INTRODUCTION
Mr. Chairman and Members of the Committee, I am Karen Midthun, M.D., Director, Office of Vaccines Research and Review (OVRR), Center for Biologics Evaluation and Research (CBER) at the Food and Drug Administration (FDA or the Agency). OVRR regulates the development and licensure of vaccines. We appreciate the opportunity to participate in this hearing on autism and to respond to the Committee's concerns regarding a potential link between vaccines and autism. It is important to note that to date, the existing data do not demonstrate a causal relationship between vaccines and autism. Nevertheless, we want to assure this Committee, the public, and, especially the parents that are here today, that FDA takes these concerns very seriously and we want to explain FDA's ongoing efforts in response to the issue of vaccines and autism.
Childhood vaccines have contributed to a significant reduction of vaccine-preventable diseases, (e.g., polio, measles, and whooping cough). In fact, vaccine preventable infectious diseases are at an all-time low and now it is rare for American children to experience the devastating effects of these illnesses. Before vaccines were routinely administered, there were over 175,000 cases of diphtheria annually (1920-22), over 147,000 cases of pertussis (1922-25), and over 503,000 cases of measles (1951-54) reported in the United States (U.S.). These diseases have essentially disappeared in countries with high vaccination coverage, such as the U.S. Up until 1985 and the introduction of an infant vaccine, an estimated 20,000 cases of invasive Haemophilus type b disease, primarily meningitis, occurred annually in the U.S. Now, because of vaccination, the number of cases of invasive Haemophilus b disease has been decreased by more than 98 percent. All of the diseases mentioned above were associated with significant mortality and morbidity.
BACKGROUND
Like all products regulated by FDA, vaccines undergo a rigorous review of laboratory and clinical data by highly trained scientists and clinicians to help ensure the safety, purity, and potency of these products. From an FDA regulatory perspective, there are four stages in vaccine development: the pre-investigational new drug (IND) stage (before the product is used in people), the IND stage (where human use occurs under limited study conditions), the license application stage for vaccines (where FDA reviews the results of the clinical studies and the manufacturing process), and the post-licensure stage (following approval of the product for marketing).
A sponsor seeks licensure of a complete product as it is formulated for use, not of individual components. Evidence of any acute toxicity from the use of an investigational drug, including vaccines, is included in safety data from human clinical studies, as required under Title 21, Code of Federal Regulations (CFR) Part 312. If any ingredient or ingredients causes acute toxicity, the pre-market safety data would most likely indicate acute toxicity from use of the vaccine product. Such data, however, generally would not show whether any particular ingredient or combination of ingredients is the source of toxicity.
Like other approved drug and licensed biological products, vaccines licensed for marketing may also be required to undergo additional, Phase IV, studies to further evaluate the vaccine or to address specific questions about the vaccine. For example, the manufacturer of Varicella Virus Vaccine committed to perform a post-licensure study with fifteen years of safety follow-up. These studies will provide information about the effects of the vaccine in a population larger than that exposed during clinical trials. If additional side effects are identified during the post-marketing phase, either pursuant to adverse event reports filed by health care providers or consumers, or pursuant to Phase IV studies, FDA would take appropriate regulatory action to protect the public health such as, among other options, changing the product's labeling information to reflect the possible side effects, or, in cases of imminent or substantial hazard to the public health, ordering a recall of the product.
Because of the complex manufacturing processes for most biological products, each product undergoes thorough laboratory testing for purity, potency, identity, and sterility. Manufacturers may release lots only after this testing is documented. FDA may require lot samples and protocols showing results of applicable tests to be submitted for review, and where appropriate, further testing by FDA. The lot release program is part of our multi-part strategy that helps ensure product safety by providing a quality control check on product specifications.
Vaccine Adverse Event Reporting System
Licensure of all vaccines marketed in the U.S. is based on a benefit-to-risk analysis of the safety and efficacy data submitted by sponsors to FDA. During the pre-market review process, manufacturers and FDA focus on identifying and understanding risks before an overall risk-benefit decision can be made on the product's licensure. When using any drug or medical product, a patient runs the risk of experiencing reactions. For pharmaceuticals, including vaccines, these reactions are commonly termed "side effects." They usually are identified in clinical trials conducted before licensure and are described in a product's labeling. Known side effects, discovered in the course of clinical trials, upon which a product's licensure or approval is based, comprise the majority of reported adverse events after licensure.
