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MARCH 8, 2001

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The Advisory Committee met in the Versailles Room, Holiday Inn, 8120 Wisconsin Avenue, Bethesda, Maryland, at 10:33 a.m., Robert S. Daum, M.D., Acting Chairman, presiding.


ROBERT S. DAUM, M.D., Acting Chairman




PAMELA S. DIAZ, M.D., Member



PRESENT (Continued):





DIANE E. GRIFFIN, M.D., Ph.D., Member

SAMUEL L. KATZ, M.D., Member


STEVE KOHL, M.D., Member







NANCY CHERRY, Executive Secretary

This transcript has not been edited or corrected, but appears as received from the commercial transcribing service. Accordingly the Food and Drug Administration makes no representation as to the accuracy.



Introductions 4

Conflict of Interest Statement 5

Introduction to Topic, Marion Gruber, Ph.D. 9

Workshop on Pneumococcal Conjugate Vaccines:

Carl Frasch, Ph.D. 33

Dr. Lydia Falk 38


Questions to the Committee and Discussion 74


(10:33 a.m.)

ACTING CHAIRMAN DAUM: I'd like to call the open session, session seven, of our meeting to order, please.

We'll begin by asking each of the committee members seated at the table to introduce themselves, and then we'll turn the floor over to Nancy Cherry for announcements and conflict of interest.

DR. KOHL: Steve Kohl, Oregon Health Science University.

DR. STEPHENS: David Stephens, Emory University.

DR. KIM: Kwang Sik Kim from Johns Hopkins.

DR. GRIFFIN: Diane Griffin from Johns Hopkins.

DR. DIAZ: Pam Diaz, Chicago Department of Health.

DR. KATZ: Sam Katz from Duke University.

DR. GOLDBERG: Judy Goldberg, New York University.

MS. FISHER: Barbara Loe Fisher, National Vaccine Information Center.

DR. INSEL: Richard Insel, University of Rochester.

DR. WHARTON: Melinda Wharton, CDC.

MS. BROOME: Claire Broome, CDC.

DR. BUTLER: Jay Butler, CDC.

DR. EMERSON: Scott Emerson, University of Washington.

MS. LIBERA: Dolores Libera, Allergy and Asthma Network, Mothers of Asthmatics.

DR. McINNES: Pamela McInnes, National Institute of Allergy and Infectious Diseases, NIH.

DR. DECKER: Michael Decker, Aventis Pasteur and Vanderbilt University.

DR. GIEBINK: Scott Giebink, University of Minnesota.


And I'm Robert Daum from the University of Chicago.

Nancy, you're on.

MS. CHERRY: Okay. Announcement. It was brought to our attention yesterday that it gets pretty noisy in this room. Not only do we have the sounds of construction, but some of you have laptops, and so I would ask that there be a minimum of whispering among the audience members because it makes it hard for everyone else to hear.

I also would ask a really big favor, and that's that you turn off your cell phones.

I want to call your attention to the front desk that you passed as you came in. If there's anything that we can do to help anyone, contact the FDA staffers at the front desk. Denise Royster is out there. She's the one that has done much of the work to put this meeting together. Also Sheila Langford is out there today.

And now I will read the conflict of interest statement.

The following announcement addresses conflict of interest issues associated with open session of the Vaccines and Related Biological Products Advisory Committee meeting on March 8th, 2001 and is related to the discussions on developing new pneumococcal conjugate vaccines for U.S. licensure.

Committee members Snider and Manley are unable to attend this meeting, but no votes are expected today, and no temporary voting privileges have been extended to any consultants.

To determine if any conflicts of interest existed, the agency reviewed the submitted agenda and all financial interests reports by meeting participants. As a result of this review, the following disclosures are being made related to the discussions today.

Drs. Goldberg and Insel have been granted waivers in accordance with 18 USC 208(b)(3), which permits them to participate fully in the discussions.

In addition, Dr. Giebink has been granted a limited waiver which permits him to participate in the discussion by sharing his expertise and experience.

Drs. Broome, Butler, Daum, Goldberg, Griffin, Hall, Kohl, Stephens, and Ms. Libera have associations with firms that could be or appear to be affected by the committee discussions. However, in accordance with 18 USC 208 and Section 2635.502 of the Standards of Conduct, it has been determined that none of these associations is sufficient to warrant the need for a waiver, a written appearance determination or an exclusion.

With regard to FDA's nonvoting invited guests, the agency has determined that the services of Dr. Michael Decker as a non-voting industry representative are essential. He has reported that he is employed by Aventis Pasteur as the Vice President of Medical and Scientific Affairs. He is also a vaccine researcher who has had previous associations with all U.S. vaccine manufacturers.

In addition, he has a financial interest in a firm that could be affected by the committee's discussions.

In the event that the discussions involve specific products or firms not on the agenda and for which FDA's participants have a financial interest, the participants are reminded of the need to exclude themselves from the discussions. Their recusals will be noted for the public record.

With regard to all other meeting participants, we ask in the interest of fairness that you state your name and affiliation and any current or previous financial involvement with any firm whose products you wish to comment on.

Copies of all waivers addressed in this announcement are available by written request from the Freedom of Information Office.

ACTING CHAIRMAN DAUM: Thanks very much, Nancy.

There's one additional clarifying announcement that I would like to make. Yesterday we had one question that was subjected to committee vote. The question was are the available data adequate to support the efficacy of DTPa-HepB-IPV vaccine when given to infants in a primary series at two, four, and six months of age. The correct committee vote for anyone who came away confused -- I apologize -- was five members voted, yes, they were adequate; six members voted, no, they were not adequate; and one member abstained. I just wanted to clarify that.

Today we turn to the simpler topic of pneumococcal vaccines, and we will begin with calling on Marion Gruber again to give us an overview from the FDA regarding this topic.

DR. GRUBER: Good morning. My name is Marion Gruber. I'm with the FDA Office of Vaccines.

And I would like to welcome the members of the committee and all others to the important topic of strategies for licensure of new pneumococcal conjugate vaccines.

The committee will be asked today to discuss licensure strategies for new pneumococcal conjugate vaccines that are currently in clinical development. The purpose of this presentation is to summarize the various approaches under consideration for U.S. licensure of these new products and to outline the issues that are pertinent to these approaches.

As you know, the Wyeth Lederle subvalent pneumococcal conjugate vaccine Prevnar was licensed by FDA in February of 2000. This vaccine is indicated to protect infants and toddlers against invasive pneumococcal disease that are caused by the seven serotypes contained in that vaccine. And this vaccine is administered as a four dose series.

The prophylactic efficacy of Prevnar against invasive disease was demonstrated in a large field efficacy study conducted in the United States by Northern California Kaiser Permanente Health Care System, and a high level of efficacy in preventing vaccine serotype invasive pneumococcal disease was demonstrated in the primary analysis and was 100 percent.

Efficacy in preventing invasive disease due to all pneumococcal serotypes was 90 percent.

Next slide, please.

Published results by Juan Estola, et al., in the New England Journal of Medicine of the clinical trial of Prevnar in prevention of acute otitis media that was conducted in Finland showed that the efficacy of this vaccine against any cause of acute otitis media was six percent. Efficacy was 34 percent against all pneumococcal acute otitis media, and was 57 percent against vaccine serotype acute otitis media.

And a supplement for an acute otitis media indication for Prevnar is on file with the agency.

Next slide.

In order to increase protection provided by pneumococcal conjugate vaccines to other prevented pneumococci in the United States and worldwide, vaccine manufacturers have generated new pneumococcal conjugate vaccines that contain many more serotypes than those contained in Prevnar.

And these vaccines differ with regard to the polysaccharide antigen concentration, the protein carrier chosen for conjugation, and vaccine valency. Some of these antigens are combined with vaccine antigens directed against non-pneumococcal pathogens, and Phase 1 and 2 clinical studies for these products are either ongoing or have been completed.

CBER has received clinical development plans from vaccine manufacturers for these new pneumococcal conjugate vaccines, and those include alternative approaches for obtaining approval for these products.

And under current considerations are to conduct noninferiority studies based on select immune parameters for the seven serotypes common to new vaccine in Prevnar; to conduct clinical endpoint efficacy studies for invasive disease endpoints outside the United States; to submit data from completed controlled efficacy trials for acute otitis media endpoints; and to submit data from completed controlled efficacy trials for pneumonia endpoints and/or combination of these elements are also likely. In some cases, more than one vaccine indication may be sought.

If licensure of pneumococcal conjugate vaccine is to be based on noninferiority studies comparing immunologic responses, the parameters which would best predict protection would need to be quantitatively defined.

However, a whole lot of protection against invasive disease could not be derived directly from the efficacy trial for Prevnar due to the paucity of vaccine failures. Therefore, immune parameters that are perhaps less clearly associated with vaccine efficacy may need to be considered.

And very recently, on February the 26th, an FDA-NIAID sponsored workshop has taken place to discuss various immune parameters that could be used to assess noninferiority of vaccine responses, and thus potentially serve a basis for a head-to-head comparison of new vaccine product to Prevnar, and a synopsis of the outcome of this workshop will be presented to you following this presentation.

Next slide. Thank you.

I'd like to take two minutes to briefly review the regulatory approach that was taken by the center during the licensure process of Prevnar. As you may recall, the Advisory Committee meeting of November '99 was dedicated to the discussion of Prevnar and the results from the manufacturing bridging studies were present.

And this manufacturing bridging study was conducted to perform an immunological bridge between lots that were prepared at commercial scale and to the pilot scale that was used in the efficacy trial.

Anti-pneumococcal responses between groups immunized with vaccine lots prepared at full manufacturing scale compared with those of a group immunized with a single lot prepared at pilot scale, and this comparison was based on the percent of subjects responding with antibody levels above a pre-specified antibody threshold level.

And the chosen threshold to antibody levels provided maximal discrimination between naive and immunized individuals at seven months of age by determining concentrations where the greatest percentage of immunized individuals were above that threshold and the lowest percentage of naive individuals were above that threshold.

And now I'd like to briefly show you all this using serotype 6B as an example. In the red curve, you see that's the reverse cumulative distribution curve for the immunized population or the immunized group. The green curve then represents the RCD of the unimmunized group, and the black curve is the difference between these groups.

And the antibody threshold level for serotype 6B that maximally discriminated between immunized and unimmunized individuals was .25 microgram per mL.

Now, conceptually the percentage of individuals with sero-responses above threshold antibody concentrations could be considered a criteria for establishing noninferiority based on a head-to-head comparison of a new pneumococcal conjugate vaccine with Prevnar.

And of course, the statistical criteria for comparability to Prevnar would need to be discussed and would need to be defined, and as an example, criteria that have previously been used for determining the adequacy of bridging are the ratio of the geometric mean antibody concentrations not less than .5, for noninferiority of the new pneumococcal conjugate vaccine relative to Prevnar, and less than a ten percentage point difference in proportions responding above the predefined antibody threshold barrier or titer.

Can I have the next slide?

It has also been proposed or it's conceivable to use single antibody concentration cutoffs for all vaccine serotypes, and one might choose for this purpose an antibody concentration at or above the highest threshold level observed for any of the serotypes to assure that more stringent criteria are met for all these serotypes.

And then, of course, the additional immunological parameters such as opsonophagocytic activity, measurement of antibody avidity, or a combination of the above that may perhaps be considered as predictors of efficacy, and the relevancy of these parameters in this context were discussed during the recent NIAID-FDA workshop and will be presented to you shortly.

I would like to note, however that establishing of noninferiority based on sero-response rates, GMCs and/or additional immune parameters vis-a-vis the licensed product Prevnar could be a difficult standard to meet. With seven serotypes in various sets of endpoint criteria, the statistical analysis complicated by issues of multiplicity due to the various comparisons that would need to be made, as well as issues regarding a level of correlation of these different measures.

So the probability of failure to demonstrate noninferiority for one of the parameters will increase with each comparison that is made and could be due to chance alone.

And going back to antibody levels for a second, because Prevnar was highly efficacious in preventing invasive disease, the antibody levels attained following Prevnar may be in excess of levels required for protection from invasive disease. That is, other vaccine formulations might still be effective even if the antibody levels achieved are significantly lower than those achieved following immunization of subjects with Prevnar.

I'd like to briefly talk about the concept of performing clinical endpoint efficacy studies. Demonstration of preventive efficacy for clinical endpoints remains the gold standard to support licensure of vaccines.

However, efficacy data based on clinical endpoints are likely to be difficult to obtain for future pneumococcal conjugate vaccines. As discussed, Prevnar was shown to be highly efficacious in a large trial for the primary endpoint of invasive disease, and as a result, Prevnar is currently recommended for universal immunization of infants in the United States, and this recommendation has been made by the American Academy of Pediatrics, American Academy of Family Physicians, and the Advisory Committee on Immunization Practices.

Now, if efficacy studies are required, then to obtain U.S. licensure for a new pneumococcal conjugate vaccine, such studies would need to be designed either as noninferiority studies using Prevnar as a comparator or superiority studies using placebo or an unrelated vaccine in the comparator group, depending on the availability of Prevnar in the host country.

In the latter case, if clinical efficacy was demonstrated for a new vaccine in either placebo controlled or non-pneumococcal vaccine controlled studies, one might still question whether the new products were as effective as Prevnar, and thus the efficacy estimate was very high.

And some would argue that all pneumococcal vaccine studies should be conducted as comparative studies using Prevnar in the control group regardless of availability of Prevnar in the host country, and this is based on ethical concerns.

Clearly, the ethical evaluations and considerations of placebo controlled pneumococcal vaccine studies are very difficult and complex, and these are currently being discussed by FDA or between FDA upper management and the Office of Vaccines.

Next slide.

If efficacy trials conducted in foreign countries are to be used in support of U.S. licensure of new pneumococcal conjugate vaccines, immunological bridging to the U.S. population is likely required.

However, age specific disease incidence and population differences in genetics, nutritional status and background infection may affect the efficacy as well as the immune response induced by a particular vaccine.

So if efficacy is demonstrated in a non-U.S. population, demonstrating that the immune response is adequate in the U.S. population may be difficult in the absence in a true correlate of protection.

Next slide.

Studies demonstrating noninferiority clinical endpoint efficacy for invasive disease would be substantially larger than placebo controlled trials, but in order to more fully evaluate the regulatory options on which to base licensure of new pneumococcal vaccines, the Division of Biostatistics within CBER has estimated sample sizes for efficacy trials using noninferiority trial designs.

And since future pneumococcal conjugate vaccines will likely contain more than the seven serotypes that are currently contained in Prevnar, it is plausible that fewer cases of all pneumococcal disease would be observed in the group receiving the higher valency vaccine than in the Prevnar group, but serotype specific efficacy in the Prevnar group may still be superior.

So, therefore, the more appropriate endpoint for comparative efficacy studies might be disease caused by any pneumococcal serotype, and of course, if studies are conducted in non-U.S. populations, differences in the epidemiology of pneumococcal disease may also affect the efficacy of vaccine.

So in computing sample sizes for noninferiority efficacy studies for invasive disease due to all pneumococcal serotypes, the statisticians have made various assumptions of vaccine efficacy and pneumococcal disease rates, and these I will show in the next few tables.

But I would like to stress that the sample sizes reflect estimates rather than precise numbers, and the computed margins for the acceptable difference in vaccine efficacy between the new vaccine or the new product in Prevnar of ten, 15 and 20 percent that we show do not necessarily reflect CBER's thoughts on what would have constituted an acceptable difference.

Now, the first table that shows sample size estimates for invasive disease studies in the low incidence population evaluating noninferiority of new vaccines to Prevnar, and the assumption is made that the invasive disease case rate in the unvaccinated population is about 1.5 in 1,000, and what you can see here in the left column is the Prevnar vaccine efficacy estimate, the point estimate that we have specified to be between .7 and .9, and note that the efficacy for Prevnar in terms of protection against all pneumococcal disease was 90 percent in the Kaiser trial.

The next column then here is the disease probability in the Prevnar group specified for these different point estimate of vaccine efficacy for Prevnar, and these three columns represent the case rates for the new vaccine group corresponding to a difference in efficacy between Prevnar and the new vaccine of ten, 15, and 20 percent.

So, for instance, if the true efficacy for Prevnar were to be .7, the disease probability in the new vaccine group could be no greater than six in 10,000 for this vaccine to be considered noninferior over the ten percent margin.

But the sample size required to show this would be 250,000 subjects per group. Now, if you assume a vaccine efficacy of .9, the sample size would drop to about 80,000 per group, but the disease probability in the new vaccine group could not be more than three in 10,000.

So what this table shows us is the numbers that would be required for such trials are very large, and that they increase as the Prevnar vaccine efficacy estimate decreases and as the acceptable margins between vaccine efficacy of Prevnar and new vaccine decreases.

And of course, the sample sizes are so large because the disease case rate in the unvaccinated population is so low.

Can you show -- okay. Thank you very much.

This slide shows basically the same thing, only here we have assumed that the invasive disease case rate in the unvaccinated population is about five instead of one in 1,000. And so now if you look at the Prevnar vaccine efficacy estimate of .9, you will need about 25,000 subjects per arm to demonstrate noninferiority of the new vaccine group within a ten percent margin.

Can I have the next slide, please.

Available efficacy estimates for Prevnar in preventing otitis media due to serotype specific pneumococcal disease are substantially lower than for invasive disease, and the level of preventive efficacy that is supportive of an otitis media indication is currently under review by the FDA.

If the level of efficacy reported in the Finnish efficacy study is deemed sufficient to support an otitis media indication, an indication for prevention of otitis media based on noninferiority to Prevnar could be requested by manufacturers without prior demonstration of protection against invasive disease.

And efficacy studies based on otitis media endpoints would likely be conducted in countries like Finland where tempanocentesis as therapy for acute otitis media is standard of care.

So in planning noninferiority trials for the efficacy endpoints for otitis media due to all pneumococcal serotypes, our biostatisticians have made assumptions based on data from the Finnish otitis media trial of Prevnar in calculating sample sizes, and this is shown in the next table.

Next table.

And here we assumed, and these are the data from the Finnish trial, that the true vaccine efficacy point estimate for prevention of cases due to all pneumococcal serotypes is 34 percent, and that was the efficacy for Prevnar.

The left column then shows -- this table is set up a little different -- this column shows the acute otitis media case rate in the unvaccinated population per person-year, and this is then the case rate in the prevnar group assuming that the vaccine efficacy is 34 percent.

And, for example, using a case rate in the unvaccinated population of .4 and a vaccine efficacy for the new vaccine of 30 percent, you would need about 6,000 subjects per group to demonstrate noninferiority of the new vaccine, and the sample sizes do drastically increase as the case rate in the unvaccinated population decreases and as the acceptable or the vaccine efficacy of the new vaccine compared to Prevnar narrows.

Now, recommending bodies, such as the American Academy of Pediatrics or the ACIP, may not be completely assured that vaccines that are licensed based on prevention for otitis media will be as effective as Prevnar in preventing invasive disease. However, neither does demonstration of noninferiority of immune parameters provide this assurance in the absence of a quantitative immune -- for invasive disease.

And I would like to conclude here and present you with the following items for discussions for this afternoon.

First, please discuss whether noninferiority immune response trials comparing new pneumococcal conjugate vaccines with Prevnar are sufficient for inferring efficacy against invasive disease for the new product, and if so, what immunological parameters should be considered?

Next slide, please.

Please discuss the criteria that should be considered to evaluate the serotypes not contained in Prevnar.

And next slide, please.

Please discuss the following scenario. An invasive disease efficacy study may be performed in a non-U.S. population with a new pneumococcal conjugate vaccine. If efficacy is demonstrated could data derived from such a trial support licensure of the vaccine in the United States?

And if so, what are the immunologic parameters that should be used to establish comparability to Prevnar in a U.S. bridging study?

And the next slide.

Please discuss if efficacy studies -- if invasive disease efficacy studies cannot be done, please discuss if data demonstrating clinical efficacy against acute otitis media for a new pneumococcal conjugate vaccine can also be used to infer efficacy against invasive pneumococcal disease for this new product.

Next slide.

And in the last slide now I would acknowledge the contributions and invaluable help that I received from my colleagues in putting the briefing document and the slides together, and especially Dr. Douglas Pratt and Pamela Getson and Peter Lachenbruch, who were our biostatisticians.

Thank you.

ACTING CHAIRMAN DAUM: Thank you very much, Dr. Gruber.

I would like to ask the committee at this point whether they have questions specifically to clarify items in Dr. Gruber's presentation. We will obviously be addressing the bigger issues beginning after Drs. Frasch and Falk present the synopsis of the workshop.

Dr. Kim.

DR. KIM: In immunologic parameters, you talked about single antibody concentration curve and opsonophagocytic assays, and antibody avidity assays, and you gave us a sort of a graph utilizing serotype 6B and to discriminate vaccinated versus unvaccinated.

Are you able to make such discrimination curve using other parameters besides antibody concentrations, such as opsonophagocytic assay and so on?

DR. GRUBER: I am actually not sure about this at this time. I don't really know if the data are available. Perhaps this is a question that we could ask the manufacturers who are looking at these assays more closely than we have seen these assays.

