U.S. FOOD AND DRUG ADMINISTRATION

 

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CENTER FOR BIOLOGICS EVALUATION AND RESEARCH

 

ALLERGENIC PRODUCTS ADVISORY COMMITTEE

 

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MEETING

 

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THURSDAY,

APRIL 7, 2005

 

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The Advisory Committee met at 8:30 a.m. in the Versailles Ballroom of the Holiday Inn Select, 8120 Wisconsin Avenue, Bethesda, Maryland, Dr. Melvin Berger, Chairman, presiding.

 

PRESENT:

 

MELVIN BERGER, M..D, Ph.D., Chairman

LYNELLE C. GRANADY, M.D., Member

PETER R. HAUCK, Non-Voting Industry Representative

SUSAN MacDONALD, M.D., Member

HAROLD S. NELSON, M.D., Member

CHRISTY OLSON, R.N., Consumer Representative

JAY M. PORTNOY, M.D., Temporary Voting Member

MICHAEL E. WEISS, M.D., Member

MARSHA WILLS-KARP, Ph.D., Temporary Voting Member

GAIL DAPOLITO, Executive Secretary

 

FDA PARTICIPANTS:

 

NORMAN BAYLOR, Ph.D.

KATHRYN M. CARBONE, M.D.

MARY A. FOULKES, Ph.D.

RONALD RABIN, M.D.

JAY E. SLATER, M.D.

 


A-G-E-N-D-A

 

Welcome and Administrative Remarks................... 3

Melvin Berger, M.D., Ph.D., Chair

 

Meeting Statement.................................... 6

Executive Secretary

 

FDA Perspective

Introduction and Overview...................... 8

Jay Slater, M.D., Division of Bacterial, Parasitic and Allergenic Products, CBER, FDA

 

Cockroach Allergen Standardization............ 11

Jay Slater, M.D.

 

Q&A........................................... 32

 

Research Overview............................. 41

Ronald Rabin, M.D., Division of Bacterial, Parasitic and Allergenic Products, CBER, FDA

 

Q&A........................................... 58

 

Reclassification of IIIA Allergenic

Products...................................... 62

Jay Slater, M.D.

 

Q&A........................................... 84

 

Open Public Hearing................................. 88

(no speakers)

 

Committee Discussion................................ 90

 

FDA Critical Path Initiative Update

Kathryn Carbone, M.D......................... 105

Office of the Director, CBER, FDA

 

Mary Foulkes, Ph.D........................... 114

Office of Biostatistics and Epidemiology, CBER, FDA

 

Committee Discussion............................... 120

 

 


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

8:37 a.m.

DR. BERGER: Good morning. I'd like to welcome everyone to the FDA CBER Allergenic Products Advisory Committee Meeting. My name is Mel Berger. I'm a Professor of Pediatrics and Pathology in the Allergy/Immunology Division at Case Western Reserve University in Cleveland. I think our first step will be to go around the table and have everyone introduce themselves, and I guess we start with Marsha.

Oh, sorry. The microphones, you push to turn the microphone on, and then you have to push it to turn it off.

DR. WILLS-KARP: Good morning. Marsha Wills-Karp, Professor of Pediatrics at Children's Hospital in Cincinnati. My area of interest is the immunobiology of asthma and allergies.

MR. HAUCK: Peter Hauck, Alk Abello. I'm the industry rep for the panel.

DR. WEISS: I'm Michael Weiss, Dr. Michael Weiss, Clinical Professor of Medicine, University of Washington in Seattle.

DR. GRANADY: Dr. Lynelle Granady. I am in private practice in New York, and affiliated with Mt. Sinai Medical Center.

MS. DAPOLITO: Gail Dapolito, acting executive secretary for the committee.

DR. MACDONALD: Susan MacDonald, Professor of Medicine, Johns Hopkins Division of Allergy and Clinical Immunology, and Associate Chair of the Department of Medicine.

DR. NELSON: Harold Nelson, allergist, National Jewish Medical Research Center in Denver.

MS. OLSON: Christy Olson. I'm the nurse educator for the Allergy & Asthma Network, Mothers of Asthmatics. And I'm a consumer representative.

DR. PORTNOY: Jay Portnoy, Professor of Pediatrics at the University of Missouri, Kansas City School of Medicine, and the Children's Mercy Hospital. And I'm also the director, the Chief of Allergy.

DR. BERGER: I think I'll ask Jay and Ron to introduce themselves also, please.

DR. RABIN: Ron Rabin, senior staff fellow in the Laboratory of Immunobiochemistry in CBER.

DR. SLATER: Jay Slater. I'm the chief of the Laboratory of Immunobiochemistry at CBER.

DR. BERGER: Hopefully you've all seen the proposed agenda, and perhaps looked at some of the materials. We'll have several presentations by Drs. Slater and Rabin. We will have an overview of this issue of reclassification of allergenic products which had previously been classified as IIIA.

This will be an informational presentation to give a context to what the committee -- to what Jay and his colleagues at the FDA will be doing, and what the committee will have to consider in the future. But this is not for the purpose of actually making any formal recommendations at this time. So I don't think there will be any formal recommendations or motions to propose nor to vote on. I would remind you that if the committee wants to make a recommendation, then that is a very formal process, and so we don't normally have motions and things that follow sort of Robert's Rules of Order. Either we have discussion or we have a formal recommendation process. And again, there doesn't seem to be any action item which would require the latter at this meeting.

As you know, an important part of the meeting is to allow time for public discussion. We have set aside an hour for that. We do have a peanut gallery here for members of the public. No one has formally requested to appear, but if someone appears then we will give them a chance to have their concerns entered into the record and addressed.

I think now I'll turn it over to Gail who has some housekeeping details.

MS. DAPOLITO: Thank you, Dr. Berger. I'd like to read the conflict of interest statement for the meeting.

The following announcement addresses conflict of interest issues associated with this meeting of the Allergenic Products Advisory Committee on April 7, 2005. Pursuant to the authority granted under the committee charter, the director of FDA's Center for Biologics Evaluation and Research appointed the following individuals as temporary voting members for the committee discussions: Drs. Jay Portnoy and Marsha Wills-Karp.

The Food and Drug Administration has prepared general matters waivers for the following special government employees: Dr. Harold Nelson and Dr. Jay Portnoy, who are participating in today's meeting of the Allergenic Products Advisory Committee for the discussion of a proposed strategy for the reclassification of Category IIIA allergenic products being held by the Center for Biologics Evaluation and Research.

Unlike issues before a committee in which a particular product is discussed, issues of broader applicability such as the topic of today's meeting, involve many industrial sponsors and academic institutions. The committee members have been screened for their financial interests as they may apply to the general topic at hand. Because general topics impact on so many institutions, it is not practical to recite all potential conflicts of interest as they apply to each member. FDA acknowledges that there may be potential conflicts of interest, but because of the general nature of the discussion before the committee, these potential conflicts are mitigated.

Mr. Peter Hauck will be participating as the non-voting industry representative acting on behalf of regulated industry for this meeting. Mr. Hauck's appointment is not subject to 18 U.S.C. ? 208. He is employed by Alk Abello, and thus has a financial interest in his employer. FDA participants are aware of the need to exclude themselves from the discussions involving specific products or firms for which they have not been screened for conflicts of interest. Their exclusion will be noted for the public record.

With respect to all other meeting participants, we ask in the interest of fairness that you state your name, affiliation, and address any current or previous financial involvement with any firm whose products you wish to comment upon. The waivers are available by written request under the Freedom of Information Act. Thank you, Dr. Berger.

DR. BERGER: Sorry. Again, push the button to speak and push the button when you're done. And Dr. Slater will begin with an introduction to the FDA and the laboratory.

DR. SLATER: Thank you, Dr. Berger, and thank you all for coming. I think we have an interesting day in store for you today. We're going to be covering a lot of different topics. As Dr. Berger indicated, the core we think of the discussion is going to be the discussion later on this morning and early this afternoon about the reclassification of the IIIA products. But we do have other items of interest that we are going to cover today. And this is sort of an overview of the agenda. We will be giving a very brief lab overview. That'll take about five to 10 minutes. Then I will give the committee an update on the Cockroach Allergen Standardization Project, which is ongoing. Ron Rabin will talk to you for about a half hour, giving you an overview of our research activities in the lab. Then we'll talk about the reclassification of the IIIA products. Then finally this afternoon, after our discussions, Drs. Carbone and Foulkes will join us to give us a brief discussion of the Critical Path research activities in the Center for Biologics.

So let's talk about the lab overview. We'll talk about staffing, lot release, and reference maintenance. This is just an introduction to the people in the lab. And those of you who are here from my lab, when I mention your name just stand up and wave, please. I'm Jay Slater. I've been the lab chief now for six years. Ron Rabin, whom you'll be hearing from a little bit later, has been with us for four years. Our postdoctoral fellows, Bo Chi, Jinsong Zhang, and Nicki deVore have been with us for three years, two years, and two years respectively. Our research technicians in the lab are Mona Febus, Marc Alston, Cherry Valerio, and Katia Dobrovolskaia.

This is a cartoon or a graph that I've been showing since I came here. And the basic message is that after a few years of instability at the beginning, we've really had a fairly stable staffing of LIB. The only people counted on this graph are the research technicians. And the reason for that is that they're the ones who really bear almost the full brunt of the ongoing regulatory activity, the lot release, the reference maintenance activities. And we're really at a level now -- we lost Al Gam this past summer. He retired. But we really are at a level in which I think we're in very good shape in terms of handling the manufacturer's workloads. And I think our performance has reflected that.

What are our routine regulatory activities? Well, lot release is the main regulatory activity, but we also spent a lot of time on reference distribution and reference maintenance. And the reference maintenance includes semiannual checks to make sure that our references are maintaining their potency and their complexity. And in addition, when references either run out or clearly are not being maintained, we replace them.

Lot release activities. This past year we reviewed 417 protocols that were submitted by our manufacturers. In terms of reference distribution we sent out over 1400 vials and 83 separate shipments to our manufacturers this past year. Just to give you some context, over the last five years these are the lot release protocols that have been submitted to us. And you can see that 417 is really very much consistent with the previous submissions. And so we neither seem to be on an upswing nor a downswing in that. In terms of reference distribution, these are the number of shipments and these are the number of vials shipped. You can see that there was a significant drop-off between 2002 and 2003. In 2002 I made an appeal to the manufacturers to be more economical in their use of the references that we sent them. And they've obviously heeded my request. We're dispensing much less in the way of references than we had before.

I'd be happy to take any questions. If not, then I'd like to proceed to the next item of business, which is an update on our German cockroach standardization activities. Now, I spoke to you last year about our initial in vitro activities with German roach. I've given you in past years the rationale for standardizing German cockroaches. By the way, for those of you who are wondering and haven't seen these pictures before, these are Madagascar Hissing Cockroaches, in fact as large as this piece of birthday cake. And we are not working with them, thank goodness. These are the more standard American, German, Oriental roaches.

I gave you the rationale behind doing this. We've actually discussed this at length in previous advisory committee meetings. Just in a nutshell, roaches appear to be associated with inner-city asthma. A review that we did of available commercial German roach extracts indicated that they tended to be of very low potency, and of variable quality. And we decided to proceed with the next stage in this, which was to make a concerted effort to determine the biological potency of several German roach extracts using the ideal testing method. And I'm actually going to spend a good portion of this presentation reviewing the ideal testing method with you because it's not something that people are typically very familiar with. This is the method that was used in the 1990s and earlier to standardize grass pollen allergenic extracts. It is a method that utilizes highly allergic individuals. It is a quantitative method using serial three-fold dilutions in which the major effort is to establish the dilution at which the erythema response is 50 millimeters. And that dilution is called the D50.

When you do an intradermal skin test, you get both a wheal and a flare. For statistical reasons, this method uses the erythema response rather than the wheal response. The sigma E that we're measuring is the sum of the longest diameter, indicated here as Diameter A, and the midpoint orthogonal diameter, which is indicated as B. If you add those two up, you get the sigma E and those are the data that are utilized.

So the testing approach in this first of all is to identify those highly allergic individuals. And in order to do that you do a screening test, a straightforward puncture test using a bifurcated needle with a concentrate. You then go ahead and do the serial threefold dilutions, record the wheal and the erythema size, and calculate the sigma E at each concentration. What you get then is a plot, and this is a plot from a paper from the 1970s using histamine. You plot the mean sum of the erythema diameters of the sigma E on the ordinate. These are the serial threefold dilutions. The shorthand that is used here is that these are actually in negative log units. So a dilution of 4 is a 3-4 dilution, and so on down the line. You plot them out. Then going from the ordinate at the 50 millimeter line. You then figure out what the D50 was, and in this case the D50 was 5.56. Which means that a dilution of 3-5.56 this individual tested would have been predicted to have a sigma E of 50 millimeters.

Just to wrap up the background discussion on this. When testing was done previously, the normative response to highly potent extracts was found to be a D50 of 14. Therefore, a D50 of 14 was defined as 100,000 BAUs per ml. Working from that you can calculate the BAUs per ml by this simple formula from the D50. So when you do this method, you generate a D50 for the extract, and then you calculate the BAUs per ml based on this empiric relationship and the consequent formula.

Some of the rules that you follow when you do this, and I'm going to take you through a highly idealized set of D50 testing, and then we'll actually look at the real data and you'll see why you need rules to help you work this through. The skin test response, the sigma E, should fall within the limits of 0 and 125 millimeters. Each more concentrated dilution should produce a graded erythema response. In other words, as you give more and more concentrated extract, you should get larger responses. And the dilutions, at a minimum we want to have two dilutions on either side of 50 millimeters. In other words, we want to bracket the 50-millimeter point.

So I'm actually going to walk you through a theoretical set of skin tests at this point. Typically we start with a dilution of 3-17 or what's called the 17 vial. And in this study subject, we're testing three allergen extracts. One is the yellow one. The other is the blue one, and the last one is pink. The first series of tests indicated by the green arrow are five tests, one for each of the extracts, one for histamine, and one for saline. And what we see here is that the saline and histamine responses confirm that the subject is neither dermagraphic nor hyporesponsive. None of the three extracts appears to be eliciting any response. We plot it out here at the -17 log dilution. All of them are at zero. Therefore, in our protocol, in order to be economical in terms of the number of injections that we do for these study subjects who undergo a very large number of injections, we then if we get no response we skip three log dilutions rather than just one log dilution. So the next one for all three of these will be at -14. And here are the responses that we get. Both the yellow and the blue extracts continue to yield minimal or no response. But we can see with the pink one that we have a small response developing, which we can plot out on our graph. Therefore, the next injection for the pink one will be at 10-13 and the next injection for the yellow and blue will be at -11.

