Thimerosal
Thimerosal is a preservative used in vaccines to prevent spoiling,
to inactivate bacteria used to make certain vaccines, and to
prevent bacterial contamination in the finished vaccine. Several
reports have linked the thimerosal in vaccines to mercury poisoning
because thimerosal contains a mercury related compound. Since
infants receive many vaccines, the reports have pointed to mercury
poisoning from thimerosal containing vaccines as a possible cause
of autism. Mercury can cause immune, sensory, neurological, motor,
and behavioral dysfunctions. The FDA is
working towards eliminating or reducing the amount of thimerosal
in vaccines.
How does the FDA evaluate vaccines to make
sure they are safe?
FDA's Center for Biologics Evaluation and Research is responsible
for regulating vaccines in the U.S. Before new vaccines are licensed,
they are tested extensively for safety in the laboratory, in
animals, and in successive stages of human clinical trials, called
phases. When a new vaccine is first tested in humans, a sponsor
(a vaccine manufacturer, academic investigator or other individual
or organization) must first submit an Investigational New Drug
Application to the FDA. If data at any stage of clinical development
raise significant concerns regarding the safety of the product,
the FDA may request additional information or may halt ongoing
or planned studies.
Phase 1 studies typically enroll less than 20 participants and
are designed to look for very common adverse events.
Phase 2 studies may include up to several hundred individuals and are
designed to look at the overall safety profile of the vaccine
for local reactions such as redness and swelling at the injection
site, as well as general side effects that may occur with some
vaccines, such as fever. For phase 3 studies, the sample size
is often determined by the number required to establish efficacy
of the new vaccine, which may be in the thousands or tens of
thousands of subjects.
Phase 3 studies are usually of sufficient
size to detect less common adverse events, such as those
occurring at rates of 1 in 100 to 1 in 1000. For vaccines given
concomitantly
with other vaccines under the routine immunization schedules,
the safety of new vaccines typically is studied with concurrent
administration of these other vaccines. In addition, the
FDA carefully reviews information on the manufacturing process
of new vaccines, and testing is performed on individual lots
for
safety and potency. If product development is successful,
the
completion of all three phases of clinical development can
be followed by submission of a Biologics License Application
(BLA).
Following the FDA's review of a license application for a new
indication, the sponsor and the FDA present their findings to
an expert advisory committee in an open public meeting for comment
and advice. The advisory committee provides advice to the FDA
on approval or
disapproval. Vaccine approval also requires the provision of
adequate information (labeling) to health care providers and
the public on the vaccine's proper use, including its potential
benefits and risks, and its indications and contraindications.
The safety of new vaccines continues to be monitored following
licensure in several ways. The Vaccine Adverse Event Reporting
System, co-administered by the FDA and CDC, is a national passive
surveillance system for the collection of all reports of adverse
events following vaccination. As a spontaneous reporting system,
VAERS has several limitations including under-reporting, incompleteness
of reports, lack of consistent diagnostic criteria, and the inability
to establish a cause and effect relationship. VAERS is useful,
however, for raising "red-flags" and subsequently
generating hypotheses that can be tested further in controlled
clinical trials or epidemiological studies. As part of a post-licensure
commitment, the FDA often asks the manufacturer to conduct additional
clinical studies (sometimes called phase 4 studies), to further
evaluate safety, and to provide this information to the FDA in
a timely manner. In addition, coordinated epidemiological studies
may be conducted using pre-established large-linked databases,
which have improved ability to detect the occurrence of more
rare adverse events. One such system is the Vaccine Safety Datalink,
administered by the CDC.
What are preservatives and why are they
added to vaccines?
Preservatives are compounds that kill or prevent the growth
of microorganisms, such as bacteria or fungi. They are used in
vaccines to prevent bacterial or fungal growth in the event that
the vaccine is accidentally contaminated, as might occur with
repeated puncture of multi-dose vials. Vaccines, both in the
United States and throughout other parts of the world, are commonly
packaged in multi-dose vials. In some cases, preservatives are
added during manufacture to prevent microbial growth; with changes
in manufacturing technology, however, the need to add preservatives
during the manufacturing process has decreased markedly.
Preservatives
have been used in vaccines for over 70 years. The requirement for a
preservative in multi-dose, multi-entry vials was placed into the Code
of Federal Regulations (21 CFR 610.15) in January 1968. There are
exceptions to this requirement for preservatives, primarily involving
the live-attenuated viral vaccines.
The general need for preservatives in multi-dose vials has been
attested to by a number of examples of multi-dose vials being
formulated without preservatives becoming contaminated during
use, and causing the death of vaccine recipients; cf. the Narrative
Section on Thimerosal.
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