FOOD AND DRUG ADMINISTRATION

CENTER FOR BIOLOGICS EVALUATION AND RESEARCH

VACCINES AND RELATED BIOLOGICAL PRODUCTS 
ADVISORY COMMITTEE

OPEN SESSION

Friday,
July 27, 2001

		The Committee met at 8:30 a.m. in the Grand Ballroom at the Gaithersburg Holiday Inn, Two Montgomery Village Avenue, Gaithersburg, Maryland, Dr. Robert S. Daum, Chairman presiding.

PRESENT:
ROBERT S. DAUM, MD      Chair
NANCY COX, Ph.D.        Temporary Voting Member
KATHRYN EDWARDS, MD
THEODORE EICKHOFF, MD
WALTER L. FAGGETT, MD
BARBARA LOE FISHER, MD
SAMUEL L. KATZ, MD
STEVE KOHL, MD
JUDITH D. GOLDBERG, Sc.D.
DIANE E. GRIFFIN, MD
MARTIN MYERS, MD       Temporary Voting Member
GEOFFREY SCHILD, MD    Temporary Voting Member
MARK STEINHOFF, MD     Temporary Voting Member
DAVID S. STEPHENS, MD
NANCY CHERRY            Executive Secretary

	A-G-E-N-D-A

Call to Order and Administrative Matters	3

Question 1
	Discussion	5

Open Public Hearing
	DR. BART CLASSEN,	64
		President and CEO of Classen 		Immunotherapies