And here are those responses. Well, things are going well for both the blue and the pink extracts. The next injections for both of these will be at single dilution increases, going from 11 to 10 for blue, and from 13 to 12 for pink. However, as we plot out the yellow response, we see that we've made a mistake with yellow in that we now are already above the 50 millimeter point for the yellow extract. Since we need to bracket, we need to have at least two on each side of 50 millimeters, we're actually going to backtrack next with the yellow extract and go to dilution of -12.

And here's the next series of responses. Now we seem to be on track for all three of the extracts. We will now proceed with a single dilution increase for both the blue and the pink. However, the yellow one, if we went up a single dilution we would just cover ground we've already covered. So we can go to the next dilution for the yellow one. Here are the responses that we get for that. The good news is that we're now above 50 millimeters for all three of these extracts. However, we want to have at least two valid data points on either side of the 50 millimeters, so we're going to do another higher dilution. Which we can plot out this way.

Examining the data, we conclude that we now have clearly sufficient data for the pink extract. However, we have problems with both the yellow and the blue extracts, both of which are rectifiable. Blue for some reason, the next concentration, we seem to have plateaued. Therefore we're not getting a uniformly increasing curve, and we really need to go at least one concentration higher to get more valid data. With the yellow, looking back on the data, we see that we really only have one data point below 50 millimeters. And so we're going to go back and do one of these more dilute concentrations for the yellow. And what we can now see is that we actually have valid data for all three of them. And we can proceed to calculate the D50s for these.

Now the purpose of this exercise was to take you through an ideal case. I'm now going to take you into the project itself. We'll show you some of the data, how we tried to analyze it, how we decided alternative methods of analyzing it that might be better. Let's look at what our objectives were here. Our objectives were to take three commercially available allergenic extracts for German cockroach and really check in a good statistically designed study what the potency would be biologically. It was in our interest in doing this to pick three extracts that were different from each other, so we would get some idea of the spread of potency and try to relate this to some of the in vitro measures. So we picked three, and these are readily commercially available extracts from manufacturers A, B and C. They in fact were from two different sources. The source material preparation methods are outlined here. And the extraction methods are outlined here. Basically, there were no really great differences between these. They all started from German roaches. Some of them were used in a source material that was ground to powder before they extracted it. Others were ground in a blender during the extraction process. But fundamentally they were starting with the same materials and using very similar methods for extraction.

There are certain things that it's easy to do with allergen extracts and that is to try to measure known allergens, and to try to measure the relative potencies. That's what we did. INDOOR Biotech has a two-side ELISA method for measuring both Bla g 1, Bla g 2, and Bla g 5. We also used our standard competition ELISA technology to determine the relative potency of these three extracts compared to a highly potent extract that we had from some years back. We did this using pooled human serum, as well as rabbit sera that we made by injecting rabbits either with German roach or with recombinant Bla g's 1, 2, 4, and 5.

The specific allergen data are indicated here. E2CG is the reference standard that we have been using provisionally for some years in the lab that was made especially for CBER in the 1990s. As you can see here, all three of the commercial extracts contained Bla g 1. All three of them contained detectible Bla g 2, although there were some variations. Notably, only extract B contained Bla g 5. The other two really had almost non-measurable amounts of Bla g 5.

When we measured the potency using the three methods, RP1, relative potency 1, is the one using pooled monospecific rabbit sera against Bla g's 1, 2, 4, and 5. RP2 using rabbit anti-German roach serum. And RP3 using the human serum pool which we've called S1CR. Again, you can see that extract B appears to be the most potent by all three methods. This is consistent with the Bla g 1, 2, and 5 data that we had. Lots A and C appear to be somewhat equivalent in potency by using the pooled monospecific anti-sera. But when we use the human serum pool, Lot A appears to be almost devoid of specific activity, whereas Lots B and C have some detectible potency.

The clinical study to determine the potency of these three extracts could not have been done without the very active interest of the Division of Allergy, Immunology and Transplantation at NIAID. This was an IND that they put together. There were four sites. This is through the Inner-City Asthma Consortium. The four sites were in Baltimore, Washington, D.C., Chicago and Denver. And people often save thanks for the end of talks. I think the thanks here should go smack in the middle of this talk. This study really could not have been done without the real interest and commitment of the Inner-City Asthma Consortium. Individuals who were extremely helpful included Robert James and Herman Mitchell at Rho, which is a company that does the organizational work as well as the statistical analyses for the Inner-City Asthma Consortium. Peyton Eggleston was the PI in Baltimore, Andy Liu the PI in Denver, Jacqueline Pongracic in Chicago, and Sampson Sarpong in Washington, D.C. These folks all worked very hard to make this project work.

The purpose of the IND was to determine the biological potency of three commercially available German roach extracts and to test their bio-equivalents. The patient population was the patient population of the Inner-City Asthma Consortium: adults with a history of allergenic disease or asthma and a demonstrated sensitivity to German roach allergen. It was a multi-center open label trial. We planned to enroll 61 study subjects. We actually enrolled 62. This was an adult group. This was not a pediatric trial. It was predominantly female, and the ethnic background of the study subjects is precisely what you would expect from the Inner-City Asthma Consortium.

Once we accumulated the data, which actually this group completed patient enrollment and data collection within five months. It was really quite impressive how quickly it happened. We then were confronted with how to go about analyzing the data. Now, linear regression is the standard method that was really included in the protocol. This is what was used in the ideal protocol in the 1990s and before. The idea here is to draw a best-fit line through the data, determine the D50 in that manner. And the problem was, as we looked at the data, it was quite clear there were a number of study subjects for whom there would be extremely poor correlation coefficients. This was not surprising. In previous studies using this protocol, poor correlation coefficients were a major source of data invalidation. And in the current study it was clear that several of our study subjects were non-linear. And this is just data from eight study subjects. What you're looking at here in the black is the actual data points, either a solid line or a dotted line or a dashed line. Each of those is one of the allergen extracts, and each panel is one study subject. And you can see that in spite of the fact that all of these study subjects were screened with puncture skin tests, some of them were essentially flat lines. They really never got above the 50-millimeter point at all. They were hyporesponsive. And obviously, regardless of the analytical method you use, you can't include these study subjects in your analysis.

Some study subjects had curves that were -- it seemed pretty reasonable to do linear regression analyses. But others it seemed almost impossible to attempt. So Dr. James, the statistician at Rho, thought up another approach, and that was just a linear interpolation approach. In the linear interpolation approach, rather than assuming a mathematical relationship, the simpler method would be simply to take the serial dilution at which the plots cross the 50-millimeter line. And basically what you're working with in that situation is two points: the point below 50 millimeters and the point above 50 millimeters. And you use that to determine your D50. Now, if you remember some of the images of the actual data, you can see that that can be problematic as well. And so we established a set of rules by which one could use this method in an organized way. And then we applied it to the data to see how the data would look.

The first rule is that you use the first crossing of the 50-millimeter line. So study subjects that would go up and down, you would look at the first crossing that was followed by at least two consecutive non-missing dilutions above. So, if you went up and down, you would use the first crossing that was followed by a consistent staying above the line. Now, if the above criterion doesn't apply, and the data's most concentrated dilution is above 50 millimeters, we assume that any more concentrated dilutions, had they been collected, would have remained above 50 millimeters. In that case, we would be using the last crossing as the actual crossing that we would record for the D50 purpose. And if the extract for a subject does not cross the 50-millimeter line at any serial dilution tested, or whenever the line is crossed the first two criteria don't apply, then the D50 simply can't be calculated. And that makes intuitive sense.

So in this case, I've taken the same eight study subjects and we've simply plotted. And I know it's very hard to see, but maybe you can see it on your handouts, the points that were actually chosen, these are indicated in blue spots. Obviously, this one, there is no crossing, and so there are no D50 to determine. But what you can see here, and just by a direct comparison of the regression versus the interpolation method for two study subjects, you can easily see how the regression method generates a result that doesn't make nearly as much sense as the interpolation method does. Now, even in this study subject whose data is very hard to interpret, the interpolation method gives you something that certainly makes more intuitive sense than a projected value out here, or this value back here.

But there is another method that can be used, and I'm sorry, this is the one slide that didn't quite come out in translation to a different computer, and that's the four-parameter logistic model. The four parameters being the minimum, the maximum, the EC50 and the D or Hill slope. And this is also known as a sigmoidal calculation. You can see back here under these words the sigmoidal curve calculating the D50 in that manner. This has the intuitive advantage of using the most data. Remember, the linear regression uses all of the data, but the data at the extremes tends to dominate the calculations more than the data in the middle. The linear interpolation method uses the data right around the D50 the most and kind of ignores the data elsewhere. The four-parameter model is the most intuitively attractive because it uses all of the data. And you can either plot it out, or you can do it algebraically. When you're doing it algebraically you calculate the concentration at which a 50-millimeter point occurs. The D50 is then the log of this concentration divided by the log of three.

So, needless to say, what we did in this case, and you can see here again that several of the curves really look sigmoidal, and the projected or calculated curves which are in color really look very close to the actual curves themselves. So needless to say we did the data all three ways, and compared them. And this is the D50 data from manufacturers A, B and C by the interpolation method, the linear regression method, and the four-parameter fit method.

Looking very quickly at it, you can see that the data are not all that different in D50 values. But remember, when we turn them into BAUs they will be somewhat different. What also you can see is that the interpolation and the regression method have the advantage of using more study subjects data. Out of the 62 study subjects, you can see that nowhere near all of them had analyze-able data. If you're below the 50-millimeter line, the data can't be used no matter what you've done. But using the four-parameter method, we could only use between 42 and 43 study subjects, whereas by both the interpolation and regression methods, we could use between 48 and 55 study subjects. So that gives us an advantage for those two methods.

Looking over at the standard deviations, you can see that the interpolation and the four-parameter fit methods had substantially smaller standard deviations than the regression method. Which gives an advantage to the interpolation and the four-parameter fit over the linear regression. We went back and forth about this a number of different times, and came to the conclusion that the interpolation method really had the advantage over the other two. But I'm going to show you all three of the data.

So again, the potency data, calculated BAUs straight from the D50s by that calculation that I gave you before. You can see that by the interpolation method, the BAUs were 1,700 to 8,500. The regression method 2,100 up to 12,000. Four-parameter fit, 1,300 up to 5,000 or so. And these are the 95 percent upper and lower limits.

So the conclusions were that the D50s calculated using the interpolation of four-parameter fits had slightly tighter standard deviations than the regression method. The interpolation and regression methods maximized the number of study subjects whose data could be analyzed. Interestingly, bioequivalence which we had set at the beginning of the study as a delta of less than 20 percent among all three of the D50s, using all the methods, the three extracts were essentially bioequivalent. But, there were statistically significant differences between A and B, and between B and C. In other words, B was from a statistical point of view the most potent of the three, although by our preconceived bioequivalence limit they were all bioequivalent. And A and C were not statistically different from each other.

So the next relevant question is what in vitro test best reflects in vivo potency. Now, we are not there yet. We have not determined this yet. But we do have enough data to begin to try to address these issues. And what I'm putting here is all of the data put together in one place. These are extracts A, B and C. This is the Bla g 1 content, Bla g 2, Bla g 5. These are the relative potencies by three methods. And these are the BAUs, and we just used the interpolation data here.

One way to look at this in the aggregate is to simply normalize all of the data to product B, which was the most potent. So in this analysis you just take product B and you set it as 1, and then product A and C for each of these is just a ratio of that value to product B. And just by looking at this you can see that on first blush the BAUs and the Bla g 2 level seem to be the most closely related in aggregate. And this is an important caveat here. In the aggregate, the Bla g 2 data appear to best reflect the overall potency, but in order to do this we actually need to look at this study subject by study subject. And that's what we're going to do. We will be examining the IgE specificities of each of the individual 62 subject sera and correlated to their D50s.

But even though we're not finished with the process, we can start to look at German roach extracts and see where this fits in the constellation of other extracts that we know about their potencies. And just for review, the grass pollen extracts, with the exception of Bermuda grass, are 100,000 BAUs per ml. Ragweed extracts, based on an estimate of 350 Amb a 1 units per ml, equaling 100,000 BAUs per ml, are typically somewhere between 30,000 and 100,000 per ml. Bermuda grass, 10,000. Cat, between 5,000 and 10,000. And the geometric mean of those three extracts that we tested was about 3,300 BAUs per ml. So you can see here that when tested in a highly allergic population, the potency of the German roach extract is clearly lower than the others. Then the question is well it's lower, but is it still going to be useful. And the answer is probably yes. Skin testing doses -- this is from a practice parameter from 1995 -- have been estimated to be certainly 100 to 1,000 BAUs per ml. This can certainly be achieved with most of the German roach extracts. Immunotherapy doses are a little hard to find. This is from a review that Paul Turkeltaub did in 1999. This is from another practice parameter. If in fact we're shooting for 2,000 to 4,000 BAUs for dosing, that's going to be difficult to achieve with these existing extracts, and in fact will probably not be readily achievable with most of them. However, if we can get away with lower doses, then we probably can achieve that. This is something that will need to be the subject of future studies.

Another aspect in which it's ? it's just interesting to look at where this fits. I don't have to tell the people on this committee what my thinking is about the value of using major allergens on allergen extracts. But it is useful to look at where this fits in the context of major allergens. And also perhaps gives us some insight into what the important allergens are in Bla g 1. If you re-analyze the data that Dr. Nelson presented in 2004, looking at some common standardized extracts in the United States, and you recalculate the data as major allergen content per 10,000 BAUs, what you find is that the range in these extracts: cat, Timothy looking at Phl p 5, fescue looking at Fes p 5, D. farinae and D. pteronyssinus looking at the group 1 allergens, you find a range of between 15 and 172 micrograms per 10,000 BAUs of extract. When we look at the data that we have from the roach extracts, first of all we can't really compare the Bla g 1 data to these data because Bla g 1 is in arbitrary units. It's not in micrograms. But looking at the two allergens that we've measured in these extracts using the same ratio, micrograms per 10,000 BAUs, we see that the Bla g 2 content is right dead set in the middle of this range from Dr. Nelson's work. So this is actually I think a little bit more of an argument that Bla g 2 may in fact be a good surrogate for the skin testing. What we also see here is pretty good evidence that Bla g 5 will probably not be, at least in most study subjects. But again, I have to warn you that our aggregate data are not necessarily going to guide us. If, for instance, we find that for three quarters of the study subjects Bla g 2 is the major determinant, but for another quarter Bla g 1 is, we will have to account for the content of both of those in our standardized extracts when that happens.

