold saline drip and a
cooling blanket to induce hypothermia and at time zero they induced a
hypoxic episode by lowering the FiO2 to 11 percent. They had monitors
placed on the forehead, the ear, and the fingers, as well as a radial
arterial blood catheter for sampling. The circles, or these little dots
here are the blood draws.

And we see that in about 20 seconds in their protocol, the ear and the
forehead drop down below their test threshold of 95 percent sat., but
it\'s not until 3 minutes later that the fingers finally begin to fall
and on the resaturation, the same 3-minute lag time tends to occur.

One of the things I want to point out in here is that two fingers were a
good 15 or 20 seconds different from one another. So one of the things
that Paul Batchelder was referring to is the importance of having a
stable bed so that the location of the catheter and the saturation at
the sensor site, whether it\'s an index finger or middle finger or foot
or a hand, they all need to be at the same level for us to compare those
two and draw an accuracy.

They may all be completely accurate. In fact, each of these oximeters
was completely accurate, I believe, for the saturation in the tissue bed
that it was measuring, but the saturation wasn\'t the same at the
various tissue sites.

When we do laboratory controlled studies, we generally don\'t do
accuracy studies in this environment of a peripheral vasoconstriction.

DR. LISBON: Dr. Mannheimer, can I ask you to finish up in about two
minutes or so?

DR. MANNHEIMER: Yes. So lastly, this is my last slide, my recommendation
in 510(k) submissions for neonatal reflectance pulse oximetry is to
treat it as any other pulse oximetry, independent of sensor geometry. We
should validate and under controlled laboratory conditions from 70 to
100 percent on healthy adults, using a site that\'s representative of
whether the site we would recommend for use on the neonate. For
specifying a reflectance probe for the chest of a neonate, I\'d
recommend we test it on the chest of an adult, on the back, we test it
on the back and the forehead, the forehead. If one wanted to design a
sensor to go over the temple, I wouldn\'t recommend it, but that\'s
where it should be tested.

We can verify the appropriateness for the neonate with form, fit and
function testing to demonstrate the physical safety and appropriateness
of the probe. An adhesive, for example, might be too aggressive for a
neonate. This is something that we can verify with testing. I\'d rather
verify the contra to that, the appropriateness, rather than the
inappropriateness.

And lastly, we would recommend that convenience samples taken on
neonates, spanning a range around 90 percent sat where neonates do exist
in the clinical environment, to confirm the system accuracy. I want to
make this point fairly clear, because I don\'t think it was made very
well by Paul previously. He didn\'t amplify on this. What we\'d
recommend doing is taking a predicate device and simultaneously testing
it and the new device to show that whatever new product we\'re creating
or introducing, is performing at a level that\'s comparable to what has
been used in clinical practice for many years and has been shown to be
safe and effective.

So it may not be possible to get an accuracy spec with a laboratory
equivalent, but we can show that what the new device is performing at is
comparable to what current practice is using.

Thank you.

DR. LISBON: Thank you very much.

DR. MANNHEIMER: Do we have time for some questions?

DR. LISBON: You have time for one question.

Does anybody have a question?

DR. COTÉ: Why wouldn\'t it be possible to do studies, as you said,
comparing with currently available oximeters, but put multiple different
sites at the same time. I mean the baby would look like you wallpapered
him with sensors, but this might give you a better feeling of the
equivalency of putting something on the interior chest, the back, on the
shoulder, on the upper arm, and then you have real time data of multiple
devices at once.

DR. MANNHEIMER: In the clinic or in the laboratory?

DR. COTÉ: In the clinic.

DR. MANNHEIMER: I think that\'s not unreasonable. It fits within the
practice of caring for that patient. I think that\'s open to discussion.

DR. COTÉ: It\'s obviously not going to be within the care of the
patient, but it\'s going to be

\-- there are parents that will consent to do research on their children
if they understand what it\'s for.

DR. MANNHEIMER: But we can\'t make them hypoxic.

DR. COTÉ: No, no. I didn\'t say that. I said I\'m agreeing there are
clinical situations that develop. How well do these devices track
compared to each other and compared to different locations on the body.

DR. MANNHEIMER: If the saturation is all around 98 percent, then we\'re
only testing one little region and that tends to be where inaccuracy is
least \-- where the performance is.

DR. COTÉ: Correct, but you\'ll be able to generate some information as
opposed to no information.

DR. MANNHEIMER: That\'s true.

DR. COTÉ: And these children typically desaturate every time they\'re
suctioned, so you\'ve got a very predictable event that can be examined.

DR. MANNHEIMER: Do they have an A line placed?

DR. COTÉ: Well, you wouldn\'t necessarily. You\'ve already said in the
adult patients that you have equivalence in terms of performance, but
now what you could do is track the old performance with the new
performance, time response and you\'re right, the gold standard is to
get a blood gas and that\'s not practical except in \--

DR. MANNHEIMER: I think that\'s worth considering and should be part of
your discussion amongst yourselves.

DR. LISBON: Thank you very much, Dr. Mannheimer. We have a presentation
by the Nonin Medical Group. You gentlemen each identify yourself, that
would be great.

MR. ISAACSON: Good day. I\'m Philip Isaacson. I\'m Managing Director and
the founder of Nonin Medical.

MR. PEDERSON: I\'m Brodie Pederson. I am a Senior Design Quality
Engineer. I work in the quality regulatory department assuring the
safety and effectiveness of our devices.

MR. ISAACSON: And I\'m going to start out talking about pulse oximeter
applications and specifically some of the sports applications. Brodie
will finish up talking about, again, consumer application and aviation
usage.

And he\'ll discuss a little more of the difference that we consider for
consumer, over the counter, and prescription. Let\'s see, myself, I have
been involved in design of pulse oximeters for over 20 years.

And Nonin has been selling pulse oximeters since 1986. And, at one time,
a few years back I gave a talk about the ubiquitous pulse oximeter.

It\'s showing up in many places everywhere. And there\'s going to be a
number of applications that are not discussed at this meeting, a number
of applications which are outside of the scope of this meeting.

And I\'m just going to talk about a couple of the applications we have
which are consumer as opposed to medical applications. But, I think the
lessons were learned there, are applicable, and we\'re thinking about in
the discussion of over the counter.

And also, in terms of policies devices we have and medications, we\'ve
had the patients call up to buy a pulse oximeter. We told them, go back
to your doctor, get a prescription, fax us the prescription, we\'ll sell
you the pulse oximeter.

And this has been typically patients with CHF, COPD, and asthma. And
I\'ve had some anecdotal stories about the home use of these oximeters,
that the patients have requested prescription from their doctor.

It has significantly changed their quality of life. And, in one case,
the patient wouldn\'t be alive if she hadn\'t gotten a personal pulse
oximeter.

Okay. Nonin has offered pulse oximeter for sports use. And the sports
use people that are most interested in that right now are people working
at high altitudes and such.

Again, it\'s not over the counter in that we make no medical claims.
That is, we make, quote, no clinically significant diagnostic
indications for use.

And, I can show you, the device that we have \-- I\'ve got one in my
hand here. The device that we offer for the sports staff and the flight
staff, which Brodie will talk about, is in fact identical to our medical
device, although it need not be.

It differs in the packaging and labeling. And some of the key
applications \-- let\'s see \-- is a mountain climber. And, basically,
about every expedition to Mount Everest will have a number of these
along with them.

Again, there\'s a case where a number of years back Public Broadcasting
had a NOVA episode on Mount Everest. It showed the guy trudging up the
trail.

He pulls out one of these out of his pocket. Let\'s see what you\'re
doing. He said, well, you\'re at 70 percent saturation. Well, let\'s
rest a little bit and see what you\'re at.

Anybody in this room that\'d be at 70 percent saturation, you\'d be
rushing them to the emergency room right now. But, the application we
have, again, for hikers, again, not just the normal hikers, but people
hiking in the mountains at altitude.

They use it quite often to check what their saturation is and adjust
their breathing patterns. So, we\'re looking at the normal desaturations
with altitude and exertion, and breathing.

One of my formal partners went hiking with his son. He brought the pulse
oximeter along. He saw he was desaturating, breathed a little more
heavily.

You know, you\'re doing great. The son wasn\'t doing that and was
exhausted very quickly. So, other places, of course, in the health club.
I go to work out at the health club all the time here now.

I\'m not exercising. I\'ve been doing mostly strength exercises where I
don\'t go to the point of exertion. And typically what happens under
those circumstances is really for a handy way of measuring the heart
rate very quickly and easily.

And my oxygen saturation as I exercise rises a little bit, which says
I\'m not an elite athlete. Typically an elite athlete, as they push
themselves to the level of exhaustion, will slowly desaturate, while
somebody like me that\'s not in such great shape rises until it hits the
limit and then drops rapidly.

But it\'s, you know, useful, again, in health clubs, health
institutions, people exercising. They can judge when they are really
hitting the limit of their body\'s ability to provide oxygen \-- or the
heart and lungs to provide oxygen to the body.

And this one was designed for use \-- there are many applications, high
altitudes, light, dark, cold, in fact, many of the cases the hands are
very cold but it\'s being used.

But the thing that\'s quite often done is really trying to avoid the
systemic anaerobic condition. In other words, it doesn\'t tell whether
muscles are getting anaerobic.

But it tells you whether your body as a whole is getting anaerobic.
Again, usefulness, particularly at high altitude, is to recognize when
the hiker is getting anaerobic to slow down, to prevent getting the
altitude sickness.

And so, again, the \-- for instance, going to Mount Everest. At the base
camps they will be checked. Typically they\'ll check them. People will
adjust their breathing, wait to see that they can adapt to altitude
before they go on to the higher altitudes.

And the biofeedback usage SpO~2~ information to just see the effects of
changing breathing patterns. Again, at sea level here there\'s not a
difference.

You get up into mountains, you see a difference. I see a difference when
I\'m flying in an airplane. If I\'m just sitting there not doing
anything, particularly the high altitude long flights, I\'ll saturate
into the upper 80\'s.

Take three quick breaths and I get back up to 97 percent normally. So,
is that helping me avoid some of the ill effects of travel? I don\'t
know.

But, again, it\'s a non-medical type of application to see what the
effect of breathing or not breathing in an airplane is and breathing.
That affects me as a passenger in a commercial jet.

Brodie\'s going to talk more about the usage of the pulse oximeter by
pilots where it\'s far more critical. All right.

MR. PEDERSON: Much of the success of these consumer products is based
upon the many guidance and articles written by physicians and other lay
members of these consumer markets that have found usability of these
devices for their application, some of which the articles I\'ll be
noting in my presentation.

The FlightStat is used primarily by pilots to detect hypoxia when flying
without oxygen. When flying at high altitudes can impair the ability to
reason, think, see, talk.

And these cognitive functions are very important when you\'re flying a
plane and to protect yourself and your passenger\'s safety. Depending on
the age and overall health conditions, hypoxia can occur as low as 5,000
feet.

This is documented in several articles. And, particular importance has
been placed on night vision by organizations such as the FAA. I\'ll show
you another reference later on.

Why do these consumers need a pulse oximeter? For both pilots and sports
enthusiasts, pulse oximeters can detect potential problems caused by
decrease of oxygen in the blood caused by thinner air at higher
elevations.

The decrease in the blood, you know, we\'re all aware, impairs judgment,
decreases physical stamina, causes dizziness and nausea, and other
symptoms that could cause potential harm.

I\'ll turn to some published information that I\'ve pulled out, some
articles that I have quoted. The Federal Aviation Regulation, which is
more than 20 years old, and is showing its age, requires oxygen use
above 14,000 feet for any time the pilot exceeds that altitude, and
continuously if you extend above 12,500 for more than 30 minutes.

This is to protect the pilot, of course, and the integrity of the
aircraft. The FAA also recommends \-- they\'ve revised and recommended
oxygen use in the last ten years for any time you\'re flying above
10,000 feet during the day and 6,000 feet at night.

And, again, this is to address the concern of loss of night vision with
hypoxia. Pulse oximeters may be used in these situations to help pilots
or sporting enthusiasts identify earlier that they need oxygen to
prevent hypoxia from setting in.

Even trained individuals may not be aware of the effects of the hypoxia
on their own. And, you know, the guidelines just show that there is an
increase in understanding of the effects of hypoxia on individuals in
the broader public, and not just in the medical community.

One article said you can ask pilots about oxygen usage and they\'ll tell
you what the regulation states, which doesn\'t really say a whole lot.

It tells them that they should be using oxygen, but doesn\'t tell what
flow rates, how much, how often, how to adjust breathing patterns. So,
you know, most of them don\'t know.

And most of those pilots, again \-- this article credited at the bottom
of the page there stated that most people don\'t recognize the effects
of the hypoxia that they\'re experiencing.

Personal tolerance to altitude can vary from day-to-day. So, one person
who may have gone through training and testing in that field of
application may not have the same effects on a different day.

Or, if they\'re having some sort of other condition or lack of sleep, or
other factors that might play into the role. One source has stated that
in the clinical environment the patient is not considered to be of sound
mind unless their SpO~2~ is above 90 percent.

Given that, you must decide whether you want less for yourself when
you\'re flying a plane. So, it just kind of underscores the importance
of knowing where your body is at at various elevations, especially when
you\'re controlling an aircraft.

To assure proper oxygen flow, a pulse oximeter can provide an almost
instantaneous read-out of one\'s blood oxygen level and heart rate. Just
to cite the references, you know, this quote, hypoxia equals stupidity.

Once you\'re there you\'re too stupid to save yourself and problems can
occur. And, there\'s lots of articles and literature which on the
following \-- at the end of my presentation I\'ve listed out several
articles and literature sources that provide information further to
these points.

So, this just goes to show there are other uses for pulse oximeters
other than in the medical community. And they are being used on a daily
basis by many individuals to protect their life and livelihood as well
as their \-- the passengers on their aircraft.

There\'s, you know, there\'s the threat even to the passengers at these
higher elevations as well, not just the pilot of the aircraft. And so, a
lot of these pilots that are now more aware of the effects of hypoxia
have been increasing, the use of oxygen among their passengers as well.

To summarize pulse oximeter application various market controls, today
we have prescription devices and we have consumer devices. The
prescription provides safe, effective devices with controlled
distribution when doctors need to get data and information about their
patient\'s percent oxygen level.

In the consumer market, there are no regulations. The FAA does not
regulate the use or the production or manufacture of a device, or any
requirements on the device\'s performance for use in the aircraft
because the device can be taken out of the aircraft.

It\'s not affixed to the aircraft, and therefore the testing and
regulations don\'t apply. So, some of those consumer products, the
SportStat, FlightStat, are very useful for altitude and exercise in
those environments.

But there are other products out there that are less rigorously designed
than ones that we present. And that can yield somewhat of a risk. The
over the counter market does still control safety and accuracy and
effectiveness \-- are all regulated.

It just allows more people to have access to the technology and provides
added reliable health information to the public and possibly to
physicians that, you know, as Dr. Goldman had suggested, may provide
earlier diagnosis or assistance in diagnosis of certain conditions.

So, you know, again, here are the \-- some additional references.

CHAIRPERSON LISBON: Thank you, Mr. Peterson. We have time for one or two
questions.

DR. BIRNBACH: I\'d like to start by way of confession, middle age is a
little over rated. And I have a hard time reading the published
references without a microscope.

But it doesn\'t appear that there\'s any data there about the use,
validity, accuracy. Have these things ever been tested and compared with
either the quote, unquote gold standard or with clinical conditions.

MR. PEDERSON: I can speak to our devices. Since our FlightStat and
SportStat are technically identical to our medical device, it has been
tested and is reliable and accurate.

And we have done that testing according to the standards and guidances
in the regulatory arena.

