UNITED STATES

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

1:10 p.m.

EXECUTIVE SECRETARY FREAS: I would like to thank everybody for joining us this afternoon, for this our 19th and most technically advanced Allergenic Product Advisory Committee Meeting.

We are broadcasting from Room 4NN15 in Building 29 on the NIH campus. In Conference A on the first floor of this building there is a speaker phone reserved for the public. The public is welcome to participate in the entire portion of the meeting, however they must participate through the speak phone and the video machine down in Conference Room A.

Those people who have been on the line for the last 30 minutes realize why this is necessary. Those people in the public cannot understand it.

Today's entire meeting, of course, is open to the public, as advertised in the Federal Register.

At this time I would like to go around and check with each of our video stations first, and then I'll check with the audio stations to make sure that we can both see the visual and hear your audio.

So I'll go around and introduce you. I will start with our Chairman, Dr. Samuel Lehrer, research professor of medicine, Tulane University Medical Center.

Dr. Lehrer, could you say good afternoon and count to ten slowly.

CHAIRMAN LEHRER: Good afternoon.

EXECUTIVE SECRETARY FREAS: That's good. You don't have to count ten.

Actually, we did not pick up a video. I'm sorry, could you talk to ten?

CHAIRMAN LEHRER: So you're picking me up on video now?

EXECUTIVE SECRETARY FREAS: Your audio is loud and clear, but we do not have a video. We're checking on it right now. And we'll go on to the next committee member, with your permission.

CHAIRMAN LEHRER: Certainly.

EXECUTIVE SECRETARY FREAS: And see if we can pick Dr. Burks. Dr. Burks is professor of pediatrics, University of Arkansas for Medical Sciences

Dr. Burks, can you count to ten for us?

DR. BURKS: Wesley Burks, and I can see you now but I couldn't see Sam when he came on earlier.

EXECUTIVE SECRETARY FREAS: Okay. We appreciate you being there.

And, again, you know hopefully everybody has the audio number. If you give up on the video, we do have this audio number. But, hopefully, we're going to get this video to work but we're still trying to get the bugs out of the system.

Dr. Rebecca Gruchalla, you were the first one who joined us this morning. Thank you very much.

She's associate professor of internal medicine, University of Texas, Southwestern Medical Center.

Can you say good afternoon, Dr. Gruchalla.

DR. GRUCHALLA: Good afternoon, Dr. Gruchalla. Sorry. Well, I just had to do that.

EXECUTIVE SECRETARY FREAS: Oh, I appreciate a little levity. Okay.

PARTICIPANT: Like good say good night, please.

EXECUTIVE SECRETARY FREAS: Dr. Melvin Burger, are you there?

DR. BURGER: I'm by telephone, but apparently I'm not hooked up by video at all.

EXECUTIVE SECRETARY FREAS: Okay. And, of course, Dr. Burger is professor of pediatrics and pathology, Case Western Reserve School of Medicine.

Dr. Burger, I'm sorry you weren't able to join us by video, but we greatly appreciate you joining us by teleconference.

Dr. Susan MacDonald. I saw you earlier. She's associate professor of medicine, Johns Hopkins University School of Medicine.

Dr. MacDonald, can you speak to us?

DR. MacDONALD: Good afternoon. I can't see you at all, but I can hear you fine and you can see me.

EXECUTIVE SECRETARY FREAS: Yes. We're very fortunate. We hear you loud and clear, and see you, and everything looks good. Thank you.

On the audio portion only, is there -- Dr. Harold Nelson, have you joined us?

DR. NELSON: Yes. Good morning.

EXECUTIVE SECRETARY FREAS: Good morning.

Dr. Nelson is senior staff physician, Department of Medicine, National Jewish Medical Center.

Also on the line is Dr. Maria Soto-Aguilar, physician in private practice in Hudson, Florida, specializing in allergy, rheumatology and immunology.

Dr. Soto-Aguilar, can you hear us?

DR. SOTO-AGUILAR: Yes. Good morning to everybody.

EXECUTIVE SECRETARY FREAS: Thank you.

