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
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
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, ARMS, 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.
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