ACTING CHAIRMAN DAUM: Other clarity questions for Dr. Gruber?

Dr. Giebink, Dr. Broome next.

DR. GIEBINK: Dr. Gruber, along the same lines, I wonder if in the licensure of the 14 and 23-valent polysaccharide vaccines was this approach of antibody difference between immunized and nonimmunized subjects ever used or discussed?

DR. GRUBER: No, it was not used as far as I know. That has not been used, and I doubt that it was discussed. People that have the history at CBER could perhaps comment on this.

Dr. Frasch, would you like to make a comment?

DR. FRASCH: Yes, I happened to be here during the approval.

No, the only thing that they had to demonstrate was that they had a comparable fourfold increase in antibodies -- remember we're talking about adults now -- in antibodies to the types not included in the 14-valent vaccine, and show that each of the new types induce functional activity, i.e., opsonophagocytic activity.

There was no discussion about thresholds.


Dr. Broome, please.

DR. BROOME: Marion, I'm curious in your sample size calculation. Your background rate appears to be invasive pneumococcal disease, but of course, the efficacy of 97 percent is against vaccine type pneumococcal disease.

So when you look at the vaccine efficacy estimate, I assume you need to factor in the proportion of types covered by the vaccine, i.e., you have to compare a disease rate that's for the same spread of serotypes as the efficacy rate.

DR. GRUBER: Yeah, that point is acknowledged. I think what we've done really purposely is we've said that we wanted to consider really invasive disease against all pneumococcal serotypes, and so, therefore, in computing the sample size calculations we have actually looked at perhaps vaccine efficacy estimate for Prevnar than it was actually demonstrated.

But it's clearly true that disease epidemiology and other preventive serotypes then need to be factored in if you want to make precise sample size estimates for such trials in a specific setting.

ACTING CHAIRMAN DAUM: I would think the same argument would be extended to the otitis media issue as well.

DR. GRUBER: That's right. And this was only to give you really sort of a ball park figure, you know.

DR. BROOME: But, yeah, I think what we're saying is the realistic overall efficacy of Prevnar would be more like --

DR. GRUBER: Well, more like perhaps 90 percent, but then, again, you know, if you look at a Third World -- I don't want to say that. I don't want to --

ACTING CHAIRMAN DAUM: Developing country.

DR. GRUBER: Right. In developing countries, there may be other pneumococci serotypes, pneumococcal serotypes prevalent, and so the vaccine efficacy for Prevnar may even drop because perhaps other serotypes would be responsible for invasive disease.

ACTING CHAIRMAN DAUM: Ms. Fisher, please.

MS. FISHER: As natural exposure to pneumococcal organisms is widespread in the U.S. in most populations around the world, will the presence of maternal antibodies or preexisting antibodies from natural disease exposure to any of the vaccine serotypes affect the qualitative and quantitative measurement of post vaccination functional antibodies?

In other words, could the vaccine's efficacy using serologic immunologic markers be over or underestimated because of the potential confusion between vaccine and disease induced antibodies?

DR. GRUBER: Well, I think you have to -- I mean, I'm hearing you actually saying two issues. One is the material antibody issue, and the other one is disease induced antibodies. I think these are two different things.

In terms of maternal antibodies, since we're looking at -- if we were to look at antibody threshold levels, we would be looking at seven months of age basically where you have completed giving a primary series of vaccine, and at that point, from the data from what we've seen is that the antibody levels really have dropped by six, seven months of age.

So I, and other people may comment on this as well, I would not necessarily expect maternal antibodies to be really a significant confounder there.

In terms of antibodies due to vaccine, to -- induced by disease, it's difficult. I'm really -- I mean, I don't really see right now how we can really apply this here because if you have an infant that has invasive disease, like at three, four, five months of age, you probably would not really --

MS. FISHER: It doesn't have to be invasive disease, does it?

DR. GRUBER: No, it doesn't have to be invasive disease.

MS. FISHER: Simple exposure to the --

DR. GRUBER: That's right. It can be exposure. Well, I guess that's a potential.

MS. FISHER: I think it's an important potential.

DR. GRUBER: Well, I think we may have to factor this in or comment on this in this afternoon when the committee discusses this issue.

ACTING CHAIRMAN DAUM: I think we could return to that issue later should you so wish it, but we're looking for questions to clarify Dr. Gruber's presentation right now.

DR. KOHL: I think you alluded to a ten percent difference in terms of acceptability for noninferiority, and yesterday we heard a plea by one of our statisticians that the FDA join the rest of the world and use a five percent difference. Is there any validity in that or any thoughts on FDA's part about what kind of difference?

DR. GRUBER: You know, I do not, yeah, really think that a decision in this regard has been made. The data that I showed was really that we have previously induced in the bridging study that was done for Prevnar. So I think we need to have perhaps further discussions on this issue.

But Dr. Lachenbruch would like to make a comment.

DR. LACHENBRUCH: Peter Lachenbruch, FDA. I'm one of the statisticians.

I believe -- I wasn't here yesterday, but I believe the issue was the confidence level should be 95 percent as opposed to 90 percent, not the lower bound of the interval on vaccine efficacy, and that's a little bit different, a lot different.

ACTING CHAIRMAN DAUM: Thank you for clarifying that.

I think at this point we'll thank Dr. Gruber very much and ask Drs. Frasch and Falk to present a summary of the pneumococcal conjugate vaccine workshop.

As they get set up to present, I guess I'd like to compliment them in being able to get the synopsis together in near record time, as fast as it took to fly from Washington to Chicago and back it seems.

We're going to have both their presentations, and then, again, I would ask committee to offer clarifying questions specifically for the issues raised in their presentation.

DR. FRASCH: Okay. You've already heard some mention of the correlates of immunity workshop we held, that was held on February 26th. This was a joint workshop organized between the NIAID and CBER.

But first, I would like to give you a little bit of the history how this workshop came about.

Next. Okay. We just passed one.

All right. This whole thing got started shortly after the hemophilus conjugate vaccines were being developed. In 1986, NIAID, WHO, with WHO support, had a workshop on the NIH campus in which they looked at the need for a pediatric pneumococcal conjugate vaccine, and this workshop was where they actually had some of the experts of the world set up on the blackboard and select what they thought were the seven most prevalent types.

And as it happens, those are the types that are in the licensed vaccine.

Next slide, please.

Then in 1987, NIAID put out an RFP for production of a clinical lot of seven-valent pneumococcal conjugate vaccine.

Next slide.

Then in 1988, Praxis Biologics was awarded that contract, and ultimately was able to provide a five-valent vaccine, and you will see a number of publications relating to a five-valent pneumococcal conjugate vaccine, and this all came from the studies sponsored by NIAID.

And then finally -- next slide -- in 1994, NIAID held a workshop on the potential uses of a pneumococcal conjugate vaccine, and one of the potentials they saw was for infants, also adults, but also pointing out that the need of a pneumococcal conjugate vaccine may even be greater in other countries than just in the U.S.

So with that background -- next slide -- I want to give sort of the rationale why we held the workshop a couple of weeks ago.

First, as you heard today, there are going to be immunological comparisons between conjugate vaccines, and therefore, we need to have a scientifically sound basis for considering new conjugate vaccines and clinical evaluation of future pneumococcal conjugate vaccines will certainly include studies of antibody response.


Thus, the purpose of the workshop was to discuss our current understanding of the mechanisms of immune protection against invasive pneumococcal disease, and then to identify those in vitro immune measures which can serve well as correlates of immunity in future vaccine trials.

Now, next slide.

I would like to momentarily take you back a few years and look at the historical perspective gain from the Hib vaccine experience, and I'm sure you're going to hear about hemophilus conjugates against today because the hemophilus conjugate was the first licensed conjugate vaccine.

So what we see is that in October and December of 1990, the first two hemophilus conjugate vaccines were licensed. These both were licensed on the basis of randomized controlled efficacy trials conducted at the same time.

Next slide.

Pasteur Merieux, now Aventis Pasteur conjugate vaccine was actually approved in 1993 over two years after the other two conjugates. Thus, what was the mechanism that the Aventis Pasteur vaccine became licensed, U.S.? I'll go through those.

First, they were randomized comparative immunogenicity in infants with a similar currently approved product.

Two, the persistence of antibody after the primary immunization series and up to the time of the recommended booster dose was looked at.

Third, they were able to show as all conjugate vaccines should that the infants were primed by the conjugates for a subsequent booster response to the native hemophilus polysaccharide given six to nine months after the primary immunization.

Why was this important? Because this would simulate natural exposure and demonstrate immunologic memory. The importance here is that antibody levels at seven months is what is critical for protection, but in an older individual, memory also becomes quite important.

So next slide.

So the last point was they had to show functional capacity of the conjugate induced antibodies by either measuring opsonic or bactericidal activity. Well, bactericidal activity was okay for hemophilus. For the pneumococcus, one would have to concentrate on opsonic activity.

So the focus on the workshop was invasive disease. Why was that focus? The focus is because -- I'm quoting now from the Prevnar package insert -- "Prevnar is indicated for active immunization of infants and toddlers against invasive disease caused by pneumococcal types included in the vaccine, and these types are 4, 6B, 9B, 14, 18C, 19F, and 23F, and the routine schedule is a four-dose schedule at two, four, six, and then 12 to 15 months of age."

So next slide.

Here are some important items that were discussed during the workshop which will be greatly expanded upon very quickly by Dr. Falk.

First, the mechanism of protective immunity was discussed.

Second, the measures of immunity that correlate best with protection.

Next, the immunological parameters that would need to be evaluated in a head-to-head comparison of a pneumococcal conjugate vaccine with a currently licensed product.

And finally, how to evaluate the immune response to serotypes not contained in seven-valent vaccine. As you know, the newer vaccines will have higher valency. So what to do about those types not in the current vaccine.

Thank you.

DR. FALK: Well, I want to thank Dr. Frasch for inviting me to share with you some of the highlights of the CBER-NIAID workshop that really specifically dealt with addressing some of the issues of the correlates of immunity as we understand them currently.

And as was mentioned, this workshop occurred just about a week ago, and so what I will be presenting to you is really an attempt to just abstract some of the main items and conclusions that were generated from that workshop.

And also, as I go through the talk, I'm going to focus on the particular presentations that we had and some of the highlights, following by a summary of what the expert panel and discussees had come up with, some conclusions, and also at the very end, which I'm sure everybody is going to be happy to see, are a list of unresolved issues, and I think that that will certainly play into -- no comment on how long that is relative to the rest of the talk -- that will certainly play into your discussions this afternoon.

Now, if I could just have the next slide, please. Next slide.

I'm here today. What we see here is the workshop objectives, and I'm here today on behalf of NIAID serving as a rapporteur for this workshop, and so that was the role that I played, along with Mark Steinhoff was a co-rapporteur.

Well, we can see here the objectives of the workshop were really showing a partnership between NIAID and CBER in an attempt to come to grips with a very difficult question that is necessary to deal with in order to advance the public health interest in regarding pneumococcal vaccines and also combination vaccines which include pneumococcal antigens.

So what we were dealing with here is a mechanism that we were hoping to move forward that would advance the clinical development of these conjugate vaccines for their use in children, and the main objective was to identify and discuss the immune measures as correlates that we could be taking for clinical studies, which Marion Gruber had highlighted early in her talk, and also hopefully to develop a framework for evaluation of pneumococcal conjugate vaccines for their use in children.

If I could have the next slide.

Just to give you a sense of the make-up of this workshop, there were certainly a panel of experts that had been invited to serve as the main input for the workshop, and a number of those experts had given very brief presentations on a number of specific topics which you'll see later.

We had industry representatives there as well. We had NIAID staff, and CBER staff.

With regard to the experts, you'll see them mentioned specifically for those who had given presentations, but I also wanted to highlight some additional persons who were there.

Dr. Donna Ambrosino; we have Steve Black, you'll see; George Carlone from CDC. Bob Daum had participated. Ron Dagan; Kathy Edwards; David Goldblatt. We had Helena Kayhty, Daniel Musher, Lawrence Moulton, Moon Nahm, Mark Steinhoff, Benjamin Swartz, and Mathuram Santocham, Jeffrey Weiser, just to give you a general overview of who was at the table for these discussions.

It was a very interactive session that allowed participants who were not at the table to also interact.

If I could have the next slide, please.

The presentations were specifically asked to focus on mechanisms of protection for pneumococcal conjugates and pneumococcal disease, correlates of protection, antibody quantitation focusing on ELISA and opsonophagocytic assays. Also a comparative response from different vaccines was also included in this.

Issues of immunologic memory, and the challenges of choosing endpoints for clinical studies based on comparisons to Prevnar.

Next slide.

This is the beginning of an introduction to you with just abstracting some of the main bullets from each of the individual invited talks that we had had. The first one shown here was by Dr. Musher on the mechanisms of protection against bacterial pneumococcal disease.

And what you can see here is that he basically talked to us about what was shown with passive transfer of polysaccharide antibodies in rabbits and how that was used to identify serotype specific protection.

He also discussed age related differences in protection following polysaccharide vaccine. This is straight polysaccharide. This is not conjugate. And also he highlighted that nonfunctioning antibodies, i.e., non-opsonophagocytic or protective antibodies, may be elicited following infection. So it sets the stage for how complex the immune response can be.

Okay. Next slide, please.

Our next speaker was Dr. Santosham, and what he was asked to talk about here was what was known about correlates of protection, and this was really lessons learned from passive transfer, and what we have here is he described to us some of the information that was obtained for hemophilus polysaccharide induced antibodies that were shown to demonstrate passive protection.

He also had immunologic findings based on the polysaccharide, but also clearly indicated that it may not -- that what we know obtained from data obtained from polysaccharide vaccination may not be relevant actually for consideration for conjugates.

He also described for us some information that was obtained using a bacterial polysaccharide immunoglobulin passive transfer for what we know about protection. The BPIG is a complex antibody mixture and was used to look at Hib, Haemophilus influenza short-term protection and pneumococcal -- and conjugate following -- I'm sorry. That should be pneumococcal protection following the bacterial polysaccharide immunoglobulin. That's a typographical error.

If I could have the next slide.

His conclusions were that breakthrough cases suggest that antibody titer may not always been protective. Passive immunization also suggests that there are similar thresholds for pneumo and Hib polysaccharides induced, and this is short-term protection.

Next slide, please.

The next talk we had was really a synopsis presented to us by Dr. Black which is information that was obtained from the Prevnar efficacy study, sine he was one of the principal investigators from that study.

And what he discussed for us and presented for us was type specific protection and also what we might have gained about knowledge about correlates of protection from the Kaiser efficacy study for Prevnar.

As summarized here is just a brief overview of what the information was surrounding that trial. It was a double blind, randomized, controlled trial in approximately 38,000 infants. The efficacy results, you'll see various numbers for efficacy, and it really depends on when the efficacy analysis was calculated based on follow-up time, but the results he presented were that there was 97 percent efficacy from base of disease; 87 percent for pneumonia; eight percent for otitis media visits; and approximately 25 percent for ear tube replacement.

If I could have the next slide.

What he also presented to us was some breakdown on what information was available on type specific protection, and what we see here is serotype specific efficacy, was approximately 100 percent for types 14, 18C, and 23F, and 85 percent for 19F, and it also needs to be noted that there were instances where there were no cases for certain serotypes in the vaccine. So a protective efficacy could not be determined in those cases.

Next slide.

Dr. Black also presented some of the immunogenicity data post dose three that was derived from a subset of children in the efficacy study, and basically what he tried to do was to focus on looking at two antibody threshold levels and looking at the percentage of responders that were observed in the efficacy study.

The first threshold that he evaluated was the percentage of subjects with greater than 0.15 micrograms per mL of anti-pneumococcal antibody, and what was shown here is that 100 percent of the subjects that were evaluated for immunogenicity showed a response greater than .15 for all of the serotypes except for 23F.

If you then looked at a cutoff value, a threshold value of 0.5 micrograms per mL, you see a slightly different pattern, and there 87 to 90 percent of the children achieved that level of 0.15 for all the serotypes except for serotype 6B, where only 72 percent achieved a 0.5 microgram per mL level.

He also noted that from the study there appeared to be a GMC range from 1.4 to five micrograms per mL for various vaccine serotypes, and the take home message from this was that the protective levels may differ by serotype and by disease, and when I say disease, I mean might differ for invasive disease versus pneumococcal pneumonia, versus otitis media.

If I could have the next slide.

We then had the opportunity to hear from Dr. Kayhty from Finland, where she presented data on studies on the immune response to different pneumococcal conjugate vaccines as evaluated in

Finnish infants.

I view this as a rather important part of our discussion because here it was an evaluation of different types of vaccines, and the different types of vaccines may be impacted by the fact that they might be on very different carriers, and also, they also may have very different conjugation processes, and so this was actually looking at the ability to look across vaccines to look at their immune responses.

And some of the summaries from that particular talk were that the immune response to different pneumococcal conjugates could be compared across studies, and the response to serotypes may differ from vaccine to vaccine, but they should actually have an opportunity to look at a number of different populations, as well, from different countries and what was noted, that the populations can show differences in immune responses even to the same vaccine.

And also, she had provided some information about a comparison of kinetics across vaccines and how that might actually help in understanding some of the mechanisms of immunity.

Next slide, please.

We also wanted to have a discussion of the group regarding the particular assays that are available right now for evaluating pneumococcal responses, and Dr. Nahm presented us with some data and some information about antibody quantitation by ELISA as it compares to opsonophagocytic activity, and you'll see later that one of the conclusions from some of the early animal studies is that opsonophagocytic activity is a very good predictor and correlated with protection, and so that was the reason why we wanted to bring in what is known about the ELISA, which is what most of the particular comparisons that you've heard about today would be focusing on.

Dr. Nahm had highlighted that the opsonophagocytic assay is actually very difficult to standardize. Optimizing of the ELISA assay was moving forward, and a lot of discussion was focusing on the fact that there may be a need to absorb sera to get rid of cross-reacting antibodies and substances; and that this cross-reactive antibody issue may actually be more relevant in adults and higher in adults than in infants; and also that depending on a number of different serotypes, that the correlation between opsonophagocytic activity and the ELISA titer actually can vary depending on the particular serotype that's being evaluated.

And it was also shown that antibodies with higher avidity are more likely to correlate with the opsonophagocytic activity.

And if I could have the next slide.

The presentation by Dr. Goldblatt was to address the issue of what we know about immunologic memory and what are the various mechanisms for evaluating immunological memory or on the other flip side of that is also just demonstrate priming followed by conjugate vaccine administration.

Dr. Goldblatt for us summarized a number of the features of memory shown here, is that basically you can demonstrate memory by showing that a previous nonresponder now becomes a responder.

Memory has a rapid response, which means the kinetic of response is very quick. It's dominated by IgG1 antibody subclass, and that in the induction of memory you have an increased affinity avidity over time, and what was pointed out is that it appears that with conjugate vaccines, and pneumococcal conjugate, in particular, the avidity appears to increase over the course of the primary series.

Normally when people are discussing the issue of priming versus memory, it's in the context of administering a conjugate vaccine in the primary series, and the you follow by a polysaccharide only boost, and then show that you can get an enhanced response, a quicker response or people who were nonresponders are now responders.

What was shown here, and personally was very interesting, was that with the conjugate vaccines you actually see some of the hallmarks of memory showing up even over the course of the primary series.

And if I can have the next slide.

Dr. Dagan was tasked with, I think, a very difficult presentation, and attempting to summarize for us and raise to the table the dilemma of choosing endpoints for future comparative studies. One of the things he had pointed out was that for study design it's most -- you know, most envision that it would be a double blind comparative study to Prevnar.

It was also proposed from Dr. Dagan that this is going to be a difficult question and that you're actually going to have a constellation of immunogenicity endpoints to be evaluated, present responders for short and long-term protection, as an example, an evaluation of geometric mean concentration, also an evaluation of functional activity, as well as the concept of avidity maturation and memory.

Next slide, please.

With regard to some of the additional components of studying a vaccine for licensure, comparing it to Prevnar, we cannot overlook the fact that safety would also be an important part of that characterization and requirement for licensure.

He also raised the possibility that an evaluation of the pneumococcal conjugate vaccine effects on carriage might also be important information to highlight that may be able to be factored into the comparative analysis.

And it was felt that the demonstration, the bar would be set for noninferiority to Prevnar, and also attempts would be made to try and see if there were new correlates for the new serotypes. What would we be using for those new serotypes because they obviously were not going to -- we can't draw on the Prevnar experience in that case.

Next slide.

Dr. Dagan raised the very difficult question here of what would be the proposals for how would you evaluate these multiple endpoints, and one provocative I'll say proposal that he put before us was that you would actually be looking at an accumulation of the total score across all of the new serotypes plus the Prevnar serotypes.

He also discussed possibility of weighting responses for the various serotypes based on a number of different parameters. Shown here is the possibility of having a weighted average based on serotypes that might be associated with antibiotic resistance.

Also, should we be weighting the average to be based more on its comparisons to the common serotypes with Prevnar, and how do we weight the impact of the new serotypes that are not in Prevnar?

Next slide, please.

As you can see here, a common theme was focusing on obviously the immunological quantitation of the antibody response, and we were very fortunate to have Dr. Kohlberger provide us with one possibility statistical approach to establishing this threshold.

