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.