Next on the telephone our industry representative, Peter Hauck, Executive Director for Scientific Affairs Allergen Products and Manufacturers Association and works for ALK-Abello. Mr. Hauck?

MR. HAUCK: And good afternoon everybody.

EXECUTIVE SECRETARY FREAS: Good afternoon. Thank you for joining us.

EXECUTIVE SECRETARY FREAS: And next I would like to welcome a brand new member to this committee, Dr. Lynelle Granady. She's an associate physician with ENT and Allergy Associates in New York, New York. Welcome, Dr. Granady.

DR. GRANADY: Good afternoon. Thank you.

EXECUTIVE SECRETARY FREAS: I'm sorry to announce that our consumer representative, unless I'm mistaken has not joined us, and that's Delores Libera. She called me this morning. She has a high fever and was not feeling well and sends her disappointment that she could not join us.

Again, hopefully you all have this telephone number. If you get dropped from the video portion of the teleconference, you can dial in with the -- excuse me. The video portion you can dial in on the teleconference.

Now, I would like to just quickly go around and introduce the members in the room, starting over here with Dr. Karen Midthun. Dr. Midthun, if you would raise your hand once the camera gets to you.

Dr. Midthun is the new Director of the Office of Vaccines, Research and Review. Thank you very much.

Sitting next to her is Dr. Jay Slate, Chief of Laboratory of Immunology, Immuniobiochemistry.

Next is Dr. Richard Walker, Director, Division of Allergenic Products and Parasitology.

Next is Dr. William Egan, Deputy Director, Office of Vaccines, Research and Review.

In the corner over here is our technical chief.

I will start around here. WE have joining us Dr. Ronald Rabin, who is Senior Fellow in the Laboratory of Immunochemistry.

Next we have Ms. Jennifer Beidgewater, Consumer Safety Officer.

And we also have Jane Brown, who is the Committee Management Specialist responsible for getting this putting this meeting for us.

In the other corner with Dr. Robert Stumphey, our technical expert who is helping us with all the audio and the sounds.

I have been asked to remind you that this video conference is voice activated. And so please try not to all speak at the same time. And if you just wait a second, it'll be your turn to talk. And whoever speaks, the cameras will zoom in on them.

Now I'm going to read the conflict of interest statement which is required to be read for all advisory committee meetings.

The following announcement addresses the conflict of interest issues associated with this meeting of the Allergic Products Advisory Committee on April 8, 2003. To determine if any conflict of interest existed, the agency reviews the submitted data and agenda. The Committee agenda addresses update issues only. The Committee members were screened for their financial involvements with firms that could be mentioned in this updates.

We would like to note for the record that Mr. Peter Hauck is participating in this meeting as a non-voting industry representative acting on behalf of regulated industry. Mr. Hauck's appointment is not subject to 18 USC Code 208. He is employed ALK-Abello, Incorporated and thus has a financial interest in his employer. Mr. Hauck also serves as Executive Director for Scientific Affairs Allergen Products and Manufacturers Association. In the interest of fairness, FDA disclosure that his employer is a manufacturer of allergen extracts.

In the event the discussions involved specific products or firms not on the agenda and for which members have a financial interest, the members are reminded that they need to exclude themselves from such discussions. Their exclusions will be noted for the public record.

With respect to all meeting participate, we ask in the interest of fairness that they address any current or previous financial involvement with any firm whose products they wish to comment upon.

Dr. Lehrer, that takes care of the administrative introduction to the meeting. I would like to turn the microphone over to you.

CHAIRMAN LEHRER: Thank you very much, Bill.

I'd like to welcome everyone to the Advisory Committee broadcast.

Earlier this year I spoke to Dr. Slater about the format of this meeting. And since there were no regulatory issues that required the Committee's formal advice, we thought it best to hold a video conference to keep the Committee up to date on FDA's research activities and related allergen standardization issues. And certainly if you'll remember from the last meeting, allergen standardization was of importance to the Committee.

So Dr. Slater will be making up the update presentation.

I'd like to encourage of the Committee members to make comments on these presentations. We will have time for questions at the end of each presentations. And a time following all of the presentations for our comments.

And it's important anytime you make a comment, please identify yourself.