So the next steps. We do in fact have sera from all of these study subjects. We will be determining their IgE specificities using Westerns, ELISAs and ELISA inhibition. Based on both the aggregate data and the individual data, we need to determine the appropriate surrogate test for standardization. And finally we will need to determine an appropriate set of reference standards for this.

And I'm happy to take questions about German roach. Yes, Dr. Nelson.

DR. NELSON: It used to be that the skin tests were done in triplicate. Were these done in triplicate?

DR. SLATER: Actually they were not done in triplicate. We were faced with that decision, but -- and in fact, when they -- occasionally the skin test would be repeated. About five percent of the time, a skin test at an individual dose had to be repeated. When that happened we actually analyzed the data completely separately for first skin test doses and second skin test doses. We found that there was no real difference between repeated doses, at least in those that we could look at. But we did not have it worked into our protocol to do it in triplicate. Our problem was that we really needed to get data on at least three extracts in order to try and do the analyses that we were hoping to do. And I suspect had we done it in triplicate, we probably would have gotten -- been able to use more of the study subjects. Fortunately, the data that we got was significant. Dr. Portnoy.

DR. PORTNOY: Yes, two questions. First of all, what happened if you ran out of space on the back? I mean, did you ever do so many that there wasn't enough room, and how far apart did these have to be so that one test did not interfere with another? And the last question I have is were there difficulties in interpreting the results based on the degree of pigmentation in different people's skin making it difficult to actually see the results?

DR. SLATER: Three very good questions. No, we never ran out of space on anyone's back. But think about the reason for that. Basically, you started a dilution of 3-17 . At maximum you get to 3-5. We never went above 3-5 on anybody. So if you get no reaction, which is the subject in which you're going to get the maximum number of injections, you go from 17 to 14 to 11 to 8 and to 5 and that's it. And there's certainly more than enough room to do that on any adult's back.

The distance between each of the injections had to be 2.5 to 3 centimeters between each of them. And we did not run into trouble with overlapping. I think it's an indication of the low potency of these extracts that we didn't run into trouble. I think had we done this test with grasses we probably would have had to space them more widely.

Pigmentation was actually -- it was an exclusion criterion. If either from very deep pigmentation or from other skin conditions we felt that we would not be able to read erythema, that patient would be excluded. The fact is, you can read erythema on people even with fairly deep pigmentation. It really can be done. So I'm not aware that we actually excluded anybody for that reason.

DR. PORTNOY: And one additional question. Were there differences in skin reactivity with different races? Or different degrees of pigmentation?

DR. SLATER: We haven't analyzed that yet. I thought you were going to ask if there were differences among the four centers geographically. And we haven't answered that yet either. We haven't looked at that. We may not be able to. We may not get -- you know, with only 15 study subjects at each site, we may actually not be able to learn that yet.

DR. NELSON: You always start at the top and work down. Has it been looked to be sure there's not a gradient over the back and erythema?

DR. SLATER: We actually didn't always start at the top. In the example that I showed, just for simplicity of showing it, we started at the top. The actual protocol called for sort of going back and forth starting. We always started on one end and worked to the other. But we didn't always start on the top. That was randomized. Dr. Granady?

DR. GRANADY: Can you comment on using the erythema versus the wheal size?

DR. SLATER: I can. It's for statistical reasons. The line that you get -- and you can think this through sort of intuitively. The line that you tend to get with the wheal size tends to be much flatter. And therefore, smaller errors in measurement lead to greater errors in the calculation of the D50. So when these studies were initially done I understand. The original papers on this were from the 1970s. When this was originally done, they did both with sigma E and sigma W for wheal size. And you can get valid data both ways. But the error of the measurement is greater with the wheal than it is with the erythema. Dr. Weiss?

DR. WEISS: Do you recall back 20 or 30 years ago when Paul Turkeltaub sort of designed this protocol for the measurements, did he have some of these unusual sort of curves that you showed where it goes up and down?

DR. SLATER: Oh yes. But when these original studies were done, those study subjects were excluded out of hand because they didn't actually meet the -- we were trying to look for a way to include as many subjects as we could. Those individuals, for instance Dr. Eggleston had been part of an earlier study in the 1990s, an ideal study. And one of the things that he said was they ended up excluding more than half of the subjects after they were skin tested because of just this. And we were looking for ways, statistically valid ways that we could include as many of the subjects as possible.

Remember those rules that I gave you before, that it had to be uniformly increasing skin test responses, two on either side of 50 millimeters. Many of those subjects would have just been excluded out of hand. And using the regression analysis was not very satisfying either, because the regression curves that you would get, while they would be valid best fit linear regression curves, didn't seem to make much sense in terms of what was going on. You're absolutely right. Mr. Hauck.

MR. HAUCK: Jay, did you analyze the puncture testing results? Were there any subjects that you included that were skin test, puncture test positive to one extract and negative to the other two? Did they, all three, puncture test positive?

DR. SLATER: We did have a preconceived notion from our prior testing that extract B was going to be the most potent, and extract A was going to be the least potent, simply from our in vitro testing. So we picked extract C, the intermediate potency one, as our screening test. We did not screen for all three. We only screened for one of them. I was afraid that if we screened for the most potent one, we would have a lot of flat lines for the other two. So we picked the intermediate one.

We also went back and analyzed at great length how we could have done the puncture testing better so that we wouldn't get hyporesponsive study subjects. And we had several of them who just had no responses at all. And we went back, we looked over their puncture tests. There was no way we could have picked these people out. It was almost as though the screen test was unrelated to how they ultimately did on the IV testing. It was very surprising.

DR. MACDONALD: Jay, in general, what is the incidence of a puncture positive/skin test negative in other extracts? Do you know?

DR. SLATER: I don't know the answer. Dr. Portnoy?

DR. PORTNOY: Did you ever in any of these patients who had the strange up and down pattern, did you ever repeat that to see how reproducible the curves were in individual patients? I mean, are these reproducible or are they just different each time they happen?

DR. SLATER: That's a great idea. I don't think anybody in the study even conceived of the notion of asking somebody to come back and do this again. But it would be a very good thing to do. We just didn't do it.

DR. PORTNOY: And any idea why there were differences in the potencies of these extracts? Is it the way they were manufactured, or do you have any clue about specific processes that are used to produce extracts that affect the potency?

DR. SLATER: Well, extract B was started with a different source material. And so that's one thing that we are looking into. But aside from that, I don't really see much in the way of clues. I do think that source material, you know it's an obvious statement, but I think source material is very important. And I think that it's one of the things that we need to look at as we move along with this. Dr. Berger?

DR. BERGER: So, in keeping with Jay's last question and your answer, do you think that the presence of glycerol in extract B made a difference? Do you have any way to look at that?

DR. SLATER: So you picked up on that? Yes, what Dr. Berger's referring to is that in extract B the glycerol was actually in the extracting solution, whereas in extracts A and C the glycerol was added after the extraction was completed. It may in fact be a real difference for this particular extract. I don't know that it's been shown to make a difference for other extracts.

DR. BERGER: Another question, which you could determine with the same kind of assays, which may have implications for the use of these subsequently in immunotherapy. Have you done any studies of concentrating the extract, say by ultra-filtration or lyopholization, or something like that?

DR. SLATER: We have not. We have not done that.

DR. BERGER: So it would be very interesting to take a concentrated extract tenfold.

DR. SLATER: Yes.

DR. BERGER: And then see if you got a tenfold higher reading from your method. That would also be a --

DR. SLATER: Yes. It would be very interesting. You should remember, though, that cockroach is one of the extracts that is fairly protease-rich. And so it's certainly possible that as we concentrate it, we're going to cause more degradation to occur. I don't know how to handle that.

DR. BERGER: If you would come to the microphone and identify yourself, please.

MR. THOMAS: I'm Mark Thomas. I'm with Antigen Laboratories. We have an in-house study, which shows that products -- this is relating back to the biological activity of the product and source material when it's extracted. Products that are extracted in the glycerin solution have a higher biological activity than products that are extracted in saline. So that may play into that glycerin response there.

The other thing, back to this doctor here's response on the wheal and the flare. Studies show that you find histamine in the tissue in the wheal, but you don't find histamine out in the erythema. Which would indicate that you don't have mass cell degranulation occurring out in the erythema, but you do have it occurring in the wheal. So I think that really both things need to be maybe addressed, or included, I don't know. But in my opinion, or at least it's my understanding you get a better response, a true allergic response, with mass cell degranulation and histamine release from the size of the wheal than you do from the erythema.

DR. SLATER: Thank you.

MR. THOMAS: Thank you.

DR. SLATER: Thank you.

DR. RABIN: Well, I should introduce myself. I'm Ron Rabin. I'm a senior staff fellow in the Laboratory of Immunobiochemistry. As I think most of you know, we in CBER are privileged to have some time to be able to devote some of our time to basic research. We do have active research projects in the laboratory, and I'm going to give you a brief overview of what we have going on, telling you a little bit about what -- just running by quickly what Jay is doing. And then I'm going to give you an overview on the two projects that I have currently ongoing.

So, these two projects that I have ongoing are the role of the multidrug resistance proteins in T cell activation, regulation of T cell responses by the respiratory syncytial virus. Jay has already told you about cockroach allergen standardization, and he's discussed some of these issues. And then I think last year he discussed the issue of endotoxin and allergen vaccines.

We've had a few publications out of the lab, a couple in which our collaborative efforts of Dr. Chi, my fellow, and myself with Peter Collins, and one with my old laboratory which is now in PNAS. And then we've got a manuscript that should be submitted within the next couple of weeks that I'll be discussing with you. We've got a number of review articles. Jay, three papers on recombinant allergens, allergen characterization and such. One review on RSV, and its role perhaps as a predisposing factor for the development of asthma and allergy, and then one that I have in preparation with Dr. Arnold Levinson and Dr. Andrea Apter at University of Pennsylvania where we're reviewing the coincidence of autoimmune allergic diseases both in epidemiologic and mechanistic analyses.

We have been active as far as our participation in meetings and such, most recently at the American Academy of Allergy, Asthma and Immunology with a number of posters. I presented some work regarding the regulatory process of human studies at last year's AAAAI meeting, and will be discussing the issue of standardization of recombinant and modified allergens at the Paul-Ehrlich Seminar in Germany this coming October. Jay discussed of course his expertise on latex allergy, allergen immunotherapy, and allergen identification at last month's meeting.

We both have a number of outside active collaborations, only of which a few are listed. But Larry Arlian, Jay is working with Dr. Arlian on some of his studies, and Dr. Patrick Murray on his endotoxin study, and with Dr. Nelson on some standardization studies in conjunction with the Immunotherapy Committee of the American Academy. My RSV work, I'm privileged to work with Dr. Peter Collins who's a molecular biologist who's really done the bulk work of molecular biology and vaccine work with RSV. And Dr. Mario Roederer at the Vaccine Research Center who is a longtime collaborator and a friend of mine from our days back at Stanford.

My work, from my days back at Stanford, go back to looking at T cells. And while the relevance of T cells are not immediately apparent to a regulatory body that looks at allergen standardization, in fact T cells of course are allergen responsive and secrete cytokines that are involved in the allergic response, and allergen immunotherapy does work by modifying T cell responses. And so novel approaches towards modifying T cell responses may provide novel therapeutics for treatment of allergic diseases and asthma. And the link between respiratory viral infections and wheezing is mediated at least in part by T cells. And so understanding the T cell responses to respiratory viruses will provide insight into the mechanisms of allergy and asthma.

And so this is what I study. And what I'm going to discuss with you then very briefly is an overview of my two research projects, first looking at novel approaches towards modifying the T cell responses that might provide novel therapeutics for treatment of allergic diseases and asthma. And this study actually arose out of a serendipitous observation that I made. When I was at NIAID and I was studying chemokine responses by flow cytometry, and I have a background in flow from my days back in the Herzenberg lab at Stanford. And we published a few papers looking at calcium responses to chemokines by flow. And we were basically looking at some patients in a cohort of subjects with Wegener's granulomatosis, and their response to chemokines by flow cytometry.

And I just happened to really notice that these subjects with this inflammatory disease, their cells had less of the calcium probe. Now, this is a fluorescent probe that is -- and all that you really need to know about it for this particular purpose is that once it's in the cells it's an anion, and it's exported actively by the cells. And the idea here in my little cartoon is simply that the slope of this probe is actually indicative of the amount of calcium that's in a cell. And that wasn't any different between the normal controls and the subjects with the inflammatory disease, with Wegener's. What was different was just simply the amount of probe that they had in the cell. So I wondered, you know, a number of years ago, whether or not these people who are known to be in an inflammatory state, whether this might affect the probe concentration, and that the probe concentration would affect gene expression of a probe transporter, and does this probe transporter then perhaps modulate activation of inflammatory cells.

And that brought me to the multidrug resistance family. Now of course these are proteins that are well studied by people in cancer chemotherapy, in the field of cancer biology, because they're proteins that transport substances across cellular membranes, across a concentration gradient in an energy dependent manner. They're often referred to as ABC proteins because they have ATP binding cassettes that contain a distinctive nucleotide binding domains. The genes are highly conserved across species. The first member and the best known is MDR1, which is also referred to as P-glycoprotein. And its best substrates are large, hydrophobic cations. But another protein that's been studied quite a lot lately is what's called the MDR-associated resistant protein, or MRP1, which was first described in 1992. And its substrates are organic anions. And also, it certainly has a known physiologic role in that it exports glutathione, glucuronide, and sulfate conjugates, and it is the mechanism by which cells export leukotriene C4, a mediator that's known to have a role in many inflammatory diseases, and most certainly asthma.

