### SUMMARY MINUTES

### MEETING OF THE ANESTHISIOLOGY AND RESPIRATORY THERAPY DEVICES PANEL

**OPEN SESSION**

**May 13, 2005**

**Hilton Washington, DC North**

**Gaithersburg, MD**

**Anesthesiology and Respiratory Therapy Devices Panel Meeting**

**May 13, 2005**

**Attendees**

**Chairperson**

Alan Lisbon, M.D.

Beth Israel Deaconess Medical Center 

Boston, MA

**Voting Members**

Charles J. Coté, M.D.

Northwestern University

Chicago, IL

Kenneth Drasner, M.D.

University of California

San Francisco General Hospital

San Francisco, CA

Avery Tung, M.D.

University of Chicago

Chicago, IL

**Consultants**

David J. Birnbach, M.D.

University of Miami School of Medicine

Miami, FL

Andrea M. Kline, R.N., M.S., PCCNP, CPNP-AC, CCRN

Children's Memorial Hospital

Chicago, IL

Jacqueline M. Leung, M.D., M.P.H.

University of California, San Francisco

San Francisco, CA

Robert A. Mueller, M.D., Ph.D.

University of North Carolina

Chapel Hill, NC

**Industry Representative**

Babatunde A. Otulana, M.D.

Aradigm Corporation

Hayward, CA

** **

**Consumer Representative**

Carolyn Petersen, M.S.

Mayo Clinic, MN

#  

**Food and Drug Administration**

Julian M. Goldman

Visiting Scholar, FDA Medical Devices Fellowship

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

Chief, Anesthesiology and Respiratory Devices Branch

Chiu S. Lin, Ph.D.

Division Director

Neel J. Patel, M.Eng.

Executive Secretary

Sandy Weininger, Ph.D.

Electrical Engineer, Division of Electronics and Software Engineering

# 

**CALL TO ORDER**

**Panel Chair Alan Lisbon, M.D.,** called the meeting to order at 8:00
a.m. to discuss and make recommendations regarding pulse oximeters.
**Panel Executive Neel J. Patel, M.Eng.** introduced the panel members,
and read the conflict of interest statement. A waiver was granted to Dr.
Robert A. Mueller for his interest in a firm that could be affected by
the Panel's deliberations. The FDA also took into consideration matters
regarding Drs. Cote and Leung; each have reported current or past
interest in the firms at issue but in matters not related to the day's
agenda. They were allowed to participate fully in the panel's
proceedings.

**FDA PRESENTATION: Challenges and Opportunities on the Critical Path to
New Medical Devices**

**Sousan S. Altaie, Ph.D., Scientific Policy Advisor, CDRH**, presented
information on the Agency's Critical Path Initiative. The FDA effort
started with a white paper analyzing the hurdles of medical product
development and calling for more collaboration between government
research institutions and manufacturers.

Critical path research leverages basic science to help bring the
products to the public faster and more safely. The FDA considers this
path a "critical path" rather than a translational path because
completing the path is required for the device to reach the market. In
the FDA's view, critical path research tools can have an impact on three
areas: device safety; the medical utility of medical products; and the
industrialization of those medical products.

Dr. Altaie said that the FDA is involved in this area because it has a
uniquely broad perspective on why products fail or succeed and make it
to the market. Critical path projects being developed include tools to
move *in vitro* assays to the market; computer models of human
physiology; a clear regulatory path with a consensus from the obstetric
community for intrapartum fetal diagnostic devices; a pathway for the
statistical validation of surrogate markers; work with medical specialty
organizations to develop practice guidelines for appropriate monitoring
of permanently implanted devices; and a consensus about the extent of
the neurotoxcity of contact materials.

**FDA PRESENTATION: Condition of Approval Studies: Recent Changes in
CDRH**

**Thomas P. Gross, M.D., M.P.H.,** discussed the updated functions of
the Office of Surveillance and Biometrics (OSB). The office provides
support for premarket reviews, tapping a recently increased staff of
epidemiologists; monitors a nation-wide passive adverse event reporting
system; looks for potential device problems through their Medical Device
Reporting System; conducts safety and risk issue analyses; coordinates
the Center's response to important public health issues; and interprets
medical device regulations.

Condition of Approval (CoA) studies are ordered for PMA devices; this
includes the periodic investigation and reporting of the safety,
effectiveness, and reliability of the device for its intended use. In
2002 the FDA began looking at the CoA program by examining the 127
approved PMAs between 1998 and 2000. They focused on the 45 PMAs with
clinical CoA orders. This examination uncovered a number of
difficulties: the CDRH had limited procedures for tracking study
results; their IT systems were found to be deficient; many lead
reviewers had left which resulted in a lack of continuity; and they had
limited premarket resources. Their strategy for change includes
obtaining timely and useful postmarket device information; gathering
information on real world use; characterizing the device's risk-benefit
profile; and adding to their ability to make sound scientific decisions.

To accomplish this, CoA studies have moved from the premarket side of
the agency to the postmarket side (to OSB). In addition, they've
developed an automated tracking system and added epidemiologists to the
PMA review team to develop a postmarket monitoring plan during the
premarket review period. Dr. Gross said that these changes are expected
to improve motivation for good study conduct on the parts of both the
agency and industry. He added that when companies do not show due
diligence in conducting CoA studies, the Agency is allowed, by virtue of
Section 522 authority, to use enforcement strategies such as hefty
monetary penalties. This would be done only as a last resort.

