FDA's William Egan testifies on vaccine additives
Acting office director, office of vaccine research and review, spoke to the Committee on Government Reform, U.S. House of Representatives on July 18
Table of Contents
Introduction
Purpose of vaccine additives
Thimerosol and mercury
Progress and continuing actions on removal of thimerosal
FDAMA report
Conclusion
Introduction
Mr. Chairman and Members of the Committee, I am William Egan, Ph.D., Acting Office Director, Office of Vaccine Research and Review (OVRR), Center for Biologics Evaluation and Research (CBER), Food and Drug Administration (FDA or Agency). We appreciate the opportunity to discuss the issue of additives in childhood vaccines, in particular thimerosal.
Vaccines, licensed for use in the United States (U.S.) by FDA, have been protecting our nation's children from deadly infectious diseases for over fifty years. In fact, immunizations represent one of the most significant public health achievements of the 20th century. Vaccines can be credited for saving more lives and preventing more illnesses than any medical treatment. Without question, continuing to ensure our children are vaccinated with licensed vaccines is critical to protect their health and to prevent disease outbreaks. Prior to licensure, each vaccine undergoes a rigorous review process to establish its safety and effectiveness. FDA considers all vaccines currently available to be safe and effective.
It is essential that children continue to receive all vaccines according to currently recommended schedules. The risk of the emergence of devastating childhood diseases like whooping cough, bacterial meningitis, tetanus, polio and diphtheria is real. The risk of these devastating childhood diseases from failure to vaccinate far outweighs the minimal, if any, risk of exposure to levels of thimerosal or mercury in vaccines.
Nevertheless, FDA has been actively addressing the issue of thimerosal as a preservative in vaccines. An FDA review of this issue one year ago found no evidence of harm from the use of thimerosal as a vaccine preservative but raised questions about the potential exposure of infants to mercury from thimerosal in vaccines. Based on this review, the Public Health Service (PHS) acted quickly, urging vaccine manufacturers to reduce or eliminate thimerosal in vaccines. Much progress has been made to date. The Agency has been working with other PHS agencies, the American Academy of Pediatrics and manufacturers, particularly those that manufacture childhood vaccines, to eliminate thimerosal from vaccines and to further evaluate the potential health effects of thimerosal.
Purpose of vaccine additives
In addition to the actual immunogen, vaccines may contain preservatives (e.g., thimerosal), adjuvants (e.g., the aluminum salts), and stabilizers (e.g., gelatin). The vaccine may be a liquid preparation in a suspending fluid such as buffered saline. Adjuvants are materials that, when used in combination with vaccine immunogens, increase the strength and/or duration of the immune response. At present, the only adjuvants that are found in U.S. licensed vaccines are the aluminum salts.
Preservatives are added to vaccine preparations to help minimize the consequences of inadvertent microbial contamination; with certain exceptions, they are required by regulation for multi-dose formulations. There are four preservatives that are currently contained in U.S. licensed vaccines. These are: thimerosal, phenol, 2-phenoxyethanol, and benzethonium chloride.
Thimerosol and mercury
Thimerosal is an effective preservative and has been used in some vaccines and other products since the 1930s. Thimerosal contains mercury in the form of ethyl mercury. Thimerosal is the most widely used preservative in vaccines. FDA estimates that it is used in more than 30 licensed vaccines and biologics currently marketed in the U.S. Thimerosal is used as a safeguard against microbial contamination. Disease outbreaks have occurred following contamination of multi-dose vaccine vials. While use of thimerosal as a preservative does not eliminate the possibility of bacterial contamination (multi-dose vials with thimerosal have become contaminated), the likelihood of contamination can be markedly reduced.
Mercury is a metal that is found in elemental form (such as the mercury used in thermometers), as inorganic salts, and as organomercurials (such as thimerosal). Humans may be exposed to organic mercury in the form of methyl mercury from eating contaminated fish. The magnitude of exposure to mercury (especially methyl mercury) and the degree of risk from fish consumption depend on the level of mercury in the fish consumed and the amount of fish an individual consumes. Very high levels of mercury are toxic. Because mercury is found naturally in the environment, it is not possible to prevent all exposure to mercury, however, the industrial uses and releases of mercury have been reduced very substantially in recent decades in the U.S. and most other industrialized countries.
Although mercury is found in the environment, in food and in household products, exposure to mercury is of concern and, when possible, should be avoided. For this reason, various Federal agencies have been addressing the health risks of mercury. One type of mercury, called methyl mercury, is found in fish and has received particular attention because high doses have been associated with adverse health effects. FDA, the Environmental Protection Agency (EPA) and the Agency for Toxic Substance and Disease Registry each have developed guidelines for intake of methyl mercury. As noted thimerosal contains a related mercury compound called ethyl mercury.
It is very important to remember that safety margins are incorporated into all acceptable mercury exposure limits. There are no convincing data or evidence of any harm caused by the low levels of thimerosal that some children may have encountered in following the existing immunization schedule.