And so the first thing that we did was we just looked at members of the MDR family gene expression in T cells and sorted T cells, CD4 nave and memory cells, CD8 nave and memory cells, and then other lymphocyte mononuclear subsets. And what we found through this 35 cycle RT-PCR is that MDR is at MRP1, is expressed preferentially in memory cells, okay? And in fact, it's really when you look at a true naive subset, that is, cord blood cells, you don't see any MRP1, and after three days of activation you see quite a bit of expression. You can contrast that with MRP3. That's really not expressed very much. And then in any of these cells, and for that matter I think it's MRP5 -- it's not shown here -- is expressed pretty much equivalently.

So we saw really all possible combinations, but MRP1 had a provocative pattern that suggested it was worth looking at a little bit more. And what I'm not showing you here for the interests of time is that we looked at activation and rest, just with some in vitro protocols using cytokines such as IL-7, and could demonstrate that we bring the gene expression of the transporter does fall down when you bring the cells to rest, and rise again when you activate them. So there is a small molecule inhibitor. There are no real good monoclonals, unfortunately, that either for detection or for neutralization studies. But there is this small molecule inhibitor called MK-571, which at micromolar levels does block MRP1 activity. It's known to do that.

And here we stimulated PBMCs with the superantigen TSST-1 at 10 nanograms per ml, and you could see that cells after an overnight stimulation take on a typical morphologic appearance of aggregates. And here in the presence of the MK-571 they don't.

And when we look at expression of an activation marker, CD69, now we're looking -- we've stained the cells for V beta 2, which are the T cell receptor, which TSST-1 pretty much selectively stimulates. You could see that in the absence of the small molecule inhibitor, almost all the V beta 2 cells expressed CD69, and a percentage of those are expressing interfering gamma, and this is completely blocked with the inhibitor.

This blockade is dose-dependent, and so works with all the inflammatory cytokines so far that we've looked at. So here on this intracellular staining we have interleukins-4 and interferon gamma on the X axis. These cells were stimulated by a combination of superantigens so that we could get the number of IL4-expressing cells up to something we could interpret reasonably well. And you could see that this number falls nicely in a dose-dependent manner as one would expect. And in fact, if we look at cytokines that are secreted in supernatants, we see the same sort of thing. Whether we look at interferon gamma, IL-10, IL-2, TNF.

What again I'm not showing you is that we have looked at viability assays to ensure that we weren't simply killing the cells, and certainly at levels below 75 micrograms per ml the viability of cells that are treated with MK-571 is no different from cells that were stimulated with a combination of superantigens alone. We also looked at time dependency studies and demonstrated that the blockade has to occur either before or simultaneous with the activation of the cells. It doesn't work after that.

So what this manuscript has basically been waiting for is some issues of mechanism. And to just clean it up. And our current hypothesis, our current model is that by blocking the receptor, what we're doing is we're increasing -- or blocking the pump, I'm sorry, the MRP1 pump, what we're doing is we're increasing an endogenous ligand for PPAR-gamma. PPAR-gamma, for those of you who are not familiar with it, is a transcriptional repressor. It does have some known ligands, endogenous ligands, prostaglandin J2. It has a known synthetic ligand ciglitazone. And so what we're doing is we've got -- the studies that we have that are looking at this are twofold. One, we're doing some EMSAs, and this was done with luciferase and it's really -- the quality isn't very good and we've bitten the bullet and gone to the radioactive studies. And we should have the answer by next week as to whether or not this is real. But at least on these studies, with these Jurkat cells that were stimulated with PHA in the absence of MK-571, we do see an increase in PPAR in retardation of the probe due to presumably to binding of activated PPAR. And so we think that this is a reasonable model that we have.

Now, with regard to actually trying to determine what's going on in the cells, we are making cell extracts. And we are fortunate in CBER to have Robert Boykins who is really quite the expert on chromatography and mass spec. And we have found certainly leukotriene C4 within these extracts. And at least on only one study we've found some interesting peaks as well in some of these inhibitory cells, or one interesting peak that one can at least at this point I guess fantasize might be a novel agonist for PPAR-gamma. And so that's where we are with this.

And so, what I've shown you here is that using the small molecule inhibitor, we've blocked T cell activation. It doesn't decrease the viability. It doesn't weaken -- I've also not shown you, we can wash out the MK-571 and we reverse the inhibition. And we believe that it is activating the transcriptional receptor PPAR-gamma, and we think that there are endogenous ligands. And by determining what those endogenous ligands are, we might be able to propose molecular mimics of PPAR-gamma that may be viable therapeutics for inflammatory diseases such as asthma and allergy.

The second project that we have going on that is primarily the work of Dr. Bo Chi who is here today is the link between viral respiratory infections and wheezing. This link is mediated at least in part, and perhaps to a great part by T cells. And so again, understanding these T cell responses would be important. Now, this is, as the review paper in process, as I discuss in that, this link is at least, again at least in part, I'm sure determined by the genetic background of the individuals. And one thing that's particularly interesting in this regard is that although this is characterized much better with asthma than with severe RSV, but when gene linkages are looked at, there's some overlap in IL-4 genes, IL-4 receptor genes, and in toll-like receptor genes in polymorphisms that predispose to both asthma and to severe RSV. And these may, at least again in part, provide some explanation as to the documented observations that infants who are severely infected with RSV have a higher incidence of asthma.

Now, there are a number of studies that have looked at cytokine responses and responses of T cells to RSV of course. And most of these, almost all of these have looked at responses to killed virus in in vitro cultures. And part of the reason for that is because you can't really use the live virus because the live virus has been -- it's been known now for over 20 years that RSV depresses proliferation of these cells to itself or to any other stimuli, and it also depresses cytokine responses. And while there have been a number of explanations in the literature as to why this might occur, none of them have really stood the test of time. And so Bo really wanted to look at this in detail with the idea that if we could determine what's going on here we would, number one, solve a question that may very well be important in the field, may very well provide important information for the design of vaccines, and for that matter might allow us to look a little bit better than what currently has been done at in vitro responses. Once we can determine what's going on and what can block it, and how we might be able to block it. So the published data have implicated various cytokines and inhibitors, but most really, as I say, haven't stood the test of time.

And part of the issue, at least from my standpoint, was that there really -- the experimental models that have been using have been pretty complicated. To put it into the context -- to analogize it, I guess, to high school algebra, there's one equation with more variables, with three or four variables. So we needed to cut down the number of variables so that we could solve the equation appropriately.

And so what we did was we decided instead of just using PBMCs, the mishmash to use monocyte-derived dendritic cells and to expose them to RSV, add purified lymphocytes which then would be stimulated with SEB, and look at tritiated thymidine. And that's where we started, and in this particular case, just to demonstrate that this particular design worked, here's tritiated thymidine with SEB alone. Here's flu when we added that. That increased tritiated thymidine. Not a big surprise. Parainfluenza decreased it some, and RSV decreased it even more. If we used CMV rather than SEV you would see the same sort of thing except here the RSV would block it pretty much completely, and RSV of course, this is just the response to either nothing, the flu, parainfluenza, or RSV. You can see there's just nothing happening there.

So the first question that we had was of course lymphocytes themselves are a mixed population of cells. And there were some reports that suggested that CD8 T cells were critical, and K cells are critical. And so what she did was she isolated CD4 T cells from this mix to ask the question of whether or not we could just limit this to these two cell types, monocyte-derived dendritic cells and CD4 T cells. And in fact you could. Here's the response with all the lymphocytes, and there's the blockade of proliferation, and here it is with CD4 T cells only. And you could see very nicely that we've blocked the proliferation. And so the CD4 T cells and dendritic cells are sufficient for the suppression of proliferation.

And that brought up the question, since it's only the dendritic cells that are being exposed to the RSV are they being productively infected by RSV? And again, fortunately, through our collaboration with Peter Collins, we have use of this green fluorescent protein expressing RSV, and we could demonstrate, yes, there is productive infection of the RSV within the dendritic cells. And it's probably about 10 percent or so, if you look at, there's that cell there, which is probably that guy there. But it's not an overwhelming number, but it's about 10 percent of the cells are productively infected.

Now, to really simplify the model even further, one particular issue that people have been asking is whether or not this suppression is contact-dependent. And in certain models it has been published that it is contact-dependent. We asked whether or not it could be transferred in the supernatant. And so here, Bo took the monocyte-derived dendritic cells, exposed them to RSV, took the supernatant, added it to CD4. Now, in our hands, using the SEB from sigma, the CD4, purified CD4 T cells will proliferate just fine on their own. It's probably because the SEB's a little messy, but we've taken advantage of that at least because it just simplifies things even further.

And the answer is clearly yes. Here it is. Here's the soup with RSV and we've inhibited proliferation quite nicely in these I guess five subjects here. There's the control. In this particular set of studies there's a little bit of decrease of proliferation if the RSV is killed with UV light. But in fact, we've gone on and done a number more of these studies, and this has not held true. Which is what we would expect.

So we've gone ahead and we've looked at a number of different cytokines. We think that we have a pretty good idea of what's going on here. But the results are still preliminary, and I'd be happy during the break to discuss this with anyone who's interested. But for right now what I'm sharing with you is that we've simplified this experimental system so that we could look and see exactly what's responsible for this immunosuppressive activity, and we can demonstrate that it can be transferred in supernatants. And so now we've really simplified the model, and we should be able to determine, at least with this experimental system, what's causing this inhibition of proliferation. And by blocking it, then we'll be able to have a bit of a novel approach to looking at responses, in vitro responses, to live virus, not only in human and not only in adult cells, but fortunately a colleague of mine who works at Navy, a pathologist for whom I was getting some tonsils, fresh tonsil specimens from a number of years ago, is returning, and so we'll be able to look at T cells from children as well, and to look and see what these differences, and what these responses are.

I just want to acknowledge a few people. Jinsong Zhang is the postdoc who's working on the MRP study. Hui Huang actually started that study, and then went off to do a clinical fellowship. Bo is working on the RSV study. Marc Alston is "Super Tech." He has really worked on both studies, and helped with really a lot of this work, and been able to shift back and forth from either project as he's needed. Of course, it's all been done with the help of Jay Slater, and Peter Collins is an invaluable collaborator, and Mario Roederer and Steve Perfetto have helped as well.

And I think that is it, and I can take any questions.

DR. WILLS-KARP: Very nice, very interesting study. On the RSV, have you looked in sections from humans or animals to see if dendritic cells actually are infected with RSV?

DR. RABIN: No, not with the animals. We started doing some studies with tonsils, actually with the green fluorescent protein. And Bo started working on that and it became a little too unwieldy for her.

And the bottom line is preliminarily it looks like that they are, okay? It looks like what we saw was that we took the tonsils and what we did was we would cut them such that we could use the epithelial surface of the tonsils. And you would see that the epithelial cells of the tonsils, and then we'd drop some RSV on it, would be infected, would turn green. And we think we saw some dendritic cells beneath the surface that would be infected with the RSV as well. Now, we just started that, and then we, you know, focusing is always an issue, and so we're hoping to go back to that once --

DR. WILLS-KARP: Well it'd be curious, as I think that the epithelium are going to be the cells that are going to be primarily infected, to see if they have a similar effect.

DR. RABIN: Of course.

DR. WILLS-KARP: Can you collect some immunosuppressive compound from RSV-infected epithelial cells that may be similar to --

DR. RABIN: Oh. Yes, that would be interesting to do that. I guess -- yes. Yes, sure. Sure. Sure. I think that as we're getting a handle on what it is, we can know what to look for, which would even be better.

DR. MACDONALD: If it is true that the dendritic cells are infected, they're a potent source of the interferons, particularly interferon-alpha. Have you tried inhibiting the effect with an antibody?

DR. RABIN: Yes. Yes, we have. We've inhibited the effect of the interferon-alpha receptor, and we get -- in some of the studies we get a little bit of a partial reverse. And we think that's part of the story, but not the complete story.

DR. BERGER: Do you think there's a connection by which the dendritic cell either by contact or by the dendritic cell supernatant might actually induce wheezing?

DR. RABIN: No. No, I don't. What I think that the dendritic cell does -- what I think that the virus does, is I think that the virus exploits the immature immune system of children, that is basically a Th2, you know, a Type 2 weighted system. I'm sure you're familiar with the work of Patrick Holt and so on.

And I think that the way in which the virus exploits this is twofold. One, you have these genetic linkages that are overlapping. And the other is that I suspect that this -- or at least I hypothesize that this immunosuppression is -- what it's going to be doing, I mean for example, it's known that there's a blockade of interferon-alpha by RSV. We do see some interferon-alpha in the soups. We do reverse it some. But it's known that the non-structural proteins of RSV block interferon-alpha synthesis in response to RSV. It's known that RSV blocks interferon-alpha signaling. And so I suspect that RSV, by causing this immunosuppression, allows basically the immune system to respond to what is a phenotype of wheezing, and more important for the virus --

DR. BERGER: Kind of the innate setting --

DR. RABIN: Yes, exactly. And you know, because it's -- the virus, I don't know that the virus cares one way or the other about wheezing, but as we all know, people who wheeze cough, and the virus certainly cares about that.

DR. WILLS-KARP: One last question in that regard. Does the RSV infection have any influence on the type of dendritic cells?

DR. RABIN: Well, you know --

DR. WILLS-KARP: You can't tell that in the studies.

DR. RABIN: We're using the monocyte-derived dendritic cells. The published data demonstrated that as one might expect, the plasmacytoid dendritic cells make more of the interferons than the monocyte-derived dendritic cells. As I'm sure you're aware of the studies of John O'Shea and Christine Byron, you can make the myeloid dendritic cells into -- you know, they can behave as high interferon-alpha, interferon secretors. I think that your question is going to be most prescient in human studies or in mouse studies once we know what we're looking for. We can look in tissue, you know, and we can look for it. Now, obviously, even though the interferons are responsible, you see interferons all over the place with all kinds of viruses, and yet this is the only one that causes secretions. So clearly it's playing a role, but its presence alone is not the role.

DR. MACDONALD: Just to follow up on Marsha's question, have you actually tried plasmacytoid dendritic cells? I mean they're pretty easy to isolate with the BDCA antibody?

