Should patients who volunteer to be in Covid-19 vaccine studies, but who are assigned to get placebo, be offered the vaccine? As companies and regulators raced to start clinical trials in the summer, that question was left open.
But for Pfizer and partner BioNTech, the answer now is not if but when.
In a memo to researchers conducting the clinical trial, a copy of which was obtained by STAT, Pfizer said that it is working to find a way to eventually give the vaccine to volunteers who were assigned to receive placebo. But that would not occur until the Food and Drug Administration has granted an emergency use authorization or another kind of regulatory approval.
“If our potential vaccine receives an EUA, we would propose amending the study protocol to create a process so that interested, eligible participants who received the placebo could ‘cross-over’ to the vaccine arm of the study,” the memo reads. “Such a change would require input and approval from regulatory bodies, and we are actively exploring this now.”
Before making that offer to participants, Pfizer would have to “unblind” the study — that is, tell volunteers whether they were in the vaccine arm of the trial or the placebo one. In many clinical trials, if a drug or vaccine is proven effective, the process of unblinding and then offering the drug or vaccine before approval to the placebo participants is common.
But the timing of the decision is complicated in the case of Covid-19, with potential consequences for clinical trials. The FDA has indicated it wants vaccine manufacturers to keep their trials blinded for as long as possible; early unblinding could mean that safety and efficacy results would be less reliable after that point. That’s because volunteers who received the vaccine could no longer be compared to an untreated placebo group.
Consent documents given to participants in the Pfizer/BioNTech study, as well as to those in the study of the vaccine developed by Moderna, do not make any reference to whether shots are made available to placebo patients if the vaccines work. Participants are told that if a vaccine becomes available, they are allowed to take it. Copies of the documents were obtained by STAT.
In a consent form for the ongoing study of J&J’s Covid-19 vaccine, the question is addressed directly.
“If you received the placebo, you may be offered the study vaccine at no cost if and when the study vaccine has been shown to be safe and that it works, but it is possible that this may not occur until 2 years after vaccination,” the J&J document reads. “This will be determined after consultation with the national health authorities in your country.”
In an interview earlier this week, William Gruber, a senior vice president of vaccine clinical research and development at Pfizer, said that the company planned to switch people from placebo to a vaccine if there was a regulatory approval and, perhaps, clearance from an expert panel organized by the Centers for Disease Control and Prevention.
In other words, Pfizer would offer the vaccine to volunteers who might be able to obtain it outside the trial. That could mean only a subset of participants at a time — for instance, only health care workers, one of the first populations expected to have access to a vaccine that is authorized, or people over 50. It depends what regulators decide.
But Gruber said that his hope is that the FDA, at that point, would issue a regulatory authorization that would include everyone in the trial. In that case, all the patients on placebo would receive the vaccine.
“Apart from the ethical obligation to make sure they can get the vaccine to which they would otherwise be entitled, I don’t want to lose that data,” Gruber said. “So we’re going to encourage them to stay on the trial and get the vaccine as part of the trial proceedings, but only those that would qualify.”
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Thousands of people are dying and millions hospitalized of the virus and they have a vaccine. Why not start issuing the the vaccine now??
It’s quite intriguing trying to figure out if you were injected with sodium chloride! I had the first shot of the Novavax vaccine (5mcg) or saline yesterday and I really cannot tell. I didn’t quite get fever but my temperature went gradually up to 100.2F (peaked 6 hours after getting the shot) and it’s fine today. My arm was only very mildly sore a few hours after the injection and I felt some intermittent, again mild, aches on the right side (shoulder and back). My arm was definitely more sore when I had the flu vaccine so I would expect more of a reaction if it was the real thing.
While I was in the waiting room and because there was a long wait after my initial checks (medical history, blood tests, swab test etc), the receptionist told me at 12:29 that it would take exactly 10 minutes and they would get me at 12:39 because they had to thaw the vaccine. Now, I know that the Novavax one does not need to be frozen and were it the Pfizer one it would have been a really nice clue but would they freeze saline?
Yes, as it is blinded to the staff giving it so both would be frozen.
That makes sense. Could the saline solution cause a gradual rise in temperature, up to 100.2F? I guess if it is the real vaccine I am more likely to experience more noticeable side effects after the 2nd dose is administered. My right side feels slightly more sore today (arm, shoulder, back).
Hey John, Great work on participating in the trial. I’d suggest you look at the Phase I data of that vaccine, if it’s available, to see what the side effects were from the 1st shot. Arm pain and fever, in the Pfizer trial, was only associated with those receiving the vaccine. There was 0% fever in the placebo group, and less than 20% arm pain. Saline can cause some soreness I’ve read, but very mild compared to an active vaccine. Also, in blinded studies, the person administering the vaccine would be the only one to know if it was real or placebo. They have to randomize your info, then prepare the shot, but I think it generally takes long for all participants. I took the Pfizer vaccine, and the team who helped me called it “cooking the shot” which seems to infer a thawing. It did take them almost 30 minutes to get it to me though, and based on my own fever, aches, fatigue, chills and arm pain, I’m pretty sure I got the real one. Hopefully you did too, as it makes all the effort worth it down the road to know you helped yourself and humanity in general. Most people I’ve told about it look at me like I’m crazy, but I don’t think they take the time to read the Phase I studies and assess risks… they just believe in the hype that it’s dangerous unfortunately.
