Cdc Prostate Cancer

>>>good morning, it's a pleasureto be able to present here to the advisory committee and it'salways nice to see so many friends and colleagues here oinlittle bit trivalent live attenuated fluinactivated influen the compara safety studies in children.we were really charged with trying to assist the g.r.a.d.e.process in doing an evidence review for flu vaccine safety inchildren 2-8 years of age. this work was done by acollaborative group called the pediatric flu vaccines safetyevidence review group.

it consists of folks from thecdc, and folks from the clinical immunization safety assessmentproj cisa. i don't know how many of youare familiar with cisa, it's a network of folks from theimmunization safety office and seven research centers.>> charged with doing a vaccine safety public health service.we do investigations, research studies related to vaccinesafety, revive review adverse e at safety issues regardingimmunizations, so this follows under that rubric.>>> just to look at potential

disclose yures for conflict ofinterest, i must be more conflicted than my colleaguesfrom vanderbilt so our objectives were to evaluate theevidence for the safety of trivalent live attenuated fluvaccine compared with trivalent inactivated flu vaccine inchildren age 2-8 years of age, using the acip gradingrecommendations or the g.r.a.d.e. process.and i think lisa is going to, this is kind of a segue tolisa's talk. so the acip flu working groupcame up with an assessment much

as lisa showed for outcomes forefficacy, we, they set some guidelines for chose outcomesfor safety analysis, among these were immediate hypersensitivityin anaphylaxis. febrile seizure, medicallyattended wheezing, syndrome, other respiratory outcomes andsymptoms. these graded four of these ashaving critical importance, as two as being important.now, we took of these safety outcomes, and discussed themintensively and in our smaller working group and also in thelarger cisa working group.

and some of these outcomes, thelast two being other neurologic outcomes and respiratorysymptoms, which were graded as important, were really fairlynonspecific. so we actually did not keep themto, for our final safety analysis.we did look at anaphylaxis and febrile seizures, we did notselect them for this review. for several reasons.mostly because these events are fairly rare or uncommon.and if you're looking at the comparative studies, looking atlaiv, versus iiv, there's

limited information for review.we decided to keep medically attended wheezing as an outcomefor review, because this is common and clinically important.again, guillen bar syndrome, there's none for review in thestudies comparing laiv and iiv. fever was added as an outcomefor these studies, because it's common, it's medicallyimportant, it's somewhat comparable across the studies.and it's a potential proxy for febrile seizure risk.so we added that as an outcome. and we added certificate justadverse events as an outcome.

we considered it important, it'sbeen used in other safety reviews.and includes some of the these rare and less-common events.when you're looking at the studies for laiv versus iiv.>> so the methods that we used for our evidence review, therewere eight publications that directly compared laiv to iiv 3.that were selected for review. these manuscripts were usedusing grading sheets, outcome definition, study design, theseason in which the studies were conducted, ages of the studypopulation.

and sample size.we also then looked at limitations or potentials forbiases and the randomized trials.we looked at allocation concealment.blinding, loss of follow-up, failure to adhere to intentionto treat analysis. stopping early for benefit orfailure to report an outcome. for the observational studies,we looked to see if the studies failed to apply or developappropriate eligibility criteria.if there were flawed measures

for exposures or outcomes.or failures to control for confounding.we also graded or looked at each study for indirectness in termsof the population, the intervention or to see whetherthe outcome or intervention differed from that of interestor to see if the vaccines compared with each other or withpatella te placebo or not one another.reviewed within the pediatric safetygroup and the cisa investigators and also have been reviewed withthe acip flu working group.

so amongst the trials, therewere three that were initially chosen, but then were excludedfor various reasons from the safety assessment.there was the clover study, which was conducted years 86,87, population of children 3-19 years of age.it was a double-blind placebo-controlled study.of around 200 children. comparing iiv and nasal placeboto sailen placebo and bivalent laiv.however no safety outcomes described in that study.we eliminated it from our safety

assessment.kathy newsle's study previously mentioned, was conducted over afive-year period. it was initially conducted inpersons between 1-65 years of age.her report reported on subjects under 16 years of age.it was a randomized controlled trial.however if you're looking at the outcomes of interest, in themanuscript, only fever was described as one of theoutcomes. and the study was a littleproblematic in doing comparisons

in that the group 2 who receivedthe laiv only containing two flu a strains, also received aninactivated monovalentb strain, so you couldn't do ahead-to-head comparison. so we omitted it from ouranalysis as well. the last study, who wihollarhnopen-label community-based intervention in children 5-18years of age. a fairly large number ofsubjects, but our safety outcomes were not described inthis study. so that left five evaluationsfor our safety assessment.

some of these you've heardmentioned today. the ashkanazi study and thefleming study are fairly comparable studies, done in thesame year or same season. the ashkanazi study was done inyounger children who had recurrent respiratory tractinfections. whereas the fleming study wasdone in children of-the-6-17 years of age with asthma.they were both open-label randomized studies.about the same number of subjects, 2,000 in each study.and children and adolescents

were randomized to get eitheriiv 3, or laiv. the belshi article or paperdescribed studies done in the years 2004 and 2005.it was conducted in children 6-59 months of age.and this study did include some children with wheezing orhistory of asthma. it didn't exclude thosechildren. it was a double-blindplacebo-controlled study. where children received eitheriiv and laiv placebo, or received iiv 3 placebo and laiv.and around 8,000 or more

children were enrolled in thatstudy. the last two studies were moreobservational studies. conducted over slightlydifferent time periods. the tobak study was anobservational study in younger children.24-59 months of age. where as the baxtra studyincluded children in a slightly older age range.these were observational studies done mostly through the kaisersystem and included fairly large study populations.if you look at our outcomes of

interest, fever, medicallyattended wheezing and serious adverse events, the first threestudies describe those as outcomes, the last two studiescan be used to look at medically attended wheezing and seriousadverse events. so we set out to do this, andthought, well we'll start tackling this by looking atfever, thinking that that would be a fairly simple outcome tolook at. well, it's much like the dukesyracuse basketball game, kind is a little up tointerpretation, was it a block

or a charge?i happen to think it was a charge.but anyway, moving on, fever was described somewhat differentlyin each study. so if you look, each of thesearticles did describe fever. the measurements were differentfrom study to study. it was axillary or rectal, oralor axillary, oral or rectal depending upon the study.the measurement intervals differed from study to study.ten days up to 15 days. and the methods what theydescribe as how they measured

fever it was a little bitdifferent than how they described fever in the results,so from paper to paper, they were quite differentdescriptions of fever. making it a little bit morechallenging. however, if you look at theoutcomes, you can directly compare in each of the studies,children received laiv to children who received tiv.so foror the first paper, the ashkanazi paper, t erature duri11-day period. if you look at temperatureelevations over37.5 and 38.6,

you can see afternddoses 2, no significant differences between the laivgro.in the fleming paper, looked at the fever over a 15-day period.they reported four different levels of fever.remember, these were older children.only received a single ofe.and looking at the comparisons, again no observed differencesbetween children who received children whoat that point, tiv or iiv. the last paper did observe someebelshi arte is only thepaper as.

