Pfizer and its partner BioNTech plan to offer their Covid-19 vaccine to any clinical trial volunteer who received placebo by March 1, several months earlier than initially planned.

The decision represents the conclusion of a complex and public kabuki dance between the Food and Drug Administration, Pfizer, and vaccine volunteers, as well as with Moderna, which developed its own Covid-19 vaccine. The FDA and its advisers pushed hard for volunteers to remain on placebo as long as possible to gather more safety and efficacy data about the vaccines, while the companies argued volunteers should receive the vaccines sooner for both ethical and practical reasons.

Among some trial participants, the issue had become fraught, with many protesting further delays in heated messages on social media and in letters to media organizations, including STAT.

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Michael Tovar, a volunteer who had been publicly campaigning for Pfizer to offer the vaccine more quickly to participants in the 44,000-person clinical trial, thanked the company and its chief executive on Twitter.

“Thank you for listening and for changing your study protocol to allow for speedy vaccination of your placebo arm,” Tovar wrote. “You have made this New Year so much brighter for the 22,000 placebo volunteers that stepped up for this vaccine.”

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Pfizer and BioNTech revealed the decision on a website for clinical trial participants and in a letter, obtained by STAT, that was sent to researchers conducting the clinical trial.

The letter to researchers indicated they are also asking participants to take additional Covid tests, to be conducted by clinical trial volunteers at home, to help understand whether the vaccine, which reduces symptomatic infections by 95%, also prevents asymptomatic infection. The answer to that question is important; currently, there is no way to know whether people who received the vaccine can still transmit it to others.

In medicine, the most reliable answers about treatments and preventatives come from double-blind placebo-controlled trials. This means that patients are randomly assigned to receive either the treatment, in this case a vaccine, or placebo. Neither they nor their doctor knows what they have received. In many trials, such as those for cancer, it’s simply assumed that patients who received placebo will get the treatment once the study is completed. This step is known as crossover.

But the matter of how placebo crossover should be handled during a pandemic was left open by both the FDA and the U.S. government’s Operation Warp Speed effort, which sped vaccine development, when the studies began in July. Consent forms given to volunteers, obtained by STAT, made no mention of when or if those who received placebo would get the two-dose vaccine.

At a Dec. 10 meeting of an advisory committee regarding the emergency use authorization of the Pfizer/BioNTech vaccine, the FDA discussed how the placebo crossover should be handled. At that session, Steven Goodman, associate dean of clinical and translational research at the Stanford University School of Medicine, argued that there was no ethical reason that volunteers in the placebo group deserved to receive vaccine before the general public.

Goodman laid out a complicated scheme, known as a double-blind crossover study, in which all volunteers who wanted to be sure they received the vaccine would be offered two more shots. Those who had received the vaccine would be offered placebo, and those who had received placebo would be offered the vaccine.

William Gruber, one of Pfizer’s top vaccine executives, argued that this plan was unworkable. Essentially, it would require running a large part of the study a second time.

Instead, Pfizer set out a plan in which volunteers who wanted the vaccine could receive it when they would be eligible to receive the vaccine in their local area. Health care personnel or residents in long-term care facilities, who were already eligible to be vaccinated, would get the vaccine immediately.

“If you are not health care personnel or a resident in a long-term care facility (or in any other future added group), we will discuss an option to transition from the placebo group to the vaccine group at your fourth study visit, approximately six months after you originally received your second injection,” a letter sent to participants in late December said. “We respectfully ask that you wait until Study Visit #4 to discuss the Vaccine Transition Option.”

This complicated process was moving forward quickly, because many of the participants in the study were health care providers. According to the letter obtained by STAT, 2,000 volunteers who received placebo have already gotten their first dose of the Pfizer vaccine. But it was clear that others would have to wait.

But then, on Dec. 17, the FDA held another advisory meeting, this time for Moderna’s vaccine, which had been developed more closely with Operation Warp Speed. Again, Goodman made his presentation. A researcher representing Moderna made a case, as Pfizer had, that his idea was impractical, and laid out a plan for giving placebo-receiving volunteers the vaccine much faster than Pfizer would. They would not have to wait until they were eligible to get vaccinated outside the trial.

The FDA’s advisers spent considerable time comparing Goodman’s plan to Moderna’s, eventually agreeing that Goodman’s was unworkable. But they spent little time comparing Pfizer’s plan, which delayed vaccine longer, to Moderna’s.

That left Pfizer in a bind, as more and more volunteers publicly protested that they should be offered the vaccine if they received placebo.

Alan S. Goldsmith, a retired physician in Florida who volunteered for the Pfizer trial, told STAT that he and his wife, who also volunteered for the study, did not even expect they’d get the vaccine if they were in the placebo group. They just wanted to know if they had already received the vaccine.

“What it would allow us to do is know our vaccination status which might allow a little more freedom to do things like visit our grandchildren,” he wrote.

On Dec. 23, Moncef Slaoui, the head of Operation Warp Speed, told reporters that he thought volunteers who had received placebo should receive the vaccine at once, contradicting the FDA. He also called the Pfizer plan intellectually elegant but impractical, saying that with different requirements for vaccination in all 50 states, it would be difficult to administer.

Pfizer was apparently already working to make its plan for crossover more like Moderna’s. New language posted on its website for trial participants on New Year’s Eve stated that vaccine doses had been secured, and that it and BioNTech aimed for all participants who received the placebo to have the opportunity to get their first dose of the vaccine by March 1, if they choose to.

A letter from Nicholas Kitchin, a senior director in Pfizer’s vaccine clinical research and development group, struck a cheerful tone for a clinical document.

“We recognize that our clinical trial participants are selfless volunteers who have made the important choice to make a difference and fight this pandemic,” Kitchin wrote.

“While the study continues to be blinded to answer important public health questions such as persistence of protection, longer term safety and protection from asymptomatic infections, we are committed to ensuring that our trial participants are recognized for their contributions and that placebo recipients who wish to can receive BNT162b2 within the study.”

Source: STATNEWS.COM

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