Dr. Lisbon noted for the record that the Panel members constituted a
quorum, and he began the agenda items.

**FDA PRESENTATION**

**Ann A. Graham, CRNA, M.P.H., Chief, Anesthesiology and Respiratory
Devices Branch, CDRH**, presented information on the regulatory aspects
of pulse oximeters, noting that they are Class 2 devices subject to
510(k) premarket regulations. Their intended use is the noninvasive,
continuous or spot-checking monitoring of oxygen saturation, distributed
by prescription. The device's patient population is adult, pediatric,
infant, and neonate. The application site can be the finger, the
earlobe, the back, and forehead. They are used in a variety of settings:
operating room, critical care, post-anesthesia, and the recovery room.
However, their use has been moving recently into the home and other
environments outside of medical or health facilities.

Ms. Graham went over the requirements of a 510(k) application. They
include a description of the device, the device's design, its
comparative performance data with a legally marketed predicate device,
and labeling. She noted that the accuracy specifications for the pulse
oximeter depend upon the type of device sensor and the intended use
population. For the transmittance wrap and clip device, the accuracy
specification must be ≤3%; however, when used for neonates, the
specification has a 1% degradation factor added to it, for a rate of
≤4%. This is a result of the Agency's agreement to accept adult data for
neonatal use. Transmittance ear clip and reflectance sensors are not
cleared for infants or neonates.

In the last couple of years her office has cleared about 35 510(k)
applications annually---this is a substantial part of their workload.
Most of these are for transmittance sensors, single use and non-sterile.
The number of pulse oximeter applications into her office has
dramatically increased since 1986, when they began to be used in
clinical practice; there has also been a significant increase in the
last 5 years.

She described the two documents the branch uses extensively, and how
they need to be amended. The 1992 FDA CDRH guidance document on pulse
oximeters needs updating on neonatal and labeling issues and
over-the-counter (OTC) use. The 2005 ISO standards document does not
offer the branch all of the guidance it currently needs, specifically on
test methods and the differences between reflectance and transmission
sensor types.

The Panel asked to define the term "neonatal." She said there is
guidance that defines neonates as under 30 days old with an upper weight
of 10 kilos (See page 11 for her additional clarification offered later
in the meeting). In response to another question, she noted that the
guidelines exclude fetal use of the pulse oximeter. The FDA has two
other oximeters categories of devices, she added: fetal oximeters are
Class 3 devices requiring a PMA, and in-dwelling tissue oximeters. To a
question about the use of predicate devices, she said that the standard
has been evolving, and that manufacturers use both fairly new technology
as well as older predicates for the 510(k) comparative performance data
requirement.

**Sandy Weininger, Ph.D., Office of Device Evaluation, Anesthesiology
and Respiratory Devices Branch, CDRH**, presented the regulatory history
of pulse oximeters, the 1992 guidance document, and the branch's
thinking about pulse oximeter regulation given the changes in the
technology since the early 1990s. He addressed the Panel's earlier
questions to Ms. Graham, stating that manufacturers will not necessarily
have the same definition of neonatal as FDA, and that the FDA requires
substantial equivalence of a device---that is, the manufacturer is
required to demonstrate that their device is substantially equivalent to
a legally marketed device.

CDRH published their 1992 oximeter guidance roughly 10 to 15 years after
the devices appeared on the market. He went over what the FDA asks for
in a 510(k), including identification of the configuration of any probe
and monitor combinations (possibly with clinical accuracy validation),
as well as any accessories---these have all been shown to affect
accuracy. They also ask for engineering drawings and a description of
any functional elements, alarms and alarm limits, and the defaults the
manufacturer may have on these features. Manufacturers must compare
their device to a predicate device, provide information on intended use,
use indications, functional verification, and accuracy verification of
the human subject testing. He noted that this last requirement is the
most important piece of information they can get on a pulse oximeter.

The FDA also asks for a desaturation study, with a minimum of 10 healthy
subjects, a range of age, skin tone, and gender, and a report on the
root mean square error (A~rms~). They request the collection of neonatal
convenience samples, while recognizing the limitations of being able to
do this. To compensate for this, they degrade the adult accuracy by 1
percent. It is recommended that the manufacturer supply at least 200
data points, over a saturation range of 70 to 100 percent SaO^2^ (He
noted that the standard does not call for this), with paired
observations. They must reveal any environmental factors, including
surface temperatures, electrical safety, electromagnetic compatibility,
and mechanical testing of the device. Pulse rate accuracy measured using
*in vitro* calibrators is required, set to lowest values. They also ask
for sensor specifications labeling that outlines environmental
specifications, sensor/monitor combinations, application time, use
indications, continuous use and spot checking use specifications, and
associated alarms.

For reusable probes, the manufacturers must demonstrate their ability to
clean the probe and have it return to its normal and safe condition,
over the lifespan claimed. The new oximeters are very software
intensive, so the FDA wants to make sure that the manufacturers use the
agency's software safety guidelines to demonstrate the device's safety
and that the software development process is appropriate. The
manufacturer must also present results of biocompatibility review for
all materials used. Reprocessed single use devices (SUD) are now a
larger part of the branch's review activities; manufacturers must
demonstrate the probes' accuracy after the number of claimed
use/cleaning cycles. They do not have to show electrical leakage or
electromagnetic interference validation.