if you look at the blaapplication, actually it is broken out.over several day several-day perie in the papersdday two of fever, after the ant low or fever over 37.8,there was a significant 5.4% in children who ergot laiv, versus 2% in childr who got the tiv.for higher fevers over 38.9, there was no differencereported. so in grading the evidence, welooked at the four papers, the ashkanazi paper, the populationdiffered a little bit from that

of interest.it was some of the children were younger.these were children who had for the fleming paper, it wasdowngraded somewhat, because these were some of thesechildren were older. they also included asthmachildren. and in the belshi paper, somewere younger and none of the children were in the six to 96months age range in the population of interest, which is2-8 years of age. in terms of grading the evidencefor limitations and potential

for biases for a randomizedtrial, for ashkanazi and fleming, we downgrade a littlebit. because they were not blindedstudies. and all three of the studiesthere was some loss to follow-up.for which it downgrade the evidence a little bit.moving on to our second outcome of interest.medically attended wheezing. these definitions are a littlebit different from study to study.as well, making it a little bit

different to compare between thestudies. the ashkanazi paper definedwheezing episodes observed by medical practitioner.fleming incidents of asthma exacerbation acute wheezing,illness associated with hospitalization, any unscheduledclinic visit or new prescription including rescue medication.and belshi ascribed medically attended wheezing as presence ofwheezing on physical exam, conducted by a health careprovider, with a prescription for bronco dial ator, he e oratrespiratory distress.

and aths marks reactive airwaydisease, encompassing individuals with a diagnosis ofasthma, cough variant asthma, exercise-induced aths maxt theterm wheezing or shortness of breath, including the diagnosisof wheezing and dysapnea and short nez of breath.the time intervals did differ a little bit from paper to paper.ashkanazi admitted the first ten days after the dosing in theirobservation period which one might consider an important timeinterval. to look for medically attendedwheezing after dosing.

fleming looked at the 42 daysafter each dose as did belshi and tobak and baxter.the results reported for each of these studies are reported alittle bit differently this was a little bit confusing to try totease through. but if you look for theashkanazi and fleming papers, they looked at the percentdifference in wheezing between the laiv groups and the tivgroups. and they did not observe anydifference in wheezing episodes between either of their groupsfor these papers.

after the first dose and forashkanazi paper after the second dose.belshi reported adjusted rate differences between, in wheezingbetween the laiv group and or difference between the laivgroup and the tiv group. and you can see here there wassome difference in the overall group.but when you age stratify, most of that difference is really inthose children, as we all know, under 24 months of age.with the difference being 1.18%. this held true for those whowere unpreviously unvaccinated,

not in those who had beenpreviously vaccinated. and not after a second dose.>> here's where it becomes more problematic.looking at the observational studies.they looked at hazard ratios, comparing rates of wheezing ormedically attended wheezing in children after receiving laiv oriiv. and you can see here, whenyou're comparing in the hazard ratios, you're getting hazardratios of .38, comparing laiv to iiv.meaning a lower rate in the laiv

group to the iiv group.and this was true for both the bam ter andbaxter and toebiccomparis comparisons.it has to do mostly with the current recommendations with howwe give tiv and laiv. meaning laiv is not recommendford children who have underlying medical conditions,such as asthma. so naturally you would expectwheezing episodes to occur in a higher rate in the iiv group.so these data are confounded. grading the evidence, againthese looking are pretty similar

to what we looked at before.population differs from that of interest.yes, for ashkanazi, fleming and belshi.adding the toebic and baxter papers.toebic, the population differed a little bit in that there werenone of the children were between six and 96 months of ageand the baxter paper, none of the children were between 24 and59 months of age. then if we downgrade theevidence a little bit for the ashkanazi paper, as i mentionedbecause medically attended

wheezing wasn't reported in thefirst ten days after receipt of the vaccine dose.if you look at other limitations for the randomized trials,again, this looks familiar to the last slide.ashkanazi and fleming were not blinded, there was loss tofollow-up in the three studies. if you are looking at theobservational studies, as i already mentioned, toebic andbaxter can be downgraded for failure to control confoundingthis brings me to the last outcome of interest, seriousadverse events as an outcome.

again, the definitions, somewhatdiffer or in some of the papers really weren't well described.what, whatn't a serious adverse event.but for the fleming and belshi paper, i think these are fairlystandard definitions. the time intervals for lookingat serious adverse events were for most of the studies, at thefrom the time of enrollment through the influenzasurveillance period for the observational studies for toebicand baxster. it was in the 0-42 days postvaccination.

relatedness in most all of thesestudies was determined. the categories ranged frompossibly, probably or potentially.and they were all determined as per investigator in each of thestudies. so in looking at serious adverseevents, rates were fairly comparable between in theashkanazi paper, between the laiv group and the tiv group.5.8 and 4.7%. there was a small number ofvaccine adverse events or serious adverse eventsconsidered related to study

product in both of those papers.in that paper, particular paper. in the fleming paper, the ratesfor serious adverse events were again comparable with a few ofthese events in the laiv group and tiv group being ascribed asrelated to the vaccine. and if you look there, there wasone episode in the laiv group of pneumonia and asthma attack onday two that was considered vaccine related.in the belshi paper, this one again reported similar rates ofserious adverse events in both groups.they do note in the manuscript

that most of the serious adverseevents were hospitalizations, interestingly when you look athospitalizations which usually in all studies constitutes aserious adverse event, the rates were fairly similar, if you lookat the whole population, 3.1%, and 2.9%.when you age-stratify, looking at children who were between sixand 11 months of age, you see that rates of hospitalizationi'll call it hospitalization, were higher in that group, 6%,versus 2.6%. again, this is outside the agerange of interest for our

particular evidence review.if you look at the other age groups, there were no ratedifferences. if you look at vaccine relatedsaes, there were a fair number of respiratory events.pointed out in you can point out in the laiv group, bronco litis,asthma, breathing, reactive airway disease, there were civilin the div group, pneumonia, wheezing, and to point out, twofebrile seizures. in the toebic observationalstudy the the rate of serious adverse events was slightlyhigher in the tiv group.