DR. BIRNBACH: So, the device has been tested. What about the users to
see whether users actually use it appropriately or know what they\'re
doing, or how they\'re reading these things?

MR. PEDERSON: Do you have anything on that?

MR. ISAACSON: There are papers published about the need for it and the
\-- there have definitely been papers published about the need for it,
use for it.

They are not rigorous scientific studies. They are more the anecdotal
type of published papers.

MEMBER COTE: On your website you say it\'s operating altitude up to
30,000 feet. Have you tested it at that altitude to see if in fact it\'s
accurate at that altitude?

MR. PEDERSON: We\'ve tested the effect of altitude on the device and \--

MEMBER COTE: On the device in what way though?

MR. PEDERSON: On its operation at altitude with simulators.

MEMBER COTE: Oh, with simulators. Okay.

MR. PEDERSON: Yes.

MEMBER COTE: So, you put it in a pressurized compartment and \--

MR. PEDERSON: Yes.

MEMBER COTE: \-- and a patient or a volunteer in a pressurized
compartment?

MR. PEDERSON: The simulator on a device at altitude to verify its
performance.

MEMBER COTE: I guess we\'re not communicating. I\'m trying to find out,
does it work on a human being accurately at 30,000 feet? Or, does the
accuracy of the device drop of \--

MR. PEDERSON: No, the device is not \-- the electronics and the
operation of the device are not affected by the altitude.

CHAIRPERSON LISBON: All right. I\'d like to keep moving. We\'ll have
time, I believe, as catch-up for questions right before lunch. Thank you
very much.

MR. PEDERSON: Thank you.

CHAIRPERSON LISBON: We now go to the open public hearing. This is the
first of two open public hearing sessions for this meeting. There will
be a second one that follows the panel discussion this afternoon.

At these times the public attendees are given opportunity to address the
panel to present data or views relevant to the panel\'s activities.
We\'ve been given advance notice of one person who wishes to address the
panel.

That\'s Dr. Dale Gerstmann from Utah Valley Regional Medical Center. Are
there other people that wish to address the panel that are here? So,
just raise your hand. All right.

I just want to remind Dr. Gerstmann that you have ten minutes for your
presentation and about five minutes for questions. Speak into the
microphone because the transcriptionist is dependent upon hearing it.

And also, we\'re requesting that all persons making statements during
these open public hearings disclose if you have any financial interest
with the sponsor or products under consideration.

And, before making your presentation to the panel, in addition to
stating your name and affiliation, please state the name of your
financial interest in the product under consideration, who is paying for
your attendance in this meeting.

DR. GERSTMANN: My name is Dale Gerstmann. I\'m a neonatologist from Utah
Valley Regional Medical Center. I\'m here on my own. I will state that
the hospital I work for has a contract to evaluate experiment sensors
for Nellcor/Tyco Healthcare.

And I don\'t have any financial interest in any companies.

CHAIRPERSON LISBON: Thank you.

DR. GERSTMANN: What I would like to do is comment on functional
performance, which relates to your discussion on neonatal validation.
Next slide, thank you.

And, in particular I would like to make some comments about what I have
been able to see about bios, precision, and resolution on neonatal
oximetry.

Next. Just a short comment to say that this is a level three \--
information from a level three nursery, which is a very typical kind of
nursery, 40 beds, 500 emissions per year.

We do high frequency jet ventilation, inhale nitric oxide. But we do not
take care of babies with complex congenital heart disease who have
complex pediatric surgical problems or do ECMO.

The data covers a period of 2002 to 2005. Next. This information covers
114 patients. The birth weight and gestational age distributions reflect
very similarly to what our admission characteristics are.

About a quarter of the infants are under 1,500 grams or under 32 weeks.
Next. All of these data have been collected under two \-- actually
there\'s three RMB approved protocols.

But all of the SpO~2~, AO~2~ pairs where the AO~2~ is functional
saturation determined co-oximetry is done under informed consent. There
are about 1,250 pairs of data that go into the following slides.

First let me talk about bias. Bias is the difference between the pulse
oximeter and the functional arterial saturation. And here it\'s plotted
in Bland-Altman plot for data from an older generation device, Ohmeda
Biox, with a disposal sensor.

On the Y axis is the bias or SPO~2~ minus SAO~2~. On the X axis is the
average. And, as you can see, the slope of this information, or the data
plotted, is quite negative.

Even though the bias is a plus 2.2, the precision is here depicted as 95
percent confidence limit with a precision of six. And the A~rms~ is 3.7,
which, under your current standards, would be acceptable.

However, this kind of bias would not be clinically acceptable. As you
can see, in a saturation of 85, the pulse oximeter is actually reading
six or seven higher typically.

Thank you, next. This is similar data using a non-disposable generic
probe for the Ohmeda Biox. The negativity of the slope is not as severe.
The precision is slightly better in the A~rms~ under three.

Next. This is current information, 250 samples using the Masimo Radical
with the neonatal sensor. And, as you can see, this device and sensor
combination also has a very negative slope.

Although the bias, which is the average bias for all of that data is
only slightly positive, the precision is 4.4 and the A~rms~ is 2.3. This
negative slope, however, does continue to indicate that as the
saturations drop, the pulse oximeter reads higher than actual.

Next. And, just to point out that for some sensor monitor combinations
the bias can actually be appropriately zero, and that would be ideal.

That is a device sensor combination that does not have a bias. This is,
you know, for SoftCare sensor information with a precision of 5.2 and a
A~rms~ of 2.7. Next.

Similarly, this is the infant MAX-I sensor from Nellcor with 100
samples. It also has a \-- essentially zero bias and an A~rms~ of 2.3.
Next. And the MAX-N, which is the neonatal MAX sensor for Nellcor shows
a similar negative slope.

The bias is slightly for positive. And the A~rms~ is 2.7. Here is a
table summarizing the previous graphics indicating the sample size and
the bias.

And, as you can see, for the most part, there are only three devices
where the bias is close to zero. Otherwise it\'s positive, indicating a
negative slope to the Bland-Altman curve.

What I would like to do is just illustrate all of that information in
this graphic and make a statement saying that, as you can see fairly
easily, the average bias by saturation is not uniform across the range
for which we typically see saturations in sick neonates that are on
ventilators and whose oxygen is being controlled.

And, as the saturation drops for almost all of these device-sensor
combinations, the bias increases. It would be much more clinically
acceptable to have a device that has flat performance, even in this
narrow range of normal saturations.

We don\'t have any low saturation data because we don\'t keep babies
with saturations under 80. We attend to them immediately. And the other
point is that blood gasses are being done more and more infrequently in
neonates.

There are some nurseries who don\'t draw any blood gasses any more on
ventilated neonates who have uncomplicated courses. So, convenience data
is going to be harder and harder to obtain.

Next. My preference is to actually plot the regression slopes on a
graphic like this that shows the 95 percent confidence intervals and
very clearly demonstrates the two devices that have regression slopes
that include zero in their 95 percent confidence limits.

And these two devices would obviously be preferable \-- the
device-sensor combinations to the other ones, which have negative
slopes. Next. Now I\'ll comment on precision.

This is a similar table summarizing the data off of the previous
graphics. And, as you can see, the A~rms~ values are all of them under
which you would currently accept as four percent or less.

But, please note that, except for the very old combination of Ohmeda
Biox and disposable sensor, all of them are under three. And most of
them, some of them are very close to two.

So, I would concur that the addition of the one percent fudge factor is
absolutely unnecessary. And, in fact, in functional performance in NICU,
the A~rms~ values are well within the context of less than three
percent.

My bias, however, is not to use the A~rms~, but to use the precision
measured as 1.96 standard deviation, which is in fact the 95 confidence
interval.

Next slide. To illustrate that the A~rms~ as well does not have stable
values over the range of 80 to 100 saturation, this graphic illustrates
that point.

Note that the precision worsens as the saturation goes up. And, for data
that I don\'t have on this graph from older data, the precision also
worsens as the saturation goes from 97, 98, 99, to 100.

We don\'t keep babies at high saturations. And so, I don\'t have any
blood gas values with saturation at 99 or 100. And that\'s why they\'re
not there.

The best range of A~rms~ is obviously for most devices somewhere between
92 and 95 or 97, somewhere in that narrow range. Next. To illustrate the
point on the 95 percent confidence intervals, this is simply a graphic
of SaO~2~, versus SpO~2~.

And, from the data that I\'m just showing you, I\'ve extracted the 95
percent confidence intervals for the Nellcor plus SoftCare over the
range from about 86 to about 99 percent.

The line in the center \-- I guess that is not a pointer \-- is the
50^th^ percentile. And the upper and lower lines are the 95 percent
intervals. And I would submit that clinically it is very difficult to
expect to manage a baby that in this example the arterial saturation
would be 90, but the pulse oximeter could be reading anywhere between 88
and 96.

And that\'s very typical performance for all of the neonatal \-- the
current neonatal oximeters. Next. This is the Masimo device. And, on
this graphic you can see the effect of the bias as the 50 percentile
line is really laid over very horizontal.

It should be following that green line. The same situation with the 95
percent confidence interval exists across a wide range of saturation
where it is not uniform. Next.

And finally, I\'d like to make a comment about resolution. Resolution is
an instrumentation term in my thinking. And it relates to what you see
on the display.

If you look at a pulse oximeter, it says 90, it says 91, it says 89. The
precision of the monitor itself or the resolution is plus or minus one.

It doesn\'t show you anything more than that. Next slide. And, if you
would clock that against what the 95 percent confidence intervals are on
the measurement, there\'s this wide discrepancy between what\'s actually
shown on the monitor and what that data really means.

I can tell you that the clinician looks at the monitor and sees it go
90, 91, 89, and thinks that\'s how accurate this device is. That is what
I think is happening to this patient.

When, in fact, if you look at the data, the pulse oximeter reading could
actually be plus or minus four, plus or minus five. And the clinician is
not seeing that on the monitor. Next.

What I would like to see in terms of device response is something much
more close to this where both the precision and the bias is acceptable
and is very close to what the resolution of the monitor actually shows.

That would be a clinically acceptable device. Next. So, let me
summarize. The bias as a summary statistic actually does not reflect a
dependence on SaO~2~.

But, for neonatal bias you would want it to be zero. And I presume that
would be an achievable result for adults as well. The only way to
actually look at this and to analyze it in a comprehensive way is to
look at the slope of the Bland-Altman curves.

In terms of precision, a summary statistic there in terms of A~rms~ also
does not reflect the SaO~2~ dependence of the precision as it changes
across saturations.

The 95 percent confidence interval are really fairly large for any
clinical specificity. And it would be much better if the A~rms~ was
close to one as opposed to less than three or four.

And finally, the final comment on resolution it would be ideal to have
the 95 percent confidence interval or the accuracy of the device
reflected in the device resolution as it\'s displayed to the clinician.
Thank you.

CHAIRPERSON LISBON: Thank you very much. Are there questions for Dr.
Gerstmann?

DR. BIRNBACH: Is any of this data published?

DR. GERSTMANN: A smaller data set has been published in the Journal of
Prenatalogy two years ago. And I\'ll be working on a manuscript here.
This is brand new information.

CHAIRPERSON LISBON: Are there other questions? Jackie?

DR. LEUNG: I have a question, kind of taking the physical data down to
the real life situation. I mean, I think one of the myths about pulse
oximetry is that we, you know, transfer the wavelength differences into
numerical value, they\'re continuous, giving one an impression that
it\'s a continuous scale.

In fact, clinically, the way we use pulse oximeter is either it\'s
normal or abnormal. So, really beyond a certain level, we don\'t really
know what it means.

And your data adjust that, because you don\'t have a lot of points
really below 80, as you said, because we don\'t keep people in that
situation for a long time.

CHAIRPERSON LISBON: Charlie?

MEMBER COTE: I think you are to be congratulated for trying to get some
real information that the manufacturers keep telling us they can\'t get.
Thank you.

DR. GERSTMANN: Thank you.

CHAIRPERSON LISBON: Avery?

DR. TUNG: It is obviously disturbing to see positive bias at low sets.
It opens the door for false negatives. Did you see any in your study?
Did you have any adverse events related to false negatives?

If not, how did you avoid, you know, mis-interpreting a set of 95 \--
really setting in the mid 80\'s?

DR. GERSTMANN: I have to acknowledge that I had no part in the clinical
care of these babies. Okay, so any decisions \-- in fact, there were \--
I can\'t answer that question, whether or not there were decisions made
off of these values that might have made an effect or a difference to
the child.

DR. TUNG: Is it possible to debrief nurses and understand how they
adjusted, as they must have done in three years, to, you know, what
seems like very large biases at low sets?

DR. GERSTMANN: They have been educated to know that a saturation of 89
may actually be an arterial saturation much lower than that. So, the
caution is, look at the patient or do some physical evaluation to try
and ascertain whether that saturation is meaningful or not.

CHAIRPERSON LISBON: Dr. Otulana?

DR. OTULANA: Going back to the transmitters, the reflectance issue that
was mentioned earlier, was any particular type of probe \--

DR. GERSTMANN: These are all transmission.

DR. OTULANA: They are all transmission? All right.

CHAIRPERSON LISBON: All right. We have about ten minutes before lunch.
And what I\'d like is that if there any \-- some of the speakers were
cut off.

If there are questions for any of those previous industry speakers, we
could entertain those at present. So, just ask who you\'d like to ask a
question to.

And then we need that speaker to come up to a microphone so that we can
record that.

DR. MUELLER: I have a question of Pederson and Isaacson. Let\'s say that
you have a group of six U.S. citizens who are going to tackle K2 for the
first time.

They\'re going up there for a four week visit. Would you recommend they
purchase a number of monitors equal to the number of people, or twice as
many, or three times as many?

MR. PEDERSON: I wouldn\'t \-- you know, not knowing how they organize
their trip, I don\'t know what I would recommend. There are always \--

DR. MUELLER: What I\'m trying to get at \-- excuse me for interrupting.
What I\'m trying to get at is what\'s the reliability of this under the
conditions, let\'s say, of the climb to a high altitude where the device
might get wet, it might get knocked about and so forth?

Do they have to take several spares? Is there some \--

MR. PEDERSON: From that point of view, you know, one is sufficient. I
mean, these things very rarely fail. It would be more operation, less of
a chance you\'re going to lose one, something like that, rather than is
it going to fail?

But, if they want to be 100 percent certain, they better have two of
them.

DR. MUELLER: Do you have a program so they can return it to be fixed?
And, if so, what\'s the return rate on these for repair per year?

MR. PEDERSON: Let\'s see, our medical devices, I think we\'ve got a
three year warranty. And what is it per year?

MR. ISAACSON: That would require a bit of research and consulting with
our return department to get accurate numbers. I\'m not certain what the
return rate is, especially divided between SportStat, FlightStat, and
the medical device.

DR. MUELLER: Sure. Okay. The man is up on the mountain. Does he have
anything? He looks at his machine and it tells him that, you know,
there\'s a number there that\'s too good to be true.

What do you have in terms of a, quote, pocket restandardization of your
device so that it could be reset or reprogrammed or re something in
order to become reliable and predictive again?

MR. PEDERSON: None of our pulse oximeters have any means to recalibrate.
They are calibrated by design. And, our particular design \-- again,
I\'ll get into some of the technical details in the way we implement it.

But, we run both the red and the infrared channel signals through the
same signal chain. So, we\'re not going to have to worry about drift of
one channel relative to the other.

They both run identical. So, most \-- except for, we\'ve got some analog
front end, everything else is done digitally, and that doesn\'t drift.

But, I say \-- from the very beginning, there never has been a means to
adjust any pulse oximeter that Nonin has ever made.

CHAIRPERSON LISBON: When these devices fail, in which direction do they
typically fail? Or is it just completely random?

