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The Vaccine Tightrope

We’re getting closer to having to deal with a number of tricky issues around the first Emergency Use Authorizations (EUAs) for coronavirus vaccines. These have never quite come up in this way before, because (for one thing) EUAs for vaccines are relatively rare events, and (for another) we’ve never had so many simultaneous vaccine trials against the same disease before.

So let’s just stipulate that Somebody (be it Pfizer, Moderna, AstraZeneca, whoever) asks for an EUA before all the other Somebodies, and that this request is granted. I don’t know when this is going to be – December? January? Whenever. Someone is probably going to be first, and it could well happen somewhere around then. The actual date doesn’t matter so much as what happens relative to the event.

At that point, it means that there is a coronavirus vaccine that has been authorized for human use. Immediately we have all the rollout concerns about who gets it, in what order, where, how much vaccine is available and how it’s going to be distributed. We’ve talked a bit about that here, and there seems to be a lot of planning going on around these questions (as there had better be!) But what if you were in the placebo group of the very vaccine trial that led to the EUA? Will this trial be unblinded, or not, and will such participants be given the chance to be given the actual vaccine? What if you’re one of the (many thousands) of people who are in the placebo group for the other vaccine trials, the ones that have not yet been authorized for use?

Steve Usdin goes into these questions here at BioCentury (article is free to read). He notes this recent FDA guidance document that goes into some of these issues:

It is FDA’s expectation that, following submission of an EUA request and issuance of an EUA, a sponsor would continue to collect placebo-controlled data in any ongoing trials for as long as feasible and would also work towards submission of a Biologics License Application (BLA) as soon as possible. FDA’s recommendations regarding the safety and effectiveness data and information outlined below are essential to ensure that clinical development of a COVID-19 vaccine has progressed far enough that issuance of an EUA for the vaccine would not interfere with the ability of an ongoing Phase 3 trial to demonstrate effectiveness of the vaccine. . .

“As long as feasible” is a well-crafted way of putting it. But we need to ask just how long that might be. You can see from the latter part of the quote that one of the considerations for issuing an EUA at all will be whether it might fatally disrupt the ongoing Phase III, and indeed, the FDA goes on to say that they don’t consider a vaccine EUA itself as grounds for unblinding. This leads us to the various clinical trial designs and interim data analyses, and how they fit in with an EUA request. It’s important to understand what the interim data readouts are designed to be able to say, which (translated into English from statistics) is something like “the distribution of coronavirus cases observed so far is not inconsistent with the vaccine having an eventual efficacy at the end of the trial of at least X per cent, at a certain pre-defined confidence level”. This sounds rather less definitive than what I think the general public might imagine the unblinding of clinical trial data looks like, and I should also add that it can take longer than you’d think (once you have the unblinded data) even to be able to say that much. This is not like rubbing off a lottery scratch ticket, that’s for sure. Rarely does a trial read out in a way that you look at the raw data and say “Holy guacamole, I think that stuff kicked butt”, although it should be said that obvious butt-kickings in the other direction are somewhat more common,

But I’m not expecting any of the latter, to be honest. Clinical trial success rates for vaccines against infectious diseases are (according to these estimates) the absolute best in any therapeutic area in the whole industry. Now, that means that a full one-third of those trials are successful, as opposed to about 3% of the oncology trials (to pick the therapeutic area at the other end of the scale!) But we’re going to do even better than that. Thanks to the SARS and MERS epidemics, we had a real advantage on this coronavirus, in terms of what the most likely antigen might be for a successful vaccine, what to look out for in animal models, and so on. If we get some weirdo pandemic from a less-studied group of viruses, it’s going to be a lot harder, and let’s hope we never get a chance to find out just how much. No, I expect the current vaccines to all work to some degree, and the whole point of running the trials is to figure out what that degree is and how it compares to what we need.

Thus all the statistics, and thus all the hard decisions. We may get into a situation where an interim readout of the data show that a vaccine may well be working, but that granting an immediate EUA has a real danger of blowing the statistics for the complete trial. That is truly the worst outcome: ending up with something that might be useful, but being unable (despite all the time and money and effort) to able to say if it really is. We’ve got to avoid that.

Update: turns out that Pfizer is apparently already saying that if their vaccine candidate gets an EUA that they will vaccinate eligible placebo group patients. This is something that they’re going to have to thrash out with the FDA before any such authorization is given. . .

But the patients involved in all these trials may have other ideas. Each individual that decides to leave the trial protocol may feel that loss of their own data is not enough to affect the overall result, but if enough people think that way, that result will most certainly suffer – a tragedy of the clinical commons. It’s important to remember that the “tragedy of the commons” doesn’t have to happen every time it could: there are plenty of examples of it being avoided, and we have to make sure that this is going to be another one. The considerations run the other way as well – it may end up being incumbent on the trial organizers, from an ethical perspective, to break the blind and offer the vaccine to all participants. “We should have such problems” is my first reaction to that possibility, but we’ll have to make that call carefully, not ruling out such a decision but not leaping to it, either.

But let’s get back to the question of what happens to the other vaccine trials. In the same way that you can’t force the participants of the emergency-authorized vaccine trial to stay in it, you also can’t force the participants in the other trials not to get the newly authorized one. An additional problem is that I strongly suspect that many participants across all the US trials have a good idea of whether they’re in the placebo group or not. AstraZeneca has been giving a meningitis vaccine in the control group in the UK (and other countries?), but their US trial (and Moderna’s, Pfizer’s, and J&J’s) are using saline control. I’d have to figure that someone who got notable site-of-injection reactions knows they got the real vaccine, while someone who hasn’t (especially after a second injection) figures that they’re in the control group. What’s to keep the latter from going out and getting vaccinated, if another vaccine is available to them?

And how will all this affect the coming clinical trials for other vaccines? Novavax is an obvious example – they have a recombinant protein vaccine coming along, which is a method that hasn’t been into human trials yet for the current coronavirus, and has potential advantages for storage and distribution. Then you have various companies investigating things like nasally-administered vaccines, which also could have advantages that will only be made clear in large controlled trials. How will anyone run them, if there’s another vaccine (or two, or three) available? One answer, as the BioCentury article goes into (based on the FDA documents) is that you might have to switch over to using the authorized vaccines as the control group and run “non-inferiority” trials instead of placebo-controlled ones. That’s going to be a tricky gear shift, though. Here’s Usdin:

It is far from clear, however, that non-inferiority trials of COVID-19 vaccines would be feasible. Moreover, the difficulty of doing this could preface pressure on FDA to accept external control arms or real-world data as controls. Demonstrating non-inferiority to an effective intervention can require very large trials or the acceptance of large confidence intervals around the results. The placebo-controlled Phase III COVID-19 trials already include at least 30,000 participants, and there will be little acceptance of uncertainty about the efficacy of a vaccine to prevent a life-threatening disease.

These considerations are getting less hypothetical all the time. As noted in the BioCentury article, J&J is already openly asking the FDA and the other vaccine developers to work together and ensure that an EUA and unblinding event doesn’t create a de facto monopoly in the vaccine space. There will be a number of ways to get this wrong, and I’m glad that the issues are at least out there being talked about. Next come actions.

Update: see also Jon Cohen’s article here, which I had missed last week! He has a lot of good quotes from experts in this area that illustrate that even these people don’t always come down on the same side of these issues. Everyone can agree that we need to thrash these issues out, but the thrashing itself could get messy (and see the Pfizer-related update above for an illustration!)

Update II: signs that the FDA is worried about these issues and that it may well affect the entire idea of issuing an EUA at all.

203 comments on “The Vaccine Tightrope”

  1. myst_05 says:

    Does it really matter, from a practical human perspective if all the other trials start to suffer? If the EUA vaccine can save the majority of people and stop the pandemic, who cares what happens to all the other vaccine candidates? Let’s all get vaccinated as fast as possible. I know I’ll be first in line to get one, no matter what.

    1. CraigP says:

      @myst_05

      Because one of those other vaccines might be better? Because the first vaccine to receive the EUA might turn out to be less effective than initially thought? Because the first vaccine might be effective for only part of the population, and another vaccine might fill in those gaps or simply be effective for a wider number of people?

    2. Dan says:

      Depending on the effectiveness of that first vaccine, the timescale on which rollout occurs, and the durability of immunity, it could matter a lot. If the first one to read out is moderately effective (significantly reduces your chances of getting infected, reduces the likelihood of a severe case if you do, but doesn’t have as much effect on your ability to further spread the virus) and needs regular boosters every year or so to continue being effective (though that’s something we wouldn’t know at the time of an EUA), it won’t eradicate the virus on its own and we’d want to keep looking for a better one. If the first is an absolute knockout punch that lasts for a decade or two, it doesn’t matter as much, although even then it could be a problem if it limits the supply because only one company is making it.

    3. Duncan says:

      It matters too in the sense of value for money. Given the sums spent on this it’s not a second-order question. I have considerable sympathy for your point by the way. But surely the point of trialling (and funding) all these different platforms was to work out which is/are effective. Dead money helps no one.

    4. BackSeatDriver says:

      Fear and haste rarely lead to good outcomes.

      Further, this isn’t smallpox. The stats about how lethal it isn’t are repeated in enough places that I won’t do the same here except to say that CFR is already declining sharply and if you’re under 70 you’re more likely to die from any of many common causes.

      I believe that any sort of rush other than for a ‘super-trial’ with a specific, limited group (such as nursing home staff) would be a destructive option.

    5. Alan Goldhammer says:

      I worry that the best vaccine will be delayed with the first mRNA vaccine EUA. One only need look at the development of statin drugs where atorvastatin was fifth to be approved yet had the best benefit/risk profile of all the drugs in the class. It became the statin of choice for cholesterol control.