again, one might ascribe that tothe fact that the tiv group is generally a sicker potentiallysicker population. with more medical compromised orunderlying medical conditions. there were a fewvaccine-related saes described in the laiv group.one was a child with a right middle lobe infiltrate and feverand one child with ino sus separation in the baxter articlethe rates for saes were not noted to be different.in the laiv group there were two.and another child with bell's

palsy.two days post vaccination. looking at grading theevidence, the population differing from that of interest.is the same as previously described.on for the other outcomes. and if you look here atlimitations, of the observation, randomized trials, again theseare the same as described for the other outcomes.for the observational studies, these studies again failed tocontrol for confounding, for a serious adverse events.and for the toebic paper, all

the saes were described as beingdiagnosed in the hospital setting, possibly excluding somechildren who may have had saes outside the hospital setting.in conducting this review, there were several limitations, a fewstudies that directly compare laiv versus iiv.several of the studies didn't assess outcomes of interest.the definitions for the outcomes of interest are notstandardized, which is a particular problems for studies.follow-up intervals varied across studies.the observational studies were

somewhat confounded.the findings observed for fever and medically attended wheezingreally only pertained to one study during a single season.it's difficult to judge any risk of serious adverse events fromthese trials. and it's difficult todistinguish if a temporal association between flu vaccineand adverse event is coincidental or causal.some caution which review was limited to trivalent influenzavaccines that were given, according to current indindications and it's really does

not include any data on the newquadrivalent products. in summary, when givenaccording to the current indications, there's no evidencefor any increased risk of serious adverse events ormedically attended wheezing after laiv versus tiv in thisage group. there is evidence for sometransient increased risk of mild fever after the laiv.one influenza season. thank you.any questions or shall we move on to dr. grohskopf?any questions?

hearing none, dr. grohskopf.r .>> all right. hello again.okay, with that to set the stage to hopefully sort of illustratethat the safety evaluation is a little bit on the complicatedside at least felt that way to us i think relative to efficacy,we can describe what we did as far as g.r.a.d.e. for thesafety. so when we do the g.r.a.d.e.evaluation, dr. walter laid out the characteristics ofindividual papers and studies.

what we're going to be dealingwith next is pooling of data from those studies.as you've seen it's not always easy to do that.because of the way definitions and procedures vary acrossstudies. so we have made an effort topull out some information that is hopefully clinicallymeaningful. but at the same time is notoverwhelmingly complicated. and i'm anticipating we will getsome assumptions on this and things that could be done eitherdifferently or with some

different thoughts.just a couple of comments that will apply more or less to thewhole presentation, which will be somewhat briefer in overview.fever, medically attended wheezing and serious adverseevents. focusing exclusively on theyounger children, 2-8-year-old age range.we made a decision in doing this in our group to exclude theobservational studies. we've had the chance to discussand present information on them, but there is some particular forthe safety evaluation, an

underlying concern thatdifferences in the underlying health status of the twopopulations, the one that receives the live attenuatedversus the inactivated vaccine may affect the results ande terpretation of safety focus exclusively on therandomized trials. so we're going to just discussinformation for children eight years, 2-8 years.the first set of slides, four of them relate to medicallyattended wheezing and the data all come from the belshi study.belshi 2007.

the reason for this is that wewere able to get a fairly consistent definition acrossseveral different categories of children. in the study.we were able to get information limited to children 24-59 monthsof age which we thought was important because there's beensome concern about the younger kids and the occurrence ofwheezing in the younger populations who aren't assumed,aren't approved, well sorry, not were included for ive laiv.example in the ashkanazi paper. the first slide one of thethings about ashkanazi, the

belshi study is that thechildren in the study could either have received one or twodoses of influenza vaccine. some were vaccine naive and gottwo. the children a who weren'tvaccine naive got one. and the data reported along thelines of after dose one, afterd. and so we were able to breakthis out in several ways. just as it is in the paper.so for this slide, this is data following dose one withoutregard to previous vaccinations. some of these children wouldhave been vaccine naive, some

not.follow-up is for day zero to 42. and this is data limited tochildren age 24-59 months. so they're all within theindicated age population for laiv.considering the characteristics of the all the characteristicsthat fall under risk of bias and indirectness, we decided thatthe, there was not a serious risk of bias or indirectnessconsidering all that information.we did, however, downgrade on imprecision, because we have afairly wide confidence interval

that straddles 1.0.overall there was not in this particular slice of the data, asignificant difference in the risk of wheezing between the twovaccines. and we assessed this as type 2or moderate quality of evidence. looking instead to sameinformation sort of same framework, 24-months,follow-up 0-42 days. also information following thefirst dose. however on these are thechildren who were not previously vaccinated, these were allchildren who would go on later

to get a second dose, butvaccine naive at the time of the first dose in this case wedowngraded imlarly for imprecision.we have the points estimate of risk does fall a little closeron the side of favoring the it should say iiv rather thancontrol. on that figure.however, the confidence interval is fairly broad, and straddlesactually representing no significant differencebetween two vaccines. we did downgrade forimprecision.

so we have moderate quality ortype 2 evidence here. the next slide, thisfollowing dose one, but the children in this particularsection have b vaccinated.so these are not vaccine-naive children.point estimate falls more on the side favoring laiv.which we might anticipate because it's not, they're notvaccine-naive. still we have a broad confidenceinterval. which straddles 1.so we have again also a fairly

broad confidence interval,downgrading for overall quality of evidence,moderate. and lastly, among the childrenwho were vaccine-naive following dose 2, point estimate iswell over into the side favoring laiv.it does cross one just barely with an upper bound of 1.06.we would still call this asigni the two vaccines.we also dow imprecision here. serious conceimprecision, we get an overall quality of again type 2,moderate.