MR. PEDERSON: The typical failure is something like, well, it doesn\'t
automatically turn off when it should, as a common failure.

CHAIRPERSON LISBON: But they don\'t go falsely high or falsely low when
they break?

MR. PEDERSON: I\'m not aware of that having happened. I\'m going to have
to check all of our records.

CHAIRPERSON LISBON: Charlie?

MEMBER COTE: These are calibrated down to 70 percent plus or minus two.
I\'m not a climber, maybe somebody here has experience. But, the
saturations at 4,500 meters are 70 plus or minus 38 percent.

So, how can you \-- if the device is not accurate under 70 percent, how
can you use this to make a decision at the very point where the accuracy
falls off dramatically?

MR. PEDERSON: Okay. Well, our device is, you know, we have certainly
tested our devices down to 50 percent.

MEMBER COTE: Only down to 70 according to your \--

MR. PEDERSON: We don\'t \--

MEMBER COTE: Your package insert says 70.

MR. PEDERSON: We haven\'t been specifying it below 70. But we do have
data down to 50 percent. It\'s rather sparse data. But, generally,
again, I have to look at the \-- I don\'t have the numbers with me.

You know, what sort of data we can support, but since the data we have
is \-- we have tested then down to 50 percent.

MEMBER COTE: I guess, how is the climber who is not a necessarily
medically knowledgeable person to make a decision as to what\'s
dangerous and what isn\'t?

And, at least this one paper that I found, suggested that the only
predictor of high altitude sickness was desaturations while they\'re
asleep. If they\'re asleep they\'re not using the device.

It has no prediction while they were awake. So, I guess I\'m kind of
missing something here. Part of it I\'m sure is my lack of knowledge of
high altitude climbing.

MR. ISAACSON: A lot of the usage in this area relies upon the
individual\'s experience level and conditioning and experience in that
environment. Typically these expeditions, they\'re going to these
extreme conditions, spend many, many months training and working and
becoming knowledgeable about the tools and usages that they\'re going to
be using during the expedition to the highest of elevations.

And so, they\'re going to gain a knowledge and understanding of their
own performance and comfort levels as far as how they feel and other
things and can use the oximeter as an adjunct to that other information.

MEMBER COTE: So, they\'re using themselves as their own control? Is that
what you\'re saying?

MR. ISAACSON: Essentially. And that\'s part of the, you know, the
conditions of use of the device. We make no claims medically on the
SportStat device as to how they should use it.

That\'s up to them and their experience level and their understanding of
the technology.

DR. TUNG: Dr. Cote mentioned the need to actually validate on a human at
high altitude. I\'ve got to agree with him. The primary physiologic
response to altitude hypoxemia is to hyperventilate.

People can push the ph\'s, their blood ph up past 7.6, almost to 7.7. I
don\'t know if validation of pulse oximetry at that kind of Ph is, you
know, the world might be different there.

And, you know, there may be a need to validate that.

MR. PEDERSON: We have not validated at such. To my knowledge, the Ph
does not affect the color of the hemoglobin. And that\'s what we\'re
looking at.

So, I would have no expectation that there should be any difference. But
we have no data to prove that.

CHAIRPERSON LISBON: Carolyn?

MS. PETERSON: I had two questions for Mr. Pederson and also one for Dr.
Goldman with regard to the statement that the pulse oximeters were used
by many individuals to protect their live and livelihood.

I\'m wondering if we have any outcomes data that match readings with the
decisions that individuals actually made based on those ratings, either
for aviation or sport uses?

MR. ISAACSON: I guess my statements were based off the articles that I
read and cited in my presentation as the articles that provided
information anecdotally.

The pilots who have since started using pulse oximeters have become more
judicious about their oxygen usage in that environment. And they made
statements in their papers regarding that statement that I made.

MS. PETERSON: Okay. But there\'s no sort of recorded instances, readings
\--

MR. ISAACSON: Not that we have, no.

MS. PETERSON: \-- decisions. Okay. And my second question had to do with
the type of training that you provide or require your purchasers to
undergo so that they can use the product properly.

MR. ISAACSON: In the consumer market there\'s no requirement for
training.

MS. PETERSON: But, do you provide any or do you require your purchasers
\--

MR. ISAACSON: We provide instructions in the manual as to how the device
is operated. And then it\'s up to them to do research and investigation
to figure out how to interpret those results.

MS. PETERSON: And, do you clearly state that they need to do research to
understand how to interpret the results your device \--

MR. ISAACSON: I\'d have to review the indications for use. I can\'t
recall off the top of my head, sorry.

MS. PETERSON: All right. Thank you. Dr. Goldman? In your presentation
you mentioned that when there is an error it tends to read low in
saturation rather than high, or to very quite a bit.

Is there a general trend that is accepted among users so we can say
it\'s five percent low, it\'s ten percent? Or is it variable?

DR. GOLDMAN: I think we know that, historically, with pulse oximetry
certainly the older conventional pulse oximetry designs that some of use
have come to hate, despite the fact that they have saved lives and made
practice much easier, we know from clinical practice and from much data
that typically they read low in the presence of low profusion and motion
conditions, for example.

That\'s \-- and we have a deeper understanding now of why that happens
and probably partially because of that that\'s been corrected in some of
the newer designs.

So, it\'s pretty clear that a shivering patient is going to read low,
they won\'t read high, and that because of the physiological effect.
That\'s that part.

So, if an instrument has been \-- an improved instrument is available
that\'s been designed to deal with that situation, it\'s probably going
to read accurately.

If it isn\'t designed to do that, it may read low. The likelihood that
it will read high is much less, based upon what we know about the
physiology.

It seems that \-- and there isn\'t anything published on this aspect of
it. But, it seems that, based on when you try to troubleshoot high
readings with pulse oximeters, which are quite uncommon I think for most
of us to observe, it seems to be due to an equipment problem more
frequently than not.

It\'s difficult to figure out physiologically why an instrument would
read high. There isn\'t another substance or absorber really that\'s
pulsitile that we know of that produces a saturation ratio or color
ration, absorption ratio, that would drive the number high.

We just don\'t know of things like that. So, it would have to be
something else in the optical path. Or it would have to be a fault with
the device.

In my experience, I\'ve only seen this a few times, it\'s usually been a
cable problem, a physically damaged cable. You can usually change it and
you can see an improvement in the value.

But there isn\'t much data on this. So, generally speaking, I think
it\'s not commonly found to have high values.

MS. PETERSON: But, the question that I\'m trying to get at pertains to
how a recreational user might interpret the data if we know that \-- or
if it\'s generally common knowledge among say climbers that if they\'re
untrue values, they read low, and people perceive, oh, it\'s always five
percent low, or it\'s ten percent down, so really my saturation is X
amount, so I\'m okay. That\'s the concern I\'m getting at.

DR. GOLDMAN: Oh, I see.

MS. PETERSON: If users may \-- themselves to what they\'re reading
assuming that it\'s too low.

DR. GOLDMAN: Well, I think we have to take all the data into
consideration. And I think we saw some very interesting data today that
shows a positive bias in the lower range that might be \-- at least in
that patient population.

I think that\'s the challenge, is to identify \-- to some degree this
cuts to a very important part of the issue which is, just how much can
you rely on laboratory testing to indicate the performance in the real
world?

And, under ideal conditions we see a set of certain limited \-- we have
limited information in a set of performance. And, if we don\'t ever test
on the population of attended use, there probably will continue to be
surprises like this.

So, I think that\'s a very reasonable question to ask. And, the
challenge is getting this kind of data. I certainly am all for getting
data. I\'m for getting data in the clinical conditions of use and the
population of use.

But, part of what should be discussed and considered is when can you,
how necessary is it to get started, should it be required before
clearance of a device, or should it be considered afterwards?

Those are all part of the discussion. It\'s a good point.

CHAIRPERSON LISBON: I think our morning session is done. I\'d like to
thank all of the participants for a very lively and informative
discussion.

Lunch is in the restaurant out towards the front. And I gather there are
reserved tables for the panel members. And we will start again precisely
at 1:00 p.m. Thank you very much.

(Whereupon, at 12:03 p.m. the above-entitled matter recessed for lunch.)

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

1:04 p.m.

CHAIRPERSON LISBON: All right. I would like to call this meeting back to
order. We\'re now going to continue with the agenda. And this part is
the panel discussion.

What we\'re going to do here is that we\'re going to put each of the
questions up and we\'ll discuss each of them. Dr. Cote has graciously
agreed to start the discussion of each of these questions.

And then we\'ll go around the table and get everybody\'s opinion. And,
hopefully we\'ll be able to wrap this up on time. So, may we have the
first question up, please?

MS. GRAHAM: You may as soon as the projector gets warmed up.

CHAIRPERSON LISBON: All right.

(Pause.)

CHAIRPERSON LISBON: All right. So, the first question \-- do you want me
to read this into the record?

(No verbal response.)

CHAIRPERSON LISBON: All right. Pulse oximeter sensors may be implemented
in either transmittance or reflectance configuration. In both
configurations, light is scattered by blood, which has time dependent
characteristics and bone and other tissue structures which are not time
dependent.

Transmittance sensors are configured in a manner where the emitter
outputs light, which travels through tissue, finger, toe, or an ear and
is received on the opposite side by the detector.

Reflectance sensors are configured with an emitter and detector in the
same plane. Emitted light must reach the detector by reflection off of
the surface, which typically results in smaller signal strengths in
comparison to transmittance sensors.

And, the FDA would like us to discuss the clinical differences between
transmittance and reflector senses and in the discussion comment
specifically on any differences in performance between the two sensor
types, whether the differences in performance would lead you to
recommend different pre-marker evaluation methods and standards and, if
so, what these would be and whether the differences in performance would
exclude certain indications for use for one type compared with the other
and if so, what would those be? Charlie?

MEMBER COTE: Okay. I think we heard very nice presentations this morning
indicating that in the laboratory situation the ideal adult volunteer
patients, that the two types of oximeter probes have reasonable
parallelness in terms of function and accuracy.

But I think where it falls down is the actual clinical application. And
this is why I think these devices do require a different kind of
evaluation as part of the process, because it\'s clear that if a surface
oximeter is applied to different parts of the head over an artery versus
not over an artery over an area that\'s like in the back of the patient
if they\'re lying on it.

It might be different than if you put it on the abdomen. We need to have
very clear data to support where these devices need to be placed and how
they need to positioned in order to achieve the same accuracy as the
device when it\'s used in the perfect ideal laboratory situation.

There have been a number of public studies indicating, at least one
paper looking at five or six different locations on a baby\'s head for
the transmittance oximetry demonstrating that there are certain areas
that are very good in terms of getting a nice pulse plethysmograph.

But, because they\'re near an artery, it creates an artifactually low
reading. And then, other areas where there\'s no signal at all, and then
other areas like the cheek where there\'s a reasonably good sensor,
cartilage between the pulse plethysmograph and the reading of the
oximeter.

There\'s indication in the literature and it was described by several
people that if there\'s a problem with venous congestion, perhaps in,
for example, in children with congenital heart disease where they have a
high CVP, that there\'s simultaneous reading of venous and arterial
blood, which, again, results in an artifactually low reading.

So, from my standpoint, I think that before we can say the device is
equivalent, we have to define more precisely where on the body, at what
age patients this device works in the same way as it does in the ideal
laboratory situation.

CHAIRPERSON LISBON: Charlie, number C, or letter C, what differences in
performance would exclude certain indications? Can you list any of those
indications where one type would be preferable to another?

MEMBER COTE: Well, I think it goes both ways. There are situations where
you have patients that \-- for example, I used to take care of burn
children.

And there was no digit that you could apply such a sensor to. But there
may have been a surface that we could apply it to. That might be one
situation.

The reverse would be a patient who\'s very edematous or, as someone
mentioned \-- position, where the surface electrode would not work as
well as a transductant silicone.

CHAIRPERSON LISBON: Great. Thank you very much. I can either take
volunteers, or I can go around the room. Does anybody want to volunteer
to go next?

(No verbal response.)

CHAIRPERSON LISBON: In that case, why don\'t we start down at the end of
the table and just work back towards me?

MEMBER DRASNER: I have very little to add to what he\'s saying. I think
the variability and where the device is applied really makes this little
different than previous devices.

And I think, as he stated so clearly, I think we need some data on how
these perform specifically in specific locations on specific population.

DR. MUELLER: Yes. I would only concur that the clinical situation,
simply the probes, one type won\'t be appropriate, they won\'t stick, or
they\'re in the way of the nursing care so that it\'s a practical matter
as to where to put them.

And I think that\'s best solved by the practitioner at the time of use.

DR. TUNG: I\'d agree as well. You know, I feel myself like clinicians
aren\'t very sensitive to the idea of signal quality. You know, you can
tell just by the way we put pulse ox probes anywhere we can find a
place.

And that\'s really the primary issue when it comes to where these
reflectance probes are located on the body and how well they work. And,
you know, we have to learn all that.

You know, and so, the result is that more data would probably help us
get started in learning about how to use that kind of information in
assessing the quality of a signal.

CHAIRPERSON LISBON: I get to go last.

DR. LEUNG: The one comment that I have is, currently, when you open
pulse oximeter probe, you know, it\'s in a little plastic bag. And
there\'s really no instruction to the user.

It\'s kind of implied that when you have access to that you know how to
use it. And that may not be true based on what we learned today. And
that may be one.

You know, one consideration is to include that information as almost
like a drug insert with respect to the different sensors. There are many
conditions in which the sensors wouldn\'t work.

And that might help the users to decide whether the information is real
or not. I mean, frequently we don\'t change our clinical decision based
on one number.

But, what I\'m hearing is that, you know, more and more we\'re using
this device to drive our clinical decision making. We\'re no longer
using blood gasses.

And so, I think we need to know the limitations.

DR. BIRNBACH: Taking what Jackie said one step farther, we haven\'t
gotten the information of how, what percentage of anesthesiologists
actually use one type or the other.

My gestalt would be that we almost always use transmission devices in
the operating room environments. Anyway, that may be different. It\'s
clearly different in the neonatal experience and probably different in
the ICU experience.

It would probably be helpful to have some kind of analysis of what
different positions you\'re using, when, why to have that data. And then
the next step would be o have better instructions with warnings, for
example, which I don\'t think exist right now.

DR. OTULANA: I think I agree with Dr. Cote that based on the
presentation we saw today, there\'s probably no technical differences
between the two forms of pulse oximeter.

But, the clinical use, I think, is where needs to be focused in terms of
the application of the sensor to the different parts of the body. So, in
response to the FDA question then, perhaps the focus has to be the
testing of the oximeter on the \-- of the sensor rather, on the relevant
part, where it would be recommended for use.

So, if it\'s going to be on the forehead, if it\'s going to be on the
back, I think data needs to be generated specifically for these areas.

MS. KLINE: I too practicing in the pediatric ICU world, am not familiar
with, have not used the reflectant technology. But I agree with the
comments of the other panelist and Dr. Cote as far as looking at these
devices further and looking at their performance, as well as having more
information on exactly where to place these on the patient\'s body.

MS. PETERSON: I concur with the other panelists\' comments and with Dr.
Cote.

CHAIRPERSON LISBON: Okay. Charlie, go ahead.

MEMBER COTE: Yes, I think we are particularly concerned with the
so-called neonatal and the premature neonate, again, because the skin
thickness is so dramatically different in those children.

Perhaps the skin profusion might be different in those children. But, in
fact, many moment-to-moment decisions are made in terms of oxygenation
because the concern that we have in taking care of pre-term babies is an
excess amount of oxygen could lead to the development of retrolental
fibroplasias.

So, there\'s this general recommendation that you keep the saturation
somewhere between 88 and, you know, 95 or 93 percent, it depends which
nursery you\'re in.

