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February 15, 2021

The US Regulatory System and COVID-19 Vaccines: The Importance of a Strong and Capable FDA

Author Affiliations
  • 1Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland
  • 2Medicine and Infectious Diseases, Georgetown University, Washington, DC
  • 3In-Q-Tel, Arlington County, Virginia
JAMA. 2021;325(12):1153-1154. doi:10.1001/jama.2021.1961

For many in public health and medicine, the coronavirus disease 2019 (COVID-19) pandemic in the US has been a frustrating journey from one disappointment to the next: late access to testing, insufficient staff and inadequate funding for contact tracing, jumbled communications, and, at the end of 2020, a chaotic launch of vaccination efforts. But in one area, from the beginning of the pandemic to the present, the US has excelled: facilitating the rapid development of COVID-19 vaccines. Much of the credit has justifiably gone to the scientists who adopted and created the technology, to the companies that made the vaccines, to the participants who volunteered for clinical trials, to the National Institutes of Health, and to Operation Warp Speed, which funded several candidate vaccines, minimizing financial risk for the companies. A less recognized partner in this effort—but no less essential to its success—is the US Food and Drug Administration (FDA).

In early spring 2020, the quest to develop vaccines was described as a competition between nations, with anticipation that countries first to vaccinate would gain a geopolitical advantage.1 As the virus spread from country to country, governments had to decide among dozens of competing technologies, many with a plausible argument for success. Biomedical researchers from across the world joined the effort to develop a vaccine. Global efforts to develop vaccines provided early funding, and national leaders planned to spend whatever resources would be necessary.

From the start of this effort, a pivotal question was how to define success. What evidence would be required to assess risks and benefits and to know whether a vaccine is ready for broad use?

The FDA approached these questions by engaging colleagues at the National Institutes of Health, working with scientists at the companies, hearing from academic experts, and then, most importantly, by relying on the experience of the agency’s own scientists in the Office of Vaccine Research and Review, many of whom have spent their careers overseeing and assessing vaccine development. Early questions included what toxicology studies were needed, how to assess safety and immune response in the early human trials, and how to select a dosing regimen.

The FDA then had to decide on the types and amounts of scientific evidence needed to determine that a vaccine candidate is safe and effective for use by millions of people. The agency came under substantial pressure to consider authorizing vaccines based on immunogenicity data that measure a vaccine’s ability to induce an immune response. However, given limited scientific understanding of what constitutes protective immunity to severe acute respiratory syndrome coronavirus 2, the agency, with support from many leading scientists, insisted on meaningful clinical outcomes.2 In a widely read guidance released in June 2020, the agency said that for licensure, a vaccine would need to achieve at least a 50% reduction in COVID-19 disease, with confidence intervals that excluded less than a 30% reduction.3 This guidance required companies to establish safety and efficacy of their vaccines by conducting large, diverse, controlled phase 3 clinical trials involving tens of thousands of patients. The FDA scientific staff then worked closely with the World Health Organization in efforts to promote high standards globally.

Not all nations waited for clinical results before using vaccines widely. In August 2020, Russia approved its vaccine and reportedly had administered it to more than 2 million people before completing trials or releasing data about its safety and efficacy. Neither naming their vaccine Sputnik nor declaring the race over answered serious questions in the scientific or clinical community. In September, China began vaccinating thousands of people, including employees at state-owned businesses, government officials, and company executives, also before clinical trials were completed.

In October 2020, the FDA built on its earlier guidance on standards for licensure to explain what data would be needed to support the potential interim step of Emergency Use Authorization.4 The agency’s scientists and, ultimately, Commissioner Stephen Hahn resisted White House efforts to prevent the issuance of this guidance and to establish a low bar, such as relying only on very early and interim data with minimal safety information. Instead, the agency required a minimum number of clinical cases, including serious disease, to occur in the clinical trial cohort before reaching an efficacy end point, and required a median of 2 months of safety follow-up, as well as submission of a full data set for its own analysis of the data.

In November, Pfizer-BioNTech and then Moderna announced positive results of their clinical trials. The FDA quickly conducted its own analyses of the companies’ raw data, confirming high efficacy and a reassuring safety record across age groups during the postvaccination period to date, while providing new insights from its analyses, including about potential safety issues to monitor going forward. The FDA released its detailed review publicly as it convened its advisory committee twice, once for each vaccine. The agency livestreamed the committee’s many hours of deliberations.

This transparency mattered.5 Anyone who wanted could appreciate the FDA’s detailed review and understanding of the data and listen to experts and members of the public debate difficult questions. Science journalists reported on these deliberations and their outcomes: resounding votes of support to move forward with authorization and a program of careful monitoring. By the start of 2021, the US had constructed a powerful, public case for why, in the setting of a devastating pandemic, the benefits of the vaccines outweighed the risks, a precondition for a successful vaccination campaign. Compare this process of establishing and publishing standards, making data publicly available, and allowing the public to listen to the discussion between an advisory committee and the FDA with the process in Russia, in which trial results were reported 5 months after approval and without independent reanalysis of the data or significant public discussion.