    6. Hopeful Layman says:

      I’ll be “first in line . . .” as well, but not necessarily for the first vaccine to get rolled out. If I’m counting correctly, we’re lookng at seven “Warp Speed” candidates (incl. Novavax, running a little behind the others), right? I’m perfectly willing to wait until they have all gone through the full approval process (I admit I’m eager to see Novavax’s data, since their early trials seemed very promising, and I still have hope that the adjuvant in their vaccine will give it some added “oomph”).

      I certainly want to do my part in helping to get some truly meaningful mass immunity going, especialy now that Dr. Fauci is predicting that even with a good vaccine, we’re going to be masking and “distancing” until at least 2021 (so much for my family reunion next Christmas, I guess!) —

      1. Hopeful Layman says:

        Sorry — I mistyped. Fauci says now that we’ll be masking and “distancing” until at least *2022*, even with an effective and safe vaccine. So I’m feeling more urgent than ever to do my part and get vaxx’d as soon as I can . . .

        1. confused says:

          Given how poorly people are complying with masking/distancing *now* in much of the US, I see little chance there will be very much “into 2022”, even if public health experts advise it!

          1. Dark Day says:

            Right now, the numbers are spiking catastrophically. If that’s not enough to spur some rational behavior in people, then we’re doomed (and I mean that quite literally). I’m really g*ddamn fed up with having to read these ongoing, gut-wrenching daily reports of people getting sick and dying by the tens of thousands because a bunch of selfish fools don’t “feel like” acting responsibly. And if that behavior continues after a vaccine is rolled out but before it’s actually safe to let down our guard, the bad news will just keep on coming. When will people start looking at reality instead of following their “feelings”???

          2. confused says:

            Eh, I think that’s overly pessimistic. The US historically responds really badly to challenges/threats at the beginning, but somehow manages to muddle through anyway.

            And I wouldn’t rule out a vaccine dramatically improving the situation far earlier than 2022, especially if it’s decently effective for the elderly.

          3. Dark Day says:

            Uh , folks — It’s eight months into this thing. Upwards of, and 220,000 people have died. When do we declare the “beginning” to be over, stop “responding really badly,” and get our “muddling” arses in gear?

          4. confused says:

            Well, I was thinking of things like the Great Depression where it took several years & a Presidential election to change the US response, and the US was totally caught off guard in the Pacific theater

            I’d expect – for most places – the approach will change significantly over this winter/early spring if Biden wins.

            But some states probably won’t play along (public health mandates are a state power, not federal). OTOH if current trends continue, probably most of the population of places like the Dakotas will be infected well before 2022…

            (South Dakota reported 1132 cases today – which is like 0.13% of the state’s population – with a positivity rate of 21.4%, so probably that’s only a small fraction of real infections…)

          5. confused says:

            sorry, today’s 1-day positivity rate was 21.9%. Not 21.4%.

            https://doh.sd.gov/news/Coronavirus.aspx

          6. Dark Day says:

            Well, back to “tragic irony” — the “good” (?!) news is that you’re probably right about the percent of the population who will have been exposed to the virus by the time a vaccine is rolled out. We keep hearing estimates of 10% or so, but if this keeps up, it may well be closer to 20%. Sickening and utterly disheartening to think how many people will end up being “collateral damage” on our quest for population immunity.

          7. confused says:

            How long do you think it will be between the first limited-group vaccine approval and say half of the US population getting vaccinated?

            I think that even under an optimistic timeline (Pfizer gets good results and submits application in mid to late November, and FDA gives at least some kind of limited approval super-quickly after that) the current “wave/surge” will be over well before a vaccine can affect it.

            Given that, I think 20% is rather low. We’re at well over 8 million confirmed cases – what do you think the proportion of confirmed to total is? 10% now would mean over 1 in 4 of all infections have been confirmed, which seems rather high given just how bad testing was early on.

    7. Paul Thompson says:

      Well, one vaccine might have a longer-lasting protection than another. So, it can matter what happens to the other vaccine trials.

  2. Zambo says:

    Due to initial low available dose numbers, I doubt approvals this year/early next year would have a large impact on other trials, as even if someone wanted to get the approved vaccine, they’d have a hard time getting it (unless they’re in a designated high-risk group for rollout). I could see it being extremely difficult to run vaccine trials, say, next spring if approved vaccines become much more widely available though.

  3. Chris Phillips says:

    Isn’t “if another vaccine is available to them” going to be rather an important qualification in practice? Isn’t it going to take several months at least after authorisation before a vaccine becomes available to most people? In the UK it’s being suggested the policy is going to be to vaccinate only about half the population anyway.

    1. Duncan says:

      I think the point is though that the people who need the vaccine are the ones who would get it under an EUA. That was kind of the point I think made in the UK – those of us not in the vulnerable group (however you draw that) can and should wait. But we’re not really the ones who need to be trialled on here or given it under EUA.

      As I say in another comment I think that there is a wider question here about the wisdom of EUA per se. But in saying that I am conscious that what we need now are vaccinations, whether it is with the best vaccine is a question for another day – we can’t just go on destroying people’s lives for any length of time.

  4. Anonymous says:

    I believe that is what Derek is trying to explain. An EUA may be issued based on preliminary data, but after all data is in, may be proven to be ineffective (we’ve already had at least one example of that in the small molecule space). Worse and maybe counterintuitively, having an approved product may make it more difficult to find out if it actually IS effective, or if other prospective treatments are effective. It’s not an easy decision – do you wait until you’re sure, or do you go early knowing that you might help a lot of people, but you also might do a lot long-term harm.

    1. Anonymous says:

      This to myst_05

  5. Billy Bob says:

    “Demonstrating non-inferiority to an effective intervention can require very large trials or the acceptance of large confidence intervals around the results. The placebo-controlled Phase III COVID-19 trials already include at least 30,000 participants”

    I guess its a good thing there are millions of cases (patients) and growing?? Im not sure how to think about that. Obtaining statistical non-inferiority with such a presumably tight margin of efficacy could take millions, which seems like a deal breaker. But when have you had such an unmet medical need affecting enough patients where this is possible? Crazy times we are in.

  6. EngProf says:

    Is it possible, Derek, that you didn’t finish editing the paragraph that ends “Holy guacamole, I think that stuff kicked butt”, although it should be said that obvious butt-kickings in the other direction are somewhat more common,”? Obviously you wouldn’t end a paragraph with a comma, but I *suspect* that you might have meant to eliminate or clarify the entire concessive clause about “butt-kickings in the other direction.” The reason that I suspect that is that the next paragraph begins with “But I’m not expecting any of the latter, to be honest” and it seems to me that he’re you’re really talking about apparent successes of the holy-guacamole sort rather than apparent failures which is presumably what you meant by butt-kickings in the other direction — i.e. the former in the sentence as posted, not the latter. Maybe I’m all wet, but would you give the thing another look? Thanks.

    1. Patrick says:

      No, he goes on to say that he expects more or less all of the current vaccines to work. So it is meant in the sense stated (No butt kickings (ie, abject failures) *of one of the vaccines*, just possibly of the virus), and despite the comma there is no missing reversal.

      1. EngProf says:

        I think we agree about what’s intended. “The latter” refers to vaccine successes, whereas of the two options in the previous sentence the first (it’d be “the former”) is successes and the second is failures.

  7. MIchael says:

    You need to redact the Novavax comment. They have been doing human clinical trials for months, including a successful P1/P2 trial that is peer reviewed and published in the NEJM. Currently they are doing P2b trials in South Africa and P3 trials in the UK. Novavax has been considered “Best in Class” by many researchers based on their data compared to others.

    Shoddy journalism there. If you want people to partake in the trials, you have to report correctly.

    1. johnnyboy says:

      Derek is not a journalist, and he doesn’t need to redact anything, as what he has written is correct. You however need to brush up on your reading comprehension.

  8. Sc says:

    The Pfozer trial guys told us if it gets an EUA they’d break the blind and give placebo patients first crack at the real vaccine, fairly directly. My hope is that the signal is so strong that efficacy in the first readout isn’t even a question, but we’ll see.
    It’s true that blinding is hard on this one. I got soreness at the site plus fatigue after the first one, fatigue plus muscle aches and general crappiness for two days after the second. I’ve never had that kind of reaction to a vaccine before, though it beats the heck out of covid.

    1. Liam says:

      Who is us, out of curiosity? Are you in the trial?

      1. Sc says:

        My dad and I both went at the same time. You can tell this is streamlined because they had us do everything together. Makes sense when there are 40k in the trial on short notice. They also had one of the site managers giving injections. That said, in spite of it being insanely hectic everyone including the PI seemed very upbeat which was encouraging.

        1. Anon says:

          The “streamlining” may be a consideration for the instability of the mRNA construct after thawing a multi-use vial. They would want to consume the whole vial as rapidly as possible to minimize waste of the vaccine.

          1. Sc says:

            I don’t think they are using multi use vials. Each of us was dosed from a different and apparently single-use vial. There was a 30 minute wait for them to thaw.

    2. RF Bruns says:

      If the trial participants know from the presence or absence of side-effects whether they received the vaccine, is there a danger that the individuals who received the vaccine will engage in more risky behavior, believing that they are protected? We could get the paradoxical result that the vaccine group shows a higher infection rate than the placebo group. I’ve never seen this idea mentioned, but it seems like an obvious possibility based on how people behave.

      1. Sc says:

        Absolutely a potential problem. I know I got the real dose but I am still staying home as much as possible and masking up with a p100 half face respirator when I’m out. But it is easy to let it relax you a bit and feel like some risks might not be as dire.
        On the other hand, if the vaccine isn’t good enough to overcome that effect it isn’t good enough period imo.