But, there\'s always this narrow range that you like to keep it in. And
you don\'t want the baby at 100 percent. If this oximeter is
under-reading and says that the baby\'s saturation is 80 percent when in
fact it\'s 87 percent, that could have significant implications for the
baby, because then you\'re going to give them an excess of oxygen and
actually be causing a situation that could potentially cause retinal
injury thinking that you\'re providing optimal care.

And I guess that\'s one of my concerns in terms of the use of this
device in pre-term babies. In full term babies it\'s not an issue.

CHAIRPERSON LISBON: All right. I guess I get to make the last note on
this question. I agree that there needs to be further comparative data
on these two devices, these two techniques for obtaining a pulse
oximetry, particularly the lower oxygen saturations.

They are used under different clinical situations and signal \-- ratios,
and those such things are important in the various devices. I\'d also
like to see more data out there as to how these should be placed and
where they should be placed.

And I\'d like to see more validation data for that. And, with that, I
believe we\'re done if none of the panelists have further comments on
question number one

MEMBER COTE: Actually, I\'d like to go and make a \-- I talked about
this with one individual in the audience during lunch. And, I think
these types of validation studies are doable.

We conducted a study in children under anesthesia examining four
different oximeters all used at the same time. And we randomized digits
that we applied them to.

It seems to me a similar study could be designed with these surface
oximeters where you randomize the location but apply multiple different
sensors to the same patient.

And then from that you can figure out which is the optimal location that
consistently provides you the most useful information avoiding the
orbital area, avoiding the temporal artery, whatever it is that changes
things.

But I think that\'s the only way you\'re going to get it. And, the
published studies that I\'ve seen out there have been very different
where they look at it at one location and they take it off and they
reapply it to another location.

That\'s not really a pure comparison because things could change between
one moment and the next. So, I think the study design is very critical
in terms of being able to assess the accuracy of these devices.

CHAIRPERSON LISBON: Are there any other comment on question number one?
Dr. Lin?

DR. LIN: If I may, there are so many panelists that keep talking about
we need more data. Now the question is that this data should be
collected post-clearance or are you recommending this data should be
collected during the pre-market? Somebody can come and that will be \--

CHAIRPERSON LISBON: I would think that certainly for any device going
forward, collecting this before it reaches the market would be
important.

And, for devices already on the market, I certainly would like to see
some post-marketing data. I mean, some of these devices were approved,
predicated on older devices.

And, you know, I think that as has bee pointed out by multiple speakers
here, the algorithms have changed, the processing has changed, and the
devices are better.

And we need to know how much better they really are. Jackie?

DR. LEUNG: I just also want to make a comment. You know, in my
experience, pre-marketing data is usually very rigorously collected.
Whereas post-marketing could be anecdotal case series.

It\'s quite different. And I think that\'s a big decision the FDA has to
make in accordance with the industry. Because I think the two are really
quite different.

And, what do we do with the data post-marketing? Who is going to review
that?

CHAIRPERSON LISBON: Anybody else? Yes, Charlie.

MEMBER COTE: Yes. I think we need to maybe think of this the same way as
drugs. This has been a very evolving process over the years in terms of
drug approval.

I think it was in 1994, Dr. Kessler promulgated the new rule and with
that, re-interpretation of 1938 Food and Drug Cosmetic Act, he said that
companies were required to prescribe \-- to develop prescribing
information from drugs that had widespread use.

And so, he interpreted that to mean drugs used in children. But, the
caveat was that he allowed the manufacturer \-- drug manufacturers to
use the available literature.

So, if there was a wide body of literature that was published, even
though it didn\'t meet the rigorous FDA standards typically required for
drug approval process, after presentation to the FDA, the FDA would
allow some of that language to be adopted into the label.

I don\'t see why the same thing can\'t happen with devices that, if you
have good clinical trials that were well controlled and well conducted,
why can\'t that information be accepted by the FDA into the label just
like for drugs?

CHAIRPERSON LISBON: Jackie?

DR. LEUNG: I just have one kind of comment. You know, pre-marketing \--
the studies are usually sponsored by the manufacturers. So, the question
is, who is going to sponsor the post-marketing, you know, studies?

Who would be interested to sponsor that? The motivation would be much
less, unless there\'s an investigator initiated. It may be easier for
devices and for drugs.

For drugs it\'s very difficult, once a drug is on the market, to find a
sponsor. So, I think there is some with just co-consideration in terms
of how the studies will actually be funded?

CHAIRPERSON LISBON: Is there other discussion?

MEMBER COTE: Well, I think some of that money for those studies, or some
of that research, was funded by the user fees that drug companies paid,
at least for the things going forward.

Maybe that\'s where some of that money could be coming from since the
companies are now required to have some kind of a user fee when they
file for a new application. That would be one source of funding.

CHAIRPERSON LISBON: Are there any more comments on question one?

DR. BIRNBACH: So, you\'re suggesting that the FDA fund these studies?

MEMBER COTE: Or the industry could put money in a pot to help. The
oximeter industry as a global industry could contribute to a pot that
would allow support of such studies.

CHAIRPERSON LISBON: All right. Have all the issues been addressed on
this particular question? Is there any other information that any of the
panel members would like from any of the participants in the audience?

MEMBER COTE: This goes to question two, and that is \--

CHAIRPERSON LISBON: Not on question two, but on question one.

MEMBER COTE: Well, performance differences exclude certain populations.
I think we have to be concerned with patients with cyanotic heart
disease with all devices.

CHAIRPERSON LISBON: Any other questions of the audience?

MS. GRAHAM: Could you clarify the statement \--

MEMBER COTE: Clarify the statement about cyanotic heart disease?

MS. GRAHAM: Yes, the level of concern.

MEMBER COTE: Many children with cyanotic congenital heart disease will
have saturations in the mid 70\'s, sometimes even in the high 60\'s.
And, since these devices all are calibrated to a standard down to 70,
the accuracy drops off whenever such a patient gets into trouble.

We don\'t know what those numbers really mean. We just know the patient
is in trouble.

MS. GRAHAM: Okay. Take it the next step.

MEMBER COTE: That creates a potential medical legal issue with us. You
know, well Doctor, how long can a patient tolerate a saturation of 30
percent?

I don\'t know whether it\'s really 30 percent, or it\'s 50 percent,
because each device is different. That\'s why it kind of overlaps with
question two. Maybe we should \--

MS. GRAHAM: So, are you recommending then, in that case, that there
should be a specific label not for use in certain population? I\'m
trying to \--

MEMBER COTE: No, I don\'t think it should have a specific label saying
not for use. I think there needs to be some questioning of the validity
of the data when the saturation gets below 70 percent.

MS. GRAHAM: Okay.

MEMBER COTE: Let\'s go to question two, because I think this plays right
into it.

CHAIRPERSON LISBON: Did you have a comment?

DR. BIRNBACH: Yes, would you be suggesting that perhaps the labeling
would say that if you have a situation where the number is less than 70
then a confirmation is desirable.

MEMBER COTE: Yes, but that\'s question two.

CHAIRPERSON LISBON: Have we addressed all the issues on question number
one?

(No verbal response.)

CHAIRPERSON LISBON: Okay. Then let\'s move to question number two, which
I will read in for the record. And then, again, we\'ll start the
discussion.

The Agency currently recommends that pulse oximeter sensors are
clinically validated to a stated accuracy plus or minus two percent from
70 to 100 percent on healthy adults under ideal laboratory conditions.

The, for transmittance sentences intended for use in neonates, a one
percent degradation factor is added to the stated accuracy so it\'s plus
or minus three percent to compensate for uncertainty due to the
inability to perform suitable calibration studies in the apparent
affective fetal hemoglobin on saturation measurements.

There is some evidence that co-oximeters, the reference device used to
analyze blood, is inaccurate at high concentrations of fetal hemoglobin.

Please discuss whether you believe that the Agency should continue to
follow this recommendation to validation of transmittance sensors
intended for use in neonates and if this same recommendation should be
followed for validation of reflectance sensors intended for use on
neonates.

If the panel does not feel that this recommendation is appropriate,
pleas provide the Agency with suggestions and recommendations as to how
the validation of accuracy for neonatal use should be revised.

And then part B of this question, please discuss whether you believe
that labeling for sensors, especially those for neonates, should contain
information on how the saturation accuracy specification was developed
and validated. Charlie?

MEMBER COTE: I think there was very good information presented both by a
review of the literature by one of the manufacturers this morning as
well as the pediatrician that presented his data.

There doesn\'t seem to be a need to have a one percent difference
anymore, that the performance seems to be same in the neonate as it is
in the older patient.

I\'m a little confused though because I\'ve seen plus or minus two
percent and plus or minus three percent. And then, in the discussion
this morning, it was plus or minus three percent, plus or minus four
percent.

So, I guess we need to have some clarification there because \--

DR. WEININGER: That was just an example of the question to show what the
\--

MEMBER COTE: That was a sample? So there wasn\'t a number. Okay. So we
are plus or minus two and plus or minus three for newborns.

DR. WEININGER: And the question in question number two, that was just to
show as an example to see what the impact of the plus or minus one
percent degradation would be.

MEMBER COTE: I see. Okay.

DR. WEININGER: It wasn\'t meant to say that that\'s what the
recommendations are these days.

MEMBER COTE: Okay. Then I guess my \-- if I interpreted this correctly
as well as the literature on fetal hemoglobin, it would seem that there
is no longer a need to make babies have a different tightness in the
perimeter compared with adults.

CHAIRPERSON LISBON: Okay. Thank you. We\'ll again start at that end of
the table.

MEMBER DRASNER: Again, I agree with him. I think that there seems to be
a consensus that fetal hemoglobin is not a significant factor and the
same standard should apply.

DR. MUELLER: Yes, I would agree was well. I think that the evidence is
clear that the fetal hemoglobin is not the problem. I think the problem
remains, however, exactly how would you validate the number that comes
down to 70 or 68 or 72?

We still haven\'t really resolved that. And I guess the only answer
might be to go to some situation where in fact you do have an A line and
saturation\'s that low.

In my experience at least, that\'s only during cardiac surgery for these
patients in order to get away from risk to patient issues. So, that
would be my suggestion, that the attempt be made to pick a clinical
situation where in fact that might be possible to get both co-oximeter
and saturation values that might be interpretable.

CHAIRPERSON LISBON: Avery?

DR. TUNG: With respect to the one percent, I\'d agree also. I am struck
by the large bias shown in that presentation by the Pete\'s intensivist
and wonder whether information about such bias can be made more
available to clinicians or somehow represented in a way that makes us
more able to see that, you know, at different saturations there can only
be worse accuracy, but also a significant bias in a certain direction.

CHAIRPERSON LISBON: Jackie?

DR. LEUNG: Are you suggesting a peer review article in the form of \--
is that what you are \--

DR. TUNG: I would guess more like, say, sat dependent accuracies or sat
dependent biases. I mean, to see ten points on a set of 70, that\'s a
big deal, I think.

DR. BIRNBACH: I agree with all my colleagues. The one thing that I was
impressed by is that it appears that different sensors have very
different values. And, as a clinician, I don\'t believe that the
information\'s available that if you\'ve got ten different systems to
choose from, that the bias may actually be different depending on which
system you use.

And so, I think that deserves, A, some post-market research, and B, some
publication, and C, some work from the companies to perhaps if there are
eight different systems available and four of them are much \--
associated with a much lower bias at low saturations, that those should
be marketed preferentially for the neonate.

DR. TUNG: Yes, it\'s a good reason to get more data because, at least in
theory, machines can be de-biased if you know where the bias is.

CHAIRPERSON LISBON: In my previous life as an electrical engineer,
sometimes when you buy a piece of equipment, it comes with a calibration
curve.

And there\'s really \-- and this probably speaks to our B, but there\'s
no reason that some of these devices couldn\'t come with calibration
curves which show how they actually respond, the particular device \--
not as a group, but as a particular device over the range of saturations
where they\'re going to be used. Go ahead.

DR. BIRNBACH: Actually, to take it one step further, I\'m still a little
confused at why the FDA needs to only look at the entire system as one
with the device that goes on the finger, for example, and the cable, and
the machine when you can, as an end-user, clearly substitute 12
different probes on the same hardware machine and that\'s being done.

Then, why shouldn\'t the analysis also be a mix and match kind of thing?

DR. WEININGER: It absolutely should. When you substitute a third party
or other probe onto that pulse oximeter system, that has to be cleared
with the same degree of rigor.

So, it has to have validation data that says what it\'s good for and
where it \-- you can\'t \-- did that answer your question?

DR. BIRNBACH: Not really. Because, if I come up with a new probe
tomorrow and sell it, I don\'t have to test it against the 14 different
base units, do I?

I only have to do it against one. Whereas, I\'m not so sure that it
shouldn\'t be tested against all of the units that are currently being
used by clinicians.

MS. GRAHAM: It\'s similar to a question that we have talked about
internally as the interchangeability of the box and the sensors. No
resolution, but we\'ve talked about it.

CHAIRPERSON LISBON: Let\'s keep going. Dr. Otulana?

DR. OTULANA: Well, the question of interchangeability \-- I think not
only in devices but diagnostics and other products that the Agency
approves.

You start trying to manage it with labeling, at least letting the
consumer know that studies have not been done where a certain sensor is
used with a certain oximeter.

I think it will be really burdensome to say that someone who wants to
get a sensor approved has to test it on so many other oximeters that are
made by different companies.

So, I just made that side comment. But, on the question on the percent
degradation factor, I agree that I think there is now enough evidence to
say that that should no longer be added on for neonatal accuracy
estimate.

CHAIRPERSON LISBON: Ms. Kline?

MS. KLINE: I agree with the comments by Dr. Cote. And I too think that,
based on the information presented today, that we could eliminate the
one percent degradation factor.

CHAIRPERSON LISBON: Ms. Peterson?

MS. PETERSON: I concur with Dr. Cote and the panelists.

CHAIRPERSON LISBON: All right. I get to speak again. Again, I would drop
the one percent. I feel pretty strongly we need validation data for
neonates.

And, as kids are becoming sicker now, I think that 70 to 100 percent
number probably needs to be dropped because, as Charlie alluded to,
there are times when we\'re using these devices down in the 60\'s.

And we need to know that they are accurate down there. And, as I pointed
out previously, you know, if we\'re going to allow interchangeability of
these devices, we need to have some sort of calibration curves for each
of these probes with particular boxes that are doing the algorithms for
them.

Anybody else? Is there other discussion now?

MEMBER COTE: Are we \--

CHAIRPERSON LISBON: Well, we\'re sort of going into B now, yes.

MEMBER COTE: All right. Then I\'m going to say what I was going to say
for B.

CHAIRPERSON LISBON: Okay.

MEMBER COTE: And thank you for being so agreeable. Everybody has agreed
with everything I\'ve said so far. I think it\'s very important to have
a handle on the bias at each range at which we use these devices.

So the bias is different from 90 to 100 percent. It\'s different between
80 and 90 percent. And it\'s different between 70 and 80 percent. We, as
the clinician need to know how far off this device is likely to be when
we\'re getting into that low range.

And then, if there are data available generated through other methods
other than the volunteers, which can only go down to 70 percent, that
information also needs to be provided.

So, again, we have some guidance as to how to interpret the accuracy of
these devices in children with cyanotic heart disease. And,
unfortunately, that information is not available.

Looking at the literature, it appears that if you compare different
boxes and different manufacturers, that this bias is dramatically
different, as was presented earlier.

And so, how does Joe Schmo and Podunk General figure out which box and
system to buy for his or her hospital or his or her population that\'s
going to provide meaningful information?

I\'d say, for the vast majority of patients, all pulse oximeters do a
great job in giving us an early warning that something is going wrong.

But, those of us that take care of critically ill children that are
cyanotic to begin with, we\'re kind of left in limbo. And I\'ll give you
an example of this.