A member Panel asked Dr. Weininger how manufacturers track can SUD
reprocessing. He stated that the SUD manufacturers must have a tracking
process in place that the Agency will review. The Panel also addressed
the question of how well distributed the 200 samples must be. He said
that they must be equally distributed across the entire range between 70
to 100 percent.

Dr. Weininger's second presentation examined the pulse oximeter standard
and highlighted the differences between the standard and the 1992
guidance document. ASTM created the F1415 standards prior to 1992; this
led to the ISO 9919 standard and the European standard (EN 865). ASTM
completed ISO 9919 (entitled *Particular Requirements for the Basic
Safety and Essential Performance of Pulse Oximeter Equipment for Medical
Use*) in January 2005, with a large number of clinicians and engineers
contributing to it. The FDA is in the process of recognizing it.

The standard covers safety and performance, while the 510(k) process
looks at substantial equivalence requiring the manufacturer to show by
objective evidence how their device compares to a predicate device. The
standard applies to all originally manufactured equipment, reprocessed
probes, and extender cables. There are extensive requirements for
labeling, documentation, and information annexes.

The standard's accuracy specifications must be defined over an evenly
distributed range of 70 to 100 percent SaO2; the A~rms~ must be less
than 4 percent. Dr. Weininger said that he hopes that the recommended
desaturation profile becomes the standard profile in the next version of
the standard. The standard requires that if there is a physiologic alarm
there also be a low SpO2 alarm; the low SpO2 default limit in the 1992
standards was 80 percent saturation, but that has been raised to 85
percent. The device must also include a description of the signal
adequacy indicator. The standards ask for information on how the device
is being used, addressing patient population, the body part, and
environmental information about the application of probe. The maximum
application time must be disclosed, as should the rationale for that
limit. The standards require a variable pitch tone on the oximeter,
where the pitch lowers as the SpO2 reading lowers. They also require
information on safer surface temperature standards. The IRC 60601-1
General Standard coming out this year or next year raises the surface
temperature from 41^◦^C to 43 ^◦^C, based on a required risk analyses.
The ISO 9919 adds more constraints to this: for adults it allows 41^◦^C
for four hours, 42 ^◦^C for 8 hours, and 43 ^◦^C for 4 hours, with
neonates limited to 41 ^◦^C. The standard also requires an automatic
reset after 4 hours. He stated that many of the burns reported in the
literature are actually pressure contusions.

Dr. Weininger discussed what items are not in the standard. The standard
does not require a disclosure of the oximeter's possibly poorer
performance in neonates. There are no requirements or test methods
outlines for motion artifact or low perfusion, and no single test method
for accuracy and surface temperature. He believes a single test method
would be helpful.

The Panel directed several questions to Dr. Weininger. Panel members
were concerned about the standard for audible tones on pulse oximeters,
and that there are still devices in the market where the tone does not
drop as the saturation drops. Dr. Weininger said compliance with the ISO
standards is voluntary, and there is no recommendation in the 1992
guidance to address this. Several members said that the FDA must
consider a tone requirement in their guidance documentation. The Panel
also addressed concerns about the fact that the surface temperature
standards are based on adult data, with no data on neonates. Dr.
Weininger said that the standards committee tried to identify the "worst
case scenario" for neonates in an incubator, and that they believe that
41^◦^C is safe in that situation.

Panel members discussed how a pulse oximeter is cleared. Dr. Weininger
said that the FDA can use the standards in their decision as to whether
a device meets substantial equivalence, but it is not a requirement. The
predicate device still exits in the market place as long as a safety
hazard has not been identified. Manufacturers can get clearance by
establishing substantial equivalence to a predicate device even though
they do not meet the standards set by the FDA, as long as there is no
obvious safety risk. The Panel asked for clarification between
requirements and recommendations. Ms. Graham said that in a 510(k), the
FDA makes recommendations while recognizing voluntary standards. There
are regulatory requirements in a 510(k) set out in the CFR, but those
are generally a broad list of requirements, including labeling and
manufacturer's discloses. With respect to pulse oximeter alarms, Ms.
Graham said that there are expectations that these will be present in
the device. Because these devices have now become primary clinical
decision making tools, the 1992 guidance document asks for *in vitro*
validation of the pulse rate and other data they expect the manufacturer
to submit. However, this is a recommendations document that does specify
requirements.

The Panel also raised the question of the origin of the 1 percent
degradation for neonates. Dr. Weininger said that he believes that it is
based on concerns raised in the mid-1990s about the influence of fetal
hemoglobin (HbF) on the co-oximeter. In 1989 a NIH consensus panel
discussed HbF influence, but they did not believe it to be clinically
significant. The compromise was to allow a 1 percent degradation.

Ms. Graham clarified the definitions of neonates, as requested earlier
in the meeting. On May 14, 2004 the FDA published *FDA Guidance for
Industry and FDA Staff: Premarket Assessment of Pediatric Medical
Devices* in which neonates are defined as from birth to 1 month, infants
from greater than 1 month to 2 years, children from greater than 2 years
to 12 years, and adolescents from greater than 12 years to 21 years. The
document recommended that industry use these categories.