It was clear, as Dr. Gruber had pointed out, that the fact that Prevnar has such a high efficacy rate created a bit of a problem for trying to establish a correlate of protection, and so what we were ending up with is a discussion really of how to establish a threshold of comparison.

And I'm happy that Dr. Kohlberger is in the audience. So if he has any comments on the slides, he would be the most appropriate person to direct that to.

But here was kind of taking some lead on the fact that thresholds had been established for Prevnar for a very different purpose, as Marion Gruber had mentioned earlier. Here we were going to basically be looking at an ability to try and set a threshold that would hopefully be relevant to the level of efficacy seen with Prevnar.

And show here is population probability of disease. These are just some of the bullet points form the talk. The population of the probability of disease was relative to the proportion of subjects with an antibody concentration less than the threshold. So as you are below this threshold, your probability of having disease would increase.

And that was the premise, and so how did we get to setting this threshold? One proposal was based on the only efficacy data we have, was based on the Kaiser efficacy study, and it was looking at the reverse cumulative distribution curves for the various populations of the Prevnar group and also we also in that particular study, we had a meningococcal control group.

When we looked at the responses to Prevnar, Dr. Kohlberger had indicated that if you look at the aggregate of the responses for all of the serotypes, it appeared that there was greater than .18 micrograms per mL correlated with vaccine efficacy, meaning that as you looked across the reverse cumulative distribution curve, as you got close to the .18 microgram per mL range, you had close to 100 percent of your subjects responding, which is relative to the efficacy seen in Prevnar.

One of the assumptions is that, in this model, is that there's no difference in serotype specific efficacy.

Could I have the next slide, please?

And this basic model assumes that all subjects were exposed, but that true exposure rates cancel in vaccine efficacy calculations, and it also assumes that all populations are alike for efficacy and immune response.

And one thing that did have to come out from this talk is that there is an impact of assay standardization and also comparability between assays to be able to begin setting your threshold. Of course, these special values that we talked about were really from the Wyeth Lederle laboratories, and so another manufacturer's laboratory has an assay that behaves slightly differently. It's very hard to just take an absolute threshold value from that.

The next slide I'd just like to share with you what the panel was actually -- the specific questions they were asked to discuss, and the first question was a variety of animal models point toward the pivotal role of anti-polysaccharide antibodies and the protection against invasive pneumococcal disease.

What is known of the functional basis for protection?


Based on what is known about the mechanisms of antibody mediated protection, what are the characteristics of the antibody response most associated with protection?


What in vitro assays are most relevant to measure for these particular immune parameters? If new pneumococcal vaccine conjugates are compared to a licensed conjugate, what critical immunological parameters should be evaluated in the clinical studies?

Next slide.

Based upon our present understanding of protection, are the currently available immunological assays adequate to assess parameters that form the basis for immunological bridging to clinical efficacy?


How should the immune response to serotypes not included in the licensed vaccine be evaluated? What is the importance of functional assays in this evaluation?

And also we invited the panel to discuss any other issues.

Now I'd like to get to the summary. I'm not going to address each of these questions specifically. I'm just going to give you an encapsulated version of what the responses were to these questions.

The panel felt that the animal data certainly supported the role for functional antibody production as the basis of protection. The caveats though: functional antibodies may be difficult to standardize. Standardization efforts are more advanced for the ELISA method.

The next point was that antibody avidity may contribute to protection. Also, antibody concentration is important for short-term protection and memory for long-term protection.

Next slide.

The GMCs and percent responders are important parameters. We should focus on threshold level, not a protective level because it was felt that a protective level could not be identified from the Kaiser study.

Direct comparison of vaccines head to head is important to help control for assay variability, and there's also a caution against relying too heavily on our Hib experience, and cited here is the fact that we really need to look at pneumococcal conjugates in and of themselves and partially due to the fact that the disease and organism profiles are different for pneumococcal than Hib.

The conclusions that the panel had come up with were that ELISA antibody levels are meaningful. A protective level may not be identified from the efficacy study or was not identified. Avidity and functional antibodies may also be important.

Highlighted here was that this importance might be weighed perhaps a little differently for new vaccine serotypes, and that it was noted that this particular comparison of the functional antibodies to ELISA may be appropriate to evaluate in a subset either prior to the pivotal study or during the Phase 3 study, and that one of the limitations of measuring avidity and functional antibodies is due to the difficulty in standardizing these assays.

Next please.

Following much discussion, it appeared that the -- well, the group felt most strongly that the primary endpoint should be the percentage of responders achieving a predefined threshold.

They noted, however, that multiple endpoints should also be evaluated.

Reverse cumulative distribution curves are also important measures of comparing the different population responses in the comparison.

It was also noted that antibody responses post dose three and post dose four are important. Post dose three antibody responses should be considered as primary endpoints partially because that might be the most critical comparison and most sensitive comparison with regard to the quantitation of antibody.

It was also noted that the kinetics of the response are also important in this comparison, and also a demonstration of memory was a component that they felt was necessary for the pneumococcal conjugate vaccine comparisons.

And for new serotypes in particular, the issue of priming versus memory and memory are very important and should be considered as part of the evaluation.

The next slide gets to the unresolved issues. Although they agreed that memory was an important component of the antibody profile, how do you test for memory if Prevnar is a four-dose series? What is an appropriate control group? Will it be necessary to compare the historical controls? Should memory also be evaluated for serotypes where field efficacy was not established?

Should avidity maturation and carriage also be evaluated?

Next slide.

With regard to the establishment of a threshold value, should a single threshold value be assigned or should the criteria be serotype specific? Should the aggregate response from the Kaiser efficacy study establish the single threshold? Should a single more conservative threshold be used? Could the lowest RCDC curve from the efficacy study be used as a minimum threshold?


This one our statisticians will probably appreciate. What will the impact of noninferiority criteria -- will what be the impact of noninferiority criteria, given the number of antigens and endpoints to be evaluated?

Should the importance of serotypes be weighed for Prevnar versus non-Prevnar serotypes? How do you consider those serotypes for which field efficacy was not demonstrated? How do you weigh the importance of serotype response based on disease prevalence?

Next slide.

What will be the impact of noninferiority criteria? The same question, but now the last point: how do you weigh the importance of serotypes associated with antimicrobial resistance?

I hope that this summary will help you in your discussions this afternoon with regard to the experts' evaluation of what is and is not known with regard to evaluating pneumococcal conjugate vaccine responses.

Thank you.

ACTING CHAIRMAN DAUM: No, thank you. That was an absolute "tour de force."


ACTING CHAIRMAN DAUM: And I'm sure the committee is very grateful for all that information.

What I'd like to do now is to have some committee discussion questions regarding Drs. Frasch's and Falk's presentation for clarity purposes, and then we'll have open public hearing. We'll go to lunch, and then we'll come back and deal with the easy questions that we've been posed by our FDA colleagues.

I'm going to start with Dr. Kohl, Dr. Hall, then Dr. Wharton.

DR. KOHL: Dr. Falk, thank you, and can I ask you to elaborate on some of the points of Dr. Kayhty's presentation? In particular, tell us a little bit about different immune responses in populations with the same vaccine.

DR. FALK: Sure.

DR. KOHL: And how that's pertinent to this country, as well.

DR. FALK: Okay. What I'm going to do is I'm going to start with a caveat. This meeting happened one week ago, and I am going to be very couched in the specifics in fairness to the presenters until we've had time to actually go over the slides and present them in the correct format, but I will give you a very general synopsis though.

What was found in her evaluation, she had looked at similar vaccines assayed or evaluated in a number of different countries, such as Finland, the Philippines, and Israel. What she found when she looked at the immune responses was that there were different levels of antibody responses in the various populations, and the Philippines seem to have been pretty much an outlier so to speak because the responses were much higher to the vaccine.

And so I think the pertinence of that is to say that when you are evaluating responses, you have to understand that depending on the population you're evaluating them in, they may or may not be readily translatable to, for instance, a U.S. licensure, and that could present a problem.

ACTING CHAIRMAN DAUM: Thank you very much.

Dr. Hall is next. Then Dr. Wharton, Kim, and Goldberg.

DR. HALL: Thank you.

I'm wondering if you have more information about the associations with antibiotic resistance in the serotypes, both in the vaccine currently and what would be proposed.

In particular, is there a correlation with those serotypes which are more frequent or with particular clinical disease or with immunogenicity? In other words, also what would be the effect, I'm trying to get at, of the vaccine on antibiotic resistance in those serotypes, particularly those that are not included in the vaccine or those for which there was no efficacy shown?

DR. FALK: This particular workshop really presented no data as to the antibiotic resistance profile for the serotypes or the impact of vaccination on the generation of resistance. So that was not actually discussed in any detail at the workshop.

It was just raised as a possible public health issue that may or may not play into discussions of how you evaluate the importance of meeting noninferiority criteria for a number of different serotypes.

But I don't know if Dr. Frasch wants to comment any more outside of the workshop.

DR. FRASCH: I would only say that as it turns out, all of the really important antibiotic resistant strains, serotypes are included in the present seven-valent vaccine, and that it's really not an issue if we talk about greater multi-valency versus that.

ACTING CHAIRMAN DAUM: Okay. As we move on, I'd like to remind committee members that we're asking for clarification for the presentations we have here. We will have time to return to antibiotic resistance and vaccine serotypes if you so wish this afternoon.

I have Drs. Wharton, Kim, Goldberg, Faggett, and Broome.

Dr. Wharton, please.

DR. WHARTON: I just wanted to clarify what was in the presentation from Dr. Santosham about the lessons learned from the bacterial polysaccharide immune globulin. I understood that there was a correction of what was on the slide, and it wasn't clear to me if the lessons were about Hib or pneumococcal disease or both.

DR. FALK: His discussion focused on the ability of measure the efficacy for Hib and pneumococcal disease following BPIG administration, and what he had shown is that there appeared to be some degree of similarity with regard to the threshold that was needed to demonstrate short-term protection because, of course, this was given like every three months.

ACTING CHAIRMAN DAUM: Dr. Kim, please. Oh, sorry.

DR. FRASCH: I should point out that only the Hib data has actually been published.


DR. KIM: Sine this workshop was with experts, I'm just curious to know whether there was any discussion about immunologic responses to a particular serotype, for example, why 19F is a poor immunogen compared to other serotypes.

DR. FALK: They did not really delve into the specifics other than trying to acknowledge that there might be something related to the particular organism that might be involved in eliciting lower responses, but it was not really talked about in detail.

DR. KIM: And the second issue is that since, as you indicated, immunologic assays may not be standardized, I wonder why there was, you know, emphasis on some in vivo models for looking into the protection, such as animal model, which you briefly indicated in your earlier slide.

DR. FALK: I'm not sure I understand the question.

DR. KIM: The question is that, again, you say the opsonic assays and the antibody avidity assays, all of these assays, based on, again, your presentation appeared too difficult to standardize. So the question comes up is why not add some more traditional assays to look at the function of antibodies, such as animal protection studies, which you indicated in your earlier slide.

DR. FALK: Right, right. The sequence of events there was to actually lead you into -- lead into the understanding that antibodies (a) are important, and that was from the early work with the animals.

I think that the animal studies are also difficult to try and standardize and also perhaps are not as amenable to the quantitative comparisons that we would be looking for when we're trying to do the evaluation.

And so we stepped from introduction of the work we knew and the information we knew from the animal models to the fact that it appeared that the function -- a functional antibody was the important parameter, and then we had to bridge to how do we incorporate that information into our considerations for licensure.

Dr. Frasch, did you want to add anything?


Drs. Goldberg, Faggett, Broome and Insel.

Dr. Goldberg, please.

DR. GOLDBERG: On the discussion of choosing endpoints for clinical for the comparative studies, there stuff in here about multiple endpoints, and you're talking about immunogenicity and other parameters. Was there any consideration given to discussion of combination endpoints, what I would call combination endpoints?

You know, the first occurrence of one of the illnesses that this vaccine could theoretically prevent, and in combination, you know, was any of that discussed? We can discuss it later as alternate ways of developing clinical trial designs.

DR. FALK: Well, this particular discussion focused really on the immunological parameters. So I think you might want to take that back up in the afternoon for possibly expanding that.

And Dr. Lachenbruch is, I think, wanting to respond.

DR. LACHENBRUCH: Dr. Moulton proposed a weighted sum of scores, and that turned out to be somewhat similar to things that we had been considering in the Division of Biostatistics.

DR. FALK: But, Tony, that's still related to immunogenicity.



Dr. Faggett, please.

DR. FAGGETT: Yeah. I realize this meeting was designed to look at in vitro immune measures that represent correlate's immunity for use in future in clinical trials. However, Dr. Dagan apparently in discussing the dilemma of choosing endpoints looked at studies for licensure to include safety in carriage.

What was talked about there?

DR. FALK: With regard to the safety, it was just the acknowledgment that whatever type of comparative study you propose would have to have safety as a component as well, period.

Carriage was another issue where in the absence of what was accepted to be a true correlate established for the antibody titer, that perhaps we could gather additional types of more clinical endpoints in the conduct of the study, and that was just a proposal that he had put forth, that that might be something that might weigh into the equation.

DR. FAGGETT: So safety would be discussed in another forum. Is that --

DR. FALK: Well, it was just assumed that it would be a standard safety evaluation, but Carl would like to expand.

DR. FRASCH: As you must know, for a vaccine to be utilized by the FDA it has to be shown to be safe and effective. Okay? So the workshop dealt with the second of those two. Okay?

ACTING CHAIRMAN DAUM: Dr. Broome, Insel, Giebink, and I think we'll do open public hearing.

DR. BROOME: I was curious about whether you could give us a little more information about the correlation between opsonophagocytic assays and ELISA, and the variability based on serotype. In particular, was this of a magnitude which we really need to factor into our afternoon's discussions, i.e., you cannot make a generic statement about correlation?

DR. FALK: Without having reviewed the data before this meeting in such a way to be able to answer that specifically, the general consensus was that for some serotypes there appeared to be a better correlation.

There was also some -- but not necessarily -- we didn't have an opportunity to see whether that was true for which particular serotypes. I do not recall those data in enough detail to feel comfortable presenting those in this forum, and I think that the fundamental take home message would be that the ability to demonstrate opsonophagocytic activity would be important whether there was -- you know, along the path to going to an ELISA endpoint, that needs to be factored in.

And, Carl, did you want to add to that?

It needs to be part of your I guess I would say clinical development program to support an ELISA endpoint, is to have this piece of data.

DR. FRASCH: I would only add to that in that there is a clear correlation between opsonophagocytic activity and ELISA. Now, these correlations are usually carried in R values, but it's not quite clear how good is good.

And the other point I would like to make is that these are two different assays, and the sensitivity of the assays are quite different, and so we cannot hope that the opsonic assay have the same sensitivity. It's simply not going to happen as the ELISA.

ACTING CHAIRMAN DAUM: Dr. Insel and then Dr. Giebink.

DR. INSEL: Two questions. The first with respect to opsonophagocytic assays. Was there discussion as far as trying to make the assays more sensitive? Because what we heard today is under microgram per mL we're losing sensitivity.

Is there a movement on behalf of the community to make assays more sensitive? Was this discussed at the workshop?

DR. FALK: Well, on a very superficial level it was mentioned that there are some steps in that direction, such as agreement on using a particular cell line. So, you know, that's the level that they dealt with on that, but acknowledged that that was going -- you know, the ability to standardize that assay was going to be difficult, but there are some attempts.

But Carl is more of an expert on the ins and outs of exactly what those steps are.

DR. FRASCH: I think all I should add is that even strains within the same serotype vary in their ability to be opsonized. So the opsonic assay itself is reasonably well standardized now based on the publications that are coming out of CDC.

The problem is strain selection. There are some problems to be worked out, but we've been working on this for a good number of years.

DR. INSEL: The second question with respect to memory that was discussed at the workshop, it was proposed that there would be an important assay for memory, especially for serotypes where field efficacy has not been established.

And a very quick question is: does the polysaccharide, the 23-valent polysaccharide vaccine -- will it suffice for all of the serotypes that the different manufacturers are planning to incorporate in new vaccines? Are they all covered in the 23-valent vaccine?

DR. FRASCH: Yes, yes. There's been no proposals to include any types that are not presently in the 23-valent type.


Dr. Giebink, not least.

DR. GIEBINK: because the issues of extrapolating from a population outside the U.S. to the U.S. population are so important in the afternoon's discussion, even though we've been cautioned to be careful about extrapolating from Hib experience to pneumococcal experience, there was a lot learned about population differences in the late 1980s with Hib vaccines, and at least two of our committee members and Dr. Frasch have that information.

Was that discussed, Dr. Frasch in the historical portion of the meeting, those population differences?

DR. FRASCH: Yes, it was, and in addition, there was data presented on the response of Philippine children to exactly the same batch of pneumococcal conjugate as Finnish children.

And as you well known, the case in Chile and Venezuela with the hemophilus conjugate was pretty much what they saw with the pneumococcal conjugate in that there was a substantially higher response for reasons we are not quite clear about to the vaccines in those two populations than in the Finnish population and, I should say, in the U.S. population.

So this is one of the very strong caveats we have to consider when we're looking at efficacy trials in another country. Can the data actually be bridged to the United States?

ACTING CHAIRMAN DAUM: Thank you very much. I think we've had a very lively discussion and some fine presentations this morning.

We now need to move on to the open public hearing. Is there anyone that wishes to address the committee?

(No response.)

ACTING CHAIRMAN DAUM: In that case, we shall adjourn for lunch. It's 12:02 here in the Eastern time zone, and we will reassemble precisely at one o'clock.

Thank you.

(Whereupon, at 12:05 p.m., the hearing was recessed for lunch, to reconvene at 1:00 p.m., the same day.)



















(1:11 p.m.)

ACTING CHAIRMAN DAUM: Good afternoon and welcome back.

I trust everybody had a good lunch, not too big a lunch. We've arranged for that thumping that you heard this morning to occur at irregular intervals this afternoon should anyone nod off. We continue our upgrading to Holiday Inn Select.

We'd like to ask Dr. Gruber, please, to first put the items for discussion -- run through them again. Then we'll put the first one on the screen, but then we'll ask the committee to begin talking about whatever issues are of interest to put on the table to them. We'll have some free discussion like that for a while, and then eventually we will start focusing on the questions themselves.

So, Dr. Gruber, would you start us off, please?

DR. GRUBER: Yeah, thank you.

The first question is or the first item for discussion: please discuss whether or noninferiority immune response trials comparing a new pneumococcal conjugate vaccine with Prevnar are sufficient for inferring efficacy against invasive disease for the new product. If so, what immunological parameter should be used?

And, number two, please discuss the criteria that should be considered to evaluate the serotypes not contained in Prevnar.

Number three, please consider the following scenario. An invasive disease efficacy study may be performed in a non-U.S. population with a new pneumococcal conjugate vaccine. If efficacy is demonstrated, could data derived from such a trial support licensure of the vaccine in the United States?

If so, what are the immunologic parameters that should be used to establish comparability to Prevnar in a U.S. bridging study?

And question number four, please discuss if data demonstrating clinical efficacy against acute otitis media for a new pneumococcal conjugate vaccine can always be used to infer efficacy against invasive pneumococcal disease for this new product.

And go back to slide number 19.

ACTING CHAIRMAN DAUM: Thank you very much, Dr. Gruber.

I'm going to leave item for discussion number one on the screen. We don't necessarily have to speak to that yet, depending on how the discussion goes.

So who wants to start off? Dr. Kohl, then Dr. Griffin.

DR. KOHL: I have two questions that I'd love anybody in the room to answer. We know from published and maybe some unpublished work that there are otitis media efficacy trials, one that recently appeared in the New England Journal. Are there any serologic data that have emerged or that anyone here has from those trials that can help us in associating efficacy levels, immune correlates versus efficacies since the Prevnar trial for invasive disease has such a high efficacy that there's a very little amount of information we can actually gather from that.

ACTING CHAIRMAN DAUM: Anyone from FDA, do you want to tackle that? Dr. Frasch, I was looking for you.

DR. FRASCH: I would first caution us in that antibody values that we may get out of otitis media trial may not be directly translatable to invasive disease. So any discussion would have to consider that caveat.

ACTING CHAIRMAN DAUM: Having said that, is there information?

DR. FRASCH: I think one should ask some of the actual players maybe in the room that worked on these trials.

ACTING CHAIRMAN DAUM: Okay. If that's the way we're going to go, then I guess I'd ask audience members to help out here. We will ask you to clarify or provide information about committee questions if there is information available. Is there someone in the audience who has information about this?

Dr. Siber.

Everybody who does so will have to state who they are and what their affiliation is.

DR. SIBER: George Siber, Wyeth.

We don't have information, but we can tell you the information that's likely to be forthcoming. In the Finnish trial sera were drawn on half of the cohort after the primary series, and on the other half after the booster dose, and those sera are being assayed or have been assayed, and the antibody levels seen in those sera will be correlated with the subsequent occurrence of type specific otitis media.

ACTING CHAIRMAN DAUM: Those data would be most valuable, I would think, in trying to sort out some of the issues here.