One of my cardiac surgeons came up to me last week and said, what do you
think of the nurse writing in the record that the patient\'s saturation
was 25 percent, and to continue recording that?

And I looked at him, and I said, what are you talking about? And he
said, well, we had a patient who was \-- got into serious trouble. And
we\'re concerned that the lawyers are going to come back and say, look
what you did to this patient, you didn\'t do anything about his
saturation of 25 percent.

And I looked at him and said, I don\'t think that\'s a meaningful
number. You just know that the child is in very, very serious trouble.
But the actual number doesn\'t mean a thing.

But the labels don\'t say that. And that\'s what I was getting back to
this earlier. Somehow we need to get at how does the clinician interpret
a saturation of 50 percent that sits there?

Is it really 50 percent? Is it 40 percent? Could it be 60 percent? We
don\'t know how much the variability is from patient to patient. And I
think the manufacturer doesn\'t know that either.

So, somehow we need to either put in the label a disclaimer, as you
said, that we don\'t \-- so it protects the physician somewhat. Or we
need to get our hands on that information.

And, what was alluded to by one of my co-panelists is there are
populations of patients that we can get that information from. We can
get it from children that have cyanotic heart disease that are
undergoing cardiocatheterization because they put in an arterial
catheter for that.

So, simultaneous data can be obtained there. We can get it for children
undergoing repair of their congenital heart disease. And we can get it
for the children, the newborns that are admitted to the intensive care
unit that do have an arterial line put in that are stabilized prior to
their coming to the operating room.

So, there are populations that can be studied. It\'s difficult, it\'s
expensive. You have to go to centers that have a lot of these kids so
that your payoff for the money invested is there.

But it can be done. And it should be done.

DR. MUELLER: Yes. Just let me bring out the elephant that we\'re sort of
dancing around. I think the one percent is really a testament to the
unreliability of the number.

And the lower reaches below 70 was a good example. But the problem is
not the pulse oximeter. It\'s not the device. The problem is the
patient. We\'re looking at problems in metabolism, problems in
hemodynamics that we\'re not measuring at that point adequately in order
to interpret it.

So, what we really have to do is to label it appropriately, that when
the pulse oximeter gets in a person of such and such year, gets below a
value of 75 or such, 70, that at that point the care team needs to focus
on other issues that are also determining the well being of that
individual.

And it\'s not necessarily the probe, or the device, or the cable. It\'s
the patient.

CHAIRPERSON LISBON: Any other comments? Dr. Otulana?

DR. OTULANA: Yes. I just want to add to the last comment. I agree
completely. And I will say that that is true not only for neonates, but
for adults as well.

So, if this is going to be addressed in the labeling, I think we need to
be cognizant of the fact that those factors that have just been
identified in neonates will apply, maybe less commonly so.

But there are adults who are also at that lower end of the spectrum
where the accuracy is less dependable.

CHAIRPERSON LISBON: Thank you. David?

DR. BIRNBACH: There\'s a certain silo mentality. We heard this morning
that we were excluding fetal pulse oximetry today. But, there in lies
the problem in that you do have a growing database right now using pulse
oximetry with very low SpO~2~s.

And I think that the data, the technology, and some of the issues from
fetal pulse oximetry should be finding their way into this debate as
well.

I\'m not quite sure how that happens with one being in group two versus
group three. But, we\'re getting information with low pO~2~s and pulse
oximetry in that population.

And I think that somebody should be analyzing that.

CHAIRPERSON LISBON: Is there anybody else?

(No verbal response.)

CHAIRPERSON LISBON: I would like to thank Dr. Gerstmann for presenting
his data and also for showing us that it is possible in sick kids to
collect this kind of data and to show us what the inaccuracy is there.

So, thank you very much for coming to do that.

DR. WEININGER: Two quick comments?

CHAIRPERSON LISBON: Yes.

DR. WEININGER: Yes. Just two quick comments. As already has been pointed
out, the observational studies that we\'ve seen \-- I\'ll refer to them
as clinical studies.

And we\'ve seen a lot of causes of uncertainty in those studies. And,
again, we\'ve got to make sure that we\'re comparing apples to apples
and not apples to oranges in terms of the different types of diseases
out there.

And it\'s a very difficult challenge. It\'s very expensive. And, to try
to communicate that information back to the clinician in a practical
manner, as you can imagine, is a very difficult task.

CHAIRPERSON LISBON: But Sandy, people don\'t put these on for different
types of diseases. They put them on as a routine monitor. And they\'re
put on whether you have some lung disease or whether you have some
cardiac disease, or some metabolic.

DR. WEININGER: I understand. And so, it\'s a challenge to the whole
community, as well as us, to figure out what\'s the best way to convey
that information.

I\'m not trying to take a stance. I\'m just trying to present what the
magnitude of the problem is, or at least define what the problem is.
And, the second historical fact, a long time ago in the ISO and ASTM
committees, they debated whether they should do bias and precision of
the different decades, 70 to 80, 80 to 90, 90 to 100.

And the feeling at that time was that clinicians are already overwhelmed
with the data that they\'re looking at. And, to try to handle, for
example, six parameters, telling you what the accuracy of your pulse
oximeter is, by some precision over those three decades, would be
something that would go \-- I don\'t want to say over the clinician\'s
head, but that they would be able to assimilate that amount of
information and make use of it.

And that\'s why the summary statistic, A~rms,~ root means square error,
tries to capture as much of the salient information over the operating
range, 70 to 100, as possible.

CHAIRPERSON LISBON: But we\'re simple people. And if you tell us that,
look, it\'s not so accurate between 70 and 80 and it\'s really accurate
between 90 and 100, we\'ll go away with that message, regardless of what
kind of statistics are \--

DR. WEININGER: And I have to go back and look at the labeling more
carefully and see what manufacturers do state. In fact, we can ask the
manufacturers in the audience.

But, I suspect that they already have some information about that in
their labeling?

CHAIRPERSON LISBON: Charlie?

MEMBER COTE: I\'m going to raise a voice of caution about this because I
know of at least one fatal accident that occurred in a pediatric patient
who was receiving opioid and happened to be a sickle cell patient.

And the nurses called the intern and said, saturation is 85 percent. And
he said, oh, the kid\'s got an abnormal hemoglobin, it doesn\'t work in
those kids, and ignored it.

And then the child was found dead an hour later. So, we have to be
careful we don\'t tell clinicians that 85 percent isn\'t accurate
therefore, don\'t pay attention to it.

We have to educate them that, if it\'s a change, that that\'s what\'s
important. The actual number is less important than the fact that the
patient is deteriorating clinically.

CHAIRPERSON LISBON: Right.

MEMBER COTE: So, that\'s a very important nuance that must go in the
labeling if we make that change.

DR. WEININGER: And it\'s not a nuance when you\'re starting to talk
about educational aspects of how to use the oximeter. You\'re almost
outside the realm of what you can control.

MEMBER COTE: But I think what was presented is we open up these oximeter
probes and there\'s no insert. So, maybe we need to provide a very
simple \-- especially if we\'re going to tell people where to put it.

They need a picture of exactly where we put the darn thing so that it\'s
not misapplied or put on backwards or something like that.

DR. WEININGER: If you want, we can ask the manufacturers on what they
include in their insert in their package labels.

CHAIRPERSON LISBON: Do any of the manufacturers wish to speak to that?

(No verbal response.)

CHAIRPERSON LISBON: Yes, please approach a microphone. And please
identify yourself, if you would, and who you represent.

MR. MELNIKOFF: Donald Melnikoff from Smiths Medical PM, formerly known
as BCI. Relating to that, the instructions are in every single box of
disposables, reusable reflectance probe.

The problem that comes in is if you take a look at like a box of
disposable, you\'ll actually have an insert be a big triple sided \-- or
double sided with multiple languages.

What\'s happening, and I see it in different environments, is the nurses
will take the probes and then put them into a bin. And they don\'t
necessarily keep the instructions for use with the actual probe, because
there\'ll be multiple probes within one insert.

But the inserts to cover a couple things that have been mentioned. First
and foremost is below 70, it says unspecified. And that\'s for all the
manufacturers have the same thing.

So, it does say that all bets are off below 70. Above that, some
manufacturers do specific different criterias of what their accuracy is
during different values.

So, I think part of the issue is that the inserts are so burdensome if
you talk to some of the users because they are so big and they have all
the actual disclaimers already in there that most of them \-- that you
guys have discussed.

They are in the literature. But they don\'t typically get attached to
each probe because they are so thick. And the manufacturers end up
actually putting them in with the box instead of with each probe. Thank
you.

MEMBER DRASNER: Just to continue where Charlie left off, we\'ve heard
that the biases can be enormous below 80 or especially 70. We\'ve heard
that there are some clinical implications, not to mentioned
medical/legal implications of having a pulse oximeter reading of 25 or
35.

Why can\'t the machine give you a no value reading below 70 if the
manufacturers below that quote, unquote, all best are off below 70, why
don\'t the machines just tell you, less than 70 when you hit 70?

And then there\'s no question of interpretation. You know that the value
is less than whatever that number is. And you pick the magic number, 75,
70.

But that\'s your cutoff. And, if we don\'t know what 40 means, why
should the clinician be given 40 and asked to interpret that?

DR. MUELLER: On the other hand, if you\'re trying to interpret what\'s
the real problem, what\'s the basis for the value being so low, if you
give them some red cells or increase the cardiac output or whatever, and
you don\'t have a number? You won\'t know.

DR. BIRNBACH: If you\'re below 70 and it goes to 80, you have a number.

MEMBER DRASNER: It seems to me that you want those numbers even though
they\'re low because the trend has maybe some significance to you even
if the absolute value doesn\'t.

And I think what really needs to be \-- and, as he said, you can stand
with a three page insert. But, what you need is really some very, very
simplified guidelines of what the validity of these numbers mean at
different levels, not something that\'s buried in three pages of a
handout, but something that is very clearly and specifically stated.

DR. LEUNG: I think that one of the points that I was trying to make
earlier is that the data really are truncated below 70. And we seem to
want to believe that it is a continuous scale when it isn\'t, because we
don\'t have any data to follow that regression.

And I can only speak for adults. I mean, we would never leave anybody
below even 80 for a long time. And, if your intervention doesn\'t go
above 90, you really wouldn\'t believe those numbers.

So, I think for adults it\'s probably less important whether it\'s 50
versus 70. That\'s not my goal. But, for pediatrics it\'s different.

MEMBER COTE: That\'s what I was going to say. I think that we\'re
talking about two completely different issues. One is the routine
application to the 99.9 percent of the population where the range that
it\'s in now is perfectly fine and accurate.

And then we\'re talking about that less than one percent population that
has serious issues with oxygenation. And so, maybe what we need to be
talking about here is what was brought up earlier, is taking some of
this technology that\'s been designed for fetal oximetry and having that
kind of an oximeter with that kind of accuracy and a low saturation
range with the indication to be used in patients who are cyanotic
already.

That might be a way around this. Then you\'ve got an accurate device for
that particular population of patients. Alternatively \-- again, I\'m
not an engineer.

I won\'t pretend to be one. But, my understanding is that for oximeters
to work in the low range, you have to change the light emission range.

And, when you do that, they become less accurate in the high range. I
don\'t know if it\'s possible to have an oximeter that starts off in the
high range and then will default to a different wavelength if the
patient reaches a certain saturation so you can get more accurate data.

But that might be an approach. I can see my friend in the back laughing.
Maybe he\'s already thought of that, I don\'t know.

CHAIRPERSON LISBON: Any other comments? David?

DR. BIRNBACH: I\'ll pass.

CHAIRPERSON LISBON: Anybody else have anything else they wish to say?

DR. BIRNBACH: Well actually, maybe I won\'t pass. It goes to Dr.
Drasner. And maybe one of the engineers can answer this. The gestalt out
there is you can trend this and that it\'s valuable to know that it goes
from 50 to 60.

I don\'t actually think that that\'s the case. And so, I wonder whether
or not there is any data that there\'s a difference, for example, if it
goes from 54 to 59 or from 48 to 60.

Because, if there isn\'t, then there are a whole lot of clinicians who
are looking at or interpreting numbers wrongly.

CHAIRPERSON LISBON: Can anybody speak to that in the audience? And
again, even though we know who you are, please identify yourself so the
transcription will be able to \--

MR. ISAACSON: Philip Isaacson from Nonin Medical. I just want to say, we
have data. We\'ve run our sensors and gotten data down to 50 percent. We
have chosen not to make the claims because \-- well, there are various
reasons we chose not to make.

But, it does diverge more down below 50 percent. And it can depend a
little bit more on careful sensor placement. But, is the trend good?
Yes.

When down at \-- we give a reading of 40 percent, well, maybe it\'s plus
or minus 10 percent. But if it says 40 percent and it\'s trending up,
it\'s trending up.

So, for somebody that wanted to know that they\'re doing something right
and improving the patient, it\'s a very valuable number. If you had a
diagnostic procedure or somebody in sleep study that was going to do a
different treatment based on 40 versus 45 percent, you\'ve got a little
more work to do.

But internally we have characterized our devices down to 50 percent.

DR. BIRNBACH: Do we have any published data? Has anyone ever looked at
that from the company, the other manufacturers who have done series of
patients rather than mountain climbers, patients who are being tested in
other ways?

DR. MANNHEIMER: Well, I think there is historical \--

CHAIRPERSON LISBON: Say your name just so they \--

MR. MANNHEIMBER: Paul Mannheimer from Nellcor. I think if you look in
the packet of information that we provided to you, there\'s a lot of
publications of pulse oximetry collected over the years, 1980\'s to
current, that has seen neonates down in the very low sat range, 40 or 50
percent.

I think some of the data is collected. It\'s not falling off the cliff.
The performance is still trending generally down the line of identify,
it tends to get more scattered.

To amplify a comment that was just made, the reason the manufacturers
don\'t specify performance below 70 isn\'t because it doesn\'t work
there, is because it puts a burden on us to validate every product we
make with every sensor-monitor combination, works down below 70.

And the test environment to do that is less available. To go into the
clinic makes it even more difficult to achieve.

CHAIRPERSON LISBON: Any other points? Avery?

DR. TUNG: I agree with Dr. Dresner. I think the pulse ox works so well
at least in part because it\'s a tremendously intuitive device. And,
when you take away a quantitation, even though it may not mean precisely
what it says it means down below 70, you\'ve sort of changed the way
people respond to it.

You, the pulse ox is a number of very sort of decision making that\'s
very emotional in nature often. And, to have a number in \-- sometimes
speeds things up when you need it to be speeded up.

It may not speed it up as well when you just have a blank thing.
Because, then you\'re not sure what. If there\'s some uncertainty there,
and it can be misinterpreted.

CHAIRPERSON LISBON: Are there any other comments on question number two?

(No verbal response.)

CHAIRPERSON LISBON: Have we covered all of the issues for this? Does
anybody have any questions for either the other people on the panel or
for the audience?

(No verbal response.)

CHAIRPERSON LISBON: Okay. Let\'s move on then to question number three.
And, before we do that, I was wondering if Ms. Graham could inform us as
to the difference between over the counter and consumer products and
what the implications to us are for that.

Because, I think many people \-- at least on the panel \-- seem to think
that over the counter and consumer was pretty much the same, even though
it\'s not the same.

MS. GRAHAM: Right. The main difference is that over the counter devices
would have a medical claim associated with them. So, for example, a
pulse oximeter for OTC use would identify an intended use and a patient
population.

A non-medical device, such as the devices we saw earlier today,
SmartStat, are not medical devices because they make no medical claims,
even though we did hear it\'s the identical product.

When you think about an OTC product in terms of clearance through FDA,
the level of evidence required to make that determination of substantial
equivalence would be the same whether it\'s an OTC product, or a
prescription product.