DR. RABIN: No, it's been published. As far as the interferons are concerned, it's been published. And you know -- again, I think once we -- I'm becoming -- this has been a little bit of a high-risk project. And I'm becoming a little bit optimistic now that we're going to solve this question. And I think once we solve this question, we know exactly what we're looking for, then we can look for it. And we can look for it in plasmacytoid dendritic cells, we can look for it. But rather than looking for simply an in vitro activity of inhibiting thymidine incorporation, which is fraught with all the difficulties of the misery of doing something like that, we can look for what it is we're interested in. Thank you.

DR. BERGER: Okay. So I think that our speakers from the FDA have been very good about preparing concise presentations, and we've all been very good boys and girls about keeping within the designated time for discussion. So we're actually a little ahead of schedule. And I would propose that we take a 20-minute break and be back at 10:30 for the discussion of reclassification. Thank you.

(Whereupon, the above-entitled matter went off the record at 10:10 a.m. and went back on the record at 10:37 a.m.)

DR. BERGER: Okay, if we could take our seats, please.

DR. SLATER: Okay. Welcome back. What we're going to talk about for the next 45 minutes or so is the reclassification of the IIIA allergenic products. And a good portion of this presentation is going to be history, because this is a history that certainly before I came to the Agency I had not been aware of, and I would not expect anyone in the room to have more than a passing awareness of what I'm going to talk about at the moment.

So I am going to be talking about the history of allergy and allergy treatment very briefly. I will then focus more on the history of allergen extract regulation, both before the FDA took over the process and since. And then what I'm going to finish with is a description of our task, meaning at the FDA, which is the completion of a process that the FDA began back in 1972 for the classification of allergenic products.

Very briefly, it was in 1819 that Dr. John Bostock first accurately described hay fever as a disease affecting the upper respiratory tract. It wasn't until 1869 that the first skin testing was done. Dr. Charles Blakely, investigating his own hay fever, performs the first skin test by applying pollen through a small break in the skin. He first introduced the concept that pollen caused hay fever. And it was in 1911 that Noon and Freeman made sterile extracts of pollens and demonstrated that repeated injections improved the clinical tolerance to allergen exposure, establishing for the first time the basis of allergen extract immunotherapy.

They used aqueous extracts. The first aqueous extracts actually had been made by Curtis in 1900. And finally Noon and Freeman's observations, the first systematic investigations on extraction methods were made by Wodehouse and Walker in 1917, and by Caulker in a series of papers in the 1920s.

In the early days, allergists, physicians, prepared their own extracts in their own offices for their own patients' uses. But eventually, not surprisingly, physicians began to prepare extracts from others. And as late as 1953, a textbook, A Manual for Clinical Allergy by Sheldon, et al, contains 30 pages of instructions on how to produce your own allergen extracts. Before this, though, the practice had clearly evolved to independent laboratories preparing extracts, and laboratories evolved into licensed manufacturers, the first license having been issued in the 1920s. So this is an allergen extract timeline that I'm going to use to orient us a little bit, and you can see the first two entries are the first extracts in the 1900s, and the appearance of manufacturers in the 1920s.

What I'm now going to shift to is a very bare bones description of allergen extract regulation. And the first regulation that's important is the Biologics Control Act of 1902. As often happens in this history, acts of Congress are preceded by catastrophes of one sort or another. The catastrophe in this case was in 1901, 13 children in St. Louis died after receiving diphtheria antitoxin that had been contaminated with tetanus spores. This spurred Congress into passing the Biologics Control Act, which put the control of biologics into the hands of the hygienic laboratory at the Public Health and Marine Service Hospital, which is the direct predecessor of the National Institute of Health, subsequently the National Institutes of Health.

In parallel, other catastrophes, scandals about poisonous preservatives that were being added to drugs, scandals in the meatpacking industry, Upton Sinclair published "The Jungle" in 1906 which spurred a great outcry, Congress passed the Food and Drugs Act of 1906. In the interim, the Food and Drug Administration was established in the 19-teens. The FDA then pushed Congress to pass a more aggressive act, the Food, Drug and Cosmetic Act of 1938, which was immediately preceded by the catastrophe of 1937 in which 107 people were killed after taking sulfanilamide that had been contaminated with diethylene glycol.

What's important to note here is that the regulation of biologics remained under the control of the Biologics Control Act of 1902, and ultimately under the Public Health Service Act of 1944, in the hands of not the FDA, but the NIH, initially through the Hygienic Laboratory, the National Institute of Health. From 1955 to 1972, NIH had a dedicated unit, the Division of Biologics Standards that regulated all biological products. It was in 1972 that the regulation of biologics transferred to the FDA, and the Bureau of Biologics became the part of the Agency that regulated biological products. Subsequently it was supplanted by the Center for Drugs and Biologics, and then the Center for Biologics, which is where it is today.

The reason 1972 is a very important date is that within just a few months, almost immediately the FDA began a comprehensive review of those products for which it had just assumed responsibility. Now what I'm going to talk about for the next few slides in fact was a review that involved all of biological products. But we are just going to focus on the allergenic products from this time forward.

The FDA convened a series of classification panels, which were covered by Regulation 601.25. And the purpose of these panels was to review biological products that had been licensed prior to July 1, 1972, that they are safe and effective, and not misbranded. This language straight, "safe and effective and not misbranded," from the Food, Drug and Cosmetics Act. So in other words, the purpose of these panels was to look over the existing biologics for which the FDA had taken responsibility to see if they met the requirements of the Food, Drug and Cosmetics Act. In the context of this review for allergenics, data was requested from manufacturers in two Federal Register notices in 1974. And the Allergenic Products Panel met from May 1974 through August 1979. They submitted their report in March 1981, and that report was published in the Federal Register in January 1985.

That report, that over 200 pages of report was actually sent to the advisory committee members, and I'm sure they all enjoyed reading it. But what's important to note is that this report is huge. It's 200 pages of very small print. It involved a tremendous amount of work by these individuals. And it's actually, at its heart, a tremendously scholarly and yet at the same time very practical piece of work that because it was published in the Federal Register notice nobody ever gets to read except for you lucky folks who are going to have the opportunity to do that now if you wish to.

So on our timeline, the classification panel met from '74 to '79, and it met under the Regulation 601.25. Now who were these people on the panel? This was a very illustrious group. Dr. Paul Seebohm from University of Iowa. Dr. Elliot Ellis from SUNY-Buffalo. Dr. Ralph Hale from University of Kansas School of Medicine. Dr. David Levy from Johns Hopkins. Dr. Frank Perlman from University of Oregon School of Medicine. Dr. Robert Reisman, also from SUNY-Buffalo. And Dr. Thomas Van Metre, also from Johns Hopkins. Max Samter was a distinguished consultant for the committee as well. Dr. Frank Perlman's membership actually ended in 1978 with an illness and with his death in 1979, but he was an active contributor to the entire process, and certainly had an important role in the process involved over the previous several years. Their task was daunting. Their job was to review over 1500 extracted substances with the goal of evaluating safety and efficacy in accordance with 601.25 which we'll talk about very shortly. Their job was also to review labeling and to submit a report on their conclusions and recommendations.

So what are the standards for safety and efficacy? And these standards were set out in 601.25. The standard for safety first. Obviously that the product be relatively free from harmful effect. And the proof shall consist of adequate tests by methods reasonably applicable, including the results of significant human experience. So for safety purposes, the panels were also being given the opportunity to look at human experience in the aggregate and make a decision as to whether the products were safe under 601.25.

What about efficacy? Efficacy was defined as a reasonable expectation that the biological product will serve a clinically significant function in the diagnosis or treatment of disease. Proof shall consist of a controlled clinical investigation, unless this requirement is waived, and it can be waived for a number of reasons. It can be waived because it's just not reasonably applicable, or it's not essential to the investigation, and -- and this is important -- that there are alternative methods of investigation that are adequate to substantiate effectiveness. So the panel was charged with the responsibility of determining that there was affirmative evidence of efficacy for each of these 1500 products.

601.25 also demanded that the panels classify each of the allergenic products into one of these products. Category I products are safe, effective, and not misbranded. Category II products are either unsafe, or ineffective, or are misbranded. And category III products are those for whom the data is insufficient for classification. Now within category III there are two different groups. One is the category IIIA, which are thought to have a favorable risk/benefit ratio, and were allowed to remain on the market pending completion of testing. And category IIIB were those products that were thought to have an unfavorable risk/benefit ratio, and were removed from the market pending completion of testing.

So, armed with these definitions and these requirements, the panel went to work. And the panel then went about deciding how they were going to evaluate the evidence that they were presented with for immunotherapy. I should preface this by saying the panel immediately realized that they in fact had not 1500 reviews to do, they had 3,000 reviews to do. Because for each product they had to decide whether it was safe, effective, and not misbranded for the purpose of diagnosis, and also safe, effective, and not misbranded for the purpose of immunotherapy. So these were actually two separate parallel evaluations.

For the purpose of immunotherapy, they set standards for deciding whether the evidence was either conclusive, acceptable, circumstantial, or insufficient. And let's go through each of those. Well, conclusive evidence is pretty much what you would expect conclusive evidence to be today, I would think. Evidence that the product is effective in skin test diagnosis, and that there's a placebo-controlled trial demonstrating reduction in symptoms, and that there is in vitro evidence that the changes that you're observing are in fact biological.

What would be acceptable evidence? Well, the acceptable evidence is basically the conclusive evidence without the placebo-controlled trial. It has to be effective in skin test diagnosis, and instead of a placebo-controlled trial there has to be long experience suggesting a reduction in symptoms. But we do have to have some in vitro changes that suggest that this is a biological effect. That's acceptable evidence. Circumstantial evidence is acceptable evidence minus the in vitro changes. Effective in skin test diagnosis, and long experience suggests a reduction in symptoms, but nothing further. Insufficient evidence is either it's not effective in skin test diagnosis, the reduction in symptoms is only anecdotal and no in vitro change have been demonstrated.

Applying those evidence standards, then, to the categories that 601.25 requires, the panel drew the following lines. Obviously something for which there was conclusive evidence could go into category I. But the panel also allowed products with acceptable evidence to go into category I if there was widespread acceptance and use, the clinical syndrome was well documented, the in vitro changes that were shown were favorable (in other words, there was really strong in vitro evidence), there had been systematic observations for possible adverse events, and the natural history was understood. So in other words, remember the difference between conclusive and acceptable evidence. The acceptable evidence didn't have the placebo-controlled trials. What the panel was basically saying was they were willing to pass on the absence of placebo-controlled trials if the other stuff was really very convincing. These were products that went into category I. Safe, effective, and not misbranded.

Who went into category IIIA? Well, category IIIA remember is data insufficient for classification, but it was a favorable risk/benefit ratio and was allowed to stay on the market. Those are products with acceptable evidence, which is pretty strong, or circumstantial evidence. In other words, products that only had acceptable or circumstantial evidence, but remember acceptable without the widespread use, the really powerful evidence, were put into category IIIA, which meant the panel wanted to see more, but that pending seeing more, the panel would allow the product to stay on the market.

Category IIIB, insufficient data, not staying on the market, would be products that were either insufficient evidence. And they could go into category II straightaway, depending on the strength of the data, the lack of safety, and the risk/benefit ratio.

So what did the panel actually do? Well, the panel actually made lists. They made lists of the products, and every product was put into category I, II, IIIA or IIIB for diagnosis and for therapy purposes. But they went beyond that. They also made recommendations about manufacturing principles. They made recommendations about the studies that they wanted to see on the IIIA products. And they made a very strong endorsement to the idea of allergen standardization and how that should be done. We're just going to focus a little bit more on the studies that they recommended for the IIIA products.

And again, the recommendations that they made were exactly the recommendations that I think you would all make if you were in their shoes. They wanted to see good collaborative studies. They allowed inference among related allergens. This is an important principle. If one allergen clearly works, and we know that the other allergen's closely related to it, they certainly permitted inference among related allergens. Obviously they wanted FDA approval for all the studies. They thought there ought to be separate protocols for diagnosis and for therapy. And they admitted that for some of the extracts, the requirements could be modified, and certainly they left the door open of accepting powerful in vitro data in some cases.

Now, when this report came out, it included not only the panel's recommendation but the FDA staff's responses to their recommendations. And one of the responses was in shorthand terms the IIIA recommendations have now been superseded by another rule, which was 601.26, which we'll talk about in just a minute. Basically what happened was that FDA decided that it was no longer appropriate to put products in IIIA, that it was the Agency's responsibility to come to a decision about these products, and that the IIIA products would have to be reclassified.

So, just to review where we are, the panel completed its job in 1979, submitted its report in 1981. The report was published in 1985. As a consequence of their report, the category II and the category IIIB products were removed from the market, and category I and category IIIA products remained. And we are now for the rest of this endeavor going to focus on the category IIIA products. The category I products, safe, effective, and not misbranded, and are not subject for further discussion at this time.

So where are we in terms of today's presentation? We've covered most of the ground. We are now up to talking about 21 C.F.R. 601.26. 21 C.F.R. 601.26 called for reclassification panels to be convened. And their job was to take all the IIIA products and reclassify them as category I or category II. Now, I didn't go through a listing of what the first panel did, but it won't surprise you to learn that most products ended up in category IIIA. That it was the original panel's conclusion that the evidence was not strong enough to put most of the products into category I. Most of them ended up in IIIA. So the reclassification panel needed to look at the IIIA products and reclassify them as I or II. This panel met from November 1982 to June 1983, put together their report in December 1983.

And that panel had several members who were the same, Dr. Seebohm, Dr. Ellis, Dr. Hale, Dr. Levy and Dr. Van Metre were now joined by Dr. Clifton Furukowa and Dr. Floyd Malveaux. And their job was to review all the IIIA products. What were their recommendations? Well, for diagnosis, for the most part, the IIIA products were recommended to be reclassified as category I. There were certain exceptions, and I'm not going to go through all of them. Certain molds, pollens, avian/mammalians, and inhalants were recommended for reclassification into category II. Most importantly, the panel reemphasized what the first panel had pointed out, that they thought that no products should really be approved unless they actually had genus and species names associated with them. And that was an important thing that was reemphasized by the reclassification panel in terms of diagnosis.