Another housekeeping issue, we would like to --

DR. MacDONALD: Excuse me. I can't hear anything either.

(Off the record while adjusting audio equipment)

EXECUTIVE SECRETARY FREAS: Dr. Lehrer, why don't you just talk for one second. And if you don't mind, I would just like to recap that you welcomed the Committee members and possibly maybe we should turn the host microphone over to Dr. Slater.

CHAIRMAN LEHRER: Yes.

EXECUTIVE SECRETARY FREAS: Would that be acceptable? Here I can only apologize to you for the technical difficulties that we are encountering. And if there's some way we could check and see what the matter is to get your audio back, we will. And also, if you would check in your local station to see if there's a problem down there that can be correct. And if not, I guess I will try to relay what you say to the rest of the Committee members. If that's agreeable with everybody?

Okay. So, at this time, Dr. Lehrer, I'm going to turn the microphone over to Jay Slater, who will be giving us the initial presentation.

Again, Dr. Slater is the Chief of the Laboratory of Immunochemistry.

DR. SLATER: Thank you very much.

First of all, again, I want to thank all of the Committee members for putting up with all the technical issues here. And I want to thank everybody for their patience in participating in the meeting in this manner.

We do have some interesting things to talk about today. But before we do, I just wanted to show this. This is a copy of today's newspaper. This in case, you now, given the unusual times, there was any doubt in anyone's mind that this is in fact a live broadcast. This is not being videotaped at an undisclosed location. We are all here and we are ready to go on.

DR. NELSON: For those of us not on the video, can you just tell us what it is?

DR. MacDONALD: What paper is it?

DR. SLATER: It's April 8, 2003. That should be enough, right. Okay.

So let's go ahead and proceed.

I'm going to start showing the slides. Now, we do have people that are viewing this conference in several different technological formats. Those of you who are viewing it on the monitors that's being generated by us don't have to listen to anything that I'm going to say, because I'll be controlling the slides.

Those of you that are looking at it on your own PCs, please set telepoint to slide show because there are some situations in which it will appear differently in slide show than it will if you're just looking at it in the normal view. So if you're looking at it on the PC, hit F5 now so that you'll be at the beginning of the presentation.

If you're looking at it in hard copy, just bear with me. When I say next slide you can advance visually to the next slide. If I say click, stay on the same slide. It just means that there's an animation that you're not going to see. There aren't too many of those, so bear with me.

We're now on the second slide of the presentation in which I'm just giving the outline of what we're actually going to do today.

First we'll have a very brief lab overview. Then we'll talk about a couple of interesting operational issues that have come up. And finally in the longest portion of the presentation, I'll be giving you a research and regulation update covering some of our recent endotoxin studies and covering some of our work in our attempts to go forward with cockroach allergen standardization.

Next slide, please.

So for the lab overview, we're going to talk about staffing issues, lot release issues and reference replacement issues.

Next slide. You should be on a slide that shows that I'm the lab chief. The two principal investigators in this laboratory are myself and Dr. Ron Rabin, who is starting his third year as a Senior Staff Fellow in the laboratory.

We have two post-doctoral fellows, Jonny Finlay and Bo Chi. Jonny is also starting his third year and Bo just started with us, since she's working with Dr. Rabin, and he started earlier this year.

Next slide, please.

We have research technicians in the laboratory. Al Gam, Mona Febus, Marc Alston, Cherry Valerio and Katia Dobrovlskaia. At this point if we were all the same room, I would have them all stand up and bow. But you'll understand that that's not possible in the format today.

Next slide, please.

This is a graphic that shows the staffing. This is the biologist staffing in the laboratory. And each of the colored arrows at the bottom covers a 12 month period. So what you can see from this is that after sort of ups and downs of lab building, really until the last year and a half we've been at a fairly stable position with 5 biologists performing both our research and regulatory work. This is a good number for our purposes and we're very happy that we've been stable at this point.

Some of you may have noticed that we have had some shifts in our staffing, though, that aren't reflected in this. Dr. Melissa has moved to Cedar and the past year and Melissa Patterson, who is a biologist in the lab for several years, left the lab to become a full time mother.

