U. S. Department of health & human services




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statistically significant there was concern because of

an increased risk in the first and second week after

the first vaccination and a change in the typical age

of intussusception was somewhat earlier in infancy

following vaccination.

Actions taken, on 7/15/99 the CDC made a

recommendation of cessation of vaccination and

initiated a case control study. After consultation

with the FDA, the manufacturer notified the vaccine

purchasers via telephone of this information, hand

delivered a Dear Doctor letter to cease vaccination

pending further data collection. You can see that

happened fairly prompted. In addition, fairly

promptly, the manufacturer went with personal visits

to the purchasers and places do not use stickers on

remaining vaccine inventory in the purchasers

supplies.

A multi center research group was

initiated, with participation by government entities,

NIH, CDC and FDA, universities and industry. The

major concerns of this multi center group are the fact

that there is some disagreement and a large amount of

unknown information about what exactly causes this

intussusception. There are some theories about

physical issues and mechanical issues, but the actual

pathogenesis and mechanisms really are not known.

And then, of course, the major issue of,

is Rotavirus vaccination associated with an increased

risk of intussusception? This group is addressing

this in a clinical epidemiology standpoint, of course,

the CDC case control study qualifies there, pathology

of the children affected and if there are any surgical

materials available to evaluate that. And, of course,

basic scientists gather to discuss pathogenesis, a

mechanism to further evaluate this problem.

Just a little information about the CDC

studies that have been initiated. There is a case

control study headed by Doctor Warden. At this point,

the study has 400 enrollees, that does not mean 400

people with vaccine associated intussusception, I

wanted to make that clear, thats simply children

enrolled in this study, a one to four case ratio to

controls. Enrollment will end late October, and then

the data will be analyzed, and, of course, its not

appropriate to present or analyze the data prior to

finishing the enrollment, so that will come later.

A cohort study has been initiated by

Doctor Chens group, based on several medical care

sites, and a retrospective review of another large

database similar to VAERS, vaccine safety datalink, to

detect whether other vaccines or other diarrheas may

also be associated intussusception, also by Doctor

Chen.

The case control study that was mentioned,

which will end in October, gathers information on all

cases of intussusception, and focusing on states with

the highest distribution of Rotavirus vaccine. Thats

simply to get enough numbers to provide a meaningful

study.

The study includes all cases with

radiographic or surgical confirmation diagnosed

between these dates in children age one to 11 months.

There are age match controls with no intussusception

selected from infants at the same hospital as the

cases, and the comparison will be of expected

intussusception rates based on the placebo subjects

and changes in these rates, if any, seen in vaccinees.

So, in summary, Rotavirus causes

significant disease in the United States and

tremendous death internationally in infants. There

has been licensure of a new Rotavirus vaccine. There

have been administered over a million doses, and they

were associated with a rare but serious adverse event

intussusception, and the data are insufficient at this

point to decide whether theres causal association.

CDC, FDA and other groups are pursuing

additional clinical, epidemiological, and scientific

data to determine if association is causal, and

further regulatory actions will be taken pending

review of this new information.

Thank you.

DOCTOR DAUM: We continue to do well in

terms of scheduling, so we have time to discuss Doctor

Carbones presentation or ask questions of her.

Doctor Ferrieri?

DOCTOR FERRIERI: My question is whether we

know anything about pathology within the abdomen at

surgery in those infants who underwent surgical

correction of the intussusception, were there other

abnormalities found? For example, lymph node

enlargement, anyone with an associated other

abnormality or congenital defect.

DOCTOR CARBONE: That issue is actually

being studied. Thats part of the multi center group

and the pathological assessment. Its difficult to

give any numbers or significant data because it simply

has not been studied. We receive reports post fact,

and surgical reports after the fact.

However, some surgical reports that we

have have noted some lymphadenopathy, enlargement of

the lymph nodes, and some have noted some death to the

bowel, its intussuscepted, of course, the blood

supply is cut off if its a long enough time.

But, as far as detection of other

pathogens, theres been no organized search because

these are clinical cases. In the retrospect, the

pathological group is going to be evaluating exactly

that.

DOCTOR DAUM: Ms. Fisher, I think you were

next.

MS. FISHER: Its my understanding that

there have been 100 cases of intussusception following

Rotavirus vaccine reported to VAERS and two deaths.

Is that correct?

DOCTOR CARBONE: As of September 9, 1999,

there were 99 cases reported to VAERS, people

reporting intussusception in children who had received

vaccine. In addition, there have been two deaths

reported in children who have received vaccine, who

later  one of those cases  let me say, those cases

are currently under review, theres some information

on one of those cases that the infant may not have had

intussusception at all based on pathology reports, but

thats very preliminary information, and those cases

require  are currently getting further review.

MS. FISHER: I have one more question 

DOCTOR CARBONE: Excuse me, VAERS is a

passive reporting system, and the first 15 cases that

were reported were reported completely passively.

Those arrived at the FDA with no prompting. All

subsequent cases, and theres been an enormous bump,

have been reported following publication and

announcement by the CDC. That we can really not

consider passive reporting any longer. So, the

increase in rate following the CDC report may simply

be an increased awareness in the public, and we

consider those reports very seriously. Its not like

we dismiss them. However, in terms of numbers, the

change pre and post that day are a difference between

passive and more active reporting.

I just wanted to make that clarification.

DOCTOR DAUM: Do you want a follow up

question?

MS. FISHER: One follow up. In the

original licensing studies for this vaccine, what was

the length of follow up, what was the follow up period

to look for such things as intussusception?

DOCTOR CARBONE: Good question. The

studies, of course, are numerous and varied. Length

of follow up were usually no less than 42 days

following vaccination, and in some cases were up many

months beyond that. In some cases, the studies went

for two seasons, so the children were actually

followed for over a year.

DOCTOR DAUM: Doctor Adimora?

DOCTOR ADIMORA: I may have missed this in

your presentation, but to what extent was RotaShield

marketed and distributed internationally?

DOCTOR CARBONE: Well, Im U.S. FDA, so

its licensed I the United States and we follow the

U.S. distribution. I dont know if anybody would care

to comment on international distributions.

DOCTOR DAUM: Is there someone in the

audience, Peter, who would like to comment? Come up

to the microphone and identify yourself.

EXECUTIVE SECRETARY CHERRY: Please use the

microphone.

DOCTOR DAUM: Can you talk to the

microphone and tell us who you are?

MR. RUSSO: Im Carlo Russo from Merck.

RotaShield was approved in Europe in May, so it was

licensed in Europe.

DOCTOR DAUM: Has it been used?

MR. RUSSO: That I dont know.

MR. PARADISO: Thank you, Peter Paradiso.

It was licensed in Europe. It has not been

distributed or used anywhere outside the United States

to date.

DOCTOR DAUM: Thank you for clarifying

that.

Other comments? Doctor Faggett?

DOCTOR FAGGETT: Yes. The 99 case, what

was the average there of incidence, and also, you

mentioned, what, four to six as the average age, Im

used to the age being a little older. Thats a two 

part question.

DOCTOR CARBONE: Those data are difficult

to come by, and let me explain. In various data,

because they are reported to us, there is no control

over possible selection biases, so these data can be

analyzed, but as to what they mean we dont know.

It turns out theres only about a month or

a month and a half difference in age, with the

children in the various databases. Preliminary

analysis, let me emphasize, may be slightly younger
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