What about therapy? Most pollen extracts, most mammalian and avian extracts, many mold and insect extracts were actually recommended for reclassification to category I. Species definitions were required, once again. Miscellaneous inhalants, and basically all food extracts were put into category II for immunotherapy, and this based on the lack of evidence of safety certainly at that time for the use of food extracts for immunotherapy.

Well, the panel finished its work in the 1980s. We're now going to fast-forward two decades. Time is passing. Seasons are going by. And the panel's recommendations had not been implemented. But it is now time to turn our attention to this, and to implement what these panels had done with their hard work. Our task at hand is to review the 601.26 reclassification panel's recommendations regarding the IIIA products. It was our feeling that rather than simply implementing their recommendations wholesale, which is one option that's open to us, that it would make the most sense for us to review all the data that's appeared since 1972. Remember, the classification panel reviewed data that appeared up to 1972, and the reclassification panel did not add new data. They simply took what the classification panel had done and made decisions based on what they had. So we have essentially 33 years' worth of subsequent data that we thought we ought to look through before we complete this process. And then, looking at the recommendations, looking at the data that have appeared since then, our next job is to determine the FDA's position on the reclassification panel's recommendations, and go forward from there.

So here is where we are. We are now in this period, where we're at the review and implementation task, reviewing all of the data and implementing the conversion of IIIA products into category I or category II products. So what are we going to do? Well, the first thing that we need to do is we need to establish a provisional process by which these products will be reclassified and implement the process. This has got several parts to it. First of all, collecting the data on the products since 1972 and establishing criteria to be applied when reviewing the data, and then review the data and make decisions. At that point we will need to publish a proposed order in the Federal Register. That will include the FDA's full list of reclassification of the IIIA products. It will also call for a period of public comment after the issuance of this proposed order. And considering the public responses, we will then revise the order as necessary. The last part of the process is to publish a final order in the Federal Register that will include the final classifications and provisions for the revocations of the licenses of those products that were reclassified into category II.

So what is our review process? Well, what's the data that we're going to collect? Obviously Medline is going to be our richest source of material. Our proposal is to look at the English-language literature from 1972 to the present. We also can and will look at all manufacturer's data that have been submitted, or that will have been submitted to this process, any files that have been submitted to the FDA by other interested parties, and we will be looking at Medwatch and the Vaccine Adverse Event Reporting System for evidence of safety problems.

When we look at Medline papers, how will we categorize them? Well, we will look at the study design, whether they're case reports, observational cohorts, case control studies, placebo-controlled trials. We'll be looking at whether the studies are human or animal, what the vehicles are that are used, what the potency tests are that are used, whether these are single lot studies, or whether these are on multiple but identified lots, what the kind of study is, whether it's a diagnostic study using prick, ID, whether it's quantitative data, the form of the immunotherapy studies, the statistical analyses, and the kind of analysis that's actually done on the data.

What are our criteria going to be? And it's important to keep in mind at this point that we are completing a process. We are not starting the process, we are completing a process that was initiated by panel number one in the 1970s, was continued by panel number two. So we are now looking at how to look at this subsequent data, in view of what recommendations were already made. And for that reason, for efficacy, we're simply looking for some uncontradicted evidence that the product works for the purposes that it's being described. And for that purpose we said two or more well described case reports that are uncontradicted. For safety, we want to look at the absence of species-specific serious adverse events reported from any source greater than the case reports. And certainly if we have both adverse events and efficacy, we will consider the risk/benefit ratio in our decision.

Well, what's the rationale for this? We are requiring positive additional data for efficacy. Well described case reports are sufficient. Controlled trials for our purposes are not going to be necessary. And as I'm sure you're all well aware, although there are many controlled efficacy trials for allergen immunotherapy, they have been typically performed only with a few highly prevalent allergens that are extracted. And many, if not most of the allergens that we will be reviewing will never have been addressed in a placebo-controlled trial at all.

For the safety data we consider, at least for our purposes, negative safety data to be sufficient. We know that there is a baseline of adverse events for both skin tests and for immunotherapy. We know that the most potent extracts have higher than baseline adverse events associated with them. We know as well that there are good studies that suggest that most of the adverse event problems have to do with patient and practice risk factors, rather than risk factors associated with the extracts themselves. So unless we see dramatic positive evidence of safety problems, we will not consider any individual extract to have more problems than the average of all allergen extracts have problems, which we know the baseline is certainly there.

This is a big job that we at the FDA are going to be doing. And so one of the important things that our group has been worrying about a great deal is how we're going to keep track of what we're doing and not go back and reinvent the wheel over and over again. So we are going to have an extensive database that we are collecting on this. We've established our report formats. These will include extract names, aliases, groups, the manufacturers, the category according to the first panel, the reclassification category, citation from the original panel report, and then all of the literature that we've retrieved, including our search strategies, will be documented. All of the cited literature is going to be saved in digital format for retrieval by our group. We will certainly be saving all the cited literature as I said, all submitted manufacturer's data, all committee reports, and all committee discussions. If a manufacturer submits proprietary data to us, it will of course be considered proprietary for all purposes.

So, this is a process that we are just about to begin. It is the completion of a review and regulatory process that was started back in 1972. I was in college in 1972. We have approximately 1200 products to review. It will involve extensive documentation of review materials and deliberations. And we will of course be reporting to the advisory committee. Why are we presenting this to the advisory committee? Well, it's an important process. It was an important process 30 years ago and it's an important process now. And it is our job within the FDA to bring this process to completion, but it is one in which we certainly value your suggestions as to how to proceed. We have done a lot of the work, but we haven't done the really hard work which involves the nitty gritty of collecting the data, meeting, talking, and making decisions. And so your recommendations and your thoughts about this process are what we are looking for today. Thank you.

DR. NELSON: Are you going to collect data on the ones that are already classified in I? Or only those that are in III?

DR. SLATER: That's a very good question. No, it is not our intention to look at the category I products. It is not our intention to look at the standardized products. We are focusing our attention on the category IIIA products.

DR. NELSON: Can you give us some idea of just how broad category I is? I mean, is it all the usual pollens and epidermals and such?

DR. SLATER: Right. I'm sorry. Let me restate what I just said. We are not going to focus on the products that were classified as category I by the initial panel. The recommendations of the reclassification panel, which took IIIA products and decided whether they were I or II, that is going to be reviewed by us, because we consider that to be provisional at this point. The recommendations of the original panel, whose report you have, those category I products we will not be reviewing.

And you have that list. It's not very broad. Let me look at some numbers here. For diagnosis, the overwhelming majority of the category I products from the first panel were pollens. And in fact, for diagnosis, most of the pollen extracts, 118 out of 191 were categorized as category I. For therapy, almost no products were categorized as category I. This is in the Federal Register notice that you have. Only four pollens were categorized as category I by the original panel. Those were all pollens. But we will be looking at all of the IIIA products that were reviewed by the second panel. Regardless of what they decided.

DR. NELSON: But you did say that, for instance, cat and the two house dust mites would not be looked at because they're standardized?

DR. SLATER: Right. Standardized products, we are not reviewing the standardized products. There's -- well, they would pass. There's a lot of data on the standardized products, and that would not be an issue. But you're correct, we are not going to do that.

DR. WEISS: Jay, can you just tell us a little bit, the second sort of committee that got together and made some decisions based on the old data, and then the FDA I guess did not implement that. What was the reasoning for the committee to make some decisions and the FDA not to implement it?

DR. SLATER: That's a good question. The implementation -- I'm focusing, and I think you're all correctly focusing on the sort of academic process of going through each product and deciding which one to review in the literature. And that's a very arduous process. The process of implementing the decision, putting together the proposed order, dealing with the comments, putting together a final, that's also a very big process, and it just was not a priority during that interim period. It was something that everyone was fully aware was happening and that needed to be done, but the decision has now been made that it is a priority and we are going to do it.

MR. HAUCK: Just a procedural question. Do you expect your findings, whenever you come up with your findings, would be published in the Federal Register, and there would be a period of time for notice and comment?

DR. SLATER: Yes.

DR. MACDONALD: Jay, this is an enormous project, and I complement the FDA for doing it. I have one comment because of the background coming from Johns Hopkins. Unfortunately we had a sentinel event, and that has changed the way we do clinical research pretty much throughout the country as far as academic clinical studies. This event would not have been -- was not detected in a PubMed search. Unfortunately, it was detected after the fact in a Google search. Since the public has so much access, you might have to reconsider and add a third search to some questions, that being Google, unfortunately. I know that probably adds another umpteen searches, but those are the facts.

DR. SLATER: So you're suggesting that we cast a much wider net on safety issues?

DR. MACDONALD: Judging from the experience that we had at Hopkins, I would say you have to cast a wider net, unfortunately.

DR. SLATER: That's a very good suggestion. Thank you.

DR. NELSON: Just out of curiosity, was anything rejected as being misbranded?

DR. SLATER: Well, I think the misbranding issue probably is more an issue of inadequate labeling. For instance, I think one of the reasons that both panels came down very strongly on the idea that you had to have genus and species designations was to avoid misbranding. And I don't remember any specific instances, but I think that's what both panels were focusing on with the genus and species designations. I'm sure among the 1500 products there were some that were misbranded, but I don't remember.

DR. BERGER: Okay, so at this point I would like to remind the committee that one of our major agenda items for this afternoon is to discuss the process with Jay in the way of advising him on the procedures and this reclassification issue. That's one of our major discussion issues for this afternoon. So at this point I would open the public hearing part of the meeting and invite any members of the public who would like to address the committee to come forward to the microphone.

Okay. So we had received no notice of anyone who wanted to address the committee at this point, and if no one in the audience wants to address the committee at this point, then I would propose that we break for lunch and return at 1 p.m.

Okay, so the suggestion has been that we continue with the discussion at this point, and see how much discussion there is, and that we break at noon rather than now. So that certainly is fine with me. I don't know how other members of the committee feel. I'm seeing nods. So I think we will go ahead and discuss this topic with the members of the FDA.

I would like to once again remind you that our purpose here is just to have an open discussion with the way of helping Dr. Slater and his colleagues to get advice. Our task here is not to make any specific recommendation, and I don't think that they have any specific questions they have asked us to provide recommendations on.

I would like to, since I have the mic open, to sort of follow up with Dr. Macdonald on the issue of the sentinel event at Hopkins. Do you know if a Medwatch report was filed?

DR. MACDONALD: I'm sorry, could you explain what a Medwatch report is?

DR. BERGER: As I understand it, Medwatch is a standard form that's used to report adverse events to the FDA.

DR. MACDONALD: I certainly know that the entire incident was both investigated by the FDA and -- fully -- and the NIH. So I -- without knowing specifically, I can't say specifically, but I would say with 99.9 percent assuredness since the FDA thoroughly investigated this particular event, that a Medwatch must have been.

My point was not to add more work to this committee, but knowing the investigators personally at Hopkins that were involved in this, they really did do their homework, and they presented everything to the IRB, the institutional review board for approval with all of the facts from PubMed. And unfortunately, PubMed didn't have one of the facts that Google had. And that's why I brought it up.

DR. BERGER: I think it's a very important point. And the important -- I am not aware if allergen immunotherapy and extracts that are used for immunotherapy are considered vaccines which are in the VAERS system. But even with the vaccines that are recommended by the Advisory Committee on Immunization Practices, and for which there is a compensation program operated by the government, even then VAERS is a voluntary reporting system, and certainly the use of Medwatch is a voluntary reporting system. And I think that all individuals concerned with reading those reports and evaluating that data commonly expect that there's under-reporting because these are voluntary systems, and not mandatory or comprehensive, and frequently we have no idea what the denominator is when we look at such things. So certainly any other way of bringing adverse experiences and adverse events to our attention would certainly be warranted. You know, the issues of documentation and so forth, then you'll have to deal with on a case-by-case basis.

DR. PORTNOY: I have a couple of questions about the process. First of all, I know that the process is going to look at these different vaccines for any evidence of effectiveness or harm. But does that consider the different routes of administration? Because there's injection, and soon there's going to be sublingual immunotherapy. If it's effective for injection, does that also mean it would be effective for sublingual? If it's not effective for sublingual, then it'll be different? How is that going to be separated or kept track of?

DR. SLATER: I think that for our purposes we will probably look for evidence of immunotherapy by any route. This is not -- one of the subtleties of this that the first panel addressed, and I'm sure it occurred to all of you, is that when the panel reviewed White Oak pollen extract, they didn't review White Oak pollen extract from each different manufacturer, and aqueous versus glycerinated, with phenol, without phenol. They just were reviewing this genus and species, and saying what evidence is it that aqueous extracts from this work somehow.

Likewise, I mean we're certainly living in an era where there are now data that are coming out that there are other routes of immunotherapy that can work. I would propose that the panel consider immunotherapy data by any route, because this is sort of a generic discussion about each of these genus and species. And so rather than being so specific and narrow, we're going to broaden it and look at whatever route.

DR. PORTNOY: And my understanding is that you're only going to consider the effectiveness of treatment, or are you going to look at diagnostics also. And if you look at diagnostics, what if it's effective for diagnostic but not for treatment, or for treatment but not diagnostic. How do you separate those out?

DR. SLATER: So that's actually something that you've seen already. You've noticed that foods say that they're for diagnosis only. So a product that is category I for diagnosis, and category II for immunotherapy remains on the market as a diagnostic agent. And theoretically vice versa as well.

DR. MACDONALD: Jay, I have a question. How many people are going to be involved in this process? How many hundreds of people are going to be involved in this process?

DR. SLATER: Well, if you're talking about the whole process, there will be many, many people involved in the whole process because the process again involves not only the review, but putting together the proposed order, implementing it. It will be -- I can't think of what the number is going to be. In terms of the review process, we have a panel of the willing of 10 people right now who are going to be doing this. And it's going to be hard work for those 10 people.

DR. BERGER: Are those FDA employees or those are outside experts?

DR. SLATER: Full-time FDA.

DR. BERGER: And is there an intent to recruit outside experts? That's just a question.

DR. SLATER: It's not our intent at this time to recruit outside individuals. I think with the work of the first few panels, and with really the powerful tools that we have to collect data at this point, I think we should be able to handle it. We're fairly fortunate. We have a lot of people in CBER who are really expert in allergenic products. So I think this is a group of 10 people that really can do this job, but it's going to be a big job for them.

