UNITED STATES OF AMERICA

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, A_RMS, and that actually is defined in the ISO standard which we'll get to in the second part of the presentation.

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

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

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

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

Next slide, please.

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

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

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

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

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

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

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