	DR. PAUL GLEZEN,	66
		Professor Baylor College of Medicine

Question 1 (cont.)
	Final Vote Results	115

Question 2
	Discussion	116
	Individual Votes	179
	Final Vote Results	205

Question 3 & 4
	Discussion	207

	P-R-O-C-E-E-D-I-N-G-S
	8:39 a.m.
		CHAIRMAN DAUM:  Good morning.  I apologize for banging on a gavel, particularly at this time of the day, but my bell is broken.  So, until we have that repaired --
		DR. EDWARDS:  Maybe that wasn't accidental, Bob.
		MS. CHERRY:  Someone needs to go to the Mall Of America and get a new one.
		CHAIRMAN DAUM:  So, we have administrative matters.  Let me turn the floor over to Nancy.
		MS. CHERRY:  I have none.
		CHAIRMAN DAUM:  We have no administration matters, which is a good thing.
		So we'll move right away to asking Dr. Levandowski, whom I've seen, to begin with posing the questions for the Committee's discussion.  And then we will talk about further procedure when he's done.
		We've been having a huddle on a procedural matter, and the procedural matter just relates to how to divide up this morning's discussion.
		What we're going to do is look at the first question, which is a complicated question relating to efficacy of the FluMist vaccine for which we heard yesterday.
		I've then asked Dr. Mink to initiate the Committee's discussion on this first question by summarizing the viewpoint of FDA, what the FDA thinks is important regarding this efficacy question.  
		And then we will stop and have Committee discussion on the efficacy, and then we'll repeat the whole procedure for question two, which concerns safety. 
		MS. CHERRY:  And then we have an open public hearing somewhere in there.
		CHAIRMAN DAUM:  And we'll have an open public hearing, Nancy, I promise, somewhere in there.
		So, let's roll with question one and Dr. Mink.
		DR. MINK:  Question for efficacy and the Committee we're asking for a vote:  Are the data adequate to support the efficacy of Flu Mist in:  
		(a)  The pediatric and adolescent population from 1 to 17 years of age?  If so, please discuss the appropriate schedule, i.e., one dose vs. two doses.  If two doses are recommended, please discuss the age range for this regimen and the recommended timing, i.e., the interval for the doses.
		Also please discuss the adult population 18 to 64 years of age.
		In your discussion please address the adequacy of the challenge data submitted in support of efficacy against H1N1 influenza strains.  
		If the data are not adequate for specific age ranges, please discuss what additional data should be requested.
		George, Dr. Daum has asked me to reshow slide 40 from my presentation yesterday.
		CHAIRMAN DAUM:  Who is George?
		DR. MINK:  I'm sorry.  Any George.
		CHAIRMAN DAUM:  Good morning, George.
		DR. MINK:  We got it all down right.
		CHAIRMAN DAUM:  George, we get a sense of how you're coming.
		DR. MINK:  The efficacy conclusion from yesterday's presentation, first efficacy against culture confirmed influenza-like illness was demonstrated one or two doses in healthy children from 15 to 17 months of age in year one and again after revaccination in year two.
		At one site, however, contrary to protocol when cultures were obtained in the first 11 days after immunization influenza-like illnesses occurred in children who shed cold-adapted influenza viral strains.
		In adults an effectiveness study was performed. We do not have efficacy data against culture confirmed illness in adults.  In this effectiveness study in adults there was no significant decrease in any febrile illness during influenza outbreak periods, which was the primary end point in the study.
		Secondary end points including sever febrile illness and febrile upper respiratory infections did have demonstrated efficacy, however the lower bound for SFI was 1.4 percent and for FURI was 5.5 percent in CBER-generated confidence intervals.
		Also we have no field efficacy data for H1N1 in either the pediatric efficacy trial or in effectiveness experience in adults.
		In a challenge virus study performed in pediatrics it was challenged against vaccine strain H1N1.  And the adult wild-type challenge there were only about 30 subjects who were in study participation.
		Anything else, Dr. Daum?
		CHAIRMAN DAUM:  No, I think that's a superb start.  And we're going to want to use you, of course, and the sponsor's group as a resource in our discussions, so we may need you to come back.  
		But you could probably scoot back to the FDA table if you would.  And if we could have the lights.
		Could we get the question back on and sort of leave it on, George, when you have a moment.  This George.
		And so now I'd like to have sort of just general Committee discussion regarding this question, number one.  And please feel free in your discussion to ask people to show you stuff that you saw yesterday that you want to see again or hear framed again.
		And let's sort of do it generally at first, and then we'll begin to focus on the questions themselves.
		So, the floor is open.  Dr.  Goldberg, Dr. Edwards, Dr. Katz.
		DR. GOLDBERG:  What data do you have about repeated administrations of the vaccine over more than two years?  I mean, I think there was a little bit of data shown, but I just want to make sure that I understand all of the data.  So how far have you gone with repeated annual administration of this vaccine in adults and in children?
		CHAIRMAN DAUM:  It's a question for the sponsor, I guess.
		DR. GOLDBERG:  Yes.
		CHAIRMAN DAUM:  This is George also. Yes.  It makes it easy for me.  You want to see a slide, just ask for George.
		DR. MENDELMAN:  These are the data in children for repetitive dosing.  The 4,771 for second annual season.  1,999 for a third.  And 549 for a fourth consecutive season.
		CHAIRMAN DAUM:  Yes.  That's a good way to proceed. We're going to have questions right about this issue, and I still have the sequence with Dr. Edwards next.  So Dr. Katz.
		DR. GOLDBERG:  One more second.
		CHAIRMAN DAUM:  Sorry.  Dr. Goldberg then Dr. Katz.
		DR. GOLDBERG:  Is there anything in adults and do you have an efficacy data on the third and fourth administrations?
		DR. MENDELMAN:  The efficacy data is only for the first and the second year, it was a two year study in the efficacy trial on children.
		The effectiveness trial on adults is a single year, single season study.
		DR. GOLDBERG:  Okay.  Thank you.
		CHAIRMAN DAUM:  Dr. Katz, just about this.
		MR. KATZ:  Just about that slide, Paul.  When you give us numbers such as those, those are just the vaccine recipients, not the controls, is that correct?  When you say there are 2700 children 1 to 8 years of age; is that 2700 vaccine recipients or 2700 total in the study?
		DR. MENDELMAN:  Vaccine recipients.
		MR. KATZ:  Thank you.
		DR. MENDELMAN:  Individual unique children.
		CHAIRMAN DAUM:  Dr. Griffin about this slide and then Dr. Schild about this slide.  This is a popular slide.
		DR. GRIFFIN:  Well, I think it's sort of a crucial slide for some of the questions.
		And that's whether you have any data on serology on what boosting actually did and how necessary boosting was, because in general these were the same vaccine that was given over and over, right?  Or these are different formulas in the first, second, third, and fourth years?
		DR. MENDELMAN:  In the pediatric trial the H1N1 strain changed between year one and year two.  The year three they did not change.  In year four they did change.  So, there were several formulations that were given to the children. 
		In the revaccination in year three it was a safety study only there was no serology in year three, however we did do serology in the fourth study season.  And the children in the H1N1 group had a boost in their antibody responses.  Most of the children to age 3 in B were already seropositive from prior years of vaccination.
		DR. GRIFFIN:  We heard the conclusion, but I don't remember seeing the data with respect to the fact that they tended to respond to only two of the components the first time and you really needed a second dose to get a response to all three.  Do you have data that you can share with us on that?
		DR. MENDELMAN:  Yes, and Dr. Belshe's slides in the -- backup, George.  
		CHAIRMAN DAUM:  Dr. Edwards be patient.  Your next when we finish this issue.
		DR. MENDELMAN:  These are the data from the subset and study 006. After two doses of primary vaccine in the first year, you can see the 96 percent seroconversion and baseline seronegative children for the H3N2 in the B strain and the 61 percent seroconversion for the H1N1 strain.
		DR. GRIFFIN:  This is after two doses?
		DR. MENDELMAN:  This is after two doses.
		DR. GRIFFIN:  Do you have any data for what happens after one dose?
		DR. MENDELMAN:  Oh, sure.  
		DR. GRIFFIN:  I assume it's worse.
		DR. MENDELMAN:  I can tell you what's in my brain.
		DR. GRIFFIN:  Okay. 
		DR. MENDELMAN:  The seronegative children after dose one to H1N1 was 16 percent after one dose.
		DR. GRIFFIN:  1.6?
		DR. MENDELMAN:  Sixteen percent.
		DR. GRIFFIN:  Oh, 16.  Okay. 
		DR. MENDELMAN:  And then boosted to the 61 percent as noted on the slide.  The response at H3N2 was over 90 percent after the first dose and the response to the B virus was about 89 percent after the first dose.  
		CHAIRMAN DAUM:  So there's a difference with H1N1, obviously, in terms of the --
		DR. GRIFFIN:  That's the main problem it sounds like.
		CHAIRMAN DAUM:  This issue.  Okay.  This issue.  Okay.
		DR. STEPHENS:  In terms of the dose, the one or two doses, the question has to do with efficacy.  Because as I recall the efficacy after one dose despite the immunological data was almost equal, is that correct, at least to the H3N2, but --
		DR. MENDELMAN:  For both the H3N2 and the B, and the one dose cohort the efficacy was at 90 percent for those two strains after a single dose, 88.9 percent.
		CHAIRMAN DAUM:  But then H1N1 becomes the issue again?
		Dr. Kohl?
		DR. KOHL:  It's reiterating this the same question, and I don't think you can answer it.  The question is do you need two immunizations.
		DR. MENDELMAN:  I'm sorry.  State again.
		DR. KOHL:  The question is do you need two doses for children.
		CHAIRMAN DAUM:  A rhetorical question.
		DR. KOHL:  And the data, at least in my mind, is not added by the serological response since you've already shown us that the serological response doesn't necessarily correlate with protection.  And it looks like unless you have data that you haven't shown us yet, that there's no efficacy with H1N1 other than challenge because there weren't any H1N1 in those years.
		Per chance, did you challenge any individuals who only got one dose in that pediatric challenge study, or were they all double dosed?
		DR. MENDELMAN:  Well, they were all revaccinated in the second season.
		DR. KOHL:  So they were triple dosed?
		DR. MENDELMAN:  And then the challenge was five to eight months after that second season dose.
		DR. KOHL:  Okay.  The question is do you need more than one immunization to protect against H1N1?  And the answer is we don't know?
		DR. MENDELMAN:  My answer would be to get optimal protection against all three strains, you would need two doses.
		DR. KOHL:  But you're just saying that; you can't support that?
		DR. MENDELMAN:  We know that if you have a high immune response for serum HAI, that does correlate with the efficacy.  And there are data, as you saw in the adult trial, that in spite of a lack of a response to the H1N1, those adults were still protected against H1N1.  In the young seronegative child we want an optimal response to all three strains and the data we're presenting is that one dose was sufficient for the H3N2 and the B.  H1N1 didn't circulate for five years between '95 and this year.  		So, it's in a sense a combination vaccine that we want.  Going from 16 percent seroconverion to 61 percent would mean to me as a clinician that we're maximizing the response of H1N1 circulated.
		DR. GREENBERG:  I think Bob Belshe has historical data in his head and has other comments to make about two doses versus one dose.
		DR. BELSHE:   Yes.  For Dr. Kohl, actually I think this data shows that the second dose of at least trivalent vaccine serological shows infection with H1N1 virus after one dose.  So this is, in a sense, an equivalent challenge although it's a challenge with trivalent vaccine.
		And, George, could you put up the H1N1 historical efficacy data?
		Now, there's really quite a good literature on efficacy of H1N1 vaccine.  The largest study was actually conducted by Dr. Edwards, and she might want to comment on that as well.
		A summary of the 11 efficacy trials with H1N1 vaccine is shown here.  The first five are monovalent vaccine and you can see the efficacy has ranged from 34 percent to 100 percent depending on the study.
		Second series of studies are for trials using bivalent H1N1 with H3N2 vaccine, the largest one being Dr. Edwards' study, which showed in year one 78 percent efficacy against H1N1 and in year four of that study in which H1N1 circulated, 91 percent efficacy.  That study includes both children and adults.
		And then we've presented here the two studies with trivalent vaccine.  The children's challenge model, which shows 83 percent efficacy and the adult challenge model, which included H1N1.
		CHAIRMAN DAUM:  Thank you, Dr. Belshe.
		DR. GREENBERG:  Bob, do you want to just briefly comment on your historical trials of one dose versus two doses, which was another question?
		DR. BELSHE:  Yes.  We've had an opportunity to examine both bivalent vaccines and trivalent vaccines for one dose versus two doses.  And really the best data is from AV006 demonstrating 16 percent serologic response rate with dose one, 61 percent after two doses.
		CHAIRMAN DAUM:  Thank you.
		There are some people here that may have comments about this very issue.  I have Drs. Schild, Myers and Faggett.  Are they all about this issue?
		DR. SCHILD:  Yes, but mine is a more general issue.
		CHAIRMAN DAUM:  Can you hold then?  I'll put you on the general list.
		Dr. Myers, this issue?
		DR. MYERS:  The data is all pooled, and I was wondering if it's possible to see both efficacy and the immunogenicity data specifically for the 12 to 24 month old child?
		DR. MENDELMAN:  In the FDA briefing document and the slide that Dr. Mink showed yesterday, the efficacy and my memory is 84 percent of the children under two years of age.
		CHAIRMAN DAUM:  Do you want to see it again, Marty?  We can get to work on that while we hear someone else's comment.
		CHAIRMAN DAUM:  Drs. Mink and Geber, and et al.
		DR. MYERS:  Well, for example, this is pooling all of the data.  We're being asked specifically about a one year recommendation.  And the immunogenicity data we just saw was pooled data from 15 months to 71 months.  And I suspect the H1N1 response is different in the first year of life than it is in the third year of life.
		CHAIRMAN DAUM:  Dr. Mink is mobilizing George and we shall have the data you wish in a moment.
		I want to stay fixed on this issue.  Dr. Faggett?
		DR. FAGGETT:  Dr. Myers asked my question already.  Thank you.
		CHAIRMAN DAUM:  Dr. Stephens this issue.
		DR. STEPHENS:  I have a question concerning the timing of the dose.  In the 06 study the timing of the dose was 60 days, yet the proposal is for 30 days?  Can you clarify that difference?
		DR. MENDELMAN:  The timing was 60 plus or minus 16 days.  So 46 to 74 days.
		DR. STEPHENS:  But your request is for 30 days.
		DR. MENDELMAN:  Correct.  
		George, can you go to the GMT responses and AV007.
		In the lot consistency trial, AV007 we did a sub-analysis.  In that study 500 children were dosed.  100 received placebo, the other four groups were three consistency lots 100 children each and a 100 children getting efficacy vaccine.  And in that study children could receive vaccine as early as day 28.  
		And these are the time interval data.  If children got a dose -- where -- day 28 to 41 on this column here compared to if they got day 42 to 60.  And you can see the seroconversion rate are similar in this analysis for each of the three strains.
		CHAIRMAN DAUM:  Thank you.  WE're ready to see the data that Dr. Myers asked for.  Could we put them up, George, please?
		DR. MENDELMAN:  If I could just comment.  Also in the FDA briefing document they note this analysis in their document.
		CHAIRMAN DAUM:  Thank you, Dr. Mendelman.
		DR. MYERS:  And is there any data for 12 through 15 months in the serology.
		CHAIRMAN DAUM:  Let's look at the data you asked for here first, since they're ready.
		DR. MINK:  This is the efficacy by age that was requested.  I didn't bring a pointer.  But to go through, you can see -- thank you.
		Under 24 months there were 223 subjects that were in the analysis.  Any strain, which includes H3N2 and B -- remember there's no H1N1 field data -- the efficacy against any strain was 84.7 percent.  And what I noted yesterday for you is there are wide confidence intervals, especially against type B.  And the reason being that there's such a small number is what we presume.
		There's efficacy that was comparable for all of these age groups, but again all the n's are small so some of the confidence intervals, especially against type B, are pretty wide.
		Did you want to see gender and ethnicity, too?  I don't remember.  Slide 15 please.
		CHAIRMAN DAUM:  Dr. Faggett would like to see that.
		DR. MINK:  Okay.
		CHAIRMAN DAUM:  So as long as you're up there, let's do it.
		DR. MINK:  There were no differences noted in efficacy against any strain for males and females, and they were comparable, obviously, to the analysis for the whole study cohort.  Remember this is subjects enrolled in two doses, which is different than the primary n point, which was subjects who had definitely received doses.
		And then for ethnicity, there was about 85 percent of the subjects that were caucasian and 155 that were non-caucasian.  And the efficacy wasn't appreciably different between the groups in any strain.
		Wide confidence intervals again when the numbers are small.
		CHAIRMAN DAUM:  Thank you very much.
		DR. KOHL:  Can I thank you for finally the ethnicity data.  We've been asking for that for years and I think is the first time we've ever seen ethnicity data presented to us.
		CHAIRMAN DAUM:  We're asking both FDA folks and sponsor folks to be very nimble with their data this morning, and I recognize that.  We're asking them to put up slides out of sequence and on virtually no notice. And the Committee thanks you in advance, because it's very helpful to our deliberations.
		We're going to move on to a different subject now.  Dr. Edwards is the next speaker, then Dr. Katz and Dr. Schild.
		DR. EDWARDS:  Well, I guess the first question that I raised my hand for was how many patients or how many children between 12 months to 15 months have been immunized?  This is indicated for 12 months, and I'm not sure I know how many kids 12 to 15 months have been enrolled.  So, that was the first question.
		And then I did want to comment on the data that Dr. Belshe put up about the study that I conducted and reported in 1994 regarding H1N1.
		Maybe I could comment while they're getting the number of children between 12 to months.
		I think one of the issues that's really important for people to understand is that the cold-adapted vaccine sometimes will have a much more brisk immune response with the H3N2 and sometimes much more brisk response with the H1N1.  And interestingly, our study that we did that was NIH funded that enrolled 5,200 plus people, we found during that time that the H1N1 was very immunogenic and, indeed, generated a much higher -- well, a significantly higher immune response with the cold-adapted vaccine than the H3N2 did, which is really in contrast to what we're seeing in the Aviron study.
		So, I think that there is some variability between the strains bearing different H1N1.
		Our study was done with the single dose of cold-adapted vaccine in all children.  And, in fact, our children only received a one to ten dilatation of the vaccine.  So, obviously, a less concentrated vaccine.
		In that situation, as Dr. Belshe showed, we had one year that was matched very nicely with the vaccine strain and one year that was a drift strain.  And just as he had mentioned, the efficacy in adults and children was exactly as he sad, 78 and 90 percent for culture confirmed disease.
		In contrast, the H3N2, which was less immunogenic that year, in terms of culture confirmed disease, and granted there are many caveats.  This is a drop vaccine.  We did not have the funding to do the intensive surveillance that was done, so those caveats are all there.  But the efficacy with one dose of H3N2 was 59 percent for a drifted strain and 56 percent for a well-matched strain.
		So I think that the vaccine does have efficacy after a single dose for H1N1 and for H3N2, even if it's not an optimal immune response.  But whether that's what is wanted, whether the optimal response after two dose versus one dose is something we need to discuss more fully.
		DR. KOHL:  Kathy, is this the same vaccine as Aviron's?
		DR. EDWARDS:  No, it's not.  This is a vaccine made by a different manufacturer; the same master strain, however.  And, again, I'm not trying to say this is comparable, but I'm just saying that there are some differences in the immune response to different vaccines.
		CHAIRMAN DAUM:  Thank you. 
		Dr. Katz?
		DR. MINK:  I can answer the age question if Aviron doesn't have the data.  Do you want me to do that one first?
		Under 12 to 15 months of age, according to Dr. Rida and our statistical review, we have accountable 200 children in studies in the FDA database.
		DR. MENDELMAN:  This slide is the updated numbers.  The cut off data in the FDA briefing document was as of April 30th.  
		The statisticians from Aviron are working on the number between 12 and 15.  And Dr. Mink, I believe, will be correct; it'll be in that range.
		The cut off shown here, 12 to 18 months of age, is 813 FluMist recipients, 19 to 35 months of age 3,395 and then you see the other breakdowns.
		CHAIRMAN DAUM:  Dr. Mink, do you want to comment?
		DR. MINK:  I can just give you the numbers that we have in our database, if you'd like.
		From 12 to 15 months for FluMist recipients our n is 200.  From 16 to 19 months the n is 507.  For 20 to 23 months it's 547.  And that gives us a total of 1254 subjects under 24 months of age.
		CHAIRMAN DAUM:  Not incompatible with these data, just a different way of breaking then down?
		DR. MINK:  Different age group and an early dataset.
		CHAIRMAN DAUM:  Thank you.
		Now I think we're ready to go on to Dr. Katz.
		MR. KATZ:  My comment, really, rather than question is a much more generic one.  But we've been asked to look at data supporting the efficacy of FluMist.  And I'm very comfortable with what we've seen.  But I think it has to be made very clear to the public that, you know, influenza is but one infection of what we're going to be coping with.  And the overall reduction of acute febrile respiratory illness is going to have to include respiratory sirsal virus, the parainfluenza viruses, the adenoviruses.  And my concern is not with the vaccine, but with how it's presented to the public and the health providing community in that there will be great disappointment if we still see lots of febrile respiratory illness, which we certainly are going to, but it's not going to be due to influenza viruses.
		I think it's terribly important to prevent influenza virus illness.  And as Paul Glezen and others have shown very convincingly it doesn't even have to be respiratory illness.  It can be ill-defined febrile illness, particularly in the younger infants whom we're discussing now.
		So, I think there has to be a great deal of clarity whatever the decisions are and however it's eventually presented that we're preventing specifically influenza virus illness and not respiratory disease in daycare centers and in infants in the first years of life.
		CHAIRMAN DAUM:  We do, of course, have the same problem with the current immunization vaccine schedule, do we not?
		MR. KATZ:  Right, but it's poorly if at all used in the pediatric age population, except perhaps for high risk children.  Whereas, I think the ease of administration of a nasal vaccine and avoiding the pin cushion effect I think will have very definite assets.  
		And there are already people in the pediatric infectious  disease community who are pushing for universal immunization of infants and children, both to protect them and to interrupt transmission to adults.
		CHAIRMAN DAUM:  On this point, before I call on Dr. Schild whose next and Dr. Kohl, would someone care to comment about the data in adults that there was no decrease in acute febrile illnesses?  I believe those data was taken from a time when influenza virus was very heavily circulating in the community.  And vis-à-vis Dr. Katz' question, I was curious as to what comment sponsors or FDA or Committee members, or anyone had about that issue.
		DR. GREENBERG:  I think Kristin Nichol will comment.
		DR. NICHOL:  Sure. I would certainly be interested in commenting.
		It is absolutely true that the primary n point for the clinical effectiveness trial in health adults did not show a statistically significant reduction as we discussed yesterday.  The primary n point or outcome definition that we selected for that trial was any febrile illness.  And that was very sensitive but nonspecific outcome.
		Recall that this was a clinical effectiveness trial designed to very broadly access impact across a number of different outcomes, not only illnesses per se, but also health care use.
		I think it's important to recognize that even if the primary n point is negative, is there something else that these data can tell us that is important and useful regarding the question does the vaccine work?  That is, is the vaccine efficacious, which is a slightly different question from the primary question in the clinical trial, which was is the vaccine clinically effective across a broad range of health economic parameters.
		If one is interested in asking does the trial provide useful information on whether or not the vaccine works, is it efficacious, which I believe is the question in front of this Committee, then I think it's important to ask which is the most appropriate outcome definition to look at and by what way it's measured.
		And I believe that then one looks at the most specific illness definition that we included as the prespecified definition, and that would be febrile upper respiratory illness.  We recognized that when we were looking at different illness definitions in the study planning stage and from some studies published since that trial was conducted, including that Dr. Arnold Manto published in the Archives of Internal Medicine, I believe last year looking at the positive predictive value of various clinical syndromes, we do believe that the febrile upper respiratory illness definition, which most closely approximates the CDC's ILI surveillance definition, is the most specific for influenza.
		So, that's why I look at the most specific illness definition in asking the question does the vaccine work in adult populations rather than it is clinical effective across a number of outcome parameters.
		Then the question is what is the most efficient way to measure that.  And I'm, perhaps, a bit chagrined in admitting in retrospect we chose for the primary n point only, to look at proportions of people having any event.  And recall we were looking at any febrile illness.
		Well, it turns out that people can have more than one event because many of the febrile illnesses are not due to influenza.  And so if one wants to look at the most efficient way to measure the outcome, one should look at events rates.
		So I would propose if the question is does the vaccine work, that one might look at events rate and in particular at the febrile upper respiratory illness category or the severe febrile categories as being more specific.  And if you look at the slide shown here -- I don't have a pointer -- but you can see that the reductions are as they are shown.  
		I don['t want to shine this in anybody's eyes.  With more precise estimates than we saw when we were looking at proportions.  And, in fact, the lower confidence bounds for those reductions I have here. I don't have them on the slide.  I apologize for that.  But for febrile upper respiratory illness, the lower confidence bound for the percent reduction is 12.7 and it goes to 33.2 as the upper bound for the 95 percent confidence interval.
		CHAIRMAN DAUM:  Thank you very much for that helpful comment.  Comment on this point?  Dr. Goldberg?
		DR. GOLDBERG:  Excuse me.  Dr. Nichol --
		CHAIRMAN DAUM:  Dr. Nichol?
		DR. GOLDBERG:  Am I correct in your saying that for any febrile --
		CHAIRMAN DAUM:  Dr. Goldberg, if you could get that mike right up close.
		DR. GOLDBERG:  For any febrile illness you used the proportion of patients with the event?  For essentially first event?
		DR. NICHOL:  For the primary --
		DR. GOLDBERG:  And for the others you used an event rate?  Is that what --
		DR. NICHOL:  For the primary outcome a single outcome in measure --
		DR. GOLDBERG:  Right.
		DR. NICHOL:  -- we looked at the proportion of people having any febrile event.  We also measured the proportion of people having these outcomes as well.
		DR. GOLDBERG:  Okay.  
		DR. NICHOL:  And we showed that on a previous slide.
		The point I'm making is there's a single primary outcome, but then if we're asking --
		DR. GOLDBERG:  Back up. On this slide am I seeing the effectiveness --
		DR. NICHOL:  These are event rates.  These are event rates.
		DR. GOLDBERG:  Also for any febrile illness, is that an event rate as well?
		DR. NICHOL:  These are all event rates.
		DR. GOLDBERG:  Okay.  
		DR. NICHOL:  The numbers of episodes.
		DR. GOLDBERG:  That's all.
		DR. NICHOL:  I'm sorry.
		DR. GOLDBERG:  Thank you.
		CHAIRMAN DAUM:  We'd like to move on now.  Thank you, Dr. Nichol.
		To Dr. Schild, whose been patient and eager to raise a point for our consideration.
		DR. SCHILD:  A general point, Chairman.
		Like Professor Katz, I've found quite a lot of satisfaction in the efficacy data presented yesterday.  However, it would be good to see field data for H1N1 virus.
		But I'd like to address the issue of the protective efficacy in the face of antigenic and genetic variation of the viruses.  We had good data about a two year period of antigenic drift for the H3N2 virus, which showed good cross protection.  And I think it would be highly desirable in the long run to know much more about protective efficacy of all three types of vaccine in relationship to progressive antigenic and genetic drift of the virus.
		And also in the long run, to be able to relate that sort of information by immunological markers.  There's considerable scope for learning much more about the sort of protective efficacy induced by this virus in terms of antibodies local in circulation and in terms of other markers.
		In terms of antigenic variation, I think it would be interesting also to know a bit more about the neuraminidase contribution.  These are long term issues.  I don't think they're issues that can be resolved within a short period of time.