Dr. Giebink.

DR. GIEBINK: The only animal model that looks at both middle ear protection and invasive protection is the chinchilla model, and in that model using two different conjugate vaccines we have consistently seen across serotypes and across vaccines that antibody levels required for protecting the ear are considerably, not logrithmically, but in the neighborhood of two to fourfold higher than those levels required for protecting against bacteremic disease.

I don't know how you'd scale that to a human, but I obviously have my bias.

ACTING CHAIRMAN DAUM: Well, save it. We might like to hear your bias, but we'll ask Dr. Griffin next for comment.

DR. GRIFFIN: Okay. I don't have comments on this, although I'd certainly be interested in the answer.

ACTING CHAIRMAN DAUM: We're in free form here.



DR. GRIFFIN: Since this is not an area in which I work, I would be -- I would benefit from understanding better how the ELISA test particularly is done.

Being sort of a fan of functional antibody assays and knowing that ELISA is basically going to give you binding antibody and is not going to tell you whether the binding is to the relevant portion of the antigen in question, first of all, I assume that they're done with purified polysaccharide as the antigen. Is there any way of knowing whether the antibody that's being measured as against the relevant part of the polysaccharide, which I assume is the part that's poking out on the surface of the bacterium?

ACTING CHAIRMAN DAUM: We will turn to Dr. Frasch first for response to that.

DR. FRASCH: Okay. We've been working with the World Health Organization with CDC sine 1993 in standardization of the ELISA assay. The ELISA assay uses purified pneumococcal polysaccharides that are obtained from the American type culture collection, which obtains vaccine quality polysaccharide from Merck. So, therefore, the polysaccharides used in the assay are the polysaccharides that pass the requirements for vaccine quality polysaccharide.

This said, due to the very nature of the pneumococcal polysaccharide, there are some other contaminants unavoidably present, very small quantity, and there's an absorbent C-polysaccharide that's normally used by everybody and most everybody uses the same source. So that helps standardize the assay.

But, yes, the antibodies measured are antibodies that bind to the polysaccharide, and it is possible that some of those antibodies that bind are not functional.

Now, this has not been seen in sera from children, as we're talking about, today, but it has been seen in looking at sera from older individuals, elderly individuals. The ELISA measures quite a bit of nonfunctional antibody in that population, but today's discussion is with young children.

DR. GRIFFIN: Okay. One follow-up sort of technical question. When people are talking about measuring avidity or avidity of antibodies to these polysaccharides, are those assays ELISA based assays using urea washes or what, again, are we talking about specifically there?

DR. FRASCH: Again, that's essentially the same assay in which a kayotropic agent, usually sodium thiocyanate, but it could be urea, is used to either block initial binding of the antibody or to a loosely bound antibody, and having done the assay in our lab both ways, we get very similar answers by either method, but basically it's using a kayotropic agent in exactly the same assay as used for normal quantitation of the antibodies.


Dr. Kim, please.

DR. KIM: I guess knowing that, these immunologic assays have not been standardized and variable, is there in your -- I guess these are two related issues. One, is there an attempt to have a reference serum which can be used by everybody to do everything, do the functional assays and the binding assays, everything, to see the degree of variation if that has not been discussed or has been discussed, then was there any actual performance of such assays being done with a serum which has been shared by all investigators or manufacturers, including CBER?

ACTING CHAIRMAN DAUM: Dr. Frasch, would you like to respond again?

DR. FRASCH: First of all, I've got to clarify something. It's not that the assays are not standardized with individual laboratories. Our work over these years has been to standardize assays between multiple, multiple laboratories.

Number two, there is a standard reference serum supplied by the FDA to all interested parties throughout the world. It's called reference serum 89SF, and it has assigned values to each of the relevant serotypes, and we're also working on a set of what we will call calibration sera that can be shared among laboratories.

DR. KIM: Can I just have one follow-up?


DR. KIM: I have one follow-up question. Does that serum contain antibodies against the serotypes that are under discussion or serotypes have been limited?

DR. FRASCH: The origin of this serum was BPIG plasma, and if people remember what BPIG plasma is, this is from individuals who are immunized, adults that were immunized with the 23-valent pneumococcal polysaccharide antibody, and we now have antibodies quantitated to all 23 different types of which we're only really interested in about 11 of the types now.


Dr. Stephens.

DR. STEPHENS: I'd like to follow up on a question from Dr. Griffin and ask for comments about the avidity ELISA, which has been suggested both here and at the previous meeting as potentially being an assay that can tell us -- that correlates better with opsonophagocytic activity, as well as also correlating with memory, and I just would like Carl's comments or other comments about the avidity ELISA and their thinking about that.

DR. FRASCH: Well, the data that was actually presented during the workshop did not really deal with avidity versus opsonic antibody, but it dealt with looking at something called avidity maturation after immunization with a conjugate versus a polysaccharide.

And basically what they found was that if you immunize with a polysaccharide, you really didn't see much increase in the avidity of the antibody over time, whereas with the conjugate just looking at the post dose three versus the pre-booster, one saw with the conjugate an increase in the avidity of the antibody, and some suggested at the workshop that this might be a good surrogate marker for memory.

ACTING CHAIRMAN DAUM: That is to say the presence of the high avidity antibody would be the surrogate, not any boosting capability.

Dr. Insel.

DR. INSEL: What is the basis for making that assumption? It may correlate, but all antibody titers, avidity will increase for any T-dependent antigen with time. If you just wait long enough, things do increase, but does that speak directly to the fact that that host will respond to the isolated polysaccharide when presented? Are these just two different findings?

Do we know that that assumption is correct? Because avidity increases, you'll see responses to a polysaccharide vaccine in those prime cells?

DR. FRASCH: I mean, the problem is the same population you're studying shows the increase or avidity maturation and shows priming or a memory, but where they're one and the same event, the data wouldn't show that.

DR. STEPHENS: Just as a comment, I think there's reasonable data, and Carl or others may correct me, in the Haemophilus influenzae literature suggesting that there is a correlation between avidity maturation and memory responses in terms of polysaccharide challenge as another means of assessing memory.

I'll let others comment on that.

DR. INSEL: With hemophilus, I mean, you can prime probably in the absence of any avidity maturation. They don't have to go hand in hand. I mean just the fact that even with one dose of conjugate vaccine you can prime for a polysaccharide response.

In fact, in Jani Eskola's (phonetic) data, where immunized in the newborn period, about 30 percent of those infants were primed to respond at four months of age to a dose of polysaccharide vaccine, and that was occurring probably even in the absence of any kind of evidence of avidity maturation per se.

I think they can go hand in hand, but I'm not sure that one necessarily follows the other, and the question is whether or not one needs to be looking at -- the question is whether one needs to be challenging with a polysaccharide, especially for the vaccine serotypes that we don't have field efficacy data on as we go forward here. I mean that's the question I'd just like to throw out to the group.


DR. GIEBINK: Another subject. I'd like to elicit some discussion on the antibody threshold method that has been presented where the antibody concentrations in a vaccinated group are compared with those of an unvaccinated and the difference plotted. You'll remember that graph.

I have two concerns with that method. The first is that in the studies I'm familiar with, there's an indirect relationship between the degree of the antibody response after vaccination and the pre-vaccination antibody concentration. The higher the pre-vax concentration, the lower the fold increase.

And, secondly, there are differences in antibody concentrations among populations in unvaccinated populations. We've compared, for example, a Minnesota population to a Columbia, South America population and found quite different concentrations to several different serotypes in these unvaccinated groups.

So both of those issues would bear on that methodology of drawing the difference, and I wonder. I just want to raise the question and see if others have thoughts.

ACTING CHAIRMAN DAUM: A comment on Dr. Giebink's question?

Dr. Gruber.

DR. GRUBER: Yeah, I would like to comment on that. When I presented this graph, that was really actually providing with a piece of history. So it was really an approach that we have been using to look at the bridging, the manufacturing bridging that Wyeth had to do, looking at their commercial lot versus the pilot lot that was used in the efficacy study.

One might question, however, that a method that was used there would be even applicable to what is being discussed today since we may not have the situation that we have, an unimmunized individual there.

So what we may have to look at if we compare a new vaccine X with Prevnar is really looking at antibody concentrations induced by one vaccine versus the other, i.e., perhaps looking at reverse cumulative distribution curves.

I mean, I'm just throwing this out, but I doubt that the approach that we have used at that time is the exact approach that we will be able to use for the purpose of comparing the new vaccine to Prevnar.

ACTING CHAIRMAN DAUM: Scott, do you want to follow up on that?


DR. GRIFFIN: Could I ask another question that's along this line?


DR. GRIFFIN: Can somebody just give me an idea of the order of magnitude we're talking about when we're talking about different baseline levels for Minnesota versus South America or even in the responses like in the Philippine children versus the Finnish children?

I don't know if we're talking about twofold, tenfold. You know, I just don't have an idea of the order of magnitude of differences that we're dealing with.

DR. GURUNATHAN: The Colombian Minnesota study, the biggest differences that we saw by serotype were in the neighborhood of two to threefold, and we speculated that that may have been due to serotype exposure because type 5 concentrations were quite high --

DR. GRIFFIN: That would make the most sense.

DR. GURUNATHAN: -- in Colombia and very low in Minnesota. I don't know about vaccine response.

ACTING CHAIRMAN DAUM: Before we call on Dr. Kohl and then Dr. Decker, Dr. Falk, do you remember, or Dr. Frasch, from the pneumococcal workshop there were some data presented there from the Philippines which were kind of striking? And do they bear on Dr. Griffin's question? But I can't remember them.

DR. FALK: I unfortunately would not feel comfortable exactly quoting a fold difference, but I believe that they were striking in that we're looking at I think it was more the two to threefold increase, but I hesitate to say take that as gospel

ACTING CHAIRMAN DAUM: Dr. Frasch, do you want to deal with that issue?

DR. FRASCH: Well, that's pretty much the range, but the problem there is if we're trying to bridge to a U.S. population, and already the levels are two to threefold and we're allowing much less, so it makes bridging more problematic.

DR. GRIFFIN: I think that's sort of my point, you know, that it's very hard -- it becomes hard to sort of compare these populations.

DR. FRASCH: Yeah, that's why it's important to know the epidemiology of the population that you intend to do a trial in.

ACTING CHAIRMAN DAUM: Dr. Kohl and then Dr. Decker.

DR. KOHL: Could someone address these same issues on a more local level? That is to say what do we know about minority urban communities in this country, and can someone refresh my memory on the Native American experience, which there was a considerable amount?

ACTING CHAIRMAN DAUM: Did anybody want to take that on, anybody at the table?

Is there anybody in the audience that can shed light on that?

DR. KIM: The only information that I have been informed of that is a serotype distribution differs in Native Americans compared to rest of the U.S. population. So that, I think, needs to be considered in looking to vaccines.

ACTING CHAIRMAN DAUM: Dr. Butler, I was hoping you would.

DR. BUTLER: Particularly in Alaska Natives and in the Navajo, serotype 1 is more common compared to non-Native populations in the United States, and I guess the next question then in terms of immune response, there's one study looking at the OMP vaccine that compared Alaska Natives, Navajo, and children in a Southern California HMO, which showed very little in the way of significant differences.

I think the response to the first does was somewhat attenuated in the Alaska Natives who had higher pre-vaccination antibody levels, but after completion of a primary series, there was practically nothing in the way of significant differences.

ACTING CHAIRMAN DAUM: And that's the H. flu. OMP vaccine?

DR. BUTLER: No, that's the pneumococcal OMP vaccine. I will have to defer to someone from Merck to tell whether or not protocol 014 -- how that differs from the vaccines that they're most interested in now.

ACTING CHAIRMAN DAUM: Does anyone from Merck care to respond to that issue?

Okay. While we're doing that, perhaps we could hear from -- does anyone from Wyeth Lederle care to respond to the issue with respect to the Native American trial that is in advanced analysis now? Because that bears on this question also.

DR. KOHBERGER: With respect to the Native American pneumococcal data, the database has been clean, locked, and is to be sent to Johns Hopkins within the next two weeks. So the analysis is ongoing. So we really can't say anything about what those levels are yet. It will be several months.

ACTING CHAIRMAN DAUM: Several months? Too bad.

Okay. Dr. Decker and then Dr. Diaz.

Well, are you guys ready? All right. Before Dr. Decker speaks, we will. You need to tell us who you are again.

DR. SILBER: Sure. Jeffrey Silber, Merck.

Maybe we could let Dr. Decker speak. I don't know how long this is going to take.

ACTING CHAIRMAN DAUM: It looks like it's real close.

All right. Dr. Decker.

DR. SILBER: Oh, here we go. Okay. This was protocol 14, a study conducted by Merck a number of years ago in which we looked at Native American, Native Alaskan, and general U.S. population infants. These are post dose three data. All children received Tetramune concomitantly, and for the purposes of this study, we look at a threshold level of 0.5 micrograms per mL. You see the sample sizes here.

And if we just want to focus perhaps on the geometric mean titers or the threshold responses for this particular lot of vaccine, the non-Native races across all serotypes trended toward having lower geometric means and sero-responses.

ACTING CHAIRMAN DAUM: And the assay here is?

DR. SILBER: This was a binding ELISA.

ACTING CHAIRMAN DAUM: Is it one that's entered into the protocol -- I don't know what the right word is -- but the protocol standardization?

DR. SILBER: Oh, yes, our laboratory.

ACTING CHAIRMAN DAUM: And is that the same -- is that a vaccine you have in trial currently?

DR. SILBER: This formulation is not in -- this particular formulation is not in trial presently.


I think now we will go to Dr. Decker. Thank you very much.

If you could, throw the first question back on the screen for us before you run off.


DR. DECKER: You know, we have four questions with multiple sub-questions raising some very complicated issues, and I wonder if we can't simplify our approach a little bit by looking at some practical considerations that might weed out some of the underbrush.

For example, I assume that it's sufficiently a given good that this committee and the FDA would like to see other vaccines licensed and would like to see the number of serotypes increased so that we wouldn't adopt a stance that blocks either of those two approaches.

It seems to me also that if we said an efficacy trial had to be conducted for a serotype not in Prevnar, that we would understand we were, therefore, saying we did not expect to see additional serotypes added because if a company could come forward with a seven-valent identical to Prevnar and get licensed without an efficacy trial, but had to do an efficacy trial to license any additional serotypes, we would be putting a monumental barrier to the introduction of these additional serotypes.

So I think we're not likely to say that, and given the enormous difficulty of conducting an efficacy trial against Prevnar in terms of sample size, I think the slide earlier made it clear that it was impossible even with the very optimistic assumptions in the FDA slide.

Then I think as a practical matter we probably are recognizing that we're going to have to come up with a pathway to licensure other than efficacy trials, with serologic unless we can think of some third alternative.

And if we accept that, that there will be a serologic pathway to licensure, then I think that further simplifies things because if there will be a serologic pathway to licensure, then nobody is obligated to go the efficacy trial route, although, of course, that would still be an option. And if there's a serologic pathway to licensure, there's no obligation to go into these populations overseas that have very different antibody responses to American kids raising all of those thorny issues.

It would seem to me that it would be possible then to do trials Prevnar versus new vaccine in the U.S. and moot a lot of these issues. Now, there may be holes in my chain of reasoning there, but if any of that holds up, then perhaps the practical questions in front of us are much simpler and more answerable than the theoretical questions, which are very difficult.

ACTING CHAIRMAN DAUM: Well, that's an interesting comment for us to think about. It really goes to discussion item one, and I'd like to sort of hold it in abeyance and have people consider it as a comment based on this discussion item, but continue some free form discussion until we focus on it, which will be soon.

Dr. Diaz, then Dr. Goldberg. Dr. Insel.

DR. DIAZ: Just following along on the thoughts that were raised about doing studies abroad, I think it's certainly clear to me that having a basic understanding of the epidemiology of pneumococcus in any population that's going to be enrolled into any kind of clinical trials is really critical, especially when you talk about having to bridge perhaps trials overseas to the U.S., knowing for instance just the strains that cause -- that are more prevalent in terms of causing disease in those areas, perhaps even the prevalence of carriage of certain strains and preexisting antibody may all play a role in trying to or in complicating, I guess, any kind of bridging studies that would occur.

I know that in the United States there's a lot of data being collected regarding antibiotic resistance for pneumococcus, but I was curious if anyone knows if there's any data being collected perhaps in the ID sites or other places regarding prevalence of carriage of strains or any current epidemiology of pneumococcus other than invasive disease in this country.

ACTING CHAIRMAN DAUM: Are you talking about in places where vaccine is in use or --

DR. DIAZ: Just talking about in general looking at sort of what's going on with the epidemiology of carriage of strains in this country and those strains that are still causing diseases being monitored. But I'm not sure if I have a good feeling of the epidemiology as it exists currently.

ACTING CHAIRMAN DAUM: Carl, do you want to respond to that? Are there post marketing things that were put into place with respect to carriage?

DR. FRASCH: Well, my interpretation was it wasn't necessarily following vaccine. So, therefore, I would ask Dr. Butler to.

DR. BUTLER: I'm not sure how well I can address the question for the country as a whole. We're actually doing quite a bit of that in Alaska in primarily two settings. One is the rural village setting where rates of disease are extremely high, building on a baseline of work that was done in an intervention of judicious antibiotic use, but it has provided three years of baseline data which we are continuing to collect data, basically looking at carriage across all age groups within 17 villages.

We also have a project specifically looking at the impact of, post marketing impact of conjugate vaccine in the Anchorage area, and that's really a broad population, Native, non-Native, also a public clinic population, looking primarily at preschool age children.

I suspect there are similar studies going on in other communities in the U.S. thought.

ACTING CHAIRMAN DAUM: Scott, do you have data about Dr. Diaz's question?

DR. GIEBINK: Just to clarify, there are carriage studies going on at a number of sites in the United States, all related to the efficacy testing of new antimicrobial drugs for acute otitis media, and those actually -- a number of those studies were reported in town here about a month ago at a license application from one of these manufacturers.

So I don't have those at my fingertips, but it's pretty well known that resistance rates among pneumococci carried in the upper respiratory tract are considerably higher than the rates of resistance in invasive disease, and there's quite a bit of regional information in the United States available on that.

ACTING CHAIRMAN DAUM: Do any of the manufacturers, Wyeth, in particular, want to share any thoughts regarding carriage surveillance and places where the trials have been done?

(No response.)

ACTING CHAIRMAN DAUM: I take it that means no. Okay. Well, Dr. Diaz, I think that's a very good question. We just don't have a lot of light.

Dr. Decker, on this question?


ACTING CHAIRMAN DAUM: Because I have three people ahead of you.

DR. DECKER: No, an answer to this question if you want.


DR. DECKER: Out of a study reported in IDSA last year, supported by Wyeth Lederle and conducted by Kathy Edwards and colleagues at Vanderbilt looking at children who received Prevnar and who were followed very intensely for surveillance of carriage with an average of nearly a dozen cultures obtained during the first year of life, and let me just give you some key results here.

I can give you specific numbers, but in summary -- actually I said Prevnar, but it was the nine-valent vaccine -- carriage rates were extremely high, with carriage rates of, for example, pneumococcal isolates of over 80 percent in both the vaccine and the control group were resistant to penicillin among ill kids. Over 70 percent were resistant to penicillin among all kids.

The rates of carriage of vaccine strains were reduced both in well and ill kids, but still relatively high, but statistically significantly reduced.

And one second here. Vaccine recipients were 19 percent less likely to carry the vaccine strains at well baby visits and 29 percent less likely to do so at sick visits, but there was no overall reduction of the carriage rate of all pneumococci and no reduction in the carriage rates of penicillin resistant strains.

I'm not sure if those data answer your question directly. If not, put it to me again because I may have the answer in here.

DR. DIAZ: That's fine.

ACTING CHAIRMAN DAUM: This is obviously a very complicated area that needs more light shed on it.

Dr. Siber, can you shed light?

DR. SIBER: Well, I'll tell you there will be some light coming from the Navajo trial which was a trial in which there was community randomization between the pneumococcal conjugate vaccine, Prevnar, and a meningococcal vaccine, and one of the sub-studies by Kate O'Brien in that study, together with CDC investigators, is to look at the herd immune impact of pneumococcal vaccine in a whole community of children and their older siblings, and I believe the earliest reports from those studies will be reported at ICAAC this year, if not at SPR. I don't remember.

I think you're familiar with a very extensive set of studies done not in this country, but Israel by Ron Dagan, and without going into those, I think what's striking in the Dagan studies, which were in a day care center setting, is that the nine-valent vaccine reduced carriage by 40 to 50 percent in the recipients of vaccine versus control, reduced antibiotic resistant strain carriage significantly, and it also reduced carriage by vaccine types and by antibody resistant types, in the siblings at home of the children who were immunized as composed to the day care attendees who got the control vaccine.

So there are clearly effects on carriage and carriage of antibiotic strains at least in that very controlled setting in Israel.

ACTING CHAIRMAN DAUM: And taking people out of order who can speak to this very issue, Dr. Kim.

DR. KIM: I think there was a somewhat interesting article published in Nature recently implying that in their case they were talking about vancomycin, but antibody resistant Strep. pneumoniae had greater capability of transformation than with acquiring other antibody resistance, as well as transmission with potentially other capsular genes.

