On Sunday, Aug. 30, Food and Drug Administration (FDA) Commissioner Dr. Stephen Hahn signaled a willingness to fast-track the approval process for a COVID-19 vaccine through an emergency use authorization (EUA). In this post we examine the standard process by which vaccines are approved.
Commissioner Hahn indicated that an EUA could be granted to a vaccine before Phase 3 clinical trials have concluded. We have previously written about EUAs, which have a less rigorous review process and standards than traditional approvals.
In the U.S., the FDA Center for Biologics and Evaluation Research is the entity charged with the task of regulating biological products for human use, including vaccines. This authority is cited in Section 351 of the Public Health Service Act along with sections of the Federal Food, Drug, and Cosmetic Act.
In contrast to expedited approval avenues, there are multiple steps leading to the traditional licensure, or approval, of a vaccine. First, there is the pre-licensure phase. Initially, this phase includes the development of the vaccine itself by its manufacturer, requiring laboratory testing to ensure the vaccine has potential and that it is safe to use in people. A vaccine sponsor must also submit an Investigational New Drug application to the FDA, which describes the vaccine, how it is manufactured, and what quality-control tests will be conducted.
The next part of the pre-licensure phase includes clinical trials. As we discusses in a previous post, clinical trials are a vital component of the development process for vaccines, medications, and other medical treatments. At this writing, there are 36 vaccines for COVID-19 in clinical trials on humans and another 90 preclinical vaccines under active investigation in animals. The New York Times Vaccine Tracker provides a snapshot of where vaccines stand in the approval process.
Clinical trials include the following distinct phases:
- Phase 1: The objectives of this phase are to determine whether the intervention being tested is safe and determine an appropriate dosage. Usually, fewer than 100 healthy people receive the intervention and are closely observed to identify any adverse reactions or side effects.
- Phase 2: In this phase, the objective shifts to testing whether an intervention works in treating a particular condition, and the trial enrolls people with that condition. At this stage, more people may receive the intervention (usually 100‒300). Researchers continue to monitor side effects and gather other key information they need to begin designing Phase 3 of the clinical trial.
- Phase 3: The objective of this phase is to prove that an intervention works in treating the condition, particularly when compared to other existing treatments for the same condition. This phase requires randomization ― for example, giving some participants the new medication being tested and giving other participants an existing medication used to treat the disease. Side effects continue to be monitored, and researchers may enroll as many participants as the study design requires at this stage, often 1,000 or more. The FDA also emphasizes the importance of adequate representation of racial and ethnic minority populations in clinical trials since these populations have been adversely affected by COVID-19.
If there is successful completion of all three clinical trial phases, the vaccine sponsor submits a Biological License Application which is then considered by an FDA review team. Following this review, the sponsor and the FDA may present their findings to the FDA’s Vaccines and Related Biological Products Advisory Committee, which makes a recommendation to the FDA. The approval process also requires the submission of adequate product labeling to allow healthcare providers and consumers to understand how to use the vaccine, along with potential risks and benefits.
Following the completion of these activities, the vaccine may be approved by the regulatory agency and can be marketed. This also marks the post-licensure vaccine safety monitoring period. The FDA collects data to monitor adverse events associated with the vaccine, which is housed in the Vaccine Adverse Event Reporting System (VAERS). This is a national system used by both the FDA and the Centers for Disease Control and Prevention (CDC) to collect reports of adverse events happening after people receive the vaccine. Additionally, scientists also use the CDC’s Vaccine Safety Datalink to perform studies to determine if side effects reported to VAERS are related to specific vaccinations.
In June, the FDA issued guidance on the development and licensure of COVID-19 vaccines, asserting that “the goal of development programs at this time should be to support traditional FDA approval by conducting studies to directly evaluate the ability of the vaccine to protect humans from SARS-CoV-2 infection and/or disease.” However, the guidance also states that consideration for the FDA’s accelerated approval process may be available to vaccine candidates if an immune response or another measure likely to predict clinical benefit is identified. The same guidance indicates that any potential EUA for a COVID-19 vaccine would be made on a case-by-case basis and be data-driven, noting that the FDA would only approve an EUA for vaccines that demonstrate at least 50% efficacy.