…Now there are two different possible approaches to the SARS CoV-2 Virus. In the past, advanced countries would approach outbreaks of infectious diseases by identifying the infected individuals and then isolating both those infected and those who may have been in contact with those infected. If that did not do away with the pathogen, vaccines and other pharmaceutical remedies were developed.
Less developed countries mostly had to hope that the infectious disease plays itself out, or that advanced countries would help them contain the outbreak. For example, in 2014, President Obama poured significant resources into the successful fight against the Ebola outbreak. These resources included the 101st airborne division.
Today some advanced countries are well along in eradicating the SARS CoV-2 Virus by identifying the infected individuals and then isolating those infected and those who may have been in contact with those infected…
To some extent, it might be said, that the USA is betting on a vaccine, rather than undertaking the vigorous efforts that eradicating the virus with massive testing and contact tracing would entail. With the other coronaviruses MERS and SARS, the companies that were developing vaccines never got to commercialize them, because, in the developed countries, the outbreaks were ended by identifying those infected, tracing all of those in contact with anyone infected and isolating those individuals as necessary. That is occurring now in the countries that are making good progress towards eradicating the virus…”
https://seekingalpha.com/article/4357276
Rodney, Also I wanted to add that if you took the antibody test 2 weeks after the 1st shot, that’s way too early. In the Phase I trials they looked at 7 days after the 2nd shot, and in the Phase 3 trial, they’re testing antibodies 4 weeks after the 2nd shot. That’s because the way antibodies work, they build up over time and not immediately, and you may want to try another antibody test now that time has passed. Lastly if you could advise what forum you found where people were unblinding themselves with testing, i’d love to know who has tests that can unblind. As I mentioned, commercially available tests here in Texas are all testing for the wrong N protein and I’ve not been able to find any commercially available Spike protein test.
Take a look here — there are quite a few people who took antibody tests to effectively unblind themselves:
https://www.reddit.com/r/CoronavirusMa/comments/ilyzun/pfizer_vaccine_trials/
Thanks for the link. I read through all the posts, and it does seem those who got positive antibodies did the test through a medical setting, i.e. local hopsital, and their antibody test was not specified. One person said they got the Abbott test through Labcorp which only targets the N protein, and not the Spike protein antibodies, so that is a faulty approach to detecting vaccine generated antibodies. I think it’s best to wait at this point until the unblinding because there is literally nothing we can do to change what has happened, and if we did get placebo, we’ll then also learn how soon we can get the actual shot.
I’m a participant in the Moderna trial and received my second shot mid September. Tested negative for antibodies mid October but realized, from these messages, that the test I used targeted the N and not the Spike – if anyone can tell me where I can get the correct antibody test in Austin, TX I would be very grateful.
I am in the trail. +65 with existing conditions. So hopefully they will allow a subset of those in the critical group priority. I could understand waiting on those below 50 to continue the blind testing as long as possible.
Those receiving the vaccine exposed to covid 19 to ascertain they are immune?
As a participant in the Pfizer trial, I think it’s only fair that placebo participants receive vaccination immediately upon the unblinding of the study. That’s not to say that this should happen upon EUA, but certainly once the 164 case endpoint is reached. All participants, including those who received a placebo, stepped up and took a risk that others were unwilling/unable to in order to get us to where we are today. These participants in the placebo arm should also be recognized and rewarded for this once the vaccine begins being distributed upon approval.
The study is already unblinded. It was from the first moment they chose saline as the placebo. 100% of the vaccinated arm experiences lingering pain at the injection site, 0% for saline.
Not true. I was in the trial, experienced 4-5 days of acute soreness at the injection site after both injections and tested negative for antibodies, indicating that I received a placebo.
It could be that “placebo” is not merely saline, it may include adjuvant, which may cause a reaction in some people. A friend in medical research says using only saline has screwed up some results in the past in other vaccine studies.
No, it’s clearly stated in the consent form (as well as in person) that placebo injections are saline only.
Thanks for the info. I should be reading the materials they gave me – I am in the study, I am pretty sure I did not get the vaccine. I am in Northern California in the San Francisco area. I did not have any reaction to the shots. I got an email from the head of the research company Pfizer is using out here, and it is clear there is a lot of interest in getting the vaccine among study participants but it looks like we are going to have to wait if they ration it as they say they are going to.
