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Ensuring The Safety And Effectiveness Of A COVID-19 Vaccine

Anand Shah, M.D.

By Anand Shah, Peter Marks, and Stephen Hahn

The COVID-19 pandemic has significantly disrupted society, with necessary social distancing measures to reduce the risk of transmission resulting in the closure of businesses, schools, and other aspects of daily life. To help protect individuals from infection and support a return to normal, the United States government is focused on supporting the development of a vaccine for COVID-19. However, vaccine development, even under normal circumstances, is an arduous endeavor.

Given that recent polling indicates evidence of vaccine hesitancy among Americans for COVID-19, it is also necessary for public health officials to offer reassurance that any potential vaccine will be safe and effective. The Food and Drug Administration (FDA) has taken two key steps on this matter. First, the agency established clear recommendations for vaccine performance prior to the initiation of Phase 3 trials to provide assurance that any authorized vaccine will meet appropriate standards for safety and effectiveness. Second, FDA has committed to use an advisory committee composed of independent experts to ensure deliberations about authorization or licensure are transparent for the public. In this blog, we will clarify the ongoing government activities for a COVID-19 vaccine and detail the steps FDA has taken to ensure the safety and effectiveness of a potential vaccine.

The Landscape Of Federal Activities On COVID-19 Vaccines

The United States has taken a whole of government approach to the COVID-19 pandemic response. This same approach applies to the process of vaccine development. Key initiatives include Operation Warp Speed (OWS) and Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV).

OWS is an initiative led by the Separtment of Health and Human Services and the Department of Defense to fund the development of COVID-19 therapeutics, devices, and vaccines, prioritizing candidate medical products based on scientific merit. OWS has currently selected 5 vaccine candidates for funding to facilitate accelerated development. The public-private partnership is also focused on ensuring adequate supply of potential vaccines through investments in manufacturing capacity and through the development of a distribution methodology informed by multiple factors – such as pandemic influenza planning and COVID-19 impact on populations).

The goal of ACTIV — established by the National Institutes of Health in April 2020 — is to develop a framework for identifying therapeutic and vaccine candidates and support coordination across government partners to ensure regulatory consistency and clinical rigor.

In assisting each of these efforts, FDA’s role has been to provide expertise on evidence requirements, regulatory processes, and safety considerations.

As a whole, the government is focused on accelerating vaccine development where possible due to the urgent public health need for such products. However, prioritizing development does not mean that FDA’s responsibility for review and standards for approval have shifted. As a science-based regulatory agency, FDA decisions will continue to be made in accordance with the agency’s established legal and regulatory criteria for safety and effectiveness.

Guidance For Vaccine Development And Licensure

To provide regulatory clarity to the medical and scientific community, FDA outlined key considerations for a COVID-19 vaccine in its June 30 guidance. This guidance provides technical details for developers on study design and recommends the type of evidence sponsors need to provide to demonstrate that a potential vaccine is safe and effective for use in diverse populations. While the agency advises interested parties to refer to the guidance for full details, key considerations are described below.

First, it recommends that clinical trials for COVID-19 vaccines be sufficiently powered to demonstrate meaningful effects for the intended population. Given that the virus has disproportionately affected specific populations (e.g., racial minorities, elderly adults, individuals with comorbidities), sponsors should ensure that study populations for clinical trials include adequate representation from these groups. The guidance document also includes recommendations for how sponsors should approach the enrollment of specific populations, such as pregnant women and frontline health care workers.

Second, the guidance recommends that sponsors follow best practices for clinical research, with FDA recommending the use of randomized, double-blinded, and placebo-controlled study designs. FDA recognizes that the pandemic poses unique challenges to clinical trials and has previously issued guidance on this topic. The agency has also included considerations for how sponsors can use adaptive trial designs as well as trials with a shared control arm in the June 30 guidance.

Third, FDA provides recommendations about the standards for the safety and effectiveness of a COVID-19 vaccine. The agency recommends that sponsors use placebo-controlled randomized trials to test vaccine candidates which, to be considered effective, should prevent COVID-19 in at least 50% of patients. FDA believes an endpoint estimate of at least 50% is a reasonable threshold for a COVID-19 vaccine based on the public health situation and the evidence on preventive vaccines for other infectious disease.

For example, the Centers for Disease Control and Prevention indicates that flu vaccines typically reduce Americans’ risk of illness by between 40% to 60%. For a pathogen like the novel coronavirus, which is highly transmissible and has claimed the lives of more than 160,000 Americans, a vaccine that could prevent the majority of people from becoming infected would be a tremendous step forward towards herd immunity and a return to normal life.  Furthermore, prospectively  recommending this primary endpoint estimate for approval should provide transparency to patients, providers, policymakers, and industry about how FDA intends to review evidence from completed trials. For safety, we recommend that sponsors follow existing best practices for preventive vaccines, which includes a pre-licensure safety database comprising at least 3,000 participants.

Fourth, FDA is committed to engaging in post-licensure safety evaluations for COVID-19 vaccines, which may include the submission of a pharmacovigilance plan and a requirement for sponsors to complete a post-marketing safety study.

Committing To Scientific Integrity

Access to a safe and effective vaccine will be a critical component of the public health response to the COVID-19 pandemic. FDA is hopeful that its proactive guidance on key issues such as trial design and statistical considerations will provide regulatory clarity to sponsors that are currently in the process of planning clinical trials. For example, many sponsors have set enrollment targets for tens of thousands of patients to ensure that studies are adequately powered to demonstrate safety and effectiveness. These developments are necessary steps to help ensure that evidence on potential vaccines is of high quality.

FDA is also committed to ensuring that data from COVID-19 vaccine trials is reviewed in a transparent, deliberative manner. To this end, the agency intends to convene its Vaccines and Related Biological Products Advisory Committee (VRBPAC) when data from trials becomes available. VRBPAC is one of the many advisory committees at FDA, and is composed of independent experts in the fields of vaccine safety and infectious disease. By convening VRBPAC, FDA will ensure public transparency around discussions of vaccine safety and effectiveness tp provide a window into its decision-making process and help address potential concerns from vaccine-hesitant populations.

As trials reach completion in the coming months, we are committed to ensuring the agency impartially reviews the evidence and reaches decisions based on established regulatory standards.

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