We maintained our full compliment by moving Katia Dobrovolskaia from a predominately research position into the visiting associate position, in which she can do both research and regulatory work.

Next slide.

Our "routine" regulatory activities, routine is in quotes because it often is anything but routine, include lot release activities, reference distribution and reference maintenance activities.

Next slide.

In the past year we have reviewed 357 protocols. One of those protocols was withdrawn by the manufacturer. We have distributed nearly 2,000 vials of reference materials in over 100 shipments sent to the manufacturers. To put that in context, please switch to the next slide.

This table shows the protocols that have been submitted in the past four years. And you can see that this year is somewhat lower than previous years, but my guess is this is just a normal year-to-year statistical variation.

Next slide.

You're see the referenced distribution in numbers of vials over the past four years. And you can see that that has varied as well with the peak in 2000. But basically our level of activity in 2002 is roughly where we have been for the last several years since I came here.

That ends the brief introduction to the overview of the lab's activities. I'll be happy to entertain any questions on that short section of the presentation.

If there are no questions, then we're going to proceed to the next portion of the presentation, which is operational issues in the Laboratory of Immuniobiochemistry.

Go to the next slide. You should be now one slide beyond the title slide operational issues.

What we're going to cover in this is a presentation of some issues that came up with the replacement of our cat and ragweed antisera. And we're also going to talk about our transition to ISO compliance.

Next slide, please.

We use sheep antiserum to measure, M being one content of ragweed allergen extract and one content of cat allergen extract. The antisera are raised in sheep and are sent out to our manufacturers for them and for us to use in the measurement of these allergen for lab release.

And this past year it became clear that both of our antisera needed to be replaced. As to a cat serum, it was originally released in 1988. S6 ragweed serum was released in 20000. And we replacement programs for both of these in the spring of 2002.

Next slide, please.

When we embarked on this, we thought this was a fairly standard procedure that was going to go uneventfully, but as you'll see we had some difficulties with it.

Our plan of what is after a prebleeding of the sheep that we were going to immunize them with 25 micrograms of allergen. Then a month later we boosted them with another 25 micrograms. We did a test bleed 3 weeks later. Following the results of that bleed, we determined that we needed to give another boost. And then the plan was to go ahead and plasmapheresis them in September of last year.

The next slide gives you a graphic representation of that plan with the three immunization doses followed by a plasmapheresis that we thought would give us a good supply of useable plasma sometime in mid-October.

Switch to the next slide, please. Next slide, please.

What we learned, though, in August was that the farm where the sheep were kept notified us that another sheep, not one of our two sheep, that had arrived in the farm in mid-July developed neurological symptoms at the end of July and it was sacrificed in the first week in August. But the presumptive diagnoses was that sheep was scapies. If that wasn't bad enough, next slide, please.

We were then notified about a week later that a sheep that had arrived in the farm in late June also developed neurologic symptoms, was sacrificed with a presumed diagnoses of scrapies. On autopsy both of these animals were found to have that disease.

Next slide, please.

So now we're going to review the transmissible spongiform encephalopathies, a topic for those of you are on this Committee 2 years thought and hoped I'm sure you'd never hear from again. But let's just review it very briefly.

There are several animal forms of the TSEs. Scrapie occurs in sheep and goats. Chronic wasting disease appears in mule, deer and elk here in North America. There's a transmissible mink encephalopathy. And, of course, there's the bovine spongiform encephalopathy. The feline is lightly considered to be derivative from the bovine form, contracted by cats who eat contaminated bovine material.

Next slide, please.

Of course, there are several human forms of the transmissible encephalopathy, and the one that's of greatest concern to us is, of course, Jakob disease, especially in the new variant that's associated with bovine TSE.

Next slide, please.

Scrapie is really one of the best described of the TSEs. It has been described in Europe for over 250 years. And it first appeared in the United States in 1947 when a sheep fogger imported sheep from Europe for local use. It now infects at least 1,000 flocks in the United States and is considered to be endemic.

It is transmitted both vertically and horizontally. Horizontal transmission is presumed to be by contamination of animals with placenta and blood during lambing season.

