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UNITED WAY/COMBINED FEDERAL CAMPAIGN

#9119

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"Protecting the health and informed consent rights of children since 1982."

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* March 2001 FDA Meeting Transcript - 5 in 1 vaccine

* New York Times - NVIC quoted

NVIC Note: The following excerpt is from the March 2001 meeting of the FDA licensing committee. This is a discussion on the 5 in 1 vaccine that was licensed this week. Barbara Loe Fisher is the consumer voting member at this meeting.

Excerpts from:

UNITED STATES OF AMERICA

FOOD AND DRUG ADMINISTRATION

CENTER FOR BIOLOGICS EVALUATION AND RESEARCH

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VACCINES AND RELATED BIOLOGICAL PRODUCTS

ADVISORY COMMITTEE

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MEETING

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WEDNESDAY, MARCH 7, 2001

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.

MS. LOE FISHER: I'll just do my comments and my vote at the same time, if that's all right. I mean I only have to speak once then.

CHAIRMAN DAUM: It's --

MS. LOE FISHER: Save time.

CHAIRMAN DAUM: Economy is a good thing.

MS. LOE FISHER: My answer is no. That there needs to be a larger trial of this new combination vaccine in the U.S., in genetically diverse populations, with a 2, 4, and 6 month schedule.

And with a longer follow-up period than fourteen months to assure long-term immunogenicity with all antigens, particularly pertussis and hepatitis B. As well as an attempt to characterize the mechanisms for achieving immunity at the cellular level. MS. LOE FISHER: Is it too late to ask the manufacturer a question?

CHAIRMAN DAUM: No, I don't think so. As it pertains to the statement on the screen.

MS. LOE FISHER: Yes.

CHAIRMAN DAUM: No, please, go ahead.

MS. LOE FISHER: During the trials, after which adverse events did you discontinue vaccinating with the combination vaccine and was the same criteria used in control arms?

And the second part of that question is, when a vaccine adverse event occurs with the combination vaccine, do you have any idea which component is responsible, which of course is relevant in terms of contraindications to continue vaccination after an adverse event occurs?

CHAIRMAN DAUM: Thank you, Dr. Howe?

DR. HOWE: Let me just make sure I understand your first question. You're asking in the context of the clinical trial for what type of adverse event would you intentionally discontinue vaccinating the child?

MS. LOE FISHER: Did you discontinue? Did you decide you were not going continue to vaccinate? They dropped out, then?

DR. HOWE: In the clinical trials, the typical type of precautions for further vaccination were specified in the protocol, which means hypersensitivity reactions, allergic reactions to any previous dose.

The precautions to DTP-whole cell, which apply to DTPa as well would also be precautions to further vaccination and those children could have been withdrawn. But other than that, there were no other mandates for withdrawing or discontinuing a child from continuing in the trial. The usual practice.

MS. LOE FISHER: Well, I want to be real specific about this. I think it's important in terms of the outcome of the trial. So, children in the trial who had high fevers, over 103, over 105?

DR. HOWE: It is 40.5, I believe.

MS. LOE FISHER: Children who had high pitched screaming or unusual crying?

DR. HOWE: Yes. Seizures.

MS. LOE FISHER: What about seizures? What about restlessness?

DR. HOWE: No.

MS. LOE FISHER: So it was basically three things. It would have been --

DR. HOWE: As well anaphylaxis, obviously to the previous dose.

MS. LOE FISHER: Anaphylaxis, but you didn't have that in there.

DR. HOWE: Right.

MS. LOE FISHER: And then, do you have, did you have any idea which component was involved and what would you consider a contraindication? Would it just be those three reactions?

DR. HOWE: I mean the contra, first of all we wouldn't know in a combination vaccine exactly which component would be causing an adverse event. However, if there was an adverse event explained or reasonably associated with a component of the vaccine based on historical data, such as for pertussis, one might presume that an AE such as that would be related to that component. But we don't really know when an AE occurs which component to attribute it to.

MS. LOE FISHER: So with the combo you'd basically want to, if an event occurred, you'd have to not vaccinate with any of the components.

DR. HOWE: Well if a contraindication to further pertussis vaccination occurred with the combo, you would stop vaccinating with this combo.

CHAIRMAN DAUM: Okay.