  9. David E. Young, MD says:

    One of the problems is that you know. I am on the Moderna Vaccine trial, having a shot and a booster shot. And I visit the research clinic we make no mention of which arm I am on, placebo or vaccine. But when my reports, all 20 of them, inform the clinic that I have had absolutely no side effects at all, then we sort of wink at each other and it is “you know that I know that you know that I know that I am on placebo.” I don’t need it unblinded. It is obvious that I got the saline shot.

    I am okay with that. But as a physician who potentially is coming in contract with Covid19 patients, I am very willing and hopeful to get the actually vaccine. If Moderna is approved, I would like to get their vaccine.

    I will probably not jump ship if someone else’s vaccine is approved. Not for a while, at least. But then again, if it takes several months and Moderna’s is not approved…. well… there will be a time that I will jump ship. The investigator knows that and has imformed me that they actually expect that. I do hope to wait for the Moderna vaccine to be approved soon after, if it is not the first to be approved. And if I do get the real vaccine I am still on study. I still fill out forms, get phone calls and get clinic visits.

    Derek is right, though, this does throw a monkey wrench into the whole phase III trial concept.

    1. Matt says:

      Likewise I am on the Moderna Vaccine trial and likewise I felt nothing after the initial shot and booster. Not even a sore arm, and yes its very much a wink wink how was your reaction to the “shot”? I like the approach that AstraZeneca took where you receive A vaccine just maybe not THE vaccine.

      I brought this very question up when I first registered and the response I got was Moderna was not planning on giving the placebo arm the vaccine in the event of an EUA. Now, maybe that has changed with Pfizer’s announcement although Moderna is running this with the NIH so they might not have much say in this. When I asked about getting a vaccine that might be approved thats not the Moderna they didn’t really have any response outside of leave the trial.

      Personally it will come down to efficacy of any vaccine that is approved. If we are talking something around 50 percent I probably would ride it out in the placebo arm for a while. If something is more like 70 or 80 percent it gets a lot trickier for me. For the sake of the research I want to stay in it until the end, but if there is something available that works well i’m going to have a hard time doing that for a full year and a 1/2.

      1. daksya says:

        There have been some studies showing a possible protective effect from vaccines for other pathogens.

        If the control arm intervention does have some protective effect, and since the outcome measure compares *symptomatic* infections, isn’t there potential for an active control to diminish measured efficacy?

  10. Liam says:

    >> you also can’t force the participants in the other trials not to get the newly authorized one

    Why not? Why can’t the trials say “Listen, we know there’s another vaccine out there. We’ll pay you $X to not get it and stay in this trial.”

    1. Matt Gruner says:

      Didn’t see your comment at first. This is my question as well. These trials will be used to determine the best strategy for inoculating ~7 billion people over the next few years. It seems very important to get as much good data as possible at this stage.

      1. eyesoars says:

        How can you prevent them from getting an alternative vaccination on the sly?

        You can certainly measure the patients antibody titers, but it’d likely take some pretty fancy detective work to figure out the patients are responding to an under-the-table vaccination rather than having had COVID or responding to your vaccine.

    2. David E. Young, MD says:

      Okay….. as long as that is clear from the start. If you are going to stipulate that you will pay a person to stay on trial (presumably stay on the placebo control group) and not get someone else’s vaccine, then make that clear from the start. Have that as part of the consent form.

      There was nothing about that in the consent form that I signed. And before I signed it I asked about what would happen if another vaccine go approved and I was on the placebo arm. The researcher acknowledged that he would not reprimand me for jumping ship and get another vaccine.

    3. Mantis Toboggan says:

      Offering money to that is incentivizing, but not forcing. You still can’t force people to do anything. Some people might value the potential protection a vaccine offers more than financial incentive whatever that may be.

      1. Hopeful Layman says:

        RE: Offering money – I’ve heard it suggested that one way to increase participation in the U.S. trials among high-risk groups who are nonetheless hesitant to participage (e.g., people of color) would be to offer financial incentives. Would this be considered ethical? If so, why hasn’t it been done?

    4. Riah says:

      They are offering £4,000 per participant in the deliberate infection trial of the AstaZ vaccine in the UK! That might be enough to temp a few people.
      After the 2 TM/ME cases and the death in Brazil (which we don’t actually know for certain is in the Numenrix (placenbo) arm), the macaques that were put to death after 7 days ( why didnt they let them live longer to gauge longer term effects?), and the fact that all the monkeys did get infected (even though they did not get a ill) I think I will give that one a miss.
      Which are the most promising of the attenuated vaccines?

      1. WST says:

        “They are offering £4,000 per participant in the deliberate infection trial of the AstaZ vaccine in the UK!”

        Source of information about AZ ? As far as I can check, there is no vaccine identify for this challenge trial that is still bit hypothetical.

  11. Me says:

    I joined the Pfizer study specifically because I was promised that once EUA was granted, the trial would be unblinded and if I got the placebo I would get the real thing. This is important to me, because I am sure I got the placebo.

    1. debinski says:

      I am also in the Pfizer trial but they never told me anything about the blind being broken if an EUA is granted. I also believe I got the placebo and would want an active vaccine as soon as possible, as I’m in a high risk group. I don’t think any amount of money could keep me from getting it, but if somehow they could promise me I’d get Regeneron’s antibodies, early on, if I got infected, I might think about that.

      1. me says:

        You might want to check the multiple pages they gave you. Mine is in writing in that.

  12. Duncan says:

    Sorry if this is a dumb question – but how are other countries handling this?

    The Chinese must face a similar issue? Probably the Russians. The Indians have multiple vaccines in the pipeline and presumably they will all run into the same issues? There are multiple trials going on in the UK, Germany, France etc.

    Clearly there is absolutely zero public interest in wrecking trials, not least given the amounts of money that have been spent globally on this. One other possibility of course might be not to have an EUA at all and just go for a standard authorisation, but I wouldn’t want to have to pick the ethical bones out of that one.

  13. Matt Gruner says:

    In the event of an EUA I have a question. Would it be ethical to provide incentives to study participants to remain unblinded in the study? Current estimates find physical and social barriers such as mask wearing can offer significant protection. If we offered participants $10,000 (guesstimate) to remain in the study it might be enough to shift the cost/benefit. If we are going to vaccinate 7 billion people over the next 2-4 years we need good data badly!

    1. paperclip says:

      That would probably not pass ethical review. Trial participants should weigh the risks and benefits of a trial without a large sum of money coercing them. Also, a rich person might say “10K is nice, but I’d rather be vaccinated,” while a poor person might say “Wow, imagine what I could do with that money!”, so you wind up with a situation where it is the poor who are not taking the vaccine on the market and subjecting themselves to the potential risks of an unproven vaccine.

      1. confused says:

        Yeah – not even “rich”, just “not poor”. I’m a bit below median US income and I would *absolutely* consider getting an even moderately effective vaccine to be far preferable to $10,000.

  14. Marko says:

    Since any vaccine that gets an early EUA is going to have a limited supply of doses to roll out , why not issue the EUA restricted to a particular subgroup. Then only that subgroup in all the trials would have any incentive to drop out , since the rest couldn’t get the vaccine anyway.

    There are myriad ways to slice and dice the data to find a subgroup : age , sex , race, comorbidities , etc. You might be inclined to focus a limited early rollout on a high-risk group in the first place – say , those over 70 yrs. of age – so why not restrict the EUA to that group. Then , all vaccines would remain in a competition to seek EUA approval for the next subgroup(s). At the end of the trials , you’d have one or several vaccines that get full approval for one or more subgroups , and still have the potential for non-inferiority approvals to broaden the market for those with only limited subgroup approavls.

    1. Michael says:

      This is a really clever approach. Makes sense to me.

      1. Marko says:

        Thanks. The main difficulty I see is the possible need to deviate from the pre-specified subgroup analysis if you want to dice into smaller subgroups. For instance , say one of the pre-specified subgroups was age >65 but you wanted to restrict the initial EUA to age >70 or 75. I’d think the statisticians could sort it out. It might even require an extra month or two of data maturation , though I wouldn’t consider that much of a downside , since it would give us a better chance to detect a safety signal.

        1. Gary Cornell says:

          Statisticians can sort it out, it is a bit more work and unfortunately often requires more data and time. They should have stratified it by age deciles in the original design, surprised they didn’t. See my blog: https://garycornell.com/2020/10/22/we-are-unlikely-to-have-a-vaccine-that-is-proven-effective-for-seniors-for-a-long-time-unless-dramatic-action-is-taken-now/

          1. Hopeful Layman says:

            Difficult to tell exactly how representative some of the trial populations are, I think — Moderna is making a pretty big deal of their attempts to recruit a “diverse” population (e.g., ethnicity, age) for their Phase III trials, and I seem to recall J&J claiming “encouraging” results among the few 65+ individuals in their Phase I/II trials.

            For the most part, though — and someone correct me if I’m wrong — it looks as if most of the companies are going with a pedominantly younger-to-middle-aged popuation, and then hoping for the best when the actual vaccine gets rolled out. I certainly see no evidence that anyone is going to wait until further data on older patients becomes available; to the contrary, after front-line healthcare providers, the “elderly” are identfified by almost everyone as one of the earliest target populations in the rollout.

  15. Steve says:

    If we get effective therapeutics before the spring that would make vaccine challenge trials more feasible.

    1. Some idiot says:

      Re: challenge trials: I saw this one yesterday:

      https://www.abc.net.au/news/2020-10-21/healthy-volunteers-to-be-infected-with-coronavirus-in-uk-trials/12796142

      I am not aware of any others, but would be happy to be corrected!

      It sounds like they will be at least starting with quite small doses of virus. As far as I understand, this is not a “challenge trial” per se, but may involve vaccine challenges.

      Hopefully it will be very interesting…

      1. marko says:

        Good to see. That study will provide a lot of information that we’ve been mostly guessing about so far , like inoculum size vs. disease , precise viral kinetics from infection to resolution , etc.

        Can’t wait to see the results.