Like all other medical products, vaccines are not entirely risk-free. While serious complications are rare, they can occur. Vaccines are unique medical products in that they are generally administered to a large number of healthy individuals, primarily children. Therefore, it is very important to identify even rare adverse reactions. CBER and the Centers for Disease Control and Prevention (CDC) jointly manage the Vaccine Adverse Event Reporting System (VAERS), a cooperative program for vaccine safety. VAERS is a post-marketing safety surveillance program that collects information about adverse events that occur after the administration of U.S. licensed vaccines. An "event" is simply an outcome. However, any outcome that an individual, whether a health care provider or a consumer, believes may have resulted from the administration of a vaccine may be reported to VAERS. Such report will be included in the system, regardless of whether there appears to be a causal relation to the vaccine. Under FDA regulations, 21 CFR, Subpart D - Reporting Adverse Experiences, section 600.80, licensed vaccine manufacturers must report to FDA adverse experience information, and establish and maintain records.
It should be emphasized that adverse event reports can be made by anyone, including health care professionals, patients, and parents. If a patient's physician does not file a VAERS report, the patient can do so. FDA protects the confidentiality of patients for whom an adverse event has been reported. FDA encourages individuals to report to VAERS any clinically significant adverse event occurring after the administration of any vaccine licensed in the U.S. Individuals who want to make a report to VAERS can call VAERS at a toll-free number, 1-800-822-7967, to obtain a reporting form. Forms and reporting instructions also are available on the Internet at www.fda.gov/cber/vaers.html and at www.vaers.org.
Follow-up Study of VAERS Autism Reports
FDA has taken seriously VAERS reports of developmental delay following vaccination and wants to assure the public that the Agency is researching any possible relationship between vaccines and autism. CBER proposes to conduct a follow-up study of VAERS reports of autism. As part of the study, CBER, in conjunction with outside autism experts, will review available medical records and develop an interview questionnaire for parents and others who have reported autism after vaccinations. The goal of the interviews is to gather information about demographics, clinical features, potential risk factors, family history, vaccines administered, time interval from vaccination to autism onset, rapidity of symptom onset, and interval from diagnosis to submission of reports. Though this study cannot determine whether vaccines cause autism, it might suggest hypotheses that could be further evaluated in subsequent controlled, epidemiologic studies.
Autism-related Laboratory Activities
FDA is actively pursuing research involving the characterization and development of the first virus-induced animal model for autism - Borna disease virus (BDV) infection of the neonatal rat. There is no direct evidence for any relationship between BDV infection and human autism. However, BDV is used as the environmental damaging agent because it infects the brain of newborn rats. It is important to note that BDV is not a cause of autism. The damage it does and the disease syndrome it produces in rats are used only as a "model" to study general biological principles of autism. The features of this model, which FDA scientists have developed over the past ten years, have excellent correlation with what is known about human autism including neuroanatomical, behavioral, and neurochemical correlations. This model is being used in laboratories throughout the U.S. and internationally.
Thimerosal
FDA, together with other U.S. public health agencies, recognizes and supports the goal of reducing exposure to mercury from all sources. Consistent with this goal, FDA has encouraged manufacturers for several years to develop new vaccines without thimerosal as a preservative and to remove or reduce the thimerosal content of existing, licensed vaccines. This joint effort by manufacturers and FDA is reflected by the licensure of thimerosal-free products such as Comvax [Haemophilus b Conjugate Vaccine and Hepatitis B Vaccine (Recombinant) manufactured by Merck & Company, Inc.], licensed October 2, 1996, Infanrix [Diphtheria and Tetanus Toxoids and Acellular Pertussis (DTaP) manufactured by GlaxoSmithKline], licensed January 29, 1997, and Prevnar (Pneumococcal 7-valent Conjugate Vaccine manufactured by Wyeth-Lederle Vaccines and Pediatrics), licensed on February 17, 2000, and the removal or reduction of thimerosal from previously licensed products.