As with the other TSEs, there's typically a long incubation period and there's been no evidence of human transmission at anytime.

Next slide, please.

Sheeps are of varying susceptibility to scrapie associated with polymorphisms in their prions, especially at codon 171. The form of the animals that are most susceptible are QQ or glutamine/glutamine at the codon 171 site. The animals that are arginine/arginine at that site are highly resistent. And the animals that are QR are the intermediate resistance, although they are pretty resistent, they're not halfway between susceptible and the resistent animal.

Next slide, please.

The USDA has a well established scrapie eradication program that consists of three essential elements. The first is preclinical testing and surveillance. This includes a live animal test. It turns out that a third eye biopsy can reveal scrapie before neurologic symptoms appear. However, even the third lid biopsy may take months to years to turn positive in an affected animal.

The second key element is the tracking of infected and exposed animals. And the third key elements is cleanup strategies which involves identifying and genotype exposed animals. When there's an animal in a flock that develops scrapie, all of the remaining animals are supposedly genotype. The QQ animals are destroyed immediately. The RR and QR animals that are exposed are tracked for the development of the disease, but they may be slaughtered for human consumption.

Next slide, please.

Scrapie is not believed to pose any risk to humans. There's been no recognized human transmission in three centuries of exposure in Europe. And our sense is that these serum that we obtain from our animal, which you'll recall are only in the same farm with the affected animals, our feeling is that these sera was probably safe. Again, because there's no documented transmission to humans. The contact of our sheep with the affected sheep was limited. They were not in adjoining pens at anytime. They were at least 30 feet apart. And finally, because normal BSL 2 precautions should be in place for all work with all animal sera. And this should be certainly more than enough to give an extra element of safety. However, it was also our sense that in order to maintain a serum reagent that is as safe as possible, we were going to have a somewhat different approach.

Next slide, please.

So what we began to do, is we began to immunize two new sheep. We went ahead and processed the plasma from the two exposed sheep, and we initiated an immediate process of conserving our current and existing stocks of both of those previous antisera.

Next slide. Our approach is that if the new sera are available before we run out of the old sera, then the sera from the exposed sheet will be safe frozen for possible future use. However, if we have a shortfall, then sera from the exposed sheep will be used until the new sera are available.

Next slide, please.

The advantages of this approach is that we're offering the highest degree possible of safety to the workers that are using the sera for diagnostic purposes. And in addition, we're collecting what we think are going to be vast supplies of these sera for the future that we certainly will be able to use. The disadvantage was the possibility of two serum switches in a relatively short time, and obviously the time and expense.

That ends that segment of the presentation. Let me just tell you that we actually are going to be able to go forward with the new ragweed serum fairly soon. We've tested that and we will be able to go forward with that.

With the cat serum, we've continued to have some technical problems with even the new cat serum that we're using. And what we're in the process of doing in order not to have a shortfall is we're actually going back and retrieving some of the original sera that -- the components of the original sera that we had used in previous years. We're testing that out and we're going to -- we think we'll be able to have about a year's supply of that that will give us some time to work out some technical issues that we're having within the serum. So we're hoping that we will be able to avoid -- we certainly will be able to avoid shortfalls with both of those new sera.

That ends that portion. If anyone has any questions, I'd be happy to answer.

MS. LEE: Jay, this is Dr. Lehrer. Could I ask a question about your immunization?

DR. SLATER: Sure.

CHAIRMAN LEHRER: You used advance -- 25 microgram doses and I think there were 3 doses and complete/incomplete. It's just 25 micrograms struck me as being somewhat as a low dose for a kilogram basis with such a size animal. But I haven't had a whole lot of experience with sheep, so I just wanted to ask you about that in terms of your choice of antigen.

DR. SLATER: It's a good question. We actually got very, very good titers with the exposed sheep and with the subsequent sheep. So I think you're asking a good question, but we did end up getting very good titers.These were some previous protocols that were used in the laboratory.

CHAIRMAN LEHRER: I see. Thank you.

MR. HAUCK: A question, Jay.

DR. SLATER: Yes.

MR. HAUCK: This is Peter Hauck.