So, the test is still the same for prescription and OTC. But, for OTC
there some additional pieces of information that we would like to see.

We would like to see labeling so that we can assure ourselves that those
patients or clients purchasing a pulse oximeter at K-Mart have a
reasonable assurance of using that device for its intended use.

And, as we heard earlier, a schematic or a cartoon of some kind for
where the sensor should be placed. We also would be concerned about
environmental conditions.

If the patient lives next to a microwave tower, you know, will the
operation of the device be altered? We\'re concerned about temperature
and humidity in the home environment or outside a controlled
environment.

And, I think one of the concerns that we have \-- and we don\'t have a
clear sense of how to label this and where we need your advice is there
may be certain patient populations for which the use of an OTC pulse
oximeter may not be appropriate.

Let me just say that, or it might be more appropriate. So, we recognize
that there might be, for example, a family with an asthmatic child or
someone with COPD may want to have a pulse ox at home.

The concern is that the user will be able, just as we heard earlier
today, the same concern with the clinician. Do you want the user to have
\-- we want the user to have as clear instructions as possible so they
know to take additional action or to not take additional action based on
that number that\'s being displayed.

So, that might be a difficult prospect if we can\'t even convince
clinicians to do that. SO, those are the \-- I don\'t mean to \--
that\'s not an all inclusive list of concerns.

But those are some of the issues that we are thinking about when we
think of clearing a pulse oximeter for over the counter use.

MEMBER DRASNER: I have a point of information. If you clear this device
as an OTC pulse oximeter, does that have any impact on the pulse
oximeters that are marketed as consumer devices?

In other words, they still stay on the market as a consumer device?

MS. GRAHAM: Yes. And, actually, what it would do \-- I mean, I think the
upside of that would be that if the A~rms~, for example, is disclosed in
the OTC device, which it would need to be, as you compare it to a
predicate, that information may be more than is available now for the
REI devices, for example, devices being sold for high altitude sickness.

CHAIRPERSON LISBON: You have a question Avery?

DR. TUNG: Yes. When you use the term medical claim, do you mean claims
in terms of outcomes such as we\'ll help you live longer, or in this
case say reduce the number of hospitalization due to COPD?

Or you can just say may help, or you can say could help. How does that
specifically working terms of phrasing?

MS. GRAHAM: It depends on what the manufacturers claim for the device
will be. And that is a variable according to the manufacturer. The
general claim now for pulse oximetry is to monitor either spot check or
continuously for functional oxygen saturation.

Any claims beyond that I would suspect would need some validation. And
you can imagine that a claim like reduces emergency room visits by
pediatric patients with asthma would be possibly an onerous study.

Well, not really. The other thing that would be different between the
OTC product and the non-medical use product are \-- is the manufacturers
would be required to conform to GMPs.

So, there would be more control over quality systems and manufacturing
processes for the medical devices versus a non-medical product.

CHAIRPERSON LISBON: Yes, Mark?

DR. WEININGER: Just one final comment. There\'s also a requirement for
corrective and preventative action on the part of a manufacturer who is
going to go OTC as part of the quality system regulations.

MR. MELKERSON: I\'m Mark Melkerson, Acting Associate Director for the
Office of Device Evaluation. Just a quick point. You\'re wrestling with
consumer product versus medical device.

And I\'ll use a different example just for explanation. Exercise
equipment for the purpose of exercising, a treadmill, can be a consumer
product. The same product, if intended to rehab muscles or restore
function would be a medical claim and considered a medical device.

So, when you\'re thinking about the issues that were discussed this
morning on a pulse ox, for the purposes of exercise, you can be a
consumer product.

If you want to then make a diagnosis or claim, it then kicks it into a
regulated medical device product. I hope that helps.

CHAIRPERSON LISBON: Thank you. All right. Let me read question three
into the record. To date, the Agency has not cleared any pulse oximeters
for medical uses as over the counter devices.

Please comment on the risks and benefits of over the counter pulse
oximeters, specifically discuss under what circumstances and for general
specific clinical conditions or indications \-- asthma, COPD monitoring,
for example \-- if any should the Agency allow the clearance of an OTC
pulse oximeter and whether you believe adequate labeling can be written
to ensure the safe and effective use of an OTC pulse oximeter including
directions for use, contra-indications, warnings, and precautions.

If so, please comment on what specific elements or statements should be
in such labeling and thirdly, whether the significant chance for misuse
of OTC pulse oximeter exists if cleared or approved by the Agency for
OTC use and what the potential risks would be.

Charlie, this one may be a little bit harder.

MEMBER COTE: It\'s going to be a little bit harder because I was
thinking about these trekking expeditions when I was putting my thoughts
together.

I guess my personal viewpoint would be that, if someone is sick enough
to need a pulse oximeter at home, that should be under the direction of
a physician.

And, in pediatrics we do have children that are on pulse oximeters at
home. They tend to be children with bronchial pulmonary dysphasia or
children with cyanotic heart disease that need \-- some of them get by
on half a liter per minute of nasal oxygen.

Some of them need two liters a minute of nasal oxygen. And the parents
are very good at being \-- you know, gyrating up and down as needed. And
they do use this to make a decision to come into the hospital because
the child is deteriorating.

But that\'s under the Director of a physician with the physician
providing them parameters for advice. My concern would be making this
available \-- and I don\'t have enough experience with adults.

But, I\'d be concerned for the asthmatic example that you used, that a
child has an asthmatic attack. The parents give the child a beta blocker
and the saturation goes from 90 to 95 percent and they say, oh, he\'s
getting better.

But he\'s not really. He\'s a little bit better but he\'s not better,
better. And so, would that interfere with the normal decision making
process?

Would it delay that child seeking help in the emergency room for the
extra shot of epinephrine or whatever is needed to deal with the asthma?
So that would be my concern.

I think these devices are devices used to guide oxygen therapy and to
save lives and when there\'s a critical change in circumstance. If we
put this into the home, then it has to be used in the home the same way
I guess we use it when people are asleep in the ward and are receiving
opioids.

It\'s a warning device that something has changed while the patient is
sleeping. Maybe that is an indication that could be used. I just don\'t
know enough about adult medicine to comment one way or the other.

So I\'m going to defer that one to my adult colleagues.

CHAIRPERSON LISBON: Why don\'t we start down at the end and keep going
that way?

MEMBER DRASNER: Well, this is probably the first place I\'ll disagree
with Dr. Cote, finally.

MEMBER COTE: Disagreement is good.

MEMBER DRASNER: You know, I think it\'s correct. But I think that the
parent that has a sick child, I don\'t think is going to run out and buy
a pulse oximeter in the absence of had discussions with the physician.

And, if they are monitoring this oxygen saturation, I think they\'re
going to seek counsel when the oxygen saturation is going to change. I
think it\'s going to be a rare individual that\'s just going to use this
and go off on their own.

And my main reason for thinking that as an over the counter device it
should be marketed is right now it\'s being marketed as a consumer
device where it\'s really like the Wild West.

I mean, there\'s no regulation, no instruction. There\'s no guidance for
what this is being used for. And I think if this was marketed as an over
the counter device, not just the instructions that come with, and the
guidance that comes with it, I think, would spill over a little bit into
the consumer products.

And I\'m particularly concerned about certain claims that are sort of
implied but may not be correct. I know Dr. Cote dug up an article which
I thought was very interesting that the oxygen saturations on the
mountain that people read when they measure their pulse during the day
appear to have no relevance to the climbers getting sick.

But, the nocturnal dips were the important factor so that there\'s no
restriction on people marketing these devices to actually make
statements like that.

And I think this actually will bring a little bit of law and order to
the old west, so to speak.

CHAIRPERSON LISBON: Okay.

DR. MUELLER: Well, I certainly agree with Dr. Drasner on the points he
made. I think my own concern is what happens to the patient who is using
this, again, without medical advice?

And I guess the question or the concern I have is how does the user
decide that the device has a problem? Well, what could the problems be?
It could be that the values \-- let\'s say very low numbers, when in
fact they\'re not low.

That\'s the way many of our other pulse oxers get in trouble. So this
means, what could they do before they call the 911 or go to the ER, or
more appropriately probably call their doctor to see that the device is
working.

So far I haven t\-- I\'m not familiar with the device. And so, I
apologize for talking from ignorance. But, it would be nice if we had
some way that you could in fact have a calibration device that the
patient could have with this.

And, as Dr. Weininger pointed out in his presentation under annex FF,
simulators, calibrators and function testers for pulse ox equipment \--
and perhaps it wouldn\'t be too much of a stretch of imagination with
all our knowledge of dyes and diffraction gratings and different
composition of plastic or translucent compounds, that maybe you could
have a stick that if you put it through your pulse ox machine you would
have one calibrated at 95 and one calibrated at 91, one at 86 and one at
81 so that the person could take his stick and shove it in there and
wait a minute and see if the thing comes up with an appropriate number.

Or, if it doesn\'t, then, you know, go seek medical advice. The same
thing could hold the other way if in fact it says that, you know,
you\'re in great shape.

We usually don\'t have the problem of pulse oxes reading falsely high.
So, presumably that would be a problem they wouldn\'t see. But again,
some sort of non-electronic stick calibration that you could put in the
thing in order to reassure them as something other than just, gee, do I
have to go buy another one of these?

Or do I go to the ER? I think would really make them much more useful to
the patient and \-- incidentally I suppose \-- much more marketable as
well.

CHAIRPERSON LISBON: Dr. Tung?

DR. TUNG: I\'m going to agree with Dr. Drasner too. I think this thing
would help if it went out there for medical use. In the real world not
everybody has a doctor, someone to guide their care, and may need to
somehow find that way themselves.

Moreover, not everybody may have a diagnosis of sleep apnea or of
asthma. You know, and nowadays with the internet and with many people
taking healthcare into their own hands, this may help people sort of
diagnose things that previously had gone missing.

The biggest operation problem with a pulse oximeter, I think, you know,
in the hospital is that it cries wolf. That is, most often reads low
when it\'s not finding something.

And so, people can often look at the low reading and think well, it\'s
just not reading right, when actually it is. But, you know, the pulse ox
is sufficiently intuitive.

Many people figured that out very quickly. I find at least, you know,
with experience \-- and so, as a result that, in my opinion, shouldn\'t
be a reason why you should hold it out.

CHAIRPERSON LISBON: Okay. Jackie?

DR. LEUNG: I think I have a different opinion. I have a question and
then several comments. I think the implication for clearing over the
counter pulse oximeter could be pretty far reaching or substantial
because it\'s going to be used by lay people in the community.

And so, my first question is, is there a dialogue already existing
between the industry and the FDA that there\'s an intended population to
which they want to target this over the counter device?

(No verbal response.)

DR. LEUNG: So there isn\'t? So then, it\'s really up to the industry to
think of who they want to target. So I think the first step from the
FDA\'s standpoint and my view, is to select that patient population and
do the validation studies in that population.

Now, given the expert presentation this morning, there\'s quite a
difference between spot check and continuous checking. And I imagine in
the community people would be doing spot checking more than continuous
because they would be ambulatory, most likely.

And, given the lag time, you just put it on one finger. What is the
value of that? And so I think a lot of thought has to be put into that
before we say yes, go for it.

Now, I also put the argument, and I think I do by initially that because
most of the errors is false positive \-- therefore it\'s a good thing,
people can seek medical attention quicker.

I\'m not sure that\'s a good thing. You know, do we expect them to rush
to the emergency room and knock on the door every time they put a thing
on and it says 60 or 70?

I mean, our ERs are already congested, packed to the gills. And training
the lay people to use a medical device, unless it\'s really fool proof,
I think it\'s quite challenging, in my view.

And lastly, if we propose to do a spot check, I think a few of the
panelists already alluded to that if one is already hypoxemic, I wonder
cognitively, can you really interpret a number versus you\'re doing
trending?

I just want to do like a blood pressure check, you know Q12 hours or Q8
hours. So, I don\'t know if I can make a recommendation. I think I would
like to know who the target population should be before we can make
recommendation.

DR. BIRNBACH: I was all set to say sorry Charlie. But, to hedge my bet a
little bit here, I would suggest a compromise. I agree with Ken that I
see way more positive than negatives to open this to OTC.

On the other hand, I also agree with Jackie that there might be some
real negatives. And we have no database at this point about could people
be trained?

What kind of package insert question actually work? What would
appropriate inserts be? So, rather than go for it, I think the answer
would be, go for a trial of opening this up to one community and see
what happens if this \-- and again, I\'m not quite sure about the
legality of doing that as part of a study to see what happens if you
allow this to be used in a population.

So, that\'s the first issue. The second \-- and, at the risk of opening
a brand new market that no one has thought of, I\'m not quite sure
whether having this as an over the counter would do this.

But, in my own personal experiences \-- and this is following on Mr.
Isaacson\'s presentation. I was recently on a plane where a co-passenger
had a cardiac arrest and died on the plane.

And this was over the Atlantic to Europe. And they asked, is there a
doctor on the plane? You know, we\'ve all seen this Hollywood kind of
thing. And, here was a guy who had died several seconds before.

And, when I asked them for the material that they have on this plane,
this was a fully equipped ICU. They had a laryngoscope, endotrachial
tube.

I had to lie on my stomach to intubate him. They had oxygen for three
hours. But we were four hours from land in either direction. They had
every IV drug that I\'ve ever seen in a fully stocked ICU, including
some that you don\'t ordinarily see, Amernone, Britillium.

And they didn\'t have a pulse oximeter. So I just \-- did not. I just
wonder whether or not any place you have a defibrillator, you might also
have an OTC pulse oximeter.

And whoever is smart enough to learn how to use a defibrillator is also
smart enough to know which numbers are going in the right or wrong
direction.

And it gives the emergency people some knowledge.

CHAIRPERSON LISBON: I agree. We do agree with you. And the interesting
thing is, before you were bringing that up, I was thinking that we
managed to come up with these automatic defibrillators which have all
these instructions and what to do.

And it would be child\'s play to take your oximeters and program onto
the chips what you should do with some of these values. So if you \--
you know, it\'s been 100 and now you\'ve dropped and you\'ve got good
pulse wave forms and you drop 12, 15 points, it might say, you know,
buddy, you\'re getting kind of sick. You aught to probably go to the EW.

But there\'s certainly a lot of electronic adjuncts that could be added
to these things that would be very helpful in the consumer world.

DR. OTULANA: My comments are very similar to the ones from Jackie in
terms of identifying the target population, the disease population where
we think this will actually add value.

If I put on my \-- position hat, the conditions we\'d be thinking of,
the COPD, very serious COPD, asthma, pulmonary fibrosis, patients with
significant chronic lung disease who all right eon oxygen, you have to
question whether you want those patients to wait until they have
significant hypoxemia before they present, especially in asthma for
instance.

So, I think we have to hear from the community, the medical community,
the people who treat these patients, whether they think a pulse oximeter
at home will actually enhance the care of these patients.

There are already means for monitoring them. If you are on long-term
oxygen therapy for instance, you will be asked to get spot checked your
SpO~2~ at home.

It\'s done under medical attention. The physician would tell you when to
turn on your oxygen, when to increase your oxygen flow and so on. If
we\'re going to leave those decisions to the patients to make, I think
we need to understand what advantage they are getting before we go down
that path.

So, off the top of my head, I can\'t think of a disease right now where
making this available \-- at least in adults \-- making this available
will enhance the current state of therapy without physician
intervention.

So, I think that is the place to start. We need to identify whether this
would be of value. And then we can discuss whether it should go over the
counter or it should continue to remain on that physician intervention.

CHAIRPERSON LISBON: Ms. Kline?