So I think this issue about antibody resistance would be potentially important not only before the licensure, but also post marketing surveillance.


As a clarification, those isolates weren't resistant to vancomycin. They were tolerant. That is to say they were not killed, but they were not resistant.

Dr. Katz, is your question about this issue? Would you go ahead, please.

DR. KATZ: It wasn't a question. It was just a comment in that I think what we're hearing is the problem of the heterogeneity of different populations. What I didn't hear mentioned, I believe were Dr. Keith Klugman's studies from South Africa, which were in some ways quite different from those in Israel, and I think it just highlights the idea that you can't generalize from one population to another as to what the effects of vaccine are going to be depending on what the ambient organisms are and what is the situation of the population whom you're studying.

So that I think if you're going to study what happens in the United States, it may be different from Montana to Massachusetts, but at least it makes it implicit, I think that any recommendations you're going to make for this country are going to depend on what the data are for the United States and not a study done elsewhere.

ACTING CHAIRMAN DAUM: Well, let me throw out an idea that I think I'm hearing weave through people's comments and see if people like it or don't, but I'm getting a sense that you just sort of can't go off and study pneumococcal disease anyplace you like and believe that we can take the messages home, if you will, and bring them back to the U.S.

And so if an alternate site is contemplated for study, we've got to know something about the baseline there. What's the epidemiology? What's the carriage? What's the responses to vaccine? How does it compare with what we have in this country?

And then one can undertake study of choice, and then we can interpret the data based on those baselines.

I mean, I think that's what people are saying in about ten different ways. Does anybody want to comment on that or does anyone agree with it or disagree with it?

Dr. Broome.

DR. BROOME: I mean, I'd never deny that there's a lot of variability and idiosyncracies, but I also think for the serotypes producing invasive disease, there's actually been remarkable consistency over time and geography. There's exceptions, but you know, big picture, I don't want us to be so nihilist that we ignore what I think could be valuable data on IPD protection in other countries.

I do think the carriage area is enormously complex, and I look forward to further understanding.

ACTING CHAIRMAN DAUM: Yeah, I accept that as a -- that's a clarification, I think, in one area where that might not be quite so true, but anybody else want to comment on this? Dr. Griffin, Dr. Butler?

DR. GRIFFIN: Well, yeah, he's going to be able to comment more knowledgeably. I was just going to ask if the same thing was true about otitis media as it is for invasive disease when it comes to the serotypes most likely to be causing disease. Is that also -- we don't have much of a database.

DR. BUTLER: I don't know. My comment was, you know, I think the distinction between carriage and invasive disease is very important, and to sneak ahead and look at some of the other questions coming up, we need to keep in mind that same difference probably applies to otitis media versus invasive disease.

And if any two of these three are similar, it's probably carriage and otitis media.

DR. BROOME: But you have to be real careful about how certain you are of the causative isolate, and you know, otitis has its own set of complexity.

ACTING CHAIRMAN DAUM: Well, to come back to you, do you agree with the summary statement that I made, with the exception of invasive disease? I mean, I think we've got to try and struggle with this because it's going to come up over and over again.

Does a country that is going to have a study undertaken and it needs some definition of what goes on there before the study is undertaken.

Anyone want to comment on that? Dr. Decker?

DR. DECKER: You know, in evaluating our alternative measures of implied efficacy, other than doing an actual efficacy trial, the considerations that have been given are being given to antibody levels or let me phrase more generally.

Immune response, however we decide that ought to be measured, or various thought relevant or clearly relevant clinical outcomes, like occurrence of otitis, carriage with pneumococci and so on, and those clinical outcomes are attractive to use either as primary or secondary endpoints because they're relevant clinical outcomes.

But I think there's a lot of danger in them also, and they're at least as dangerous as any serologic criteria. For example, as we've just heard, the characteristics of colonization and the impact of the vaccine on colonization differ markedly from population to population in such a way that you can't presume -- I mean, the same vaccine basically is shown to be highly effective in preventing colonization in one population and marginally effective in another. So a candidate vaccine might look highly effective or marginally effective when, in fact, it's no different at all from Prevnar based on which population you did this in if colonization were an endpoint. So that's a dangerous endpoint.

If otitis is the endpoint, I've got a number of concerns. One is that, again, the mechanisms involved in otitis are not the mechanisms involved in -- the same as in invasive disease.

The FDA raised the question or whether or how the committee would respond to a vaccine that was brought in simply for licensure on the indication of prevention of otitis, and that's a very interesting question, but let's set that aside and suppose the question is: how do we respond when otitis prevention data are being used to support a claim of efficacy against invasive disease?

Well, I've got a number of concerns with that because I suspect, for example, that prevention -- this is based on largely extrapolation from Hib, but I suspect the prevention of otitis may be more dependent on GMT, whereas prevention of bacterial disease or bacteremic disease depends upon a minimum protective level; that there may be different mechanisms.

And I suspect it's possible that a vaccine that's effective against otitis might be more or less effective than Prevnar against invasive disease.

So extrapolating from otitis to invasive disease may be at least as shaky as extrapolating from any serologic criteria. I mention that just to give caution because I think there's a natural tendency to favor the clinical criteria, and they may not, indeed, be any more reliable.

ACTING CHAIRMAN DAUM: Okay. We have Dr. Goldberg, Dr. Insel, and Dr. Giebink lined up for comment, and we're starting to get near a time when we will start focusing on these questions.

DR. GOLDBERG: I want to bring up something I think we should talk about, and I don't know if it's reasonable in this arena, but in many instances when you have an endpoint that's very rare, but very serious, you have other endpoints, clinical endpoints, that also can be assessed in the same population.

And it seems to me that one possible approach to this is to do in quotes clinical efficacy trials using a combined endpoint, which is really the occurrence of a series of events that could be prevented by this vaccine, such as the invasive disease such as otitis media.

And you can prioritize them in order of severity so that you would have the worst first, if you will, I mean, the details to be thought about, but something starting to think along those lines though opens up an arena where you would be doing a clinical efficacy trial on a population, on a sample size that was considerably smaller than the one that you'd need for the invasive studies, quite larger than the ones that have been proposed for the immunogenicity studies, and begin to give you enough data that would accumulate on safety and ways of assessing the immunogenicity in relation to these various endpoints.

And I think I'd like some discussion of that. If it's off the wall, I accept that, but I know that in other arenas it is not.

ACTING CHAIRMAN DAUM: Anybody care to respond to Dr. Goldberg's comment?

(No response.)

ACTING CHAIRMAN DAUM: Got no takers right now.

Dr. Insel.

DR. INSEL: With respect to question one and two, one theme that I've heard this morning was the importance of measuring functional antibody, and yet I'm troubled by the utility of the current opsonophagocytic assays and whether or not they're going to prove useful in this regard.

There's an article this month in the Journal of Clinical and Diagnostic Laboratory Immunology by Helena Kayhty where she and colleagues have compared four different opsonophagocytic assays that have been developed worldwide, and one theme that comes through in the article is the lack of sensitivity of those assays, especially as one gets into the concentrations of less than one microgram per mL.

And yet when it comes to ELISA assays, I'm hearing that we're willing to use ELISA values of, let's just say for the sake of argument here, say, less than 0.5 micrograms per mL, and I'm wondering if somebody from this community can just at least begin to address how are we going to use opsonophagocytic assays as a functional assay if we don't have the requisite sensitivity today or even in the short term. I'm not sure where the field is going, if that could be addressed.

ACTING CHAIRMAN DAUM: I think we should ask Dr. Frasch to respond to that first, and then we can have other responses, if you would.

DR. FRASCH: Well, I think one response to that is just for the sake of argument, 0.5 microgram per mL, somewhere in the vicinity of 90 percent of recipients have greater than that following post dose three. So what has been done in the past is take those recipients who have made antibodies in excess of one microgram and then find out if those particular individuals' antibodies are functional.

So that's the approach that's been followed, and I'm not sure that you can say that if you have .2 microgram of antibody that antibody is going to be of lower quality than an individual who makes two micrograms.

DR. INSEL: Again, I'm not sure what the basis of that statement is either. I mean, I'm concerned that, you know, we start talking about levels of .2 as being the criteria based on ELISA, and now you say, well, secondly we have to measure functional antibodies, and yet it's only a subset of that group in which we can measure functional antibodies, and presumably those individuals who are making higher antibody titers may be making antibodies with higher affinity and may have more functional activity.

And so I'm not sure one can extrapolate just from the select group of individuals who make one to ten micrograms per mL as far as what's going on with the whole group, and I think that's going to have to be addressed if this is going to be used as a criteria.

ACTING CHAIRMAN DAUM: Dr. Giebink had his hand up, and then Dr. Kohl. We're going to stay on this issue for a bit and try to explore it.

DR. GIEBINK: No, I just wanted to weigh in on this issue myself.

ACTING CHAIRMAN DAUM: You're next to speak anyway.

DR. GIEBINK: My understanding from the report out of the workshop was not that avidity assays or opsonophagocytic assays would be used in the same quantitative way that ELISA results are used, but rather that avidity assays and opsonophagocytic results would be used to characterize the response that a vaccine elicited in an early phase experience with that vaccine, and that if it had the same characteristics as the Prevnar response, you'd move along, but you'd do so with ELISA.

And I guess I just want clarification, Carl, if that is the gist of what the workshop discussion was.

DR. FRASCH: Yes, yes, because what you're really trying to show is is the vaccine capable of inducing functional antibodies, and to do that you don't have to look at antibodies in every single individual that were immunized because what we're concerned about is does the chemistries, the chemical modifications, required to make the polysaccharide able to chemically link to the protein, do these chemical modifications have an effect on the ability of the resulting conjugate to induce functional antibodies?

So that's partly where we're coming from from the standpoint of looking for the ability of the vaccine to induce functional antibodies.

ACTING CHAIRMAN DAUM: Dr. Falk, then Dr. Kohl.

DR. FALK: I just wanted to speak directly to Dr. Giebink's question.

I think you encapsulated the sense of the workshop very well in that the end result would be an evaluation by ELISA for the pivotal study, but that during the course of the product development and clinical evaluation, there would be an evaluation of the ability of the ELISA to correlate with opsonophagocytic and avidity endpoints as well, but not necessarily -- the workshop did not get into in my mind the specifics about how that was to really happen, just that it could be done in a subset during the pivotal study or prior to the pivotal study.

ACTING CHAIRMAN DAUM: Okay. More about this -- sorry, Claire. What did you want to say?

DR. BROOME: I just wanted to comment on this point.

ACTING CHAIRMAN DAUM: Would you, please?

DR. BROOME: I mean, it seems to me there's actually two ways in which the functional assay could be helpful. One is what I think Carl is referring to, which is the generic question: does a serotype for which we don't have efficacy data elicit functional antibody, you know, at all, in which case the higher titers presumably are relevant?

But I think the other issue that Dick and I was sort of interested in was could the functional assays help up with this issue of what is a meaningful threshold value, in which case you really need to focus on the ELISA values that are in the lower range.

And I'd just still be very curious as to whether there is, you know, any progress in both reliability and sensitivity of assays in that range or whether it's an impossibility. I just don't know enough about the mechanics of the assays.

ACTING CHAIRMAN DAUM: Yeah, I think this is an important issue to ask people here to speak to if they have knowledge about it because we're groping with this functional assay business, and it really looks like the higher titer sera are the easier ones to measure and that we've seen the most data about, but they may also be the sera with the most functional antibodies.

So what do we know about low ELISA titer sera and function? Dr. Kim, what do you know?

DR. KIM: I guess I also want to, you know, raise one more issue related to that. Again, I want to raise this issue to Carl. He's, you know, performing a functional assay, such as opsonophagocytic assays. I know there are probably ten, 20 different ways you can set up the opsonophagocytic assays so that, you know, the question is, again, going back to some of the issues that Dick Insel raised about sensitivity: are you able to sort of set up the assay in a way that you will be able to measure functional activity of those sera regardless of concentration of antibody measured by binding assays to elicit functional activity?

DR. FRASCH: I would like to preface that in that the in vitro opsonic assay in itself is very different than in vivo. So it's a very artificial set-up right away.

Now you're asking us to twink the artificial assay such that it becomes sensitive enough to now measure antibodies at our proposed threshold value.

I'm not sure we're going to gain anything by making it maybe more artificial.

ACTING CHAIRMAN DAUM: Before I call on anybody else, is there anyone here who has information about this issue that's been nagging us, or is this the state of the art right now?

State of the art, Dr. Giebink nodding his head as an expert pneumococcal guy.


ACTING CHAIRMAN DAUM: All right. Dr. Kohl first, then Dr. Decker. We have some uncertainty identified.

DR. KOHL: I'm still on this same question, and I'm coming from it sitting on this side of the table as a beleaguered hireling of the FDA, and I'm looking down the road having a company come to us. We're basically talking about one, and I think we've accepted the first part of that one that we're probably going to accept noninferiority immune response, and we're talking about the second thing now, which is --

ACTING CHAIRMAN DAUM: I would ask you not to assume that.

DR. KOHL: Okay.

ACTING CHAIRMAN DAUM: For your comment.

DR. KOHL: Well, that's where I am.

ACTING CHAIRMAN DAUM: I don't think I've heard a clear consensus on that at all.


DR. KOHL: Well, as I'm sitting here, I'm thinking about a company that comes to us and says, "Well, here is our cutoff level, and we've made all of the whatever we decide, the hoop that you have to jump through for that, and now here's our opsonophagocytic level."

And what do we on this side of the table need to see? Do we need to see that 80 percent of the high titer serum achieved a certain level of the OPK? I'm trying to figure out how that's going to help us, and I'm hearing the very vague comments about, well, it will be used in early studies to show that the antigen is capable of eliciting an opsonophagocytic response.

I don't know what that means. Eliciting it in 100 percent of people or eliciting it in high titer people or eliciting it in two month old children?

And we're being led to think that the opsonophagocytic assay is somehow close to the human situation because it seems to be correlated with animal models, but what about with polys -- I presume we're talking about polymorphonuclear leukocytes as the prime actor here -- what about polymorphonuclear leukocytes in a six week old or in a three month old where the action is, where those pneumococci are?

So it's very complicated, as Dr. Insel was, I think, implying, and I think as Dr. Decker also said.


Dr. Decker. Dr. Hall next.

DR. DECKER: There's current discussion. I think it may be best addressed by coming back to what Dr. Goldberg said because I think, again, on a practical level that's likely to be the way we end up heading.

If, and I agree with Steve on this notwithstanding my deep respect for the Chair, I think we're probably headed towards taking a -- eventually identifying some immunologic pathway to licensure. If we do that, we're going to want assurance that that in vitro measure has in vivo meaning, and that assurance may come at least in part through identifying some specific other immunologic test, such as opsonophagocytic antibodies, or it may come from some of the clinical endpoints that I cautioned against using as determinative earlier, but which I think clearly we might want to use as supportive.

And that brings us directly to what Dr. Goldberg was saying. For example, I can contemplate a checklist where, yes, we've achieved antibodies measured by ELISA in the total immunized population, study population, that meet these criteria with comparison of Prevnar for the strains contained in Prevnar.

And in addition, we've shown that in an appropriately selected subset in whom it can be done, we've demonstrated activity of these antibodies, and in addition, we've shown an impact on some clinical endpoint which is reasonably comparable to what you achieve in that endpoint with Prevnar, and therefore, we have taken one from column A, one from column B, and one from column C. Let's ship our order. It's ready to go.

ACTING CHAIRMAN DAUM: Okay. I think we may as well swing into question one, but let's hear from Drs. Diaz and Goldberg, and, Dr. Hall, you had your hand up first. I lost.

Let's go with Dr. Hall, DR. Diaz, Dr. Goldberg, and then we're going to go right into question one.

DR. HALL: Still on the same question obviously, coming back to what Dr. Broome said earlier, which I think is really important, is how much variability between the functional assays and ELISA exists in terms of serotype, and I'm wondering if anybody has more data or if Scott perhaps has it at least in the animal model.

And secondly, since we appear to know that the pre-titer does affect the ELISA titer, is that also going to affect the functional assay?

ACTING CHAIRMAN DAUM: Anyone want to address that question? I'm sure I'm missing some information here.

DR. GIEBINK: Yeah, I got put on the spot here.

ACTING CHAIRMAN DAUM: All right. Who put you?

DR. GIEBINK: I think I need to say on the table for all to know that the correlation between opsonophagocytic titers and ELISA titers is in some cases good and in many cases not so good.

DR. HALL: By serotype.

DR. GIEBINK: By serotype, and in no case is it great. So I'm not going to put numbers, Rs on those, but really there's quite a scatter. So I have a lot of concern about using opsonophagocytic titer as a surrogate for protection because I feel better about ELISA titers, IgG titers and their relationship to protection, but neither is perfect.

ACTING CHAIRMAN DAUM: So are you saying that the focus, and hearing the footprints of issue one coming, the focus ought to be on measuring ELISA because like it or not, that's the best we've got, and then some kind of functional assay, I presume we would want to work in there, to make sure that what we're measuring by ELISA works?

DR. GIEBINK: Yes. That's what I -- I think that's what the workshop concluded, and I would agree.

ACTING CHAIRMAN DAUM: But then we're getting squishy as to what that something should be and how it should be done is what I'm hearing.



DR. GIEBINK: Yes. That's true. I think we may have to be comfortable with the squishiness for right now.

ACTING CHAIRMAN DAUM: Dr. Frasch, on this issue?

DR. FRASCH: Yes, but I don't think -- if you read question one, I don't think it infers like you're saying, one assay, one measure, one immune parameter.

ACTING CHAIRMAN DAUM: Well, there's a little parentheses at the end, but it certainly asks about it. You're the interpreter of the questions. I mean, is that not what you're asking?

PARTICIPANT: No, not really.

DR. GRUBER: I was just accused of having written this question, and you have no idea through how many revisions we went to arrive at this, but let me comment.

I think what is meant here really is what immunological parameter. I think we're thinking of perhaps being able to define today a primary parameter and then leave space for some secondary parameters that could be perhaps translated in secondary endpoints or something like that.

ACTING CHAIRMAN DAUM: It sounds like that's what you're going to get.

Dr. Diaz, please.

DR. DIAZ: I'm going to hold my comment or it will come up later.

ACTING CHAIRMAN DAUM: All right. Dr. Goldberg.

DR. GOLDBERG: Yeah, I just wanted to clarify something in what I said because, Dr. Decker, I mean, I think I agree with you, but to a point. I think that this, quote, clinical trial would also have the immunogenicity assays done. You would use those to bridge the secondary immunogenicity trials, but that would be the link.

And you would also be in that trial -- hopefully it would be sized so that you could at least for some of the endpoints or the combination of endpoints develop the relationships between the titers and the clinical endpoint.

So I wouldn't call the clinical, this thing, purely supportive. I would say that this would be in a sense -- it would have to be an agreement because it wouldn't be your standard clinical trial with all of the criteria tied up nicely, but in a sense, I would view that as, you know, one of two parts, and it would be a package of the immunogenicity trial with this that would determine your efficacy.

ACTING CHAIRMAN DAUM: Dr. Faggett, please.

DR. FAGGETT: Dr. Goldberg, just for clarification, so in effect you're saying the clinical trials would be available to validate pretty much some of the other --

DR. GOLDBERG: But it would be a modification of the kind of efficacy trial that we talked about.

DR. FAGGETT: Yeah, I thought that's what you said, and my concern was that we're moving towards eliminating the availability of clinical trials, and to me I think that would be a mistake.

ACTING CHAIRMAN DAUM: I think we're trying to decide what their components should be.

Dr. Kohl and then Dr. Giebink.

DR. KOHL: I'm wondering as we move approaching question one if we can mandate a large post licensure trial, a bridge of immunology to licensure, and then a large post licensure trial, in particular focusing on rare adverse events and also breakthrough cases of pneumococcal disease, in particular, invasive pneumococcal disease, which may then give us a handle on serotype breakthroughs in particular, which will be unusual, but may be very telling.

ACTING CHAIRMAN DAUM: We are, of course, an advisory committee that mandates nothing, but we can certainly make the suggestion, and I know our colleagues are listening carefully to what we say.

Dr. Giebink.

DR. GIEBINK: Just a comment on the efficacy trial that Dr. Faggett mentioned. If I were acting from an ethical basis on the conduct of a clinical trial, because it's an equivalence or this scenario, I guess, called the noninferiority, but some of us think of equivalence trials; if this were an equivalence trial, I would require serologic evidence of equivalence before conducting the clinical trials.

So that, in fact, the first threshold in my mind is the serologic equivalence.

ACTING CHAIRMAN DAUM: Well, Scott, let me reframe your comment and make sure we're on the same page.

If we look at this item, this item basically asks about that, whether a noninferiority immune response, immune response, comparing a new vaccine with Prevnar are sufficient. So it really deals with what you're saying, doesn't it?

DR. GIEBINK: No. It's the issue of going on to clinical efficacy.

ACTING CHAIRMAN DAUM: To clinical, not this?

DR. GIEBINK: I was addressing this issue here.

