This Op-Ed by the U.S. Food & Drug Administration was originally published in USA Today. Placement of this Op-Ed does not imply promotion, nor unofficial or official endorsement, by the United States Air Force Office of the Air Force Surgeon General.
Trust means everything. Trust in vaccines facilitated the incredible positive impact that vaccination had on public health in reducing illness and death over the past century. In the middle of a global pandemic, it is precisely a safe and effective COVID-19 vaccine that will help bring life back to normal if people are willing to receive the vaccine because they have confidence in it. Therefore, it is critical to be open and transparent about the process that the U.S. Food and Drug Administration will follow to help make safe and effective COVID-19 vaccines available.
At the FDA, we uphold globally respected standards for product quality, safety, and efficacy. We monitor the entire process of vaccine development from beginning to end and then follow these products after they are made available to the public. And we pledge to do our duty to the best of our ability, independently and without conflicts of interest.
How we test vaccines
Before any vaccine is made available, it must undergo a rigorous development process. Manufacturing is critical - every dose must be consistent and of high quality. Additionally, extensive testing in clinical trials is conducted. Initially, a vaccine is given to small numbers of people to see if it is safe (phase 1), and then to see if it produces an immune response (phase 2). If it shows enough promise after these phases, it is rigorously tested in one or more large clinical trials in which people are randomly assigned to receive the vaccine or a placebo (phase 3). For vaccines approved over the last several years, the number of participants in all three phases of development has ranged from 5,000 to 65,000, with an average of 21,750 per vaccine.
In phase 3 trials that are designed to show whether a vaccine really works, neither people receiving the vaccine nor those assessing the outcome know who received the vaccine or the inactive comparator. Only an independent monitoring group can access this information, when necessary, to protect the safety of trial participants. To evaluate efficacy, the number of clinical events, such as getting the disease that the vaccine is supposed to prevent, are counted in a systematic pre-determined manner.
During the entire time that the efficacy of the vaccine is being evaluated, safety events are also closely followed. The specifications for success are also determined in advance. If the evidence from the clinical trial meets these specifications, the trial can potentially be submitted to FDA in support of a Biologics License Application (BLA) or a request for Emergency Use Authorization (EUA).
Several COVID-19 vaccines are now being studied in phase 3 trials. These trials already involve, or will eventually involve, 30,000 or more people each. Such large trials may be able to show clear and compelling efficacy within a few months if the virus that causes COVID-19 is circulating sufficiently in the area in which the study is being conducted to cause enough cases to occur.
What is “clear and compelling” efficacy? For a vaccine to be successful in these phase 3 trials, FDA has recommended to manufacturers in guidance that the vaccine be at least 50% more effective than the inactive comparator, and that the outcome be reliable enough so that it is not at all likely to have happened by chance. Of course, it is hoped that the vaccines will prevent a much higher percentage of cases, but the 50% figure establishes the minimum efficacy of a COVID-19 vaccine that FDA could find acceptable.
Following clinical trials, manufacturers normally spend months analyzing data prior to submitting a BLA to request approval from FDA to market the vaccine. A BLA can encompass tens of thousands of pages, and usually takes FDA several months to review. During this review period, FDA may present the data at a public advisory committee meeting for input, prior to making its final decision on whether to approve the vaccine.
But these are not “normal” times. In the United States, we have seen many hundreds of people die every day from COVID-19. Because of this public health emergency, manufacturers may choose to submit a request for an EUA. Congress established this pathway after the terrorist attacks of 9/11 to ensure that, during public health emergencies, potentially lifesaving medical products could be made available before being approved. Under the Federal Food, Drug, and Cosmetic Act, the statutory criteria to issue an EUA are that the product “may be effective” in preventing a serious or life-threatening disease or condition, and that the product’s known and potential benefits, when used to prevent such a disease or condition, outweigh its known and potential risks.
How this EUA standard is applied of course depends on the product and how it will be used - if a product will be used to treat hospitalized patients for whom there is no other therapy, the potential benefits may outweigh the risks even if there is uncertainty about effectiveness and there are real, but acceptable, safety concerns. On the other hand, where a vaccine will be given to healthy individuals, the risk-benefit analysis is different. For a COVID-19 vaccine that could be administered to millions of individuals, including healthy people, FDA will only issue an EUA if a vaccine has demonstrated clear and compelling efficacy in a large well-designed phase 3 clinical trial, much like would be required for a BLA.
Careful evaluation and no rushing
This process will not be rushed. There will be no shortcuts in developing the relevant phase 3 efficacy results. Any vaccine showing efficacy must also be very safe. While the duration of safety follow-up for a vaccine authorized under an EUA will be shorter than with a traditional BLA (which the agency expects will ultimately be submitted by manufacturers of vaccines that are authorized under an EUA), extensive safety monitoring will be conducted on the millions of individuals who receive a vaccine.
This monitoring is done for other newly-approved vaccines. It will detect new, unusual and rare side effects after vaccination that might not have been observed during clinical trials, as well as monitor for increases in known side effects.
In addition to this careful evaluation by staff at FDA, we intend to take any COVID-19 vaccine EUA or BLA submission to a public advisory committee meeting for open discussion. FDA’s Vaccines and Related Biological Products Advisory Committee consists of leading independent scientific and public health experts, carefully screened for any potential conflicts of interest, who provide input to FDA. The materials discussed during open sessions of these meetings, which will be live-streamed, will be posted on FDA’s website.
We hope to ensure public confidence in COVID-19 vaccines by being transparent about FDA’s decision-making process. Whether a vaccine is made available through an EUA or through a traditional approval, FDA will ensure that it is safe and effective. With high uptake, COVID-19 vaccines have the potential to save many lives in the United States that may otherwise be lost. And saving as many lives as is possible must be the goal that we strive to achieve together.
Dr. Peter Marks is director of the Center for Biologics Evaluation and Research at the U.S. Food and Drug Administration.