DR. BAYLOR: Norman Baylor, FDA. What we're trying to do is we're not trying to redo what the panel did. So we don't feel it's necessary to create a new external panel. What we're trying to do is take from that last panel, and just provide an update. Since it has been several decades, just to sort of update, look at the current literature. So we feel that we can do that internally. We're not trying to reestablish another external panel review.

DR. NELSON: I'm not sure I understand that last statement then. So the group of 10 then who generates the literature review will then make the final decisions on the extracts?

DR. SLATER: Yes, that's correct. That's going to be our job to do that. And then that will come out as a proposed order. There will be a comment period, and then the final order will come out.

DR. NELSON: So then the decision by the earlier panels to limit extracts to identified genus and species will be applied?

DR. SLATER: Will be applied?

DR. NELSON: Yes.

DR. SLATER: Yes. Well, okay. It's certainly our feeling that that's a good recommendation. Without having gone through the 1200 extracts, I'm not sure there won't be exceptions to that somehow. But it is certainly -- we agree with that recommendation wholeheartedly, and it's our intention to implement it, but there may be exceptions.

DR. WEISS: Will we be including new potential extracts that may have come out since then, such as latex, which was not an issue in 1970s, as a diagnostic categorization?

DR. SLATER: Well, this -- remember the process here. The process is that we are reviewing products that were in existence, basically, on July 1, 1972. And that's our intention to do that. And that's what we'll be reviewing. This is not a mechanism for reviewing products that haven't been approved yet by any means.

DR. BAYLOR: Let me just address that. To pick up on Jay's point, because remember the intent of the 1972 panel. I mean, we were not -- there was no requirement for efficacy at that time, pre-1972. The products that are coming in for licensure over the last I don't know how many years, the requirements, we're evaluating those products for safety and efficacy now. So there's no need to go back and do that, since we're doing that with all the new products that are being licensed.

MR. HAUCK: Just a quick comment. Jay Portnoy had mentioned about, and you had talked about different routes of administration. I think the panel has to understand that because you review and approve something for category I based possibly on, say, sublingual immunotherapy doesn't necessarily mean that that product is now approved for sublingual immunotherapy. Can you just sketch out your timelines on this? Just how you think this process is going to go, and when it would be published?

DR. SLATER: It's my hope that we can complete this process in time to discuss the end of our process with you next year at this time. So I have been hoping to complete this within six to 10 months. I can't honestly tell you just how realistic that is. Certainly it's in our interest -- we very much wish to complete this process quickly. But we also feel like we have to do it well, and do a comprehensive job. It may just take longer. But we are certainly shooting to do this well and quickly. I'll know better in about three months.

DR. BERGER: So could you explain how the committee -- how the Allergenic Products Advisory Committee will interact with the various stages of bringing this into effect?

DR. SLATER: That's a good question. I think that we'll probably continue with what we're doing now. And that is, again, this is a process that we have laid out, and as we get into it, we will probably change things about. We will probably see things that are not working well, either minor technical things or even some broad items about it. We really don't have a good sense yet of what we're actually going to find, what the literature is. I did a couple of sort of trial searches on several extracts, some that I knew there would be a fair amount of literature on, others that I found literally nothing on. So we have to get into this process to really see where we are. There will be changes in the process that will occur. If the changes are minor, in other words if our focus remains the same, and the broad outlines remain the same I think we will be presenting this to you after we have completed it, at that point.

If things happen that we need more guidance from you, we do as you know schedule two meetings a year with this committee, and we can also come back to the committee on an ad hoc basis if necessary for further advice. My hope is that things go smoothly, and that what we will be doing is presenting our work to you after the fact, around the time or shortly before the proposed order.

DR. BERGER: But for example, would the FDA request a formal recommendation by this committee to approve the proposed order? Something like that?

DR. SLATER: It's not our intention to do that. It is not our intention to ask for that kind of formal review. Remember, and I've said it three times already, we're completing a process that was already started and approved. And we're simply bringing it to what we think is a reasonable conclusion. Unfortunately, the reasonable conclusion involves hundreds of hours of work on our part. But that's the most reasonable way to do it as far as we're concerned.

DR. BERGER: That question was just for my own edification. It does seem to me that the context of this meeting of which there is public notice served would provide a good context for the public comment on the proposed order after it has been published in the Federal Register.

DR. SLATER: Well, I hope so, and I also just want to reiterate that while I think the lion's share of the data that we'll be working with will come from PubMed, it's certainly possible that there are other data, either proprietary data or other in-house data, and we certainly welcome receiving those data on any and all of the extracts. In fact, it's something we want.

DR. BERGER: And would there be an individual notification or a letter going out to manufacturers who -- I don't know how well manufacturers are represented here today, and I'm not -- I didn't actually see whatever notice the Joint Council sent out. But would there be a formal notification of manufacturers that the process of reviewing or re-reviewing these -- I guess the word is reclassifying -- their products has commenced? And inviting them to provide proprietary information if they so choose?

DR. SLATER: Well, I think this context is that notice. I think this is -- we're announcing that we're starting this process. We have representation both on this panel and in the audience of industry, and I consider the word to have gone out at this point. Correct me if I'm wrong.

MR. HAUCK: Absolutely, you've got it. We all have email, too.

MR. THOMAS: Mark Thomas with Antigen Laboratories again. Giving the immaturity of the science of allergy -- we're still on the cutting edge of discovering a lot of things -- is this the panel to end all panels? Meaning that are these products all going to move either in or out, or will some of them remain as IIIAs and still be available?

DR. SLATER: No. The purpose of this panel is to end the IIIA classification.

MR. THOMAS: Okay.

DR. GRANADY: Jay, for those extracts for which you have not been able to find sufficient data, what will happen to those? Will there be an opportunity for data to be obtained, or is this based on literature that exists at this moment?

DR. SLATER: That's a very good question. The original panel report which if you remember was published in 1985, put forth a clear request, and not only a request but a prescription as to how these studies should be done on these IIIA products. Remember it was never the first panel's intention that IIIA products should be enshrined and should remain on the market forever. It was their intention to alert the industry and the Agency that there was truly insufficient data for those products. And in the original panel report that appeared now 20 years ago, there was a request for industry and for academia to prepare data on these products. I think at this point we need to make a decision based on what we have. That being said, as Peter Hauck indicated my response, this process could take a little bit longer than I thought, and we certainly will accept data at any point during the process. So one could consider this an opportunity now to produce some data.

MR. THOMAS: My reason for that question was that the data may end up being insufficient to make a decision, and will they still remain in that category or be removed? And then of course, obviously once they're gone they're gone. And as a clinician you'll never have them to use again. And that's the concern.

DR. SLATER: Well, I think -- first of all, I should make it clear as well that we agree with the original panel's recommendation that cross-reactivity data may be used. So if we have a product that we know from clinical data is effective, both from old data and from continuing data, and we have no evidence of safety problems either with the search strategies that we've laid out, or the ones that Dr. Macdonald has suggested, and we have cross-reactivity data linking that product to several other products. Then my guess is we would probably err on the side of allowing those products to stay on the market, based on the cross-reactivity data.

But, if after 33 years since transfer of these products to the FDA, if 20 years after the panel requested for data to be produced there really are no data to support the efficacy of a product, then those are products that we really are bound to look for some evidence of efficacy.

MR. THOMAS: That's fair.

DR. GRANADY: Jay, removal of a product at this time would not necessarily mean that the product would be gone forever. Would that be an opportunity to go back and continue to collect data and bring it back at another time?

DR. SLATER: Well, I think what the previous question was referring to is that the -- the short answer to your question is yes. You could reintroduce the product. But it would be a new product application, and that's a greater barrier than presenting data at this point to keep it in the list. So from a practical point of view it's harder, that's all.

DR. NELSON: I gather then that sort of class analogy will not be used. Say for instance if one particular animal dander works, then other animal danders won't pass just because they're in the same category.

DR. SLATER: No. Thank you for clarifying that. What you have said is exactly correct. When I'm talking about cross-reactivity data, I mean immunochemical cross-reactivity data, not a broad botanical statement that something is the same type of allergen. Thank you.

DR. BERGER: Is there any other discussion of this topic? I'll ask again if there are any other members of the public who want to come forward and make any statement at all related to this topic or not related to this topic. Okay, in that case I would propose that we break for lunch. And when should we consider returning? Okay. So why don't we -- I think we're considerably ahead of schedule. Why don't we try to return at 1 p.m. Let's try to return a few minutes before 1:00, and we will reconvene at 1 p.m.

(Whereupon, the foregoing matter went off the record at 11:41 a.m. and went back on the record at 1:03 p.m.)

DR. BERGER: Okay, at this time I'd like to introduce Dr. Kathryn Carbone who is the Associate Director of Research for CBER. And she will tell us about the FDA's Critical Path Initiative.

DR. CARBONE: Good afternoon. Thank you very much for offering us this opportunity to introduce a new initiative that's come out of the Office of the Commissioner from the FDA. And the initiative is one that I think from the perspective of CBER we've always had a good appreciation of, and we are greatly enthusiastic about the Office of the Commissioner engaging in this area. And it basically is the understanding that there's a scientific process behind the approval of products demonstrating their efficacy, safety, and manufacturability or industrialization, and that we need to focus on this kind of science, and underappreciation of this science may be hindering development of good products.

As we all know, there are many diseases that are quite serious, that afflict much of the population, and for which we have no specific treatments. In the past, the medical technology advances that have been tremendous appear that they are not being directly and easily translated into actual products, because of the huge increase in biomedical research and the huge increase in potential candidate products are not being reflected in cures. This is an example, and there are many reasons perhaps for this, but at least one reasonable hypothesis for the reduction in submissions to the FDA and CBER and CDER, which these slides show over the years, is that with high technology products, that our ability to regulate these products from a scientific perspective may be lagging behind. And therefore, as much as focusing on the science of product creation and invention, we need to focus on the science of product development.

What is the Critical Path? Well, we had to come up with different language than translational medicine because that was already taken. And this is involving a different part of the pathway that's in addition to translational medicine. And as you can see, that of course there's basic research in prototype design or discovery. That's the point at which you see the press release and the test tube being held up saying `We have a candidate vaccine for X,' or `a candidate product for Y.' But what needs to happen after that, of course, is the testing of the product and often it starts out with safety testing, but some preclinical efficacy testing is also done. The product passes this muster, then it often goes into clinical development as you well know from early stages in safety testing all the way to major Phase III trials. Then market application. The product has to be industrialized, potency testing, ability to detect problems with the product, consistency, et cetera, have to happen, and then of course the product gets licensed.

This is, as we know, quite an expensive proposition, and one of the things to consider in Critical Path is that a very important part of it is to have better assessment of products in this stage of development, because it's an interesting concept, but failure of a product here is a good thing. Failure of a product here is not a good thing. A lot of time and effort and limited resources get invested. So some of this work may be designed to actually be putting the red light very early, and if it's accurately and well done, then the products that enter into the expensive and prolonged phases of development have a higher likelihood of success.

For this group, obviously it's a very sophisticated group and understands the FDA processes well, but these are the three basic areas of Critical Path and product development. Assessment of safety. How can we predict the potential product will be harmful? Obviously preclinical assessments that are reflective of the clinical outcomes are very good, and as well as the proper design of clinical trials. Proof of efficacy. How can we determine that potential product will have a medical benefit? Biomarkers for humans obviously ease the ability to show efficacy because the disease prevention often requires many more subjects. Industrialization. This is a particular area that the FDA and industry are quite expert on, and probably is again underrepresented in terms of the general field of research, and that is in these complicated products which are sometimes living, in the case of a live viral vaccine, or certainly produced by living cells, how do you manufacture these complicated products consistently and at high quality? Sometimes a product will make it all the way through and then fail because they are incapable of making it in sufficient quantities to market the product. And then of course determining quality standards and assays is obviously something that this advisory committee focuses a great deal upon, and it's quite difficult for some products.

So the FDA's initiative is to actually become a proactive member in helping the product development process. And that is to develop and apply new science to improve predictability, and not focusing exclusively on scientific discovery, and that the scientific knowledge and tools, both of which are important, to develop those that can better effectively assess the candidate product.

As I mentioned, reducing costs by focusing their resources on the best candidate products early in development is the hoped outcome of this, and also to develop more quantitative and less empiric and more predictable ways of assessing efficacy, safety, and industrialization of products. Predictability is a major feature in product development. If we have very novel, unusual, different products which have no regulatory history, that becomes somewhat risky for development pathway, since there's no clear pathway to walk down for the industrialization partner.

So the FDA hopes through talking about this Critical Path initiative, which by the way is currently an unfunded initiative, but it's important to get at least the message out. We hope to bring attention and focus to the need for targeted scientific efforts to modernize the techniques, methods, and information that we use to evaluate safety, efficacy, and quality.

Now why the FDA? There are a lot of people that do research in the outside world, and in reality we envision this as really a triumvirate of activity; that there's work that FDA intramural scientists can and should be doing, there's work that FDA intramural scientists can and should be collaborating with stakeholders and outside efforts, and there's also a lot of work that needs to be done completely outside the FDA, but the FDA can contribute leadership, and information, and guidance to those efforts.

FDA scientists have a particularly unique position to understand this kind of science in that they are involved in the review process. We see the successes, failures, and developments across entire product categories. So we're not necessarily talking about supporting a product and moving a product along at all. What we're talking about is categories of products.

The FDA guidance documents need to be based on science, and foster innovation to improve chances of success. And I'm sure this committee has had experience that it's very difficult to write a guidance when it's a best guess instead of actually based on data. We'd really like to have data in these sort of living documents. Convening and coordinating a role for new developments in product regulations such as biomarkers, new clinical method development, clinical method reviews, and Dr. Foulkes will talk more about clinical trials and markers.

So how this is envisioned. This comes from an article that's on our FDA website on Critical Path, the public website that was authored by Dr. Woodcock. And what's important about this is we always have used the phrase `Science-based review, science-based regulation.' But to put a real visual information to that, basically the applications come in, and in every application a problem is identified. In many cases, it's a problem specific to a whole product category. If we don't know a particular issue, it makes it very difficult to do our best job of reviewing. So as these problems are identified as scientific research in this specific area, the needs are identified, academia, FDA, other government scientists, industry, are all encouraged to focus on researching this issue. A scientific solution is identified, and then public input through committees like this. It's discussed. This scientific information then is directly applied to guidance and standards, and that the application process then becomes easier. This information provides increased quality of review and quality of submissions.