**Julian M. Goldman, M.D., Departments of Anesthesia and Biomedical
Engineering, Massachusetts General Hospital, and Visiting Scholar, FDA
Medical Devices Fellowship Program**, clarified the issue of variable
saturation tone in pulse oximeters, raised earlier in the meeting. The
ASTM and the ISO standards do not require use of a variable saturation
tone, but they state that if one is present it must function such that
the tone decreases if the saturation decreases, and vice versa. Some
pulse oximeters are designed for spot checking and therefore have no
need for physiological alarms.

Dr. Goldman's presentation covered the clinical considerations of pulse
oximeters, as related to the three questions the Panel has been asked to
address. He stressed that it is important to understand the underlying
assumptions of the pulse oximeter model. One important assumption is
that the change in finger blood volume over time is important. As well,
the Panel should keep in mind that the clinical use of the pulse
oximeter will be most successful if the use conditions match the model's
assumptions, and if the calibration is performed on healthy adults under
laboratory conditions---not on sick patients in the hospital. When
clinical conditions diverge from laboratory conditions, inaccuracies may
appear.

He covered the FDA's questions for the Panel and the issues related to
these questions. Question 1 deals with the differences between
transmission and reflectance pulse oximeters. Dr. Goldman noted that
both techniques are based on the same model and the same assumptions,
but there are still a number of other effects that may be different
between the two. He went over some of these differences, but asked if
there was something that could be done from a design or educational
perspective to have clinicians use the devices properly. As well, he
raised the issue of whether reflectance probes should be specified for
use only on validated sites, and whether it clinically acceptable to
specify the use of a probe for other sites.

With respect to Question 2, he raised the issue as to whether the 1
percent degradation is clinically appropriate. While the rational is
unclear and supporting data is lacking, experience in the clinical
setting does seem to support the current approach. Postmarket
convenience samples may be useful to support clinical assumptions.

Dr. Goldman addressed the third question, dealing with OTC use of the
device. He noted clearing the devices for OTC use would require
premarket submissions and assessments of the instructions for lay
persons. This raises issues about incorrect applications leading to bad
data and bad outcomes, and how accurately would lay persons interpret
the data. He noted that most errors produced show falsely low
numbers---most consumers, he believes, would follow instructions and
call a clinician for advice. The benefits to allowing OTC distribution
of pulse oximeters may include empowering patients, moving healthcare
into the home and creating the "ambulatory practice of the future," and
prompting additional applications.

The Panel asked Dr. Goldman about the use of pulse oximeters in the
home. He said that the benefits from distribution of the devices in
homes would include giving clinicians better information about their
patient's condition than simply a report by the patient of how they
felt. He and Panel members suggested that data looking at the
possibility of erroneously high saturation values during OTC use would
be valuable.

**INDUSTRY PRESENTATIONS**

**Paul B. Batchelder, LCRP, RRT, Chief Clinical Officer, CLINIMARK**,
presented an evaluation of 43 articles in peer-reviewed journals looking
at pulse oximetry accuracy in the clinical environment for adults and
neonates. This literature review resulted in three primary points. The
first is that the pulse oximeter accuracy is not dissimilar between
adults and neonates in hospital setting; second, that the influence of
HbF is not clinically significant, making the 1 percent degradation
based only on anecdotal evidence; and, finally, that most neonatologists
surveyed stated that collecting a statistically meaningful number of
neonates to verify accuracy of SpO2 and SaO2 numbers over the range of
70 to 100 percent is unfeasible.

Accuracy rate for adults was 3.26 percent (± 1.32 percent) between the
laboratory and the hospital, and the neonates had a rate of 3.44 percent
(± 1.35 percent)---showing essentially no difference, he said. He
suggested that the 1 percent degradation factor may actually reflect the
laboratory-hospital difference, and not a difference between neonates
and adults. The factor may have resulted from when the Nellcor N-100 was
evaluated in the 1980s.

He offered a number of suggestions for how to acquire workable data and
suggested that the adult laboratory accuracy validation combined with
physical tests in the intended population and convenience samples
continue to be used. As well, he suggested that the 1 percent
degradation factor should be discontinued and clinical use performance
should be clarified in the device labeling.

**Paul D. Mannheimer, Ph.D., Principal Scientist, Nellcor/Tyco
Healthcare**, discussed the difference between reflectance and
transmission pulse oximetry in adult and neonatal applications.
Reflectance and transmission pulse oximetry technologies should be
treated equivalently; there is value in manufacturers' ability to
provide products using both reflectance and transmission pulse oximetry
devices; and both geometries should be treated the same when validating
new products for the neonatal population.

He discussed the principles of pulse oximetry, noting that they are the
same independent of emitter-detector type and position. Transmission
sensors are used on parts of the body that are thin enough to allow
light to transfer from the emitter to the detector, such as fingers and
earlobes. Reflectance probes diffuse light parallel to the body's
surface---they do not reflect light, despite the name.

Dr. Mannheimer noted that there has been a renewed interest in
reflectance oximetry. Early reflectance devices, from the mid-1980s,
could not tolerate extremely low pulses---however, he said that their
performance in these situations has dramatically improved. He presented
the accuracy performance data for the Nellcor N-400, a reflectance probe
designed for use on fetuses.

