8/26/24, 12:53 PM
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`Vaccine Development – 101 | FDA
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`Vaccine Development – 101
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`Español (/vaccines-blood-biologics/development-approval-process-cber/el-desarrollo-de-las-vacunas-101)
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`The U.S. Food and Drug Administration (FDA) is the regulatory authority that has oversight of the safety, effectiveness
`and quality of vaccines that are used in the United States.
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`Vaccines to prevent infectious diseases are given to millions of babies, children, adolescents and adults and it is critical
`that they are demonstrated to be safe and effective. Vaccines have prevented countless cases of disease and disability
`and have saved millions of lives. Ensuring the safety and effectiveness of vaccines is one of FDA’s top priorities.
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`FDA’s Center for Biologics Evaluation and Research (CBER) ensures that FDA’s rigorous scientific and regulatory
`processes are followed by those who pursue the development of vaccines. Vaccine development is a complex science.
`FDA’s scientific and regulatory advice to vaccine developers, as well as FDA’s evaluation to determine the safety and
`effectiveness of vaccines, are among the most robust in the world.
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`How Vaccines Work
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`Vaccines work by mimicking the infectious bacteria or viruses that cause disease. Vaccination stimulates the body’s
`immune system to build up defenses against the infectious bacteria or virus (organism) without causing the disease.
`The parts of the infectious organism that the immune system recognizes are foreign to the body and are called
`antigens. Vaccination exposes the body to these antigens.
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`Some vaccines contain weakened versions of a bacteria or virus, other vaccines contain only part of the bacteria or
`virus. Some vaccines contain only the genetic material for a specific protein and direct the body to produce a small
`amount of that protein. The body’s immune system reacts defensively once it detects this protein.
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`After vaccination, the immune system is prepared to respond quickly and forcefully when the body encounters the real
`disease-causing organism.
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`Below is the typical process that FDA expects vaccine developers to follow to generate the information it needs
`to assess the safety and effectiveness of a vaccine to prevent an infectious disease:
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`It Starts in a Lab
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`https://www.fda.gov/vaccines-blood-biologics/development-approval-process-cber/vaccine-development-101
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`BioNTech-Pfizer Exhibit 1148
`BioNTech SE and Pfizer Inc. v. ModernaTX, Inc. IPR2023-01359
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`Vaccine Development – 101 | FDA
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`Research and Discovery Stage Scientists develop a rationale for a vaccine based on how the infectious organism
`causes disease. The scientists then conduct laboratory research to test their idea for a vaccine candidate;
`sometimes this testing occurs in animals. This is considered the Research and Discovery Stage. Once a scientific
`finding is thought to have practical applications, in that it may be feasible to develop a vaccine candidate based on
`that finding, the research moves forward.
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`Research Moves Forward
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`Before a vaccine can be tested in people, a company or researcher performs additional laboratory research and
`testing in animals to obtain information about how the vaccine works and whether it's likely to be safe and work well
`in humans. These tests are known as the Pre-clinical phase.
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`Testing the Vaccine in People
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`When the company/researcher is ready to begin studies in humans, they compile the results of their laboratory and
`other preclinical testing, as well as information pertaining to the manufacturing technology and the quality of the
`vaccine and submit these to FDA in the form of an Investigational New Drug application (IND). FDA evaluation
`includes an assessment of the preclinical data and a determination whether these tests were conducted according
`to Good Laboratory Practices. FDA also conducts an assessment of the product, its quality and safety, and the
`technology to manufacture it, to determine whether it is reasonably safe for testing of the vaccine to move forward
`in people. Studies conducted in people are known as the Clinical Development stage and typically cover three
`phases under the oversight of FDA.
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`https://www.fda.gov/vaccines-blood-biologics/development-approval-process-cber/vaccine-development-101
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`BioNTech-Pfizer Exhibit 1148
`BioNTech SE and Pfizer Inc. v. ModernaTX, Inc. IPR2023-01359
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`Vaccine Development – 101 | FDA
`Clinical trials are conducted according to plans that reflect FDA’s considerable expertise in clinical trial design –
`these plans are called “protocols.” Vaccines intended for children are generally tested first in adults, with a step-
`down clinical development program to children and infants.
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`The phases of the studies may progress sequentially, but it is also not uncommon for the phases of development to
`overlap.
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`Phase 1- Emphasis during this phase is on safety and generally includes 20–100 volunteers who haven’t been
`exposed to the disease being studied and who are generally otherwise healthy. These studies are used to
`determine whether there are adverse reactions with increasing doses and, if possible, to gain early information
`about how well the vaccine works to induce an immune response in people.
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`Phase 2- In the absence of safety concerns from phase 1 studies, phase 2 studies include more people, where
`various dosages are tested on 100’s of people with typically varying health statuses and from different demographic
`groups, in randomized-controlled studies. These studies provide additional safety information on common short-
`term side effects and risks, examine the relationship between the dose administered and the immune response,
`and provide initial information regarding the effectiveness of the vaccine in its ability to generate an immune
`response. Standardized and validated tests are used to evaluate the immune responses. These vaccine studies
`typically also include a control group consisting of people who may receive an FDA-approved vaccine, a placebo or
`another substance. People receiving the vaccine under study are compared to people in the control group.