It is not difficult to imagine how the US might have stumbled. Had the FDA not insisted on rigorous requirements for clinical trials, the data emerging in the fall of 2020 might not have been convincing, and the US might still be confused, as other nations are, about data gaps such as how well a different vaccine works in older adults.6 Had the FDA not released comprehensive analyses of study data, trust in vaccines, already at risk, likely would have been further compromised.7,8 Had the White House been perceived as influencing the FDA’s review (as had previously happened with the authorization of hydroxychloroquine, later shown ineffective for treating COVID-19), multiple governors were ready with their own committees to review the data on their own. The ensuing confusion would have created substantial new doubts about the vaccine.

A year into the pandemic, it is clear that the search for vaccines against COVID-19—while still perceived in many quarters as a competition among nations—is more fundamentally a confrontation between humanity and the virus. With the need to distribute the vaccine equitably across the US and provide access across the globe, as well as with the emergence of new variants that may evade vaccines and therapeutics, many lives are at risk. In the coming weeks to months, the FDA will lead the review and potential authorization of additional vaccine candidates, assess the duration of immunity and the need for booster doses, and continue to collaborate with the US Centers for Disease Control and Prevention and global public health to monitor vaccine long-term safety and effectiveness. The FDA will also have to define pathways for assessment and authorization of modifications to COVID-19 vaccines that can, as needed, address new virus variants. To meet these and other difficult challenges, it will be essential for the FDA to remain true to the guiding principles of scientific rigor, integrity, and transparency.

Despite numerous failures during the pandemic, the US succeeded in developing safe and effective vaccines, and, at the start of 2021, the nation is well positioned to work with global organizations and other nations to address the many challenges ahead. US success and global leadership will continue to depend on innovative science, sufficient resources, and a strong and capable FDA.

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Article Information

Corresponding Author: Joshua M. Sharfstein, MD, Bloomberg School of Public Health, Johns Hopkins University, 615 N Wolfe St, Room W1033D, Baltimore, MD 21205 (joshua.sharfstein@jhu.edu).

Published Online: February 15, 2021. doi:10.1001/jama.2021.1961

Conflict of Interest Disclosures: Dr Goodman reported receiving personal fees and nonfinancial support from GlaxoSmithKline and Intellia Therapeutics, and nonfinancial support from US Pharmacopeia outside the submitted work. Dr Borio is a vice president at In-Q-Tel. No other disclosures were reported.

Additional Contributions: We acknowledge Margaret A. Hamburg, MD (Nuclear Threat Initiative), for her suggestions. She did not receive compensation.

Additional Information: Dr Sharfstein served as the former Principal Deputy Commissioner of the US Food and Drug Administration (FDA) from 2009 to 2011. Dr Goodman served as chief scientist of the US FDA from 2009 to 2014. Dr Borio was director for medical and biodefense preparedness policy at the US National Security Council from 2017-2019 and the acting chief scientist at the US FDA from 2015 to 2017.

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2 Comments for this article
Proper Role of the Principle of Self-autonomy?
Paul Dexter, MD | Hospitalist
I agree with the authors on the profound success and speed by which effective and safe vaccinations were made available to the public. As they indicate, credit goes to the scientists, to companies, to participants, to the National Institutes of Health, and to Operation Warp Speed. Such diligent efforts are necessary to build confidence in the many individuals who remain skeptical of vaccine safety.

However, in the interests of the principle of autonomy and self-determination, and in the face of a virus with significant risks of mortality and morbidity, I would raise the question of whether a
more flexible system that accommodates vaccination at earlier stages in the testing process would be useful.

Outside of randomized trials, which were not available to “everyone,” there were no options for vaccination for 9 months. Given uncertainties associated with both the virus and vaccines, some of us would have chosen vaccines at a relatively early stage (e.g., perhaps after the first 100 vaccinated individuals with a minimal follow-up period). There would be value to a dynamic informed consent, given that knowledge about both the virus and vaccine changed markedly over time.

The randomized trials do need to proceed for all the reasons outlined by the authors, including rampant skepticism about their safety. However, if a few million adult individuals had chosen to take an incompletely proven vaccine, follow-up of this cohort would only supplement scientific evidence with respect to the vaccine. The primary question is whether recruitment into the trials would have slowed if there had been other methods to obtain the vaccine.

The question with respect to the appropriate role for self-determination has value primarily for purposes of preparing for any future pandemic. If the mortality rate of such a pandemic were markedly higher, it would push the case to provide an option for earlier emergency use of vaccination while trials proceed. Given that the value and safety of mRNA technologies has become much clearer, that might also tilt the case for earlier mRNA-based vaccination in future pandemics.

An ethicist might appropriately best work through the various issues. There are principles of autonomy, societal safety, whether only allowing the possibility of vaccination as part of trials is coercive, whether an informed consent should be regarded as a dynamic document.
FDA Status Quo or Activist
Greg Schwemer, MS, Ph.D. | Private Practice
In the wake of the pandemic, the FDA delayed the approval of the first two mRNA vaccines until both submission and advisory committee approval. This is status quo for the agency. This comment is to suggest an alternative in emergent situations. Just as the media would "embed" reporters in combat situations, perhaps we should consider such a scenario in a pandemic setting. How many lives would have been saved if the FDA had embedded reviewers in concert with the leading companies with the intent of emergency conditional approval when efficacy was highly likely? Safety monitoring would assure public health concerns and early launch mechanisms would jump start the vaccination process.