		CHAIRMAN DAUM:  There are influenza experts here who might like to say something about that, or we'll just take it as a reflection?
		Dr.  Schild, we thank you for your reflection.
		Dr. Kohl, then Dr. Snider, and Dr. Stephens.
		DR. KOHL:  We're going to spend a lot of time on side effects later on, I guess.  But my question is related to the interaction of side effects and effectiveness.  And what I'd specifically like to ask Aviron is do you have any data, since there are a lot of side effects; some of them bothersome.  I think there's an increased fever, especially in young children, which might bring these kids into the emergency rooms.  There's clearly a huge increase in "a runny nose," which on some occasions might bring very young children in to see their private doc.  And that is balanced by the effectiveness, the number of cases of influenza that are prevented and saving money.
		So, have you or any of your colleagues done a time benefit analysis, a cost benefit analysis to see what this is going to do in the trenches to the pediatrician and the pediatric patient?
		DR. GREENBERG:  Before we answer that question, getting back to how many children between 12 and 15, we were digging through to give you that number. That's 271.  I can't remember asked, but you all wanted to know the number.
		Steve, the question you asked is about fever and runny nose.  And I think the best thing to do would be to call up the -- Paul, you're doing that?
		DR. MENDELMAN:  Dr. Kohl, I can tell you the number of differences.  The percent with low grade fever between vaccine and placebo.
		DR. KOHL:  No, but that's not what I want.  I want to know a cost benefit analysis if it's been done.
		DR. MENDELMAN:  Well, I understand the question.
		DR. KOHL:  You had done that for adults and it's included in the packet and $30 looks like a break even point.  What does it look like for kids?
		DR. MENDELMAN:  Are we talking about economic issues?
		DR. KOHL:  I'm talking about economic issues.
		DR. MENDELMAN:  Okay.  
		DR. KOHL:  But it's more than economic issues. It's life issues for pediatricians and pediatric patients.
		DR. MENDELMAN:  Okay.  There's an article coming out in Pediatrics next month.  The article is a cost economic analysis based on data from the efficacy trial AV006 and a list of assumptions therein.
		The analysis team was Brian Luce's group at Medtap International and the various investigators, Dr. Belshe included and Dr. Zangwill and others who are the investigators in the 06 trial.
		There were two numbers.  As I remember them, if the parent has to take off time from work for two hours to take the child in for an immunization, the data look identical to data that Dr. Mary Nettleman has published previously with the inactivated vaccine in children.  And that is, about $4 to $5 cost savings.
		If there's an alternative to give vaccine, like a vaccination clinic where the parent doesn't have to take time from work, again identical to the inactivated vaccine data that Dr. Nettleman and her group has published, it's about $28 cost savings.
		CHAIRMAN DAUM:  Steve, you could feel free to return to this issue when we get to discussion point four, which is what additional data you would like to see generated.  But I'd like to move on to --
		DR. GLEZEN:  Dr. Daum, could I make a comment that directly responds to Steve's question?
		CHAIRMAN DAUM:  I think you may.
		DR. GLEZEN:  I'm Paul Glezen from Texas.
		The last slide that Paul showed yesterday looked at the relative risk of visits for acute respiratory disease in zero to 14 days after vaccination and compared it to prevaccine rates and rates 15 days and greater.  And now in three years data with almost 15,000 doses administered, the relative risk for a visit for a acute respiratory illness is less than one for all acute respiratory disease categories.
		So, from that standpoint we don't see any increased burden on the medical care system by these side reactions to the vaccine.
		CHAIRMAN DAUM:  Thank you, Dr. Glezen.
		Before you sit down, are you today, Dr. Glezen, distinguished academician from Baylor or are you speaking now on the sponsor's behalf?
		DR. GLEZEN:  Well, I don't know how to separate that.
		CHAIRMAN DAUM:  Well, we need to know that you can't.  So, thank you very much.
		Do you have affiliations with the sponsor?  We need to know how to interrupt your comments.
		DR. GLEZEN:  Okay.  The study that we're doing in Texas is based on an NIAID grant, but Aviron provides the vaccine and, of course, holds the IND on the vaccine.  And we have, obviously, participated in a lot of safety evaluations for Aviron, which will be submitted to the FDA for this consideration.
		CHAIRMAN DAUM:  I thank you, sir.  And thank you for your comments.
		Dr. Snider, you wished to make a comment?
		DR. SNIDER:  I wanted to ask a couple of questions as they relate to efficacy.  I know that the manufacturer's not asking for an indication at this time in persons 65 years of age and older. However, there was some data presented or someone alluded to the fact that there was some information available that suggested that combination of the inactivated vaccine, which we know in the older age groups is not as efficacious as it is in younger age groups, typically that protection might be boosted by having FluMist and the inactivated given in combination.  And so although I understand the reason why people over 65 were randomized to placebo in FluMist, I just wondered if there was any data for those over 65 as it relates to receiving both vaccines?
		And also had a question about that I haven't raised, and that is -- I mean, I think I know the answer, but I'd like to hear the answer about the concomitant use of antivirals neuraminidase inhibitors, for example?
		CHAIRMAN DAUM:  Do you want to comment on that?
		DR. GREENBERG:  There were two questions asked. One was the question about over 65 combination therapy and the other was the susceptibility of these vaccines to antivirals?
		DR. SNIDER:  Yes.
		DR. GREENBERG:  So the first question, the combination experiments were mentioned by Dr. Murphy yesterday.  And those were not Aviron studies, those were studies carried out by Dr. John Treanor and colleagues, whose in the audience,  And I think Dr. Murphy pretty well summarized them yesterday showing added effect of a combination.  But those are not Aviron studies.
		If you have a more detailed question, I think you have the PI for those studies here.
		As far as the second question goes, we do have antiviral data which I think is being called up.  And the vaccine are susceptible both in neuraminidase inhibitors and to the older antivirals rimantadine and amantadine.
		DR. SNIDER:   Could someone remind me of the magnitude of the marginal benefit of adding FluMist to inactivated?
		DR. GREENBERG:  Dr. Treanor, can you just step up?  
		CHAIRMAN DAUM:  Before you start, I apologize, we need your name and affiliation.
		DR. TREANOR:  Okay.  John Treanor, University of Rochester in Rochester, New York.
		CHAIRMAN DAUM:  And relationship with the sponsor?
		DR. TREANOR:  We have participated in a number of NIH funded studies that involved cold-adapted vaccine in the years prior to it becoming FluMist, and then also where the vaccine was supplied by Aviron.
		And the study that we're referring to here was done quite a number of years ago using a cold-adapted vaccine which was monovalent H3N2, because our observation had been that in nursing homes pretty exclusively in terms of influenza A viruses, we would see outbreaks of H3N2.  And so that study randomized nursing home residents to receive inactivated vaccine and then either intranasal placebo or intranasal cold-adapted H3N2 virus.  And this was done over a three year period of time.	
		And in nursing homes where there were outbreaks of influenza A we saw about a 50 percent reduction in the rate of laboratory confirmed respiratory illness due to influenza A in recipients of combined vaccine.
		Now, I think, you know, there are obviously several things to keep in mind about that study.  It's relatively small.  It was designed really as a pilot study and not a pivotal trial and it involved monovalent vaccine in a fairly unique population of nursing home residents who are extraordinarily susceptible to illness due to influenza A in that sort of intense exposure environment.
		CHAIRMAN DAUM:  Thank you very much.
		Let's move on to Dr. Stephens next.  It his about this very issue?  Okay.  Then I'll put you on the list.  There's Dr. Stephens, Dr. Griffin, Dr. Edwards.
		DR. SNIDER:  Bob, I didn't get an answer to my question.
		DR. GREENBERG:  I'm sorry.  
		CHAIRMAN DAUM:  Could you speak into the microphone?
		DR. GREENBERG:  Yes, I put up this slide and the antiviral part?  As I said, and maybe it went by too quickly, the vaccines are -- I think I -- we have the two neuraminidase inhibitors here, rimatadine and amantadine.  And what you have here are pairs, the wild type parent and the cold-adapted and inhibitions.  And as you can see, when the wild type virus has a sensitive neuraminidase A sort and has a sensitive neuraminidase.  And the type As are susceptible to amantadine and rimantadine.
		And a B virus, do we have that here?  Yes.  B virus is resistance, as you would expect.
		CHAIRMAN DAUM:  Thank you.
		Maybe I should check.  Dr. Snider, does that take care of your questions?  Good.
		Dr. Stephens is next and then Dr. Griffin, Dr. Edwards.
		DR. STEPHENS:  My questions concern efficacy in the older adult population and specifically data in the 50 to 64 year old group. I think that's the other end of the spectrum that there may be limited data concerning efficacy.
		And the second question concerns efficacy in immuno-compromised populations, which is an area we haven't heard a lot of data on at this point.
		CHAIRMAN DAUM:  Let's hear the answer to that and remember that it isn't really part of question one, but might be something to revisit under discussion point number four.
		DR. STEPHENS:  It is part of the question.  It's part B.
		CHAIRMAN DAUM:  Let's hear the answer to that, because it's an important part of question one.
		DR. GREENBERG:  We're not totally seamless in calling up slides.  
		DR. NICHOL:  Forgive me if I'm creating a little delay here in moving forward and asking some questions.  
		With regard to the clinical effectiveness trial in the healthy working adults, a subgroup analysis has been done using both an under 40 and greater or equal to 40 age split, which approximates a 50/50 split in terms of the age distribution, the participants.
		We've also looked at an over 50 versus under 50 split, and there's no evidence of a decrement in the benefit of the vaccination in the older age group, as I recall, in any of the outcomes that were looked at.  Because of the subgroup analysis some of the numbers, obviously, are small.  But in terms of interaction between age and effectiveness, there's no evidence of an interaction.
		Does that --
		DR. STEPHENS:  Do you have this broken down between 50 and 64 is the specific question?
		DR. NICHOL:  Yes.  I'm sorry, I guess that's where I created some confusion.  This is the 40 split and then these are -- it's not quite the way I was expecting the data to come up, but this is an analysis looking at the 50 over versus under 50 showing statistically significant p-values for effectiveness.  But what the question really is, I believe, is is there a difference in effectiveness between under 50 and 50 and over.  And there's no evidence of fall-off in effectiveness.  Those p-values when comparing under 50 to 50 and over are generally all about .5 or greater.
		Does that --
		DR. STEPHENS:  Yes, that's helpful.  And the n number on these data?
		DR. GREENBERG:  The numbers over 50 were what, Paul?  The numbers are getting smaller.
		DR. MENDELMAN:  The numbers are approximately 439 FluMist recipients and 200 plus placebo recipients in that analysis that you just saw, 50 to 64.  
		And this is the analysis you just asked for, and Kristin, if you could present that?
		DR. NICHOL:  Right.  What we've shown here in terms of percent reduction and outcomes, the comparisons are between under 50 versus 50 and over.  So it's a question of is there a difference in effectiveness.  And you could look at occurrence of illness or days of illness across all of the various outcome definitions.  You'll see that the -- oh, I'm sorry.  The n's are up there.
		The n's are 3,920 for under 50 for all participants and 641 for participants 50 years of age and over. And again, as you'll look across the rows there, the p-values are for differences in efficacy or effectiveness between the age groups.
		CHAIRMAN DAUM:  A couple of those comparisons the p-values are significant.  Do you want to make any comment on those or not?
		DR. NICHOL:  The ones that are significant here are in the categories of missed work or healthcare provider visits where it looks as if there was some difference by age group. And I will just note that in those cases, it appears as if the benefit was greater in the older age group both for the category of febrile upper respiratory illness.
		CHAIRMAN DAUM:  The healthcare provider was --
		DR. NICHOL:  Pardon me?
		DR. DAUM:  The healthcare provider is --
		DR. NICHOL:  Right, both missed worked and healthcare provider visits looked as if there was a greater reduction in the older age group.
		CHAIRMAN DAUM:  Thank you.  That was pretty nimble.
		Dr. Griffin?
		DR. STEPHENS:  A second part of the question --
		CHAIRMAN DAUM:  Sorry.
		DR. STEPHENS:  -- had to do with the immuno-compromised --
		CHAIRMAN DAUM:  These two partners are getting to me a little bit. I'm sorry.  You want to state the question again, David.
		DR. STEPHENS:  Well, my concern, we've heard a little bit of data about the HIV -- there was a small study in the HIV population.  There is some VA data.  But I mean, obviously, influenza is an important issue in immuno-compromised populations, and I just wanted to feel reassured, if you will, that the efficacy in those populations, renal failure for example, diabetes; those populations in adults that may benefit most from this vaccine.  Do you have data?
		DR. GREENBERG:  No, we don't.  We do not have efficacy data in those high risk populations.
		CHAIRMAN DAUM:  And it's keying in on that part of what you said that I thought you could reraise that as part of discussion point four what additional data are needed.  And I agree with you.
		DR. GREENBERG:  I do want to remind you, although I know you know it, we're not seeking an indication for those populations.
		CHAIRMAN DAUM:  Dr. Edwards?
		DR. EDWARDS:  Yes.  I wanted to talk a little bit about a practical issue, and that's because I'm a mother and also a pediatrician.
		I know that many times children have runny noses constantly.  So the practical issues of the administration of the vaccine in the face of URIs or how is a pediatrician or a family practitioner going to -- what kind of instructions practically do you have?  And do you have any data if there is some runny nose present whether the take is okay or whether adverse events are unacceptable? I know we're not talking about safety.  I'm just talking about efficacy.  But if you have a little safety, you might want to throw it in.
		CHAIRMAN DAUM:  We wouldn't be offended.
		DR. BELSHE:  There is no backup slide on this, but there is some anecdotal data.
		First of all, let me comment a little bit about the way in which we collected data and the children given a placebo versus vaccine, the normal allantoic fluid.
		I got the impression that people were concerned that normal allantoic fluid was causing 20 percent runny nose.  That's not the case.  We enroll children and selected only children without a runny nose at time zero on day zero, and then gave them vaccine or allantoic fluid internasally.  And by the time those children get home, the mother's check on the diary card on day zero 10 percent of the time that children have runny nose.  And then on day two it goes up to 20 percent and it stays at 20 percent for the duration of the diary card.
		So what we're seeing is a return to normal baseline rate of 20 percent runny nose in children on any given day.  And so it's not the normal allantoic fluid, in my opinion, that's causing that 20 percent rhinorrhea, it's just the nature of children 20 percent of the time have a runny nose.
		So, in year four of the efficacy field trial we did enroll a small new cohort and changed the entry criteria so that they could be enrolled and have runny nose.  And there is just a handful of data on that, and the data do not suggest, although it is almost anecdotal to be so small, that runny nose in anyway inhibits response to the FluMist.  There's no inhibition.
		CHAIRMAN DAUM:  No inhibition of what?
		DR. BELSHE:  In a small number.
		CHAIRMAN DAUM:  Of what?  Of immune response or --
		DR. BELSHE:  Of antibody response to FluMist.
		CHAIRMAN DAUM:  Thank you, Dr. Belshe.  That was a helpful orientation.
		Is there other Committee input on this question one?  Dr. Griffin?
		DR. GRIFFIN:  Part of question 1(a) is if two doses are recommended, please discuss the age range for this regiment and the recommended timing of the doses.
		Okay.  We talked a little bit about the timing, but I haven't seen any data that supports the current request that it be for children under the age of 9.  And so I just wondered where that data comes from that chooses that cut off point for two doses before 9 and once does after?
		DR. MENDELMAN:  In part, we accepted the epidemiological data and the decisions of the inactivated vaccine for two doses to be administered to children under 9 years of age if they've not been previously vaccinated.  And then children over 9 would receive a single dose.
		And Dr. Glezen in the audience could comment further.  I believe he presented data at ACIP and possibly to this Committee in the past.  I think Paul would be the right person to address that epidemiologically.
		CHAIRMAN DAUM:  Would you like to hear that, Dr. Griffin?
		DR. GRIFFIN:  Yes, please.
		CHAIRMAN DAUM:  Okay.  Dr. Glezen, are you available, willing?
		DR. GLEZEN:  Yes.  Paul Glezen.
		We've looked at this in relation to the recommendation for inactivated vaccine, and I think that's the origin of this recommendation is that traditionally inactivated vaccine we recommend two doses for kids under 9.
		We considered this related to when natural priming occurs.  Because if a child has been primed by natural infection with flu, they respond very well to inactivated vaccine now we're talking about, not live.  And in our longitudinal studies of children in the Houston Family Study, and I know Bill Gruber had some data and we talked about this at the time.  We found that almost all children have had experience with all three circulating strains by the time they enter school at 5 or 6 years of age.  And we thought that this could be safely dropped.  But for some reason or other when I proposed this, there was some technical reason that had to do with studies of -- well, I can't remember.  But it was rejected. And the rejection came from an objection by the FDA liaison to the ACIP at that time, I remember.
		But basically the studies show that kids respond very well.  Now, when it comes to the live attenuated vaccine our experience is that a single dose, and when you look at the data for one dose, that mostly comes from Houston.  We found that one dose is effective.  In all our previous studies we've used a single dose.  And whether we're talking H1N1 or B or H3, we've found that one dose has provided very good protection so that we haven't felt the necessity to use two doses for any of the kids.  But I'll leave that argument until later.
		DR. GREENBERG:  Can I just --
		CHAIRMAN DAUM:  On this very point?
		DR. GREENBERG:  Yes.
		CHAIRMAN DAUM:  Okay.  
		DR. GREENBERG:  I just wanted to clarify for Diane and for the Committee, it's two doses for children under the age of 9 for the first time. Once they have received the vaccine, it's one dose.
		CHAIRMAN DAUM:  Dr. Eickhoff, this very point.
		DR. EICKHOFF:  A question for Dr. Glezen.  Would you be content with just a single dose for a 15 month old child?
		DR. GLEZEN:  My main consideration is public health implications. I think that being the current state of affairs that if we gave a 1,000 kids a single dose, we'd be a lot better off in giving 500 kids two doses for the community and our general health status.  And it's pretty hard from a public health standpoint to recommend two doses when we're not doing a very good delivering vaccine to our total population.  So if we can get single dose to everybody, we'll be a lot better off.
		CHAIRMAN DAUM:  But that's not the choice before the Committee. We're asking you to --
		DR. GLEZEN:  Yes, I understand that.  I understand that.
		CHAIRMAN DAUM:  step into a perfect world where there's a 100 percent coverage and everyone does the right thing.  Do we need one or two doses?
		DR. GLEZEN:  Right.  Well, I've been tempted to get up several times when you've talked about H1N1, because this past winter we gave vaccine in the face of an H1N1 epidemic in Texas.  5,000 kids were given H1N1 New Caledonia strain.  This was a new variant and previous studies had shown very little cross protection by previous H1N1 strains. And we were quite delighted to find that a single dose resulted in apparent good protection from our unblinded study in that we only saw one breakthrough.  And if we looked at the culture positive illness in age eligible kids in the same community and compared it to culture positive illnesses in vaccine recipients, and this is a rough very crude estimate of efficacy, it would have been 91 percent protection against H1N1 culture positive illness in our study last winter.
		And that was a total of several hundred kids being cultured, so that I feel very comfortable, the efficacy standing point with one dose in any age group.
		DR. KOHL:  Paul, these were previously unvaccinated.  Paul  Glezen.  These were previously unvaccinated children who got one dose of vaccine?
		DR. MINK:  And the youngest age group:
		DR. GLEZEN:  The youngest, 18 months.  And the youngest -- over 2,000 got their first dose.  And there were 3,000 -- we had the data broken down by whether or not they got vaccine 98, 99 or 2000, whether they had multiple doses and all that.  And the protection looks good for both delivery of vaccine in 99 or 2000.
		CHAIRMAN DAUM:  Dr. Griffin had a comment or question for Dr. Glezen also?  No.  A comment on this issue?
		DR. GRIFFIN:  Yes. I just want to make sure I understand that what the basis of the data on which we're being asked to vote, basically, on a two dose schedule and the age range which a two dose schedule would be recommended. And it's my understanding that this is based purely on the ACIP -- those CDC recommendations for the inactivated vaccine  and that there are no specific data addressing this point from Aviron.
		CHAIRMAN DAUM:  Well, I think we heard some about sero-conversion rates for H1N1 with one and two doses.  And I think --
		DR. GRIFFIN:  No, we didn't that broken down by age and so we didn't have that broken down by age in this range from, you know, under two, under three, under four -- you know.
		CHAIRMAN DAUM:  Let's take that point to the finish line.  Do we have those data broken down by age, because they're obviously very important to this issue?
		DR. GREENBERG:  We don't have it on a disk, but we can get it.  It's in -- we have it, but we don't have in front of us.  
		Are you saying we can get it and bring it to the Committee?  So can we just table that.  Can Diane wait --
		CHAIRMAN DAUM:  We can.  We can.
		I have Dr. Katz and Steinhoff scheduled as the next two.  I'd like to try and ask the Committee now to really bring their thoughts to bear on question one and to focus now on comments that have to do with your ability to directly deal with this question.
		What I'd like to do is have issues that haven't been raised and need clarification flushed out in the next few minutes.  Then go to the open public hearing, which you must do before a vote, and then vote on this question one.  Because we need to spend time on question two, the safety question, the same depth as this and it's very important that we come to some closure.
		So, I have Dr. Katz and Steinhoff scheduled to speak.  We hope that Dr. Greenberg, et al, can provide these serology data for us on the two dose one dose issue. And then I'd ask additional speakers to really address question 1, issues that haven't been raised.
		Dr. Katz?
		MR. KATZ:  I'll defer to the Congressman from Maryland.
		DR. STEINHOFF:  I'm not a congressman, thank you very much.
		Actually, this is an observation about the two dose for the first time immunization of infants.  It's an observation.
		And that is if you want to do that and if you think about the child as the child goes through time, if you ask for two doses and then another dose the next year, which is the intention, that child will get three doses in a 12 month period.
		If you say well one dose is enough, and from what I've seen it looks like one dose probably is enough in terms of effectiveness and efficacy, perhaps not for immunogenicity.  If one dose is enough, then that child will get two doses within a 12 month period.
		CHAIRMAN DAUM:  Thank you. That's very helpful.
		Are we ready?  Okay, give me a signal or something, that's what to do.
		As we approach the thinking on the question, I would remind the Committee to try and do a mental gymnastics exercise which is very important.  And that is to consider in your voting on this question and dealing with it the data that are submitted in the BLA.  We've heard a lot of data, some in it, some not in it and I'm not I must say 100 percent certain myself which is which.  And we might ask Dr. Mink and Geber and anyone else at the table to speak to that issue before we actually come to it. But the Committee is asked to reflect on data on the BLA in addressing these questions.
		Dr. Edwards?
		DR. EDWARDS:  I think one of the problems that I'm having is trying to separate what has been presented for the licensee of this product and the bulk or a lot of data that has existed before with a slightly different product.  And also the data that is still out there that we hope will shed some light on some of the struggles we're having.
		I think we're being asked to license a vaccine -- or to recommend the licensing of a vaccination for children that are one to two in age and we have 200 children that are in that group.  
		We're being asked to vote whether one dose is adequate and the data that we have with this product is, at least in 006, is less than 200 children.
		So we're being asked to make important decisions on really relatively small numbers.  That's not to say that the previous experience wouldn't suggest that one dose may be adequate and that it may be adequate in young children.  But I think it's very difficult to know, and perhaps this is just rewording what you were just warning us about, what we are to comment on.
		CHAIRMAN DAUM:  Thank you very much.  I must say before we go to Dr. Greenberg, I know you're there, we are not voting to license anything.  And it's very important we understand that.
		DR. EDWARDS:  I know.  I'm sorry.  I know what I'm supposed to be doing, so I'm sorry I misspoke.
		CHAIRMAN DAUM:  But it's important that everybody understand.  We are voting merely to advice the FDA of our opinions about the questions that we're being asked.  And so it's an important distinction.
		Dr. Greenberg?
		DR. GREENBERG:  I was confused by Dr. Edwards comments.  It's 1812 under 2 years of age.  I wasn't sure whether you said there was 200 under 2 years of age.
		DR. EDWARDS:  No.
		DR. MINK:  For efficacy minus --
		DR. GREENBERG:  Yes, right exactly correct.
		DR. MINK:  For efficacy data the --
		DR. GREENBERG:  And the second thing is the efficacy data, you've seen our efficacy data.  There is no more efficacy data coming in.
		DR. MENDELMAN:  There are four trials, and Dr. Mink showed these yesterday on her slide.  In the BLA that was filed at the end of October, that is study AV006, the two year efficacy data.  Study 11, which is the H1N1 challenge data.  And then the two trials in adults, AV003 that Dr. Nichol presented yesterday and AV009.  Those are the data to support licensure as we're proposing it for adults and children.
		The data Dr. Glezen noted to you, which is NIH grant, it's a community protection trial in children 18 months to 18 years of age multi-year.  
		And the data Dr. Glezen was noting to you is the effectiveness data of the cold-adapted vaccine FluMist in the trial that he's conducting.  Those data have not been presented to the FDA.  And in our discussions with the FDA Dr. Glezen's trial is a large safety trial.
		In our discussions with the FDA we were not asking for herd immunity claim based on Dr. Glezen's study when that study was filed several years ago.  
		So that data is available to the community.  The ACIP and eventually it will be published for the readership and for public health issues.  It's nice to know the data that Paul's quoting, but it is not needed for the application.
		CHAIRMAN DAUM:  Dr. Katz, this very issue.
		MR. KATZ:  Now the lower half of that slide, Paul, I don't understand.  It's 9 to 17 years and then it says 12 to 18 months and 19 to 35 months.
		DR. GREENBERG:  You've found a mistake.
		MR. KATZ:  I really only wanted the numbers, Harry.
		DR. MENDELMAN:  Let me have the pointer. Thank you.  Okay.  
		The numbers are over 12,000 children 1 to 8 and over 6,000 children 9 to 17.  So this is in error.  And over 19,000 children total.
		We probably better, George, to go back to the other slide.
		This is the table that the FDA has in their briefing document as of April 30th and we wanted to update it with the current numbers in the database for the Committee.  And the numbers as noted to you, 1812 under 2 years of age.  And on the next slide, if you just focus on the children under 3 years of age -- George, could you go back to the prior slide?  Thank you.  It's 813 children 12 to 18 months of age and over 3,000 children 19 to 35 months of age.
		Dr. Mink is correct, there's 265, whatever the number I gave Dr. Greenberg, children between 12 and 15 months of age.  So 600 children are over 15 months of age in this cohort.
		Historically we have looked at the data with the cold-adapted vaccine with the same master donor virus.  The numbers are 800 children under 18 months of age and approximately 265 children under 12 months of age.  Historical data, not Aviron data, not under review by the FDA the number is 271 in the 12 t 15 month age group.
		CHAIRMAN DAUM:  Thank you.
		Dr. Snider, you had a new comment about question one that we haven't discussed before.
		DR. SNIDER:  I had a question because with all the data I'm tending to get lost, but this is not a one time vaccine, presumably an annual vaccine we would anticipate based on our experience with inactivated vaccine that the efficacy may vary from  year to year and with different types.
		I'm trying to remember how many years of efficacy data we have for the different age groups, if the sponsor could remind me of that, I would be most appreciative.
		CHAIRMAN DAUM:  Let's ask Dr. Mink first to respond to that?