Looking at the vulnerabilities of transmission and reflectance pulse
oximetry, he said that there is no practical difference between the two
types. Both probes can be improperly applied---often resulting in
shunting---or applied to an inappropriate location. All of these
vulnerabilities are present in adults, children, and neonates.
Reflectance probes offer additional value in that they can be uses on
parts of the body that are not opaque---such as the back or the
forehead. A recent abstract (Bebout DE, Mannheimer PD. *Anesthesiology*
2000; 96:A558) showed little vasoactivity when a reflective probe was
used on the forehead and the patient was sifted from 74 ^◦^F to 58 ^◦^F.
In another study (MacLeod DB, et al. *Anesthesia* 2005; 60 (1):65-71),
researchers briefly induced hypothermia in a healthy adult to evaluate
the delay in the blood reaching monitoring sites.

He suggested that neonatal 510(k) submissions for pulse oximetry should
be tested as for any other pulse oximetries, independent of sensor
geometry. They should be validated in controlled laboratory studies on
healthy adults; form, fit, and function tests should be done to
demonstrate physical safety and appropriateness on neonates; and that
convenience samples should be taken on neonates around the 90 percent
saturation rate to confirm system accuracy. He recommended
simultaneously testing predicate device and the new device, to make sure
the level of performance is comparable to what is being used clinically.

The Panel asked him why it would not be possible to do studies with
multiple monitor sites on the neonate. Dr. Mannheimer said that it is
not unreasonable, as long as the patient is not made hypoxic.

**Philip Isaacson, Founder and Director of Nonin Medical, Inc.,**
presented information on pulse oximeter applications for sports. He
noted that they are showing up in many places, including among patients
who receive prescriptions for them. Nonin Medical makes no medical
claims about their product, the SportStat Fingertip Pulse Oximeter,
because it is being sold for consumer use rather than for medical use
(i.e. prescription or over-the-counter (OTC) use).

Their consumer use product is used by mountain climbers to avoid acute
mountain sickness, high altitude pulmonary edema, and high altitude
cerebral edema. Hikers, skiers, bikers, and those who work out in gyms
have also used the device The product has been used in a variety of
environments, including outdoors in extreme cold and heat and at high
altitudes.

**Brodie Pedersen, Senior Quality Design Engineer, Nonin Medical,
Inc.,** spoke on the consumer and aviation applications of pulse
oximeters. Pilots have used these devices to detect hypoxia while flying
without oxygen. He noted that hypoxia can occur when a pilot is flying
as low as 5,000 feet. Personal tolerance for high altitude can vary
daily, and he said that Nonin's device helps consumers understand how
their body is responding to various conditions; consumers might not
recognize when they are in need of oxygen because their mental acuity
will be dulled when their oxygen levels drop. Using their device can
help pilots constantly monitor when they should adjust oxygen flow. He
briefly noted that when the device is sold over-the-counter (OTC),
safety and effectiveness are regulated; when they are sold in the
consumer market, safety is not regulated.

The Panel asked Mr. Pederson and Mr. Isaacson whether any of their
products have been tested and compared to the medical device under
clinical conditions. Mr. Pedersen said the consumer devices are
identical to the medical device. The Panel expressed concern that
consumers may not have the training to use the devices appropriately.
The Panel also asked whether the manufacturer has tested the device at
30,000 feet, the level at which they claim operational efficacy. Mr.
Pedersen said that they have been tested in simulators to show that the
electronics in the device are not affected by that altitude, but the
tests did not involve humans.

**OPEN PUBLIC HEARING**

**Dale Gerstmann, M.D., Director of Neonatal Research, Utah Valley
Regional Medical Center,** discussed his study of the functional
performance of neonatal pulse oximeters, specifically addressing bias,
precision, and resolution. The patient sample was taken between 2002 and
2005, from a 40-bed, level-three NICU with about 500 admissions
annually. The NICU does not take care of neonates with complex
congenital heart disease, complex pediatric surgical problems, and
neither do they conduct extracorporeal membrane oxygenation (ECMO). The
study included 114 subjects. All data were collected under two
IRB-approved protocols (SpO2:SaO2 pairs with informed consent, and SpO2
recording with anonymous waived consent). There were 1,248 pairs of
data.

Bias is the difference between the pulse oximetry and the arterial
saturation. He presented Bland-Altman plots displaying bias, precision,
and A~rms~ for six different devices. A bias measurement at 0.0 is
ideal, but only three devices come close to this level. He noted that
the average bias by saturation is not uniform across the range for which
clinicians typically see saturations in sick neonates on ventilators and
whose oxygen is being controlled; as the saturation drops, the bias
increases. More clinically acceptable would be to have a device that
shows flat performance. Blood gases are drawn less frequently on
ventilated neonates with no complications; therefore, convenience data
is becoming harder and harder to obtain. Dr. Gerstmann presented a table
extracted from the same data showing that all of the A~rms~ values are
under what is currently acceptable (\<4); this shows that the 1 percent
HbF adder is unnecessary.

Resolution is an instrumentation term that relates to what a clinician
would see on the device's display. The precision or the resolution of
the monitor is ±1. However, after plotting the 95 percent confidence
intervals, a wide discrepancy appears between what is shown on the
monitor and what the data really means, he said---the accuracy reading
could actually be ±4 or 5. A clinically acceptable device would ideally
show readings that are closer to where precision and the bias is
acceptable, and be closer to what the resolution on the monitor shows.

