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.
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.”
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.”
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My understanding is that current approval is only emergency approval, shouldn’t this discussion happen after the full approval? How would they get full approval if they dilute the trial data further?
Separately, if placebo group gets vaccine sooner, I guess we would never know what the long term effects are and vaccine adoption could get compromised?
Santosh – I think as far as long term effect, though a placebo group’s integrity is the gold standard, there are two points to make.
1. The study can not maintain the placebo group for very long – large numbers of participants will go get the vaccine as available.
2. The long term effects of vaccine will have to be determined by comparison to norms for the demographics of the placebo group – that may not be perfect, but since we are giving out the vaccine to millions now, we will have a very, very large group to look at soon.
I guess we won’t be studying ling term effects.
They can still study long-term effects in the vaccine group. They can also study asymptomatic transmission in the vaccine group. So there is much that they can still accomplish without a placebo group. Besides, the end point number of cases has already been reached so that efficacy will not change statistically even if the placebo group remained intact. We did this to benefit society
Many of the participants in the phase 3 trials are at high risk for COVID and for severe cases. To deny them access to vaccination for 2 years would be criminal
Umm… wouldn’t this amount to destroying the control group, and making it impossible to perceive long-term complications?
Isn’t that unethical, with regards to society? That’s what these individuals signed up for — the corporation should not be given a pass on long term safety under the guise of pseudo ethics.
The participants in the Pfizer trial did not agree to remain blinded for two years. We were told from day one that we are free to quit the study at any time. Nothing in our contract states that we are expected to remain blinded for two years. Once the vaccine was granted emergency approval, our ethical obligation to remain part of a control group ended. People are going to quit the study if we have to opportunity to get the vaccine early. Better to have unblinded data from 40,000 participants for two years than have none after April. I’m glad Pfizer is starting to do the right thing. Imagine the problem getting volunteers for the next vaccine if there is such a high profile failure to do the right thing for the trial volunteers in this very high profile trial.
John,
You’ve accomplished nothing, by volunteering for a vaccine everyone else gets shortly thereafter, and destroying the control group.
It’s like you didn’t even participate.
MXM – participants got the vaccine to the point of mass distribution – without us, there would be no vaccine to distribute to you or to other members of society – and you can’t even say “thank you”.
Efficacy has been established at arounf 95% – and this after the end point number of cases were counted – this is a statistically significant number that no continuation of a trial will change. As far as long-term effects go, most are recorded within 6 weeks of the shot – with rare ones observed after the vaccine has been in use for months or years – thus we will depend on people like you to take the vaccine and report any long-term effects. Really what could a small group of trial participants tell you any better than the millions of vaccine recipients could?
I am in the Moderna trial and want to participate in the crossover event because I am virtually certain I was in the placebo group. I was told by my study site that I would be unblinded as I requested and given the vaccine in one to two weeks. I cannot get through to my contact. What do you know about the Moderna crossover and where can I get more information. Thank you.
Why isn’t this “pharmacist” wearing gloves while handling a syringe and medication? Seems pretty unsanitary and gross.
Because it’s a silly stock photo. This is one of many many examples of sending the wrong message that I’ve seen since the pandemic began.
I think if you are going to volunteer for anything then you should see it to the end. If that means the study/volunteer time is 2 years to gain important info then that’s how long you signed up for and should hold to your obligation. You should not be able to quit until the study is completed regardless if you are in placebo group or vaccine group.
You are assuming some facts about the vaccine trials. The people who got the Pfizer vaccine never agreed to not get any vaccine as soon as they could, from any source. I could be in the Pfizer study and go get the vaccine from my doctor (hopefully that will be possible soon for many people) at any time. No one promised to “see it through”.
I am kind of sympathetic to the idea of keeping a gold standard double blind comparison group to look at possible vaccine reactions in a longer time frame. If something bad comes up, we need to know and halt the vaccine campaigns, but as the article says, the integrity of the placebo group is already compromised by medical folks in study getting vaccinated in first tier, so it is no longer a realistic goal.
