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Behind the Scenes of COVID-19 Vaccine Review

A vaccine card, an NC State-branded bandage and a syringe containing the Janssen vaccine

Since last year, Anastasios “Butch” Tsiatis, professor emeritus of statistics, has served on the Data and Safety Monitoring Board for the U.S. government-sponsored clinical trials evaluating COVID-19 vaccines such as those developed by Moderna, AstraZeneca, Johnson & Johnson and Novavax.

Tsiatis had previously served on other vaccine trial monitoring boards and as a statistical consultant for the World Health Organization.

He talked to us about the work of the Data Safety Monitoring Board and how statistics expertise can help in evaluating the COVID-19 vaccines, some of the most scrutinized pharmaceuticals in history.

Describe the charge and composition of the Data and Safety Monitoring Board.

The purpose of the Data Safety Monitoring Board (DSMB) is to ensure the safety of study participants and the rigor and integrity of the clinical trials that it monitors. The COVID-19 vaccine DSMB is part of Operation Warp Speed and is responsible for reviewing and monitoring all U.S. government-supported clinical trials of candidate COVID-19 vaccines.

The board consists of 11 members from the United States, Brazil, South Africa and the United Kingdom, and includes experts in infectious disease, vaccinology, immunology, biostatistics, pharmacoepidemiology, public health and biostatistics.

When did you begin serving on the board, and how were you appointed? Had you served on this type of board before?

On June 9, 2020, I received a letter from Dr. Anthony Fauci inviting me to serve on the COVID-19 vaccine DSMB. I was honored to be asked and immediately accepted to serve.

I’ve been serving on DSMBs for government-sponsored clinical trials for almost 40 years, including clinical trials for vaccines for AIDS, cancer, diabetes and cardiovascular disease.

What has been your role on the board?

The other DSMB members and I review all the accrued safety and efficacy data for the trial being monitored. My focus is on the statistical aspects of the reports. When a clinical trial is first proposed, the other statisticians on the board and I carefully review the statistical analysis plan and check all the calculations that describe the sample sizes being proposed and the analyses that will be conducted. We also review all the tables and plots that will be presented to the board to ensure that all the relevant information will be captured so that the board can make the most informed decision regarding the study.

How does statistics expertise apply to this project?

At each meeting, we are presented with a plethora of data on both vaccine efficacy and adverse events. Statisticians are best equipped to understand and interpret these data. We are trained to understand uncertainty and can help guide the DSMB to distinguish between real effects and those that may have occurred by chance.

Outline a typical review process for a vaccine. What are some factors you and your colleagues consider in evaluating them?

The DSMB meets by videoconference at least every one to two weeks, generally reviewing one trial per meeting. Prior to each meeting, members receive study reports via a secure website. Once a trial begins enrolling, our reviews focus on three main elements: trial conduct, safety and vaccine efficacy.

For each review, the DSMB examines metrics related to trial conduct such as proportions of participants in relevant subgroups (by age, sex, race, ethnicity and presence of COVID-19 risk factors) and the quality of data to ensure that the trial is proceeding as planned. The board then makes recommendations based on this data review.

When a vaccine recipient experiences an adverse reaction, the DSMB must assess the likelihood that it was related to the vaccine and, if so, whether it recommends changes to the protocol or informed consent documents or whether the trial should be paused pending further investigation.

The DSMB also reviews two types of efficacy analyses to determine whether accumulating data suggest that it is highly unlikely that a vaccine will meet specified criteria for effectiveness or whether they show convincing evidence of efficacy by surpassing stringent, prespecified criteria. In either case, we can make a recommendation regarding the future conduct of the study. This recommendation shows the DSMB believes the data are compelling and actionable and allows manufacturers to take actions such as submitting applications to regulatory agencies for emergency use authorization or full approval or notifying participants and the public of study findings.

In what ways does the work of this group add to the evidence that the approved vaccines are safe? And how has your work informed your own opinions about the vaccine and the COVID-19 crisis in general?

The COVID-19 vaccine trials have been perhaps the most politicized trials in history, even becoming embroiled in United States presidential election politics. The politicization of these trials prompted prominent figures in the scientific community to question whether vaccine approval might be rushed for political reasons and fostered public concern about whether safety would be compromised. Notwithstanding these controversies, the DSMB has focused throughout on its primary goals — the safety of study participants and the integrity and scientific validity of the trials that it is tasked to oversee — and has encountered no interference with its ability to fulfill its charge.

Personally, seeing the process unfold and the work and dedication of the DSMB, I have full confidence in the integrity and accuracy of the results from these studies. As soon as I was able to receive my vaccine, I did not hesitate to do so and have encouraged all my family and friends to also get vaccinated.

This post was originally published in College of Sciences News.

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