		DR. MINK:  I want to restate what Dr. Edwards said, that the number of children from 15 to 24 months in the efficacy trial was around 230 plus or minus.  So those kids, that's for efficacy data, those are the total number that submitted in the BLA. And then the next year, they're all a year older.
		So I don't have those final figures off the top of my head, but probably Aviron has those.
		DR. GEBER:  And if I could just add, I think that there is confusion about what data are in the BLA and what are not.  It's perhaps, as Dr. Mendelman has said in his first discussion of it, a little bit easier for the efficacy data.
		The only studies under consideration and submitted to the FDA that are going to be submitted in the current plans to the FDA are:  The AV006 years one and two; the AV011, which was the vaccine challenge study in children; AV009, which was the effectiveness study, and; AV003, which was the wild-type challenge study in adults.
		These other data are not under consideration by us.  They've of interest and helpful to you, but not in our decision regarding licensure.  And so we would like -- our comment is if you could focus in your discussion in your vote on those data.
		CHAIRMAN DAUM:  Thank you, Dr. Geber.
		Dr. Katz, please?
		MR. KATZ:  A great deal of the questions in the last moments have really related to the very young children and this, obviously, is focused in part because of the evidence that's been presented of the morbidity of influenza infection in that age group.  This may belong in discussion point 4, but the question that occurs to me is we're talking about 12 to 15 months of age, that's when we give MMR.  And the question is, are there any studies that have been done with simultaneous administration of vaccine along with another live virus preparation?
		CHAIRMAN DAUM:  Varicella might also be added into that question.
		MR. KATZ:  It eventually will be MMRV.
		CHAIRMAN DAUM:  We still give Varicella now.
		DR. MENDELMAN:  There's a study ongoing now, it's study AV018 it's in children 12 to 15 months of age.  The projected sample size to address the question is it safe to give MMR Varivax and FluMist together? Is it immunogenetic for both of the standard vaccines, is it also as immunogenetic for FluMist recipients.  So that study has approximately 200 children enrolled of the 1200 proposed.  And based on enrollment and timing, those data in that age group would not be available for at least another year.
		MR. KATZ:  Thank you.
		CHAIRMAN DAUM:  And you're right, of course, it is definitely an additional data issue that should be put on the list.
		Dr. Katz?  What's your name?  Kohl.  Sorry.
		DR. KOHL:  This goes specifically to the question Sam asked.  Does Steve Black have any data to this issue and the Kaiser Group, did they have any concomitant immunizations with the live vaccines?
		DR. BLACK:  No.
		CHAIRMAN DAUM:  Thank you very much.
		DR. MINK:  And the youngest age in that study was 18 months also.
		CHAIRMAN DAUM:  Thank you, Dr. Mink.
		DR. MINK:  I'm sorry. It was one year to 17 years.
		DR. BLACK:  The age group went down to one year, but concomitant vaccines were excluded.
		DR. MENDELMAN:  In all of our trials we by protocol precluded an inactivated vaccine being administered within two weeks and a live viral vaccine being administered within 30 days.
		CHAIRMAN DAUM:  Thank you.
		I'd like to maybe take a break, from the discussion that is, and ask for the open public hearing to go on.  And then, hopefully, Dr. Greenberg will have these data that we're seeking ready.  And then we can begin to consider the question dead on.
		So, let's go to the open public hearing.
		As I understand it, we have two scheduled speakers.  And we call on the first one, Dr. Bart Classen.  Is Dr. Classen here?  Good morning.
		DR. CLASSEN:  My name is Bart Classen. I'm President and CEO of Classen Immunotherapies.  We do vaccine safety work.
		I was impressed by really the lack --
		CHAIRMAN DAUM:  Do you have any affiliations with the sponsor?  We need to know that.
		DR. CLASSEN:  No affiliation with the sponsor.
		CHAIRMAN DAUM:  Thank you.
		DR. CLASSEN:  I was really sort of impressed by the lack of long term safety in this data that was presented yesterday.  And I would like to remind the panel that you cannot determine the safety of a vaccine based on solely on 42 days of follow up.  Attenuated viruses have different chronic adverse event profiles in the wild viruses.  And there's also concern about contaminated viruses and contaminating DNA in this production process.
		It's also important to remember that in the target population there's very, very low mortality or chronic sequelae from influenza.  And I would urge the FDA and urge the panel that before their approval of this vaccine, that the infrastructure is in place to look at the long term safety of this product, including the effect on many chronic diseases that we are seeing that have been linked to vaccines and are epidemic in this country now, including asthma, autism and diabetes.
		Thank you for the opportunity to speak.
		CHAIRMAN DAUM:  And, Dr. Classen, as always we're grateful for your comments.  Thank you.
		Let's move on to the second scheduled speaker, who is Dr. Paul Glezen.  Dr. Glezen, could you also remind us who you are and your affiliations with the sponsor?
		DR. GLEZEN:  Thank you, Mr. Chairman.
		I'm Paul Glezen, Professor at Baylor College of Medicine.  
		The main things I want to address concern our community study in Texas, which is an NIH sponsored grant and the vaccine is provided by Aviron and as such, we've had a lot of interaction with Aviron, the sponsor of this application in preparing safety data and assessments.  But I do not have any interest in Aviron financially and I'm not a consultant for Aviron or have any other connection other than our collaborative efforts in this trial.
		When I prepared my remarks I did not anticipate the questions that were raised yesterday concerning safety.  And I wanted to just clarify the study that we're doing and how we're assessing safety, because this information will be submitted along with the application eventually.
		As you all know, this is an open label trial where we are attempting to immunize the children 18 months to 18 years in a community, Temple-Belton, in Texas.  It's a community of about 70,000 people.  And there are approximately 20,000 age eligible children in that community, so it's a fairly large undertaking.
		The focus of a safety assessment has been on the ascertainment of SAEs in the first 42 days after vaccination.  And there are several levels of our ascertainment.  
		One is we give the parents a laminated card telling them what to report and how to report it.  We give them a refrigerator magnet.  They've either had a postcard follow-up at 6 weeks to let us know that everything was okay or there is a telephone contact.  And the follow-up has been at least 98 percent for that.
		Now, in addition most of these subjects are patients of Scott & White Clinic, which is a large multi-specialty clinic located in Temple.  And because of this availability, we on a monthly basis enter in the medical record numbers of all of the subjects and search the medical records for any encounter, particularly emergency room or hospital encounters.  And so we are searching not just for the 42 days, but 42 days after the last dose of vaccine has been administered for all of the subjects. So we do have fairly long term surveillance for serious adverse event for the large majority of the children in our study who are patients of Scott & White Clinic.
		Now, the secondary assessment has looked at the occurrences of illnesses including LRI that might be associated with natural influenza virus infection.  And one of these searches includes what we would consider rare events such as encephalitis, myocarditis, pericarditis, Guillain-Barrè Syndrome, febrile seizures, anaphylaxis and whatever.  And in that particular population we have found none of these rare events occurring within 42 days of vaccination for the children who are patients of the Scott & White Clinic.
		Now, the analysis for medically attended acute respiratory illness, or just the common acute respiratory illnesses associated with flu, the structure of the study was suggested by Marie Griffin, who is a member of the DSMB appointed by NIAID for our study.  And in this analysis we look for all of the common acute respiratory disease diagnoses; upper respiratory illness, lower respiratory illness and otitis media and sinusitis.
		What we do is compare the relative risk then for the occurrence of these events, and this is a medically attended now.  We're looking for visits to the clinic.  Zero to 14 days after administration of the vaccine and we compare that in the same population to their pre-vaccine experience, and then 15 and over days after vaccination.  And this is done for the period beginning with the day that the first dose of vaccine is given until 42 days after the last dose of vaccine is given.
		So, for each year this encompasses a period of four to five months.
		Now, as shown in the slide that Paul reshowed this morning, for the first two years we found a relative risk less than one for each of the acute respiratory disease categories, including LRI.  And we've now had a preliminary look at year three, which shows the same thing.  And this then includes a total of almost 15,000 doses administered to 9,700 children over a three year period.
		We could probably refine this data if there's specific questions about pneumonia or about different age groups. But we don't have all this now.
		And I will say that the date, of course, is controlled by season since we know that during the period we're administering vaccine, the incidents of these different acute respiratory illnesses increases as we approach mid-winter and also by age, of course.  So it's controlled, it's a Poisson regression type analysis controlling for both season and age.
		The other question I wanted to clarify is  yesterday in the FDA presentation they said that we accepted children with asthma.  I want to qualify that.  We exclude children who have moderate or severe asthma.  We have included children who have mild intermittent reactive airway disease who defined by not on chronic therapy and not having had treatment for asthma in the emergency room or the hospital for the prior year before vaccination.
		And in that study, also, of those children with mild intermittent asthma, we haven't seen any increase in any of the respiratory events in the first 14 days after vaccination.
		Now, I'd like to just resume to the points that I wanted to emphasize about peripheral matters, or not really peripheral, but more public health matters that relate to the possible licensure of this vaccine.
		First, I want to say that I support the application for licensure of the live attenuated vaccine.  And there are two considerations which I think make this particularly important at this time.
		One is the vaccine supply.  At a time when the priorities for annual influenza vaccination have been broadened to include everyone over 50 years of age, we have been stymied by late delivery of vaccine and for influenza, late delivery is essentially no vaccine.
		Even before the change and recommendations, we did not produce sufficient vaccine to cover all the persons given priority for vaccination. Suddenly the inactivated vaccine supply appears vulnerable.  Persons concerned about global supplies of influenza vaccine have stated that live attenuated vaccine can be produced in quantity more readily than inactivated vaccine.
		Availability of a live attenuated vaccine would not change the priorities for use of inactivated vaccine for high risk patients.  However, it would allow clinics to reserve inactivated vaccine for high risk patients and at the same time not deny protection for healthy persons who can receive the live attenuated preparation.
		I also wanted to emphasize the importance for instituting some sort of protection for children.  The FluMist efficacy trials have focused attention on the role of influenza viruses in acute lower respiratory tract infections of children.  To put this information into perspective, I would like to quickly review data on global disease burden recently published by the JAMA by Michaud, et. al., from the Harvard Medical School.  
		Now, I hope I can press the right button here.  Which one is it?  Yes, it's a slide.  Oh, okay.  There it is.  All right.  I'm sorry, I had the wrong one.
		This is an analysis of global disease burden that's based on the top ten causes of disability-adjusted life-years or DALYs.  DALYs for disease or health conditions are calculated that the sum of years of life lost due to premature death and due to disability.  DALYs incorporate a discount rate for time preference and an age weighing factor that take into account the higher social value given young adults in most societies.
		One important implication is that DALYs weigh the burden of disease for children and the items here that particularly relate to children are lower respiratory tract infections, perinatal conditions, diarrheal disease, vaccine-preventable disease and nutritional deficiencies.  Less then those of young adults, for example, HIV.
		Now, furthermore, since the number of deaths listed for LRI are those that are estimated globally for children less than 5 years of age, that's about 4 million deaths a year in children less than 5 years of age, this ranking completely disregards pneumonia and influenza mortality of predominately the elderly that is used in the U.S. and many other countries to measure the impact of influenza epidemics.
		And for pathogens that contribute to LRI mortality, obviously influenza is only one of many, but it is the most important. And, of course, it's the only one for which we have a method for prevention.
		Now, I'd like to say, though, that to put this into some sort of context and what we ought to be thinking about, if we had a pandemic next year which had anything like the pathogenicity of the 1918 flu, we'd see a greater number of DALYs than all of the top 10 here combined caused solely by influenza.  So that has to be part of our consideration also.
		Now, the authors state that there's a strong case for the U.S. to invest in health research to reduce the major causes of burden of diseases that are not treatable or preventable with the current mix of interventions and healthcare delivery systems both nationally and globally.  This has happened with HIV and AIDS.  So when you look at the funds invested in AIDS research per DALY, it's $85 per DALY.  However, when we look at acute respiratory disease down here, you can see that it's only .50 cents.  So we've come, I think, far short of our obligation to carry out research that might ameliorate this problem.
		Now although mortality  from LRI is low in U.S. children, serious morbidity is extremely high.  This graph illustrates surveillance at Texas Children's Hospital in Houston for 1998/1999.  And you can see the peak of visits through the emergency room here corresponds and correlates with the occurrence of influenza.  This is the surveillance for influenza that's illustration here at the hospital.  And this is the hospitalization peak that's associated in children with the influenza epidemic.
		Now, this peak of visits here correlates not only at Texas Children's, but nationally with periods when emergency rooms are clogged up, when hospital beds are full and when the hospitals must go on drive-by status, as Texas Children's frequently does.
		The hospitalization rates attributable to influenza based on the viral surveillance are as high in children less than 5, if you include all this, as for elderly adults during flu epidemics.  So the rates are very high. And, in fact, the rates in older children equal the rates of adults with chronic underlying conditions under 65 years of age.  And only about 20 percent of these children have underlying conditions, so these are mainly healthy children who are hospitalized during influenza epidemics.
		This shows the rates for Medicaid children in Tennessee.  This was published by Kathy Neuzil last year the New England Journal.  And these are extremely high rates for the low income kids.  And this is almost as high as the rates that we've seen with RS virus in Medicaid kids.  For RS virus it's about 7 percent.  For flu it's about 5 percent.  And they went to great effort in their study to eliminate periods of time in their analysis when RS virus was circulating.  So they tried to limit this analysis just to periods when influenza virus was active.
		So it's clear that healthy children are susceptible and vulnerable to serious complications.  And they also found appreciable numbers of outpatient visits and courses of antibiotics related to influenza virus infection.
		So I think that there's good evidence that children could benefit from universal immunization.
		Now, one obvious deficiency of the current influenza control program is the lack of protection for infants who have the highest complication rate from influenza virus infection.  Numerous studies have shown that children develop poor immune responses to both licensed and activated vaccine and the live attenuated vaccines.  However, this can be remedied by full implementation of current or proposed controlled measures.  Influenza immunization is recommended currently for women who will be in the second or third trimester of pregnancy during the influenza season.  Relevant antibodies generated by this immunization are transmitted to the infant and should provide significant protection during the first six months of life.  The effectiveness of maternal immunization for infant protection needs to be confirmed.  But then the infants would also benefit by a universal immunization by older children such as demonstrated in the recent CDC trial of children in day care showing that there was secondary benefit to household contacts by preventing spread in those kids.  So if the older kids are immunized, actively immunized with the live attenuated vaccine, then there should be sufficient indirect protection combining this with maternal immunization for the infants who are at the highest risk of influenza virus infection.
		So, in conclusion I would certainly support the application of the sponsors of this because I think this will facilitate a recommendation for universal immunization of children.
		Thank you.
		CHAIRMAN DAUM:  Thank you very much, Dr. Glezen, for taking the time to come and share your thoughts with us.
		It's 10:25 here in the Eastern time zone, and we're going to take a short ten minute break.  We will begin 10:35 with the Committee addressing the question.
		(Whereupon, the proceedings went off the record at 10:25 a.m. and resumed at 10:35 a.m.)
		CHAIRMAN DAUM:  Could everybody please get themselves settled so we can get to work?
		Before the break one of the questions that was raised had to do with immune response in young children.  Some new data or some data have been circulated to us for review.  And perhaps Harry or Paul want to quickly walk us through what this sheet shows as Nancy passes it out.
		Are these data in the BLA?
		DR. MENDELMAN:  Yes.
		CHAIRMAN DAUM:  Yes.  Thank you.
		DR. GEBER:  Yes, they are.
		DR. MENDELMAN:  Okay.  In order to address the question, the statisticians are working fast and furious.
		Part of the issue around immunogenicity with the strain changes from year to year is how do you summarize an H1 when it's changed or an H3 or B. So what we've done is go to the data at hand from the study AV007, which was the lot consistency trial.  And these are two tables were taken from the clinical study report that was submitted in the license application the end of October.  So maybe you could turn to the back table 42 first.
		DR. EDWARDS:  I don't think we have this table on this side.  
		DR. MENDELMAN:  Okay.  We're getting more copies.
		DR. EDWARDS:  Okay.
		MS. CHERRY:  There are more copies coming.
		DR. MENDELMAN:  So let me just try to introduce it.  This trial was conducted in children 12 to 36 months at the Southern Kaiser UCLA HMO with Dr. Kent Zangwill and Joe Ward as the PIs.
		The age breakdown is 12 to 17 months, 18 to 23 months and 24 to 36 months.  
		And Dr. Janet Wittes of Statistics Collaborative was involved with this analysis and can also speak to these.
		If you look at table 42, the second page of what was handed out to you, it shows the serum HAI titer prior to any vaccination by lot and the efficacy vaccine was one of the arms of the trial and placebo.
		And the scatter I think you can see here is that in this trial of this year, whether you're 12 to 17 months, 18 to 23 or 24 to 36 months, most of the children, if not all, had an undetected serum HAI titer.
		Now the question here I have from my group is -- okay.  So you see the H1, the H3 and the B.  Oh, it's up here. Okay.  You won't be able to see this.
		CHAIRMAN DAUM:  Remember that few besides yourself can see that as you point these out.
		DR. MENDELMAN:  Right. Okay.
		The three age groups big ticket 12 to 17, 18 to 23 and 24 to 36 months.  And the strain designation, H1N1, H3N2 and B are noted here as H1, H3 and B.
		The point is really to look at the titer less than one to four and you see that these are numbers of children.  So, most of the children, just look at the H1, 17 of the 18 children have no detectable titer in this lot before they get dosed.  If you look at H1 here, 24 to 24 are seronegative, 19 of 19 are seronegative before receiving this lot.  12 of 12 are seronegative to H1 and the placebo 28 of 28 are seronegative.
		Similarly for the H3, and I'll just go through the youngest age group.  14 of 18 are seronegative for the H3 to this lot.  18 of 24 are seronegative.  15 of 19 are seronegative to H3 for lot 3.  The efficacy vaccine 10 of 12 are seronegative.
		And for the B, likewise the children are seronegative before entering the trial.
		If you look at the 18 to 23 month olds, it's still the case; that if you look at the number of participants in the next row down, titer less than one to four, they're all unprotected based on serum HAI.
		That's just telling you that based on these three age groups they'll all entering the trial without antibody to the various strains.
		Now, if you look at table 64, which is the first page, and this again it's broken by lot and I just think it's easiest to focus on the row that says rate --
		CHAIRMAN DAUM:  Excuse me. Before you go on, can you just go back to table 42 for a minute?  I'm probably having trouble interpreting it.
		DR. MENDELMAN:  Okay.  
		CHAIRMAN DAUM:  But it looks to me like the children sort of have a binomial, it's not the right word, by biphasic distribution when they either have no antibody or undetectable antibody, or lots.  Is that not the way you see it, particularly the 24 to 36 and 18 to 23 month old kids?
		DR. MENDELMAN:  Could you repeat that analysis?
		CHAIRMAN DAUM:  I don't know, it's really not an analysis.
		DR. GREENBERG:  Bob, I'm just looking at this.  Obviously, this has just come up.  But, yes, but you are correct, but I think Paul has -- that is absolutely correct.  The point I think Paul was getting at is that the large percentage that were seronegative in these groups.
		CHAIRMAN DAUM:  And that point is clear.  But there's a substantial minority have antibody.
		Okay. Let's go on, Paul.  Thanks.
		DR. MENDELMAN:  Okay.  Understood, correct.
		So the next slide, table 64 presents the immune response to two doses, which is the proposed regiment in the children of this age group.  That's now shown up here.
		So looking at the 12 to 17 month old children, and I would focus on the rate percent.  So 88 percent are sero-converting to lot 1, 100 percent to lot 2, 74 percent to lot 3 for the H1N1.  
		For the 18 to 23 month old 90 percent sero-converting, 92 percent, 79 percent.
		For the 24 to 36 month old 80 percent, 93 percent and 83 percent.
		DR. GRIFFIN:  Can I just ask for -- oh, that's for H1.  Never mind,
		DR. MENDELMAN:  Okay.  For the H3N2 for the 12 to 17 month olds it all 100 percent sero-conversion.  
		DR. GRIFFIN:  But is your definition that of sero-conversion, because these are the same data as before you have a number of children who start out as already seropositive; that you've had a fourfold rise over an above what they had or this is the rate that is seropositive?
		DR. MENDELMAN:  They all start out seronegative in this table.
		DR. GRIFFIN:  Oh.  So you're taking only the sero-negative?
		DR. MENDELMAN:  Yes.
		DR. GRIFFIN:  So you have 20 or 30 percent that were seropositive.
		DR. MENDELMAN:  They're not in this table?
		DR. GRIFFIN:  Okay.  
		DR. MENDELMAN:  They're not presented.  It's only those that have no antibody.
		So for the H3N2 they're all sero-converting at 12 to 17 months of age.  At 18 to 23 nearly all are sero-converting, 196, 100 percent.  And the 24 to 36 months likewise.
		In the B virus -- and can you move this up, George?  The 12 to 17 months all a 100 percent sero-conversion of those three lots.  93 percent in the 18 to 23 month olds, 100 and a 100 and all 100 percent to the 24 to 36 month olds.
		So we see that there's also the efficacy vaccine and the placebo you can see for comparison.  But the immune response overall looks similar to two doses of the live attenuated vaccine at each of these three cuts in the age group.
		CHAIRMAN DAUM:  One clarifying question, please.  If in the case of someone with no antibody to start with, or below the limit of detection and sero-conversion is a fourfold increase, how do you do the math there?
		DR. MENDELMAN:  It's less than one to four -- or one to four is detectable.  If it's less than one to four, that's given a 2.  And then if it gets to--
		CHAIRMAN DAUM:  Thank you.
		DR. GREENBERG:  I don't want to slow this Committee down anymore.  I'm almost forgetting why we did this, but I think it was to show response rate in our youngest, whether response rate to vaccine in the youngest people was similar to older children.
		DR. GRIFFIN:  If it was in answer to my question, I was trying to figure out what percentage of children needed two doses at the different ages versus one dose.
		DR. STEINHOFF:  But this is all two doses.
		DR. BELSHE:  Could we return to that question just a minute, Harry, just to put a perspective on the data you've seen?
		CHAIRMAN DAUM:  Bob, what are you going to speak to here?
		DR. BELSHE:  Diane's question was what's the benefit of two doses versus one dose by age.
		CHAIRMAN DAUM:  Okay.  Please.
		DR. BELSHE:  And the way I would address that is to say what we need to know is the percentage of children who are seronegative to both H3N2 and H1N1 virus.  Because it's the second dose in those initially doubly seronegative that's important to add that additional antibody response to H1N1.
		And so it was really the first table that Dr. Mendelman showed, table 42, that's relevant.  And what this shows is that in the -- as children get older in the H3N2 era they're requiring antibody to H3N2.  And in a different era, it's going to be different.
		But that in the three age ranges showed up to 36 months of age, there's a fairly high proportion, about 50 percent of children by the oldest group shown, were still seronegative to H3N2 and nearly all of them were seronegative to H1N1.  So about 50 percent of children up through those age ranges would benefit from two doses.
		CHAIRMAN DAUM:  And there isn't similar data with post-dose one, I presume?
		DR. BELSHE:  There is similar data for post-dose one in the efficacy field trial.
		CHAIRMAN DAUM:  But not from this table?
		DR. BELSHE:  And we actually discussed this briefly in the New England Journal of Medicine article.  But the actual data aren't shown, so you'll have to rely on my memory.  And that was children under 2 years of age in the efficacy field trial, only 20 percent had antibody to H3N2 and virtually 100 percent, it was 97 or something like that percent, were seronegative to H1N1.
		By age five 80 percent of children are seropositive to H3N2 and 20 percent are still seronegative to H3N2.  And something on the order of 50 percent were seronegative to H1N1.
		So a minority of children by age five would need two doses using that kind of analysis.
		But remember, this depends on the era in which we live.  And right now we're primarily in a H3N2 era, and it's going to be different in the future, and we don't know how to anticipate that.
		CHAIRMAN DAUM:  Five Committee hands shot up while the slide was there, and I really want to move to the question.  But we will recognize these five people if their question specifically concern the new data that have been shown.  So we'll start with Dr. Stephens.
		DR. STEPHENS:  My question has to do with the column under efficacy the vaccine for H1N1.  And it looks like -- could you just clarify that those efficacy -- how those efficacy data were calculated in reference to what looks like a very nice serological response, yet a rather weak efficacy if I'm interpreting that correctly?
		DR. MENDELMAN:  The efficacy vaccine column is the seroresponse column.  So it was one of the lots that was used in trial AV006.  In this study it was just used for immunogenicity and safety.
		CHAIRMAN DAUM:  Dr. Schild?
		DR. SCHILD:  That's the same question, really.
		CHAIRMAN DAUM:  Thank you.
		DR. SCHILD:  The efficacy vaccine for H1N1 was 42 percent sero-conversion, which was significantly different from lots 1, 2 or 3.  Is there any explanation for that?
		DR. MENDELMAN:  You picked out the difference.  The H1N1 and the efficacy vaccine is A/Texas.  And the H1N1 in the three consistency lots is A/Shenzhen.  So it's a different H1N1 strain.
		The match is the H3N2 and the B on this table, but the strains had not changed.
		CHAIRMAN DAUM:  Drs. Kohl, Myers and Goldberg.  This issue only.  Mr. Kohl is out.  Dr. Myers.
		DR. MYERS:  Dr. Griffin asked my question.
		CHAIRMAN DAUM:  Dr. Goldberg?  Wow. Okay.
		We are that heady moment when we can begin to actually address the first question.  And, Dixie, you of course are in the seat of distinction up there.  Everyone in the Committee is grateful to you as evidenced by the affection Dr. Kohl is showing for you.
		Would you begin our discussion of question one, please?
		DR. SNIDER:  Thank you, Dr. Daum.
		CHAIRMAN DAUM:  Welcome, sir.
		DR. SNIDER:  With regard to the subpart (a) the pediatric and adolescent population data, I think that we have data from two influenza seasons in this age group, which demonstrate at least four the strains that we're circulating at the time, a reasonable degree of efficacy with at least two doses.  I don't think that we have enough data to be able to feel comfortable about one dose, although it's still an open question even though we were looking at the sero-conversion rates and trying to make some sense of them, some of the other data that was presented to us suggested that perhaps the sero-conversion rates are not really that good a measure, at least of the internasally administered vaccine.  