Nearly all recommended pediatric vaccines available today in the U.S. are thimerosal-free. In 1999, FDA conducted a review of vaccines being used at that time. The review suggested that some infants, depending on which vaccines they receive and the timing of vaccination, may have been exposed to levels of ethyl mercury that could build up to exceed one of the Federal guidelines established for the intake of methyl mercury. There are no guidelines established for ethyl mercury, but experts agree that methyl mercury guidelines are appropriate to use in this situation. It is important to remember that there are safety margins incorporated into all Federal guidelines on methyl mercury exposure. Again, any mercury exposure from these vaccines is within the safety margin incorporated into the guidelines. No children or infants were receiving toxic levels of mercury from vaccines, but FDA still believed it appropriate to pursue alternatives to using thimerosal as a preservative in vaccines.
It should be noted that other than the occurrence of local hypersensitivity reactions, no harmful effects have been reported from thimerosal at doses found in vaccines. Some individuals experience local skin reactions such as redness and swelling that may suggest a delayed type of hypersensitivity reaction following injection with products containing thimerosal. While one study found that most patients do not develop reactions to thimerosal given as a component of vaccines, even when they tested positive for thimerosal hypersensitivity, a prior history of hypersensitivity to thimerosal, or any component in a vaccine, is considered a contraindication to further vaccination with thimerosal-containing vaccines.
Progress and continuing actions on removal of thimerosal
Under section 413(a) of the Food and Drug Administration Modernization Act (FDAMA) of 1997 (Pub. L. 105-115), entitled "Food and Drug Administration Study of Mercury Compounds in Drugs and Food," FDA was required to: (1) Compile a list of drugs and foods that contain intentionally introduced mercury compounds, and (2) provide a quantitative and qualitative analysis of the mercury compounds in this list. The statute did not differentiate between mercury as an active or an inactive ingredient. The provision also required the study of the "adverse effects on health of children and other sensitive populations from exposure to... mercury."
CBER conducted a review of the use of thimerosal in childhood vaccines as well as other biologics. As part of this review, U.S. vaccine manufacturers responded to a December 1998 and April 1999 FDA Federal Register request to provide more detailed information about the thimerosal content of their products which included thimerosal as a preservative. It should be noted that the approved labeling of all biologicals including vaccines requires the listing of preservatives and the concentration on the label. (21 CFR 610.61)
While the review found no evidence of adverse effects caused by thimerosal in vaccines, except for minor local hypersensitivity reactions (as explained above), the assessment determined that the use of thimerosal as a preservative in vaccines might result in the intake of mercury during the first six months of life that exceeded recommended guidelines from EPA. The amounts, however, do not exceed the recommended guidelines set by FDA, the Agency for Toxic Substances and Disease Registry, and the World Health Organization. Of note, such guidelines contain safety factors and are meant as starting points for evaluation of mercury exposure, not absolute levels above which toxicity can be expected to occur.
Even though no major safety concerns resulting from use of thimerosal in vaccines were found, FDA concluded that reducing or eliminating exposure to thimerosal in vaccines was merited. Given the goal of reducing human exposure to mercury from all sources and the feasibility of single dose vials in the U.S., for which preservatives are not mandated, this action was justified. This review recognized the limitations of available data and recommended further studies to provide a more precise characterization of the potential risk from thimerosal in vaccines. These conclusions led FDA and others within PHS to announce the July 1999 recommendation that, as a precautionary measure, thimerosal be reduced or eliminated from childhood vaccines to make already safe vaccines even safer.
On July 1, 1999, CBER notified all vaccine manufacturers by letter that the use of thimerosal in biologic products would continue to be evaluated. As part of the evaluation, CBER requested that all manufacturers of thimerosal-containing vaccines provide information to CBER regarding their plans for thimerosal as a preservative in U.S. licensed vaccines.
The letter requested that if the manufacturer intended to remove thimerosal from their product(s), the following information needed to be discussed:
- proposed studies to assess the effect of removing thimerosal on sterility, potency, stability, and immunogenicity of the product;
- feasibility of eliminating or reducing the amount of thimerosal, using alternative preservatives, or reformulating the product solely for single dose containers;
- anticipated manufacturing changes as a result of removing thimerosal, if any; and,
- approximate time-line necessary to evaluate and implement removal.
If the manufacturer intended to continue using thimerosal in their product(s), an explanation was requested as to why that decision was made. (The letter can be found at http://www.fda.gov/cber/ltr/thim070199.htm.)
In August 1999, the available scientific information on thimerosal in vaccines was reviewed at a public workshop sponsored by the National Vaccine Advisory Committee (NVAC). The NVAC workshop was convened to examine the evidence for risks associated with possible exposures, however, there was no current evidence of a significant public health problem from thimerosal in vaccines. The meeting participants did urge that thimerosal be removed from vaccines as a prudent measure and that further research continue.
FDA's OVRR has been encouraging manufacturers to develop new vaccines without thimerosal as a preservative and to remove or reduce the thimerosal content of existing, licensed vaccines. Substantial progress has been made in the removal of thimerosal from vaccines. In August 1999, FDA approved a license supplement from Merck for a thimerosal-free hepatitis B vaccine. In March 2000, FDA approved a license supplement from SmithKline Beecham Biologicals for a thimerosal reduced hepatitis B vaccine (with more than 96 percent of the thimerosal removed from the vaccine, from a level of 25 micrograms of thimerosal per dose to less than one microgram per dose).