The Panel asked Dr. Gerstmann whether the data had been published. He
said that the smaller data set was published in the *Journal of
Perinatology* two years ago, and that he is preparing the larger data
set for publication. The Panel congratulated Dr. Gerstmann for obtaining
data the manufacturers have claimed is unavailable. They also noted that
it is disturbing to see positive bias measurements at low saturations,
and that it seems to open the door for the appearance of false
negatives.

The Panel expressed concern about the device's reliability under adverse
conditions, and whether the manufacturer had any devices returned. They
asked the Nonin representatives if they recommended that climbers
purchase spare devices to protect against device failure in extreme and
life-threatening situations. Nonin offers a three-year warranty on the
device, they said, and that they very rarely fail. There is no way to
recalibrate the device in the field. When they fail, they tend to fail
to shut off when expected. Panel members also expressed concern that the
Nonin device's accuracy dramatically falls off below 70 percent
saturation. A Nonin representative stated that they have actually tested
the device down to 50 percent, but with limited data. Panel members also
expressed concern that the manufacturers have not tested the device at
high altitude on humans, and that there is little training provided with
the device.

The Panel asked Dr. Goldman why the pulse oximeter error rate tends to
read a low saturation, and how a recreational consumer user might
respond to this. He said that historically, the older pulse designs read
low in the presence of low perfusion and motion conditions, such as
shivering. Today, there is a better understanding of why that happens,
so these errors have generally been corrected. Typically, high readings
(which are very uncommon) are due to equipment problems, such as a
damaged cable. He added that the presentation previously that showed
positive bias in the lower saturation ranges raises the question of how
heavily laboratory testing should be relied on to indicate real world
performance. He urged increase testing on the population of intended
use, otherwise there will be surprises.

**PANEL DISCUSSION**

Dr. Lisbon read the first question into the record. Panel members
generally agreed that there seem to be no differences between
transmission and reflectance oximeters; however, there are differences
in their clinical applications. Panel members suggested that pulse
oximeter device should include clear, population-specific instructions
on probe locations and positions that will achieve laboratory level
accuracy. For example, some areas on a neonate's head may be more
efficient than others. These usage instructions should be supported by
data focused on the clinical applications on specific body parts.

Panel members noted that clinicians are using these devices to drive
decision making, so they must understand more about signal quality,
device limitations, warnings, and how the devices perform using
different types of sensors. A possible answer to the need for additional
information may be to ask manufacturers to include instructional inserts
with each probe, similar to drug information inserts. Some Panel members
noted that in the pediatric world, reflectance technology is rarely
used, and clinicians would need more guidance on where to place these
types of devices on a child's body.

A Panel member brought up the issue of an excess of oxygen in pre-term
neonates and how to protect against that. If these devices are
underreading saturation, that could have significant implications. Many
Panel members stated that validation studies in the neonate population
are feasible and should be done. In fact, some suggested designing
studies that randomize where on the surface of the neonate's body the
pulse oximeter is placed to understand which will provide the most
accurate reading---this would involve multiple oximeters placed on a
single patient's body at the same time.

Panel members suggested premarket studies for oximeters not currently on
the market, and postmarket studies for those already in use. This last
effort would help everyone understand how the algorithms in the current
devices are different from the predicate devices. Panel members
acknowledged, however, that postmarket studies would involve some
logistical concerns. One member suggested that postmarket studies could
be funded by manufacturer user fees, similar to drug studies, or pulse
oximeter industry contributions to a fund.

Dr. Lisbon read the second question into the record. Panel members
generally agreed that the 1 percent degradation to compensate for the
accuracy rates between neonates and adults is unnecessary. Members
discussed how saturation measurements below 70 percent can be validated;
there are some clinical situations where this data could be collected
and interpreted, such as cardiac surgery. Some members expressed concern
about Dr. Gerstmann's presentation that shows large biases in pediatric
saturation measurements at the lower end. This underscores the need for
postmarket research, publication, as well as work by the manufacturer to
see if there are some systems that have lower biases at lower
saturations for neonates.

Panel members discussed the FDA's practice of considering pulse oximeter
systems as single units when the end users can substitute different
probes. Some suggested that there should be testing for each probe with
each possible unit, especially given the difference in device
algorithms. The FDA said that this issue has come up in their
discussions but with no resolution. This also could be managed with
labeling, noted on member, because getting each sensor approved for each
unit may be very burdensome. One Panel member suggested that the 70
percent validation limitation on oximeters for neonate use should be
dropped to 60 percent, and require additional validation testing for
these levels, to accommodate the increasing numbers of very sick
children many pediatricians are seeing.

Panel members said that it is important to understand the biases of each
range in which these devices are used, because the biases are different
at low ranges versus high ranges. As well, because the biases are
different among different boxes and probes, the average physician needs
better guidance on which probe and which box fulfills his requirements.
Physicians also need help interpreting the numbers cyanotic children may
produce. For example, 25 percent saturation isn't a meaningful number;
it only tells the physician that the child is in very serious trouble.
The labels should reflect the fact that the numbers have variable
interpretations from patient to patient. There are populations that
should be studied to understand better what these numbers mean, despite
the cost in time and money.

