TRANSCRIPT:

      Discussion: Infanrix DTPa - HepB - IPV  from SmithKline Beecham
Biologicals
      MS. LOE FISHER:  How long did you monitor children for persistence of antibodies to all antigens in the combination vaccine versus the separate injection controls to confirm long-term immunity?
      And how long did you monitor children which had acute reactions,particularly the more serious reactions, for development of autoimmune neurological or behavioral disorders following the 30 day acute observation period?
      DR. KAHN:  Dr. Barbara Howe.
      DR. HOWE:  So with respect to persistence of immunity we followed infants, after the three dose primary series up until the time of the booster in a number of the trials.       We have data with us in the context of persistence and boosting data. In the U.S. studies that included up to a mean age of 14 months, that is in study 015, we followed the children out until mean age of 14 months and administered a booster dose of, actually, separate injection DTPa and Hib. So Infanrix and U.S.-licensed Hib vaccine.  And in study 044, which was the consistency study, we followed children out to a mean age of 16 months, and administered booster doses there.  And I do have data to show that persistence was comparable in those who received the combination vaccine at 2, 4, 6, out to the mean age of 14 months as to those who had received separate administration of the U.S.-licensed products out to the mean age of 14 months.
      MS. LOE FISHER:  For hepatitis B too?
      DR. HOWE:  Yes.
      MS. LOE FISHER:  And then the reactions?
      DR. HOWE:  In terms of the reactogenicity and the safety data children were followed up until 30 days after the last dose of vaccine. Some of these children would have gone on to be included in booster trials as well, but not all of the children.
      MS. LOE FISHER:  So you don't know what happened to those children after 30 days?
      DR. HOWE:  Unless they were subsequently in booster trials.
MS. LOE FISHER:  I'm interested in the -- getting more information about the two seizure cases.  One was, I think, in the adverse event category of febrile seizure, which was then determined to be caused by an underlying seizure disorder, the other was a death that had the cause of death listed as an underlying seizure disorder.
      Was this the same patient, and what determination was made that the seizure, was this the first time that the seizure had occurred following the vaccination, had there been pre-existing seizures?  And what was the determination, how did you determine that they were not connected to the vaccine?  And I have the same question on the deaths.Because you had five deaths in the combination group and only one death in the controls. That seems pretty significant to me, and what determination was made that those deaths were not, indeed, in some way connected with the combination vaccine?

DR. KAUFHOLD:  You are right, there were five deaths in the group that received the combination vaccines.  That includes all trials that are contained in the BLA, and one death in the comparative vaccine. If you now look at the denominator you can, and the denominators between those two groups are, obviously, very different.  So if you compare the percentages the figures are virtually identical. Perhaps we can have another look at the slide that lists all the deaths, perhaps that went too fast. Altogether there were three cases of sudden infant death syndrome, the next one please, three cases of sudden infant death syndrome.  I highlighted in my presentation, in the comparative study 011 there was one case, in the group that has received the candidate vaccine and one case in the group that received separately administered licensed vaccines.  Then there was one case of neuroblastoma, and one case of congenital immunodeficiency.  And if you will read the narratives, we -- one can support only the conclusion of the investigator that stated that these cases are certainly unrelated to vaccination.  With regard to your question regarding convulsive disorder, yes, there were altogether two febrile convulsive disorders in study 011.  And one occurred after four days post-vaccination, and the other case occurred more than two weeks post-vaccination.  The case with the febrile seizure is the same, that was diagnosed to have an underlying convulsive disorder, and this child died later on.
      MS. LOE FISHER:  So it was the same patient?
      DR. KAUFHOLD:  It was the same patient.
     MS. LOE FISHER:  Earlier  when I asked the manufacturer about seizures in this study, it was my understanding that there was one febrile seizure, and it was judged to be due -- the child had an underlying seizure disorder and resulted in the death. You mentioned, it went by so fast, but seven seizures, five of which were afebrile.  Now, what is it, one seizure, seven seizures, how many seizures?
      DR. BALL:  I think it should be clarified.  I think what was referred to was the two seizures that occurred within the seven day time frame after vaccination. The first slide that I presented, I'm sorry, I can't pull that out for you right at the moment, referred to seizures that occurred during the whole vaccination course. It could have occurred six weeks later, you know, three weeks later after the vaccination.
      MS. LOE FISHER:  I really think we should have more information about the seizure picture, particularly the afebrile seizures.
      DR. BALL:  I'm sorry, what more information would you like?
      MS. LOE FISHER:  How soon after did these occur, was it the first time that it occurred in the child, did the child have a pre-existing seizure history, some more information about seizures.  And I have one more question, and then I won't ask another question.
      CHAIRMAN DAUM:  Well, before you go on to another question, is this information available?
      DR. BALL:  I think it is available, but I think the manufacturer could probably clarify or expand on the information that I have at the tip of my fingers, which is that seizures were evaluated over the full study course, and that was the first slide on the serious AEs that I presented. In addition seizures were presented, also, within seven days of vaccination.  There were two episodes of seizures within the seven day time frame.  And I think that perhaps the manufacturer would want to clarify further regarding the timing after vaccination, and whether or not there was an underlying condition.