MS. KLINE: Yes. I think my concern comes in with a false sense of
security for patients who don\'t necessarily understand the two
components of both oxygenation and ventilation, and just as you were
saying, as far as patients who have more problems with ventilation,
getting a spot check on their sats, you know, their stats are still in
the 90\'s.

They\'re probably still fine. But that very well may not be the case.
They could easily be on the bring of a respiratory failure and not
seeking medical attention at that time.

The other piece is that I \-- you know, sometimes using our clinicians
that are using pulse oximeters at the bedside every day, and are making
decisions on whether or not a desaturation or the saturation \-- if
it\'s a true number or if it\'s a desaturation, related to artifact or
movement.

Patients that are using these at home aren\'t getting this background
knowledge on you need to, you know, look at the number. But you also
need to look at, you know, the child or adult, whoever the pulse
oximeter is being used on.

So, they don\'t have the same background in putting the number into the
clinical context. I agree we would be empowering patients to take more
control over their healthcare and make more of their own decisions.

But, at the same time, would we also be discouraging them from following
up with their healthcare provider? Would they be trying to manage too
much of their healthcare on their own?

CHAIRPERSON LISBON: Carolyn? Let\'s wait. Go around the panel. And then
Julian, you\'ll be able to speak.

MS. PETERSON: With regard to this question, I see three issues that I
think we need to consider. First, this morning, through all of our
presentation across all the issues we\'re considering today, I think we
saw very clearly that pulse oximetry does involve some interpretation.

It requires the user to have a pretty solid ability to make
sophisticated interpretations or I guess to use the laymen\'s term,
guesses about what\'s going on, and then to follow through with a course
of action.

When the pulse oximeters are prescribed by the physician, we have
facilitated within that process a way for the patient to get some
training, to get a general outline of all of their personal conditions
relative just to them, that can affect that interpretation, and also
from their care provider some definite guidelines like if you see it go
below 80, if you see this or that, if you\'ve experienced these symptoms
and you come up with this reading, then you need to do this.

That is patient and consumer empowerment because a person is able to
manage a condition. If the product goes over the counter, that patient
may get the guideline or the suggestion from their physician.

Well, if want to get a pulse oximeter and check this at home, you can do
that. Or the person may see advertisements on television or in magazines
and start to do this without really understanding what is of concern
about their situation.

Their own personal co-morbidities, their personal characteristics,
allergies, for example, environmental conditions, and so on that may
affect that interpretation.

With an OTC there\'s really no way to be certain that a patient gets the
education they need to make those good decisions. I think we heard today
from one of the consumer companies that consumer products are sold
without education or without an opportunity for one to educate oneself.

If the user really wants to understand, they need to go do research.
And, by the way, we\'re not even sure that they\'re told they need to
research the product so they can understand what that reading means when
they\'re up high on a mountain in an oxygen deprived situation.

I\'m not sure we can really assume that the 65 year old COPD patient or
the single mother of a small child with asthma is going to know that
they need to do that research, will go out and do it, will get the
information, and will compile a detailed list of questions to ask their
physician so they really know what they\'re looking for and how they can
use that product for best managed care.

CHAIRPERSON LISBON: Okay. Do you have another point? Yes?

MS. PETERSON: Two more points.

CHAIRPERSON LISBON: Go for it.

MS. PETERSON: Okay. My second concern has to do with this issue of data
and outcomes. We\'ve discussed today that at the consumer level we
don\'t have any data about what happens when people use these.

And we don\'t know what the ultimate outcome was. Did they use that
information to make a decision? That is, did they actually say, this
helps me, yes or no.

Do I continue my activity? Or did they go in saying yes, give me
something to make me think I can really continue because I really want
to do this?

And that\'s a very important distinction among consumers. For example,
older people who are on a limited income may want some data or
information that lets them know they really don\'t need to go do that
expensive emergency room visit or risk another hospitalization that they
feel they can\'t afford.

So, I think that we need to remember that this is really a theoretical
benefit in terms of the consumer use at this point since we have no
data. The third issue that I see as being quite critical is that
there\'s a question of how this promotion occurs once we\'ve put it on
the market.

In 1997 the FDA issued the guidance for direct to consumer advertising
of drugs. Eight years later we are still seeing quite a bit of confusion
among manufacturers as to how they can promote those products.

We\'re still seeing the FDA post warning letters on the internet, which
all of us can look up and download if we want, that address the
inappropriate ways manufacturers and licensees are promoting these
products.

I don\'t think anyone wants to do something that\'s going to injure any
consumers or any patients. But, when we look at the track record, we
really have to ask ourselves what sort of process we want to put into
place to ensure that these products are marketed in a way that helps
patients take better care of themselves.

And that simply markets the products. I feel that any kind of guideline
or anything that we approve needs to have a pretty detailed process
identified before approval so that we don\'t wind up maybe fixing one
part of the wild west, as Ken suggested, and creating another with a
much larger patient base for whom many less esoteric activities can
trigger the crisis.

CHAIRPERSON LISBON: Thank you. I get to weigh in now. And while I in
general think that, you know, having one of these devices at home would
be useful, it\'s basically only it just feels like it would be the right
thing to do.

I can\'t base it on any studies or anything. And I would think that
there could be pretty straightforward studies done where, you know,
you\'d randomize people that either have one of these devices at home
with your asthma, with your COPD, or any number of diseases, and
actually see if it made a difference to how the care paradigm was put
forward in these patients.

So, I\'m reluctant to sort of come down on one side of the issue or not
without any studies that show that it might be useful or not useful. And
my guess is that we\'re not going to come to resolution on this
particular question.

I mean, just going around the table and hearing just sort of back and
forth here, and I gather the discussions at the FDA have been the same
way.

People are on both sides of the issue. And it\'s kind of hard to come to
some sort of consensus.

DR. BIRNBACH: I just wonder whether the OTC pulse oximeter would have to
be the same one that we\'re all used to. One of the risks is that we\'re
making a generation of people who are all little Dr. Kilters who have to
learn how to interpret these numbers.

Isn\'t it possible to have a pulse oximeter for home use that\'s
blinking red, yellow, or green depending on a range of numbers? And, the
kind of person who\'s looking for that does not actually need to know
the exact number that they have.

But, if there\'s a flashing red, you\'ve got to go to an ER kind of
thing. And then that differentiates between the one that\'s prescribed
by a physician with the numbers versus the one who wants to play at
home.

CHAIRPERSON LISBON: Julian?

DR. GOLDMAN: Julian Goldman. I appreciate the complexity and the
deliberation indeed. So, I left something out of the presentation this
morning for the sake of time.

And perhaps I should have included it. I think it helps me in looking at
this issue. And that is, we currently have available as OTC products
blood pressure monitors, sphygmomanometers.

We have thermometry. And now we have AEDs. AEDs perhaps are different, I
mean, because they\'re so sophisticated. And they have been made almost
idiot proof.

And it\'s really an engineering marvel. And I think it has impressed
many of us. But, think about the simpler things that we have come to
rely on.

I would \-- if we were discussing sphygmomanometry as a fresh topic
here, I would be very concerned about that. It\'s hard to perform
correctly.

It\'s easy to misinterpret. Patients still don\'t know the top number or
the bottom number. You know, they\'re not sure what they\'re talking
about. And yet, I think the use of it has been relatively successful.

Patients seem to either collect data or report data, sometimes try to
change their medications, get a sense of how they\'re doing. Glucometry
is another one.

Glucometers can be misused easily. And yet, diabetics manage themselves
and it\'s been shown that they can improve their outcome using a
relatively simple instrument that can be misused.

So, I think in terms of just thinking about this problem, it may be
helpful to look at the other OTC devices in this context and the
strengths and weaknesses of that perspective. Thank you.

CHAIRPERSON LISBON: Any other comments on this?

DR. TUNG: When tested in the periops setting in 1994 in expert hands,
that is the hands of physicians, the pulse oximeter had not effect on
outcome at all.

I think it\'s unlikely to think that when we give it to outcomes we\'re
going to see much of a difference. There\'s a decision making process
here that may be evolving over time, you know, that people may make
certain decisions once they get the monitor.

Five years afterwards, when their population as a whole knows more, they
may think something else. I think whatever data you get out may not
reflect how this thing eventually settles into people\'s consciousness.

What\'s clear is that, at least in the hands of physicians, you know,
this thing doesn\'t improve outcome necessarily.

DR. LEUNG: I agree with Avery. I think if we look for these hard
outcomes it would be extremely unlikely that we\'ll find it. I thought
about the use of ambulatory blood pressure monitoring glucometer and
even ambulatory ECG monitoring where we use it widely.

But, you know, for ambulatory ECG, it\'s nice. There is like, you know,
there is a hard copy. You can store it. I guess you could do it for
pulse oximetry.

But, for those conditions, there is some sort of a threshold effect.
And, with high blood pressure you\'re usually asystematic within certain
range of glucose, you\'re usually systematic.

But, with hypoxemia, hypoxia \-- correct me if you will \-- you know,
below a certain range, unless you\'re chronically hypoxemic, you will be
symptomatic.

So I\'m questioning, you know, do we want to \-- I think a trend is
important. And, if you need that to go to the emergency room, I\'m not
sure that\'s really what we\'re thinking of the indication.

I guess I\'d like to know really which population we\'re trying to
target.

CHAIRPERSON LISBON: Are there nay other comments on this particular
item?

(No verbal response.)

CHAIRPERSON LISBON: Okay. Now, what I\'d like to do at this point is
sort of move things up a little bit. We were supposed to take a break at
this point and then go to the second open public session.

But, what I\'d like to do now is open this up to the audience this
second public session and hear comments from representatives in the
audience. If you would, again, please identify yourself.

And, if you haven\'t spoken before, tell us about your conflict of
interest and things like that.

MR. MELNIKOFF: Don Melnikoff with Smith\'s Medical PM. I just want to
make a comment. As you said, it seems like everyone\'s kind of on the
fence a little bit about whether or not pulse oximetry should or
shouldn\'t be an OTC product.

We have competitors out there with the same type of products. And
there\'s multiple products out there that are spot check or finger
checkers.

So, Nonin has shown theirs. I\'ll show ours, not to be competitive. But,
there\'s a multitude of these out there. What\'s happening is I just
want to make the stance that the industry \-- actually, the customers,
they\'re waning it, they\'re needing it.

They\'re buying the commercial products. But yet, the manufacturers of
medical devices want to sell it as an OTC product with a higher
education, as we know, goes along with OTC.

And all the people around the fence, however, I just want to make a
point that eventually there is starting to be the cry from people out
from \-- people from asthma, oxygen therapy, elderly patients, that want
these devices on their own, because they\'re not going to get it per
prescription, or they\'re not going to get reimbursed from it from their
physicians.

So, it is something that is being drawn in. And I think the
manufacturers and all of us want to provide them with the solution that
they\'re educated with to be able to use and that actually offers them,
you know, a level of comfort and a level of monitoring that right now
they\'re getting from commercial devices that don\'t educate them
further on how to use it.

DR. LEUNG: I have a question for the FDA. So, in that situation, do you
just \-- let\'s just assume that the manufacturer or the industry is
applying for OTC use for let\'s say COPDers.

Do we just need to demonstrate accuracy, or is ethicacy data necessary?
Endpoint being different outcomes.

MS. GRAHAM: I think the endpoint would be in the comparison to a
predicate device. It may not be ethicacy or effectiveness, ethicacy
being a drug term.

DR. LEUNG: Right. I was thinking like therapeutically, you know.

MEMBER DRASNER: Well, if I\'m not mistaken, the pulse oximeters that are
being used now have no stated ethicacy.

DR. LEUNG: Right.

MEMBER DRASNER: They just have stated accuracy. So, I don\'t see why
something that\'s OTC would be held to a higher standard.

MS. GRAHAM: Well, I could actually. But, the \--

MEMBER DRASNER: You could?

MS. GRAHAM: The decision is a comparison to the predicate device. And
you\'re right, there is not effectiveness data required. There is
safety. And there\'s a certain performance requirement.

And, as long as those two were comparable then the Agency could make a
determination of equivalence, then it would go to OTC.

CHAIRPERSON LISBON: Is there anybody else in the audience that wishes to
speak? Carolyn?

MS. PETERSON: I had a question about the previous comment. You had
mentioned that the device industry wants to get the product out to, for
example, older consumers who aren\'t going to get it through their
physician.

My question is, if they need it, if they medically need it, as opposed
to would feel better having one, why aren\'t they getting the
prescription from their physicians?

MR. MELKINOFF: I think most are, but there are people in rural areas
that don\'t \-- let\'s say they are on oxygen therapy and they can\'t
get to the doctors, you know, frequent enough.

Their oximeter \-- for instance, most of the time they won\'t \--
doctors will not prescribe them the smaller one. They want the bigger.
There\'s this perception that the accuracy is less accurate on the
smaller devices, which isn\'t true.

They\'ll want \-- they being the customer \-- will want a smaller one
that they can travel with while they\'re walking with their oxygen. So
what ends up happening is they end actually buying the commercial or
they end up doing their own thing to try to find that device somewhere
else.

I think the majority of them do. But, there tends \-- we\'re starting to
see there tends to be a movement towards having a little bit more
ownership on your medical conditions or your own monitoring as well
before you go to the doctor to make sure, you know, here doctor, I\'ve
had this data for the past month.

I\'m starting to see something\'s going on, please help me. Did I answer
your question?

MS. PETERSON: Well, I kind of wonder how many physicians would decline
to prescribe the small monitor when a patient asked to have something
that was feasible for walking so they could test it.

But that\'s not a point we can really answer today.

CHAIRPERSON LISBON: Is there other people in the audience that wish to
speak? And, again, just identify yourself so the \--

DR. GERSTMAN: Dale Gerstmann, Utah Valley Regional Medical Center. I
just wanted to impress on the panel that in neonatal pulse oximetry,
it\'s not longer a monitoring device, it\'s a control device.

Nurseries around the country are engaged in medical control trials,
trying to use limitations of pulse oximetry range values to prevent
disease, retinopathy, prematurity.

There is some evidence to suggest that you can control the degree of
injury after interventricular hemorrhage. Chronic lung disease, a
component of that is hyperoxia.

There\'s considerations that repeated episodic hyperoxia can contribute
to the chronic long-term outcome of these premature conditions in
premature babies.

It is extremely important to have this device very accurate in the
normal range. And the data I showed you today was not in saturation
ranges that were really, really low.

It was data in saturation ranges that are commonly encountered in the
NICU between 80 and 100 \-- actually, between 90 and 100. And, even in
that range, these devices provide questionable information.

My concern is that these national studies that are ongoing are using a
device that has enough error in it that there\'s going to be confusion
in the analysis of the outcome of the studies.

And that\'s a big concern to me. Anything we can do to increase the
accuracy of these devices over the normal range would go a long way to
improving healthcare in premature babies.

CHAIRPERSON LISBON: Thank you. Anybody else wish to speak?

MR. BATCHELDER: Paul Bactchelder with Clinimark. I\'ll talk to what Dr.
Gerstmann just mentioned. And then I\'d like to make a comment about
over the counter.

Today no validation is required in the neonatal population. I think
that\'s a very important issue. And we recommend collecting in the same
range that Dr. Gerstmann just collected data.

It does show usable information. It doesn\'t necessarily provide the
same level of validation that the study in adults in the laboratory from
70 to 100 percent does.

But it provides information that we do not have today and clearly can
show viable valuable information. Then, on over the counter pulse
oximeters, I have no financial interest in over the counter pulse
oximeters at all.

However, my medical director is a pulmonologist with a very large
practice in Denver, Colorado. And he is Dr. Dennis Clifford. And, when I
mentioned that they were deliberating on over the counter pulse
oximeters he asked me to mention a couple of things to you.

First off, he would like his patients to have over the counter or pulse
oximeters. He doesn\'t prescribe them. I didn\'t go into why he does
not.