**Donald Melnikoff, Smiths Medical PM**, addressed the Panel. He said
that there are inserts accompanying disposable reflectance probes but
they are not packaged with each probe---they are placed in the box of
probes. The inserts are already very cumbersome because of their size,
so they typically do not get attached to each individual probe. These
inserts do indicate that there is no validation for use below 70
percent.

Panel members discussed why the device displays a number, such as 40
percent, that is uninterpretable. One member suggested that a solution
may be to provide no numbers below 70 percent or some other lower level.
Other Panel members noted that the trend is actually more important in
such situations, so a clinician would still want numbers below 70
percent to track a trend. The instructions may need to be simplified and
streamlined so that health care workers can quickly extract meaningful
information from them. However, other members warned that the data is
truncated below 70 percent, so there is no continuous scale to track.
This may cause additional misinterpretation of the numbers.

Before opening Panel discussion on the third question, Dr. Lisbon asked
Ms. Graham to describe the differences between OTC products and consumer
products (nonmedical). She said that OTC devices would have a medical
claim associated with them. OTC use of a pulse oximeter, for example,
would identify intended use and a patient population. A nonmedical
device, such as the SportStat, is not medical device because no medical
claims are made. An OTC product cleared through FDA requires the same
level of evidence to make a determination of substantial equivalence is
the same as a prescription product. OTC requires additional information,
she added, such as appropriate labeling outlining intended use. The FDA
would also want to include language that indicates when the use of an
OTC pulse oximeter may not appropriate, but they need the Panel's
suggestion on how to word this. Additionally, the FDA has more control
over the manufacturing processes for an OTC device than for a nonmedical
device. A Panel member asked what kind of claims the manufacturer can
make on a label. Ms. Graham stated that pulse oximeters are currently
labeled to show intended use, whether for monitoring continuously or on
a spot-check basis; any other claims would need additional validation.
**Mark Melkerson, Acting Associate Director, Office of Device
Evaluation**, noted that a treadmill marketing for general exercise use
would be marketed as a nonmedical consumer product, while the same
product intended to restore muscle function would be marketed as a
medical device.

Dr. Lisbon read the third question into the record. There was some
disagreement among Panel members as to the value a home pulse oximeter
would have on consumers' health and health decision making. Some members
who did not feel comfortable with the consumer use of pulse oximeters in
the home said that if a person is sick enough to need the device in
their home, this use should be under their doctor's direction. They
expressed concern that consumers would not know what to do if the device
showed a low saturation level, and that this would give them a false
sense of security. While this device may encourage patients to take more
responsibility for their health, it may also discourage them from
following up with their health care provider. There is no guarantee that
patients will receive the education they need to manage the decisions
brought about by the use of a pulse oximeter.

Panel members who felt that pulse oximeters should be sold OTC said that
parents with a sick child would not buy an oximeter for home use without
consulting their pediatrician. These Panel members suggested that making
the devices fall under OTC guidelines would actually improve consumer
guidance on their use and limit the claims manufacturers can make. The
introduction of these devices in the home could empower consumers and
patients, and encourage them to take actions to maintain their health.

Some Panel members suggested that the devices should include some kind
of calibration device to indicate when device is working properly.
Another Panel member suggested that to reduce the burden on consumers to
interpret the oximeter's results correctly, home-use models could simply
feature indicator lights. Other Panel members suggested that the FDA
should select a patient population and conduct validation studies in
that population before allowing the device to be marketed OTC.

Some Panel members proposed a compromise that would involve having the
device undergo trials in a single community; this may address some
members' concerns that there are no studies showing how consumers would
handle the device. Another suggestion was that these devices would work
especially well where there are public defibrillators; this was agreed
to by most Panel members. Many members noted that numerous medical
devices are OTC, such as glucometers and blood pressure monitors, and
they are being used by consumers with very good results.

**SECOND OPEN PUBLIC SESSION**

Dr. Lisbon opened the floor to members of the audience who want to make
a statement. Mr. Melnikoff asserted that customers are buying the
devices as commercial products, but industry would like to market them
as OTC products while providing a higher level of education.

A Panel member asked the FDA if they only need to identify accuracy data
for OTC use, or whether efficacy data also necessary. Ms. Graham stated
that the end point would be in the comparison to a predicate device.

Dr. Gerstmann said that the way pulse oximeters are being used today has
made it one that controls disease, rather than a monitoring device. He
said that he continues to be concerned that the national studies are
using devices that are not as accurate as they should be.

Dr. Batchelder said that no validation is required in the neonatal
population currently, as there is usable information available.
Reflecting what a colleague, a pulmonary cardiologist, has said, Dr.
Batchelder asserted that physicians would like to have pulse oximeters
sold OTC because many do not prescribe them. Consumers are buying them
on the Internet; these should have same accuracy as medical devices,
along with better information and explanations of the accuracy. He
thinks they should survey pulmonologists in the United States to solicit
feedback on how the devices are being used among consumers at home.