moving away from wheezing, tofever, again we thought this would be simple.but it wasn't. and we had a pretty goodexplanation of why that is. ideally, we would look to pooldata from multiple studies where we can, we get bigger numbers.however, it was a little bit tricky to figure out the bestway to do that in this particular circumstance.the definitions of fever did vary across studies and theywere reported out in different ways.in this particular table, what

we have a fever defined bygreater than or equal to 38.6 degrees celsius, which isroughly 101.5. for the ashkanazi paper.and for belshi, greater than or equal to 38.9, which is roughly102 degrees fahrenheit for the belshi paper.and we have pooled those. and this is follow-up for day0-10. so it's a little longerfollow-up than what dr. walter reported when he discussed someof the earlier fever outcomes for example, the slightlyincreased risk of fever in

during one season for two dayspost-vaccination. we have a slightly longerinterval here. and again, the temperaturesthresholds do differ slightly. for this, we have again, we havea slightly broad confidence interval, the g.r.a.d.e.handbook recommends considering downgrading for imprecision whenthe lower bound crosses 0.75. this goes to 0.73.so we did call this, we did make a call for downgrading forimprecision in this particular analysis.and we're calling this type 2

moderate.but no significant difference between the two vaccines.at least according to this analysis.the last data slide here, i have is saes, focusing on relatedsaes, because we were trying to get something a bit morespecific. so these again, related saeswould be serious adverse events that in the judgment of theinvestigator were probably related to vaccination.you saw some of the characteristics of some of thesesaes in dr. walter's slide.

the related ones in particular,most related to respiratory symptoms.and because those were relatively uncommon, even lesscommon than the total saes, we don't have the data are somewhatsparse. we have a particularly broadconfidence interval here. did they downgrade forimprecision? we have data that crosses 1.we have not assigned a value to this particular outcome becauseit's not a completely certain how meaningful it is.we probably will have more

discussion about that withinwork group. although there wasn't readilyapparent consensus from the work group about how they would wantto value it. we did feel it was important tolook at, because some of the more rare and serious outcomesare so rare we could not get an accurate assessment and we'rehoping to use this as some sort of proxy to see if we could findanything. but we did not.overall quality of evidence here was judged to be type 2 ormoderate.

so to summarize for these threeoutcomes, critical medically attended wheezing, nodifference. type two or moderate.fever, important values an outcome, type 2 or moderate.related saes, no difference, type 2 or moderate.moving on to limitations, dr. walter a i dressed some of thisin his talk. but i'll reiterate it because ithink it bears repeating. the definitions of the outcomesof interest are not standardized across the studies.there's differences that make it

you will fairly tricky todetermine how we might pool data in a way that's both meaningfuland will allow us to get a better assessment with betterpower from better numbers. studies also here are notadequately powered to detect differences potentiallydifferences in some of the events we've looked at.but also differences in some of the rare but serious andimportant outcomes. for example gillen bar,anaphylaxis, febrile seizure, these would be things betterevaluated in larger

population-based studies.which we haven't evaluated here. and all of the data pertain totrivalent vaccines, because those were what was availablewhen these things were done. with that, i'd like to thankeverybody that assisted with the evaluation.we appreciated the ability to have immunization safety officeand cisa input on this as we formulated the approach tothings. and also like to thank everyoneelse on this slide. thanks, i'd be happy to take anyquestions.

thanks very much for a clearand succinct presentation that pull it is all together.are there questions from the committee or liaisons?dr. karron? thanks very much.i just will a question there was one slide i think it was maybeyour fifth slide. it was first dose in naivechildren where clearly the ssed 1.but it looked like there was a trend.and i seem to remember that in our work group we had alsolooked to these, this is 0-42

days.i think we looked at a shorter interval that was more relatedto the period of laiv represently indicatiorepresent represently representlyreplication. i was wondering if you couldremind us how that was relative to this?>> there's a slide not included here, because strictly speaking,it didn't meet the criteria for medically attended wheezing.but the ashkanazi paper reported for day 0-11 they did reportwheezing as an outcome.

it was reported on diary cardsfrom the parents, so there was no practitioner verification.that that had occurred. and we did look at that in workgroup. but we didn't include it here.the take-home point from that is that there was no differencebetween the two. we were able to get someinformation from fda with regard to earlier wheezing duringearlier intervals for children 24 months and up.which basically going out during the first ten days followingvaccination to show no

difference.in the rates of wheezing. and those data came from thebelshi study. i will try to get that out tofolks following the meeting. any other comments?>> if we can then, i guess ask is it dr. coelingh?>> thank you to the committee and good morning.i have a very brief supply update this morning.on laiv. before i do that, i would liketo just show one slide that our present in yourand thi in response to the

question that was raisedearlier. about the relative efficacy oflaiv in vaccine-naive children or children who have beenvaccinated previously or have experienced influenza.and this, this slide shows there were four placebo-controlledstudies done during the clinical development of laiv.four of those studies were two-season studies.so those studies are shown on this slide.the first efficacy and this is absolute efficacy compared toplacebo.

so the first study that we'relooking at is the belshi study. first season absolute efficacyof 93%. second season, afterrevaccination, was 100%. the vesicari study, 85% firstyear, 89% second year. bracco, 74% efficacy in bothyears. of the revaccination and thenthe tamm study, 73% efficacy the first year, 84% the second year.and these studies were performed in children that are not in theexact age group that we're talking about today, 2-8 years.these children were generally

younger.then the other piece of information that's relevant tothat particular question is, in the large belshi study that wasconducted that the head-to-head trial of laiv versus tiv, and inthat study, he actually did analyze children who had beenvaccinated previously with iiv. and compared that to childrenwho weren't previously vaccinated with iiv.the efficacy was similar, whether or not they werepreviously vaccinated. if they were previouslyvaccinated, the efficacy was 51%

fewer cases with laiv comparedto iiv. in the reverse situation, whenthey were not previously vaccinated, it was 57% fewercases with, in the laiv group compared to the iiv group.so that's the information relative to that, relevant toue.so i would just like to turn then to this brief supply updatethat i need to give today. so just for clarity, theseasonal live attenuated influenza vaccine is approved inthe u.s. for eligible individuals 2-49 years of age.it contains 6.5 to 7.5 of each

vaccine strain per dose.and the quadrivalent was introduced in the united statesstarting in the current 2013-14 season.it contains no preservatives or adjuvents, stored refrigeratedand administered as a nasal spray, 75 million doses of thelaiv distributed in the united states since licensure in 2003.okay, this slide shows the total doses of laiv produced byseason. starting in 2003, when we werelicensed. and going up to the currenttime.