		But the number of participants in the one dose group is much smaller, so the evidence for the two dose versus the one dose is much stronger, but it would nice to be able to find out subsequently how much protection one would get from one dose.  Obviously, that has economic, logistic and many other implications.
		With regard to that population it's already been noted that we don't have an even distribution of participants throughout that whole population.  And particularly there's been concern with the youngest part of that population.  And therefore, the efficacy data for that particular part of the population is not as strong as it would be for some of the older groups that are included.
		The timing of doses I think we didn't as much clarification on that point as we might have liked, and I come away really not knowing what the optimal interval is between dosing.  But, obviously, we do have some efficacy data based on the dosing that was used. And we don't know if that's optimal or not, but it certainly appears to be satisfactory in that it, for at least the years examined, we saw a fairly high level of efficacy.
		With regard to the adult populations of part (b), the adult population information we have is primarily data on I guess what we might call effectiveness in the sense that we don't have the culture monitoring data in this population.  Nevertheless, as Kristin Nichol pointed out to us and many other people have emphasized, there was a substantial impact on influenza like illness in the adult populations.  We have to recognize, though, that his is a new disease every year and we have two year data for the kids and one year data for the adults.
		I think the challenge study data, obviously, everyone has said and I'll just repeat, that it would be nice to have field challenge data for H1N1, but we don't and there's good reasons we don't have the data for the time period the studies were done.  And the numbers of the subject, although relatively small, still with an attack rate, as I recall, of approximately 45 to 50 percent in placebo demonstrated a substantial protective effect against H1N1.
		So, I would like to see larger numbers, but don't have serious questions about efficacy against H1N1. So if the data are not adequate for specific age ranges, please discuss what additional data should be requested.  Obviously, I've alluded to this along, but we'd like to see more data in the younger age groups.  It would be nice to see data for, at least in my mind, the age groups that weren't included that are not being requested here.  Because I think there may be a role eventually for FluMist and enhancing immune responsiveness in the elderly.  We may in the elderly and immunocompromised populations have a benefit from this vaccine.  So ultimately I'd like to see that. But that's not an issue relevant to our advice about licensure for the indications that the manufacturer is seeking right now.
		I think I'll just stop at that point and let other people add.
		CHAIRMAN DAUM:  Okay.  I'm happy to let you off the hook, Dixie, but first you have to answer the question with a word, and that is are the data adequate to support the efficacy of FluMist in (a) pediatric adolescent population and (b) the adult population.  And all your comments have been on the money and noted, and so we just need a yes or no.
		DR. SNIDER:  The data support efficacy.
		CHAIRMAN DAUM:  That would be mean yes?
		DR. SNIDER:  Yes.
		CHAIRMAN DAUM:  Good.  Thank you.
		Dr. Kohl?
		DR. SNIDER:  I won't say how much or how strongly they do.
		CHAIRMAN DAUM:  No, I understand.  You know, the comments are helpful and are noted and recorded.  But we still need a vote on this one.
		Dr. Kohl, please?
		Thank you, Dr. Snider. I know that wasn't easy.
		DR. KOHL:  Thank you, Dr. Snider. I really missed you at the last meeting.
		I am very comfortable with the efficacy of this vaccine as administered both for the pediatric population and for the adult population.  So I would vote, yes, yes without reservations for efficacy.
		What I would like is pertinent to the second part of this question, and I think we very much need studies to determine whether one dose is as adequate as two doses.  And I'm hopeful that even though this might be contra to the economic interests of the company, which obviously would benefit from a two dose regime more than a one dose regime, that we will see those studies going ahead rapidly.
		I am also not at all sure what the age range is for this two dose necessity, if it will prove to exist.  So, again, that reenforces the need for a two dose versus one dose study.  
		And I'll stop there.
		CHAIRMAN DAUM:  I thank you, sir.
		Dr. Faggett, you're up.
		DR. FAGGETT:  Yes.  I think the data do support efficacy of this vaccine for the pediatric and adult adolescent population, but I would say from 2 to 17 I'm not real sure about the one under two.  But I think, you know, as a practicing pediatrician we really are very excited about the possibility of having effective relatively safe vaccine with ease of administration.  And we think this is going to really help us close the gap in disparity of flu immunizations in our vulnerable and underimmunized population.
		So, it does really look effective from the data.
		For the adult population, again, I agree with the first two speakers.  It does appear to be effective from efficacy data presented.
		I have to defer to some of the other experts relative to the efficacy against H1N1 influenza strains.  I didn't really think we had enough data to come to a conclusion on that one.  
		And I do agree that we need lot more information about the patients, especially the younger patient, the 12 to 24 month old.
		The point about one or two doses, again, I think we do need more data to really make a decision on that.  
		So my answers are yes, yes.
		CHAIRMAN DAUM:  Thank you, Dr. Faggett.
		Dr. Goldberg?
		DR. GOLDBERG:  Okay. Let me take them one at a time.
		CHAIRMAN DAUM:  Can you pull the microphone real close to you?  It has a longer cord.  Great.  Thanks.
		DR. GOLDBERG:  A, yes.  That said, I think there are a need for additional data, and I'll come back to that.
		And B, yes, but again additional data.
		The challenge studies, I believe, you need additional data for the challenge studies.  I think the data are promising, look okay, but they're very weak.
		For the pediatrics indication, it seems to me that you need a one dose versus two dose study.  And within that if you're going to propose two doses, you do need to study the optimal regiment in a controlled way.
		There's very inadequate data regarding the repeated annual dosing.  The second data is limited and beyond that it's very limited, and it seems to me you have to do some studies and I'm not sure sitting here what the right designs are, but you do need some studies to study the effective repeated annual dosing.  This is a new way of dealing with children and you're vaccinating them every year, and I think there are a lot of issues that are raised by that.
		You haven't presented any combination data here except for a little bit in passing during the discussion with the other vaccines that are given to the 12 and 15 month old, and I think you need some studies of that issue.  And I think you can probably combine these into the same study, that that takes care of that.
		And then in adults, your indication is for healthy adults 18 to 64.  That's a very difficult thing to implement.  What is the definition of healthy and you need to have a plan to deal with that.  You need to have a plan to expand this out to reasonably healthy and other levels of health and health changes.  So you're proposing a live vaccine yearly, and I think this needs to be addressed.  And, again, your challenge data in the adults are weak.
		And that's it, I'll stop.
		CHAIRMAN DAUM:  Thank you, Dr. Goldberg.
		Before we call on Ms. Fisher, I'd like to implore everyone in the room to help us.  That is to say cellphones, please, turned off.  Beepers please turned off and flash please not use.  Those are fairly simple rules and I hope they're simple and will help the Committee a lot concentrating on what is a very difficult task, as you can see.
		Thank you for your cooperation.
		Ms.  Fisher?
		MS. FISHER:  I can appreciate the complexity of trying to gather data for a new vaccine that would be used by virtually all age groups from infants to the elderly, and it's an enormous task.  
		FluMist appears to be effective in healthy children and adults, even though there are low levels of serum antibody, but I'm troubled by the lack of understanding of the biological mechanism for immunity and the implications of a low H1N1 antibody response compared to the other strains.  
		This, together with the increased incidents of influenza like illness including fever after flu misvaccination with compared to placebo, especially after the first dose, leads me to want to see more carefully collected efficacy data, especially in children under five years old, because these children are receiving 37 doses of 11 vaccines during that time period, and many of them are presenting at the time of vaccine with a coinciding viral or bacterial infection.  And I don't think this efficacy data is adequate to reflect the real environment in which this vaccine will be given to children.  So, I would like to see  at least 3,000 more children under the age of 5 with particular emphasis on those under age 2 evaluated with one or two doses over a period of four years to measure for antibody responses to the different strains for instance of influenza like illness and viral shedding with particular attention paid to whether there are individual genetic or other biological factors such as acute or chronic illness which contribute to variations of the antibody response, efficacy and the general health of the children over time after repeated use of this vaccine.
		It's very difficult to answer the question yes or no.  I would say that it's very encouraging that it looks efficacious but for me without the longer term data, especially in the young children, I cannot vote today to say yes on efficacy.  And so, I just, I'm going to have to say no.
		CHAIRMAN DAUM:  That's on both (a) and (b)?
		MS. FISHER:  I would like to see more data over time on adults also.  That's no on both.
		CHAIRMAN DAUM:  Thank you, Ms. Fisher.
		Dr. Stephens, please.
		DR. STEPHENS:  I sometimes feel like I've come to a house closing and I've done my walk through and found that all the rooms aren't finished and I'm being asked to close anyway.
		This vaccine has been shown to be effective and efficacious, certainly in the 15 to 71 month old group.  The 06 study clearly showed that, in my view.
		My real concern is this indication for the vaccine between 1 and 15 months, an area we've discussed at some length.  and I think the issue of concomitant vaccines in that group has not been fully explored.
		CHAIRMAN DAUM:  One and 15 years.
		DR. STEPHENS:  I'm sorry.  Between one year -- 12 to 15 months, excuse me, is my concern for the efficacy of that group where concomitant vaccines are concerned.
		I also have, because the data is limited and because of the issues pointed out earlier about what is a healthy adult, especially those in the 50 to 64 range, I think the data is quite limited in that particular population, although I do think this is, obviously, an important vaccine and an important breakthrough.
		So I have mixed feelings. My major concern has to do with the issue of efficacy in the young children, where I don't think that data in the 12 to 15 month old group is there.
		CHAIRMAN DAUM:  I'm not quite clear on where to categorize you, Dr. Stephens?
		DR. STEPHENS:  Well, I think that if part (a) was 15 months to 17 years of age, I would vote yes.  If it remains 1 to 17 years, I will vote no.  And in terms of the healthy adult population, part B, I would vote yes.
		CHAIRMAN DAUM:  Dr. Stephens, I thank you.
		Dr.  Griffin?
		DR. GRIFFIN:  I think that I feel very much the same way Dr. Stephens does, except I might extend it up to two years of age discomfort level between 1 and 2 years of age.
		We do have data in that older, between 1 and 2 months of age -- or 1 and 2 years of age group that I think does support efficacy.  And so I think that it is efficacious in 15 months old to 17 years of age, but I don't know that we know that it's efficacious when it's used the way that it will be used, which is in conjunction with all the other vaccines that are being given during that period, primarily between 12 and 15 months, but not everybody gets their doses on schedule.
		So if I were being asked to vote for the, and I am, 1 to 17 years, I have to say no.  If it were 2 to 17 years, I'd say yes.
		As far as the more data, the one to two dose schedule, as a number of other people have said, and I've commented on, I just don't think we have the data for either knowing what age that should be implemented or if it's even necessary to have two dose.
		I vote yes on the (b) population although I, like everybody else, would like more data.
		CHAIRMAN DAUM:  And you'll have a chance to say specifically what more data you need a little bit later.  So, thank you.
		Dr. Katz, please.
		MR. KATZ:  I think my colleagues have already expressed a number of the caveats or the concerns.  I think the other aspect, of course, is what one considers in the pragmatism of the implementation of recommendations.  And I'm very persuaded by Dr. Steinhoff's reminder that even if it's one dose in the first year, you're going to get a dose every year after that; if indeed the recommendation becomes one for universal immunization.  And that's another committee or another two committees and their distinctions.
		I think that we do have in my judgment sufficient data to be very comfortable from 18 months of age up.  And the 12 to 18 month I, too, would like to see additional data.  
		I'm very reassured by Dr. Mendelman's comment about the 2,000 youngsters who will be enrolled in the study of concomitant vaccines, MMR or given along with FluMist in the beginning of the second year of life.  So I think those data are already beginning to accumulate.
		I think that we forget sometimes that we have other vaccines where we've targeted different numbers of doses, the most recent being pneumococcal conjugate vaccine where we recommend three in the first year of life and two in the second, and one thereafter.  So, I don't think it's a new venture to think of different dosing.  But I'm comfortable with one dose at all ages at this point, given the fact that you're going to pick up the others as you go along and the pragmatic aspects of how many visits people are going to make at different times.
		I'm comfortable with the adult data, so I would vote yes, yes.
		CHAIRMAN DAUM:  And I thank you.
		Dr. Schild?
		DR. SCHILD:  Thank you.  I'm comfortable with the efficacy data.  I would vote yes on both issues.  However, with a strong recommendation for future work that effort is put into mapping the effect on efficacy of antigenic changes and genetic changes in the viruses.  We have only limited information on that for the moment.  And also the collection of data for immunological markers for protection.
		The conventional wisdom for inactivated vaccines is that hemagglutination inhabitation titers of equal or greater than 40 relate to protection.  And that clearly is not the case for these vaccines.  And it's going to important in terms of future developments in the use of these vaccines to get some much clearer information on markers for immunity.
		Thank you.
		CHAIRMAN DAUM:  Thank you.
		Dr. Cox?
		DR. COX:  Yes.  That was not a vote.
		I think that the efficacy data are really quite strong for FluMist vaccine.  It would nice to have additional data in the youngest children.  It would be nice to have additional data in adults, particularly in adults 50 to 64 years of age, but the data appeared to be quite solid.  
		So my answer to question one is yes.  And to question two is yes.
		I would like to make a comment about --
		CHAIRMAN DAUM:  1(a) and 1(b), Dr. Cox.  If I could just make sure we're on the same page?
		DR. COX:  Sorry.  1(a) and 1(b), yes, exactly.  Sorry.  
		CHAIRMAN DAUM:  Thanks.
		DR. COX:  1(a) and 1(b).
		With regard to the one dose versus two doses issue, I think that given what we know about inherent differences in different strains to induce antibodies and what we know about different eras of circulation of H1 versus H3, I think two doses for the first vaccination of children would be appropriate to make sure that we maximize the antibody response.  There's just a lot of data that would indicate that would be quite prudent.
		With regard to the interval between doses, clearly we don't have quite as much data as might be nice, but I think 30 days is very reasonable.  We've seen data for 30 day intervals that looks very good.  And because we already have recommendations for the inactivated vaccine that requires two doses in children under 9, that recommendation would be consistent with what we are already doing in that age group.
		CHAIRMAN DAUM:  Thank you very much, Dr. Cox.
		Dr. Eickhoff?
		DR. EICKHOFF:  For 1(a) children age 1 through 17, I'm quite comfortable with the efficacy data and would certainly vote yes on that issue.
		The question of dose, number of doses in children under nine, let's say, I believe for now I would vote to recommend two doses in children less than nine years of age, recognizing that that may in a certain sense be overkill and subsequent data may, indeed, confirm that one dose is quite sufficient. But at least for the moment I would sort of go into the same recommendation that currently exists for the inactivated vaccine.
		Question 1(b) I think I may be the minority report here, because I'm going to vote no on question 1(b) for the following reason.  I have no doubt that FluMist will be indeed -- is indeed effective in healthy adults.  The question in my mind is how effective.
		This is also a population in which in the inactivated vaccine is quite effective and FluMist or the live attenuated product may, in fact, be inferior to the inactivated vaccine.  I don't believe that's going to be the case, but I don't really see the data that would permit me to make that judgment.
		So, that's the reason I'm going to vote no on 1(b).
		Additional data I've talked about a little bit.  The H1N1 challenge study is promising, but again I would be much more comfortable with more field trial efficacy data.  And, of course, for adults who are other than healthy, a great deal of additional information is necessary.  But I think licensure is not being sought for such adults at this time.
		CHAIRMAN DAUM:  Thank you very much, Ted.
		Marty, Dr. Myers, please?
		DR. MYERS:  Well, I'm gold that Dr. Edwards asked the question about the limitation of our responses being defined by the specific studies.  It's very difficult to sometimes separate out the application studies from the others.
		I find the data for the 15 month to 71 month very compelling, but I do not think there is sufficient efficacy data to make a recommendation for under 15 months of age.  And I'm uncomfortable in the 15 to 24 month age group.
		So, like Dr. Griffin, if the question is 1 to 17, my answer would be no.  And if the question is 2 to 17, my answer would be yes.  That's taking into account also that we do not have any data on concomitant administration of other vaccines, particularly the MRR and vaccine.
		We have to extrapolate between 72 months and 17 years, because there is no direct efficacy data for that age group, but I'm comfortable doing that because of the established effectiveness both below and above that, although I'd like to see data for that group.
		I don't -- I'm unable to determine from these data about one versus two doses.  I have a prejudice that we'll need two doses for younger children, but I can't tell where that cutoff is.  And if you include data from other than those from the pivotal studies, I think it's likely that Dr. Katz is right, that the single dose will be sufficient.  But from these data, I just -- I don't think there's sufficient data to be able to address that.
		On question 1(b) even despite the fact that the nonspecific primary n point wasn't achieved, I think that the more specific n points establish efficacy.  I really would like to see data for more seasons, however, than just the one.
		And then I would, in addition to the data for concurrent schedule vaccines, I'd just like to express my concern about the real world impact of the cold chain on the application of the vaccine efficacy.  It's a whole lot different outside of the study circumstances managing cold chain.  And the data that was in the briefing book about the frost-free freezers I think is very worrisome and needs to be -- that needs to be addressed. Otherwise the efficacy will be far less than has been shown in the study.
		And then finally, I have reservations, we've been asked to comment on travelers. I have reservations about the use of the vaccine in travels to areas where avian influenza exposure is likely for the reasons that we discussed yesterday.
		I think we're going to talk about what other data we would like separately.
		CHAIRMAN DAUM:  Dr. Myers, before we leave you, on part 1(b) the adult population, I didn't get your vote.
		DR. MYERS:  Oh, I thought I'd said yes.
		CHAIRMAN DAUM:  Okay.  I didn't catch that.  Sorry.
		Dr. Edwards?
		DR. EDWARDS:  I think almost all the wise things have been said, so I would like to comment on, first, the pediatric and adolescent population.
		I think we do efficacy studies for a very clear reason in defined populations, and that is to determine what the efficacy is.  So that I take the age of the pivotal efficacy study very seriously, and so I really think I can't comment or don't feel that there's adequate data between the 12 and 15 month, as a number of people have already said.
		I do think there is adequate data from 15 months to 17 years to say that the vaccine will be efficacy for H3N2.  I think it also will be efficacy for H1N1, but I don't think that the number or the quality of the challenge trials in either the pediatric or the adult population really affirms that.
		I do think that previous experience and certainly previous experience that we've had would suggest that it will be efficacious.  So I will say yes for the pediatric to adolescent 15 to 17 years.
		I'm a little bit more concerns, as Dr. Eickhoff is, about the adult population in that I pondered some whether we've ever had an effectiveness trial to be used to license a vaccine, and I couldn't remember that we did.  Perhaps I'm wrong.
		I think that a standard for a trial such as this really is efficacy that is culture confirmed, although I agree that this is likely from -- that the reduction and the effectiveness we see is from a reduction in influenza.  But I don't really want to start a precedent of really not looking at efficacy trials in the purest sense.
		I do think that we don't have data about repeated dosing, particularly in adults.  And I think the data that suggests that immunization of adults that have previously seen these wild type viruses, the vaccine may be efficacious and I think whether it is as efficacious as the inactivated is not a question that we're asking, but I think is one that hasn't been answered.
		I also don't feel -- I'm uncomfortable with the challenge data.  It seems like there should have been a higher infectivity rate and we could have gotten a bit more information with larger numbers of individuals in those studies.
		So, I will say yes for the adult population, but not with a very warm and cuddly feeling, because I don't think it's the most optimal way to get vaccine efficacy.
		CHAIRMAN DAUM:  And, Dr. Edwards, so we can record your preference properly.  For the younger children you're --
		DR. EDWARDS:  Fifteen to 17, yes.
		CHAIRMAN DAUM:  Fifteen months to 17 years?
		DR. EDWARDS:  Yes. Yes.  Right.
		CHAIRMAN DAUM:  So the answer to the question is no, but if the question were reposed to 15 months to 17 years, it would be yes.
		DR. EDWARDS:  That's correct. And then I also did want to comment on the two dose.  I think, again, as I mentioned before pivotal efficacy study we have to use the data that was gleaned from that, which is the two dose schedule.  That's not to say that I think -- don't think that Dr. Glezen is totally right that we may just need a single dose, but I think that has to be shown.
		CHAIRMAN DAUM:  Thank you very much, Dr. Edwards.
		Dr. Steinhoff, not least.
		DR. STEINHOFF:  Thanks.  I can be brief, because I think many important comments have already been made.
		1(a), the pediatric adolescent population, I have to agree with a lot of my colleagues that the questions as posed, 1 to 17 is difficult to say yes to.  I don't think there is good efficacy data or substantial amount of efficacy data below the 15 months.
		The issue of two doses, the efficacy data did not show that you needed two doses for good efficacy.  And so I think that we need more data for the indication that's been applied for.
		So my recommendation is to have more information about the two doses.
		At what ages is it necessary for efficacy?
		Part (b) --
		CHAIRMAN DAUM:  Could you finish with part (a) first?  Are the data adequate to support the efficacy of FluMist in pediatric and adolescent population 1 to 17 years of age?
		DR. STEINHOFF:  I said above 15 months yes, but below no.
		CHAIRMAN DAUM:  Thank you.  So it's no?
		DR. STEINHOFF:  Yes.  And for (b), the adult population, I think the data for efficacy is adequate there.  The additional information that everyone seems to have mentioned, and I agree with, is that the H1N1 information, so there should be a recommendation to perhaps design a challenge study to answer that specific question.  That's a yes.
		CHAIRMAN DAUM:  Thank you very much.
		And I guess that it's my turn.  And I think since we last heard about this vaccine, that the progress has been marvelous.  And I think that the efficacy data, particularly, are pretty persuasive.  I think there's real reason to believe that this vaccine prevents influenza.  We're not there yet, as my colleagues in the Committee pointed out with their comments. There are issues to be addressed.
		I think Dr. Edwards' comments are most persuasive, that the 15 month cutoff makes more sense given the available data.  And I'm concerned mostly about the age chosen for the trial rather than the concern about the concurrent vaccines.  I think data must be there regarding concurrent vaccines.  But I guess my personal view is that that's unlikely to influence the efficacy.
		So, I'm also persuaded that I haven't seen anything that really persuaded me that two doses was necessary.  I must say, it's an interesting concept and it's one that could be developed more. But there was an improvement in the serology, to be sure, to one of the types but on the other hand, there really wasn't any change in efficacy that I could see.  And I don't know what serology means.
		I was struck by, to borrow a phrase from Ms. Fisher, "our lack of understanding of what the relationship is between immunogenicity and efficacy."  So that remains an open question.
		The H1N1 data, as everybody in the Committee has noted, a real world circulating virus would have been better. But I thought the challenge studies were pretty well done and convinced me that it was pretty likely that H1N1 efficacy was there.
		If there were two doses, I don't know what the optimal interval would be between the doses.  I must say I saw very little information that persuaded me how to evaluate that critically, and I'm not sure I have a wise recommendation as to how that should be done.
		And so, I guess I'm in the no for part 1(a), but if age were changed to 15 months, I would be in the yes.
		And for the adult situation, this is efficacy.  We're going to talk about safety a little bit later, I think the data are compelling that we saw, that this vaccine is efficacious in adults and I'm in the yes camp there.
		I hear the concerns about the repeat dosing issue.  We don't know much about that, year to year.  And adults have lots of diseases that impair their ability to respond to vaccines, and we obviously need to know a great deal more about that than we do.  But I believe that the efficacy part of this discussion is solid and a vote yes there.
		And that concludes our vote on question one.
		For question 1(a) I believe we have eight Committee members answering yes and seven answering no.  Of the seven that answered no, five of them qualified that by either saying 15 months or two years of age.  If the question were rephrased that way, the answer would have been yes.
		So you at one hand might say this is a very divided issue, but I think most of the controversy is in the youngest infant, 12 to 15 months or 12 to 23 months depending on which Committee member was speaking.
		For the adults, question 1(b) in terms of efficacy, the vote was pretty strongly in favor of yes.  Twelve in favor and two opposed.
		We'll have a final check here and make sure that's right.
		MS. CHERRY:  I got 13.
		CHAIRMAN DAUM:  Thirteen.  I forgot to count myself.  Thirteen yes and two against.
		So we're done with question one.  And I thank the Committee, as always, for their very elegant careful discussion.
		I want to go right on to question two.  And Dr. Mink, I hope, is ready, will remind us what question two is.
		I believe that the Committee can go through given the extensive discussion we've already had, discussion points 3 and 4 in a more rapid fashion.  And so I think the proper thing to do is question two up there, get that discussion started and make sure we get all the points flushed out that we want to raise there.
		Thank you, Dr. Mink.
		DR. MINK:  Question two for the Committee is are the safety data adequate to support safety of FluMist in the population in which an indication is being sought (i.e., 1 to 64 years of age)?
		Please discuss the adequately of the safety data in subjects less than 2 years of age, in the overall pediatric population, in adolescents, in adults and specifically in adults greater than or equal to 50 years of age.
		If the data are not adequate for specific age ranges, please discuss what additional data should be requested.
		And now my slides.  The safety conclusions from FDA presentation yesterday were please remember this BLA is on a 10 month clock and was initially submitted to us in October 31, 2000.  Much of our review is ongoing.
		The review of respiratory events including pneumonia, bronchitis and others not yet discussed are not yet complete.  A summary of these events have not been presented in the BLA, and this review has primarily been performed by database searches.
		Both the FluMist and normal allantoic fluid placebo were reactogenic in all age groups for which we've had data in the BLA which has made it more difficult in evaluating the reactogenicity of the FluMist.
		Most safety data have been generated in healthy subjects.  There is a risk of inadvertent exposure to individuals with underlying illness in the age group being sought, and we've seen a few high risk subjects presented in the briefing document, and there was a suggestion of increased in reactogenicity events for asthmatics.