But, many of them already have them, whether they\'ve gotten them off of
the internet or whether they\'ve bought them over the counter for other
purposes and then used them.

They are heavily involved in their own care. And they already know a
little bit about pulse oximetry. He recommends that, if we do have over
the counter pulse oximeters, he would like them to have the same
accuracy, obviously, that the ones for medical device use have.

And he would definitely like them to have better information. Because
right now, they\'re not getting information. And he also recommended
that the information be pictorially of some sort.

And then also, some sort of explanation of the accuracy. I suggest that
one very quick way to gather information about how these over the
counter pulse oximeters might be used or are being used would be very
good for us in some way to survey pulmonologists across the United
States because they\'d have patients, COPD and asthma that already are
using these.

And they could give you some valuable real life experience.

CHAIRPERSON LISBON: Thank you. Does anybody else in the audience wish to
speak?

(No verbal response.)

CHAIRPERSON LISBON: If that\'s negative, what I\'d like to do then at
this point is take probably a ten minute break so that people can just
do what they need to do for ten minutes.

And then we\'ll come back and the panel will craft the recommendations.
So, it\'s 20 of. We\'ll meet back here at ten of three.

(Whereupon, the above-entitled matter went off the record at 2:42 p.m.
and went back on the record at 2:54 p.m.)

CHAIRPERSON LISBON: Okay. It\'s time for the panel to craft its
recommendations. Does anybody on the panel have any final comments on
the subject matter today?

(No verbal response.)

CHAIRPERSON LISBON: If not, what I\'m going to do is try and sort of
roughly say what I think the panel has said. And then, if you guys
don\'t agree with me, please correct me.

And, Neal, you\'ll take this down or somebody will take this down. All
right.

For question number one, the question of whether there are any
differences in performance between the two sensor types, the
transmission versus the reflectance types, I believe that we do think
that there are differences.

But there\'s a fair amount of variability between the two devices that
each of these needs to be validated in their own right and in various
locations.

Also that they are used in clinically different ways and so that the
clinical ways they are used affect what the numbers mean when you get
them. Is that fair?

(No verbal response.)

CHAIRPERSON LISBON: Okay. Part B of that, whether differences in
performance would lead you to recommend different pre-marketing
evaluation methods and standards and what those would be.

And I think the answer again would be yes, we do believe there are
differences in performance and that they need to be validated based on
the clinical use for these sensors. Anybody else?

(No verbal response.)

CHAIRPERSON LISBON: All right. And whether differences in performance
would exclude certain indications for use for one type compared to the
other, and if so, what those would be.

And the answer is probably no to that question. I think everybody says
there\'s a caveat when you\'re using these in children with cyanotic
heart disease.

And again, where you\'re using these probably affects their validation.
Anybody have any comments on that?

MEMBER COTE: We talked about edematous patients, patients in \--

CHAIRPERSON LISBON: Yes. All right. Okay. Now, on to question number
two. And that was what should we do about this fudge factor? And I
believe that everybody believes that we should drop that one percent
fudge factor between neonates and adults.

And they aught to be evaluated under the same standards. And, again,
that the neonatal device needs to be validated in its own right and not
take the data from adults and that, I think we agreed that \-- we all
agree that there needs to be increased accuracy and increased validation
throughout the range that these devices are used.

And these devices, again, need to be validated in neonates as well as
adults, and there needs to be increased disclosure as to where this
information came from, how it was obtained, and what its limitations
are. Anybody else?

MEMBER COTE: I think we wanted a breakdown of the bias at different
ranges, the 90 to 100, 80 to 90, 70 to 80. Did I miss \--

CHAIRPERSON LISBON: No, you\'re right. And I think people also wanted
these to be packaged inserts or information about how a particular
device works with a particular processor so that if you add a Nellcor
finger probe onto an HP device, what are the implications to doing that?

MEMBER COTE: No, I think yes because \-- I don\'t think that they\'re
compatible. They say they\'re not supposed to be used across devices
because there was a burden from \--

DR. WEININGER: Pretty much today if you can plug an oximeter into a box,
it should work with it. But that\'s not guaranteed.

CHAIRPERSON LISBON: It may work, but it may not give the same results.

DR. WEININGER: Well, there\'s been a number of cases over the years of
actual burns because the circuitry was completely incompatible and stuck
a whole lot of current through the probe.

And, for the most part, manufacturers have designed proprietary
connectors so that you can\'t do that anymore.

CHAIRPERSON LISBON: Okay. But Nellcor makes how many probes?

DR. WEININGER: Right, but if \-- for example, Hewlett Packard, if they
use Nellcor probes would \--

CHAIRPERSON LISBON: I misspoke. I didn\'t mean to imply that HP was
going to be used with Nellcor. I was trying to imply that if you\'re
using various sensor you aught to know how the various sensors will give
data depending on the box they\'re connected to.

DR. WEININGER: And that\'s how they are cleared today.

DR. BIRNBACH: But the consumer doesn\'t know now which of the sensors
are more or less sensitive and which of them have more or less bias,
especially on the extremes.

DR. WEININGER: Consumer or \--

DR. BIRNBACH: Consumer being user.

CHAIRPERSON LISBON: Nor do we know what the validation curves for these
devices really look like.

DR. WEININGER: you don\'t know the validation curves, but the A~RMS~ is
listed for every probe monitor combination. You look at Nellcor\'s
catalog of however many sensor they make.

They tell you exactly what their A~RMS~ is based on the monitor and
probe combination.

CHAIRPERSON LISBON: But again, that\'s over the whole range. That
doesn\'t tell you \--

DR. WEININGER: Right.

CHAIRPERSON LISBON: \-- how it responds down to lower numbers or higher
numbers.

DR. WEININGER: So, if I understand your recommendation, it\'s for the
decades, the bias and precision over the decades?

MEMBER COTE: Decades, no.

CHAIRPERSON LISBON: Seventy to 80, 90 to 100.

MEMBER COTE: Oh, over a range.

DR. WEININGER: I thought you meant ages by decade.

CHAIRPERSON LISBON: All right. Okay. Any other comments on those
questions?

(No verbal response.)

CHAIRPERSON LISBON: All right. And then the last one. Just before we
craft our recommendation there, I just want to do a straw pull of the
panel.

How many people would recommend this be released for over the counter?

(No verbal response.)

CHAIRPERSON LISBON: Okay, that\'s one, two, three, four. How many people
would say no?

(No verbal response.)

CHAIRPERSON LISBON: One, two, three \--

DR. LEUNG: Well, I think \--

CHAIRPERSON LISBON: Wait a minute, you\'ve got to commit.

(Laughter.)

CHAIRPERSON LISBON: There\'s no hedging yet.

DR. LEUNG: Based on the current data?

CHAIRPERSON LISBON: Based \-- right now, based on what we know. So
there\'s \-- hold your hands up again.

DR. OTULANA: Voting members only?

CHAIRPERSON LISBON: No, I want to hear the whole panel.

MEMBER DRASNER: I mean, this is based on appropriate labeling, not just
releasing the device as is.

DR. OTULANA: Okay.

CHAIRPERSON LISBON: Yes, okay. So, how many people don\'t think it\'s a
good idea at this point.

DR. LEUNG: Without labeling?

MEMBER DRASNER: Is that voting members?

CHAIRPERSON LISBON: No, everybody, I just want the whole panel because
we don\'t vote on these.

MEMBER DRASNER: With appropriate labeling?

CHAIRPERSON LISBON: With appropriate labeling. One, two, three, four.
Okay. How many people are undecided?

(No verbal response.)

(Laughter.)

CHAIRPERSON LISBON: And I\'m undecided. All right. I mean, this is one
where I\'m having a hard time coming up with a recommendation because we
are split that way.

I mean, I think what we can agree that we don\'t have sufficient studies
to know whether or not it would be a good idea to release these as an
over the counter device or not.

And, for the third part of this, whether the misuse is \-- there\'s a
significant chance for misuse of this. Again, I don\'t think we have
that information. Does anybody \--

MEMBER DRASNER: Yes. You know, I think we all think that \-- or I assume
that we all do \-- need more information on this matter. As far as
moving forward, I think the answer is yes.

As far as the additional information, I think not necessarily ethicacy
data. But I think that it is important to try a population and see how
it is that these people handle data, what they do with it, and whether
this is reassuring or just basically creating more havoc in their lives
by raising red flags when it shouldn\'t be or giving reassurance when it
shouldn\'t be there.

But, I think there\'s more information that needs to be needed. But I
think that my feeling is that it should move forward.

CHAIRPERSON LISBON: I mean, I do agree with you. And I had said that in
my original statement, that I do believe that there should be studies.

And I think it was a good idea, one of the audience members suggested
pooling pulmonologists about how they see it to be used. There\'s, you
know, multiple ways this needs to go so that we can move this forward.

DR. LEUNG: But, based on the polling, it seems like the majority of the
panel think there should be just post-marketing surveillance, right?

CHAIRPERSON LISBON: Does that \-- I didn\'t hear that, but \-- who
believes we should have post-marketing?

MEMBER DRASNER: No, I think there\'s some issues that need to be sorted
out that also need to be identified before you can even know what proper
labeling of these devices are. I think there needs some work here.

DR. BIRNBACH: During the break somebody came to me saying that they used
to work bringing drugs from prescription to OTC and that the standard is
that it\'s opened in a test market first with surveillance in any one of
one to a dozen locations where they watched what occurred before the
ultimate decision was made.

And that kind of thing could happen here as well. You don\'t have to
re-invent the wheel if it works for the other side of the FDA, I
wouldn\'t think.

CHAIRPERSON LISBON: Dr. Lin?

DR. LIN: I don\'t know whether \-- this morning FDA\'s presentation make
this clear that device regulation is quite different from the thought
regulations.

So, I think that now the equation that the FDA posed for this OTC or
not, I think this morning that every presentation also made it clear
that whether it\'s OTC or it\'s prescription, that our review criteria
is no different.

The only difference is that, for the layman in there, you need to have
more scrutiny in where that \-- the layman using those devices can
perform or can use those devices effective as like if a physician used
those devices, whether they provide some type of a degree of a safety
and effectiveness.

That\'s an issue that I would like your input.

CHAIRPERSON LISBON: So, I mean, I think what we would say is that the
panel was divided as to what should be done. But certainly we need to
collect more data to allow us to make a decision about this.

DR. TUNG: I think you\'ve got to be very, very careful what you look for
because you\'re not going to find a benefit and outcome. You can\'t find
it with doctors.

You\'re not going to find it with lay people.

CHAIRPERSON LISBON: OKAY.

DR. OTULANA: But I think at a minimum though, the suggestion that the
pulmonary community, the pulmonary \-- pulmonologists should be
surveyed, and the need for this to be OTC established.

I think that is a very reasonable suggestion.

CHAIRPERSON LISBON: I think you\'re right because, none of the people at
this table are actually going to be caring for the patients that are
going to be out using this.

Most of us are hospital based physicians who take care of patients in
the hospital, and quite comfortable doing that. But we\'re not taking
care of people that live out in the community that have COPD.

MEMBER COTE: I really like the idea of putting these where those
defibrillators are, because then you know that circulation has been
reestablished, not just a heart beat.

And I think that\'s actually a wonderful, maybe first step of looking at
that.

CHAIRPERSON LISBON: All right. Yes?

DR. LEUNG: Can I just make one more remark to clarify on the record?
We\'re debating \-- this is talking about accuracy data. We\'re not
requesting ethicacy data, right?

We just wanted to show that the OTC use of these devices is just as good
as in the laboratory situation. We\'re not trying to say that the COPDer
who gets the pulse oximeter is going to have an improved quality of life
or longevity.

CHAIRPERSON LISBON: You know, if you\'re going to put it out there just
to measure something to get a number, is probably not useful. If you\'re
going to put a monitoring device and have the people spend the time to
learn how to use it and to collect a number, then you want to have them
change some aspect of their healthcare by doing that.

DR. LEUNG: That\'s right. That\'s why I think it\'s a gray zone.
Because, when you have something OTC, there\'s a medical indication. The
implication is that there is some change in your quality of life.

As we\'ve heard, you know, if you put it on in the gym, you can
calibrate your activity level, your tidal volume, whatever. So think,
you know, we should put some more thought into it.

I think for accuracy validation it\'s probably easy to do that kind of
study if that\'s all it would require. But it\'s really marketing these
devices. How do you target the consumers?

CHAIRPERSON LISBON: Carolyn?

MS. PETERSON: I think part of the reason that you appear to be divided
based on the straw poll is because it was a yes or no, either or, right
now what would you do kind of thing, approve or not.

In listening to the panel, I didn\'t get a sense that anyone was opposed
to some form of study that allows us to better identify what patients
need in terms of communications, training, education, what sorts of
materials or programs might be effective in helping them use that
product that they can purchase OTC.

And I do think it\'s very valuable to go forward in that way. I just
can\'t support saying sure, let\'s approve it today.

CHAIRPERSON LISBON: Agreed. All right. Have we addressed all of the
issues that we were supposed to address, Dr. Lin?

(No verbal response.)

CHAIRPERSON LISBON: All right. Does anybody else have any other
comments? I believe Charlie had one or two thoughts about what else in
the future would be important to discuss on this particular device.

MEMBER COTE: Are we finished with comments?

CHAIRPERSON LISBON: Yes.

MEMBER COTE: Okay. I think there are two important safety issues that
need to be considered by the panel and FDA for the future. One is the
issue that all pulse oximeters should use a change in tone to
correspondence with the reduction in oxygen saturation.

And there shouldn\'t be any holes in the system where oximeters are out
there that only allow them when the oxygen saturation gets to a certain
number.

Because this results in a delay in recognition that an event is
occurring, unless the person is actually watching the monitor. But, when
you can hear it, you don\'t have to be watching it, and you pick up much
sooner.

It\'s off patent now from Nellcor, so it\'s possible to do that.

MS. GRAHAM: The implication is it\'s a continuous use pulse oximeter?

MEMBER COTE: Yes, and for continuous use pulse oximetry, exactly. And
the second thing is, I\'ve now seen over the years a number of
malpractice cases where adults \-- pediatric \-- adult oximeter clip-on
probes were used on children, providing false information during the
most critical time during the resuscitation.

The thing becomes dislodged. It\'s much less likely with a wrap-around
device than it is with one of these clip-on devices. Somehow there needs
to be some \-- I would actually push for getting rid of all the clip-ons
completely to prevent those kinds of accidents from happening.

I think it\'s something we need to look at. And there\'s got to be some
way of indicating that the thing is properly applied or not. And, I
guess the thing I\'m concerned about is this effect where you put a
little finger in a big device and you get light shining around it.

It gives you false information. But there has to be a way of making
these things safer for all patients. And those clips, I think, are only
made in two sizes or three sizes.

And children have millions of fingers and toe sizes. So, I don\'t think
they should be used in children at all. It\'s a personal opinion.

CHAIRPERSON LISBON: Are there any other comments before we adjourn?

(No verbal response.)

CHAIRPERSON LISBON: Is there anybody in the audience that wishes to make
any comments?

(No verbal response.)

CHAIRPERSON LISBON: In that case, I\'d like to thank the speakers and
members of the panel for all their hard work and participation in taking
time out of their schedules to come down to Washington and meet and give
their opinions about this.

I\'d like to thank Charlie for being put on the spot first the whole
time and leading the discussion segment of the meeting. Thanks to Neal,
to Anne for expediting the meeting and making it go smoothly.

And, if there\'s no further business, I\'d like to adjourn this meeting
of the Anesthesia Respiratory Therapy Devices Panel. Thank you all very
much. Have a good weekend.

(Whereupon, at 3:11 p.m. the above-entitled matter was concluded.)