in the early stage, in the earlyyears following licensure, the production was very modest asyou can see. but it's increased after around2008, when the product was licensed down to age two.when it no long her to be stored frozen in a freezer.and when acip recommended routine annual vaccination ofall children. so we've seen the increase, ialso want to point out to you that large spike in 2009 is thecombination of the pandemic and seasonal vaccines.and as you can see, the gradual

increase in production for the2013-14 season. we produced 22 million doses ofwhich about 13 million have been distributed in the unitedstates. we're planning to produce about24 million doses in the upcoming 2014-15 season, unlessadditional information justifies either increasing or decreasingthat number. so i also wanted to show thisinformation, laiv has been increasingly administered tou.s. children, 2-17 years of age.and the data on this slide is

from large national insuranceclaims database. and it excludes the pandemicdoses. so this shows the percentage ofclaims filed by privately insured children, for influenzavaccine by vaccine type, and by year.so this slide shows the actual usage starting in 2007-2008 andgoing up to 2011-12, the most recent data that we have.and it shows the proportional use of iiv in multidose vials,which is shown in the white bars.the stipple bars show the use of

the prefilled preservative-freesyringes of iiv. and the solid blue bars show thepercentage of claims that were filed for live attenuatedinfluenza vaccine. over this time period, the useof multidose preservative-containing vialsdecreased from 69% in 2007-2008, to 35% over in 2011-2012.in contrast, the use of the prefilled syringes of iiv hasincreased in this period from 19% to 25%.and you can see the use of laiv has increased from 12% to 40% in2011-2012.

the information for the currentseason are just starting to come in.it looks like these trends are continuing and that for thepercentage of laiv is about 44%. so i've shown you the increasinguse of laiv and i've also shown you how we have increased ourproduction in order to meet the demand for increased number ofdoses. so in the next slide, i wouldlike to show you our capacity for responding to a potentiallygreater demand for laiv in the you so this shows the currentand projected laiv manufacturing

capacity, compared to potentialdemand. and the data on these, on thisslide, the estimates assume a 50% overall vaccination rateamong u.s. children 2-17 years of age.using any vaccine types. so that's the current coveragethat we have approximately. and looking then, at the 2013current season, you see a demand for laiv, of 16 million doses,13 million in the u.s. and three million ex--u.s.in the horizontal line, you see the manufacturing capacity thatwe have for making this.

and you note, that there is alarge amount of unused manufacturing capacity.that we're not using right now. because we have a capacity tomake 30 million doses. but we've only had to make 16million doses. if you look going forward to the2014-15 season, and you, if you took a theoretical demand that70% of all children that are eligible for laiv would get it,so you go from the current situation, where there's a 40%market share, and if you would say, what would happen if youmoved that to a 70% market

share, and in either 2-8, or2-17, you would come up with this kind of a demand, whichagain, is met adequately by our manufacturing capacity.if you move on, you can see that we would predict that in2015-16, we'll again be into a situation of excessmanufacturing capacity. because our manufacturingcapacity is going to increase to 35 million doses then.and i would add that if you assume that going forward in theunited states, if we meet the goals of the healthy people2020, where you actually reach

close to a 70% coverage rate, wewill be able to make that. even with these higher marketshares. because we plan as noted in thefootnote, that we will be going to 47 million doses.for the 16-17 influenza season. so summing up, our current andprojected manufacturing capacity for laiv is sufficient foreligible u.s. children. at both current and higherfuture laiv use. at current and higher futurevaccination coverage levels. and to meet both u.s. andex-u.s. demand.

additional increases in u.s.demand could be met by further increases in manufacturingcapacity. thank you and i'll take anyquestions that you might have. dr. karron?>> thank you, kathy. i want to understand therelationship between capacity and supply in any given year.and also, how those relate potentially to our future policydecisions. and what i mean by that is, youknow, there might be a situation where we have a clearpreferential recommendation for

laiv in a certain age group.there might be a situation where we talk about consideration ofuse of laiv in various age groups.how does that affect year-to-year supply?. that's a big question, ruth.i hope i can answer it. but i think that this slide saysa lot. so this, this shows the currentsituation. it's hard to predict what kindof, what kind of demand would be triggered by a preference in theunited states.

we just chose to look at 70%, ifyou look historically at the acip recommendations, when theacip makes a recommendation for a new vaccine, it doesn'ttrigger this automatic movement toward that following thatrecommendation. it always takes a few years forthat to go into effect. so you're kind of getting whatmight happen. but we thought that modelingthis over the next few years. would provide some reassurancethat the capacity is adequate. and that we just have to use it.because as i would point out,

we're only using half of ourcapacity now this year. right now.for the current season. and that is expanding to 47million doses by the 16-17 season, which would be adequatein our estimation to cover everybody who would be likely towant to get it. so can i just have afollow-up to that? flu vaccine is the mostperishable vaccine of all, right?it comes and it goes. and obviously a company has toweigh demand against capacity

you might not produce allthat you can production. if you can't use it.and so i guess, so i guess what i was arriving at is where interms, not just in terms of absolute capacity to produce,but as i guess trying to understand more about theforecasting process, which is probably very, too complex evento discuss, but depending on policy recommendations.how -- ruth, policy recommendations are taken intoaccount. like i said, they, it's not likean instant turning on the hot

water and you know, and peoplefollow recommendations right away.as far as forecasting, i certainly am not involved inthat. so it's very, a little bitdifficult for me to answer that question.clearly, policy plays a huge role as you well know.in how the demand for vaccines. and it's going to be even moreso going forward. with our changes in health care.>> dr. sawyer? i just wanted to make sure iunderstand this slide.