        1. Some idiot says:

          I seem to recall that they were planning to start in January (with 30 volunteers? If I remember correctly), so we will be waiting a while… But yes, this should give us some serious data…!

          As I understand it, they are partially getting around the ethical dilemmas (or some of them, at least) but inoculating (nasally) with quite small doses, so that (again, if I remember correctly) they are not expecting the volunteers to end up with serious fever or breathing difficulties. Sounds like they have done their maths on this one, and have an idea as to how much useful data they can get out of minimal dosing.

          Will be interesting to follow…!

  16. AK says:

    This is a high quality problem, but one that certainly entered my thinking when I applied to volunteer for these trials.

    Here’s a potential solution: rely on data from clinical trials outside the US, particularly in developing countries who won’t have immediate access to Pfizer / Moderna. Wouldn’t that solve the problem? Can’t the FDA use data from a trial with global sites so long as the protocols / IRB is governed by a US board?

    1. Marko says:

      Under any other President perhaps. Trump would probably slap a big tariff on any data manufactured abroad.

  17. Clyde Meserve says:

    Challenge trial time.

    1. Erik Dienemann says:

      UK to conduct “human challenge trials” in which a subset of young, healthy people are deliberately exposed to SARS-CoV-2 before vaccination to evaluate dose/response relationships, followed by larger clinical trials where young, healthy volunteers are vaccinated with various vaccines and then exposed to controlled amounts of the virus.

      I had been hoping we would do these months ago to get an early read on vaccine effectiveness and am puzzled why they’re doing these now, when we’re not far away from having final phase III vaccine trial results for multiple vaccines. My guess is these types of trials were already done with “volunteers” in places like China and Russia…

      https://www.nature.com/articles/d41586-020-02821-4

  18. Mirjan says:

    Derek, is there any chance you could comment on the Chinese vaccine? Supposedly they already immunized 400k people under the emergency use clause and are enlisting students going abroad.

    Thank you!

  19. Konstantinos Spingos says:

    I suppose that EUA should mean that the current sample size has reached the levels of significance in efficacy that were estimated to be achieved through a bigger size. The real consideration is safety concerning rare events. Normally this would not be the case for a medication treating a lethal condition but it is actually a big ethical issue in the case of healthy population vaccination.
    On the other hand, EUA should also mean that all other ongoing studies switch to non-inferiority type and abandon placebo due to ethical reasons.

  20. Marko says:

    “Volunteer in Oxford coronavirus vaccine trial dies, reportedly took placebo”

    https://www.washingtonpost.com/world/the_americas/coronavirus-oxford-astrazeneca-vaccine-trial-death/2020/10/21/3f5bedac-13c0-11eb-ad6f-36c93e6e94fb_story.html?tid=ss_tw

    This patient contracted Covid-19. I don’t quite understand , is this the same patient that was earlier reported to have developed transverse myelitis ?

    This could call into question the continuing halt on this trial in the US while the halt was lifted in all other countries.

    1. Michael says:

      No, those are different cases. The earlier case was a woman who received the vaccine, took an awkward step while jogging and suffered a serious jolt to her nervous system — I believe they couldn’t conclude whether or not the vaccine had anything to do with her condition.

      This was a doctor in Brazil who received a placebo (actually a meningitis vaccine as control) and perished from the disease.

      1. Marko says:

        Ah , OK. Thanks.

      2. Riah says:

        wonder how long that was after the meningitis vaccine (Numenrix?). Can ADE or viral interference of some sort be involved? After all, influenza vaccine is now not only connected to increased risk of coronaviruses in general and non resiratory viruses, it is now also linked with increase in Covid infection.

        1. Chris Phoenix says:

          Citations please? Sorry to be skeptical, but anti-vax people make up this kind of claim as propaganda, so we need to know the source. I’m not saying you’re anti-vax yourself; I have no way to know if you checked the source when you heard it. Anyway, assertions like these need to have original sources firmly attached.

        2. Marko says:

          This article describes the misinformation campaign , and has links to the relevant studies :

          https://www.usatoday.com/story/news/factcheck/2020/10/21/fact-check-donald-trumps-flu-shots-covid-risk-arent-linked/3623699001/

          It’s more likely true that if you get the live inactivated flu vaccine ( FluMist ) you would get some short-term protection against COV2.

      3. Oliviateseniar says:

        She died from Meningitis from the meningitis vaccine?

        1. AKD says:

          No, the Brazilian was in the control arm (did not get Covid vaccine) and died of Covid.

        2. Michael says:

          No, the doctor received a meningitis vaccine as placebo but died of coronavirus complications (he worked on a COVID ward).

          He suffered from a lack of vaccine, not his vaccination.

          1. erik dienemann says:

            Yep, this is the risk of placebo-controlled trials for a vaccine for a deadly virus. These volunteers are all heroes IMO, as they’re taking on life and death risks so that we can all benefit from the data gathered. In addition, some have mentioned needing safety/efficacy data on the elderly with the vaccine – however, ethically, can we even give high risk elderly people (all are high risk, by definition) a placebo? I’m 58 and pretty healthy, but wouldn’t volunteer for a COVID vaccine trial (and have been essentially quarantined since 3/2, which was 2 weeks before most, since my wife is immunocompromised and we’re both close to old).

            https://www.mirror.co.uk/news/uk-news/volunteer-trial-oxford-uni-vaccine-22885080?utm_source=linkCopy&utm_medium=social&utm_campaign=sharebar&fbclid=IwAR3ZM2wIrv2AFOFVoajaZ8_UvtaA4LAp-g1jhZpowVps24REfxNSxgLfyIw

      4. Riah says:

        What is your source for stating that the person who died was in the placebo arm please?? As far as I can see, Astra Z has put out a fairly lengthy statement talking about patient confidentiality saying it cannot comment on this case.

        Your info seems to be based purely on an assumption – someone wrote that they assume, from knowing the protocol, that had the person been in the vaccine arm, the trial would have been stopped. This has then gone round the world as being the oficial position.

        This does not amount to actual confirmation. This is very alarming and not good enough. Does anyone have any better information from a trustworthy source please?

        1. Michael says:

          A number of reputable news agencies — BBC, Bloomberg, etc. — have reported that it was from the control arm. And the company and regulators have all confirmed that this death does not raise a safety concern with the ongoing vaccine trials. At some point, it’s just not reasonable to infer anything else.

          1. Riah says:

            This doe not answer my question – just confirms what I said. So the company itself does not confirm it.

  21. Marko says:

    In Israel “Children are the engine of the outbreak” :

    https://twitter.com/yaneerbaryam/status/1318917775449034753

    Of course , here in the US , we know our children are not so thoughtless as to spread a deadly virus , don’t we ?

    Open the skools ! MAGA !

      1. confused says:

        I think the Atlantic (also not a traditionally Trump-friendly outlet so unlikely to skew in a “let’s open everything” direction) had a similar article recently.

        This is confusing, some evidence seems to suggest schools are low risk, other evidence goes the other way.

  22. Marko says:

    It appears that spike- or RBD-based vaccines won’t replicate the CD8+ T-cell response seen in natural infections:

    https://www.cell.com/immunity/fulltext/S1074-7613(20)30447-7

    Whether this is important for vaccine-acquired immunity remains to be seen.

    1. Riah says:

      Well T-cell response is pretty important: https://www.bmj.com/content/370/bmj.m3563/rr-0

      A further concern is ADE – what if skewing the immune system away from a T-cell response and only towards antibody production towards particular SARS-CoV-2 RBD/S protein epitopes means a worse reaction when a future coronavirus (or maybe even a cold coronavirus?) is encountered? Like in Dengue vaccine where a different Dengue strain killed people and made them seriously ill?

      Vaccines for HIV using adenovirus type-5 vectors have already been shown to significantly increase HIV infection and this is being ignored. refs can be provided later as they slow the posting up of messages. The more I researched the immunology, the more concerned I get.

      1. Riah says:

        Oops sorry, I included a wrong link in my message above re T-cells. This is the right one: https://www.bmj.com/content/370/bmj.m3563/rr-6

      2. Marko says:

        The paper I posted doesn’t suggest that vaccines will fail to generate a T-cell response altogether , rather that the response generated will be restricted to only the epitopes present in the vaccine , as opposed to the more diverse response seen with natural infection.

        It remains to be seen whether this is good , bad , or indifferent in regards to vaccine efficacy. If it turns out to be bad , then inactivated or attenuated whole-virus vaccines might be a better choice.

        1. Riah says:

          Marko, please see the article in the corrected link above (sorry I gave a wrong link) and the 3/4 studies it references which all show that diversity and intensity of T-cell response is linked to better outcomes.

          1. Marko says:

            I suspect that whole-virus vaccines will be better for just that reason , but the problem now is that we still don’t have a widely-accepted “correlate of protection” for COVID-19. If we did, we could simply evaluate vaccine candidates on that basis , which would be both faster and easier to do.

            We really need to know two correlates , one which measures protection from infection and one which measures protection from severe disease outcomes. Neutralizing antibody would seem to be more important for the former , and perhaps the T-cell repertoire is more involved in the latter. More likely , it’s a combination. Durability of response(s) is another unknown. Still more questions than answers , it seems.

  23. Bill says:

    If the course of events destroys the infrastructure of various controlled randomized trials, what’s the fall-back strategy? Can you analytically construct a placebo group from study of people participating in other trials, or even non-participants who won’t have an opportunity for vaccination for a while?

  24. Ed says:

    I was wondering whether Pfizer’s Albert Bourla’s statement that a vaccine won’t be approved before Nov 3, implied that a first interim analysis had shown that the vaccine efficacy is not more than 77%.

    1. Marko says:

      I suspect it applies more to the FDA’s recent tougher stance on the need for sufficient safety data to accrue.

      It still wouldn’t surprise me to see Pfizer deliver some sort of pre-election gift to Trump , in the form of interim results release or an “imminent intent to file for EUA” sort of announcement.