      I think that infants -- my understanding was that pre-existing conditions, pre-existing seizure disorders would have kept the children out of this study.

      MS. LOE FISHER:  Just one other one.  Nearly 5,000 of the 7,000 children came from Germany, which unlike the U.S. has a generally homogenous population with respect to genetic diversity.  And also the German children began their vaccinations at 12 weeks,rather than 8 weeks.  Can you comment on the possible significance of this, when we apply this vaccine to the U.S. population?
      DR. BALL:  Certainly.  I think that that was something that we looked at very closely, and with regard to the timing of immunization I think that the manufacturer may be able to bring up a slide. It is in my briefing material that was presented to you that looked at the timing of each dose, and the overlap between the different doses.   And there was significant overlap, particularly for the second, and somewhat the third dose.  The timing, certainly for the third dose was delayed between the infants in Germany versus the infants in the U.S.  So the question that we could readily answer is whether or not the incidence of fever, which I think we've sort of identified as one of the key focal points, did the incidence of fever differ whether the vaccines were given at 2, 4, and 6 months of age, versus 3, 4, and 5 months of age.

      I think where this becomes clinically relevant, particularly to parents, and physicians who care for infants, is whether or not that fever that would occur maybe in a 6 week old to a 2 month old, would translate to more hospitalizations, sepsis workups and so on, than perhaps if the immunization is given at 3 months of age.

      And I did show a slide that compared the rate of fever between the two schedules, 2, 4, and 6, and 3, 4 and 5, and the rate of any fever was remarkably similar between the two groups.
      MS. LOE FISHER:  It also could have an effect on death, and seizures, etcetera.  I mean, the 8 weeks versus the 12 weeks starting.
      DR. BALL:  Do you mean in terms of the occurrence of febrile seizures?
      MS. LOE FISHER:  Or afebrile.  In other words, the one month difference is going to have an impact, could potentially have an impact, both on immunogenicity as well as reactions.
      Just because 5,000, almost 5,000 of the 7,000 children came from Germany, and had the schedule, and were not genetically diverse like we are, I think is an important point to --
      DR. BALL:  I acknowledge that point, and I think that we looked at that as well.
      MS. LOE FISHER:  Thank you.
      CHAIRMAN DAUM:  Thank you, Dr. Kohl.  I didn't see other hands up. And so I'm going to ask to have the first question put up on the board again and begin a discussion about this first question and that is to say that the, this is a voting question.  It's the only voting question for the afternoon. And it concerns efficacy.

      Are the available data adequate to support efficacy of this combination vaccine when given to infants in a 2, 4, 6 regimen.  So I'd like to have discussion about this question and then after we get a sense of people's opinions and where we're going, we'll have a vote about this question.  Comments?  Ms. Fisher. + Transcript continues at:
http://www.fda.gov/ohrms/dockets/ac/01/transcripts/3733t1.rtf