In response to section 413 of the Food and Drug Administration Modernization Act (FDAMA) of 1997, FDA conducted a review of the use of thimerosal in childhood vaccines. Our review revealed no evidence of harm caused by thimerosal used as a preservative in vaccines, except for local hypersensitivity reactions. Under the U.S. recommended childhood immunization schedule, the maximum cumulative exposure to mercury from thimerosal, at the time of this review in 1999, was within acceptable limits for the methyl mercury exposure set by FDA, the Agency for Toxic Substances and Disease Registry, and the World Health Organization. Of note, such guidelines contain safety margins and are meant as starting points for evaluation of mercury exposure, not absolute levels above which toxicity can be expected to occur. However, the maximum cumulative exposure level exceeded the more conservative limits of the Environmental Protection Agency (EPA). The clinical significance of exceeding EPA's limits is not currently known.
Nevertheless, reducing exposure to mercury from vaccines is warranted. This is achievable, in part, because it is possible in the U.S. to replace multi-dose vials with single dose vials, which do not require a preservative.
We are pleased to be able to report substantial progress in the effort to reduce thimerosal exposure from vaccines. At this time, all routinely recommended licensed pediatric vaccines that are currently being manufactured for the U.S. market, contain no thimerosal or contain only trace amounts of thimerosal. The vaccines with trace amount of thimerosal licensed to date contain less than 0.5 micrograms of mercury per dose, that is, a given dose of vaccine contains less than 1 part per million.
Our efforts over approximately the past year and a half to accomplish this goal include the licensure of a thimerosal free Hepatitis B Vaccine (Recombinant) manufactured by Merck and Company in August 1999. FDA licensed another hepatitis B vaccine with trace amounts of thimerosal, manufactured by GlaxoSmithKline in March 2000. A supplement for a new formulation of Aventis Pasteur's DTaP Vaccine with only a trace amount of thimerosal was approved in March 2001. Additionally, Wyeth-Lederle Vaccines and Pediatrics now only markets a single-dose, thimerosal-free formulation of its Haemophilus b Conjugate Vaccine in the U.S.
Therefore, all routinely recommended U.S. licensed pediatric vaccines are now available in either thimerosal-free formulations or in formulations that contain only trace amounts of thimerosal. The routinely recommended vaccines include hepatitis B Vaccine, Haemophilus b Conjugate Vaccine, Measles Mumps and Rubella Vaccine, Pneumococcal Conjugate Vaccine, DTaP Vaccine, Inactivated Polio Vaccine, and Varicella Vaccine. Prior to the recent initiative to reduce or eliminate thimerosal from childhood vaccines, the maximum cumulative exposure to mercury via routine childhood vaccinations during the first six months of life was 187.5 micrograms. With the newly formulated vaccines, the maximum cumulative exposure during the first six months of life will now be less than three micrograms of mercury; this represents a greater than 98 percent reduction in the amount of mercury a child would receive from vaccines in the first six months of life.
Thimerosal and the National Toxicology Program
The National Toxicology Program (NTP) was established in 1978 by the Secretary of the Department of Health and Human Services (DHHS or the Department) to coordinate toxicology research and testing activities within the Department, to provide information about potentially toxic chemicals to regulatory and research agencies and the public, and to strengthen the science base in toxicology. The NTP has become a world leader in designing, conducting, and interpreting animal assays for toxicity and/or carcinogenicity.
NTP uses a chemical nomination and selection process as a means to best use its resources with respect to the testing of chemicals of greatest health concern. Member agencies of the NTP, including FDA, are the primary sources of nominations to the NTP. Because of the continued interest on the part of the public, as well as public health agencies, to better characterize the potential toxicity that could have accompanied an exposure to thimerosal from vaccines, FDA is in the process of nominating thimerosal to the NTP for further study to adequately assess gaps in knowledge regarding, among other things, neurodevelopmental toxicity.
CONCLUSION
Vaccines provide a great public health benefit in reducing or eliminating vaccine preventable diseases. Like all medical products, there are risks with vaccines and FDA is committed to continuing its efforts to ensure the safety of vaccines. We have worked diligently with manufacturers to eliminate or reduce exposure to mercury from thimerosal in vaccines. As stated previously, all licensed vaccines currently being manufactured for the U.S. market that are on the routine childhood immunization schedule have formulations that are thimerosal-free or contain only trace amounts of thimerosal. Although no causal relationship between vaccines and autism has been established, FDA, along with other DHHS agencies, continues to pursue research activities to increase our understanding of any relationship between vaccines and neurodevelopmental disorders.
We thank you for your leadership in this area. I would be happy to answer any questions you might have.
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