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`Phase 3- The vaccine is generally administered to thousands of people and the study generates critical information
`on effectiveness and additional important safety data. This phase includes additional information about immune
`response and compares those who receive the vaccine to those who receive a control, such as a placebo. For
`example, the number of cases of disease in the vaccinated group is compared to the number in the control group to
`see whether the vaccine reduces the incidence of disease. These studies also provide information about the
`vaccine’s safety including the identification of less common side effects.
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`Special Considerations - Public health emergencies and more information
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`In public health emergencies, such as a pandemic, the development process may be atypical or expedited.
`For example, as demonstrated by the response to the COVID-19 pandemic, the U.S. government may
`coalesce government agencies, international counterparts, academia, nonprofit organizations and
`pharmaceutical companies to develop a coordinated strategy for prioritizing and speeding development of the
`most promising treatments and vaccines. In addition, the federal government may make investments in the
`necessary manufacturing capacity at its own risk, giving companies confidence that they can invest
`aggressively in development and allowing faster distribution of an eventual vaccine.
`Recognizing the urgent need for safe and effective vaccines FDA utilizes its various authorities and expertise
`to facilitate the expeditious development and availability of safe and effective vaccines. Early in a public
`health crisis, FDA provides clear communication to the pharmaceutical industry pertaining to the scientific
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`https://www.fda.gov/vaccines-blood-biologics/development-approval-process-cber/vaccine-development-101
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`BioNTech-Pfizer Exhibit 1148
`BioNTech SE and Pfizer Inc. v. ModernaTX, Inc. IPR2023-01359
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`data and information needed for safe and effective vaccines and works quickly to provide advice on their
`proposed development plans and assessment of the data that are generated. During a public health
`emergency, if certain criteria are met, manufacturers may submit a request for Emergency Use Authorization
`(/emergency-preparedness-and-response/mcm-legal-regulatory-and-policy-framework/emergency-use-
`authorization) (EUA) to FDA to facilitate the availability and use of their vaccine during this time.
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`When evaluating the need for pre-clinical studies for a vaccine, FDA considers all data relevant to that
`vaccine and closely related vaccines, as well as the design of the specific clinical study for the vaccine in
`question. If FDA’s evaluation of these data support initiating human studies of a candidate vaccine intended to
`prevent an infectious disease without first completing additional toxicology studies, then FDA would consider
`allowing such human studies to proceed.
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`There is no predetermined timeline for vaccine development. Typically, the better the scientific understanding
`of a pathogen and the disease it causes, the more efficient vaccine development.
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`Adaptive Trial Designs: These are clinical study designs which aim to expedite clinical trial decisions based
`on preliminary results derived from earlier trials and, in some cases, from the same trial. Using this approach
`can facilitate efficient clinical development. The goal of these designs is to reduce the size and duration of the
`trial and demonstrate an effect if one exists. These adaptations are performed with close attention to
`statistical rigor.
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`Assessment of Manufacturing is Also a Key Component
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`While the vaccine is being tested in people, FDA is also assessing information pertaining to the manufacturing of
`the vaccine and the facility where it will be made. Vaccine manufacturing is complex. The process of making the
`candidate vaccine for the phase 3 studies in batches called “lots” helps the manufacturer ramp up for commercial-
`scale manufacturing. FDA requires vaccine manufacturers to submit data to support manufacturing processes,
`facilities, product characterization, and demonstration of lot-to-lot consistency. FDA works with the manufacturer to
`develop a lot release protocol – a template of tests to be conducted on the vaccine- that will be used for each lot of
`vaccine post-approval. Experienced FDA-investigators carefully examine and evaluate the facility and operation for
`compliance with FDA regulations.
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`Once a manufacturing process is developed that ensures that the vaccine can be produced reliably and
`consistently, and the preclinical and clinical development programs have been successfully completed, companies
`submit a Biologics License Application (BLA) to the FDA. A BLA is a comprehensive submission that is submitted to
`the Agency. It includes preclinical and clinical data and information, as well as details of the manufacturing process
`and facility(ies).
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`Seeking Approval
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`By submitting a BLA to the FDA, a company is seeking permission to distribute and market a vaccine for use in the
`United States. FDA evaluates the data to determine whether the safety and effectiveness of the vaccine has been
`demonstrated and whether the manufacturing and facility information assure product quality and consistency. After
`its evaluation, FDA decides whether to approve (also known as to license) the vaccine for use in the United States.
`If FDA approves the vaccine, the company is permitted to market it in the United States for use in the population for
`which it is approved.
