FDA’s Role in Protecting Your Child’s Health Through Safe and Effective Vaccines Norman W. Baylor, PhD Director, Office of Vaccines Research and Review Center for Biologics Evaluation and Research U.S. Food and Drug Administration

Why Vaccines Are Important for Children Vaccines protect against serious infectious diseases and save lives. The devastating effects of diseases such as polio, pertussis (whooping cough), rubella (German Measles) and Haemophilus influenzae type b (Hib) are now rare due to vaccines. Infant deaths due to these diseases have essentially disappeared in the United States. Viruses and bacteria that cause vaccine-preventable diseases and death still exist and can be passed on to people who are not immunized. 1

How Vaccines Work Designed to prevent infectious diseases Vaccines work by mimicking infectious agents such as bacteria and viruses that cause disease, and stimulate the body’s immune system to build up defenses against them. A vaccine contains a weakened bacteria or virus, but it doesn’t cause disease to the person. The disease-causing agents are foreign to the body, and are called antigens. Vaccination exposes the body to antigens that are similar to the antigens found on a disease causing agent. The vaccine prepares the immune system to respond quickly and forcefully if the body encounters the real disease in the future.

FDA Serves as the Gatekeeper for Assuring the Safety and Effectiveness of Vaccines Safe: “Relative freedom from harmful effect… when prudently administered, taking into account the character of the product in relation to the condition of the recipient at the time.” Pure: “Relative freedom from extraneous matter in the finished product,…” Potent: “Specific ability of the product … to effect a given result.” Vaccines must be manufactured consistently according to current Good Manufacturing Practices. 3

Vaccine Development Develop a rationale for vaccine based on how the infectious agent causes disease Identify what ingredients are needed, e.g., antigen(s), adjuvant, preservatives, etc Develop manufacturing process Test investigational product in animals for safety and effectiveness, i.e., preclinical studies Evaluate investigational vaccine in human clinical studies

Ensuring Safety of Investigational Vaccines FDA evaluates sponsor’s data to determine if it is reasonably safe to administer investigational vaccines to people. test vaccine cannot be administered unless FDA gives the go-ahead. vaccines intended for children are generally tested first in adults, with a step-down to children. Vaccine candidates go through several phases of testing in people who volunteer to participate in clinical trials FDA can stop clinical trials at any time if concerns arise. FDA sets the guidelines for the phases to assure the safety of the volunteers, good practices are followed, and that FDA’s rigorous standards are met.

IND (Investigational New Drug) Phases in Clinical Testing of Vaccines Phase 1 includes 20-100 healthy volunteers for initial safety testing evaluation of the occurrence of any adverse reactions may provide early evaluation of effectiveness of the test vaccine Phase 2 involves several hundred volunteers controlled clinical trials that provide additional information on safety, immunogenicity, and dose ranging Phase 3 involves thousands of volunteers pivotal randomized control trial to determine efficacy, safety, and immunogenicity

Biologics License Application (BLA) At the completion of the various phases of clinical trials companies may submit a marketing application (BLA) to FDA The BLA contains of all of the data gathered during preclinical (animal) studies and human clinical trials. the information in the application describes the vaccine's whole story product manufacturing and characterization facilities where the vaccine was manufactured. data and results from the clinical trials data and results from preclinical studies the composition of the vaccine, proposed labeling information for the healthcare provider and recipient. FDA reviews all of these data to determine whether the data support licensure of the vaccine for marketing authorization

Licensure of Vaccines FDA determines whether the vaccine is safe, pure, potent (i.e. vaccine immunogenic or efficacious) Evaluation of non-clinical, clinical, product, and manufacturing data and pharmacovigilance plan submitted in BLA Vaccines and Related Biological Product Advisory Committee review Pre-licensure inspection Post-approval activities: Lot release, annual/semi annual inspections, adverse event surveillance, Phase 4 studies FDA Scientific Evaluation Team: clinical, CMC, assay, statistics, biomedical monitoring, pharmacology/toxicology, pharmacovigilance, GMP inspection, labeling and promotion, communications, others

What Does “Safe” Mean? FDA takes vaccine safety very seriously throughout the vaccine life cycle A vaccine is a medication. Like any medicine, vaccines have benefits and risks, and although highly effective, no vaccine is 100 percent effective in preventing disease or 100 percent safe in all individuals. Millions of vaccine doses are given per year in the US and the vast majority have few, if any, side effects. The benefits of vaccines clearly outweigh their potential risks.