		For serious adverse events the CFR definitions of hospitalization, prolonged hospitalizations, death, congenial anomaly, cancers and overdose have been the primary criteria in searching for SAEs, as consistent with all studies in the CFR.
		Some of the studies presented in the BLA did have active monitoring performed for all SAEs, and when it was performed it was for 28 to 42 days post-dosing.
		There have been questions about an increase in reactogenicity events seen with annual dosing of children.  And the studies presented, AV006 in year one and year two and safety data in year three, there was no increase in REs noted.
		There have been few subjects at the either ends of the age spectrum and in the database presented to you the number of subjects less than 24 months was approximately 1250, although we saw an increased size from Aviron this morning.  And in subjects from 50 to 64.9 years of age, it was around 500 individuals.
		Since we're going to do the additional concerns, additional concerns include concomitant immunization, and at this time we have no data for efficacy or safety with concomitant immunization.  This included pediatric vaccines with additions of Prevnar, MMR, Varicella, DTAP, and I'm probably forgetting some, that can be used in the age group from 12 to 24 months especially.
		There are also no concomitant immunizations with travelers' vaccine, which may include additional live viral vaccines or in any age group, including the use of CAIV with pneumococcal vaccine.
		For transmissibility we've seen the preliminary data from the Finish trial in day care where there was shedding of the CAIV strain in one of 99 placebo contacts.  
		And for annual vaccination, we have no data for revaccination in adults.
		Any questions?
		CHAIRMAN DAUM:  No.  Thank you very much for orienting us toward the task at hand.
		I would now like to have some general committee discussion to clarify issues.
		Thank you, Dr. Mink.
		That you feel you want more information on a clarification on before we vote on question 2.
		George, if you could do your thing and put question 2 back up there for us, I'd be grateful.  
		And, Dr. Kohl, we'll start off with you.
		DR. KOHL:  I have several major issues, at least in my mind, regarding safety.  I believe we've heard about three separate studies regarding the possibility of pneumonia.  In one of those studies there was an increased risk of pneumonia post-immunization, and I think that was the pivotal study or post-lower respiratory tract infection.  And in two other studies, Paul Glezen's study and Steve Black's study, there was not increased risk.
		I'm still somewhat concerned about that.  I don't want to see pneumonia lurking back there the way it did with rotorvirus.  If there's any other data on that, I'd love to see it.  That's number one.
		Number two, I too felt that there was a hint of an increase reactogenicity in as asthmatics given that small study on pediatric asthmatics. I believe it was about 25 in each group where asthmatics who had an exacerbation of their disease received the FluMist and not the placebo.  And although Paul Glezen said in his study there was no increased risk in asthmatics, I think he said that, I'd like to hear Steve Black in particular comment on that, because I presume there were a number of asthmatics immunized in the California study.
		CHAIRMAN DAUM:  Okay.  Before we hear responses to those, I'd like to ask FDA folks, Drs. Mink or Geber or anyone else at the table, what is in the BLA with respect to the two issues that Dr. Kohl's asking about.
		DR. MINK:  There are no summarized data for pneumonia presented in the BLA.  The data from AV006, as I've mentioned, was from our search of the database, inspection reports, line listings, SAE reports, anything that we could find.  So, our relative risk calculations from AV006 are based on our searches with the numbers that have been submitted.
		For AV019 we have interim analysis which is not the same final total that Aviron was able to present.
		And from AV012, we don't have that data.  The only thing that's been submitted in the BLA for AV012 is year one SEA reports.  We do have some line listings from parental reports which there could have been differential reporting because 80 percent of the subjects were in Scott & White HMO, but 20 percent were not. And so some of the line listing reports that we have seem to be from those line listings.  So, it's differential.  I don't know how much to emphasize that pneumonia is or is not a problem from AV012.
		DR. GEBER:  I think, too, what you're hearing from the FDA and what we're struggling with, and I think perhaps the committee is as well, is that we have received parcel study reports or study synopses  for a number of the studies that are being discussed.  And where we have completed study reports for the particular event that you're mentioning, pneumonia, that was not summarized for us.  And so we've gone back to search the databases, and that's an ongoing process.
		And so I think that's the difficulty, that we can't come to you with our complete assessment of it at this point.  And where we are is what we've presented to you.   But that is where the confusion is.
		We've received updates throughout the period of the review and we haven't --
		DR. MINK:  Nor have we completed the search for bronchitis and bronchiolitis, which could be coded differently based on age.
		CHAIRMAN DAUM:  So what I think we should do is to hear the data that bear on Dr. Kohl's very important questions, but to remember that given the fact that FDA wishes us to consider what's in the BLA, we may not wish or may not be able to get to full closure on question 2. And we'll have to do the best we can.  But let's get the information out first and then we'll go from there.
		Dr. Faggett, is this a procedural question?
		DR. FAGGETT:  Yes, it is.  Just to look at the population in Temple, because that's a military town and I'm concerned who are the children?  How many of them are military versus civilian, all that.  Do you have a breakout on that?
		DR. MINK:  All I can tell you is that we have the SEA reports and an ongoing study report for year one.
		DR. FAGGETT:  Okay.  I'll withdraw my question, if they don't have the data.
		DR. MINK:  I can tell you the ages were from 18 months to 18 years.
		DR. FAGGETT:  Yes. My concern is follow-up because if it's a transient population, it could be a--
		DR. MINK:  I understand.
		DR. FAGGETT:  Yes.  Thanks.
		CHAIRMAN DAUM:  We're going to have to do some mental agility here, Dr. Faggett. Because I think the proper thing to do is to get all the information out that we can, and I want to do that. And so your question is a good one and an important one, but at the same time we're going to then have to sort of do some tethering in our minds because we're going to have to return to the question 2 as posed by the BLA data.
		So, with that caveat, let's hear from Dr. Greenberg with regard to pneumonia and asthmatics.  And, hopefully, he'll call on Drs. Black and Mendelman as appropriate to comment on those questions.
		DR. GREENBERG:  Thank you, Dr. Daum.
		Pneumonia was raised yesterday and this morning as an area of analysis by the FDA.  And as they noted, the analysis is ongoing.  We plan to collaborate with them fully to help them complete the analysis.
		And I think as part of that helping, I think that some data that Dr. Black present right now will be useful to the Committee, and if more is needed Dr. Mendelman can embroider that further.
		DR. BLACK:  I don't know how Paul's embroidery skills are, so we'll see what we can do here.
		Yes, this was alluded to yesterday, but here it is in blue or black and white, I guess.  The results from the final analysis data set in which there were 28 cases of pneumonia in the FluMist group and 17 in the placebo.  This is all utilization settings in all doses and the entire age range.
		The great rate ratio, as you can see here, is .82 and the p-value is .25.  So there's not any suggestion of an increased risk of pneumonia here.
		And if we go to the next slide, this shows you, again from the final analysis data set, where the cases of pneumonia occurred in the FluMist group in blue versus the, I guess, gray for the placebo.  And, again, you can see that they're is scattered throughout the time period. 
		In the next slide this breaks this down a little bit by different age groups, as you can see here, starting with 1 to 17 overall, which I've shown you, and then breaking it down into the younger age group again where there is not any suggestion.  And if we go down further in age, 18 to 35 months or 12 to 17 months, again, the numbers get small but there's not any suggestion of increased risk here either.
		CHAIRMAN DAUM:  Thank you very much.
		DR. BLACK:  Do you want me to respond to asthma now as well?
		CHAIRMAN DAUM:  Yes, please.
		DR. BLACK:  With a little help here we'll try that.
		We, in response to the initial signal that we saw in the data that we presented yesterday, which you can see is 6 cases in the FluMist group and zero in the placebo with a p-value that is significant for increased risk, went back and looked to see how many asthmatics there actually were in our population.  And, as you'll see, I think we've demonstrated conclusively that querying parents as to history of asthma is not an especially efficient means of excluding asthmatics from trial participation.  What you can see here in all ages there's somewhat more than 800 children with a history of an asthma diagnoses by a physician in our databases in the period between January 1st of 1998 and their first dose of vaccine.  So we've basically gone back on average about two years prior to first dose of vaccine and identified the subset of children who has a physician diagnoses of asthma in their record.
		There are several reasons why the parents may not have been up front about the history of asthma, not the least of which is that there was -- they knew their children had been recommended in the past to get flu vaccine and last year there was really not any flu vaccine in our population until almost the end of the year.  
		And you can see here for dose one and dose two what we have.  And this is for all ages for dose one or dose two.  What we see is a rate ratio that's essentially one.  And for dose two, again, the point estimate is a little higher, but there's not any suggestion of statistical significance.
		DR. KOHL:  Excuse me, Steve. What is that the rate of, that slide you're showing?
		DR. BLACK:  You want to go back?
		DR. KOHL:  What is that showing?
		DR. BLACK:  What this is, we took this denominator of children and then looked to see how many of them had a visit for asthma in the 42 day window following the receipt of the vaccine.  So this is, in essence -- we have to be a little bit careful here because we're using the same outcome event as visits for asthma in the 42-day observation window, but we're using a different denominator.  So this is not a confirmatory study.  It's not a separate study, but it is a different way of, if you will, zeroing in on the question do children with asthma have an increased risk or not following FluMist vaccine of a visit for asthma.
		CHAIRMAN DAUM:  This tests parental recall then over previous history of asthma.
		DR. BLACK:  No.  I don't know how -- no.  No. Basically -- well, that may -- I don't know whether you're being cynical or not.  But it does parental reliability, which I think in this case, as the question was to parents have you ever been told that your child has asthma.  And if they said no, they were enrolled into the trial.  And given the prevalence of asthma in our population, that questions eliminated perhaps a third of the asthmatics, but the other two-thirds were not identified.
		But in this age range there was not any suggestion -- in the overall age range, there was not a suggestion of increased risk.  However, if we go to the next slide, again, if you remember the original association was in the younger children 18 to 35 months of age.  And if we look here in clinic and also in the combined setting, you can see here these are the relative risks are either undefined or elevated. And there is a significant increased risk.
		Now, again, I would caution you that the numerators here are largely the same as in the prior result.  Remember, of the six children that we saw before, four of them had a prior history of asthma.  So four of them are contributing to this data.  And given the high proportion that had a history of asthma before, you would almost anticipate these results. But this answers that question more directly and I thought would inform the Committee.
		CHAIRMAN DAUM:  Thank you, I guess.
		Okay.  Dr. Eickhoff, Dr. Myers, other issues.
		DR. GREENBERG:  Dr. Daum, did you want additional data on Texas in pneumonia?
		CHAIRMAN DAUM:  With regard to pneumonia or asthma?
		DR. GREENBERG:  Which?
		DR. BLACK:  Both.
		CHAIRMAN DAUM:  Yes.  Can you hold on a minute, Dr. Eickhoff and Myers.
		DR. EICKHOFF:  This was a question for Steve Black.
		CHAIRMAN DAUM:  Okay.  Let's see the Texas data first and then we'll go to that.
		DR. GREENBERG:  Why don't we ask Steve his question while we're waiting to pull up that data.
		CHAIRMAN DAUM:  That's a good idea.  Dr. Eickhoff?
		DR. EICKHOFF:  Thank you.
		Dr. Black, the pneumonia rates that you showed in that very first slide, do you have an idea what comparable rates would be for children in the same general age group absent any inhaled FluMist or inhaled placebo?
		DR. BLACK:  Given the timing of this study and the age range of this study, normally we would compare this to other studies and I could answer your question.  But the follow-up period here is exclusively during the respiratory virus season and the age ranges and given the age distribution and the sensitivity of the results to that, that's an answerable question, but I can't answer it right now.
		CHAIRMAN DAUM:  Are we ready or do we see what Dr. Myers wants?
		DR. MENDELMAN:  This is a summary from the AV012 Texas Community Prevention Trial.  Medically attended acute respiratory illness based on the Scott & White data tapes, there are over 2000 subjects in year one and 2500 in year two.
		The relative risk shown here, so with any medically attended acute respiratory illness, which includes URI, sinusitis and LRI, there's no increased relative risk.
		And then the lower respiratory illness, which includes pneumonia, group, bronchiolitis, etcetera, there's actually a decrease. But again the point estimate is no difference.
		In the subset on the next slide of children enrolled in study 12 who by parent history or RC09 code were identified with wheezing elements or asthma is shown on this slide.
		These are the days zero to 14 period. Again, you've heard about compared to the reference period the same child being their own control from day 15 on and days prior to vaccination in the data tape.
		Looking at medically attended acute respiratory illness, relative risk of 1.1, so there's no difference.  And lower respiratory illness in this subset of children I should point out 326 in year one, 502 of these children in year two.  .7 and .8 reduced risk but no difference.  And in asthma wheezing reduced and no difference.
		DR. GRIFFIN:  Can you tell me just what the age of these children is?
		DR. MENDELMAN:  I'm sorry?
		DR. GRIFFIN:  The age range for this?
		DR. MENDELMAN:  These children are 18 months to 18 years of age.
		DR. FAGGETT:  Okay.  Are those the same children in year one and two?  Is that additional children for year two?
		DR. MENDELMAN:  These are additional children in year one, year two.
		DR. FAGGETT:  So that the 502 would be different children?
		DR. MENDELMAN:  Yes.
		CHAIRMAN DAUM:  Dr. Myers, is your issue about this issue, this very thing, or are you going to start --
		DR. MYERS:  It's related to the Houston data, but it's a separate question.
		CHAIRMAN DAUM:  Okay.  Let's hear from Dr. Goldberg.  Is yours about this very thing?  Let's hear that first and then Dr. Myers.
		DR. GOLDBERG:  Just one clarification on this slide.  The reference period is the 15 day period pre-vaccination?  Is that what you said?  I'm sorry, I missed it and it's relevant to --
		DR. MENDELMAN:  It's a good question.  The reference period in year one starts on the data -- any child being dosed, which is August 17th of '98 and ran through January 2nd of '99.  And then for that individual child who was dosed, the 14 day period after their dosing to the time before they were dosed in those dates all the way through to January 2nd, 1999.
		In year two the dosing started in September, so it's September 13th of '99 through January 13th of 2000.  And it's presented in person-months.
		DR. GOLDBERG:  Just a question, though. If the child was vaccinated early in that period, so their reference period would be extremely short.  So therefore you would have a bias against -- like if a child was having asthma or wheezing in like a two week period right before, they might not be coming in for a vaccination at that point.  So that there's a possibility that you've got some funny population --
		DR. MENDELMAN:  Well, the vaccinations --
		DR. GOLDBERG:  Or am I not understanding your data?
		DR. MENDELMAN:  Yes, the vaccination in both years of the trial ended in December.  So going through to January would have collected the additional data.
		DR. GOLDBERG:  That's the post-data.
		DR. MENDELMAN:  Sorry?
		DR. GOLDBERG:  That's post-vaccination data.  I'm talking about your pre-vaccination period that you're comparing to.  Like for a given child, it could be relatively short or up to almost as long as that whole period?
		DR. MENDELMAN:  Right, most of that would be in the post-vaccination period.  That's correct.
		DR. GOLDBERG:  All right.  Thanks.
		CHAIRMAN DAUM:  Thank you.
		Dr. Myers?
		DR. MENDELMAN:  Bob, could Dr. Glezen comment on this?
		DR. GLEZEN:  I'd like to clarify that.  Of course, if the child only got vaccine on the first day of vaccine administration, we wouldn't have any pre-vaccine period.  But if the child got vaccinated two months later, we had all their clinical data starting with the first day of vaccination.
		So there was no bias that you referred to there, as far as the data goes.
		DR. GOLDBERG:  I'm still confused then by your answer.  You're saying your post data is within two weeks after vaccination.  So are you saying the reference period includes then stuff after the 14th day post-vaccination as well?
		DR. GLEZEN:  That's right, yes.
		DR. GOLDBERG:  So it's a pre and a post?
		DR. GLEZEN:  Pre and a post.
		DR. GOLDBERG:  Okay.  That was totally unclear.
		DR. GLEZEN:  Yes.  Yes.  Yes. So we have the clinical data for the whole period, our vaccine period which would be the day one the first period got vaccine to 42 days after the last person got vaccine.
		DR. GOLDBERG:  But is there implicit -- just let me make sure I understand this.
		Is implicit in this then that a post-vaccination event is only within those two weeks.
		DR. GLEZEN:  Right.  Right.
		DR. GOLDBERG:  Supposing there was a longer term relationship with some of these outcomes then, that would be being called their reference period, is that right?
		DR. GLEZEN:  This data refers to events that occurred zero to 14 days. However, we did look at all events over the entire period to see if there was any clustering, and we did not see any. There was random distribution of events throughout that period of observation.
		DR. GOLDBERG:  Okay.  Thank you.
		DR. GLEZEN:  And one other point I wanted to make.  The year two data did include some kids who'd had their second dose and kids that had just their first dose. It was about half and half.   And we've looked at the same parameters in kids who got their second dose versus those that got their first, and there's no difference.
		DR. GOLDBERG:  Thank you.
		CHAIRMAN DAUM:  Dr. Myers?
		DR. MYERS:  We heard yesterday that obtaining cultures during the first part of the study period, I think it's the first ten days, was discouraged.  And I presume that's because of --
		CHAIRMAN DAUM:  Before 14, I believe.
		DR. MYERS:  First fourteen.  That's because of expected vaccine shedding. But we also heard a suggestion that those children had a clustering of influenza-like illness and 16 of the 17 positive cultures came from Houston.
		So I guess the question I have is there's 16 cultures that were positive in Houston, what's the denominator of the number of cultures that were obtained and could we see the data for the culture positive versus the culture negative, what the symptom clusters were for those children?
		CHAIRMAN DAUM:  Thank you.  Who wants to take this question on? Harry?
		DR. GREENBERG:  Paul, the question is about the Houston cultures, and here we are.  Would you like to come up?
		There are a couple of responses to this. Paul, why don't you start out?
		DR. MENDELMAN:  We presented this slide yesterday, and I guess you can't see it any better today.  But -- sorry.  We made a lot of slides last night. We didn't redo this one.
		The randomized comparison for the 116 children who were cultured in 14 days after dosing in study AV006 are shown on this slide.  So this is the randomized comparison.  There's 78 FluMist recipients and 38 placebo recipients.  And then just moving down the events, the symptom complexes that CBER requested that we provided were if they had any of the three reactogenicity events, 48 percent of these FluMist recipients and 50 percent of the placebo recipients had at least three events on one day.
		Looking at another definition of temperature greater than 100 degrees, cough with runny nose or nasal congestion, 9.1 percent in the FluMist, 7.9 percent in the placebo group.
		And the CDC-ILI definition 19.5 percent in the FluMist and 21.1 percent in the placebo group.
		And then these are the actual event that these events were complexed from.  And maybe you can't see, I'll just read them.
		The runny nose, 79.2, 71.1.  Sore throat 27 percent versus 18 percent.  Irritability 36 percent versus 47 percent.  Headache 14 percent versus 7.9.  Chills 11.7 versus 10.5.  Muscle aches 10.4 versus 5.3.  And decreased activity 31 percent versus 13.2.  And temperature greater than 100 33.8 versus 23.7 and a higher set point of 102 7.8 versus 7.9.
		Now, in the data presented also to you yesterday was the culture positives for children who were sick who got cultured compared to the culture negative FluMist recipients who also were sick, but their cultures didn't happen to be positive.  And I think it becomes a statistical as well as a clinical issue.  And if Dr. Wittes could comment on the statistical, I think that might help. 
		Thank you.
		DR. WITTES:  And I even have a voice today, not my usual voice but one better before.
		I think what you saw yesterday was a split.  The FDA's presentation took the FluMist and split it into two groups; those who had positive shedding and those who had negative, and that was the nature of the comparison you saw.
		That comparison, of course, is inherently problematic because it doesn't compare the two randomized groups, which is the FluMist versus placebo. And there's no way that you can identify within the group -- if you look at that placebo column, there's no way of being able to tell who in the placebo group would have shed had they been given the vaccine.  So there's a selection problem in the comparison, I believe in the comparison that you saw yesterday.
		Any variable that is confounded -- that's related to both shedding and to the symptoms will get confounded in the split that you saw yesterday. So we think you need to look at the two groups as they were randomized.
		CHAIRMAN DAUM:  Thank you very much.
		I'd like to hear from Dr. Mink on this issue as well, and then we'll call on Dr. Edwards.
		DR. MINK:  Okay.  I can try to answer both of your questions with our perspective, Dr. Myers.
		First we mentioned there was this many cultures -- there were 17 FluMist recipients who had 18 positive cultures.  16 of those 17 subjects were from Houston.  Culturing was discouraged in the first 11 days of the protocol.  After 11 days it became part of the efficacy surveillance.  
		And kids who had illness, there were illness criteria stated in the protocol to bring them in for evaluation for cultures.
		So these 16 kids at Houston in the first-- it actually turns out to be the first 11 days were brought in for culturing.
		So we looked at the total number of cultures obtained at Houston.  31 out of 144 FluMist recipients were brought in.  Of those 31, 16 were culture positive.  31 who were ill FluMist recipients at Houston.
		There were also 13 ill placebo recipients at Houston.  So the culturing rate between the groups was about the same percentage.
		We presented the data to you like this, acknowledging the statistical possibility of confounding.  We weren't looking to compare FluMist and placebo.  We were looking to compare who was ill that grew cold-adapted virus and who was ill that could have grown something else.
		As Dr. Mendelman mentioned yesterday, I think it was -- you don't have data for what the other kids may have grown.
		To be complete, we presented the placebo data.  36 of 38 subjects were negative. Two are coded in our database as other, but we presumed that's negative for CAIV. These kids shouldn't be shedding CAIV theoretically because they weren't given CAIV.
		So in looking at who was ill and of those ill people who shed virus and who didn't shed CAIV and what their illness profiles.  Okay?
		Of these kids who were ill with shedding virus, 70 percent of them had at least three RE events on the same day.  41 percent of them compared to 13 percent of them met CDC influenza-like illness criteria. 100 percent of them had runny nose.  And 70.6 percent of them had a 1.6 fever or greater.  We have not performed statistical comparisons on these.  These are just to present to you the illness profiles of these subjects.  
		With help from Aviron in gathering the data and this analysis is also ongoing, we present the negative subjects and the placebo subjects, and you can see that they're fairly comparable for those who didn't grow a cold-adapted viral strain.
		Dr. Greenberg, did you want --
		CHAIRMAN DAUM:  Thank you very much.
		Other Committee comment.  Dr. Edwards is first.
		DR. EDWARDS:  I wanted to ask whether those samples may have been saved and whether those samples from all the vaccine recipients and the placebos might be looked at for RSV or PCRed for RSV, because I think it would be helpful?
		DR. MENDELMAN:  The simple answer is, Dr. Edwards, that all 5,000 cultures taken across both years of the trial are in the freezer.
		DR. EDWARDS:  So you can answer that from the original nasal sample?
		DR. MENDELMAN:  Correct.
		CHAIRMAN DAUM:  Dr. Edwards, can I flush you out a little bit out that, though?  I think it's a very important point.
		It seems like some children who get this vaccine may get a flu-like illness.  And I agree -- are you suggesting that maybe it wasn't and it was confounded by some other virus circulating?
		DR. EDWARDS:  Well, I think if you do cultures on patients who have been given cold-adapted vaccine, you're going to grow cold-adapted vaccine.  And I think what's confounding this issue, particularly as it relates to pneumonia, is that for those of us who do these flu studies or have in the past, you get the vaccine late, you're hurrying to get all these kids immunized before flu comes.  And, unfortunately, RS comes before flu comes.  So you have co-circulating viruses.  And I think it would be helpful to shed if is there a pneumonia problem from cold-adapted vaccine?
		I mean, there are going to be kids who have reactions to -- I mean, who have runny nose and some low grade fever from the cold-adapted vaccine.  But the issue of whether we have lower tract disease I think is a very important one.  And I really think that it's incumbent that those samples be gotten out and PCRed to find out if there is a component of pneumonia, it may very well be RSV and not flu.
		DR. MINK:  I'd like to answer.  The study AV006 was initiated in August and enrollment was completed in November.  The Houston site, it's my understanding and recollection, was primarily done at the end of October and early November. So it was a little bit later than some of the other study sites.  But most of the 14 day or 11 day post-vaccination would have been completed for those kids, I would presume, by the end of November at the very latest.
		DR. EDWARDS:  Could we have a comment from Houston about when the RSV season was then?  I mean, do you remember that or -- I mean, I think it's basically kind of relevant, though, because I think one big problem is our discomfort with the pneumonia issue.
		DR. GREENBERG:  Bob?
		CHAIRMAN DAUM:  We want to deal with this question.
		DR. GLEZEN:  Okay.  
		CHAIRMAN DAUM:  Dr. Glezen, are you able?
		DR. GLEZEN:  I can just speak in general terms about this.  Tony Piedra was the PI of the Houston contribution to this, and I don't have any of the data.
		I can tell you that RSV virus isolated in Houston every month of the year.  And the epidemics have been occurring earlier and have been very severe.  This past year was the lightest year that we've had in quite a while.  But we have surveillance data from Texas Children's Hospital, does a lot of antigenic detection.
		So RS is definitely regularly present in August.  And in October it's going to be very active.
		Parainfluenza, of course, is every other year, whatever. But we also see parainfluenza at the same time.
		And my recollection is that there are other viruses isolated from these same specimens, but I don't have the data.  So we need to dig that up.
		CHAIRMAN DAUM:  Okay.  It's getting close to lunchtime.  
		Harry, did you want to speak to this issue?
		DR. GREENBERG:  The pneumonia issue, which I think Kathy Edwards absolutely and Aviron takes very seriously, I just want to clarify in my own mind.  We take great comfort in this very randomized placebo controlled data that Dr. Black just presented to you and the very clear temporal data that he presented showing that both in the FluMist recipients and in the placebo mist recipients pneumonia did not cluster in anyway temporally.  It was equally matched and occurred throughout the period giving no indication in a very large trial that pneumonia was not an issue.
		I may have totally missed the boat here.  I don't think Dr. Mink is talking about pneumonia.
		DR. MINK:  The 16 subjects in Houston, I just presented the influenza-like illness profiles of them.  There was some subject who had pneumonia who was associated with a positive culture, but only that one subject for pneumonia out of those 16.  So I can't make a comment about pneumonia other than that.
		CHAIRMAN DAUM:  Thank you.
		I'd like to at this moment call on Dr. Goldberg for a final comment.  Question about this very issue.
		DR. GOLDBERG:  Not about this issue.  Something else.
		CHAIRMAN DAUM:  Can you hold it then?  What I'd like to do is take a lunch break at this time.  50 minutes in duration and reassemble at 1:05 here and finish this safety discussion.  And Dr. Goldberg we'll start with your comment.
		(Whereupon, at 12:17 p.m. the Committee adjourned to reconvene this same day at 1:14 p.m.)