Rodney, what type of antibodies did the test you took test for? Most SARS-CoV-2 antibody tests look for antibodies to the virus’s N protein, as these are by far the most numerous for those who have been infected. But the vaccine is only going to produce antibodies to the S protein (which block the Spike the virus uses to infect cells).
I too am in the trial, and also had several days of soreness near the injection site after both injections. I considered trying to get an antibody test too, but once I realized that it probably would be looking for the wrong type of antibodies, I abandoned the idea.
Did you have any other symptoms following the injection? Fever? Fatigue? Sore throat? Congestion? If you did, I’d be shocked if you didn’t receive that vaccine.
Hi Jack,
The antibody test that I took is called a “COVID-19 Total Antibody Test”. On it, my result indicated a 0.07 value with a reactive cut-off defined as 0.99. I took it about two weeks after my initial injection, which, from what I was informed, would have been more than sufficient time to develop an antibody result that would be sufficient to be deemed as positive.
To answer your other question, I had no other perceptible reactions to either injection besides soreness. From the initial Phase 3 data read-out, I recall that there was a non-trivial number of people who received the actual vaccine who didn’t present with any reactions either, so not entirely sure, but my hunch is still that I’m in the placebo arm.
Would be curious to know whether you have any additional information on the type of antibody tests being performed, as well as any developments on the unblinding.
Hoping for the best for all!
Rodney, my understanding is that a “Total Antibody Test” means it is looking for both IgM and IgG antibodies. IgM antibodies show up earlier and fade quickly, while IgG are produced later and tend to last longer. This type of test will help detect an infection sooner – since it’s looking for IgM, it doesn’t have to wait for IgG.
But since IgM and IgG antibodies can be raised against both the N and S proteins, this doesn’t really answer the important question: which protein is the test looking for antibodies against?
Now, looking at the phase 1 data, contra OP, soreness at the injection site is more like 90% in the vaccine group and 10% in the placebo group. The other symptoms are less definitive, as large segments in both groups reported no other symptoms. And given that you had no other symptoms, it’s not impossible you are in fact in the placebo group. I’d still guess you’re in the vaccine group based on your symptoms – maybe with around 70% confidence.
But I’d say that, unless you find out your test was against S protein antibodies, you’re still blinded!
Jack — fair points, and thanks for the additional info. I did some digging after reading your initial post, and I’m still unable to determine whether the test I took actually tested for the spike protein antibody. I was on another forum, however, where there were lots of people who were in the trial who were able to confirm their participation in the vaccine arm by getting positive antibody tests. Not sure which tests or where they’re located, but I’m in NYC. I’m going to try and see if I can find a site that provides a definitive S antibody test and see what happens. And if I can’t, I think we’ll be unblinded in a matter of weeks (if not sooner), regardless of if/when placebo participants are offered the option to be vaccinated.
Rodney, you can look at this link to see if your particular test manufacturer was targeting Spike or N (Nucleocapsid) targets of the antibody test. I’m also in the study, and looked at getting tests from Quest and Labcorp, and I found that labcorp tests for N target, while Quest has 3 tests, two for N and one for Spike. It’s up to chance, so if I went to Quest, they cannot say ahead of time which of the tests its assigned to. It’s very frustrating, but it’s the reality of testing that they’re looking to test those infected and not those vaccinated. https://www.fda.gov/medical-devices/coronavirus-disease-2019-covid-19-emergency-use-authorizations-medical-devices/eua-authorized-serology-test-performance
Thanks for the heads up. Looks like I got an N antibody test. It was Roche’s Elecsys® Anti-SARS-CoV-2.
https://diagnostics.roche.com/us/en/products/params/elecsys-anti-sars-cov-2.html#:~:text=Elecsys%C2%AE%20Anti%2DSARS%2DCoV%2D2%20is%20an%20immunoassay,against%20SARS%2DCoV%2D2.
Not really sure how to go about finding a test for S, so I think I’ll just wait until they unblind at this point.
What’s all the hurry? The early announcement served its purpose of making the CEO $5M richer. That’s enough for now
The hurry is that thousands are dying daily and many others who are surviving will have life time morbidity from mental/cardiac/pulmonary disease. Every day matters!
This makes sense for another reason, especially those of us who work in hospitals and are in the trials. When the EUA is issued we will be told to get the vaccine by our hospital employer. Without knowing if we are in the vaccine or placebo arm, we would be placed at potential physical harm by being vaccinated twice (4 shots in under 6 months). We have to know. Then we can let our hospital employer know we are already vaccinated and if the placebo arm we receive the vaccine as we are supposed to.
That’s a great point. I’m in the study and developed a fever, chills and fatigue after the 2nd shot. A 3rd and 4th shot at this point may produce an even more adverse event. What I hope to know is how will people be able to access the information. Locally here, at the clinic distributing the vaccine, they barely answer their phone, and rarely text me unless I forget to do my weekly symptoms entry. They seem stretched on manpower, so hopefully there is a more centralized process to access the data other than the site clinics where there is a less control of information.