DR. HOWE: Whereas if an anaphylactic reaction, after the combination occurred, you would stop vaccinating with the combo. MS. LOE FISHER: I'm concerned about limiting the active surveillance for adverse events to four days post vaccination and total adverse event surveillance to only thirty days. And the fact that only 700 U.S. children have been evaluated the 2, 4, 6 month schedule.

And I'm concerned about the seven seizures which occurred in seven thousand children with five of these being first-time afebrile seizures which are the kind most likely to result in long-term permanent neurological damage.

And I am concerned that without an understanding of the biological mechanism of adverse events, including fever, that when an adverse event occurs, there will be few clues about which component of the vaccine is at fault, or whether it is indeed the combination, thereby leading to confusion about whether to continue vaccinating with the combination vaccine versus eliminating one of the vaccines or giving the vaccines separately.

So I would like to see a larger trial in the U.S. in 2, 4, 6 month-old children, with at least a one-year follow-up to measure for all morbidity or mortality outcomes, including the development of autoimmune and neurological disorders.

This is the first five-in-one vaccine and will have an enormous impact on vaccine policy. And we have to be sure that it's the right one at the right time. Because if it turns out to be far more reactive in a real life setting because we failed to get enough information pre-licensure, then it will ultimately negatively affect the whole vaccination system.

And I think you have to have at least three thousand more U.S. children in your total database so you have ten thousand children that you have studied on this vaccine. So that the public has confidence that you have proven safety and efficacy.

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December 17, 2002

Combined Vaccine Gets F.D.A. Approval

By DONALD G. McNEIL Jr.

The first vaccine that protects infants against five diseases has been approved for use in the United States, its manufacturer announced yesterday. The new formula could mean as many as six fewer injections in the first year for many babies.

The vaccine, called Pediarix, is made by GlaxoSmithKline and is already in use in several European countries. It combines vaccines against diphtheria, pertussis (whooping cough), tetanus, hepatitis B and polio, and is intended to be given three times, at 2, 4 and 6 months of age.

Children in the United States are typically given up to 15 injections in their first year, a schedule that experts say has led some parents to resist immunizations. The combined vaccine should cut that number to 9 for many children.

"It's good news that this is out," said Dr. Neal Halsey, director of the Institute for Vaccine Safety at Johns Hopkins University. "It'll be nice to have one product so kids don't have to have multiple injections."

Theoretically, with the combined vaccines now used abroad or being developed, the immunization schedule for infants could eventually be reduced to just three shots. Combined vaccines against haemophilus influenza b and streptococcal pneumonia are in use in Europe or being tested by Glaxo, Aventis and other pharmaceutical companies.

But Dr. Joel Ward, director of the Center for Vaccine Research at the University of California at Los Angeles and the principal investigator of Pediarix, said that it had taken 10 years to get Pediarix approved by the Food and Drug Administration and that other mixes of vaccines had thus far not provided enough antibody protection against all the diseases to please the agency.

Even under an abbreviated schedule, the vaccine against hepatitis B will still be given immediately to newborns whose mothers are infected or whose status is unknown, doctors said.

After children are over a year old, they are normally given more vaccines against measles, mumps, rubella and chicken pox. Because these vaccines are made with viruses that are weakened but not killed, they cannot normally be combined with the killed vaccines given earlier in life, vaccination experts said.

Even as it approved Pediarix, the F.D.A. said children vaccinated with it had one side effect, fever, more frequently than those given separate vaccines.

Dr. Ward acknowledged that, but said the fevers were typically less than 101 degrees, lasted less than 24 hours and did not lead to serious reactions or hospitalizations.

Dr. Karen Midthun, director of vaccine research and review for the F.D.A., agreed that the more common fevers did not cause serious problems. The Pediarix label cautions doctors to expect fevers among patients, she said, especially those getting it at the same time as measles-mumps-rubella shots.

The F.D.A. still feels the vaccine "has an acceptable safety profile," Dr. Midthun said.

Reducing the number of shots will let pediatricians consider introducing new vaccines, Dr. Ward said. Those in the works include new vaccines against bacterial meningitis, rotavirus and the flu.

Barbara Loe Fisher, a founder of the National Vaccine Information Center, which is often described as an antivaccine group, said she was stunned by the approval because an F.D.A. advisory committee of which she was a member had expressed concern about side effects and asked for more information.

Dr. Midthun said the agency had received the additional information from Glaxo and had adjusted the label accordingly.

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