      1. confused says:

        The stricter safety data requirements will probably turn out to be a good thing overall (in terms of public trust… and if Biden wins the election, as currently seems more likely, which things may be a bit less emotional by mid-November) – but it does kind of bother me. I could see for the youngest populations… but for older people, does anyone really believe a vaccine would plausibly be worse than (say) a 10% chance of catching COVID?

        1. Bill says:

          Do older people have a 10% probability of catching Covid? While their outcomes are typically worse, I was under the impression that the at-risk crowd got infected less often, due to their presumably greater attention and motivation.

          1. confused says:

            Well who knows, it was a wild-guess example. But if we’re talking about a relatively active older-to-middle-aged group where COVID has maybe a 0.5%-1% fatality rate, it doesn’t take *that* high an infection rate to be a serious risk of death.

            So it seems like it might be a win to approve it for say people over 50 as soon as efficacy is shown, even if you can’t rule out (say) a 1 / 5,000 risk of something like Guillain-Barre syndrome or transverse myelitis.

            But public perception would likely not see it that way.

  25. Brian says:

    First you shouldn’t have to unblind everyone just because there is a EUA, it is probably not going to be an EUA for every age group at first. So if you have to unblind 65+ year olds because there is a pretty effective vaccine okay.

    In terms of trialing further vaccines after you have a baseline when its going to be harder to recruit but there is still a good window. One way is to make the control another vaccine: the carrot for people is here is a vaccine you can’t access yet in the 30-40 year old group or a candidate that is probably going to work also. Such a trial would have to run longer perhaps than the regular ones but if it is a dud then you are going to sure see that the group with the new alternative has more infections, if you see similar levels then you know they are equally good etc. You also still get the safety data. The other way is to do a trial where there aren’t enough vaccines yet.

    In all probability Novavax is going to start a trial in the US in the next few weeks. They already have a trial going in the UK and the infection rate there is high. So if the outcome is we get several imperfect but good enough vaccines and it takes us a decade to learn how to make an even better vaccine that’s okay.

  26. John Liu says:

    My comments:
    1. New drugs are tested against already approved drugs (active comparators) and required to demonstrate superiority, all the time. It’s common, just not in vaccines.
    2. If the approved vaccine is 50% effective and the new vaccine is 60% effective, it will be hard to demonstrate superiority or even non-inferiority; but since the new vaccine isn’t much of an improvement, it’s not a big loss. If they are 50% and 80%, then it won’t be that hard to demonstrate superiority.
    3. Most likely the initially approved vaccines will require annual redosing, so that’s hundreds of millions of potential study subjects every year. Plenty to recruit for a study, especially when they don’t have the risk of getting placebo. I hope the vaccination programs record who gets which and when, to help with randomization of a future trial enrolled from previously vaccinated persons.
    4. On the “Covid isn’t that lethal” idea, the absolute numbers of dead (210,000 in US now) and the years of life lost (2.9 million years in US) would disagree. But even if we discount the infected, can’t discount the economic damage. If we don’t get our hands around this, and soon, we’ll be looking at a lost generation.

    1. confused says:

      >>4. On the “Covid isn’t that lethal” idea, the absolute numbers of dead (210,000 in US now) and the years of life lost (2.9 million years in US) would disagree.

      I think to some degree this is an “individual risk vs overall risk” issue. The *individual* risk of death from COVID is relatively low for most people (much worse than ordinary respiratory viruses, but most people are expected to survive). But since it’s highly contagious the overall population risk/harm is very high.

      A bit of the opposite situation of something like rabies or Ebola (super-deadly individually but much less transmissible).

      I think the concern is that for younger adults who are at relatively low COVID risk (which you’ll need to vaccinate to get a high % vaccinated – median age in the US is 38) the vaccine has to be pretty safe.

      >>But even if we discount the infected, can’t discount the economic damage.

      And not just economic, but mental health, social disruption, lost time with elderly/vulnerable family members who may not have much time left (even excluding COVID), lost education quality, etc…

      Yeah, the social effects of having a vaccine, ending the “helplessness”/hopelessness/etc about the virus, will be at least as important as its actual medical benefits IMO.

      1. Dark Day says:

        ” . . . not just economic, but mental health, social disruption, lost time with elderly/vulnerable family members who may not have much time left (even excluding COVID), lost education quality, etc. . . . the social effects of having a vaccine, ending the ‘helplessness’/ hopelessness/etc about the virus, will be at least as important as its actual medical benefits . . ”
        I agree 100%. Life is more than just being able to have a job (whether teleworking from home or going to work weating a mask) and being able to communicate with loved ones by sitting alone at home and seeing their faces on a screen. Our social rituals of gathering, celbrating, mourning, singing, etc. are essential for the survival of our human spirit. Without them, we die inside. This thing is a soul-killer, even more than it is a killer (and wounder) of human bodies.

        That being said, I’m still concerned about uptake — vaccine resistance seems to be growing, even as cases spike and restrictions on public gatherings are once again being imposed. The death in Brazil was very likely a person in the control arm; but I’m already seeing scare headlines (e.g..: https://www.cnbc.com/2020/10/21/astrazeneca-shares-slide-after-brazilian-health-authority-says-volunteer-in-covid-vaccine-study-dies.html) — and I’m sure the social medial trolls will jump on this with relish. With Trump braying that he “doesn’t listen to scientists,” with approximately 40% of voting-age U.S. citizens solidly in his corner, and with QAnon rapdily becoming the “news” source of choice for millions of Americans, I am not optimistic about making a signficant dent in vax resistance, no matter who wins the election.

        1. confused says:

          Eh I still think that actual uptake will be much better than current polls suggest, both because of actual de-escalation of opinion vs. current situation right before an election, and because the general population will not be first to get it…

          I think if the poll question were “would you take a COVID vaccine after it has been approved by the FDA for 4 months and tens of millions of people have already received it” – which is probably the likelier situation for non-elderly non-healthcare workers etc. – you’d get quite different answers.

          And uptake probably won’t have to be all *that* high… especially if reinfection is rare & 20-25% of the US has had COVID by the end of this winter (which wouldn’t really surprise me).

          1. Dark Day says:

            It will stil be problematic among people of color, though. There’s a lot of history to overcome. In a recent public meeting of the U.S. Food and Drug Administration’s vaccine advisory board, one of the panelists said, “”I firmly believe that this is another Tuskegee experiment.” That sentiment, based of course on real historical facts, is very common and widespread among academics, intellectuals, and even medical professionals as well as laypeople in the African-American community. My opinion, based on exstensive personal experience as well as articles and interviews like the one I just quoted, is that this will be a significant barrier to upake in some of the communities that need the vaccine most desperately.

          2. Dark Day says:

            And remember — in terms of nationwide results, perhaps you’re right: Uptake won’t be as much of problem as some predict. But we aren’t just one “herd” — we’re multiple “herds” with widely varying access to health care, pre-existing condidions, community health risks, and other variables. It’s entirely possible (and yes, I know I’ve said this before) that certain communities, physically isolated/ segregated from the “mainstream,” may end up persisting as “COVID ghettos” long after the “mainstream” of America has been sufficiently vaccinated.

          3. confused says:

            Possible, I suppose, and there’s enough communities in the US that it’s not unlikely to happen *somewhere*.

            But as a large-scale problem, I rather doubt it.

            At the very beginning, there will be a lot of hesitancy and suspicion; there’s a lot of fear of being a “guinea pig” — but that’s not really the situation once 50%+ of the population has had it and we’ve seen people aren’t keeling over dead.

            And, I mean, what level of immunity do we need to kick it into “post-pandemic”? I don’t think even 50% of the population got H1N1 in 1918-19, but it still went post-pandemic, and there were no flu vaccines then…

  27. x says:

    “The considerations run the other way as well – it may end up being incumbent on the trial organizers, from an ethical perspective, to break the blind and offer the vaccine to all participants.”

    I’m not sure how this is an ethical mandate.

    Let’s start here: healthcare is not a human right in the US. You can argue that it should be (I would) and what that would look like in practice, but right now it isn’t except for certain groups (military, elderly – and even then, people don’t use the word “right” but “entitlement” or benefit”). The medical industry is, presumably, satisfied with this status, and therefore it must be ethically acceptable.

    So: who is to say that anyone not vaccinated must receive the new vaccine? There are epidemiological considerations – but if trial patients in the placebo arms die from COVID, it will be no different from any of the poor people who die from lack of insulin or not getting to an ED in time or getting terminal cancer that was never found by routine checkups or whatever. Those patients are, presumably, not entitled to receive vaccination, and so they shouldn’t, because there’s important science to do.

    Mind you, I am merely applying the existing standard. If you feel that not vaccinating people would be unethical, then presumably you must support universal healthcare…

    1. FrankN says:

      You are overlooking two things:

      a.) Technically, Pfizer is testing a German vaccine, developed and owned by BioNTech, under license. Germany has universal healthcare, and constitutional guarantee of being bodily unharmed (Art. 2. No. 2 Grundgesetz). Pfizer as licensee remains bound to these German standards.

      b.) Any trial sponsor bears the responsibility to minimise potential damage to the participants. One might argue that this includes ensuring the best possible protection against damage from CoViD 19. This would imply that, once the protective quality of a vaccine has been established beyond reasonable doubt, the vaccine should be made available to all participants in the placebo arm.
      This isn’t just an ethical consideration. I can imagine that a number of lawyers would happily follow up that line of thought, should the opportunity arise.
      Pfizer obviously intend to honour their responsibility. Should the FDA rule this out for “scientific reasons”, it should IMO at the same time ensure that any possibly resulting legal claims will not fall on Pfizer, but instead on the FDA and/or the US Government.

