The sheer size of the COVID-19 vaccine clinical trials will enhance prelicensure safety and efficacy evaluation. Many post-market evaluations are in development to bolster existing surveillance for adverse events, says Grace Lee, MD, MPH, a member of CDC’s Advisory Committee on Immunization Practices (ACIP).
“The FDA typically advises a minimum population size of approximately 3,000 individuals for prelicensure assessments of vaccine safety,” Lee and colleagues wrote in a recent paper. “In contrast, Phase III clinical trials for COVID-19 vaccines are enrolling or plan to enroll between 30,000 to 50,000 individuals each, providing the largest databases on prelicensure vaccine safety to date and an opportunity to better understand safety profiles within and across vaccine candidates prior to approval.”1
A pediatrician and professor at Stanford University, Lee also chairs the ACIP COVID-19 Vaccine Safety Technical Subgroup.
“These are some of the biggest trials we’ve seen,” she says. “The reason for the size of these trials is really for the speed [of vaccine development], because they need to detect an efficacy signal of at least 50%, with a lower boundary of 30%. Because of the need for the high numbers, it actually is a great opportunity for vaccine safety.”
Typical Phase III trials with a much smaller number of participants may take many years to parse these data, she notes.
“One way to gain [statistical] power is by following people for a long period of time,” she says. “The other way is to really focus on high numbers and make sure you are in areas where they are at a high risk of infection so they can challenge efficacy. It is an advantage for safety because, typically, we don’t see trials of this size that capture safety data.”
In the United States, eight vaccine candidates have received federal support under Operation Warp Speed, and four have entered Phase III trials.
“Vaccines will be critical for the prevention and control of COVID-19 in the U.S. and worldwide, yet these efforts cannot succeed without public confidence in a vaccination program,” Lee and co-authors emphasized. “Demonstrating vaccine efficacy and safety during clinical trials and implementing a robust post-licensure vaccine safety monitoring system as the vaccine is deployed in larger, more diverse populations is central to public confidence and enabling timely and accurate policy decisions for population-level use.”1
Although it was treated as a political victory over Trump administration pressure at the time, Lee questions if the FDA fell short in requiring submitted vaccine data to include a median of two months follow-up for a least 50% of the population
“I wish it were all of the population,” she laments. “That means if you have 30,000 trial participants, 15,000 of them would have two months follow-up at a minimum.”
Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research (CBER), acknowledged the two-month period has also been questioned in a live-streamed interview. (The interview is available at: https://www.youtube.com/watch?v=43XAc5iDN9k&ab_channel=JAMANetwork.)
“While it would be nice to have [longer], we have to balance the safety we get up front with the need to try to save lives with the vaccine,” Marks said. “We have a virus that is killing some 1,000 people a day in the [United States], so there is a balance there.”
With healthcare workers designated by ACIP as the first group to receive COVID-19 vaccines, they will be the subject of active and passive surveillance systems to detect adverse events. One system that will be used is the CDC’s National Healthcare Safety Network (NHSN), which primarily conducts surveillance for healthcare-associated infections in hospitals and long-term care facilities.
“NHSN routinely collects annual aggregate data on healthcare personnel influenza vaccination rates and is currently exploring the additional capture of COVID-19 vaccination rates,” the authors noted. “Capabilities for enhanced monitoring of early COVID-19 vaccine recipients (e.g., essential workers) through smartphone or web-based surveys are also being developed to capture potential adverse events following vaccination.”1
While the larger vaccine trials will capture a lot of prelicensure safety data for short-term adverse events, “they won’t speak to anything long-term,” Lee says. “As each of these trials go on they will potentially be submitted to FDA at different time points so all of those data wouldn’t be available immediately. But cumulatively, over time, we would start to see from the various vaccines what might come in.”
Adverse events of special interest related to vaccines include allergic reactions, Guillain-Barré syndrome, transverse myelitis, myocarditis/pericarditis, vaccine-associated enhanced respiratory disease, and multisystem inflammatory syndrome in children. Vaccine safety systems include the longstanding Vaccine Adverse Event Reporting System (VAERS), which relies on clinicians, manufacturers, and public reports.
“VAERS is co-managed by the FDA and CDC and serves as an early warning system for potential safety signals that may be temporally related to vaccines,” the authors noted. “The rapid identification of an intussusception signal after widespread use of rotavirus vaccines in infants exemplifies the essential role of passive surveillance in the U.S.”1
Active systems include the Vaccine Safety Datalink (VSD), a three-decade partnership between the CDC and nine healthcare systems. VSD collects healthcare encounter data and electronic medical records to capture vaccine outcomes in more than 11 million patients.
VSD uses “near real-time capabilities for signal detection, signal refinement, and signal evaluation. … These well-established active safety surveillance systems form the foundation of monitoring COVID-19 vaccine safety,” the authors concluded.1
Regardless, some level of risk is part of any medical intervention — and much of life, for that matter, Lee says.
“There is the question of benefits and risks to a population, and there is the question of the benefits and risks to an individual,” she says. “You have to weigh the benefits and the risks to make sure, and you try to mitigate those risks as much as possible. We also see, for example, that there are vaccines that have local reactions and systemic reactions. For example, zoster vaccine can be quite reactogenic. A lot of people get pretty significant local side effects, like tender and swollen arms at the site of the injection, or some people get low-grade temps and myalgias.”
- Lee GM, Romero JR, Beth BP. Postapproval vaccine safety surveillance for COVID-19 vaccines in the US. JAMA 2020; doi:10.1001/jama.2020.19692. [Online ahead of print].