ACTING CHAIRMAN DAUM: Okay. Dr. McInnes and then Dr. Griffin.

DR. McINNES: The concern with that approach is if you took the experience we had with hemophilus and you applied that to Hib OMP, you would have failed on a noninferiority basis --

DR. GIEBINK: But had equivalence, yeah.

DR. McINNES: -- but your efficacy data was spectacular. So you have a vaccine that works or has an immune response that is not in the traditional one you're comparing to, and you potentially kill a very important vaccine approach.

So I think the issue comes that if you have clear noninferiority on either of the serotypes, that's a win-win-win all around. The question comes if you don't have clear noninferiority in all of the serotypes, how much window do you give around that, and perhaps that's the first test, is the noninferiority, and if you don't pass by whatever the passing grade is, these other alternative approaches have to be open to look at, and the onus is then on to demonstrate efficacy or use some other supporting data to make the case for what might be taken into consideration for licensure.

ACTING CHAIRMAN DAUM: I think that's a wonderful clarification for us. The language does use the word sufficient, and I take it from your comment, Pam, that you would say that it would be sufficient if it were noninferior.


ACTING CHAIRMAN DAUM: And the corollary, of course, is that that would not close the door on further considerations. I think that's what I'm hearing.

Dr. Griffin, was it you that was next?

DR. GRIFFIN: Were you going to comment on that?

DR. DECKER: Well, very briefly. I agree entirely with Pam, and that's consistent with what I said originally. I think what we will need to end up with is multiple pathways to licensure.

For example, if we endorse a serologic pathway, there is always the efficacy trial pathway. We're not closing that door.

ACTING CHAIRMAN DAUM: So let's go to question one. Let's go to the big board.

Do you want to make a comment first? The last comment.

DR. GRIFFIN: Okay. The last comment. Because the only thing I wanted to say was solidify the fact that if we go to an ELISA type of threshold, which I agree is much easier to quantitate, et cetera, as the serologic criteria that we're using, that I would agree with the comments that were made before. I guess I just wanted to reinforce it, that at some point prior to using the ELISA, you show that this particular kind of conjugate for each of these polysaccharides does induce functional antibody. I mean, this opsonophagocytic, you know, test sounds like a reasonable one, although not perfect, but that you would have to establish that, but you weren't only inducing ELISA reactive antibody.

ACTING CHAIRMAN DAUM: Okay. I'd like to start focusing specifically on this question now, and it has two distinct parts to it.

The first part is whether noninferiority -- comparing a new vaccine with Prevnar. So I'm going to presume -- FDA people, correct me -- that there couldn't be new serotypes in that vaccine for this question because then they couldn't be compared, and so if noninferiority, is it sufficient? Would it have to be done -- when you comment, would you please comment would it have to be done in the United States or could it be done, inferiority done, in South America, in Asia, in Western Europe? Noninferiority done where?

And also when each person comments, we'll need to say something about what do you mean by noninferiority. First, what assay, primarily; second, what assay secondarily; and then, thirdly, what if not every serotype meets the bar?

I'm going to throw that in as an issue that I think would be worth commenting on as we go around.

Dr. Insel, I think we'll start with you if you wouldn't mind, and then we'll go up the table here and swing around.

DR. INSEL: And if I heard you, I think it would be sufficient if it was conducted in a comparable population, a U.S. population.

I think as far as immunological parameters, I view the ELISA is probably going to be your primary criteria, but I am concerned that we are going to set the threshold so low that we have to have some kind of functional assay, I believe, to go along with this, and I'm concerned that the functional assays as they exist do not have the requisite sensitivity and show serotype differences.

I am troubled with the 19F story because it's unclear to me. If I understand it correctly, 19F does make pretty good antibody response both based on geometric mean concentration or titer, as well as a threshold type level, and yet on the invasive side there was, at least, one failure there which is obviously probably not meaningful, but on the otitis side of things, it is somewhat worrisome, and it makes me want to think that we do need to have some kind of functional equivalent if we are going to set this low threshold.

ACTING CHAIRMAN DAUM: Thank you very much.

Dr. Wharton.

DR. WHARTON: I would concur with Dr. Insel's comments, though I also want to echo a point that I think you just made about that I'm not sure that I would conclude just because noninferiority criteria were not met that the vaccines were not equivalent.

Perhaps we'll get into that later, but I'm very concerned with a vaccine where we have a fair degree of uncertainty about threshold amounts. there are assay related issues. There are multiple assays being done, that when you include that very large number of analyses and comparisons, that the failure to meet noninferiority criteria for a couple of them would eliminate a candidate vaccine, I think, could be a very unsettling discussion to be having in this room in a couple of years.

So I think that is an area that serves some additional exploration.

ACTING CHAIRMAN DAUM: Thank you very much.

So I take it both you and Dr. Insel believe that it would be sufficient.

DR. BROOME: I also think that it would be sufficient, but I think there's a number of additional points I'd like to make.

I mean, one is I think we do have to specify the precision of the assay at these low levels, assuming that the threshold is going to be under one, and so I want to know what the precision of the assay is under one, and I do think ELISA is very attractive for potential precision and ease of use for large numbers of samples, but if it's not measuring the right parameter, that really isn't that great.

I think on the whole it clearly does correlate, but I think when you're dealing with so many different serotypes and you have some evidence of, you know, if you take the otitis data different protection with different serotypes without that much difference in ELISA, it makes me want to know a little more about something that would measure protection.

It also suggests to me that rather than sort of carving the narrowest threshold, we ought to have a sort of margin of error built in. You might determine that partly based on the precision of the assay. You also might just put in a margin of error.

I think that's also something you could -- which is sort of implied in this idea that rather than try to calibrate a threshold for each serotype, you pick, you know, a threshold that meets the highest serotype, which, you know, I think is what has been done by some folks, and it doesn't worry me that much to take that kind of an approach and use essentially that number for all serotypes, understanding that's making some assumptions.

The one thing I'm not comfortable with are these measures which combine the results across multiple serotypes. I think I've seen we've tried to do that over the years, and I really think that is a counterproductive endeavor which tends to sort of mask true serotype specific variability.

So those are just some thoughts, and you know, the issue, the one you tacked on of do we need to have noninferiority for all seven serotypes, you know, I think that's a tough one. I'd prefer to have that. There's clearly some serotypes which are more prominent as causes of disease that would be priorities, but you know, I'd like to see if we couldn't do it for all seven.


Thank you. The first three speakers are just incredibly helpful, I think. So thank you. And let's see what else we can get from our group.

DR. BUTLER: Great. You've set me up, Bob. Thank you.


ACTING CHAIRMAN DAUM: Yeah, I'm sorry. If I don't say it for the fourth, they just didn't cut it.

DR. BUTLER: I think that the noninferiority of immune response trial is a reasonable approach for inferring efficacy against invasive disease, and I think I would also go as far as to say it's sufficient.

ACTING CHAIRMAN DAUM: Jay, can you speak right into the mic so we can all hear?

DR. BUTLER: That's somewhat considering also what the alternatives are and what are really logistically feasible to do, and I would qualify that by making it clear that I'm talking about a head-to-head comparison between the vaccine under evaluation with at this point in time Prevnar.

The struggle that I think we're all having is what is the definition of noninferiority. Some of the definitions that have been tossed around included some triple negatives. I find I'm having to pull out a piece of paper to keep track of just what it is we're implying.

But the question of what to do when there's, say, a single serotype that falls short, I think, is important. An example might be serotype 4. At least in the trial in Northern California that was a very unusual serotype, and it's not one of the leading serotypes in that age group in the U.S.

Does a vaccine then not go to licensure because of that?

The other issue is how to evaluate to immune response, and I think the attractiveness of the ELISA is standardization, but I think functional assays, such as the OBK and perhaps also avidity assays can provide very important complementary data, and I bring that up because that may be complementary data that would be useful in terms of sorting out what to do with the individual serotype or small number of serotypes that fall short by ELISA.

I cannot even begin to imagine how to state that quantitatively, but just as a general concept, I think that complementary data may help sort out those questions, and I think that's going to really happen with expanded valency vaccines and the fact that we're dealing with seven individual immune responses.

There's going to be differences, if nothing else, due to chance.


That was four very helpful --


ACTING CHAIRMAN DAUM: I can't keep doing it though.

Dr. Hall.

DR. HALL: Why not?

I can just say that I agree with everything that's been said in general, but I guess what I'd like to bring up again is, first of all, what of course is going to be sufficient is a question yet, but if you have populations that are comparable, which I think is the basis that everybody has said to utilize this, that means to me stepping back a minute and saying what are the criteria to determine that these populations are comparable, particularly if we're doing it in another country, and I don't think that we've really addressed that issue.

Is it the distribution of serotypes? Is it their immunogenicity on a given serotype?

I mean, there are so many different aspects so that I think those would have to be set up first, and then I would think that obviously the immunologic parameter or the major assay would be potentially ELISA, and that as Jay brings out, that there will be some that are going to fall short.

So how are you going to judge those? And in those instances, maybe it does require a combined or weighted assays of all the assays, and that again then brings up the conundrum of trying to decide how do you weight this.

But I think all of those things need to be at least set up to some degree as to what our criteria are.

ACTING CHAIRMAN DAUM: Thank you, Dr. Hall.

You're next.

DR. EMERSON: I'm in the position of being allowed to both introduce the probably greatest heterogeneity of opinion and perhaps the heterogeneity of quality of opinion.

I guess the main thing I have to address is the question of time. I mean, I think clearly eventually you have to go to the immunologic response, and my major question is: are we there yet?

And I guess I don't think we are. I haven't heard any evidence. You know, I guess I've heard it go both ways as to whether this should be necessary or sufficient. The idea of saying if you don't have the immunologic response, should we drop it like a live grenade or should we then go on to efficacy treatments? And quite differing opinions there.

And I guess I also think there are some numbers that I look at in these preliminary things that don't look that unattainable. Thirty-eight thousand people were used in the Kaiser study. There's quite a number of these sample size formulas that come up in the 38,000 range or better, particularly as you start considering that the otitis media endpoint can contribute such information.

And so I would be looking more at what I think you put as, you know, the one from column A and column B and column C approach, as the idea of saying we'd like some immunologic response, and that in combination with some more protective endpoints on the secondary ideas of otitis media would be preferable to at this stage going with purely an immunologic response to declare noninferiority.

ACTING CHAIRMAN DAUM: You know, I thank you for your comments. You've touched on many issues with them.

But to come back to this very item, do you think that noninferiority is sufficient for inferring efficacy?

DR. EMERSON: No, no.


Dr. McInnes, please.

DR. McINNES: I think we should remember the spectacular efficacy of Prevnar, and we should remember, I think, the considerable body of data that supports that antibody is protective, and I think I have no problem in supporting the use of noninferiority immunogenicity studies, but the bar is set. It's out there. It's a licensed product, and that's the guy against whom you have to get measured.

And so if noninferiority can be demonstrated by immune response, and I think there's a lot of work being done on ELISA and there has been a lot of work done on the functional assay. It's not everybody's favorite functional assay, and I think there's room for a lot more work in this area, but I think pragmatically the ELISA is working for us, and I think we should continue to try to refine the opsonophagal (phonetic) functional assay and the correlation between these two, but I am confident that these are meaningful at this point, and I have no problem supporting this approach for noninferiority of all the serotypes.

ACTING CHAIRMAN DAUM: Dr. Decker, you may choose to believe you've spoken to this already.

DR. DECKER: You know me better than that.

ACTING CHAIRMAN DAUM: I was actually going to say that, and I said, "Bob, catty. Just don't do it."


DR. DECKER: My answer to question one is yes. More specifically though, only if the question is broad enough to say that not an inferiority demonstration requires at least a little bit more than demonstrating the statistical noninferiority of the ELISAs because of the concern. Although we've got substantial evidence, as Pamela said, that antibody is the key thing, still we want to know the antibody that is being generated is functional.

Once we know that it's functional, then I think we can assume that the demonstration of numerical noninferiority is adequate.

I disagree a little bit with Dr. Emerson. I didn't mean to imply earlier that a candidate vaccine would need to demonstrate noninferiority with respect to a clinically relevant outcome; rather, that demonstration of performance against a clinically relevant outcome was one way of demonstrating that your antibody was function.

So because I don't believe that the sample sizes that would be necessary to demonstrate noninferiority of the clinical performance against any of these clinically relevant outcomes are readily obtained, and given how good our data are in support of the idea that antibody is the driving factor here in protection, I don't think it's reasonable to set that standard.

I think there are a couple of other questions that you raised that can be addressed. Can the study be done anywhere? Yes, but I think the manufacturers should proceed with great caution if they go outside of the United States because they're going to have to figure out how they're going to satisfy the committee that their non-U.S. data are bridgeable to the U.S., and that's a very difficult question, one that can be avoided by not going outside the U.S.

So I don't think that's a bar we set, but I think everybody had better recognize that they put a big hurdle in front of themselves if they go that pathway.

We also need to define noninferiority very clearly. I think one of the things that's an essential outcome of today's meeting is that the companies are given a road map to licensure. Whether this comes from the FDA in six months or it comes straight out of this meeting, but somehow because these issues are so thorny, it is incumbent upon us and our FDA colleagues to insure that the companies don't spend three or four years in a developmental process that then is met here by rejection because we didn't really mean .18. We meant .30, or we didn't really mean you had to show this functional or you had to show that functional.

It is incumbent in this complex area to offer a clear road map.

And finally, I agree with what Steve said. We've got one other safeguard here, and that's post marketing surveillance for breakthrough cases. The FDA always has the option, and this committee can always recommend that that be done, and the less sanguine we are about the strength of evidence of efficacy for a particular candidate vaccine, the more we may be likely to ask that surveillance of breakthrough cases be done to identify serotype specific failures. So that's an option we retain.

ACTING CHAIRMAN DAUM: I think caution, of course, is that this committee is advisory, and so I would think a company would be remiss to infer a road map from this discussion without input from colleagues at the agency.

Dr. Giebink, please.

DR. GIEBINK: I do believe that a noninferiority immune response trial is sufficient for inferring efficacy, but I have lots of caveats, and I must admit at this end of the table, it's hard to come up with many new caveats.


ACTING CHAIRMAN DAUM: You don't have to.

PARTICIPANT: But, Scott, I can help. Wait. I can help you.

ACTING CHAIRMAN DAUM: You don't have to.

DR. GIEBINK: But I want to emphasize a couple. I want to emphasize a couple.

As Pamela said, the bar has been set. Clearly the bar has been set, and in that respect, I believe that given all of the discussion and variance in ELISA assays that exist and the discussion that we've had, that we need to validate against the Wyeth assay. That's the assay that was used that produced the antibody results that led to licensure of Prevnar, and I think we need to -- that another product would need to bridge to that assay or at least those results.

The demographic issues of the population chosen for another vaccine immunogenicity trial is crucial, whether it's inside the U.S. or outside the U.S. The difference in demography outside is obvious.

Inside there are big differences, too, and that needs to be recognized, and the only other thing I haven't heard mentioned so far is that we have some populations in this country at exceedingly high risk of invasive pneumococcal disease and high mortality, and we should not lose sight of the fact that studies need to be done early on in these high risk sickle cell disease populations, transplant populations, et cetera, as early Phase 4 studies.

And I think just passing that along to the FDA is admonishment that those are important studies.


I would, as we continue to go around the table, remind my colleagues that we don't have to just say something. Having the force of agreement with what's been said previously counts for a lot. We'll put that right in the win column.

Dr. Kohl.

DR. KOHL: Yes. For noninferiority being sufficient, again, I agree with and hope the FDA can stick to this high bar, high bar being everything that has been said, including meeting noninferiority for all seven serotypes in Prevnar, including using an assay that they judge is reliable, including setting a level of antibody that is a fairly high level, and I can't do that at this moment, but we've heard lots of different levels batted around. I'm going for higher, and I think that bar should be set higher.

I also think that we've really made things a lot easier for our pharmaceutical friends across the table in terms of if this holds, not mandating very large efficacy trials, and I think that then hopefully the FDA feels comfortable in really setting out some very, very structured requirements for post licensure study, which unfortunately we've tried to do with other vaccines, and at times haven't succeeded, and that's come back to bite us.

I'm thinking of the Lyme vaccine, and at other times has succeeded very well. Rotavirus really has been a very good thing that's happened.

And lastly, to echo what we've said yesterday and what I know that Dr. Faggett and I feel strongly about is looking at diverse populations within this country, which are very high risk but haven't been emphasized. A black ghetto population is a very high risk population for invasive pneumococcal disease and they should be specifically included in this licensure requirement.

ACTING CHAIRMAN DAUM: Thank you, Steve. That's very helpful.

Dr. Kim, please.

DR. KIM: I want to support that noninferiority based on immune responses is sufficient for inferring efficacy against invasive disease. Again, I think an important, at least, issue to me is that, again, the assay for -- and then for this, I guess we talked about many different assays based on the other issues involved with the functional assays. I believe the binding assays, such as ELISA, would be preferred.

However, I think it is important that when we looked at the data from various individuals or manufacturers about ELISA titers, then we really need to know that those assays are, indeed, comparable and reproducible and have been consistent with a -- if there's a guideline, they're consistent with the guidelines coming from the FDA.

And then regarding whether immune responses need to occur comparable to Prevnar, I also agree that the immune responses have to be at least equivalent to Prevnar for all seven serotypes that are contained in the vaccines because that already has been shown to be efficacious and that that is a licensed product.

And, again, I think it's also -- I'd like to see some functional activities that, you know, comparing or at least supporting the data coming from the binding assays. Again, I know the issues have not been settled. I'd like to see some more discussion going on on these, you know, assays, such as opsonophagocytic assays. I'd like to see some sort of agreement among interested parties about the assays so that certainly that would be meaningful and also it would be reproducible so that we'll be able to, you know, as a committee member, we'll be able to understand what those numbers mean.


Dr. Faggett.

DR. FAGGETT: Yes. I'll start off with a caveat. As a condition, we know that laboratory data in only adjunctive to one's clinical impression, but I think I've gained a much better appreciation of some of the available tools today. So I'm very comfortable at this point to agree that noninferiority immune response trials are sufficient, again, with adequate bridging studies, including U.S. population, and that way I think we can infer efficacy of the product.

I think that the ELISA and other tests to be determined pretty much on a vaccine-by-vaccine, case-by-case basis would be the way to go, with ELISA being the most appropriate to start with.

So those would be my comments.

ACTING CHAIRMAN DAUM: Thank you very much.

Dr. Griffin.

DR. GRIFFIN: Yes on the first part, and on the second part I think I've already made it clear that the ELISA I would want to be bolstered with a functional assay to show that those antibodies do have functional capacity.


DR. DIAZ: I would agree that noninferiority would be sufficient. I think my colleagues have already addressed the areas that I'd like to emphasize, which obviously being a comparable population.

I likewise believe that there must be some functionality testing done, especially since we'll be comparing products that are conjugated to different proteins.

I feel that the bar has been set high, as was already noted, and we have a vaccine that's licensed that's extremely effective, and the bar ought to be high because this is a disease that has an unacceptable morbidity and mortality associated with it in young children.

So with that in mind, in answer to the question of what would we do if one of the components did not reach noninferiority, I would agree that they all should, notwithstanding that the door would not be shut, as was pointed out prior in terms of doing efficacy studies down the line, but that in terms of looking for noninferiority, that all seven should reach that criteria.


Dr. Katz.

DR. KATZ: I'll not try to measure up to Michael Decker, but I'll make a speech, too.


DR. KATZ: First of all, I don't like the term "noninferiority." I'd rather say "equivalence." It seem to me noninferiority is negative and pejorative almost. I would vote yes for equivalence.

But I'd like to take one second or two just to comment on a meeting that we attended several weeks ago at CDC, where we learned that there's a shortage of tetanus-diphtheria vaccine. One company is dropping out of DTAP. We had a delay in the availability of influenza virus vaccine this year. Cholera and typhoid may no longer be available, at least certain products.

I see a great fragility in the vaccine system which concerns me greatly, and I think we should be doing everything possible within scientific relevance to encourage the development and the availability of these vaccines.

Another feature of these vaccines that excites me is that they'll be beneficial to the developing world and not just the United States.

We lost Rotavirus vaccine where we have that same excitement that we had something that would be helpful to children throughout the world. So that I think we should do everything possible with appropriate scientific caution to encourage this.

So that I would vote a strong affirmative yes, and on the second part, the same caveat that Diane expressed, that the immunologic parameters by ELISA be confirmed as having functional capability also.


DR. GOLDBERG: I think that noninferiority trials are necessary. I don't think in and of themselves they are sufficient. I do believe that there are some ways to get to do some efficacy trials here.

I've already discussed that. If we were to go with the, quote, noninferiority trial, I think it would be incumbent that every component be sort of identical, and by that what I mean is that I think ten percent is too big a window, which would then increase the size of your trials, give you more safety data, and make these immunologic trials considerably larger in size and at least begin to get at some of the safety issues and begin to give you a little bit more of a feeling that the vaccine might be in the large safe.

Now, I really believe that some legitimate attempts should be -- careful attempts should be made to develop the efficacy trials in some newer paradigms, and they won't be precise efficacy trials in head-to-head comparisons of the kind that were done originally, but with broader endpoints, recognizing that what you're looking at is for a clinical impression of the vaccine in a comparative way, and I do believe that should be possible.