  28. An Old Chemist says:

    A week after COVID-19 vaccine trial goes on pause, Johnson & Johnson and FDA won’t reveal critical details

    https://www.cnnphilippines.com/world/2020/10/20/A-week-after-COVID-19-vaccine-trial-goes-on-pause–Johnson—Johnson-and-FDA-won-t-reveal-critical-details.html

  29. Me says:

    It is certainly a strange one. We know about ‘first and best’ but in this case we would never be able to establish a best-in-class product.

    In any other disease area, once the approved product becomes standard of care, other products will work with the patients who failed on SoC. Unlikely to work in vaccine development.

    And of course you can argue the ethics of withholding vaccine from the placebo patients, which is the basis of this essay.

    We live in interesting times.

    1. confused says:

      >>And of course you can argue the ethics of withholding vaccine from the placebo patients, which is the basis of this essay.

      Frankly this has bothered me for months.

      I understand that until the trial is competed it’s not considered to have shown any efficacy, so not considered to be necessarily better than nothing.

      But doesn’t prior biological knowledge have a role here? These vaccines have already shown antibody/T-cell production right?

      If the “prior probability” (in a Bayesian sense) of its working is high enough, I’m not sure you can really say that it’s plausibly not better than nothing.

      Or is the risk of antibody-dependent enhancement the reason why we can’t place a very high “prior probability” on a vaccine that’s shown antibody/T-cell effectiveness actually working?

  30. flem says:

    Hate to get off topic: Could someone explain difference between vaccines that prevent disease vs those proven to prevent infection? I understand current vaccines are testing for prevention or attenuation of disease. However it may not prevent individuals from contracting the virus and potentially spreading them even though they do not get sick. Is this correct?
    Thanks

    1. Moses says:

      @Flem:
      This article in the NY Times a couple of months ago goes some way to explaining the difference in vaccine effectiveness. Adam Finn & Richard Malley are the authors.

      https://www.nytimes.com/2020/08/24/opinion/coronavirus-vaccine-prevention.html

  31. Marko says:

    If anyone is interested in watching sausage being made , the Vaccines and Related Biological Products Advisory Committee meeting is being live streamed, starting ~ 10AM , here :

    https://www.youtube.com/watch?v=1XTiL9rUpkg&feature=youtu.be

    1. Marko says:

      This site might e a better experience than Youtube. At least they provide some tunes while you’re waiting :

      https://fda.yorkcast.com/webcast/Play/c26e83a0f77a412296949f4f43af4c981d

      The music has a bit of a “Deliverance” vibe…..

  32. Gary Cornell says:

    One thing that seems to be brushed away is that we are likely to have an efficacy signal for 18-55 year olds long before we have an efficacy signal for >55 year olds (prevalence is 1/3 roughly) and especially >75 year old (prevalence <1/15). This means that we may have to rely only on immune system markers which are hardly ideal or continue a placebo trial in seniors after an a vaccine trial on younger people is essentially finished. This seems ethically problematic at the very least. See this medium article I wrote: https://medium.com/@me_1949

    1. Marko says:

      Good point. It seems almost criminal to me that there hasn’t been a greater focus on recruiting the elderly for the trials , given that the over-65 age group accounts for ~80% of Covid-19 deaths and more than half of total life-years lost to the disease.

      I knew that prevalence was expected to be lower in the elderly , due to protective self-quarantine , etc. , but I had no idea the differences were that great.

      I thought maybe only a couple of extra months of data accrual would be necessary to confirm efficacy in elderly subgroups , but clearly that is not the case.

      1. confused says:

        >>I knew that prevalence was expected to be lower in the elderly , due to protective self-quarantine , etc. , but I had no idea the differences were that great.

        I’d imagine those states that have open bars, etc., probably contribute quite a bit to higher prevalence among the young-adult group.

        Although, honestly, here in TX a lot of middle-aged-to-elderly people don’t seem to be taking it that seriously; in some places you see a lot of masks on chins or ears, etc.

        1. Dark Day says:

          At least in Illinois, we’re hearing that a good portion of the current uptick in new cases is due to private gatherings in people’s homes, which will no doubt become more common as the weather gets colder (and, ironically perhaps, as bars and restaurants close again in response to the worsening case positivity rates).

          1. confused says:

            I’ve heard that too. I think that part of the problem is that a large proportion of the population – at least in the central US – aren’t that concerned, so official/governmental measures have less effect than might be “expected”.

  33. TabeaK says:

    Very timely article for someone like me who is considering whether to enter a trial right now!

  34. David says:

    Derek wrote: “What if you’re one of the (many thousands) of people who are in the placebo group for the other vaccine trials, the ones that have not yet been authorized for use?”

    What if you thought you were in the placebo group, but actually got an active vaccine? We won’t have any data on the safety of giving one vaccine to subjects who previously got a different one.

    For that matter, what will the safety issues be, for giving an approved, or authorized vaccine, to subjects who were in the active arms of other vaccine candidates that didn’t make it to completion?

    1. confused says:

      That link doesn’t seem to work for me for some reason.. what is it?

      1. Marko says:

        Don’t know. Here’s the source data :

        http://www.mwra.com/biobot/biobotdata.htm

  35. SCINV says:

    After the full approval of remdesivir yesterday for almost all adults and renewed eua for almost all children, is there really any doubt that what you describe above is exactly what will happen?

  36. debinski says:

    After listening to the FDA vaccine meeting off and on yesterday, I didn’t find much useful with the exception of their discussion on handling of placebo subjects after an EUA. Lots of varying ideas on that including not allowing an EUA because it will cause withdrawal of placebo subjects from Phase 3 studies. Also mentioned was a letter from Pfizer proposing to give their placebo subjects the option of switching to the active arm. That makes a lot of sense – they can get even more safety and efficacy data that way. They propose using other methods for control data. See: https://www.reuters.com/article/us-health-coronavirus-fda-vaccine/pfizer-jj-urge-clarity-from-fda-on-future-of-covid-19-vaccine-trials-once-a-vaccine-is-available-idUKKBN2772KJ

    1. confused says:

      >> including not allowing an EUA because it will cause withdrawal of placebo subjects from Phase 3 studies

      IMO, that would be really terrible. We need to have something that works as soon as possible, even if it isn’t the best possible.

  37. jdb says:

    With all due respect, no EUA means thousands upon thousands more dead.

    Not just from covid, but from war, poverty and homelessness, domestic violence, alcoholism, organized crime, and suicide.

    Not everyone has the luxury of wealth and getting Amazon and Postmates daily like the wealthy professional class (which many FDA bureaucrats are members of) do. Where is the compassion for the poor and desperate? The world does not have time for more delays than necessary.

    1. Dark Day says:

      You’re right — but would an EUA that looked untrustworthy to a significant percent of already-skeptical citizens ultimately result in diminished uptake, and thus diminished efficacy? I realize this is a horrible, tragic paradox — don’t approve, and thus allow thousands more to die; or approve, and thus risk tens of thousands more dying in the long run due to ongoing public distrust of a “rushed” vaccine.

      In a rational world, this might not be a significant problem, but in our anti-science, social-media/tweeter-twitter-twatter-infested miasma of “fake news” and conspiracy theories, it’s unforutunately the reality we have to live in.

    2. David says:

      jdb: “no EUA means thousands upon thousands more dead.”

      On the other hand, an EUA for a marginally effective product, which squeezes out later but potentially slower programs, might also lead to increased deaths.

  38. Steve Scott says:

    Trials can only do so much. Given the fact that so many people are getting infected and dying every day, you have to balance the desire for scientific precision against the real life tragedies taking place every day. Some of those with severe infections have lingering effects that could last for years. Even if adverse reactions to vaccines are later detected in a small number of people, you have to balance that against the urgency of defeating the worldwide pandemic. Once participants are unblinded, the control group factor is lost, but suddenly you can get vaccine data (though not as precise) from 30,000 people instead of 15,000. And then when 100’s of millions of people are vaccinated, you have the ultimate testing ground. Over time, adjustments can be made. Some vaccines may be shown to be more effective than others. It will be an ongoing process. None of this is perfect, but let’s balance scientific caution against the greater need to save lives as soon as practical.

  39. Hopeful Layman says:

    Looking ahead to subsequent trials of newly developed vaccines in the future — what are the ethical considerations of having a “control” arm after a vaccine has been made available? Assuming we can find enough individuals who haven’t been vaccinated, yet are willing to participate in a new series of trials (unlikely?), are we putting them at an unacceptable disadvantage by basically asking them to risk remaining unvaccinated for many more months?

    One option would be to use an already-approved vaccine as the “placebo” — this would test whether the new candidate was significantly more effective than at least one of the already-existing ones. Would this be feasible? Would the company that manufactured the vaccine now being used as a “placebo” ever go along with something like this? (Conversely, would they be able to stop it?)

  40. Hopeful Layman says:

    I realize Slaoui has a self-interest in all this, so we should take his efficacy projections with more than a grain of low-sodium salt substitute — but I still can’t help but wonder. Even if we shave 10 % or more off his projections, he seems to be either unsettlingly or encouragingly optimistic, depending on one’s point of view. If he”s right (or even close to being right), things could actuallay turn out better, and faster, than even a lot of optimists here have been suggestinmg.

    https://www.hospimedica.com/covid-19/articles/294785008/covid-19-vaccine-could-have-80-90-efficacy-and-secure-fda-eua-by-late-november-says-head-of-operation-warp-speed.html

    1. confused says:

      From a completely ‘non-expert’ perspective, I’ve been wondering about “surprising efficacy” too.

      From reading this blog, I’ve gotten the impression that modern drug development is hard/slow/expensive partially because the “easy problems” were all solved ages ago.

      But the lack of existing treatments/vaccines for COVID is because it’s new, not because it’s an “inherently hard problem” like HIV or Alzheimer’s or cancer or something.