Additionally, Wyeth-Lederle Vaccines and Pediatrics is now marketing only a single-dose, thimerosal-free formulation of their Haemophilus influenzae type b (Hib) vaccine (they are no longer marketing the thimerosal containing multi-dose formulation). The other U.S.-licensed Hib vaccines are thimerosal-free. Thus, all pediatric hepatitis B and Hib vaccines currently being marketed are thimerosal-free or greatly reduced. Vaccines for polio, chicken pox, and mumps-measles-rubella already were thimerosal-free. Based on the progress in the past year, the maximum amount of ethyl mercury that an infant may be exposed to from the routine immunization schedule has been reduced by sixty percent (60%).
At present, there are four U.S.-licensed DTaP vaccines. The DTaP manufactured by SmithKline Beecham Biologicals (SBB) does not contain thimerosal as a preservative, while the DTaP vaccines from Wyeth-Lederle Vaccines and Pediatrics, Aventis Pasteur, and North American Vaccine do contain thimerosal.
Recently both Wyeth-Lederle Vaccines and Aventis Pasteur announced plans to submit supplements to their respective DTaP licenses in either July or August of this year for thimerosal-reduced DTaP vaccine formulations. FDA is committed to the expedited review of these supplements.
To further encourage the development of thimerosal-free vaccines, CBER sent another letter to vaccine manufacturers on May 31, 2000. CBER requested an update on progress toward the goal of thimerosal-free vaccines, particularly for vaccines administered to infants and children. For each manufacturer's product noted in the reply to CBER, the following information was requested:
- actions taken to date to develop thimerosal-free or thimerosal-reduced vaccine;
- time lines for implementing proposed changes to reduce or eliminate thimerosal from the product(s); and,
- identification of which products, if any, the manufacturer intended to continue using thimerosal and an explanation of why reduction or removal of thimerosal is not feasible.
Responses were requested from manufacturers within 45 days. (The letter can be found at http://www.fda.gov/cber/ltr/thim053100.htm) In June 2000, the National Immunization Program (NIP) of the Centers for Disease Control and Prevention (CDC) convened another meeting intended to further address the potential for health problems associated with exposure to thimerosal in vaccines. CDC had recently conducted an initial study to screen for any possible association between a variety of neurologic, developmental, and renal outcomes and the amount of thimerosal in vaccines. The consensus of the group reviewing the data was that the findings were insufficient to support any causal relations between exposure to thimerosal-containing vaccines and selected neurological development disorders, but did urge that additional research be continued.
FDAMA report
As discussed above, under section 413(a) of FDAMA, FDA was required to: (1) compile a list of drugs and foods that contain intentionally introduced mercury compounds, and (2) provide a quantitative and qualitative analysis of the mercury compounds in this list. FDA published requests for data and information on mercury compounds in drugs and food. The Agency asked all manufacturers of any food, including dietary supplements, and human and veterinary drug products (prescription or over-the-counter (OTC)) containing any intentionally introduced mercury compounds, whether used as an active or inactive ingredient, to provide information about the products to the Agency.
The Agency received 41 responses to the request-for-data notices; 38 from manufacturers of products, one from an association of homeopathic pharmacists, and two from consumers. Of the 38 responses from manufacturers, 15 were from manufacturers of homeopathic drug products, and 23 were from manufacturers of drug and/or biologic products (13 drug manufacturers, eight biologic manufacturers, and two manufacturers of both types of products). Five of the drug manufacturers informed the Agency that they had no products containing any mercury compounds. One drug manufacturer was an animal health corporation providing information on a veterinary drug product, and two manufacturers of homeopathic products included information on five veterinary drug products as well as human drug products.
In November 1999, FDA made available the document prepared in response to the FDAMA section entitled "Mercury Compounds in Drugs and Foods." The document discusses drugs (including biologics) and foods that contain intentionally introduce mercury compounds. The document provides a quantitative and qualitative analysis of the mercury compounds in the products. (The document can be found at http://www.fda.gov/cder/fdama/mercuryreport.htm)
Conclusion
On April 17, 2000, Secretary Donna E. Shalala, Department of Health and Human Services (DHHS), kicked off National Infant Immunization Week by releasing a new public awareness campaign urging all parents to immunize their children. The key message is that childhood vaccines have been a success story in American public health initiatives. Childhood immunization rates have reached all time highs with more than 90 percent of America's children receiving the most critical doses of vaccines for children by age two. Reported rates of diseases, for which childhood vaccines were developed, were at or near record lows in 1998. Without vaccinations, children would be at a very high risk for contracting many of these preventable childhood diseases.
While FDA and other components of DHHS work to remove thimerosal from childhood vaccines, parents should continue to have their children vaccinated. The risks of not vaccinating children far outweigh the unknown and much smaller risk, if any, of exposure to thimerosal in vaccines.
Thank you for the opportunity to testify.
Edited by Angelo DePalma
Managing Editor, Pharmaceutical Online