i think it's based on a 50%inmumization coverage rate overall, is that correct?>> that's correct. is there a coverage rate atwhich you would no longer be able to meet the demand?let's say we were at 70% coverage rate and 70% of thosechildren received laiv? we did model that just forsimplicity and to keep the number of slides down, i didn'tinclude that i just wanted to put it all on one slide.but if you do increase that up to 70%, and also look at a 70%market share for where -- it's

adequate, yes.>> kathy stinchfield from napnap.i would like you to comment on the true eligible children.as a work group number we talked a lot about those kids for whomflu vaccine is contraindicated. what are the true contcontraindications versus that which we have in our acipstatement. healthy children and i thinkdefining it clearly does impact who you're going it to and yoursupply. if you could talk about truecontraindications.

well, i think the difficultyis, that what is a true contraindication.so i think you mean the legal regulatory contraindication, asgiven by the fda. so the contraindications in ourlabel, which is issued by the fda, are for you know, childrenwho are on aspirin therapy. and anyone who is allergic to aprevious dose of vaccine. so it could be allergic to thevaccine itself or any excipient, for example, eggs.so i can't really comment, i'm in an awkward position.you recognize to talk about true

contraindications versus whatacip recommends. because of course we, we have totake the you know the judgment of the committee.that's what this committee does. i want to follow up.i didn't mean to put you in an awkward position.i apologize if i did i think the point is to highlight thedifference between those two true contraindications, andhealthy 2-year-olds and over is quite a big difference.and we need to talk more about that.>> dr. karron?

just to sort of follow up onand i think actually we should just probably also say in termsof labels, true contraindications,immunocompromised, those categories along with aspirintherapy and allergic children. i was wondering if our nasicolleagues or i don't know if there's anyone here from the uk.places where laiv is being used in children with previoushistory of wheezing, whether they have any kind of registryor data collection to tell them about adverse events that occurin these populations because i

know laiv is used differently insome other countries. any comment from canada?national advisory committee on immunization.dewee do have a vaccine registry just as you do.a passive system for reporting. i'm not aware of particularanalysis done on laiv and i'm also not aware if there's beenany safety signals brought up. that's been brought to ourattention as far as laiv. how about dr. salisbury?>>. devon salisbury from the uk.so far we've only been

vaccinating 3-year-olds and4-year-olds this winter. we have 40% coverage with laivin those two age groups. but i'm not aware, either, ofany specific adverse events because so far we have been onlyusing theensed specified indications andcontraindications. so anything that comes from useoutside of the recommendations, certainly hasn't surfaced yet.and the other difference is we are only using one dose in allof our age groups. with laiv on the basis that theincremental advantage of the

second dose doesn't really seemto warrant its use. thank you.>> sorry, david, just a follow-up question to that.i think if i understand the contra use offlu-ns, your european product. it's children with severewheezing or active whet outside the they immunization,lawouldn't exclude children with any history of wheezing.>> it's closer to the canadian situation.yes. there was a gentleman up atthe microphone?

yes, thank you.last minor medimmune operation strategy and planning.question regarding forecasting versus planning.we do plan to produce additional bulk and finished good materialevery season above and beyond the expected demand.and then we have options mid season to produce even further.>> thank you. other comments?dr. grohskopf? i think we're ready for theproposed recommendations. all right.thanks.

so as i mentioned at the outsetof the session, at present the work group is not proposing anychanges to the recommendations for next season.we will have an opportunity to discuss more changes in june,should there be the need to do that.and there are some topics that continue to have some ongoingdiscussion within the work group.what we would have planned to do today was basically sort ofreiterate the core recommendations for anyvaccinations being recommended

for persons six months andolder. we've begun to draft a policynote for the mmwr for the next year.for this season after two years of having recommendations doneas policy notes. just with short pertinentupdates, we did for the 13-14 season go back to a full formatmmwrr and having done that we planned for next season, unlesscircumstances change to go back to the smaller policy noteformat. that document has been draftedand consists right now only of

those items that are known orassumed that they're not likely to change and the acip membershave received a kolpy of that for review and comment.any proposed changes we intent to have discussed and presentedat the june 2014 meeting. another thing to note this timelast year we had a lot of new products out or on the horizonabout to be licensed. as of this point in time, wehave not aware of any new licensures, there may be somebetween now and june. currently in the draft policynote, all of the licensed

vaccines are summarized in thedraft table, which is essentially at this pointidentical to the current season table.it will be updated as new package inserts are out and alsowith any new licensures as they occur.and any new licensures that occur between now and june willbe discussed at the next meeting.for today we're just proposing reiteration of the corerecommendations for vaccination for everyone six months andolder.

now just one little brief thing.the vaccine strain selection for next season, the world healthorganization has had its strain selection meeting and isrecommended the same composition for the northern hemispherevaccine. for 2014-15 as has been usedthis season 13-14. that will be discussed at thefda varpac meeting this week we don't know what the strains willbe for the u.s. this week, that will be discussed at vaerpac.those will be recommended in the draft with some place-holdersuntil we know that information.

i want to thank everybody that'sinvolved in preparing all of this, and in particular i wantto thank -- we've been working on the g.r.a.d.e. stuff andspending quite a bit of time together.and that is all i have for this. and any questions are welcome,please. thank you, dr. grohskopf.i see a couple of hands up. dr. harrison.>> in terms of proposed changes, what information will we have injune that we don't have now? well for one thing, asmentioned, one issue with regard

for example to any languagerelated to laiv and iiv. even if there were not to be apreference. we've done the grade analysisand will have some sort of summary of that either in orlinked to the policy note. because policy note is such ashort-format document there will probably be a url-link in thedocument. typically the entire document isnot put into the mmwr. a couple of presences back.one issue that is harmonization with aap is something we aim forand the aap will not be meeting

on this topic until april.>> dr. dushen? thanks, lisa for yourmultiple presentations this morning.i just want to follow up on the issue of preferentialrecommendation for laiv and for our colleagues on the acip whoaren't part of the influenza work group.it might have been a little bit vague.you know really strongly consider iconsidering preferential recommendation and it would begreat if they could

that in the time between now andjune since we won't have the opportunity to vote on thattoday. many of us feel it's longoverdue. and we have a vaccine that evencdc has acknowledged on a public web page is superior.in young children, yet we haven't got enough to make therecommendation, which does influence a lot of health careproviders. i want to make sure othercolleagues understand that that's under seriousconsideration for the june

meeting.>> i'd like to follow up on that point.just a little bit as well. and then also have a question.but the point is whether or not the acip members would requestof the influenza work group proceed with language and such arecommendation for a preferential use of vaccine.keeping in mind also just the timing for clinicians and healthsystems to do ordering that last-minute things, you know,ideally when i put on my clinician hat.things coming in october is

appropriate for the kind of thefollowing year for ordering. soy think we just keep that inmind. that said, the follow-upquestion i think is for dr. deutschen and also for dr.newsle. both from state of washington,where you have a preferential recommendation.for the live attenuated in children.can you provide us a little bit more information on that?>> i presume you're referring to the impact that it might havehad on the use of the laiv?