    2. Marko says:

      “….Speaking on the FDA’s new stricter guidance for EUA of COVID-19 vaccines, Slaoui said that the safety follow-up requirements would give reasonable sampling of most of the adverse events of the vaccines currently in trials. That, coupled with very strong active pharmacovigilance, upon introduction of the COVID-19 vaccines, would fully characterize their long-term safety.”

      Think about what he’s saying here. We can fully characterize the safety only after we give everyone the vaccine and then follow up.

      How reassuring. The anti-Vaxxers are gonna love it.

      1. Hopeful Layman says:

        Just thought of this — pregnant women have not been included in the trials. What are the chances of teratogenic effects from one of these vaccines? I’ve heard a few people shudder at the thought of a “Thalidomide II” . . .

        1. confused says:

          Is that biologically plausible?

      2. confused says:

        It sounds scary – but it’s *right* – tons of people are dying of COVID now.

        Even if this was 10 times worse than the 1976 swine flu vaccine in terms of side effects, it would still be an incredibly clear win – the problem with 1976 is that the disease didn’t spread so even a very low risk of side-effects looked bad in comparison to zero risk from the disease.

        But COVID is already everywhere.

  41. Marko says:

    A good review of yesterday’s advisory meeting :

    https://www.sciencemag.org/news/2020/10/there-s-only-one-chance-do-right-fda-panel-wrestles-covid-19-vaccine-issues

    “….The FDA representatives suggested a way out of the dilemma: Instead of receiving an EUA, a vaccine could be approved for “expanded access,” which would limit its use to select populations at high risk of COVID-19. This pathway typically is reserved to allow the use of experimental treatments in patients who have life-threatening conditions, but it has been used before for vaccines, such as one for meningitis B in college students. Because access to the vaccine would be limited, the approach has the advantage of allowing efficacy trials to continue.”

    This strikes me as the best way to proceed. Do something like what Russia and China did. Vaccinate front-line health care workers or the military – groups that the wider public will easily understand they don’t belong to and thus don’t qualify for the vaccine , allowing the trials to continue. Run the trials until all four current P3 candidates have one or two interim data sets at minimum.

    I’d rather see the high-risk elderly ( >65 ) first in line , but it’s pretty clear that we won’t have sufficient efficacy and safety data for that subgroup for a while yet.

  42. Hopeful Layman says:

    ” . . .Do something like what Russia and China did. Vaccinate front-line health care workers or the military – groups that the wider public will easily understand they don’t belong to and thus don’t qualify for the vaccine , allowing the trials to continue. Run the trials until all four current P3 candidates have one or two interim data sets at minimum. . . .”

    From what I can tell, that’s more or less Slaoui’s idea.

    I agree with you that his statement about assessing safety during “follow-up” sounds pretty shakey, but on the other hand, that’s pretty much how EUA’s work, isn’t it? Doing it this way would at least begin to vaccinate people at high risk of contracting the disease, and it would probably begin to have a positive effect on the case numbers (although not as much as it might have a few months ago, before the cases among younger people started spiking). I think most of the strategies for distribtion do include the elderly pretty early in the process, but it’s a little difficult to tell WHICH elderly — people in nursing homes, definitely, but I’m not sure about when older people in the general population would be targeted. (For that matter, I’m not sure how the marketing would go — will every American whose Census data shows that he or she is 65 or over be getting a letter or an e-mail? Will it be up to people to contact their doctors, the local health clinic, or the nearest phamacist and then show up with proof of age? I got my flu shot last week, and there was a wait at the pharmacy of almost an hour. I can imagine lines out the door and snaking around the block for COVID shot — make the “early voting” lines look tame!

    1. Marko says:

      The early data won’t tell us if the vaccine is effective in the elderly , and if you start vaccinating them , you’ll compromise the trials as all of the elderly in those trials will want to be unblinded so they can get the vaccine if they’ve been on placebo. When the data shows it’s effective on the elderly , sure , go for it.

  43. John Hasler says:

    > will every American whose Census data shows that he or she is 65
    > or over be getting a letter or an e-mail?

    Thereby destroying what little trust remains in the anonymity of the census. The last time they are known to have breached that trust was to intern japanese-americans during WWII.

    1. Hopeful Layman says:

      Point well taken — so how WILL they do it? I’m guessing there will be a lot of confusion over who’s eligible to get vaccinated during these various “phases” of the rollout; the wording seems unclear in a lot of cases. Or will it be up to people to seek out the place where the vaccines are being administered, stand in line, and hope they “qualify”? I’m seeing a lot of wasted hours, days off work, etc. . . .

      1. confused says:

        I think it may depend largely on states – TX has a plan for who will be prioritized and is advertising for doctors, etc. to sign up to receive/deliver the vaccine when it becomes available.

        That sounds like the federal government will buy it from the manufacturer but distribution to individual doctors/pharmacies/etc. is through the state public health agencies?

  44. wubbles says:

    Just do the damn challenge trial already. 9 arms, the 8 candidates+placebo, size it appropriately, and you kill a few people, sicken tens, get all the effectiveness data you need in a month. Then we can think about doing a gradual rollout to catch post-vaccine reactions. All these tough decisions are killing thousands a day by not getting a vaccine into their arms, and it’s all so avoidable.

    If you’re squemish about sending people to die, consider that we’re sending young men and women to serve their country in Iraq and Afghanistan, and have been for 18 years, against a threat far less malign an insidious. And I’m no keyboard warrior: I’ve volunteered.

  45. debinski says:

    Looks like FDA has given Astrazeneca and J&J the go ahead to restart their trials. J&J are still being opaque about the SAE that caused the delay in their official statement: https://www.jnj.com/our-company/johnson-johnson-prepares-to-resume-phase-3-ensemble-trial-of-its-janssen-covid-19-vaccine-candidate-in-the-us

    But unnamed sources told the Washington Post that it was a stroke in a young male: https://www.statnews.com/2020/10/23/covid-19-vaccine-trials-from-astrazeneca-johnson-johnson-to-restart/

  46. Hopeful Layman says:

    Wording is somewhat vague — I’m not seeing any precise definition of “older adults” here, and there are no actual data to show sample sizes; also, of course; “produc[ing] an immune response” is not the same as actualy showing that the vaccine works in the “real world” — but it might be cause for cautious optimism.

    1. Marko says:

      “…Oxford researchers found that the vaccine caused “robust immune responses” of protective antibodies and T cells in people aged over 55.”

      https://www.upi.com/Top_News/World-News/2020/10/26/AstraZeneca-COVID-19-vaccine-spurs-immune-response-in-adults/5241603717404/

      Apparently , the strategy for vaccine rollout to various subgroups – like the elderly – in the absence of sufficient trial data , will be to use the surrogate of “immune response” to measure efficacy.

      1. Barry says:

        Some of us remember that BCG evoke a robust immune response while failing utterly to protect against Tuberculosis in the lungs (the immune response is real; it does protect against TB infection of other tissues)
        It is always tempting to measure Abs in the plasma rather than other aspects of the immune response; it’s cheap and quick. It is not however always a meaningful surrogate.

        1. Marko says:

          I agree. I don’t think any surrogate marker – plasma Ab , mucosal Ab , or T-cell response – should be used as justification for approval until it has been definitively proven that it correlates with vaccine efficacy as measured by infection rates or disease severity. That said , I’m hopeful that the data coming out of the trials will establish that correlation.

  47. Dark Day says:

    What are the implications of this? Apparently, the EU is planning to adhere to a lower vaccine efficacy threshold than the 50% the FDA has set as the U.S. minimum standard. Could a pharma company whose product did not meet the FDA’s standard simply take its vials across the ocean and market millions of doses “over there”?

    https://www.wsj.com/articles/european-union-wouldapplylower-threshold-in-assessing-covid-19-vaccine-11603649465

    1. confused says:

      I mean, I don’t see why not, if EU regulators allowed it? I don’t think the FDA would block sales to other nations, would they?

      But 50% is a pretty low standard, if the first few vaccines to get through Phase III meet it, there might be no demand for others & all resources would be directed to better ones.

  48. Dark Day says:

    Meanwhile, it is clear that despite the much-maligned bungling of the pandemic that we’ve seen in the U.S., this latest resurgence is not “just” an American phenomenon. One wonders whether, even if an effective vaccine is rolled out over the next few months, it will be “too little, too late” to stem the tide of a years- (or even decades-) long international catastrophe.

    1. confused says:

      Nah, if an effective vaccine is rolled out, it won’t remain a huge ongoing crisis.

      Uptake may be an issue, but I think that issue will greatly diminish over the first few months of rollout, and COVID isn’t smallpox-level deadly or measles-level contagious; we shouldn’t need 90% uptake or anything.

      (Especially as I wouldn’t be surprised to see the US at like 20-25% infected by spring, which would likely reduce the level of uptake needed for herd immunity.)

      Even before anything like herd immunity, once most of the elderly have been vaccinated + we have something like a monoclonal antibody treatment… that might drop the deaths below “crisis” levels.

      (For that matter it wouldn’t remain a crisis for decades even if there were no vaccine — social distancing measures would likely make it last longer than the 1-2 years of historical flu pandemics, but not *that* much longer.)

      And yeah, while the US federal response has been terrible, it’s not uniquely so & some places even with pretty good responses seem to be having major trouble.

      1. Dark Day says:

        I think you’re probably right about the high post-infection rates by early next year (and this doesn’t include the many asymptomatic — and, probably, mildly symptomatic — people who haven’t been counted, but who would also presumably have at least some immunity.) Again, though, uptake among specific at-risk populations and communities will be as essential as “overall” uptake rate across the U.S. We need to remember to use the appropriate denominator when we think about rates. Think about it the way we think about diseases that affect certain populations — the “overall” rate of HIV, let’s say, or Tay-Sachs, or Sickle Cell Anemia in the U.S. isn’t high if we use the entre population as our denominator; but among the high-risk populations, it remains very much of a risk. The same applies here — it’s very possible that certain communities — isolated geographically, socially, culturally from the so-called “mainstream” — will remain very much at risk, even after the “overall” U.S. vaccination and uptake data look encouraging.