And you will at the same time be accumulating pre-marketing safety data.

DR. GOLDBERG: Thank you, Dr. Goldberg.

I am last, and probably also least, but a couple of comments before we finish this discussion. My basic view is that the answer to the question from my point of view is yes, that I would accept that, and I do share the comments that were made that it has to be a head-to-head comparison. I'd be upset if anyone tried to do this with historical information, and that the population has to be relevant one to the United States if that's where it's going to be licensed, and ideally should incorporate many of the groups that we have that re ethnically divers, although I note that the trial that established this efficacy was largely done in a middle class, HMO type population in Northern California. So we don't have that information about this vaccine, although the Navajo trial has helped insure that bridge very nicely.

I think the most important thing that I would like to add is that we not be rigid in how we set up parameters here, and that's a hard thing to come to grips with because the companies want guidance. The FDA wants our guidance, but I don't think it's time for rigidity. I don't think we have all the information we need to offer rigid guidance.

For example, some of my colleagues have said that all seven serotypes need to be there, and we need to be noninferior, but yet, as Dr. Siber pointed out earlier, three of the serotypes, in fact, don't have clinical efficacy and didn't have in the trial. So what do we do with those?

I would like to see a trial set up with a noninferiority -- forgive me -- kind of design, but I'd like to use the committee's expertise and the fact that we've all been to school and have higher education and all of the groups in this room that want better health care for kids, and interpret them with some common sense.

So that if, for example, there was one serotype that didn't measure up and it wasn't a major cause of disease and it wasn't one of the ones we've had antibiotic resistance trouble with, we might not be too upset with that.

On the other hand, if we had a big failure of one that was a major cause of disease or major antibiotic resistance problem, we might take a different view of that.

And so that's a brave and uncertain new kind of world, but I think it's sort of where the state of the art is right now, and I'm not sure devising a weighting system -- I can see the discussion two years from now, that we do a weighting system where this type counts for more because it causes more disease, and then it misses by .1 points in our weighting system, and we're going to throw it out then.

I think that's too rigid for the state of the art of the knowledge.

In terms of assays, we're in some trouble here because we don't have the correlates we want. The trial was such a fantastic success that we didn't get the correlates we wanted because they weren't failure patients to really get that data from.

I'd like to see the otitis media data, but I'm not sure how relevant it's going to be to invasive disease, and I think we're going to have to sit down and interpret and see what we think of those.

ELISA sounds like the closest thing we have to a working assay. I think we've got to put some weight on it even though it's got lots of problems that we've heard over and over again. I'd like to think that we could develop some kind of functional assay to go with ELISA numbers. I'm convinced after listening to this discussion that we don't know how to do it.

I think probably the best bet is some kind of opsonophagocytic assay, but I'm concerned about some of the things that have been raised with low titer serum. I think we need better assays and better methods for doing this, and I turn to NIH colleagues to keep supporting work and to how to do this better because we're nowhere near.

Avidity is an idea whose time has sort of come, and it's a very exciting concept, and I'm hearing lots of interesting things about it, but I don't know how to use it clinically yet, and I'm not sure that I want to put my weight on that.

I want to echo a comment that Dr. Broome made, I think, when we went around, and that is that we don't know enough about these different serotypes to do any kind of pooling yet, and I would be really upset if we didn't continue to consider these seven different problems.

And it may be that after we gain some experience that we'll find that they're remarkably similar and that pooling is just the right thing to do, and it may be that when we finally understand why 19F is the funny serotype that it is, we'll realize that pooling wasn't the right thing to do.

I don't think it's time to do the pooling now.

Lastly, I would like to say that whatever vaccines are put into play in this regard, there's some important issues here that have got to be addressed with post marketing surveillance and studies, and several people have called for them. I don't have any things to add to what's been said, except the possibility of antigenic shift, which I think is a concern that hasn't been completely addressed yet, and we need to know whether it's going to occur or it's not.

And I think the committee did a wonderful job addressing this question, and I would propose that we reward them with a short break, 15 minutes in duration, and reassemble at 3:15 to go right into question tow.

(Whereupon, the foregoing matter went off the record at 2:59 p.m. and went back on the record at 3:16 p.m.)

ACTING CHAIRMAN DAUM: There are a number of committee members with obligations late this afternoon, and which is unfortunate for us because we need to keep as much of a quorum as we can to finish discussing these issues, but I would like to also be a realist and try and move things along a little bit more quickly so we can get as many people's opinions on as many of these issues as we can.

So we're going to go right on to the next issue, and I hope it's up there. It is. Thank you.

Please discuss the criteria that should be considered to evaluate serotypes not contained in Prevnar.

And is Dr. Broome here? She expressed some interest in starting this conversation, but if not, we'll start with Dr. Kohl.

DR. KOHL: Well, since the other one was so easy with some data, this is a piece of cake with no data.


DR. KOHL: I'd like to say that we would need clinical efficacy trials to have licensure of these serotypes, and I believe that's unrealistic because we're getting into the rare, rare serotypes now, and you'd have to have a gigantic study, I guess, in this country, and that's not possible.

And then if you went to another country where maybe these serotypes are more common, you've got all the problems of doing a study in another country.

So I'm going to have to fall back and say I probably would be satisfied with some immunological correlates, and then I'm lost because I have zero data on which to say what correlates, and I haven't seen anything that's come forth to suggest what they should be.

So can we pull an ELISA value out of a hat or do exactly what Claire said not to do, which would be to lump all of those other ELISA data values and say, yes, let's use point-something-something?

I'm a little bit lost here.

ACTING CHAIRMAN DAUM: Okay. There's a little logic missing there, Steve. Someone as we go around the table is going to have to fill in a little better as to what correlate we use if we go the route of non-efficacy trials, but let's see what going around brings.

Dr. Kim.

DR. KIM: Well, I guess in contrast to what Steve said, I think it will be extremely difficult if these serotypes are contained in the new vaccines simply to expand the spectrum of serotypes for asking any clean-cut or efficacy data.

Therefore, I think my thinking at this time would be some sort of immunologic data can be substituted to indicate that the serotypes may provide functionally active antibodies which can be translated into possibly clean-cut efficacy.

I think for that, I think it is important to perhaps in this question we can include assays on a sort of equal basis. In previous discussions, questions we talked about ELISA for the, you know, many reasons, for the simplistic reproducibility and so on, but here we may not be able to do that because there's no data to indicate that.

So we may have to include binding as with functional data to indicate that perhaps both in vitro and in vivo -- in vivo means animal model -- to indicate that antibodies produced by these serotypes are at least equivalent to serotypes that are contained in the existing vaccines for magnitude of responses, as well as functionality of those antibodies.

ACTING CHAIRMAN DAUM: And the bottom line is?

DR. KIM: The bottom line is it would be immunologic criteria can be used to assess the sera.

ACTING CHAIRMAN DAUM: Okay. Dr. Griffin, please.

DR. GRIFFIN: Well, I'm not going to be any more definitive, but I guess what I'm struggling with is the practicality versus what you'd really like to have and also what that means downstream if you go from 11 to 15, you know, subsequently and that sort of thing.

And I guess it's really not possible. Any kind of a trial that would get clinical efficacy would be comparing Prevnar to, say, an 11-valent vaccine. So you'd have four serotypes that weren't there. So you'd have that way a placebo controlled trial in a way looking at those.

But those would be so infrequent that you really would not be able to power the study probably to be able to see the clinical efficacy there, certainly for invasive disease. Whether you could for otitis or not, someone else would have to tell me.

So in the U.S. that would be the only kind of study, it seems like, that you could talk about.

Outside the U.S., whether it's still feasible to do placebo controlled trials, perhaps not just because of Helsinki conventions, even though standard of care in other places may not be using Prevnar in the same way that we are. They would still be fairly large trials.

So I think we're probably stuck with the immunologic assays. I would definitely say you'd need function as well as ELISA activity, and I guess I would just like to see built into any of these studies some attempt to get clinical data.

ACTING CHAIRMAN DAUM: And what immunologic criteria, Dr. Griffin?

DR. GRIFFIN: Well, we've only heard about two assays.

ACTING CHAIRMAN DAUM: Right, but we've heard about many different estimates of --

DR. GRIFFIN: So I would want both of them.


ACTING CHAIRMAN DAUM: We've heard many different estimates of protection. I mean, how would you select one serotype? Supposing you added a type 99 and 100 to the vaccine. What immunologic parameter would we use to assess whether they are efficacious?

DR. GRIFFIN: You have no immunological parameter other than comparing them to what you know about the other serotypes unless you set up an efficacy study.


DR. DIAZ: I think you'd have to go with immunologic criteria also, and I agree I would want to see some data on functionality and whether immunologic memory ought to be part of that package deal is debatable, and certainly some level of antibody, although I don't know what that level is currently.

I would feel more comfortable with some clinical data behind it, and yet that would take a huge number unless perhaps there is some population somewhere that that particular serotype was more prevalent in and that data could be accrued.

But that perhaps not occurring, I think we'd be left with immunologic.


DR. KATZ: I'm a little concerned about what things I heard in the closed session versus what's been discussed here. So I'll have to be circumspect in my response except to say I would say, yes, the immunologic criteria would be satisfactory, given some of the numbers we've heard.

However, and I don't know how feasible this is, one of my other jobs is co-chairing the India-U.S. Vaccine Action Program. There are 23 million children a year born in India, and if it were feasible from the pharmaceutical firms' perspective to set up a study, that's a population with more than enough children and with the serotypes that are being added to the vaccine apparently among those responsible for disease.

I wonder if a study couldn't be done through a program such as the so-called VAP, Indian-U.S. Vaccine Action Program, where either with Prevnar as the alternative or with a vaccine, one of the meningococcal vaccines or Hepatitis B or Hepatitis A or any of the other vaccines that would prevent diseases that are common among those children as the alternate.

ACTING CHAIRMAN DAUM: You're arguing for an efficacy trial in a developing country or in a non-U.S.

DR. KATZ: I'm not arguing for it. I'm suggesting it and sort of looking at our pharmaceutical colleagues to wonder if that's something they would consider.

ACTING CHAIRMAN DAUM: Thank you very much.

Dr. Goldberg.

DR. GOLDBERG: I thought we should have an efficacy trial before, and this certainly says to me that we need an efficacy trial.

ACTING CHAIRMAN DAUM: For the novel serotypes?

DR. GOLDBERG: That's right, which if you did a trial compared to Prevnar, that means these 11 valent vaccines would be randomized again. Patients would receive the 11-valent vaccine versus the Prevnar.

ACTING CHAIRMAN DAUM: Okay. Thank you very much.

Dr. Insel.

DR. INSEL: I would go with an immunogenicity trial. I think we know the basis of immunity here, and it's antibody. I think we can learn; we have learned from the Prevnar.

Having said that, then one is forced to say, well, what are those criteria that one's going to use. I think as far as we go back to the ELISA assay, we're going to have to, I believe, set a threshold a little bit differently than what we've set for the vaccine serotypes for which we have efficacy data.

We'd want to set that threshold, I think, higher than what we've done just so we don't err.

I would also ask for functional assays, and I'd ask for proof that we have primed for responses to a polysaccharide vaccine for these serotypes that are not contained in the Prevnar.

DR. WHARTON: Given that the excellent clinical trial that was done pre-ELISA for Prevnar, in fact, did not establish efficacy for all of the serotypes contained in that vaccine, I would not impose that standard on an increased valency vaccine demonstrating efficacy for all of the serotypes in an effectiveness trial.

I'm comfortable going with an immunogenicity study using a preestablished threshold. I agree with Dr. Insel's comments that that threshold needs to be established conservatively.

I'm still very interested in the presentation which I didn't hear at the pneumococcal workshop last month about the BPIG data, and I really wonder what's in there that might have some lessons for us about thresholds for other serotypes of pneumococcal disease.

I also think the issue of priming is important, and I think that's an immunological criteria that could be readily established in a trial.

ACTING CHAIRMAN DAUM: You should know that I looked for you to start off this conversation.

DR. BROOME: I think immunogenicity is the right criteria. I would vote for a margin of error threshold, functional activity and priming.

I would like to make one comment on efficacy studies. I really think the kind of sample size required to do efficacy is extremely large, and you know, I think to advocate an efficacy study should be based on some sort of consideration of what's really involved with that.

I do think when we looked at question one we sort of didn't get back to the point of if nonequivalence is not shown. I mean, I guess we'll pick that up in question four, but I do think when we say nonequivalence is fine, I would assume folks are also going to recognize that just in case they don't meet nonequivalence, it might be a good idea to have the efficacy trial going.

ACTING CHAIRMAN DAUM: I think I heard that in a number of comments people made about question one, but thank you for emphasizing it.

DR. BROOME: But I'm assuming that would not be in the U.S.

ACTING CHAIRMAN DAUM: Correct. Certainly not for a placebo controlled.

Dr. Butler.

DR. BUTLER: I'm struggling with this idea of another efficacy trial. I'm not sure if you meant in the U.S. or not, but -- okay, good. Because if we're talking about specifically for the additional serotypes, the power calculation just becomes ridiculous.

I think the goal with the additional serotypes, the ones that are achievable are to prevent the case of invasive disease caused by those serotypes which are not contained in Prevnar. Another advantage will be less replacement disease in terms of colonization and presumably also acute otitis media.

If we could assume that the safety profile is similar for a newer vaccine and that there's no increased risk of disease, some of the data for the additional two or four serotypes becomes almost irrelevant in that these gains would be icing on the cake if you show noninferiority.

I think ultimately it's going to come down to immunologic criteria. Some of that is going to be based on the epidemiology of the serotype. If I can return to my hypothetical vaccine that fails on the basis of inferiority of immune response to serotype 4, if a candidate vaccine showed a good immune response to serotype 1 in certain populations -- certainly it's true in Alaska -- it may be more attractive.

I'm making the assumption again that we would not be able to identify efficacy. Therefore any correlate of protection would be based either on the Prevnar serotypes or would be nonexistent.

The other immune criteria that I wanted to mention because I haven't heard it mentioned so far is the impact on immunogenicity of co-administered antigens. We've focused primarily on serotype, but the newer vaccines oftentimes have different carriers, and if it reduces immunogenicity of the co-administered Hib antigen or enhances it, those are important considerations as well.

ACTING CHAIRMAN DAUM: Good point. Thank you.

Dr. Hall.

DR. HALL: Well, there's not a lot more to add to this. One of the points I was going to make Jay just made, but I think everybody would like an efficacy trial. To repeat this, it's probably not practical, particularly for invasive disease either in this country or in another country with these serotypes unless there is a country that has the additional serotypes enough to judge the invasive disease.

So that the immunologic criteria, I think, again come up as being probably what we're going to have to go with.

The only thing that I wanted to really add and that you had sort of mentioned, Jay, is that we are, therefore, in an efficacy looking potentially at other associated factors. One of those could possibly be carriage.

Now, that would require that it be used, since we know it's going to be different in different populations, that it might be matched to prevnar in the same population.

Now, I don't know that that's a secondary effect that would be usable, but it's one possibility. Another are the other things such as the effect on antibiotic resistance and other things. And if you put these two vaccines head to head, if these secondary findings come out different, that may influence one, besides the immunologic one that Jay mentioned.

ACTING CHAIRMAN DAUM: Thank you, Dr. Hall.

Dr. Emerson.

DR. EMERSON: I just would concur with the statement that was made earlier that this is really a problem that's been solved before in the sense of the Prevnar case, that we had some that we couldn't demonstrate efficacy for, but the indication still came out with all seven serotypes.

I don't think it very likely that an efficacy trial is really worthwhile to try to establish efficacy against one of the rarer serotypes, and therefore, my side would come down as I would have wanted to see a trial that was demonstrating efficacy on overall pneumococcal invasive disease, and then just commenting on the immunologic profile against the serotypes and not really trying to claim that you have prevented that or not.

Certainly in this immunologic profile, however, I think the data should be gathered as to whether there was any sort of invasive disease breakthrough, and I don't care what the immunologic profile is. If it's not backed up with prevention of those particular serotypes, that is to say if you get some serotype breakthrough, I would not give the indication in that situation.

ACTING CHAIRMAN DAUM: Thank you very much.

Dr. McInnes.

DR. McINNES: I'm thinking about this in two ways, one of which is additional serotype to the already licensed serotypes, and then a new conjugate vaccine that may contain additional serotypes, and those two scenarios may play out differently in that the new vaccine may go through an efficacy trial, and I'm going to learn from that, and I don't know what's going to come to the table first.

But it strikes me that pragmatism has to play a role here, and you're going to look at additional -- you have a core group of serotypes fitting the existing vaccine selected on epidemiologic basis largely as the most important serotypes.

We have the sort of second tier now that we think are important, and we'd like to see included, and practically speaking, the manufacturers, I think, are going to want to be dealing with those concentrations that are very close to the individual serotypes that are already in the vaccine.

So let's assume you have two micrograms of A, B, C, D, E, F, and I'm now wanting to add G. So I pragmatically go and I say I'm going to have two micrograms of that, and I do some immunogenicity, and it looks pretty good or I don't get anything.

So what choice do I have? I can up the ante on the dose concentration of the new antigen that I put in, and essentially I get what I get in terms of immunogenicity data.

If the bar is very high, I now have to weigh whether I'm going to continue to putz around on antigen G or whether I'm just going to forget about it. I've not had it in my vaccine.

So I think we have to be pragmatic about the bar we're setting for the addition of new serotypes unless there becomes some compelling reason to understand that that bar set very high is very important for safety purposes or efficacy purposes, and to some extent, you know, to guess is cheap and to guess wrong is very expensive.

I'm heading towards trying to embrace the concept of an aggregate bar thinking about additional serotypes, and I think of it differently than a vaccine that has gone through an efficacy trial in the serotypes contained in that particular vaccine.

So I'm embracing the concept of immunogenicity being used and being valid. I'm vacillating about the standard that I would set for those particular serotypes, and I think pragmatism has to play in. Otherwise the incentive to add additional serotypes if problematic.

ACTING CHAIRMAN DAUM: Thank you. You made a couple of points that haven't really been addressed before.

Dr. Decker.

DR. DECKER: I think the circumstance that we're discussing here is that we've got a vaccine that has presumptively already met whatever criteria we end up requiring or FDA ends up requiring with respect to question one, and what we're now addressing is the marginal criteria that apply to these additional contained serotypes.

And given that that's what we're discussing, then I agree entirely with Dr. Insel that this should be serologic. If we were to require a demonstration of efficacy for those marginal serotypes, we would basically be precluding licensure of a vaccine line this in the United States. There would be no point in bringing it forward. There's no economic or competitive reason to do that in the United States. Therefore, it won't happen. It will simply be licensed overseas.

And the seventh serotype will be licensed here. Now, I see no benefit in denying U.S. kids those additional serotypes, and so I feel strongly that we need to have an immunologic criterion for licensing these additional serotypes.

In that regard, the approach indicated in the FDA's presentation, slide eight, the maximal difference of GMC which showed the RCDs for the immunized and the unimmunized kids and developed the point where there was the maximal difference. I think that's a sound approach. It was endorsed pretty thoroughly at the meeting on the 26th, and although there's been some slight discussion over what's the appropriate number to use -- .18, .30 I've heard discussed -- that's a technical issue to be decided. The basic approach, I think is solid.

The question then becomes: how do you do this for these serotypes that weren't in the -- for which we don't have efficacy data that were not in Prevnar in this study?

I think you simply take your best number, and you apply it to these other serotypes, which in essence is what was done for the other three serotypes and Prevnar, and you proceed on that basis.


Before I comment, I actually have a question that I hope the manufacturer, Wyeth, can update us on.

There is, is there not, a trial going on now in South Africa with a more than seven-valent vaccine? Can someone in just one or two sentences say what that is and where it's at?

DR. WATSON: Wendy Watson, Wyeth.

Yeah, there is a trial going on in South Africa with a nine-valent vaccine. It has the seven serotypes from Prevnar, as well as a one in five as being compared to placebo.

We finished the enrolling subjects in September of this year. We're in surveillance. So we expect to have more data by a year from next September.

ACTING CHAIRMAN DAUM: Endpoints are invasive disease, Wendy?

DR. WATSON: Right. That's the primary endpoint, yes.

ACTING CHAIRMAN DAUM: What about otitis?

DR. WATSON: No, no otitis. This is Soweto, South Africa. So we're looking at HIV and HIV infected and uninfected subjects.

I will say that while there are more serotype 1 disease and 5 disease in the African continent, we're not going to -- we won't have enough cases to look at those individual serotypes. So I think even in this, I think this highlights the serotype specific efficacy is very difficult to capture.

DR. GRIFFIN: How large is that trial?

DR. WATSON: Forty thousand.

ACTING CHAIRMAN DAUM: Okay. Well, thank you very much for everybody's comments.

Dr. Goldberg, did you want to in one sentence clarify?

DR. GOLDBERG: Yeah, I just wanted to clarify. When I said efficacy trial, I was thinking in terms of a trial such as the one that was described here, not another trial within seven and seven.


