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US FDA Needs To Harmonize Postmarket Safety Plans For COVID Vaccines, CDC Advisors Urge

US FDA Needs To Harmonize Postmarket Safety Plans For COVID Vaccines, CDC Advisors Urge

Source : 'The Pink Sheet'

Harmonized safety endpoints and post-market protocols that can be deployed among multiple pharmacovigilance systems should be developed to enable faster identification and evaluation of safety signals with COVID-19 vaccines post-authorization or licensure, three members of the US Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices say.

The US Food and Drug Administration should issue guidance on harmonized safety endpoints to be used in Phase III and post-market clinical trials of COVID-19 vaccines, the ACIP members, Grace Lee of Stanford University, José Romero of the Arkansas Department of Health and University of Arkansas, and Beth Bell of University of Washington wrote in a 16 October viewpoint in the Journal of the American Medical Association. Lee and Bell are also members of ACIP’s COVID-19 Vaccine Safety Technical (VaST) working group.

This guidance should be similar to that FDA developed on clinical and immunological endpoints for COVID-19 vaccine efficacy, they said. ()

Harmonization of safety endpoints is also needed for other post-approval surveillance systems, the trio wrote.

FDA has already said it plans to make up for any limits in safety data at the time of a vaccine EUA with enhanced pharmacovigilance. () 

FDA is in the process of considering which adverse events it will focus on post-market (see sidebar) and the JAMA editorial underscores the close coordination the agencies will need to have for COVID vaccine monitoring to be successful.

Harmonized protocols for surveillance systems will help speed the time from signal identification to signal evaluation, the JAMA editorial argues, by making it easy to explore whether a signal detected in one safety surveillance system is similar to that found in other systems. Protocol harmonization will also help validate findings in medical record reviews and epidemiological studies.

The three ACIP members suggest dividing lists of adverse events of special interest into three categories: general, platform-specific and special populations, due to the large number of vaccines. General safety endpoints will be broadly applicable, while platform-specific safety endpoints would apply to particular vaccine technology like the novel mRNA platforms. Population-specific endpoints would be tied to groups like pregnant women, older adults or children.

ACIP’s VaST working group is reviewing the capabilities and protocols of existing and novel vaccine safety surveillance systems that will be used for COVID-19. The JAMA piece outlines the range of these systems available to the US, including FDA and CDC’s comanaged Vaccine Adverse Event Reporting System, which passively relies on reporting by patients, family members, health care professionals and manufacturers.

According to the ACIP members, groups are looking at ways to enhance passive surveillance systems by pairing them with systems designed to track COVID-19 vaccine administrations. This will provide some data on the total denominator of people administered a vaccine to estimate rates of adverse events in target populations.

Active surveillance is conducted by the Vaccine Safety Datalink a collaboration between CDC and 9 health systems that can get near real-time data on vaccines and outcomes of interest in about 11.3 million insured patients. The US Veterans Affairs Department can conduct active surveillance in about 6.4 million veterans and the FDA-Centers for Medicare and Medicaid Services active surveillance program has access to data on more than 50 million people older than 65.

The CDC’s National Healthcare Safety Network, which tracks health-care associated affections in acute care hospitals and long-term care facilities, is regularly used to collect data on health care personnel flu vaccinations rates and may be able to be used to get data on COVID-19 vaccine rates. This would be helpful to track the safety of COVID-19 vaccines in health care personnel who are likely to be some of the first in the US vaccinated, the ACIP members say.

Another issue for the post-market evaluation of COVID-19 vaccines is that there are some unique aspects of the virus that will create challenges for using the common “test-negative” case-control design to evaluate the real-world performance of the products, another JAMA viewpoint published on 16 October says.

Manish Patel and Jill Fedinands of CDC’s COVID-19 Response Team, and Michael Jackson of Kaiser Permanente Washington Health Research Institute, said one factor that may introduce bias into these studies is the limitations of the diagnostic assays used to test for COVID-19.

To control for this bias, investigators might want to couple a SARS-CoV-2 positive test result with a case definition for severe COVID-19 as a primary outcome of interest. They also suggested clinically adjudicating test-positive cases and test negative cases by independent expert clinicians blinded to the study design to help reduce bias.

“Postlicensure vaccine evaluations will be a crucial component of an evidence-based SARS-CoV-2 vaccine program as it is used around the world. Anticipating potential pitfalls of these evaluations and identifying creative solutions to meet challenges posed by the complex biological effects of COVID-19 will improve study validity. With such high stakes, reflexively relying on the test-negative design as a fail-safe approach for vaccine evaluations may not be prudent unless modified to address the potential weaknesses of assay validity for diagnosing severe COVID-19,”  the authors write.

By Sarah Karlin-Smith