Maybe two questions. So you anticipate there would be no disruption of protocol release or manufacturers being able to use these materials for lot release purpose?

DR. SLATER: No. We're not anticipating any delay at this point. Both the new ragweed serum and the retrieved old cat serum are in the process of being lyophilized over the next couple of weeks. We'll then do some brief testing and we should be able to send it out shortly.

MR. HAUCK: Okay. And, Jay, one last question. It doesn't sound like you'll need to, but at least two manufacturers have their own antisera for ragweed that they use for stability testing. In a pinch, could they possibly be used for lot release it came down to that? That's kind of speculation, but --

DR. SLATER: Yes, that's speculation I'd rather not get into to. I think we'd have to know more about those sera and we'd have to really be in a pinch. I think we've avoided that.

MR. HAUCK: Okay.

DR. BURGER: Jay, this is Mel Burger. Maybe I'm missing something, but why not go over to Mil's monochronials?

DR. SLATER: You're not missing anything. That would involve designing a new assay and then validating it. It's certainly something that can be done, and it's certainly something that you sort of think about a lot when you go through this process of raising a new polyclonial serum.

You know there are -- we would have to make sure that it performed comparably. When you make that kind of a big switch, you have to make sure that we're not going to have a shift in what the unitage actually ends up meaning. So it's something that certainly can be done, and I'm always looking for new and better ways to allergens. But you have to understand, it's not a process that one can use in two to three months to make up for a shortfall.

DR. BURGER: No, I wasn't advocating it as a shortfall. To make up for the shortfall, I was wondering why -- since we're beginning to focus more and more on the single most important allergen, why we don't have a long term program of shifting over to monchronial antibodies for standardization?

DR. SLATER: Well, it's certainly something that we could consider. I think it's a good suggestion. But we're going to have to make sure that it actually performs the same way as our existing assays so that the actual unitage doesn't really change.

DR. BURGER: You know, maybe that should be an experimental goal of the laboratory to develop that for one antigen and see how it works.

DR. SLATER: I appreciate the suggestion. I think that's worth thinking about.

Okay. Dr. Lehrer, if there are no further questions, with your permission I'm going to go on to the next discussion.

CHAIRMAN LEHRER: Yes. That's fine, Jay.

DR. SLATER: Thank you.

Let's go to the next slide.

I'd like to talk briefly about CBER's Laboratory quality management initiative. And I'd like to acknowledge that in the audience down in Conference A is Bill McCormick from OVRR. He is the office quality manager. And he has provided me with the information that I'm using to make this brief presentation.

CBER has committed to becoming ISO-170235 compliant in its office product testing. So for those of you who don't know what that means, let's define a couple of terms here.

ISO is the abbreviation for the International Organization for Standardization. This is a nongovernmental agency founded in 1947 and based in Geneva, Switzerland.

ISO-17025 is a document that was generated by ISO in 1999 entitled "General Requirements for the Competence of Testing and Calibration Laboratories." This is a set of guidelines for labs that do testing and calibration to show operation of a quality system, to assure technical competence and production of valid results.

Next slide.

CBER's laboratory quality management initiative has several components to it. The first is to establish a policy with a center level quality manual. The second to audit the laboratories within the center for compliance with ISO-17025. And finally, to obtain test and laboratory accreditation where appropriate. And with accreditation, of course, is the consequence of a successful third party audit.

Next slide, please.

Why is CBER becoming ISO compliant? This is a complicated and expensive process. I think that's a reasonable question as to why we're doing this. And there are several reasons.

The first is to establish recognized competence of our laboratories that do testing. To assure the test and value of our data and our processes.

The second is, we require manufacturers' labs to be i GMP compliance. This is good manufacturing practices compliant. And although that compliance is intended for manufacturers not for us, it certainly makes sense that we would try to be compliant with ISO, especially since there are international efforts of harmonization that are attempting to equate GMP and ISO requirements.

The third is that ISO is an internationally recognized standard. And, again, this is a way of assuring the value and trust of the results that we obtain.

Next slide.

We are attempting to become ISO compliant in order to implement laboratory quality management policies and practices for all the official testing activities, to document a high level of training, competence and proficiency and to establish a consistent product testing process.