yeah, unfortunately ourrecommendations don't carry the weight of a recommendation fromthe acip. and it's not really clear thatthey have the penetration that we would desire throughout theclinical community. i like to take the opportunityalways to remind our clinical colleagues that there are datathat suggest that the laiv is bet anywhere younger children.that the cdc has more or less endorsed that data by boostingthat on their own website without making the formalrecommendation.

so in the context of orderingvaccine, i think clinicians should keep in mind, that thereare already, there's already data available to suggest that'sa wise thing to do for children. we don't have a significantcutoff yet, which would be useful for some.there hasn't been any issue of shortage.the supply has been adequate. many clinicians are aware, butdo wait for a more clear guidance from the acip beforesort of changing the large system practices.>> i thank you.

dr. harrison?>> i know the meeting is in april but can we get a sense ofwhere aaip is on this issue? we haven't really discussedit. we're going to discuss it inapril as mentioned. i can tell you that i can tellyou that i can't tell you that there's a consensus yet amongstthe group. some of the information is justgoing to be presented for the first time at the meeting.>> thank you. we have dr. kemp?>> yeah, i think that the data

seems pretty strong.i think that one thing i'm wondering about is i think if infact there's a preferential recommendation made, it's goingto put front and center this issue of wheezing.and you know, as well-defined asthma is fairly straightforw dstraightforward. but as any of the primary careproviders in this room know, in young children, there's a lot ofkids that have wheezed or have wheezed in the last year.but do not have a diagnosis of asthma.i think anything if we make such

a preferential recommendation, iwould like to discuss a little bit more where the current ion,contraindication, came from. and whether we can pin that downa little bit better, given data of whatever type from othercountries, for example. dr. bennett?>> thank you. lisa, i just wanted to clarifywhat you were saying about the recommendations, the yearly mmwron influenza. were you saying if we made apreferential recommendation in june, that it would be too latefor recommendation?

oh no.no. we've had, we've had votes injune i think actually as long as i've been doing this.we've had votes in june despite trying not to have votes injune. and i apologize for that.but it just seems to happen. it is, it is too late in thesense that ordering has happened by that point.but on the other hand, because there's always so much going onwith flu, we one might make the argument we sort of have toconsider things as they come

along and try to keep thingsmoving. it wouldn't be too late to gointo the mmwr. among the concerns that peoplehave expressed about having a preference on the work group, ifi may summarize, there's the fact that ordering will havehappened already. so hard to implement for the14-15 season. on the other hand, there'sprecedent for example, i can't remember exactly when it was, itpredates my involvement in the somewhat.but as the recommendation for

vaccination was being expandedinto broader ranges within the pediatric age group, there was ayear when the recommendation was vaccinate the age group iffeasible this season implement completely by the followingseason. that's one thing that can bedone there, if that's the case. microphone, please?>> medical affairs. thank you so much for the greatpresentations, great work. we would just wondering when wewould include the -- results of the 3-8-year-olds, when that'sgoing to be presented.

the question is related towhen we will have also a review of the data available for thequadrivalent vaccine and the recent study just published withrelation to the efficacy of quadrivalent vaccine in thepopulation. so quadrivalent versustrivalent? yes.>> as usual with flu, there are a lot of topics to be discussed.and that is something we will likely be discussing at a futuredate. i can't say exactly when.>> dr. laehr.

as a member of the work groupi guess i respectfully disagree with dr. temte and focus mostlyon can't we just get a preferential recommendationagreed upon or not and not worry about the wheezing issue at thetime and ask the acip to give guidance to the work group, whatwould you need to feel comfortable voting on apreferential recommendation in june.because that's what the work group is wrestling with rightnow. my understanding that therehadn't been a preferential

recommendation are there otherissues you would like us to explore before we bring thisback in june. as many of us feel we would liketo have a vote on this. and with some language for apreferential recommendation in june.>> dr. harrison? dr. rubin, i'm sorry.>> i'm pretty much compelled with the data, as discussed in aprevious meeting, one of the hang-ups was quadrivalent laivwas a new product. and so i guess i'd like to atleast see the data as mentioned

earlier toned down on the agegroup, that we might be potentially be given apreferential to see if there's signals for seizures onparticular. and for quadrivalent andactivated vaccine as well if there's sufficient data to makethat point. dr. bocchini.>> just harmonization is really important so we have a singlemessage. i'd really like to see what thereview and we could potentially go forward together in a aharmonized way.

i think that's a veryreasonable approach and if there's anything that we can doto facilitate getting the g.r.a.d.e. information to coid,that would be wonderful. ruth is going to do that.>> at this time i think we do have the potential for a votefor the recommendations as presented by dr. grohskopf.i'm wondering if there's any motion for that?a move by dr. bocchini, and a second by dr. deutschen.any discussion? just limited to the -- actuallyif you co

you have a comment, dr. karron?>> yes, i think that the recommendations as they weresent to us had a sort of a red highlight for issues related tocontraindications with respect to laiv.and i think that that was an issue that the work group wasgoing to specifically take up and that might come up inour june meeting and so as we vote on this, i don't know ifthere is a way to incorporate the fact that we're, becausethose are part of the annual recommendations, and yet we mayreconsider those.

so i don't know the best way toapproach that. i think we can just, as partof the minister, make a strong suggestion to the work group toconsider those issues. as opposed to putting it in therecommendation per se. i guess my question is, if ivoted yes, am i voting approve the currentrecommendations for limitations of use and how does that work?>> may i comment? at least based on myunderstanding of, and please, dr. temte and dr. pickering,correct me.