So I also share the theoretical ambitions of several of the committee members in that I would really love to see efficacy data for new serotypes that are added to this vaccine, and I'm sure if Ms. Fisher were here she would say that , you know, you just can't start using the stuff if you don't know that it works.

And she's right, even though she didn't say it. On the other hand, we do have a special situation here. I mean, I guess I'm putting a lot of weight on the fact that we know that anticapsular antibody works for protection against other pneumococcal serotypes, and so we're going to close our eyes and take a leap into the pool and say, "Well, it will work against these new pneumococcal serotypes as well."

But they're not easy questions, and I think the efficacy trials are expensive probably beyond the means that society is willing to pay to do them.

There is enough data to suggest that it's likely that antibody to the capsule will be protective, and I guess it's a question of deciding how much. And I would urge that the approach be a conservative one, and I've heard several good ideas today. I don't know which is the best.

One is this RCD approach that Michael reminded us of. Another is using one of the lower GMC estimates in the existing trial. I have some issues of vaccine antigen interference to think about as we add serotypes to the vaccine, and I would hope that they'd be part of a consideration for a larger vaccine.

And that is to say as we go to eight or nine or ten or 15 or 90, will there be interference with the response of the seven that we have, and we haven't mentioned that much, but I think that it's an issue for a bridging trial of some sort.

I'm also concerned about antibody to the carrier and potentially some suppression based on cranking up the levels in a many, many valent conjugate vaccine, very high. And I think that can be dealt with, but I think it needs to be part of a trial, a serologic trial to establish going forward with this.

I also think that Dr. Butler's point is a crucial one, and that is that we need to consider the other vaccine antigens that are scheduled for simultaneous admission -- excuse me -- administration, and make sure that there's not interference in that regard.

I think the issues that people spoke of of wanting to see priming, of wanting to make sure that antibody that's generated is functional are very important and need to be done.

I'm with Dr. Hall on the importance of carriage in these studies. I don't know quite how to set up a bar that a vaccine would have to jump through. I think there isn't any to set up for a licensure prerequisite, but I would like to see it part of a study because I believe it's a very important part of how Hib vaccines work and protect our children and our population.

So with that having been said, I'd like to go on to number three, and I'm mindful of the fact that people need to go, and I'd like to try and get some discussion on all of these questions as quickly as we can.

Number three is invasive disease efficacy study may be performed in a non-U.S. population with a new vaccine, and there's two parts to this. If efficacy is demonstrated, could data derived be used to support licensure of the vaccine in this country?

And then if the answer to that is yes, what are the immunologic parameters that should be used to establish comparability to Prevnar in a U.S. bridging study?

I'm going to this time ask Dr. Broome to start and Dr. Emerson to go next, and if someone else who has to leave signals me that they need to go, we'll put them up next, and then we'll go around the table.

Dr. Broome.

DR. BROOME: Well, I mean, I think that there will hopefully be data from efficacy trials outside of the U.S., as we've heard, from South Africa and others. And I think that we would be remiss not to pay attention to that data as we wrestle with the issues related to licensure of the vaccine in the U.S.

And I think this whole issue of how do you bridge is quite complex as we've heard with the different responses in different populations.

But I think that reasonably sized bridging immunogenicity studies should make it possible to look at presumably primarily ELISA responses in the two populations and let you learn something.

I think one of the issues that's going to be very important is I think Prevnar is obviously highly efficacious as we've seen with H. flu. conjugates. You know, how much is enough?

It may well be that -- I think the thing that will be tough is if we have something where there is a nonequivalence with Prevnar, but you do have efficacy data in another setting. I think there'll be need for a lot of judgment, but I think it's reasonable to take a look at that and see that as an alternate route for licensure.

ACTING CHAIRMAN DAUM: Would such a trial be compared to Prevnar or would it be placebo controlled?

DR. BROOME: Do you mean the bridging?

ACTING CHAIRMAN DAUM: No, the efficacy.

DR. BROOME: The efficacy studies. Well, many of the ones that I'm familiar with were started before Prevnar was a licensed product, and so they're using other kinds of active control vaccines, but not a pneumococcal vaccine control.

I was toying with whether you'd like to do the bridging immunogenicity studies with a Prevnar arm in both countries so that you'd have that additional two data points.

ACTING CHAIRMAN DAUM: Would make interpretation a little easier, wouldn't it?

Thank you.

Dr. Emerson.

DR. EMERSON: I think certainly it would have to be allowable as support, and the question is how compelling support would be there. I would think with the serotypes that are covered in Prevnar, I think the standards for the immunologic picture would have to hold sway, and the issue would be safety.

I guess I would imagine that this would come up more with the idea of adding new serotypes, and then the preeminent question in my mind would just be is it safe to add those additional serotypes, and looking at the safety profile, making certain that adding those serotypes didn't alter the primary ones that are already in Prevnar and immunologic standards if that's what's being adopted for addition of other new vaccines. You'd have to make certain that it passed those hurdles here.

ACTING CHAIRMAN DAUM: Well, it may not involve adding new serotypes. I mean, for example, supposing Company X wanted to get some data about the performance of their vaccine and it was a seven-valent vaccine and so they decided to take it to "Southwestia" and conduct a clinical trial.

The question really is once that trial was established, would you accept the news that that vaccine is efficacious as appropriate for U.S. licensure.

DR. EMERSON: Well, I think with the data that's been presented on the question of how generalizable the immunogenicity is of these serotypes, my answer would be no, and with the decisions that have been made beforehand, it's saying that it's unlikely that we'll have evidence on the correlates to be able to do anything more than just apply our standards for a new vaccine.

ACTING CHAIRMAN DAUM: Thank you very much.

I think now we'll go our conventional route and come to Richard and then go up the side here and swing around.

DR. INSEL: Not much to add except the bridging and immunogenicity studies will be required. Some of the issues that can arise obviously are the issues of colonization and priming that's occurring at another locale outside the United States versus what's going on in the United States and what this would add to as far as enhancing immunogenicity.

So I think as long as we have immunogenicity bridging trials, and I think Claire's idea of doing them in both settings, I think we'd be reassured that we're on the right pathway.

ACTING CHAIRMAN DAUM: Thank you very much.

Dr. Wharton.

DR. WHARTON: Yeah, I would support such data. I would accept such data in support of licensure, and I really like the idea of doing a Prevnar-new vaccine bridging study in that country as part of the bridging assessment.


DR. BUTLER: I have little to add on this topic. I think it's hard to make broad statements. Clearly there are differences in the epidemiology, probably differences in the immune responses to the vaccine.

The joke we sometimes throw around is everything works in Finland.


DR. BUTLER: And there's some truth to that. Some of that is driven by socioeconomic factors, of course. So I think it would be wrong to ignore data from non-U.S. trials.

At the same time, the Gambia would be very hard to apply to an HMO population in the U.S. So I think it's really going to be on a case-by-case basis.

ACTING CHAIRMAN DAUM: But as a generic concept, if the study were performed and efficacy was demonstrated, you would agree or disagree with the fact that data derived from such a trial could support licensure in this country?

DR. BUTLER: I would agree that it could support.


Dr. Hall.

DR. HALL: I would also agree that it could support it. Indeed, in some instances, depending on the country, it may actually show more efficacy, if I may say so, in that particular country. It may have been more difficult to get a response.

I think the second -- the immunologic criteria that could be used or should be used as mentioned would be further supported if we did have the comparable data in that country on the Prevnar.

ACTING CHAIRMAN DAUM: Yeah. That strikes me as a very clever idea actually to solve that problem.

Dr. McInnes.

DR. McINNES: I have nothing to add. I accept the efficacy trial, but I don't see any reason not to, and the bridging study as all have previously described in question one.


DR. DECKER: A, absolutely in principle, but the devil is in the details, and some of them have been brought up.

The one thing I don't recall having heard mentioned is that I think it is my suspicion the committee would end up requiring serotype specific efficacy. That is to say if a study were done in a country in which the serotype distribution were marked different from the United States, and if overall efficacy was demonstrated, there would be concern that that efficacy was predominantly against serotypes not prevalent here.

We would want to see that there was efficacy against the serotypes that circulate here. So I suspect that that would be a hidden question here, that companies interested in doing studies overseas had better be alert to.

The other consideration is that, of course, there has to be the bridging data, and it would be impossible to interpret those bridging data unless, as others have said, there was a Prevnar versus candidate both in the other country and in the U.S. to enable us to set up ratios.

ACTING CHAIRMAN DAUM: Thank you very much.

Dr. Kohl, you're on.

DR. KOHL: I basically agree with everything that's been said, but it comes back to an issue that Dr. McInnes raised. What will we do if we have a vaccine that has really super efficacy in Country Z and then we have a bridging study which we won't even need the efficacy study if the bridging study shows high immunogenicity in this country because we've already said immunogenicity alone is going to be okay for licensure.

But what do we do with this vaccine which has wonderful efficacy, but has poor immunogenicity in the bridge? What would this committee do?

It protects super against type Q, but it doesn't make antibody, but it's not likely, but that's what we're talking about, and that's the issue that Dr. McInnes raise.

DR. DECKER: But I think the two arm bridging study in each country answers that because you'll take the ratios.

DR. KOHL: Okay. So if it doesn't make antibody in Country Z and it doesn't make antibody --

DR. DECKER: And it equally doesn't make it here.

DR. KOHL: Right.

DR. DECKER: Then you're okay.

DR. KOHL: Then we'll license it?


DR. KOHL: Even though type 6 is very common in this country? I think we'd have trouble with that.

DR. DECKER: Well, no, you might be type specific, but if the ratio of antibodies --

DR. KOHL: Type 6 is a common type in this country, right? It protects against type 6 in whatever country they've tested it in, but for some reason it doesn't make antibody or has a different kinetics of antibody and we don't see it after dose three or something crazy, and the same thing happens here, protective, but nonimmunogenic. I doubt that that's going to happen, but it's something to think about.

Because if it makes antibody well, then we don't need the efficacy study. We've already said that all you need is immunogenicity. So we're talking about something that doesn't make antibody well.

ACTING CHAIRMAN DAUM: On the other hand, efficacy is gold.

DR. GRIFFIN: Efficacy trumps.

DR. KOHL: Seriously. No antibody and you'll take efficacy.

ACTING CHAIRMAN DAUM: Efficacy is gold.

Dr. Kim.

DR. KIM: Well, I think if the efficacy is there, then it is likely that it could have immunogenicity data supporting efficacy, and if the new vaccine contains serotypes that are contained in Prevnar, then I guess certainly, you know, you can look at efficacy and immunogenicity data of those serotypes that are contained in Prevnar, which certainly would be the basis for transporting the data directly to the U.S.


Dr. Griffin.

DR. GRIFFIN: I think we should definitely accept support data that's collected outside of the U.S. could be very helpful, and that bridging would be immunologic bridge for comparability of antibody.

DR. DIAZ: I likewise feel that any clinical data, efficacy data from outside the U.S. could be very helpful, and in fact, although we've already said that noninferiority studies would be sufficient in this country or in comparable populations, I still have the caveat of saying that I would feel more comfortable with some efficacy data. I mean, it would add to obviously and be supportive of and perhaps supersede those noninferiority kinds of studies.

That already being said, I think you have to be very careful what population is chosen outside the U.S., and the bridging studies obviously would be very important.

I hope, and I would expect that we'll be back in this room probably discussing all of the nuances of every outlying vaccine or serotype issue that comes up down the line. I would hope though that when we're back in this room discussing that that we have more information on protectiveness and more information on the immune response.

And certainly having more monies and attention directed in that area is extremely critical, I think, at this time.

ACTING CHAIRMAN DAUM: And then Dr. Katz. Dr. Katz?

DR. KATZ: Dr. Katz was having his four o'clock drowsy spell.

ACTING CHAIRMAN DAUM: Fair enough. I understand the feeling.


DR. KATZ: I'd be very happy --

ACTING CHAIRMAN DAUM: We're here in the Versailles Room, and we're talking about --

DR. KATZ: No, no.


DR. KATZ: I think that if an efficacy study is feasible in a non-U.S. population, it could be done, but I don't think it should be a criterion before licensure. It might be a Phase 4 rather than a Phase 3, and I do think that efficacy demonstrated elsewhere could be bridged to the United States, given that these are unusual serotypes and we don't know what may happen with nasopharyngeal carriage and the emergence of other serotypes. I think it would be worthy to have them licensed in the United States.

And, again, I would use the same immunological parameters that we used for question two.


Dr. Goldberg.

DR. GOLDBERG: Yes, you can use the data in the U.S. I would have a Prevnar arm, and I would use that in the bridging.

ACTING CHAIRMAN DAUM: And I would end by agreeing totally that of course they're useful. Efficacy is gold, and whether it makes antibody or not, I mean, if you've got demonstrated efficacy in a carefully done trial, it works.

and then I would like to have it bridged to American kids, and I think Claire's idea of having Prevnar in the trial to help with the bridging is superb, and I would encourage anybody, any company that wants to conduct such a trial in a developing country, that we'd be very interested in hearing the results.

Let's move on to question four and try to race for the finish line here. We'll put it on the screen.

Please discuss if data demonstrating clinical efficacy against acute otitis media for a new pneumococcal conjugate vaccine can also be used to infer efficacy against invasive disease.

And this is not an easy question. Dr. Kohl, would you like to start answering it?

DR. KOHL: I did so well on the last one.

I don't think it can. I think most likely otitis media is a stronger challenge than invasive immunologically, but I'm reluctant to say that otitis media data can be used to license an invasive pneumococcal indication.


DR. KIM: Well, based on the information provided to us today, I'm not sure that we'd be able to say that efficacy data for otitis media can be directly translated into that against invasive disease.

Also, it is an interesting idea. Certainly I think it needs to be further explored.

DR. GRIFFIN: Well, I think this is a question on which intuitively I would say yes, that it's highly likely that it's going to be predictive. I think it's a question though that we're going to have more data on as time goes on from data analysis of trials that have been completed, and so we might have a stronger leg to stand on.

But if it's an antibody mediated process, then it probably requires more -- we've already heard that it probably requires more antibody at least in animal models, more antibody in order to accomplish this task.

But then you would anticipate that you would also be protecting against invasive disease.

ACTING CHAIRMAN DAUM: Thank you very much.

Dr. Diaz.

DR. DIAZ: I would say de novo that, no, it cannot be used for criteria for invasive pneumococcal disease efficacy, although I guess there are other caveats to that. If we're dealing with a vaccine that has the same serotypes as Prevnar and we're looking at, as an example, noninferiority for licensure for noninvasive disease, having data on efficacy for acute otitis media would be very supportive in my mind because I would have efficacy against at least some component of disease caused by those serotypes.

So although I don't believe for, as an example, a new serotype additional serotypes that are not in Prevnar to be able to use efficacy for otitis media to bridge to invasive disease, I disagree strongly. But I do think date about otitis media can be very supportive in looking at licensure of products for invasive disease with comparable serotypes to Prevnar.


DR. KATZ: I'm sorry Dr. Giebink had to leave because I was impressed with his comment from his chinchilla model, but the antibody data to prevent otitis were higher than those to prevent invasive disease. I would like to see that extrapolated further, obviously into human populations, and I would have to agree that otitis data alone would not be sufficient to infer efficacy against invasive pneumococcal disease, but would be very, very prejudicial towards it.

DR. GOLDBERG: I believe that you can use the same trial and define a series of endpoints that would cover invasive pneumococcal disease, acute otitis media, and the other endpoints that were observed, the other failures that were observed, in fact, in the Kaiser trial, and if you develop such a combined endpoint, the package together would let you address this issue.

ACTING CHAIRMAN DAUM: But that's not the question.

DR. GOLDBERG: It would need direct support. I think it depends on how you define your endpoints in however you define the otitis media trial

ACTING CHAIRMAN DAUM: Let me pose a question to you.


ACTING CHAIRMAN DAUM: Maybe this will help. If a trial is done and shows protection -- let's leave the number out.

DR. GOLDBERG: For otitis media?

ACTING CHAIRMAN DAUM: Against otitis. Would you agree or disagree that you could now --

DR. GOLDBERG: It would provide very strong support.

ACTING CHAIRMAN DAUM: Would you agree that it protected against invasive disease based just on those data or --

DR. GOLDBERG: Not necessarily.


DR. GOLDBERG: It probably wouldn't be large enough.

ACTING CHAIRMAN DAUM: We need that answer from you for this question. thank you.

Dr. Insel.

DR. INSEL: I have mixed feelings. On one hand, I can take the Giebink and Sam Katz model. You need more antibody in there. You've raised the bar higher, and if you can protect against otitis, that's great. It's likely then you'll protect against invasive disease, which would require less antibody.

On the other hand, I'm not sure if it's the same type of organisms that cause otitis media that cause invasive disease. That is, is it the organisms that have the ability to colonize for long periods of time that then you develop a viral otitis that then causes secondary bacterial otitis versus the organisms that you become exposed to and invade without even a period of colonization because they're different? They have differences.

And would this translate even into differences as far as capsular polysaccharide expression on their surface, susceptibility to opsonic antibody?

So from the standpoint of pathogenesis, I just throw that back out. I'd like to know a little bit more about the strings that are causing otitis media versus invasive disease, and how often do you see invasive disease occurring even after otitis and vice versa?

ACTING CHAIRMAN DAUM: Dr. Insel, I think you raised some very important points. I'd like to hear from the rest of the group.

DR. BUTLER: I would say no basically for the same reason. I think epidemiologically otitis media and invasive pneumococcal disease are distinct entities that just cannot be viewed as part of one spectrum.

Additionally, I find Dr. Giebink's data very interesting. I guess I'm still not convinced that the mechanisms of protection are similar enough to be comfortable with that either; that the role of mucosal immunity may be significant.

ACTING CHAIRMAN DAUM: Thank you very much.

Dr. Hall.

DR. HALL: I would agree that overall I would not accept it as efficacy against invasive pneumococcal. The antibody being higher is a good argument that it may be, but we don't know that, but the variability is too great with otitis media for, as mentioned before, local and other factors.

I did wonder though. It hasn't really been brought up, but I would accept more, say, the efficacy against pneumonia if that could be done, which brings up the question of the technical aspect of diagnosing pneumonia in this age group.

But if these tests were available or being worked on, then that may be another consideration.


DR. McINNES: I have nothing to add to my three learned colleagues on this side of the table.


Not least.

DR. DECKER: I consider this question largely moot. If we said previously that you can license a seven-valent analogous to Prevnar on the basis of comparable immunogenicity however defined, and if you can license additional serotypes based on comparable immunogenicity however defined, then it's hard to imagine a study design that will get you to those points, that will get you to this without having gotten you to those points.

So the only issue, the only circumstances where this question remains relevant is where you have a vaccine that is protective without being comparably immunogenic, the situation we discussed a little earlier.

So that is a very small area where you're now applying this. In that circumstance, then I would have to say no. The demonstration, as my colleagues have already said, the demonstration of efficacy -- you can't demonstrate comparable immunogenicity and all you can show is efficacy against otitis. Then you haven't crossed a high enough bar.

ACTING CHAIRMAN DAUM: Thank you very much.

I will make the last comment, and that is that mootness of the question aside, I agree with what most people are saying, that this bridge cannot be made yet between otitis media efficacy and invasive disease.

I must say that I'm very struck by the trial done in Finland and the one done in Northern California. If you really look at the vaccine serotype otitis, the numbers are the same. I think they're trying to tell us a true thing about the ability of the current version of Prevnar and its ability to prevent otitis media caused by serotypes in the vaccine strain.

I think it's true. Why is it only 50 percent though? I've heard some ideas, but I don't think we really know why it's only 50 percent, and in part it's because we don't know the mechanism of protection by antibody against otitis media. There's lots and lots of missing information.

Having the sera that Dr. Siber told us will come soon from the failure patients may provide a clue. Looking at issues like the overall disease burden where in Finland it wasn't dramatically reduced as one might hope despite the 50 percent efficacy is another issue.

Does serotype replacement or some other kind of replacement fill in for the otitis media that the child is going to get anyway if we interfere with his pharyngeal carriage by having high titer vaccine?

Lots of questions here, and not a lot of light. I'm not ready to make this leap yet. I need a lot more information.

Someone, Dr. Hall I think, raised the question about a pneumonia study, and I think there are some issues there as well, as to whether the pneumonia can be read off the invasive disease model, but I'd feel a lot more comfortable trying to make that leap than I would from the middle ear to the blood stream.

You know, if we prevent bacteremia, we expect to see the incidence of invasive disease go down, and if we prevent otitis media due to serotypes that are in the vaccine, we may or may not see the disease burden go down, and I think there's a lot more to understand here about pathogenesis and protection.

So I would not be comfortable making this bridge, and that's that.

We're at the close of our business today, which is good news for people with airplanes to make, but the committee will, of course, be trotted out one more time tomorrow morning for a final session. We will work through as efficiently as we can, but we will start at eight o'clock.

Thank you, and we need everybody here until the end because if there's no quorum, we can't do our business. So please don't go. Come tomorrow.

(Whereupon, at 4:14 p.m., the Advisory Committee meeting was adjourned, to reconvene at 8:00 a.m., Friday, March 9, 2001.)