**FDA QUESTIONS AND PANEL RECOMMENDATIONS**

**Question 1: Pulse oximeter sensors may be implemented in either a
transmittance or reflectance configuration. In both configurations,
light is scattered by blood, which has time dependent characteristics,
and bone or other tissue structures which are not time dependent.
Transmittance sensors are configured in a manner where the emitter
outputs light which travels through tissue (e.g. finger, toe, and ear)
and is received on the opposite side by the detector. Reflectance
sensors are configured with the emitter and detector in the same plane.
Emitted light must reach the detector by reflection off a surface which
typically results in smaller signal strengths in comparison to
transmittance sensors. Please discuss the clinical differences between
transmittance and reflectance sensors. In your discussion, please
specifically comment on:**

**a. Any difference in performance between the two sensors.**

**b. Whether the differences in performance would lead you to recommend
different pre-market evaluation methods and standards, and, if so, what
those would be.**

**c. Whether differences in performance would exclude certain
indications for use for one type compared to the other and, if so, what
those would be.**

a\. The Panel agreed that there are no fundamental technological
differences between the two sensor types; however, each type of pulse
oximeter should be validated in its own right to understand the
variabilities that are present. The ways they are used in clinical
settings---location of sensors and patient population---affect the
resulting measurements.

b\. The Panel said that there are differences in performance requiring
premarket validations based on their clinical use.

c\. The Panel agreed that there are no differences in performance that
would exclude indications for use for the two sensor types. However, the
Panel suggested a caveat when using these devices in children with
cyanotic heart disease.

**Question 2: The agency currently recommends that pulse oximeter
sensors are clinically validated to a stated accuracy (e.g. ± 2% from
70-100 %) on healthy adults under ideal laboratory conditions. Then, for
transmittance sensors intended for use on neonates, a 1% degradation
factor is added to the stated accuracy specification (e.g. ± 3%) to
compensate for uncertainty due to the inability to perform suitable
calibration studies and the apparent effect of fetal hemoglobin (FHb) on
saturation measurements (there is some evidence that co-oximeters, the
reference device used to analyze blood, is inaccurate at high
concentrations of FHb).**

**a. Please discuss whether you believe the agency should continue to
follow this recommendation for validation of transmittance sensors
intended for use in neonates and if this same recommendation should also
be followed for validation of reflectance sensors intended for use on
neonates. If the panel does not feel that this recommendation is
appropriate, please provide the agency with suggestions and
recommendations as to how the validation of accuracy for neonatal use
should be revised.**

**b. Please discuss whether you believe that the labeling for sensors,
especially those for neonates, should contain information on how the
saturation accuracy specification was developed and validated.**

a\. Panel members agreed that the 1 percent degradation factor for
neonates is unnecessary, and that neonates and adults should be
evaluated under the same standards. A neonate device should be evaluated
in its own right and not use adult data. There was also a request for a
breakdown of the biases and increased precision over the ranges: 70 to
80 percent, 80 to 90 percent, and 90 to 100 percent. Manufacturers
should provide increased disclosure as to the origin of the validation
data, how it was obtained, and its limitations.

b\. Package inserts should detail how a specific device functions with a
specific processor.

**Question 3: To date, the agency has not cleared any pulse oximeters
for medical uses as over-the-counter (OTC) devices. Please comment on
the risks and benefits of OTC pulse oximeters. Please specifically
discuss:**

**a. Under what circumstances, and for what general or specific clinical
conditions or indications (asthma, COPD monitoring), if any, should the
agency allow the clearance of an OTC pulse oximeter.**

**b. Whether you believe adequate labeling can be written to ensure the
safe^1^ and effective^2^ use of an OTC pulse oximeter including
directions for use, contraindications, warnings, and precautions. If so,
please comment on what specific elements or statements should be in such
labeling.**

**c. Whether the significant chance for misuse of OTC pulse oximeters
exists if cleared or approved by the agency for OTC use and what the
potential risks would be.**

Dr. Lisbon asked Panel members how they would vote on whether to
recommend pulse oximeter devices for OTC release, if they had to vote
now based on what they currently know and given appropriate labeling: 4
responded yes, 4 responded no, and 2 were undecided.

The Panel was divided on the OTC issue because most felt that they did
not have sufficient information and study results to make a final
judgment on any part of this question. Some members suggested polling
pulmonologists to gauge their sense of how patients are handling the
home use of pulse oximeters. Others suggested that OTC use of the device
might be introduced into a limited study population or place the device
with publicly accessible defibrillators.

Panel members also urged the FDA to consider two safety features in the
future: a change in tone installed in the device to correspond to a
reduction in oxygen saturation level for continuous readings; and a push
for getting rid of the pulse oximeter clips because too many accidents
have happened when children are fitted with adult-sized clip-ons.

**ADJOURNMENT**

Dr. Lisbon thanked the speakers and the Panel members. He adjourned the
meeting at 3:10 p.m.

> I certify that I attended this meeting of the Respiratory Therapy
> Devices Panel Meeting on May 13, 2005, and that these minutes
> accurately reflect what transpired.
>
> \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_
>
> Neel J. Patel, M.Eng.
>
> Executive Secretary

I approve the minutes of this meeting

as recorded in this summary.

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Alan Lisbon, M.D.

Chairperson

> *Summary prepared by*
>
> Susan C. Sanderson
>
> 5932 Lee Highway
>
> Arlington, VA 22207
>
> \(703\) 237-3696
>
> astrobuddy@mindspring.com