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`https://www.fda.gov/vaccines-blood-biologics/development-approval-process-cber/vaccine-development-101
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`BioNTech-Pfizer Exhibit 1148
`BioNTech SE and Pfizer Inc. v. ModernaTX, Inc. IPR2023-01359
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`Vaccine Development – 101 | FDA
`FDA makes its decisions based on its analysis of the benefits and risks for the intended population who will receive
`the vaccine, as well as the disease(s) to be prevented. FDA’s scientific team works collaboratively to evaluate all of
`the scientific data and information included in the BLA and makes the determination whether to approve a vaccine.
`A typical FDA team is comprised of: physicians, chemists, statisticians, pharmacologists/toxicologists,
`microbiologists, experts in postmarketing safety, clinical study site inspectors, manufacturing and facility inspectors,
`and labeling and communications experts.
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`In some cases, FDA seeks the input of its Vaccines and Related Biological Products Advisory Committee
`(VRBPAC). This committee is comprised of a panel of outside, independent, technical experts from various
`scientific and public health disciplines that provide input on scientific data and its public health significance in a
`public forum. The FDA will consider, but is not bound by, the input received from the VRBPAC when determining
`whether to approve a vaccine.
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`Prescribing Information/Labeling
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`Prescribing information for a vaccine is based on scientific data that are submitted by the manufacturer in the BLA
`and determined by the FDA to be satisfactory to support the approved indication(s), usage, dosing, and
`administration. The prescribing information is updated as needed to include the most current information about the
`vaccine that is available to and reviewed by FDA. The prescribing information does not necessarily address all
`aspects of vaccine use, such as recommendations that are specific to disease outbreaks, vaccine shortages, and
`all subpopulations with underlying medical conditions.
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`FDA Oversight Continues After Approval
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`Monitoring of Safety and Effectiveness
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`It is important to note that a vaccine is a drug. Like any drug, vaccines have benefits and risks, and even when
`highly effective, no vaccine is 100 percent effective in preventing disease or 100 percent safe in all individuals.
`Most side effects of vaccines are usually minor and short-lived. For example, a person may feel soreness at the
`injection site or experience a mild fever. Serious vaccine reactions are extremely rare, but they can happen.
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`Although the vaccine development process and FDA’s evaluation are rigorous and comprehensive, there is still a
`need for ongoing surveillance of vaccines after FDA-approval to identify uncommon adverse events or long-term
`complications that may occur, and sometimes to monitor effectiveness. In certain cases, the FDA may require the
`manufacturer to conduct post-marketing studies to further assess known or potential serious risks. (These studies
`are sometimes called Phase 4 of development).
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`Vaccines are closely monitored using various surveillance systems, such as the Vaccine Adverse Event Reporting
`System (VAERS), the FDA BEST (Biologics Effectiveness and Safety) program and the FDA Sentinel Program, the
`FDA and Centers for Medicare & Medicaid Services (CMS) partnership, and the Centers for Disease Control and
`Prevention’s (CDC) Vaccine Safety Datalink.
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`Lot Release
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`Lot release is a mechanism that provides FDA with a real-time system to continuously monitor product quality. As
`previously noted, vaccines are generally made in batches called lots. FDA requires vaccine manufacturers to
`submit data to support the demonstration of lot-to-lot consistency. After approval, the manufacturer must submit the
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`https://www.fda.gov/vaccines-blood-biologics/development-approval-process-cber/vaccine-development-101
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`BioNTech-Pfizer Exhibit 1148
`BioNTech SE and Pfizer Inc. v. ModernaTX, Inc. IPR2023-01359
`Page 5 of 6
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`Vaccine Development – 101 | FDA
`following materials relating to that vaccine lot (or “batch”)
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`Protocols: contain the agreed-upon tests.
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`Results: the results of the testing performed by the manufacturer. Testing typically includes assessment of
`purity, potency, identity and sterility.
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`Samples: generally, the manufacturer must submit samples of the vaccine from the lot in question to permit
`FDA to perform confirmatory testing.
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`Manufacturers are not permitted to distribute a specific lot of vaccine until the FDA releases it.
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`FDA Research Provides a Unique Perspective
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`Research is fundamental to FDA's ability to provide effective scientific and regulatory evaluation of vaccines. FDA
`conducts its research activities in conjunction with its regulatory activities, which provides the Agency a unique
`perspective on both fronts. A wide variety of rapidly evolving technical and scientific issues concerning the safety,
`potency, and effectiveness of vaccines requires knowledge of new developments in basic research in the relevant
`biological disciplines. For this reason, FDA scientists conduct a variety of research that contributes to policy, risk
`assessments, new methods and standards, and changes to product labeling, including promoting new techniques
`for assessing vaccine safety and potency, as well as strategies for vaccine development.
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`https://www.fda.gov/vaccines-blood-biologics/development-approval-process-cber/vaccine-development-101
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`BioNTech-Pfizer Exhibit 1148
`BioNTech SE and Pfizer Inc. v. ModernaTX, Inc. IPR2023-01359
`Page 6 of 6
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