	A-F-T-E-R-N-O-O-N  S-E-S-S-I-O-N
	1:14 p.m.
		CHAIRMAN DAUM:  Today is an airplane day, so we're most anxious to get started, lest we not be able to finish.
		There are a couple of housekeeping issues or leftovers from this morning.
		The first one is to reiterate the Committee vote on question 1(a).  The vote was 8 yes and 7 no.  Of the 7 no, 5 qualified their no.  Two individuals said they would have voted yes if the question were phrased from 2 to 17 years.  And three more individuals would have said yes if the question were phrased from 15 months to 17 years. So that is the correct and checked vote.
		On the question 1(b) 13 Committee members voted yes and 2 voted no, and there were not qualifications in that regard on that issue.
		So I hope that's helpful and clarifies one thing that people seen confused about.
		A second thing people seemed confused about were the data regarding asthma.  And I'd like to call on Dr. Black to just literally take less than 2 minutes, as he's promised, and try and explain to us what I at least misunderstood this morning, and maybe others did as well.  Dr. Black?
		DR. BLACK:  Okay.  I apologize, but I'll try again.
		Basically these are the original results that we had with 6 cases in the FluMist group and zero on the placebo group in the initial and then interim analysis dataset.
		Next slide, please.  What we did then is to go back and look using the entire dataset and asked a different question.  The original question was for all children in the study how many had a visit for asthma in the FluMist group as compared with the placebo group.  The question we then tried to ask is of the children who had a prior diagnoses of asthma in the population, which is a subset of the total population, how many of those had a visit for asthma following receipt of vaccine.  And to do that we went back to January 1st of 1998 to the first dose for each child and looked in their electronic medical record and asked did a doctor assign a diagnoses of asthma to this child either in the clinic, the ER or the hospital.
		In so doing we identified, as you can see here, 852 children out of the total, about 8 percent or so, who actually had a prior-dose diagnoses of asthma in the population.
		And then we then asked for those children what was the risk of a visit for asthma following receipt of FluMist vaccine for either dose one or dose two.  And, as you can see, for dose one for example, the risk of a visit for asthma following receipt of FluMist was essentially equal for the placebo and the FluMist group.  And for dose two the point estimate is 1.5, but again there was no statistically significant difference.
		And on the next slide what we then did is go back to the original age group where we had initially identified this problem and again asked how many children had a prior diagnoses of asthma here and then subsequently had a visit for asthma following receipt of FluMist.  And I guess the easiest thing to look at here, for example, in the clinic for both doses combined you can see that the risk ratio was 3.8; that is children who had a prior history of asthma before receipt of FluMist were 3.8 times more likely to have a visit for asthma following receipt of FluMist than the controls.  And that was statistically significant.
		Is that clear?
		CHAIRMAN DAUM:  So can I try and rephrase it and see if it's to your liking?  That you didn't intend to enroll any asthmatics in this study, but of those that managed to get in without you really realizing that they had asthma, there was a higher incidence of some kind of asthmatic episode among FluMist recipients?
		DR. BLACK:  Following receipt of vaccine for the 18 to 35 month olds.  And we used a different ascertainment method here.  For the entry into the trial we asked the parent.  To determine this cohort, we actually looked at the electronic data.
		CHAIRMAN DAUM:  Thank you very much.  That's extremely helpful and we'll take questions on this now.  Dr. Edwards, Dr. Steinhoff, Dr. Katz?
		DR. EDWARDS:  Was that seen in any other age groups or you didn't do that because you didn't notice there was a difference in that age group --
		DR. BLACK:  Go back one side.  I mean, if you look overall, we don't see anything.
		DR. EDWARDS:  Okay.  
		DR. BLACK:  And you have to remember that the numerators are very similar to the numerators in the initial analysis, because it's the same 42 day window following receipt of vaccine.  The only thing we saw, the initial elevated risk was, and it was in the 18 to 35 month old.  And, in fact, some of the events that we're seeing here are the same events that we saw in the prior analysis.  So it's not an independent collaboration of the initial observation, but basically it's answering a different question.  And I wanted to make sure the Committee understood what that question was.
		CHAIRMAN DAUM:  Thank you so much, Steve.
		Dr. Steinhoff, is it about this?
		DR. STEINHOFF:  Yes.
		CHAIRMAN DAUM:  Please.
		DR. STEINHOFF:  It's almost the same question that Kathy just asked.  The original data you presented that this asthma association in your prospective study was only seen in this age group, correct?
		DR. BLACK:  Correct.
		DR. STEINHOFF:  And that's why you've done all these other analyses in that group?
		DR. BLACK:  Yes.  And the reason we focused on this age group for this follow-up analysis is because that's where we saw the -- the only place we saw the observation in the initial analysis.
		CHAIRMAN DAUM:  Okay.  And we have Dr. Katz.
		MR. KATZ:  In this notebook that we received in advance, pages 137 to 140, two studies are described in asthmatic children.  7.8.1.3 reactogenicity in participants with asthma.  And, again, the numbers are small but what it says basically is that two out of 47 asthmatics who got FluMist allegedly had asthma, one out of 37 placebos allegedly had asthma.
		And then the next study is again somewhat similar.  And these are older children, I think, if I understand correctly.  It says 9 to 17 years and 16 to 24 years.		
		Is this the right book, Nancy?
		MS. CHERRY:  No, I'm just looking at what page you're on.
		MR. KATZ:  I'm on pages 137, 138 and 139 and 140.  The table numbers are 76, 77, 78.  Yes, that's it.  And 75.  
		DR. BLACK:  Bob, while they're looking for that, can I just comment on thing?
		We have limited power to assess older ages because by the time the children get older, they're more likely to actually have the parent be aware that they actually do have asthma, and the numbers are smaller.
		And also, the asthmatics that are here, although we can't verify this, I think are likely to be milder asthmatics.  Because, again, if they were sicker I think that both the physician and the parents would be more aware of it as well.
		MR. KATZ:  In these tables I don't think they show what is written in the text, which is a very -- they're small numbers.  But there are two with asthma in the FluMist, one in the placebo.  And in the other study it's somewhat similar.
		And I just wondered, are these the same children or are these different studies?
		DR. MENDELMAN:  These are children in -- I'm sorry, these are participants in Aviron trials.  These are not participants in the Kaiser trial.
		MR. KATZ:  Okay.  
		DR. MENDELMAN:  So study 10 was the study in 9 to 17 year olds, 48 children with moderate to severe asthma based on the NHLBI guidelines.  Randomized one to one doing a single dose of FluMist or placebo.  And study 9 is the healthy working adult effectiveness trial where 36 of these adults got into the trial because their physicians didn't tell them they should get the flu shots they could be in a placebo controlled trial.
		And you're right, in this group of 24 there were two exacerbations, that's 8 percent, within three days of getting FluMist. In this group there was zero out of 24.  The sample size is limited, that's not statistically different, but those are the numbers.  They were treated as outpatients.
		In this group there were two exacerbations of 23, so that's about 10 percent.  And there was one exacerbation of this 13 placebo recipients in AV009.
		CHAIRMAN DAUM:  Okay.  Thank you very much.
		I think Dr. Goldberg is first up with new items.  So, before you start, I'd like to just ask Committee members to remind them that this is question 2, which has to do with safety.  And so what we really want are people to pick out issues before we have the question that they need clarification on or want to discuss, or just want to make a comment on.  And we will do that.
		Dr. Goldberg and then Dr. Cox and Kohl.
		DR. GOLDBERG:  Some data were presented on the contacts of FluMist vaccinated subjects, and I can't find them in my notes.  Could you put that up again?  There was a contact study that was described.  Thank you.  Pardon?
		DR. GREENBERG:  Are we talking about transmission study, is that correct?
		DR. GOLDBERG:  Yes.  Yes.  I didn't remember the number and I'm having trouble locating it.
		DR. GOLDBERG:  Yes.  And you're asking about the slide that you saw?
		DR. GOLDBERG:  I'd like to see the slide that was shown yesterday.  Thank you.
		DR. GOLDBERG:  It's Paul's primary.  She asked to put it up again, the slide.  Next slide.  
		Is this the one that you were looking for?
		DR. GOLDBERG:  There was a cross tabulation that you presented.
		DR. GREENBERG:  I'm blanking.  This is the slide on the transmission study.
		CHAIRMAN DAUM:  Is this a time to have Dr. Zamb get ready to show us the sequence of the shed virus, which I would like to see?
		DR. GREENBERG:  I think what Dr. Zamb can do is actually, to save time, is to tell you the results very quickly.
		CHAIRMAN DAUM:  Outstanding.
		DR. GREENBERG:  Using words.  
		CHAIRMAN DAUM:  Words are good.
		DR. ZAMB:  Good afternoon.  My name is Tim Zamb, I'm from Viral Vaccines Research of Wyeth Lederle Vaccines.  
		I have spent a fair bit of time looking at the genetic stability of FluMist by doing extensive genome sequencing analysis.  And we focused on the trial that the slide was just presented with respect to the Finish horizontal transmission study that was conducted in the 1999/2000 flu season.
		CHAIRMAN DAUM:  Could you take a minute, Dr. Zamb, and just raise the microphone so we're sure we don't miss your words.
		DR. ZAMB:  So what in fact we did was to evaluate the genetic stability of these vaccines following administration to individuals in this study.  And we used three criteria in order to select them.
		One was, in fact, based on the evaluations and the Finish clinical lab with respect to the presence of influenza virus in the samples.  This was done by standard virologic culture.
		The second criterion we used was that we attempted to look at those that appeared to be single virus, vaxima virus rather than mixtures simply to allow us to do sequencing much more efficiently.
		And the third is that we were looking for optimized or maximize the potential effect of finding misincorporations.  So what we did was to tend to take samples that occurred later after vaccination than earlier.
		We attempted to sequence 60 independent genomes with respect to having 20 genome representatives for each of the vaxima viruses that were present in the trial in formulation.  That's the A/Sydney, A/Beijing and B/Harbin-like virus.  And, in fact, we did see, as we would expect a few nucleotide misincorporations in some of these viruses.  We saw misincorporations that ranged from zero to 6 per genome with an average of two misincorporations per genome. 
		With respect to that potential transmission case, we in fact did sequence that virus and found, again, three nucleotide misincorporations in that vaccine virus that was recovered from the placebo recipient.
		An identical pattern of misincorporation was found in a vaccinal virus from a vaccinee that shed that virus 5 day previously to the potential transmitter -- the vaccinal virus was shed on the 25th of February, the placebo recipient shed that same marked virus on the 1st of March, separating those two events by five days.
		CHAIRMAN DAUM:  And you conclude from that?
		DR. ZAMB:  That the transmission is a likely event and that that B virus was transmitted from that one patient, one subject, that was in the vaccine group and transmitted to one of the placebo recipients.  However, I must state that all of this analysis was done on culture amplified virus. In fact, what happened i the Finland in the clinical lab was that the swabs were taken and amplified in an MDCK cells.  Those amplified products were then sent to Aviron for further subtyping, and we received those amplification products for sequencing from them.
		CHAIRMAN DAUM:  Thank you very much.  Are those data in the BLA?
		DR. ZAMB:  No, they're not.  These are recent data.  We're generating them now and we're not finished with our analysis.
		CHAIRMAN DAUM:  Thank you.
		Dr. Cox?
		DR. ZAMB:  One additional key point is that --
		CHAIRMAN DAUM:  Please be brief.
		DR. ZAMB:  Sure thing.
		One additional key point is that the phenotypes of all these viruses were as expected, cold-adapted and temperature sensitive.
		In addition, any of the misincorporations that were found in these clinical isolates were not associated with those loci thought to be the cause of the cold-adapted attenuation and temperature sensitive phenotypes.
		In addition, that there was no increased pathogenicity associated with any of these viruses in the children that shed them.
		CHAIRMAN DAUM:  Pass received.  Dr. Cox?
		DR. COX:  Most of my questions with regard to that particular instance have been answered now.
		I guess the only additional question would be how many of the three nucleotide changes were also coding changes?
		DR. ZAMB:  They were all coding changes.
		DR. COX:  All coding changes?
		DR. ZAMB:  Yes.
		DR. COX:  Okay.  And do I understand it correctly that that virus was put back into ferrets and determined to be attenuated?
		DR. ZAMB:  No, they weren't.  They were cold-adapted and temperature sensitive.
		DR. COX:  In tissue culture?
		DR. ZAMB:  That's correct.
		DR. COX:  Okay.  
		DR. ZAMB:  And the child who shed that virus did not express any unexpected symptoms.  So it's apparently -- I mean, its attenuated phenotype is apparently maintained in the individual who shed that virus.
		DR. MURPHY:  Do you have serological data?
		DR. ZAMB:  There weren't any --
		CHAIRMAN DAUM:  Excuse me. I didn't recognize the speaker.  Who spoke?  No, I'm sorry, Dr. Murphy.  We can't do that.  
		Thank you very much, Dr. Zamb.
		DR. ZAMB:  Sure.
		CHAIRMAN DAUM:  Dr. Kohl, please?
		DR. KOHL:  I could ask Dr. Murphy's question, couldn't I?  Do we have any serology data?
		CHAIRMAN DAUM:  That would be nice.
		DR. KOHL:  That'll be 5 bucks, Dr. Murphy.  That's a joke, for the record.
		So, my first question was was there any serology on those patients.  And the second question was does Dr. Black have temporal data on the patients with the asthmatic exacerbations?
		DR. ZAMB:  With respect to the Finish trial, there weren't any blood samples taken.  It's rather difficult in Europe now to conduct a clinical trial, especially on children that requires blood sampling.
		CHAIRMAN DAUM:  Second question.
		DR. GREENBERG:  We do and we are calling it up.
		CHAIRMAN DAUM:  George has a lot of helpers in the afternoon.
		DR. GREENBERG:  George has a lot of slides.
		CHAIRMAN DAUM:  While he's calling it up, I'll say that I marvel at the dexterity with which both FDA and sponsor have been able to produce data on demand having no idea what question we're going to ask next.  And so we thank you for that. It makes the discussion of high quality.
		DR. BLACK:  Yes. It's actually a shame you said that, because we don't have a graph.  What we have, this is the graph that I showed you before on the initial data set of the six children who did have asthma following receipt of vaccine.  We've not graphed the other children from the other analysis.  We could, but we have not yet.
		CHAIRMAN DAUM:  Thank you very much.
		Dr. Kohl, are you all set?  Okay.  I have you here.
		Other Committee discussion?  Dr. Edwards and Dr. Stephens, Dr. Schild.
		DR. EDWARDS:  I did want to just go back to the slide number 70 from the FDA yesterday where there appeared a line listing of pediatric pneumonia cases.  And granted, this is still a work in progress, but I wondered if there was a possibility to shed any additional light on any of those cases or to give us a frame of reference to compare this study 006 and the one 009 in terms of relative risks of pneumonia.  Because I think this is an issue that I'm sort of grappling with. Do we have adequate data that would address the safety?
		Certainly Steve's study is large, and we have that data.  But what about the other cases, and maybe the FDA would like to comment on that.
		DR. MINK:  This is the pediatric pneumonia cases that we've identified so far in our review. As I've discussed, it's ongoing.
		We have not totaled the cases in this column intentionally.  There are varying age groups, varying times of follow-up and varying monitoring. So there is no here number on purpose.
		What this is to show you is that we have so far identified 37 cases that were pediatric age group, okay?  This is not a two to one randomization of FluMist to placebo.  These are just the cases that we've identified so far in FluMist and the cases that we've identified so far in placebo.
		For denominators, we have that for AV006.  This is a study that we mentioned before was enrollment began in August and continued through November. These kids are 15 to 71 months of age. In that context less than 21 days the relative risk was 1.98 with these confidence intervals of .36 to 24.78.
		We have also provided relative risk for study AV019, which is similar to those presented by the sponsor.  This is children from 1 to 17 years. This study was performed starting in October and we have data through December 31st -- or maybe April 30th, I can't remember for sure.  But I think it was December 31st in the interim analysis for this.
		From 1 to 17 year olds who received FluMist from October through the end of December, the relative risk was .83 with the confidence intervals of .3 and 2.28 showing for pneumonia is less than 21 days.  Okay?
		We can't give you a percentage here, nor do we mean to imply that there is twice as many in the FluMist group than the placebo groups.  These are just the studies in which we've been able to look for cases.  And in those studies we found 37 and 12.  These don't even have placebo groups, so you can't compare them. Okay?
		CHAIRMAN DAUM:  So what is your conclusion from that?
		DR. MINK:  My conclusion in AV006 is there's a signal and we need to understand more.  In AV019 there's not a signal and we need to understand more.  But, like I emphasized, it's different follow-up, different analysis -- I'm sorry. Different age groups.  And Aviron is working with us to finish this analysis.
		CHAIRMAN DAUM:  Are these data on this slide regarding pneumonia in the BLA?
		DR. MINK:  That's what I'm showing you.  This is all I have in the BLA. But the data for pneumonia wasn't submitted summarized.  We've been doing a search for it.  And this doesn't include bronchitis and bronchiolitis, which could be coded very differently.  We don't have predefined definitions of pneumonia.  
		Like in 019 it's ICD09 codes that the caregiver is giving.  In AV112 year one it's line listings from some of the parents.  In AV06 there's a combination of how the pneumonia is being identified.
		This is a lot of differences put together.
		CHAIRMAN DAUM:  Dr. Katz and Dr. Geber.
		MR. KATZ:  I think she just answered my question.  It doesn't mean a positive chest film. It doesn't mean a positive blood culture.  It just means somebody wrote down pneumonia.
		DR. MINK:  A healthcare provider.
		CHAIRMAN DAUM:  Dr. Geber, please.
		DR. GEBER:  No, I think that that's all.  I think that for some of these studies that are listed here, we don't have complete study reports yet.  And we did receive some case report forms, I believe, from all of these subjects last week.  So while the information will be available and we will be able to identify -- I think the point that we're trying to make is that in our review of study AV006 for year one, when we looked at pneumonia, these are the cases that we found, although they hadn't been summarized.
		And then the next point we're trying to make is that there are a lot of outstanding data to us, much that the sponsor has presented, some which have been submitted but have been submitted in subsequent submissions after October and are not completely reviewed by us.
		So, I think our review is incomplete  and we can't draw yet any conclusions one way or the other about pneumonia at this point.  And we recognize that the sponsor will work with us to provide additional data, but we don't have those data just yet.
		CHAIRMAN DAUM:  Thank you, Dr. Geber.
		Dr. Greenberg, you wanted to make a comment about pneumonia.
		DR. GREENBERG:  I totally agree that we will continue to work with the FDA to define these issues with great clarity.  
		I would only take slight issue with saying that they detected a signal when there is no statistical association really of a signal.  And I think we need to look carefully at all the data and what you have seen is a very large trial from Kaiser, controlled, randomized, double blind placebo control. And I just want to remind you, although you've heard it several times, that there's no increase in pneumonia and there's no clustering temporally of pneumonia.  And I won't show you the data, but from the cases AV012 in those two years there is also no time clustering of those cases vis-à-vis the receipt of FluMist.
		The FDA will evaluate that as they need to independently, but I think that will give them confidence that there isn't a signal there as well.
		CHAIRMAN DAUM:  Thank you very much. I'd like to return to the Committee at this point and see whether here are other safety issues that we want clarified or discussed in some more depth, or data from our FDA or sponsored colleagues.
		Dr. Stephens?
		DR. STEPHENS:  My question concerns the allantoic fluid "placebo" or diluent.  And I don't think we've discussed that enough, at least in my view.
		Is there any data from the manufacturer on just the "placebo" or the allantoic fluid in comparison was saline or a different placebo?  Because I guess my one concern I have is the reactogenicity of that material and we're constantly referring to it as a placebo when in essence in may not be.
		DR. GREENBERG:  Let me give you one piece of data which may or may not satisfy your curiosity.  So when these questions were raised last night, what we did is look at upper respiratory tract infection in the Kaiser study in the placebos.  Why don't we go to that one first.
		And reasoned that if there was reactogenicity in the upper respiratory tract you would see it early after the receipt placebo and it would fall off. And this is the URI coding by day in the Kaiser study across the 42 day window.  And at least by my analysis, there is no -- it does not look like there is increased reactogenicity temporally associated with giving placebo.  Now, this isn't controlled, this is just looking at placebo over time; that's the control.
		DR. MINK:  These are kids that seek medical attention or have an SAE?
		DR. GREENBERG:  Yes.  No, these are people who in anyway, as Dr. Black mentioned, have an MAE or coded in the Kaiser study for the diagnoses of URI.
		CHAIRMAN DAUM:  I think you're both saying the same thing.
		Dr. Myers and then Dr. Snider.
		DR. MYERS:  On the same issue in the adult study runny nose is reported in 26 percent of the allantoic control group.  Have you done a similar analysis?
		DR. GREENBERG:  Yes, we have, Dr. Myers.
		You've never been a straight man for me before so -- and will never be again.  
		So if you look here, this just the 7 day reactogenicity period.  The placebo runny nose really doesn't change over time.  And, again, my conclusion from this data is that this is not reactogenicity. I would expect reactogenicity due to an irritant, a nonreplicating irritant of some form or another to be higher temporally clustered with the time of administration.  And so I respectfully differ with the FDA as to whether there is evidence of reactogenicity with the allantoic fluid.
		CHAIRMAN DAUM:  Thank you, Dr. Greenberg.
		Dr. Snider, and Ms. Fisher, then Dr. Cox.
		DR. SNIDER:  On that same point, Harry, then I have trouble understanding page 10 of Mr. Mendelman's presentation on safety in children in which it shows percent with runny nose, nasal congestion day zero running around a little above 10 percent.  Then both groups having an increase in the next few days and then coming back down.
		DR. GOLDBERG:  Bob Belshe I think did a great job.  I am not a pediatrician, I'm an internist, but I am a parent and I do remember -- well, I'm not going to use the aphorism for these kids.  But I do remember when my kids were little.  But, Bob, say it again because you say it better than I do.
		DR. BELSHE:  Okay.  These children, and this is the dataset that includes AV006 and -- all integrated data.  The AV006 dataset looked exactly like this that's reported in the New England Journal.
		On day zero children are enrolled who do not have runny noses at time zero.  Now, ten percent of the mothers check runny nose later that day on the case report form.  And on day 1 and day 2 and so forth it's around 20 percent and it stays fairly level at 20 percent of the duration of the study.
		So what we're seeing here is a return to the mean of children, a typical child about 20 percent will have a runny nose on any given day.  That's what we're showing.
		CHAIRMAN DAUM:  Thank you, Dr. Belshe.
		DR. SNIDER:  Just to further clarify.  Then what you're saying is that the other ten percent were screened out the first day?
		DR. BELSHE:  That's right.  If they had significant runny nose -- if they had runny nose detected by the study nurse, they weren't vaccinated.
		CHAIRMAN DAUM:  Thank you very much.
		Ms. Fisher?
		MS. FISHER:  Yes.  Encephalitis and encephalopathy are known rare, although rare reactions after vaccination.  And certainly Guillain Barrè Syndrome has been associated with at least swine flu vaccine.
		I was wondering if you think that the numbers are not large enough to detect the occurrence of encephalitis and encephalopathy, Guillain-Barrè Syndrome, polynephephritis after this vaccine?  And if you don't think the numbers are large enough, how large they would have to be to perhaps detect that?
		DR. GREENBERG:  I don't have the size calculation on the top of my head, and I'm surrounded by epidemiologists, so I'm anxious about this.  
		Taking Guillain-Barrè as one of the examples, I would imagine you're going to need immense databases to rule out an association of Guillain-Barrè.   I mean, literally the country because the rate of Guillain-Barrè with influenza is small enough.  So it's something like that.  It's really huge.
		Dr. Mendelman whose better at this than me, says about one in a million.
		CHAIRMAN DAUM:  Thank you.
		Dr. Cox?
		DR. COX:  Yes. I wanted to bring up an issue that's related to the transmissibility of the vaccine virus, and it has to do with the inadvertent exposure of immunocompromised individuals, and in particular severely immunocompromised individuals to the vaccine.
		And I just would like to make a comment to say that influenza can, indeed, be very serious disease in bone marrow transplant recipients and others who are severely immunocompromised.  There are fairly high rates of mortality and hospitalization and serious disease.  So this is something that we would need to be concerned about.
		And so I'm just wondering if there is any way to address this to screen people who are receiving the vaccine very carefully, and so on, or if there are any studies that might bare on this particular concern?
		CHAIRMAN DAUM:  Hear from the sponsor and/or FDA on that question.
		DR. GREENBERG:  Dr. Mendelman presented to you the two small studies in HIV patients, patients infected with the HIV virus.  And as you're aware, we do not have any studies of safety of FluMist in severely immunocompromised people such as somebody who has just had a bone marrow transplant. I think that's a factual answer.
		Obviously, prevention of wild-type influenza is of great benefit and prevention of wild-type influenza in the family of people having bone marrow transplantation would of great benefit.
		And in the one case of transmission that we had, I would remind you that the virus had the phenotype of the original vaccine and was associated with no change in the child and was associated with no illness different than the other people in that study.
		CHAIRMAN DAUM:  Thank you.
		Dr. Schild, please.
		DR. SCHILD:  Mr. Chairman, I'd like to share with you some thoughts on genetics in relationship to safety and transmissibility.
		I mean the given information is that the cold-adapted phenotype is conveyed by four of the genes PA, PB 1 and 2 and M.
		We've quite a lot of interesting information about the identification of the lesions in those genes related to the phenotype.  However, that information is based on sort of consensus sequence data.  And there are now new methods of very rapid analysis of viral populations.  Polio virus is  a very good paradigm for that.  There are now routine methods developed greatly in this particular study for analyzing populations of live attenuated polio vaccine which can pick up a very small proportion of the particles which show nucleotide changes that might make them likely to revert to virulence.
		So the question is how much have population genetics been applied to these vaccines?  The sort of question one would like to answer is for any vaccine bulk population, how many of the particles contain all four attenuated lesions.  I think that can be answered.
		And also, we can use those techniques to look at the genetics of viruses excreted from those individuals who have longer term excretion and perhaps have febrile responses and in relation to transmissibility.  
		And I also think there is a need for more attention to be paid --- more studies from looking for potential for transmissibility to susceptible individuals.
		CHAIRMAN DAUM:  So the question, as I understand is, at least as a bacteriologist we would ask the question do all members of the bacterial population contain the same phenotype with respect to these mutations?  There must be an equivalent to that in virusland.
		Can someone address that question from the sponsors?
		DR. GREENBERG:  Dr. Zamb, if you're not going to address it, I'm not.
		What Dr. Zamb said to you I think is the most important thing from the -- outside of polio, one of the most extensive studies of mutations in RNA viruses shed by humans that my colleagues at Wyeth have carried out, and that is in none of the shed viruses were there mutations in any of the sites associated with attenuation of the shed viruses.  And, of course, that's interesting and good.
		DR. ZAMB:  That is in fact true.
		DR. GREENBERG:  Do you have any more data to add to what -- I think that's the best data we have.
		DR. ZAMB:  And it's very comprehensive.
		I believe you were attempting to suggest that we develop Naprocam analysis for the individual mutations.  I think the ideal circumstance is to better characterize, in fact, in specific nucleotides and their actions and call that adaption temperature sensitivity and attenuation.  And I think the best way of doing that is by plasma-based rescue where you can alter individual nucleotides and then construct viruses with those individual changes and in specific combinations to evaluate the individual mutations that are thought to be associated with that, and confirm that theory.  And I think that's the most efficient way of doing that, and we're beginning to pursue this at this moment.
		DR. GREENBERG:  Both Wyeth and Aviron are pursuing that.
		CHAIRMAN DAUM:  One follow-up question.  Go ahead.
		DR. SCHILD:  The first part of the comment was really how genetically homogeneous is your virus-- your master virus received or your vaccines pools in relationship to the attenuated lesions in individual infectious units?
		DR. ZAMB:  Again, what we need first to do is to clearly identify those specific nucleotides that do confer the attenuated phenotype.  And then once those are identified we can in fact do clonal analysis on those populations to determine the frequency of nucleotide differences, if there are any at those positions.
		CHAIRMAN DAUM:  Thank you very much.  
		I'd like to press the Committee at this point once more for other issues to clarify before we vote on question 2 regarding safety?  I think  we're almost there, but there be one or two more issues out there.
		Dr. Myers?
		DR. MYERS:  To go back to the normal allantoic fluid placebo.  Have similar analysis as we just saw been done for GI events including abdominal pain?
		DR. GREENBERG:  Dr. Myers, could you ask that question again because I'm not sure I understood it?
		DR. MYERS:  The number of GI events, including abdominal pain, seem to me to be more frequent than I would expect in both the FluMist and in the placebo groups.  And so I was wondering if you'd done the same type of analysis for that?
		DR. GREENBERG:  I think we're trying to call that up right now.  Isn't this what they want?
		DR. BLACK:  This is what we have.  This is what I showed you already.  We have looked at abdominal pain in the final analysis dataset, and that is still -- still is significantly elevated, as it was before.  And the time frame of the cases is still spread out.  We didn't make a graph, because we didn't think we really adding any new information because basically the numerators and denominators change, but the rates are still within the same range.
		Does that answer your question?
		CHAIRMAN DAUM:  Thank you very much.
		Dr. Griffin?
		DR. GRIFFIN:  I just want to ask one clarifying question, and I just can't find the chart at the moment.  And that's if you look at the deaths occurred overall in any of these studies, the majority of them are all in the COPD study group.  But in my recollection of that data, you had similar numbers of deaths in those that got FluMist as those that got the placebo.
		What I couldn't remember is over what period of time and whether there's thought to be any link to just getting this kind of vaccine and COPD.  It just seemed like a lot of people died.
		DR. MENDELMAN:  The trial was conducted by the VA Cooperative Studies Group.  And as they submitted it and completed the protocol, they were going to collect all AEs for the entire duration of the trial, including serious adverse events.
		As the trial moved forward, they continued to collect all the serious adverse events so they continued to report death throughout the trial period.
		It started in October of 1998 and went through until May -- the spring season.  
		So looking at the temporal relationship of death, there -- well, to reconcile the one number with the FDA's document, but there were 3 deaths within 28 days of receipt of inactivated vaccine and FluMist and there were five in the placebo group within 28 days that also got inactivated vaccine within 28 days.
		The FDA document has four versus four.  And the VA Cooperative Studies program study is still undergoing analysis.  But those are the numbers that they provided to us.
		So we believe the temporal relationship is what should be looked at.  Some of individuals, obviously, died very far out after there'd be any plausibility.
		CHAIRMAN DAUM:  Thank you, Dr. Mendelman.
		DR. GRIFFIN:  So the majority of people died within -- so it's about a six month follow-up?
		DR. MENDELMAN:  Yes.
		DR. GRIFFIN:  And so I guess I would -- what it looks like is that you have about five or six people dying every month along the whole period of time in both groups, is that what you're telling me?
		DR. MENDELMAN:  Sixty-four deaths over that period of time.
		DR. GREENBERG:  Diane, this population had a mean age of 68 and head real COPD, and these were people with significant health issues.
		DR. GRIFFIN:  But they weren't hospitalized at the time.  They were entered, they were outpatients and then developed these problems over the next six months?
		DR. GREENBERG:  Yes.
		CHAIRMAN DAUM:  Thank you very much.
		We're moving toward dealing with the question.  I would like to actually start dealing with the question unless there are additional unaddressed issues.
		Thank you, George, et.al.  It's up on the screen again.  I don't think we need a refresher as to its language, we've heard it a couple of times.
		Dr. Steinhoff, are you up there?  I can't see you.  Would you be willing to start the Committee deliberation with regard to your view of this question?
		DR. STEINHOFF:  Yes, I guess I could start.  
		We've seen and discussed just now a lot of data and the question is are the data adequate to support the safety in the population for which an indication is being sought.
		Overall, my feeling is that we have a lot of data on safety.  I have to say that there are still some questions that don't appear to me to have been fully analyzed, and we understand that both groups, the FDA and the sponsor, are working together to provide full information and then undertake an analysis.
		We've heard different results from different studies which were undertaken with different methodologies, so it's a little hard to compare a finding in one study that didn't show up in another study.
		The safety data that is of sort of major concern, which is the lower respiratory illness or asthma, it's either incomplete in terms of the pneumonia or with the asthma it's in very small age group and doesn't appear elsewhere, at least in the California data.
		So I guess my feeling is that I'd be willing to say yes to this question with a qualification that the analyses that have been mentioned mostly around the issue of pneumonia, and as the others speak they can remember the other ones, those should be completed.
		CHAIRMAN DAUM:  Thank you very kindly.
		DR. GRIFFIN:  Bob, can I clarify just one thing.
		DR. STEINHOFF:  But, of course.
		DR. GRIFFIN:  So the indication that's being sought for 1 to 64 years of age, that at all qualified by healthy individuals 1 to 64 years of age or is that all individuals 1 to 64 years of age?
		CHAIRMAN DAUM:  Dr. Geber, please.
		DR. GEBER:  So the indication reads -- I mean, we will work with the sponsor, obviously, but we'd appreciate your comments.  The indication is 1 to 64 years of age.  There is a contraindication section which specifies that it counter indicated in subjects with immunosuppression and specifically listed are those who might immunosuppressed due to therapeutic interventions, and then more broadly those that might be expected to have a lower antibody level to the FluMist vaccine.  But specific categories for which, for instance the flu, the influenza vaccine is recommend, you know, that have been mentioned by the Committee as renal dialysis, diabetics, they're not specifically mentioned.  They could be inferred to be included in that contraindication section.  Any thoughts that you might have on that would be --
		CHAIRMAN DAUM:  Dr. Greenberg, you want to discuss the indication, that's all?
		DR. GREENBERG:  I think we'll work with the FDA, but we are seeking an indication for healthy children.  As I said in my introduction and in all of our slides, healthy children and adults 1 to 64 years of age.
		CHAIRMAN DAUM:  Thank you. Dr. Midthun wants to comment on this, and then we'll return to you, Dr. Steinhoff.  I do see you.
		DR. MIDTHUN:  Could we clarify how the indication relates to individuals with asthma?  Can you hear me?  Could you clarify how your indication relates to individuals with asthma and how you would be seeking viewing those right for your current indications sought?
		DR. MENDELMAN:  Again, we will obviously work with the FDA, but we believe that the data we have in children and adults with asthma is not sufficient to give FluMist to adults or children with a diagnoses of asthma.
		CHAIRMAN DAUM:  Thank you.
		Dr. Steinhoff, you wanted to comment on this issue, please.
		DR. STEINHOFF:  The question really is in vote 1 we were talking about a very specific age group, and this question also is confined to a highly specific age group.  And I don't know if you want a qualification on that.
		CHAIRMAN DAUM:  One to sixty-four years.
		DR. STEINHOFF:  Yes.
		CHAIRMAN DAUM:  I suppose you're right, but if you want to qualify your answer, you're perfectly welcome to.  Everything you say is being recorded and, believe me, played and replayed by many folks with interest in this room.
		So, you're welcome to make comments or qualify your answer totally at your pleasure.
		DR. STEINHOFF:  Well, I guess the comment I want to make is that there clearly is a substantial difference of opinion regarding the efficacy data, especially in that youngest age group.  And the safety data may be less crucial in terms of that age group, but obviously if efficacy is not good in a certain age group and safety is, it has different kinds of implications.	
		My own feeling is that the safety data we've seen does appear to be fairly supportive on --
		CHAIRMAN DAUM:  You said so.
		DR. STEINHOFF:  Yes.
		CHAIRMAN DAUM:  Yes.  Just to review, there are actually -- maybe we should spend a minute here because I thought everyone had it straight.  But let's just go over it for a minute. 
		There's three parts to this question which everyone ought to be reflective about.  One is the actual question:  Are the data adequate to support the safety of FluMist between 1 and 64 years of age?  Yes/no.  Comments, of course.
		Then, secondly, please discuss the adequacy of the data in two groups:  Less than 2 and greater or equal to 50.
		And then the third part applies only if you vote no, I guess, for the first part.  If the data are not adequate for specific age ranges, please discuss would additional data should be requested.
		So all comments are welcome, of course, but these issues need to be addressed, and I think that's been done.
		Dr. Edwards?
		DR. EDWARDS:  I want to be comfortable that the children and adults who are recommended because of high risk conditions to receive inactivated vaccine each year still are recommended to receive inactivated vaccine.  And I think that's what you're saying, that the indication will be for those in individuals who are not recommending?  Okay.
		I think that it's hard to give a vaccine to a child.  If you aren't comfortable with the efficacy, it's hard to recommend that they be given in that age range.  So I think consistent with my previous statements, I feel most comfortable with 15 months to 64 years.
		I do have questions about the pneumonia, and I think that that has to be very, very carefully looked at.  Each case has to be dissected and perhaps even reviewed by an expert in pediatric infectious disease to make sure that everyone is comfortable with that, particularly that it relates to the youngest children.  And I think additional safety data regarding the pneumonia question in the group less than two years is very important.
		I think there is cause for concern in the asthma data. I don't think it's certainly clear yet that there is a major risk, but I think this is a group who should be immunized and I think that if the vaccine is to be given, that practitioners should very clearly state that if the children have asthma, that this is not the vaccine they should be getting.  They should be getting the inactivated vaccine.  Although I must parenthetically add that only 30 percent of children with asthma, even in the best situations, get the inactivated vaccine.