what dr. karron is referring tois there has been for the last several seasons, a footnote inthe table of available vaccines, that concerns one of the issueswe've discussed in the last couple of presentationssurrounding groups for which there's a precaution againstlaiv use for example folks with chronic medical conditions, andare also some wording related to asthma.and that table in the version you've seen or the footnote inthe version you've seen is red and marketed with a commentindicating there's going to be

further discussion of thatbetween this meeting and the next.my further understanding is that also there's opportunity to makechanges at any point if that's necessary, and if the committeevotes on it. for example, we tend to haveupdates to the table based on new package inserts and otherinformation. but that, that section is markedas being currently under discussion.>> is there any comment, dr. sun, from fda regaarding?>> i'm not sure what

specifically you were askingcomments on. currently there is a packageinsert which states the contraindications and theprecautions and so on. and my suspicion is those wouldnot be changed at all. those are standing.>> yes, just by way of kind of background.there are only certain ways in which we can revise the label,packaging insert. and those, the most common wayis when presented with data from the manufacturers concerning thechange.

the second method is thatthere's specific safety concern that are raised, that have cometo be known and they're such seriousness that needs to be inthe label. in which case, fda can make asafety label change so those are the only really two mechanismsto change the label. unless presented withadditional data on the wheezing and flu mist.we'll have to look at the data and consider what thatimplication would be for any changes in the label.so if there's no -- you know,

and medimmune can probablycomment on this whether they plan on submitting such data orworking with us to develop some data.>> dr. kirk? just to the point ofclarification, right now the label from the fda has fairlynarrow contraindications and kathy actually explained whatthose were. the current acip recommendationsas i read them lump together the contraindications and theprecautions. and so i think that the questionthat the work group really wants

to work on, is should those infact be lumped together as one. or should we precautions aredifferent from contraindications and should we consider thoseseparately. that wouldn't require somethingspecifically from the fda. that would require us to reviewwhat's already in our recommendations.>> dr. kim? yeah, just do clarify fromthe comment from the aafp. i think that this, i personallyhave enough information to be in favor of making recommendationin june.

but i do think it's important tomore specifically get into this. because it is going to put itfront and center. so i didn't mean to imply thatthat would hold up the decision. dr. rubin?>> i would just like do clarify what we're being asked to voteon now. as best i can tell it's areaffirmation of last year's statement with changing 13-14,do 14-15. and new players to be namedlater or something. yeah.>> i think you're calling that

correctly.i saw one hand up with dr. sun? i want to follow up with whatdr. karron had said, and perhaps it may be useful to make adistinction between contraindications and warningsand precautions in the package insert.so we do have of course have very specific definitions ofthose. and so please bear with me if icould just describe that a contraindication according tothe fda is we're describing any situation in which a drug shouldnot be used because the risk

clearly outweighs any possiblebenefit. and that there is such stangsrisk of being harmed for the patient.for whom there's no potential benefit makes the riskacceptable. and these are, are supposed tobe known hazards, not theoretical possibilities,whereas warnings or precautions in merely describes clinicallysignificant information. information that would affectdecision on whether to prescribe that drug.and also, any recommendation

monitoring that are critical tosafe use of the drug. and then any measures that canbe taken to prevent or mitigate harm.it's very different from a contraindicaticontraindication, in that one the risk/benefit may be verydifferent. and i think that's a judgmentcall based on the advisory committee or the healthdepartment. thank you.further, up at the microphone? sure, chris ambrose inmedical affairs, medimmune.

to respond to the request by dr.sun for data, we have an active submission with the fda wildfirewe've submitted the data from the fleming study, it has safetydata in children with aths marks as well as children from thebelshi study and the ashkanazi study in which children have ahistory of wheezing or asthma. and we're in conversationingwith the fda about that so we look forward to working withthem to see the resolution of that submission.>> patsy stinchfield. the reason i raised this is toplay it out and we have a

preferential laiv, but we useour existing language that precludes us from using it inchildren with metabolic disorders, i as a clinician amgoing to have a hard time talking to a diabetic and saythis is a better vaccine, but you can't have it because you'renot considered healthy. so wheezing aside, i just thinkwe have to really be clear about our true contraindications andthose precautions that would allow us to open it up for usemore. i am representing the acp andthe ama, as a clinician, i think

you pointed out we have to doour ordering now. and i think it's going to putclinicians in sort of a, a strange place.if you order now and you order based on the currentrecommendations and then come june, what you've ordered is notwhat's recommended. and or that possibility.so i -- it does put clinicians in a weird position.>> dr. dushen? thank you.two comments, one to follow up on patsy stinchfield.i completely agree and i think

that will be the test that aworking group come forward to clarify that language and toaddress those concerns which many of us feel are notbeneficial right now. that's the way they're describedin the statement. and then just secondly aroundthe issue of ordering. for my perspective, we do a lotof ordering in the public health department, we advise clinicianson ordering, we're a universal state.there's always a problem with ordering.things never synchronize.

so we have two good vaccines outthere for children. some clinicians already knowthat laiv may be better in younger children and they cantake that into account when they order now and they cananticipate they may be seeing some more strident or moredirective language from acip on this.it's not going to put them in a very poor position to have youknow, more or less laiv versus iiv.either way, because both vaccines are good.and there's always a transition

period when new recommendationsare made before everybody comes on board.so i think you know, people may not have the optimal mix theywould desire, but they certainly will have good vaccines they canuse on all their patients, either way.>> does that give enough feedback to the work group tobring things back in june? very good.the other point i'll just throw out really quickly.in my mind the biggest problem out there is we underutilizeinfluenza vaccines in general

for children.and especially in school-aged children.so is there any further discussion?why don't we go ahead and do a vote.we'll start with dr. rhinegold and go to your right.>> i vote in favor.>> i vote yes. karron, yes, with a proadviso that we expect some of the issues we described.>> yes. temte yes.>> bennett, yes. pellegrini, yes.>> rubin, yes.

harrison, yes.>> vasquez, yes. beasley, yes.>> jenkins, yes. kemp, yes.>> bow keeni, yes. thank you, the vote isunanimous, i don't believe there's any -- pardon?>> i already did. i don't believe there's any vsdresolution that needs to go with this because it's alreadyexisting.