Next slide.

But are the elements of ISO compliance? ISO compliance consists of the management of 4 different features of any laboratory testing system. People, equipment, documents and processes. Let's go through those one at a time now.

Next slide.

The management of people basically covers all the people that would be involved in the laboratory testing of these products. All the people in the lab need to have defined roles. They need to have training that's appropriate for their roles in the process. They need to be demonstrated to be proficient in what they're supposed to, and that's both demonstration of proficiency at the beginning, initial demonstration of proficiency, and ongoing on a regular basis.

And furthermore, there needs to be an authorization process that assures that people are doing what they're supposed to be doing, what they were trained to do and that their training is ongoing.

The next slide, please.

The management of equipment follows from the same kind of reasoning. All of the equipment that's used in the testing has to be appropriate for the testing. It has to be appropriately calibrated. It has to maintained. There has to be a process in place to assure that only calibrated and maintained equipment is used. And there has to be assurances of measurement traceability to accepted standards.

Next slide, please.

ISO also requires that documents be -- and those documents include policies, procedures, specifications, equipment manuals and certifications. These documents all have to be reviewed and issued and controlled and they have to be approved and issued before they are used.

Next slide.

And finally, processes have to be managed. Those processes include the approval of testing materials, environmental specifications and monitoring, handing of samples, validation and suitability, the handling of data including non-conforming data, corrective action, preventive action systems, internal audits, management review and finally, although we never have complaints, the recording and handling of complaints.

The next slide, please.

CBER has committed to the implementation of this lab quality system. CBER has established a quality board. We've developed a quality assurance structure within CBER with the appointment of a center level quality manager, with the hiring of office quality manager. Bill McCormick, as I mentioned before in our case. The appointment and hiring of division quality coordinators. With the preparation of a CBER wide quality manual and with the purchase of an integrated quality management computer software system.

So what will this mean to my laboratory? My laboratory actually has fairly extensive written protocols for almost everything that we do. So there's really not going to be extensive substantive protocol revisions for our processes. There will be changes in terms of the documentation. There will be formatting changes to make the formatting of our documents consistent across the center. And there will be some substantive changes as well.

This will probably require a more formal separation of research regulatory equipment that we've had in the past, simply because the regulatory equipment will have more extensive record keeping and maintenance than the research equipment, although certainly the research equipment would benefit from the same maintenance and calibration as the regulatory equipment.

There will certainly be a series of internal audits that we will subject ourselves to as part of this process.

And then finally, in the near future, external audits as well as we approach certification.

Next slide.

The time table for this, of course, is tentative. But the idea is for implementation in stages of this process over the next 3 years with CBER -- with all labs seeking accreditation in the year 2005. The software is becoming operational this year. The polices and quality manual is being issued this year. We are beginning the initiation of compliance audits. These are internal audits which, of course, is starting and will be ongoing. And the training and process development is ongoing as well.

That ends this portion of the presentation. Dr. Lehrer, if there are any questions, I would be happy to take them now.

CHAIRMAN LEHRER: Are there any questions?

Well, it seems to me, Jay, that you've done an excellent job in spite of trying circumstances. And also I'm pleased to know that that is really you and not your double.

DR. SLATER: Thank you. I appreciate it.

DR. BURGER: How do we know that?

CHAIRMAN LEHRER: We don't know that for sure. But I think it's impossible to duplicate Jay, I believe. I mean that in the best of ways.

DR. SLATER: Well, thank you.

CHAIRMAN LEHRER: Next we're going to move the agenda to the open public hearing. Bill, could you --

DR. SLATER: Sam, we're not quite there yet. I think you're being overly optimistic. We have some more talking.

CHAIRMAN LEHRER: I'm sorry. I have my confused on there.

DR. SLATER: I apologize. We were going to be talking -- we're going to be doing the research and regulatory update.

CHAIRMAN LEHRER: Sorry about that.

DR. SLATER: No, I apologize. I wish I were faster, we could be done now, but --

CHAIRMAN LEHRER: Oh, that's fine. I think you've done an excellent job under trying circumstances.<