So I think we're getting close to the end here, and I think I just want to end with examples of opportunities, and by that I mean Critical Path opportunities with CBER products. For example, one major opportunity in the realm of predictability and quantitation is to develop improved potency assays for specific allergens, to gain a better understanding of the effects of purity issues, the role of natural immunomodulator agents that may be within an allergenic product, the effects of viral infection on responses to common allergens. So this is obviously not a field in isolation. It's a very important field.

And then there are other -- along with other, not necessarily pertinent to this committee, but I'll just go through them. Discussions of making well characterized cell banks for manufacturing a product, so that there would be a well characterized series of cell banks that would be available, that would already be pre-characterized, pre-tested for safety, et cetera, adventitious agents. Characterization of cell therapies and links to standard outcomes. This is a big problem for us in terms of stem cell product characterization. To take a young undifferentiated cell and be fairly assured that every time it's administered it goes to the right place and becomes the right cell. And then to actually link the basic science of product characterization with the outcomes in a clinical trial for better predictability. Methods and validation of pathogen and activation for blood, plasma, tissue, and other products. Having rapid, multi-pathogen detection assays for these same tissues and products so that we can test for an ever-increasing number of pathogens without using up an ever-increasing amount of product. Improving longevity and storage of blood, blood products, and tissues.

And then we have other -- we will continue to have other priorities that develop working with stakeholders. Back in October we held a Critical Path workshop where we had discussions with CBER staff in the morning, and in the afternoon we invited stakeholders from industry, academia, other government scientists, and patient advocacy groups to come and discuss and sort of brainstorm about different Critical Path opportunities. We've been gradually publishing a series of reports of this discussion in various trade journals and professional journals. And as we do so, we'll help refine priorities both for within CBER and those that CBER can partner as well as encourage the outside research world to get involved in.

And I think I'll end there and shall we do questions now for mine? I'd be happy to answer any questions. If not, then we'll go to Mary Foulkes.

DR. FOULKES: Okay, thank you very much. I appreciate this opportunity to share with you what we discussed in our Critical Path workshop that Kathy mentioned a few minutes ago. And I'm going to be concentrating on the quantitative issues from the statistical side and other sides of our regulatory process.

In thinking about the Critical Path, one of the things that I ran across was this quote from Louis Pasteur, "Chance favors the prepared mind." And I bring it in because I think that really solidifies the Critical Path idea, particularly in terms of the quantitative sciences. The prepared mind is the really important part that there needs to be a dialogue with the quantitative scientists with regard to the kinds of Critical Path issues that we want to address.

This is a vast, vast oversimplification of the usual development of statistical methodology. And my theoretical mathematical statistical colleagues will forgive me when I oversimplify like this. But usually there's a development of a highly theoretical model or approach, and then there's a search for where it applies in reality. Well, the Critical Path approach essentially turns that on its ear, and you start with a situation where there is no appropriate statistical approach or approximation, and then begin to develop or improve existing methodologies.

In terms of the quantitative methods, the Critical Path approach attempts to maximize efficiency, the type of approach that Kathy was just talking about. And in terms of the quantitative methods, that maximization occurs by improving the analytic approaches. And one example of that would be flexible study designs, which I'll talk about in just a minute or two. And the other issue is that of transparency. In many contexts, there really aren't quantitative best practices. And one example of that is particularly in handling missing data. In missing data, the underlying assumptions, whenever you have any missing data, however you analyze that data involves some assumptions. And therein lies the problem.

The types of products -- this is just a list of the types of products that CBER regulates, and I'm sure you're all familiar with those. The issue of study endpoints can lend itself to a Critical Path type approach in that there's always an opportunity to improve the study endpoints in terms of their definition, in terms of their applicability, in terms of their relevance and their contribution to improving the developmental pathway. Identification of biomarkers or intermediate endpoints, validating those as surrogate endpoints. Composite endpoints are particularly problematic if you have a composite endpoint where one piece of that composite really dominates. Multiple endpoints are problematic -- multiplicity in any context is problematic, so I won't really go into much detail on that or on the analytic problems that arise in assessment scales.

Proteomics and genomics offer lots of opportunities for quantitative development. The existing statistical practices that apply to proteomics and genomics are really not all that well established in contrast to statistical methodologies that have been in existence for many, many decades. The multiplicity issues, and the missing data issues I just alluded to.

With regard to experimental design opportunities, there are vast areas of experimental design opportunities that are really not being utilized, even to the point of making decisions on how to lay out a microarray plate. There are lots and lots of opportunities to do things in a different way that makes a contribution to the Critical Path in terms of improving the development of a new product.

Statistics can be also applied to the manufacturing process, the industrialization that Kathy talked about. And here are two specific examples. Again, the issue of assumptions applies in a lot of places in a Critical Path scenario. With regard to the opportunities for improving designs, the context of flexible designs is one way to look at this. And in the context of new products, Kathy mentioned the kinds of things where there's a new molecular entity, there isn't a long regulatory history. In that sort of a context, you start out with guesses as to the initial parameters that you utilize in a design in establishing the design and then also in analyzing. You also make guesses sometimes in terms of the target population and the appropriate indication. So there may be opportunities to introduce flexible designs where there are interim modifications as the trial is progressing that can improve the way the trial can answer the specific question it was intended to answer.

Now, this has to be done very carefully, and in particular the changes that are introduced cannot be influenced by knowledge of the interim data. So you can see that that's a rather tricky thing to accomplish, but it is possible. And these are emerging approaches that actually utilize a lot of the new computing power that is available to us that wasn't available to us 10 or 15 years ago.

These are some of the reasons that flexible designs might be utilized in a biologics context. Let me just point out that crossover designs obviously limit one's flexibility, but there are still lots and lots of opportunities to introduce flexible designs. In terms of design and analysis, there are also Critical Path type opportunities. For example, in analyzing non-inferiority trials which applies to allergenics certainly, and the missing data issue that I mentioned earlier. Missing data is a huge area of statistical research at the moment. A lot of that has to do with the availability of high-speed computing power.

Data mining is another area where the Critical Path approach provides us with an opportunity. Data mining, for those of you that might not be familiar with this terminology, it is a statistical approach to taking a very large data set and looking for a signal. And it is used in that context in post-marketing surveillance. Again we have issues of multiplicity. You're looking at thousands, hundreds of thousands, and sometimes millions of observations, and defining what is a threshold for a signal, a signal that is at a level that one should take some regulatory action is a very difficult threshold to arrive at, or to establish. There exists an FDA-PhRMA working group to develop best practices. This is another one of those areas where best practices really aren't yet established.

And then there's the whole area of risk analysis. We often have to make -- in lots of areas of life in general, we often have to make decisions in the absence of full information, and that's certainly true in the regulatory context. And so we developed risk models that help us to identify what action we should take in terms of risk minimization, or what action we should take in terms of gathering new data to add additional information.

So I just want to end with a bullet here that our quantitative scientists need to play a role in the Critical Path, as well as all of the other scientific disciplines, and that statisticians and epidemiologists should be involved in all of the issues that we discuss in a Critical Path context as active stakeholders.

So thank you very much for your time, and if you have any specific questions.

DR. BERGER: Dr. Slater, would you like to make any more comments, or ask the committee to address any issues with which you're concerned? Do any members of the committee want to?

MR. HAUCK: Just a very brief one. It came up over lunch. There's nothing this group can do about it, it's just something to keep in mind. Regarding these category IIIAs, a few of them I'm quite sure will go category II, that there is a likelihood, and I think we have to be careful of it, is that compounding pharmacies may get into the business of -- they're currently in this business, of not necessarily compounding extracts, but actually preparing extracts. And some of these that are a very popular product that may go category II may find a place in a compounding pharmacy. You know, there's nothing this group can do about that, it's just to be aware that it could be a consequence.

DR. BERGER: If there are any other issues that had come up over lunch that should be recorded for the committee, or put before Jay Slater. I think this is a very good and important comment. And if there is anything else that came up over lunch or an informal discussion that we could try to capture, please bring those things up.

One thing that did come up I think briefly at a table I was at was the idea of trying to really be a little bit proactive in informing practicing allergists that this reclassification process is going to occur. Because I think most people probably are not aware, and may have some strong feelings which should be brought forward, or at least they should understand that they've had 20 years to accumulate data.

DR. PORTNOY: Mel, if one of the allergists has concerns, or some of the people I talk to seem to be concerned, how do they contact the FDA and make comments? What is the process?

DR. BERGER: I think Dr. Slater should answer, but I think that as part of some proactive step he might make would be publicizing how that should be done.

DR. SLATER: Well, I think there are two separate issues here. One is how we are publicizing this process before and as it's happening. Obviously what we're doing today is part of that effort. Having presented to this committee, I certainly can communicate to the Academy of Allergy and to the College of Allergy, to relevant individuals, just to alert them that the process is happening.

I want to reiterate that there will be a period during which the public, including allergists, manufacturers, everybody can comment. And that's a critical period, and that's one that formally speaking is the response time.

DR. BERGER: Perhaps we could actually send suggestions up through the hierarchy of the College and the Academy, at least to make sure that there is some notification or information in the journals and at the meetings, with some mechanism for feedback provided.

DR. NELSON: Yes, it might be very useful at the same time to go through that outline of levels of proof or confidence that you outlined, Jay, so that they'll have some idea what the minimum, and also which ones are apt to go to category II, where the cut level is, so that people have some concept of what they might have to come up with. Because otherwise it's probably going to be just a bunch of anecdotal information which I think puts it down in the II category.

DR. SLATER: Thank you. I also just want to remind -- I mean, you're all aware of this, but not only a transcript of this meeting, but all of the PowerPoint presentations of this meeting are going to appear on the website 48 hours from now, something like that?

MS. DAPOLITO: No, it would be more like a week or better.

DR. SLATER: Okay. So very shortly, everything that we've discussed, and everything that we've presented will be out there on the website. And so certainly if you communicate with other colleagues and they want to know what's happened, you obviously have a choice. You could spend an hour and a half explaining to them what happened, or you could refer them to the advisory committee website where everything will be there.

DR. WEISS: Could you explain the timeline, if something goes from a IIIA to a II, what is the period of time that it will no longer be available for practitioners? Is that next day, next month, in a year?

DR. SLATER: Well, so our internal committee will be coming to decisions during the course of the year. None of that will take effect at all during that course of the year. Remember, it all has to then be incorporated into a proposed rule. That will take some time as well. That proposed rule then will be issued. There will be a comment period. And after that the final rule will come out.

DR. NELSON: Is there apt to be enough time in there that if somebody sees their favorite extract on the II list they would have time to accumulate some scientific support, or you know, is it apt to be a year or two years, or what's the?

DR. SLATER: No. The comment period's not that long. I think there would be time, however, for someone to produce data that they already had as part of their comments. There would be an opportunity for that. But to actually initiate, execute a study, analyze the data, and present it? No, it's not.

DR. NELSON: So they need to start now. Yesterday.

DR. SLATER: April 8, 2005.

DR. NELSON: Do you have that website? For the committee.

MS. DAPOLITO: I'll be glad to -- I don't have it with me, but I'll be glad to forward it to you.

DR. BERGER: So maybe the most efficient thing would be to just draft a little something, just basically a notice calling attention to the minutes and the PowerPoint presentations on the website from this meeting for the websites of the Academy, the College, and the Joint Council.

So that way the whole content doesn't have to be reproduced, but there could just be a brief notice, notice of intent to reclassify allergenic products now classified as IIIA. You know, this will be going on at CBER in the next year, and for additional information look on the website from this meeting. And then give -- in other words, if you will, post a notification of this website once it's up. Or this -- the minutes of this meeting once it's -- I don't know if that's possible or not.

DR. SLATER: Mel, I don't think we can do that. I think as individuals you could do that. But we can't do that.

DR. NELSON: Yes, just because the question may come up Jay, do you have round numbers for how many extracts are in category I for immunotherapy and how many are in this category IIIA? Because people are going to I think be very interested in knowing what the magnitude of these two groups are.

DR. SLATER: You mean based on the original classification from the first panel?

DR. NELSON: Well, based on the classification that the '82 committee considered.

DR. SLATER: No, I don't have round numbers on that. I'm sorry. I don't have that available yet. But we will be reconsidering that in any case. And so I think --

DR. NELSON: Well, but, I mean the ones you're not going to reconsider. So are there like --

DR. SLATER: The ones that we're not going to reconsider are the ones that were category I from the original panel.

DR. NELSON: Or standardized.

DR. SLATER: Or any of those that have been standardized, that is quite correct.

DR. NELSON: Right. You don't have a real feel for how many that is, though, out of all the extracts available?

DR. SLATER: Well, the original panel, as I said, put -- I'm remembering, I think it's close to 300 extracts in category I for diagnosis. They put only four extracts for category I -- four, 0-4 -- for therapy. But there are more than that now simply because those that have been standardized we are ?.

DR. NELSON: Well there are 10 standardized, aren't there?

DR. SLATER: Right. Well, if you include the venoms there are 19, 19 products that are standardized.

DR. NELSON: Oh, okay. So it's almost everything.

DR. SLATER: Almost everything is going to be considered, yes.

DR. BERGER: So if you look at these red folders, on the right side the next to -- approximately the next to the last document is this document which explains how to access publicly available information about the advisory committees in general. And the first page is FDA advisory committees by phone, and the next page is how to access FDA on the web. And so within a few business days or very shortly, the entire minutes and all of the handouts from this meeting will be accessible by that website.

And then also, very important, right behind that is the sheet and envelope to turn in your receipts for reimbursement. There are some important things in these folders.

MR. HAUCK: One last question for Jay. Just, I'm not sure I heard correctly. The category IIIAs that were -- the second panel recommended go to category I, you're going to look at those again?

DR. SLATER: Yes.

MR. HAUCK: Oh.

DR. BERGER: Okay, then if there are no further comments, we'll be adjourned. Thank you all very much, and I'd like to thank the FDA, and Gail, and Bill Freas and their staff for arranging this meeting and facilitating everything for us.

(Whereupon, the foregoing matter went off the record at 1:37 p.m.)