Leaning on integrity: Research scientists unblind participants in COVID-19 vaccine clinical trials

Although the small team of Michigan Medicine research scientists in charge of the COVID-19 clinical trials were just as elated as everyone else when the first Pfizer vaccine became available in mid-December 2020, they couldn’t help feeling a bit apprehensive. After all, it left them with a once-in-a-career professional dilemma. 

The team was using the double-blind study method to conduct trials for the AstraZeneca and Johnson & Johnson/Janssen vaccines. The method, considered the gold standard in the scientific community, blinds both the investigator and participant as to which treatment the participant is given to avoid any biases. 

However, they knew they might have patients eligible for the now-available Pfizer vaccine. If they unblinded them, they could find out whether they were vaccinated or received a placebo, and could potentially offer them another vaccine option.   

However, to unblind clinical trial participants is rare and could potentially jeopardize the integrity of the study’s previous data. The concept went against everything they had ever been taught.

Following the ethical path

Despite their unease, they knew what they had to do. They leaned on their core values and what was in the best interest of the participants to find a path forward. 

“It wouldn’t have been ethical to not give them options to have the vaccine,” said Anna Suk-Fong Lok, M.D., director of clinical hepatology and assistant dean for clinical research. “But we were working in unknown territory. In my three decades of experience as a clinical researcher, I have never had to unblind a participant of a clinical trial. None of us have, and we are unlikely to go through this ever again.”

Lok, along with Njira Lugogo, M.D., M.S., pulmonary and critical care medicine’s asthma program director, Dan Kaul, M.D., professor of internal medicine, infectious diseases, and Courtney Oliver, the team’s project manager, formed the core team working on the trials. The four would ultimately spend countless hours, beginning Saturday, Dec. 19 and lasting through the holidays and beyond, explaining the unblinding process to all of their participants.  

“I remember the very first unblinding I did. I double- and triple-checked it, because you are taught to never unblind,” Lugogo said. “It was like taking the forbidden fruit of the science world.”

Kaul described the experience as similar to cognitive dissonance, the stress a person may feel when they participate in an activity that contradicts their beliefs, ideas or values.  

“You must get everything perfect so as not to contaminate the data, so it didn’t seem right to unblind the study at first,” he said. 

Building procedures on the fly

But the team had no time to spend feeling apprehensive. They quickly developed a first-ever standard operating procedure for unblinding, contacted all eligible patients by phone and explained options for further treatment.

“Those last two weeks of December made up the lion’s share of the calls, when the very first vaccines were coming in and the people were most anxious,” Oliver said. “Before the unblinding even started, we were already so busy, having worked about eight weeks straight, six days a week at a fast pace. We felt when the holidays came, it would be a nice time to allow the team to pause, but then this happened. Still, we knew it was important for our patients to be protected so we kept going.” 

The team called approximately 55 people in those two weeks, all in the evening since their work responsibilities kept them in the clinic or lab all day. As more groups became eligible for vaccines, the team slowly unblinded participants in each stage. Eventually, they unblinded 206 of the 250 participants. Because it was done in stages — unblinding only when a participant had a vaccine appointment scheduled, earlier data was intact. 

Even though the process had to be established on the fly, the team kept integrity and ethical standards in mind as they quickly developed procedures.

“When deciding who could make all these calls, we felt it was most appropriate that only physicians should contact the patients because of the questions the patients would have,” Kaul said. “Sometimes you had to lobby the people to unblind them as they placed a higher value on making sure the trial had a usable result than on their own protection against COVID-19. They wondered if it was appropriate and if it was good for the data. They were amazing people and all of us who eventually benefited from the vaccines owe them a debt of gratitude.”

Intense but worthwhile

All the team members agree the experience was intense, but deeply moving and worthwhile.

“There were many ways to accomplish the unblinding, but it felt right and very connected to be able to talk to each patient,” Kaul said. “We did it properly, and we are proud of that.”

“We were making a commitment to follow through,” Lugogo said. “The vaccines we worked on helped to prevent members of my household from getting COVID-19. It prevented many of our patients and those in our whole community from getting it. Because I was in the trenches, I had something to do with that.”

“We knew we should unblind and we knew it would be hard and very time crunched,” Lok said, adding, “but we knew it was possible as a team. As a joke we would tell Lugogo, our principal investigator: ‘we are behind you, just as long as you are ahead of us.’”