What Does “Effective” Mean? Vaccine effectiveness is the assessment of whether a vaccine prevents disease in the general population. Vaccine development proceeds from a study of immunogenicity to a randomized controlled trial that determines vaccine efficacy under ideal conditions. vaccine efficacy is defined as the reduction in the incidence of a disease among individuals who have received a vaccine compared to the incidence in unvaccinated people. efficacy of a new vaccine is measured in phase 2 or phase 3 clinical trials by giving one group a vaccine and comparing the incidence of disease in that group to another group who do not receive the vaccine. vaccine effectiveness depends upon vaccine efficacy.

Benefits and Risks Science provides FDA the information, but science does not provide all of the answers. FDA expertise is utilized to make decisions based on the benefits and risks for a population.

FDA Provider Patient Benefits Risks evaluates benefits/risks for the population Provider for a patient Patient in terms of personal values Benefits Risks .

Vaccine Ingredients A vaccine is made-up of various ingredients and each ingredient present in a vaccine is there for a specific reason. Different ingredients have different roles in a vaccine, and vaccines licensed for use in the United States are demonstrated to be safe and effective before they are used by the public.

Vaccine Manufacturing Once a vaccine is licensed, the manufacturing facilities used are inspected by the FDA at least every two years. Experienced FDA-investigators carefully examine and evaluate the operation for compliance with FDA regulations. Manufacturing processes for vaccines are complex Each product “lot” or “batch” is tested by the manufacturer for purity, potency, identity, and sterility. FDA requires vaccine manufacturers to submit protocols of all processes, procedures and standards with results of applicable tests, along with samples to the FDA for lot release. Manufacturers are not permitted to distribute a lot of licensed vaccine until the FDA releases it.

Monitoring of Vaccines FDA’s work continues after approval: Intense oversight of the production of vaccines continues after licensure to ensure continuing safety Vaccine Adverse Event Reporting System (VAERS), co-administered by FDA and CDC Collaboration with CDC on the Vaccine Safety Datalink Collaboration with other US government agencies: Centers for Medicare and Medicaid Services Department of Defense Veterans Administration Indian Health Service

Monitoring of Vaccines Continued International Collaboration information sharing agreements with our counterparts in other countries and the World Health Organization (WHO) FDA Sentinel Initiative FDA Amendments Act (FDAAA) 2007 developing large active surveillance, national electronic data system Strengthens FDA’s ability to monitor the safety of medical products Post-licensure Rapid Immunization Safety Monitoring (PRISM) established during H1N1 and used for active safety surveillance evolved into Mini-Sentinel pilot projects- expanding capacities to general vaccine safety monitoring and evaluation

FDA Research Unique Perspective- research activities in conjunction with regulatory activities FDA research contributes to policy, risk assessments, new methods and standards, and changes to product labeling Improve or develop new methods that enhance the safety and effectiveness of vaccines and related products

Who We Are FDA employees are parents, aunts, uncles, and grandparents and we have complete confidence in FDA-approved vaccines for our own families. The public can be assured that FDA is diligent in ensuring that the vaccines licensed for use in the United States are shown to be safe and effective.

Summary Vaccines have unique considerations for product & clinical development. FDA evaluation and regulation help facilitate the development of safe, pure, and potent new vaccine products, manufactured consistently according to current Good Manufacturing Practices. FDA’s research-regulatory staff support the science-based review and regulation of vaccines and related products. FDA’s research priorities focus upon our mandate to assure the safety, purity, potency, and effectiveness of vaccines and related products.

Questions? Contact us! By phone, toll-free: 1-800-835-4709 E-mail: ocod@fda.hhs.gov On the web: www.fda.gov/BiologicsBloodVaccines/default.htm