U. S. Department of health & human services




НазваниеU. S. Department of health & human services
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itself contains four different serotypes, four

separate viral strains, and was produced by Wyeth 

Lederle Vaccines and Pediatrics. It was licensed in

August of 1998, and recommended for universal

immunization by these organizations.

The oral vaccine is used in children, it

is administered orally and its administered three

doses at approximately two, four and six months of

age.

I want to discuss some pre licensure

clinical studies. Prior to licensure, this

reassortant was tested in studies that contained

15,000 participants. That includes vaccinees and

placebos. However, there is no immune correlate of

protection for this vaccine. What that means is, its

impossible to do a blood test, for example, to look at

an antibody level in any large scale way and detect an

effective response to the vaccine. Therefore, the

effective response of the vaccine is tested by

literally efficacy preventing or reducing the severity

of the actual disease.

The efficacy with the licensed dosing

against any kind of Rotavirus gastroenteritis is

approximately 50 to 70 percent effective, against

severe Rotavirus gastroenteritis its approximately 70

to 90 percent effective.

The vaccine was licensed based on three

major placebo controlled efficacy and safety studies,

two performed in the United States and one in Finland.

About 18,000 children received this vaccine at the

licensed dose and formulation in these studies.

However, we consider additional information from

clinical studies that were performed in the United

States, Venezuela, Brazil and Peru, and approximately

5,000 more children received vaccine in these studies.

A major concern, of course, with a vaccine

which is a prophylactic treatment is safety. The

problematic problem which concerns the safety of

causal versus associated, and let me describe what I

mean by that. In the label for this vaccine when

licensed, were included adverse reactions. An adverse

reaction is something that is noticed both in the

recipient of a vaccine and the placebo, but was

statistically seen more often in vaccinees. Two

examples were moderate fever and high fever were both

seen more often in vaccinees versus placebo recipients

in a statistical manner.

Then theres another category, which is

also in the label for this vaccine, called adverse

events. These are typically rare events, and in this

case there was some gastroenteritis reported,

meningitis, hepatitis seizures, intussusception, which

we will focus more on later, failure to thrive and

death. However, these are called adverse events

because the rates are actual similar in vaccinees and

placebos in the data, and, therefore, its difficult

to determine the causation or an association, versus

an association with the vaccine.

Today wed like to talk about a serious

and rare adverse event associated with vaccination,

and that is intussusception. First, let me discuss

what intussusception is. Intussusception is a disease

of the bowel where the bowel literally telescopes in

on itself and can often lead to bowel obstruction.

Signs of the disease include vomiting and bloody

stools. It is typically identified by radiology

study, x ray, sonogram or barium enema or enema of

some sort, and it can be treatment by a non surgical

way, usually with an enema, or by surgery, actual

surgery where the bowel is either reduced, the

intussusception is reduced, or if the bowel has been

damaged has to be recepted.

There are certain diseases which have been

associated with the development of intussusception,

including anatomical abnormalities, like Meckels

diverticulum, lymphomas, other congenital bowel

diseases, infections, adenovirus, human herpes virus

6 and 7, Epstein Barr virus, and even some bacteria

strains have been associated with intussusception.

Causality has always been difficult to prove.

Rates have been also difficult to prove in

the general population of children, but generally its

been quoted looking at studies and reports from

various health agencies of .074 to .05 percent in the

first 12 months of life. That has been translated in

other studies to suggest that we expect a reporting

rate of 14 to 16 cases per week.

Peak age for intussusception in the

general population of children is four to nine months,

however, the range, as you can see here, is quite

broad, from less than one month to almost two years.

Lets talk about the adverse events that

were noted pre licensure associated with Rotavirus

vaccine use. Pre licensure concerns are rare, but

serious adverse events prompt analysis of data and a

publication re intussusception. This is the

publication to which that is referring to by Doctor

Rennels, et. al. In this publication, you can see

theres an extremely small number of cases of

intussusception associated with the vaccine, and there

was one case associated in placebo controls.

The rates were analyzed, and the rate in

the vaccines of .05 percent was not statistically

significant from the rate .022 percent.

I put this line here to prompt a

discussion, issues of data analysis methods. As you

can see here, it becomes very difficult because only

two of these cases were in children receiving the

license formulation, while three of these cases were

in children receiving the other formulation. Some

studies the children received one dose. Some studies

they received three. Some studies they received 104,

some studies 105 lots of virus. It makes it difficult

to do comparisons among studies, and depending upon

which studies you include, and, of course, including

the appropriate placebo controls, the reanalysis of

the data has shown this number becomes .04 percent and

this number becomes .03 percent, they move closer.

So, its a very difficult analysis to perform.

Of course, we are all concerned regarding

any possible causality between intussusception and

Rotavirus vaccine, and so the association requires

further study. In pre licensure studies, however, the

RNAase distribution of vaccinees was similar to that

seen in comparative unvaccinated populations. Wild

type Rotavirus is not reliably associated with

intussusception. There are several studies that have

looked at this, the numbers are extremely small. Many

of the studies have no control population to compare

to, and the answers that they give are quite

conflicting.

The lack of seasonality noted with wild

type Rotavirus intussusception suggested that because

wild type Rotavirus seizures was not followed or

accompanied with large numbers of intussusception, or

an increase or a peak, then that was believed to also

provide more information that even wild type Rotavirus

was not associated with intussusception.

However, because this is a serious adverse

event, whether or not its associated with the vaccine

has to be looked into and continued to be studied.

Therefore, at licensure and post licensure the FDA

took action. Information regarding intussusception in

the pre licensure clinical trials was placed in the

label for the public, for disclosure, for physicians

and for patients.

A new VAERS term, thats vaccine adverse

event reporting system, a new term for intussusception

was added to the adverse event reporting system, so

the reports from physicians and general population

would be easily captured for review by the VAERS

staff.

In addition, two post marketing clinical

trials were designed, and one, a very large one was

specifically designed to capture serious adverse

events and compare them to baseline population and

intussusception was a major concern of ours when that

study was designed.

The studies I referred to, one is 20,000

infants age six weeks to six months in an HMO system

in California, and the computerized database allowed

review of serious adverse events such as

intussusception in a population of children who

received the vaccine in the HMO and a population who

did not.

Study two, which was not initiated because

of the recent events, was planned to study age 

specific adverse events following vaccination at older

ages than currently recommended in the license and

younger ages of children, to look at age associated

adverse events.

So, what did these studies and other

information reveal to us? Post licensure data that

were obtained, after an estimated 1.5 million doses

were administered between licensure and June of 1999,

revealed that in VAERS reports of 15 cases between

September 1st and July 7, 1999. What was concerning

was that this reporting rate was approximately the

same rate as seen in the population, since this is a

passive reporting system, we anticipated lower than

normal rate of reporting. So, this prompted concern.

Secondly, the post marketing clinical

trial between December and June, pardon the typo,

please correct this on your handout, nine total cases

of intussusception were reported in the large post 

marketing clinical trial in the HMO, three of them

were in vaccinees.

An MMWR analysis, you see the citation

down here, indicated a possible trend of association

with intussusception, although it was not
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