Hopefully, accurate ststistical modeling will do the job of finding any problems among the people who got the vaccine during the trial. The placebo group is important but keeping those
It may be more important to keep all people known to have been vaccinated in the study and use statistical models to check for bad side effects rather than have them wander away over the next 6 months and not get any further data on them
Lancer,
Says someone who is not a trial participant yet plans to get the vaccine as soon as it’s available. Trial participants signed an informed consent agreement which gives them the opportunity to leave the trial at any time and for any reason – so there was not an obligation to remain in the study for 2 years – to prohibit someone from leaving the trial would be, simply, slavery/involuntary incarceration.
I was unblinded by pfizer over 2 weeks ago and will be getting booster injection in 1 week from today. I am classified as 1A in Michigan and had to send proof that was sent to the unblinding committee. Guess they got overwhelmed at all of us placebos submitting from 50 different state guidelines, thankfully. I believe that vaccination centers should be open 24/7 utilizing all of us in the healthcare field to operate them in order to get some control over this pandemic. If my immunity level is at max in mid January, then that is when I should begin working 7 days a week until this pandemic is under control.
I want to know how come Moderna and Pfizer are so determined and aggressively eager for the public to be injected with their vaccines? And at the same time, they’re totally protected by being granted immunity from liabilities if anyone should suffer side effects or die after being administered their vaccines and wants to sue them for money. Personally, I don’t trust those vaccines and the companies secrecies to what are the components that makes them up! Not even that those companies have ever came forward to tell the public. If that happened, someone please verify that for me.
George,
https://www.cvdvaccine.com/
https://www.modernatx.com/covid19vaccine-eua/
The Pfizer-BioNTech COVID-19 Vaccine includes the following ingredients: mRNA,
lipids ((4-hydroxybutyl)azanediyl)bis(hexane-6,1-diyl)bis(2-hexyldecanoate), 2
[(polyethylene glycol)-2000]-N,N-ditetradecylacetamide, 1,2-Distearoyl-sn-glycero-3-
phosphocholine, and cholesterol), potassium chloride, monobasic potassium
phosphate, sodium chloride, dibasic sodium phosphate dihydrate, and sucrose.
The Moderna COVID-19 Vaccine contains the following ingredients: messenger ribonucleic acid
(mRNA), lipids (SM-102, polyethylene glycol [PEG] 2000 dimyristoyl glycerol [DMG],
cholesterol, and 1,2-distearoyl-sn-glycero-3-phosphocholine [DSPC]), tromethamine,
tromethamine hydrochloride, acetic acid, sodium acetate, and sucrose.
Pfizer aims that placebo group will have the “opportunity” to receive the first shot “by” March1. The above statement is so ambiguous that the entire long article becomes worthless to me. I’m a placebo patient who wants the vaccine as soon as possible. The letter indicated that I would receive it at my Mar2 sixth month appointment. They now aim for me to have the opportunity to receive it by Mar1. Does that mean to make a new appointment? What does the word BY mean? Does that mean everyone will get it BEFORE Mar1? Or only get the “opportunity” to make an APPOINTMENT before Mar1 for a time sometime after Mar1. I would have expected a medical website to be more exact in its use of language. I’m 70 with diabetes living in the most infected part of the most infected city in the country with a positivity rate over 20% and that is expected to double in a month.That’s why I’m experiencing anxiety. Sorry.
Turn off your t.v. and social media for a while. If you’re anxious then the media is doing its job.
I think that Moderna is being equally vague – I was told that I would have the opportunity to have the vaccine before my priority group came up, but I live in texas and my priority group has now been given access, if one can find the vaccine.
Even tho I’d like to stay in the trial, I may request to be unblinded and exit the study But then again, would they drag their heels in honoring my request so that they could have 6 months worth of data. –
I’m scheduled for my fourth appointment with Pfizer towards the end of February. The new date of March 1 encourages me to think that they are moving up the unblinding and vaccines. I got my vaccine/placebo at the end of August which I think was early in the trial so I can’t imagine they can do everyone after me in a week to meet the March 1st deadline.
Wayne…call the clinic that you participated in the Pfizer study and speak to your medical Director, the doctor, and explain your current medical conditions and ask to be seen sooner for your vaccination. I went to the Raritan, NJ facility and the staff there has been very accommodating. I’m a RN and swore that I received the placebo but was surprised to find out I received the actual vaccine. I’m now just waiting for my CDC card for verification. Please don’t be anxious, just call and get your questions answered. Stay safe and be well 🙂