		I think that the data for individuals who are over 50 if they are healthy, and I think for those of us over 50 a number of us think we remain healthy, but if they are in a age group that they would be recommended to receive the inactivated vaccine, they should receive the vaccine that is indicated for them.  So I think in that group and barring COPD, which I don't think you're asking for, that with the caveats that the FDA needs to review, particularly the pneumonia data and fully assess the asthma data, I think the data is adequate.
		CHAIRMAN DAUM:  Thank you.
		Dr. Myers?
		DR. MYERS:  I think at this time the data is not adequate to support the safety of FluMist.  That said, I think it is likely to prove to be safe, but the data and the data analysis are incomplete.  And until those analysis for lower respiratory infection, for asthma and some of the other studies have been completed, which when they're completed my answer will be different.  But in the absence of the completion of those analysis, I don't think the data is complete.
		I don't think the data, for example, is adequate to conclude the safety for children previously diagnosed with asthma.  I think we need increased data for children under 24 months of age.
		I am concerned the data, the recommendation for adults over the age of 50 because we don't have data on those who have underlying medical conditions.  Not necessarily that they be immunosuppressed, but those with diabetes, renal disease and so on.
		So, I guess again I'd like to emphasize, I really think that when these analyses are done, it is likely that I would vote differently.
		I think that we must have the definition of the flock for endogenous retroviruses, in addition.
		And then just as a comment, I find it difficult to conclude not significant from a placebo comparison for entities such as conjunctivitis and so on when the comparison is to normal allantoic fluid.  Although I think the areas where irritation from normal allantoic fluid may occur may be minor adverse events, and therefore it may not be an issue.  I just would say as a caution that that's the placebo.
		CHAIRMAN DAUM:  Thank you very much, Marty.
		Ted?
		DR. EICKHOFF:  I'm still a little uncertain as to the correct interpretation of the indications.  Should I read for use in healthy children and health adults?  Thank you.
		CHAIRMAN DAUM:  That's what we're hearing from the sponsor, so I think that people should factor that in, although comments about underlying diseased adults and children are welcome.  But the question is about healthy children and adults ages 1 through 64.
		DR. EICKHOFF:  I'm reassured by the safety considerations regarding this product.  And my vote is going to be yes, but if the Chair will permit me to do it, it's going to be a provisional yes because there are issues that are yet to be resolved with regard to pneumonia and with regard to asthma.
		I look, as we all did, the Kaiser Permanente data in 019 and it looks reassuring, and it appears to be the most cohesive dataset that we deal with.  So I'm greatly reassured, at least as far as pneumonia is concerned by that dataset.
		The FDA analysis suggests some other problems, and we are cautioned that this is an ongoing analysis.  And so my provisional yes is given with the anticipation that these issues between FDA and the sponsor will be satisfactorily resolved.
		The same issue applies to asthma, perhaps even more so.  But, again, I'm reassured by the data provided in the Kaiser Permanente study which, again, I think is the most cohesive dataset.  But that issue, too, needs resolution between FDA and the sponsor.  When those are done, my vote will change from provisional yes to yes, assuming satisfactory resolution of those issues.
		There is the lingering uncertainty that I have about turning this attenuated vaccine loose on the general population wondering what's going to combine with what.  And I'm sure Dr. Schild will have some more to say on that issue, so I'll defer to him.
		Thank you.
		CHAIRMAN DAUM:  Thank you.
		Dr. Cox.
		DR. COX:  I think that the overall safety profile of FluMist is very good, but I have some lingering concerns about what we've seen relative to asthma, pneumonia.  And I think that we all know that the data, the analysis are incomplete and we really look forward to seeing a more complete accounting of whether these may be associated with the FluMist.
		I think that there's no doubt in my mind that there's some real world issues that have to do with safety that need to be dealt with, and one has come up a number of times in our discussions, and we know that we don't have any data on concurrent administration.  And I think that's just an absolutely crucial issue for consideration of safety.
		In addition, I continue to be concerned about inadvertent exposure of immunocompromised individuals because we know that the HIV infected individuals who were in the various trials were relatively healthy.  And we have no idea how long this virus could replicate in individuals who are severely immunocompromised; if there might be a greater risk for transmission, reversion and reassortment and so on.
		I think that what I would like to say is that in my view the question of concurrent administration of other vaccines is a very, very crucial one and so at this moment I would have to say no.  But it's -- again, I'd like to emphasize that I feel the overall safety profile is very good, but there are these lingering questions I think that can be resolved, but I have to vote right now.
		CHAIRMAN DAUM:  Thank you very much, Dr. Cox.
		Dr. Schild, I'm going to ask you to wait one moment, because we're starting to get into airplane time here.  So I'm going to ask Dr. Katz to speak next, and then we'll return to you if that's all right.
		MR. KATZ:  Thank you, Geoffrey.  My vote is yes, but that I feel that, one, we need to continue the FDA analyses that we've heard about that are currently in progress of pneumonia and asthma.
		Then, secondly, that it's imperative that post-licensure phase four studies be required in order to capture any further data on rare events inapparent in the numbers that are immunized to date.  And I'm thinking especially of central nervous system events which may occur with such rarity.  But given what we have now, I would vote yes.
		And I've left my proxy with Dr. Griffin for the discussion points.
		CHAIRMAN DAUM:  Thank you very much, Dr. Katz.  We wish you a safe trip home.  
		And we'll ask Dr. Schild to now speak to us.
		DR. SCHILD:  Thank you, Chairman.
		I think safety can be considered in relationship to the vaccinee as well as the vaccinee's contacts and certainly in relationship to the general population.  I think we're asked to vote only in relationship to the licensee on this occasion, but I would like to make some comments about the broader aspects of safety, particular public health safety which I may be straying into question 4, but nevertheless I'll mention this.
		On the question of safety in the vaccinee, I think I would give a conditional qualified yes rather along the lines of Dr. Eickhoff; that certainly very careful analysis should be done by FDA of data that is available now and will become available.
		The particular issues that I think do need more attention are the asthma issue and the pneumonia issue.
		And also I'm expressing sympathy with Dr. Eickhoff's view.  Safety in high risk individual, high risk elderly individuals who I know are not part of the indication, but nevertheless it is something that really needs to be considered.  And I really also I must express some sympathy, although I didn't mention it at the time, with the view that maybe inactivated vaccine might be the best way of treating those now, the very high risk elderly individuals.
		I do believe that we need more genetic analysis in general, not only of the vaccines, but of the shed virus. And I think we ought to have in the long term much more information on the propensity of the vaccine strains to transmit.  We've only heard, I think, of one study on that.
		Safety in the general population we're not asked to vote on.  It's a very difficult field, so many unknowns.  And I think what we can offer is to mount very careful surveillance in the population for any evidence that the vaccine virus may be mutating to virulence, may be continuing to circulate, and so on.  That is not mentioned here in the question, but I do think it's one of the things that could be considered.  And I know in this country there is a very good system of strain surveillance and identification both by antigenic means by genetic means.
		CHAIRMAN DAUM:  Thank you very kindly.
		We move on to Dr. Griffin, please.
		DR. GRIFFIN:  Well, I'm reassured in general about the safety profile of this vaccine, however I do think that we don't have -- I won't say that the data are inadequate, because they may eventually be adequate, but we do not have access to adequate data yet to completely make me feel confident about the safety profile particular in the under 2 year age group.  Again, with concomitant immunization, questions of pneumonia, asthma; I just think there are quite a few unresolved issues that may become resolved in even the next few months, although the concomitant immunizations study is just under way.  So that may take somewhat more time.
		I have a lingering, perhaps irrational concern about what is a very attractive route of immunization, intranasal immunization that comes from my background as a neurovirologist.
		Do we have any other vaccines, licensed vaccines that are given by the route?  Yes, I mean we just don't have experience.  And as I say, it intrinsically is a terrific way to immunize, I just would want to pay attention to any neurologic complications that could be associated with it.  So far it appears there are no indications that that's a particular problem.
		So, I think that just based on the fact that I think that the data are as yet -- that we have in hand are inadequate, not because I think that the vaccine itself is not going to prove to be safe, I have to vote no on this question.
		CHAIRMAN DAUM:  Dr. Griffin, we thank you.
		Dr. Stephens?
		DR. STEPHENS:  I share Diane's vote as a provisional no.  I think I, like Dr. Cox and Dr. Myers and Diane feel positive that ultimately this vaccine will be shown to be safe, I just think that there is not enough data at this point to convince me that the answer to the question is yes.  Certainly under in the younger age groups, certainly the issue of concomitant vaccines, certainly the issue of those over 50 are areas of concern.
		CHAIRMAN DAUM:  Thank you, David.
		Ms. Fisher?
		MS. FISHER:  I do not think we should license a new live virus flu vaccine that will be given to children as young as one year old without adequate pre-licensure safety data in those children.
		I'm troubled by the lack of adequate safety data for this vaccine on children under 5 years old, particularly under 2 years old.  There's an incomplete understanding of the implications of viral shedding on transmissibility to close contacts, which is particularly important for children who are often in close contact with each other.
		For children and adults there are outstanding questions about why there is more influenza-like illness including fever after vaccination as well as whether or not there is a real increased risk of pneumonia, bronchitis and asthma in healthy individuals after vaccine and an even greater risk for these outcomes in acutely or chronically ill individuals.
		I believe a practical issue that needs to be resolved is whether variations in the way the vaccine is administered nasally has a significant impact on whether these attenuated viruses can end up being swelled or find their way to the respiratory tract and cause respiratory abdominal or neurological complications.
		Certainly given the fact that this vaccine will be administered to children who are already receiving 3 dozen doses of other vaccines in the first 5 years of life, there can be no confidence in the true safety profile of the vaccine in the real world unless data is generated that includes administration to several thousand children under 5 with genetic diversity over at least 4 years where you measure for all morbidity and mortality outcomes, including evaluation of immunological and genetic integrity and general health and wellness after repeated vaccination.
		We have very limited experience using inactivate flu vaccine in children under 5, and it is extremely important to be sure that widespread introduction of an new live virus flu vaccination into this child population will not ultimately negatively impact on their long term general health and wellness, even though it may indeed prevent them from getting the flu short term.
		This is a huge step because we are going to be shifting the entire flu vaccination strategy from targeting adults to targeting children, and we had better be sure we're doing this safety.
		CHAIRMAN DAUM:  Dr. Goldberg, please.
		DR. GOLDBERG:  Well, from the data presented it appears that this vaccine is safe to the extent that it's been given. I would vote no at this time.  I think all of the issues have been raised, and then I think also we're proposing administering this attenuated live vaccine annually.  And I think the data with repeat vaccination is totally inadequate to address long term safety.
		Furthermore, the safety that you follow-up in the children studies for 42 days, that post-vaccination, and then in the adult studies for 28 days; that's fine for short term sequelae, but not monitoring for long term sequelae.  And with repeat administration you don't know what the cumulative effects will be as well.
		I do think this vaccine will turn out to be safe, but from the data we've seen here I think we need more information.
		Thank you.
		CHAIRMAN DAUM:  Steve?
		DR. KOHL:  I basically concur with the majority of my colleagues.  I think and hope that eventually this will turn out to be a safe vaccination, but at this point in time because of what I think we've all discussed in absence of confident data regarding pneumonia, asthma, concomitant immunizations and also for immediate licensure, and also in terms of post-licensure studies, I would like to see a fairly large study on rare events and also inadvertent immunization of pregnant women.
		So for the first number of reasons, I'll have to vote no on this.
		CHAIRMAN DAUM:  Dr. Snider?
		DR. SNIDER:  I'm voting provisional, as others did, and I don't know if it's provisional no or provisional yes.
		CHAIRMAN DAUM:  You know you won't get away with that, Dixie.  But let's hear your comments first.
		DR. SNIDER:  Well, I mean, there are still some outstanding questions.  I mean, FDA has indicated that review is ongoing for some of the data, particularly with regard to respiratory events.  And a number of people around the table have mentioned concerns around pneumonia, bronchitis, bronchiolitis, asthma.  
		I think we've been reassured by the sponsor about a number of these issues, but that reassurance is mostly -- has to do with at what level these things are likely to occur.  In other words, they're not occurring so frequently that they're showing up in the size trials we've seen, at least it's not clear that they are, although further analysis may bear out that they are showing up here in sufficient numbers to be statistically significant.  But at the moment whether there's a signal or not a signal, there is some data that creates some concern.  And I think that concerns derives, in large part, because a lot of biological plausibility I won't go into, but which I'm sure everybody around the table understands.
		There's also the issue of the reactogenicity of the placebo and some disagreement between the sponsor and FDA about that issue.  I don't think it's a huge issue, but it seems to me that it's important to try to clarify the difference between how much nasal congestion might be caused by the vaccine versus not having anything put in your nose.  And it just is a matter of trying to quantitate for parents accurate information so that it's more of an aggravation of not having really good data on that point.
		I think it's fairly clear that there is some reactogenicity from the vaccine and we would expect local reactogenicity in the nose from something we put in the nose, just as we get in the arm or in the deltoid or in the thigh; wherever we put vaccines, we get local inflammatory reactions and, hopefully, local immune reactions as well as systemic immune reactions.  And so we would expect some local reactions as well as some systemic reactions.  And so I think, you know, the eye symptoms, perhaps some muscle aches as well as nasal congestion are to be expected.
		The conjunctivitis is an interesting issue, particularly as it relates to the allantoic fluid versus the vaccine, which is not -- I haven't sorted out completely in my mind and would like to have sorted out.
		Other people have mentioned the rare events, and the way we're going to find out about that is if we do have larger sample sizes and that becomes a tough issue with regard to whether you require more trials, pre-licensure or post-licensure monitoring.  It also impacts on what kinds of recommendations you make down the line and how rapidly you want uptake.  And these are some issues that are going to be discussed by other groups, I know, but I'm already beginning to worry about them.
		And then there are issues around the genetics that have been raised that I won't go into again, but they do concern me. There is the issue of transmission, of course. That could be good, that could be bad of transmission of the vaccine virus.  But, of course, if there's reassortment, particularly if there's reversion to a virulent strains that obviously is concern from the safety of a population standpoint, as others have already mentioned.
		So, I guess -- you're going to pin me down, so I'll go ahead and say it's a provisional no we don't have it in hand right now, but I would anticipate that FDA would be able to get these data, that the manufacturer will work to get these data.  And I would hope that it would be possible to get enough information to utilize this vaccine in the near future, because I think it does fill a nitch and would be helpful for preventing what is a very significant disease.
		CHAIRMAN DAUM:  Thank you very much, Dixie, and particularly anticipating that I would pin you down.  I'm very grateful to not have to do that.
		I guess I'll finish the discussion by saying that I think Dr. Myers may have been the first one to speak my mind, and that is that there's a great deal of data that bear on safety that are in the process of analysis and being integrated into the database here at the FDA.  So, I must join the people who voted not, but with the caveat that it be sort of a work in progress kind of no.
		I would love to have a chance to revisit this issue when all of the data that are available have been processed by both the sponsor and the FDA.  I again believe that a tremendous amount of progress has been made since I last heard about this, and that I'm on the whole, excited about the prospects for this vaccine being part of our armamentarium in the future.
		A couple of things that I would highlight are (1) I believe that there is a risk for -- at least potential for risk for a flu-like illness in the days following vaccine, and I'd like to hear more about that.  I mean, we've sort of heard about it in Houston children when cultures weren't really being encouraged in that period.  And I'd like to see that studied in a little more detail.
		The transmission issue is an important one, although I suspect from what I've heard today it's not going to turn out to be an important clinical problem.  But I think in the climate we have today with vaccines and new vaccines we've got to be very sure, perhaps even a priori sure that it's not a problem.
		The asthma issue, I think, is an important one.  I'm not sure that asthmatic children would accept this vaccine if they knew there was a higher risk for an exacerbation following its receipt. And I think that given the data we've had, they may be a tip of the iceberg phenomenon and biased against people who weren't able to report that their child had asthma.  And I'd like to see some more systematic study of that.
		Pneumonia and conjunctivitis and nasal congestion, I think there's more data that's in the mill and being processed. And, again, I'd love to hear those data when FDA and sponsor have finished reviewing them.
		The annual dosing issue I think really hasn't been addressed and I think is an important safety issue.  Although, again, I suspect that when it is addressed, it's going to be a safety concern.  But without data, who can say for sure.
		I feel very confident in the safety data I saw for healthy adults over 50, but many adults are not healthy over 50.  And it would be, I think, important although perhaps not directly germane to this indication to have some sense of what happens when you immunize people who are not 100 percent healthy.
		So, that's my view on it.
		Now, stepping back into the Chair's role, there are four votes yes and 8 votes no.  Sorry 9 -- 10.  That can't be.  What do you have?
		MS. CHERRY:  I had ten counting you.
		CHAIRMAN DAUM:  I have 9.  One second, please. I'm sorry.
		There are 10 no's.  There are 4 yes's and 10 no's.  Of the 10 no's, 6 people commented that they view this as a work in progress situation and would like to hear and review the data when the processing part has been finished. So, that's an important qualification, I think, on a large part of the no vote.  And I think that it's important  convey to the sponsor that there is a lot of interest in the progress of this vaccination and that we feel like more data on these safety issues, particularly that have been raised, would be very important.
		Dr. Midthun is concerned that we really can't accept provisional votes.  We do have the provisions that people have raised, not as provisions per se, but everybody's comments have been recorded and notes in the register and available for people who want to review the record of what was said here.
		So, I'm going to read out the votes that I have and I'm going to ask each person to at least confirm by nod of the head that they're not provisional, these are your votes.  If someone wants to discuss that again, please feel free.
		DR. EDWARDS:  Could we ask a question just about that?  If the FDA in their review find something problematic, I think that there are many of us who would be uncomfortable with that.  I guess that how are we to interrupt what they find?
		CHAIRMAN DAUM:  Well, I think that's always an issue, right?  Because we're looking at one frame of the movie right now.
		DR. EDWARDS:  But we're looking at an earlier frame than we usually see.
		CHAIRMAN DAUM:  Indeed, but that's still the frame we're shown.
		So, does someone from FDA want to comment on that?
		DR. MIDTHUN:  I think we're voting on the information that we have in front of us today. I think that it's not uncommon for people to say I vote yes or no, I have certain caveats about that. But I think what we do need to have is a yes or a no and, of course, we will note the caveats in the record.  And, of course, you know take that under advisement.
		Does that help?
		CHAIRMAN DAUM:  So here's what I have.  I have starting from your side, Dixie:  Dixie no; Kohl no; Goldberg no; Fisher no; Stephens no; Griffin no; Katz yes; Schild yes; Cox no; Eickhoff yes; Myers no; Edwards no; Steinhoff yes; Daum no.  That I believe is what you all said.
		There's your comfort, Dr. Midthun.
		DR. MIDTHUN:  Thank you.
		CHAIRMAN DAUM:  I won't reread the summary, because it's what I said a moment ago, but the Committee would like an opportunity to reconsider this and readdress this when the agency and sponsor working together deem it appropriate to do that.
		I'd like to, I think probably briefly, because I suspect that things have been said already that deal with discussion points 3 and 4, at least I hope FDA has heard things that deal with discussion points 3 and 4.  But what I'd like to do is give each Committee member a chance to speak to these.
		And with all due respect to the agency, I think I'll take them together and ask people go once around and ask for comments on items 3 and 4.
		We have item 4 on the board, which is good.  Well, we could leave 4 up. And just to remind you that 3 is Dr. Cox's favorite issue today, please discuss the need for data on concurrent immunizations, for example, in children and travelers.  
		And that's not to single you out, Dr. Cox, I think many of us feel that way, as we'll see in a moment.
		So, Dr. Snider, would you start us off, please, and we'll try and get this done.
		DR. SNIDER:  Three and 4, or just 4?
		CHAIRMAN DAUM:  Three and 4, please.
		DR. SNIDER:  Well, everyone -- or many people, at least, have mentioned the need for data on concurrent immunizations.  And, of course, would agree with that.  I think in both populations that have been identified here, children and travelers, but children in particular we know what vaccines are likely to be used concurrently because we know what vaccines are recommended at the particular ages that these children would be vaccinated.  So, no need to go through identifying those.
		For travelers, this could be a little bit more problematic, but we at least know the range of vaccines that are recommend for various parts of the world.  For some of those, it's going to be more common than others.  And I don't think it's going to be possible for some of the rarer vaccines, more unusual vaccines to get a lot of data real quickly.  Nevertheless, it would be nice to have that.
		With regard to point 4, we've had a lot of discussion about the use of this vaccine in high risk subjects.  The sponsor is not asking us at this point in time to allow them to or to make a recommendation to FDA for those indications. At the same time, we were reminded that, at least in one of the trials here, that many children either were not diagnosed with asthma, for example, or the parents did not acknowledge the presence of asthma.  So, asthma is something that is going to be problematic, it would appear, no matter if you do put it in as a counterindication right now.  So it would be, I think, very useful to gather additional data about asthmatics.
		Clearly, high risk populations, immunocompromised populations in particular are of interest.  They're of interest with regard to this being a live virus, albeit attenuated, and how it might perform in various immunocompromised individuals.  We have some reassuring data from small numbers of HIV infected people, but it would be useful to know more about those.
		High risk subjects also can refer to those who are at risk of getting influenza.  And, again, I guess the approach I would be interested in is what I had already indicated with regard to those over 65, which would be useful since there's already some suggestive data that it might be that the live attenuated vaccine would give added protection above what the inactivated vaccine gives to be able to look at populations who receive the inactivated vaccine and have one group, one arm also receive the live attenuated vaccine.
		You just alluded to he issue of annual revaccination in adults.  We don't know what's going to happen with regard to yearly administration or if we have to have it the yearly administration.  I presume we're going to start out of wanting annual revaccination.  We're likely to strains every year and we're going to have to be on the lookout for what happens with regard to safety and efficacy in that regard.
		Assessment of attenuation has been discussed, as has the potential for transmission and reversion and reassortment by those who are much more knowledgeable than I am.  All I'll say, again, is that those are issues of concern, issues for further investigation.
		CHAIRMAN DAUM:  Thanks, Dixie.  We have two members, Mr. Kohl and Dr. Eickhoff  who are needing to leave by 3:00.  So I'll ask Dr. Kohl to go next -- sorry.  A whole lot more of us.
		Well, then we'll do the best we can.  Who has to leave at 3:00 besides Dr. Kohl and Eickhoff.  Dr. Myers, okay.  No comments.
		So, let's go with Dr. Kohl, Dr. Eickhoff, and Dr. Myers and try to get them up and down by 3:00 and then we can have the rest of the Committee finish off.
		DR. KOHL:  I think it's pretty much been said, so I'm not going to repeat what we've already discussed.
		I would like to see in addition to concomitant immunization, in travelers I'd like to see a small study looking at immunization and then anti-malaria use.  Because in other live immunizations there's some doubt that anti-malaria may be immunosuppressive, if you will.
		I think some of our discussion about the risk in high risk hosts in terms of transmission has to be tempered by the fact that this is an ambiguous virus, and it reminds me a little bit of the Varicella discussions that we've had in the past, namely I think I would much rather have a high risk host get this virus than get the wild virus, and the same thing for an asthmatic.  Having said that, I still would like to see data in those subjects to reenforce that feeling that this will be a milder to asymptomatic  infection.
		I think I'll stop there.
		CHAIRMAN DAUM:  Dr. Eickhoff?
		DR. EICKHOFF: Well, this is sort of a motherhood and apple pie list, it all needs to be done.
		For the concomitant vaccines, yes, this is an absolute must, particularly I'd be concerned about the live virus antigens that may be given concomitantly.  But the killed antigens need to be looked at as well.
		In the case of adults, this would certainly include hepatitis B as well as pneumococcal vaccine and there are, you know, a number of others that would apply to children.
		High risk subjects, certainly those need to be examined within detail.
		Annual revaccination need more data, not only in adults but in children as well. 
		And the last three items, again, like Dixie I think others who are more knowledgeable than I have commented and I'm sure will comment further.
		CHAIRMAN DAUM:  Thank you, Ted.
		Dr. Myers, can we hear from you.
		DR. MYERS:  It'll be brief because everybody has listed everything on my list.
		CHAIRMAN DAUM:  Brief is good.
		DR. MYERS:  We've already talked a lot about the 12 to 24 month data that's needed. I guess I would encourage the sponsor to consider that 6 months to 24 months because of the data that Dr. Glezen showed in the burden of disease in the younger infant.
		The one versus two dose schedule needs to be examined systematically so we can make decisions about whether it's one or two.  And if it's two, at what age.
		And then more seasons of adult data I think would be very desirable.
		I think everybody else has covered everything on my list.
		CHAIRMAN DAUM:  Thank you very much.  I think that covers the folks that have to leave at 3:00, not that it's 3:00 yet.
		But Dr. Goldberg, could we resume with you, please?
		DR. GOLDBERG:  I don't have much to add. Everything I have is covered.
		The only other thing that I think at some point ought to be studied is the method of administration in relation to the risks of transmission and the variability in administering the nasal dose, whether that effects complications in the child.  As well as the probabilities of transmission should be looked at.
		And I think the other issue is I think perhaps some consideration should be given as to whether or not there's a way of assessing the presence of asthma prior to vaccination in a structured way so that you might be able to do a better job of identifying children at risk, in particular, or adults in the presumably healthy.
		CHAIRMAN DAUM:  Thank you very much, Dr. Goldberg.
		Ms. Fisher, would you care to comment on these two discussion points?
		MS. FISHER:  Well, I think it's important that whatever trials are held to generate data on concurrent vaccination or high risk individuals that the same follow-up protocol and exclusionary criteria should be used and that there should be an attempt to specifically identify biomarkers, not only for those who would be more likely to have an adverse event, but also those who are non-responders.
		I think the issue of reassortment of vaccine strains with wild-type virus is extremely important, and there should be much more investigation into this possibility that could generate more virulent or vaccine resistent strains.
		CHAIRMAN DAUM:  We thank you.
		Dr. Stephens?
		DR. STEPHENS:  I think we all share similar feelings about that we need -- we have concerns and we need more data on both of these points.  Just a couple of quick points.
		One is the fair testing model for attenuation. I think I would like to see a better, a more robust model. I realize this is the traditional model, but certainly a better model for attenuation or better issues addressing attenuation would be an area.
		Thank you.
		CHAIRMAN DAUM:  Thank you, David.
		Dr. Griffin?
		DR. GRIFFIN:  Again, most of the points have been covered, so maybe I'll just come in on some of the virologic ones at the bottom that have been less adequately addressed, although the other side of the table will be able to do this.
		Attenuation, I feel quite comfortable with the attenuation of this virus with its stability in a number of situations, so I really don't regard that as -- I mean anymore data is fine, but I don't regard that as really a major issue.
		Potential for transmission, clearly it can be transmitted.  Obviously it doesn't occur too often.
		I think, again, reversion is not a big issue, but just because I think the vaccine really is very stable.  I think it's just one of those things that's going to have to be monitored as far as transmission, and there the risks are really to other populations that perhaps would be more vulnerable when they -- that wouldn't normally be included in the normal vaccinees, you know, asthmatics or whatever.
		Lastly, I think the potential for reassortment, again, I don't consider this a major concern as long as new H1N1s aren't introduced in a pandemic kind of a situation that would have the opportunity to reassort with wild-type viruses.  And the background genes are clearly attenuated, so any reassortment that would occur in the normal kinds of situations are going to give you less virulent viruses rather than more virulent viruses.  It would be only the potential for reintroduction of new H1N1s and pandemic type situations which, obviously, would not be voluntarily done.
		And I can also represent Sam here.
		So he says you need to complete the 2000 child study on concurrent MMR.  Also might consider concurrent VZ, as well are concurrent nonreplicating vaccines, pneumococcus, H. flue, b-conjugates, DTAP, etcetera.  That's number 3.
		And number 4, more data on vaccine in asthma patients.  Issue of reassortment of vaccine strains with wild-type influenza viruses.  The question is whether in vitro and in vivo and experimental animals studies would be appropriate.
		CHAIRMAN DAUM:  Thank you Dr. Griffin and Katz.
		Dr. Schild.
		DR. SCHILD:  I would include among long term strategies the setting up of reasonably intensive viral surveillance if and when this vaccine was introduced to look for the virus itself, reversion to virulence, the presence of genes that might become linked to other viruses through reassortment and so on.
		I would also like to address issue of introduction of additional strains of vaccine that might be used in the future, new antigenic varriants.  And I think it's completely essential that we don't rely too heavily on genetic information on the vaccine strain itself, but clinical data ought to be produced in relation to every single new vaccine produced by this recombination process.
		And I think, again, looking to the future it needs to be careful discussion about under what circumstances one might use such a live vaccine in the face of a pandemic.
		CHAIRMAN DAUM:  Thank you, Dr. Schild.
		Dr. Cox?
		DR. COX:  Yes, most of my comments have already been covered by others.  I believe it was Marty who suggested that having data in the 6 months to 12 month old children would be extremely useful given the burden of disease in that age group.
		In addition, I think it would be really useful to have information about -- information in the 50 to 64 year old high risk group.  
		I think that with regard to the virologic and genetic issues, there is a certain amount of data that are available but it would be -- there are a lot of virus that could be analyzed in detail.  They're available, it's relatively easy to do the genic analysis.  It would give us just a higher degree of certainty about what is actually going on with the individual mutations that are occurring. 
		I was very pleased to hear that the sponsor is actually going ahead with reverse genetic experiments to determine the contribution of the individual mutations to attenuation.  And I think then once those studies are done, it will be very easy to screen for reversion of the key mutations.
		CHAIRMAN DAUM:  Thank you very much.
		Dr. Edwards?
		DR. EDWARDS:  Obviously, lots of the ideas have already been expressed.
		I think one possibility that is intriguing would be that if this vaccine were to be given to a large target population that could be very,either with government and industry funding that could be carefully assessed in terms of outcomes, adverse events, virologic studies and really have a very, very extensive evaluation of it in the real world given to real children and real adults.  And I think that might give us all a measure of safety and a much more controlled way that the vaccine might be introduced.
		I think the one and two dose question is very important, particularly for the public health issues that Dr. Glezen addressed.
		I think the travelers issue is very difficult, because I'm not quite sure which vaccine you would be giving to the travelers and whether everybody should have in their freezer leftover vaccine for the next year, because I can't imagine that the company would be making both North American and South American vaccines in different times, but maybe they would.  But I think the practicality of a travelers vaccine and how you would get it, and for the small number of individuals that you would be delivering would be somewhat of a difficult issue for the practitioner.
		I think repeated vaccinations in adults is very important, whether they continue to be efficacious. And I guess whether this will ever be done is another question, but I think a head-to-head comparison of the two vaccines, TIV and CA vaccine, in terms of different populations might be intriguing.
		CHAIRMAN DAUM:  Thank you, Dr. Edwards.
		Dr. Steinhoff?
		DR. STEINHOFF:  It's funny.  Either I'm the first and I don't know what to say or I'm the last and it's all been said already.
		CHAIRMAN DAUM:  It's that end-of-the-table problem.
		DR. STEINHOFF:  Right.  You know, many of the comments I have mentioned earlier or have been mentioned by others --
		CHAIRMAN DAUM:  That's fine.  I mean, you don't --
		DR. STEINHOFF:  I just want to make a couple of points.
		The first one is that I agree that we need the concurrent immunization. I think that's clearly needed, especially for infants.
		I also think that the issue of the use of vaccine in high risk subjects repeatedly mentioned, but let's not forget the major high risk group which doesn't have a disease are infants under one year of age. So once we get down to 1 year, we need to think about the lower group where there's a lot of hospitalization and clinic visits.
		The annual revaccination of adults, repeatedly said we need to look at that and it's overall effects in comparison with the current strategy of annual revaccination of adults over 65.
		That's all I'm going to add.  Thanks.
		CHAIRMAN DAUM:  Thank you very much.
		Before I make a few comments or call on Dixie, can I ask if there's Committee members that would like a cab at the termination of the meeting?  Dr. Goldberg, Dr. Snider, Dr. Schild.  We have four customers.
		Now, Dr. Snider?
		DR. SNIDER:  Just one point that is not directed to the FDA or the manufacturer, or anyone in particular, but just a notation that clinicians, I think, are going to have to address is the question of antivirals and at what point in time they can give a person antivirals in a circumstance in which there is an influenza outbreak.  And it would be nice if someone were able to answer that question for the clinicians, because otherwise they'll be struggling with that question.
		CHAIRMAN DAUM:  Thank you.
		I'd like to conclude by adding a few comments of my own.  I think that everything that's on the list for discussion points 3 and 4 does need to be done. I guess I'd express my own surprise if the concurrent immunization studies produce clinically important messages, but I do think that people will be satisfied having them done and unsatisfied if they're not done.
		One of the things that intrigues me about all this is the lack of understanding about how this vaccine protects against influenza. I voted yes on the efficacy question because I thought the data were convincing, but I'm not sure I know how to measure a surrogate for that.  And so when we approach things like these concurrent studies, I'm not sure I know how to do them or how to interpret them, and that's going to need some thought by everybody that's involved with them.
		I'm going to also mention my usual influenza saw horse.  This can be everything I'm saying does not necessarily need to be done prelicensure, but I think needs to be done at some point.
		I would like to study vaccine failures.  I don't think we really understand much about them, and I'm amazed that with influenza vaccine, unlike almost every other, we're not really focused on them.  And I don't know who fails vaccine or why.  And I'd like to put in place some kind of surveillance study and monitoring process to learn something about that.
		I'd like to know a little more about -- this is certainly a post-licensure issue -- of what the real world delivery of this vaccine is going to be.  I mean, in study conditions you can restrain an infant and give him the 0.25 mls pretty easily.  But what happens in a busy clinic or busy inner city clinic when people attempt to do this?  Will it be done carefully?  Are there cold-chain issues that are going to have to have special considerations.
		We didn't hear much about ethnic diversity in terms of subjects and most of the subjects were the kind of subjects that usually end up in these studies in their first phases.  And at some point people might want to ensure that people of racially diverse backgrounds respond with appropriate side effect profiles and immunogenicity to these vaccines.
		People have talked about young infants under a year, and I echo that.  And preparing to be sort of old-folk myself, I'm also interested in hearing more about the elderly because they, after all, are at real high risk for serious influenza.  And I think that's an important group to target for study.
		So, most of these things are suggestions for additional investigation as opposed to regulatory issues.
		And that's all I have to say.
		So, with that I'll just check with my FDA colleagues to make sure they feel like they got their money's worth, and we declare the meeting adjourned.
		(Whereupon, at 3:11 p.m. the meeting was adjourned.)