        1. confused says:

          >>and this doesn’t include the many asymptomatic — and, probably, mildly symptomatic — people who haven’t been counted, but who would also presumably have at least some immunity.

          Oh, no, I was including those people. I don’t think we will have 20% of the population (~66 million) confirmed cases!

          We are at ~8.6 million confirmed cases now. The early estimates of true infections being 10x confirmed cases are almost certainly too high for the current situation with testing being much more available.

          But if it’s something like 4-5x, that would mean ~35-43 million people or about 10-13% of the population. So I was thinking that might double by spring.

          >>The same applies here — it’s very possible that certain communities — isolated geographically, socially, culturally from the so-called “mainstream” — will remain very much at risk

          In the short term, perhaps, but I’d tend to expect a community with low vaccination uptake to end up with high immunity by infection (assuming reinfection remains relatively rare) – especially once vaccines mean people stop taking precautions.

          And high infection rates might prompt better vaccine uptake in that community.

          I really can’t see there being all that many people in the US who are “immunologically naive” to COVID a few years down the road.

          1. Dark Day says:

            ” . . .I’d tend to expect a community with low vaccination uptake to end up with high immunity by infection (assuming reinfection remains relatively rare) – especially once vaccines mean people stop taking precautions.”

            Sorry, but I still strongly resists the idea that we should simply accept the fact that “some people” will just continue to have to get sick and die in order to help bring the rest of “us” to some semblance of herd immunity. Sounds too much like those “mainstream” commentators back in the 1980s and early ’90s who pooh–pooh’d the seriousness of AIDS because it was killing “only” gay men — and, for that matter, the “mainstream” law enforcement and public health officials who turned a semi-blind eye to the heroin epidemic that devastated Black and Hispanic communities in the U.S. for decades, beginning at least as early as the late 1940s, and then only within the past few years have come around to recognizing addiction as a medical problem, now that working-class white kids have become disproportionately affected.

          2. Dark Day says:

            . . . and also — and yet again! — I really, TRULY hope we don’t see ” vaccines mean[ing] people stop taking precautions.” If that happens, it will just take all that much longer for this thing to get under control, and we’ll continue to see tragic and unnecessary human suffering in the meantime. The road to “normal” is a long one, and it’ll have to be negotiated in baby-steps.

          3. confused says:

            >> “Sorry, but I still strongly resists the idea that we should simply accept the fact that “some people” will just continue to have to get sick and die”

            I didn’t — and didn’t intend to! — say anything about “should”.

            I don’t see how it can be prevented, though, *if indeed there are communities with very low vaccine uptake after vaccines are widely distributed* – there wouldn’t be public support for mandatory public health measures, and they wouldn’t be followed anyway.

            IE – the best course is to do everything possible to ensure there are not, in fact, communities with very low vaccine uptake after vaccines are widely distributed.

          4. confused says:

            >>it will just take all that much longer for this thing to get under control,

            I don’t really think so. COVID isn’t going to go extinct soon regardless — “under control” will be the point when most of the population is no longer ‘immunologically naive’ and COVID acts like an endemic disease, not an epidemic/pandemic one.

            So people not being careful is certainly problematic — but because it will increase the number of deaths, not because it would change the timeline for ‘end of pandemic’, I’d think.

            (Unless reinfection ends up being common enough that infection doesn’t meaningfully contribute to immunity — but that doesn’t seem to be the current best guess.)

  49. Hopeful Layman says:

    I’m sorry if this is an insufferably “layman”-like question, but which vaccine is this? Or is this a “new” one that hasn’t been discussed before? Apparently it’s close to Phase III trial completion (or am I misreading this?) —

    https://www.gwhatchet.com/2020/10/25/medical-school-researchers-expect-effective-covid-19-vaccine-by-end-of-2020/

    1. Marko says:

      “…..The University is conducting the clinical trial in partnership with Moderna Inc., a biotechnology company in the third stage of testing its vaccine on an estimated 30,000 people across 89 sites nationwide, the Business Journal reported. The report states the University partnered with Moderna through the National Institutes of Health’s Coronavirus Prevention Network, “a clinical trial network” first founded to combat HIV.”

      https://www.gwhatchet.com/2020/08/06/gw-launches-clinical-trials-testing-centers-to-test-potential-covid-19-vaccine/

  50. Hopeful Layman says:

    Okay — Thanks. Sorry!

    I was also thrown off by their projection that their vaccine wouldn’t be widely available until 2022, which certainly isn’t what most of the U.S. candidates (incl. Moderna) have been suggesting.

  51. Marko says:

    Possibly a good news / bad news story regarding the D614G mutation. The bad news , as has already been reported , is that it probably increases transmissibility. The good news is that it appears to be susceptible to neutralizing antibody developed in response to the original “D” variant used in vaccine development :

    https://www.nature.com/articles/s41586-020-2895-3

  52. theasdgamer says:

    If you’re watching Sweden like I am, they’ve experienced another ramp of cases, but so far, very few deaths.

    Since we’ve entered flu season, I wonder if some of the “covid” cases are actually the flu.

  53. Marko says:

    “Eli Lilly said its antibody treatment does not work on patients hospitalized with Covid-19”

    https://www.nytimes.com/live/2020/10/26/world/covid-19-coronavirus-updates#eli-lilly-said-its-antibody-treatment-does-not-work-on-patients-hospitalized-with-covid-19

    Need to use early , probably. Ongoing trials may still be able to demonstrate efficacy.

  54. Dark Day says:

    Unless I’m misinterpreting this, Dr. Fauci is saying that even with a vaccine, the problem of asymptomatic or mildly symptomatic carriers/spreaders will not diminish. This means, I think, that “normalcy” (economic, social, emotional) is not going to be a feasible possibility for a long time to come.

    https://finance.yahoo.com/news/fauci-vaccines-will-only-prevent-symptoms-not-block-the-virus-195051568.html

    1. confused says:

      I don’t see why? Once everyone who wants to be vaccinated has been vaccinated, if the vaccine prevents serious effects, we wouldn’t need to treat COVID any more seriously than any other respiratory illness.

      I don’t think there’s any ethical obligation to limit your own life to protect people who could have been vaccinated but chose not to (unlike most vaccine-preventable diseases, COVID is least dangerous to the young, so parents’ ignorance/stupidity is not an issue here).

      1. Dark Day says:

        I do think that a lot of people will feel an ethical obligation to keep others safe, and in areas where mandates of various kinds have been imposed, they’ll stay imposed until actual case positivity rates go down significantly and stay there. I also think that if those numbers don’t go down, a lot of people (esp. older people) who’ve been vaccinated will still be hesitant to socialize freely, unmask, etc., because they’ll know they still have — let’s say — anywhere from a 25% to over 40% chance of getting infected (depending on efficacy data).

        1. confused says:

          >>ethical obligation to keep others safe

          I think that applies as long as the vaccine isn’t readily available. If you could have taken 30 minutes to get the shot and didn’t, to me that’s roughly like riding a motorcycle without a helmet (in states where that’s legal) — risky decisions can have consequences.

          As for mandatory public health measures… eh, I think relaxation of those may have at least as much to do with public opinion/politics as actual data, but that may vary by state (I think you said you’re in IL? TX, my state, is obviously rather different politically…)

          I think that it will be hard to maintain political will for anything mandatory once people stop being especially afraid of COVID – the question is more at what case/hospitalization/death rate do people stop being especially afraid.

  55. Chris Phillips says:

    According to this report, the Pfizer trial has not yet met the criterion for the first interim analysis. It seems that analysts at Morgan Stanley had suggested yesterday that the first interim analysis might have taken place (in which case the lack of an announcement would have implied an apparent efficacy of less than 77%) The report says that Pfizer will be receiving information on efficacy as the trial proceeds, and will announce it, in contrast to Johnson and Johnson, where it appears the company will be told only when/if the data allow a filing for an emergency use authorisation:
    https://www.statnews.com/2020/10/27/no-news-on-pfizers-covid-19-vaccine-is-good-news-and-bad-news/

    1. Hopeful Layman says:

      Pardon my “Layman’s” confusion (again!) — but if the baseline efficacy target is 50%, then 77% sounds pretty damn good. What’s the discrepancy here?

      1. Chris Phillips says:

        Moncef Slaoui was recently quoted as hoping for 80-90% efficacy.

        1. Hopeful Layman says:

          Yes, I saw that. Slaoui has a self-interest, of course, being the head of “Operation Warp Speed” (as well as a major investor in Moderna!), although I’m sure all of us would love to believe — hope against hope? — that he’s in the ballpark (Fauci says he hopes for 70 – 75%, but he’ll settle for 50%).

          Stll doesn’t answer my question, though. Why is the “less than 77%” criterion being applied to Pfizer? Or, again, am I misunderstanding something here?

          1. Michael says:

            Hopeful, in layman’s terms (pardon the pun), I think the issue is that 32 events isn’t very much, so if they are going to say that the interim efficacy finding is positive, they want at least 25-26 of those events to be in the placebo arm to make it less likely that a projection that it will be >50% effective isn’t a small sample size fluke.

          2. Hopeful Layman says:

            Ah — a “margin of error” issue?

            Interesting, because one very pessimistic article I read suggested that a vaccine that was assessed as being between 50 – 70% effective could actually have “real world” efficacy as low as 35% or so, if the margin of error were taken into consideration. A more statistically gifted contributor here may weigh in with either confirmation or de-bunking.

    2. Michael says:

      The CEO of Pfizer said that there haven’t been 32 events in the trial yet, so the interim analysis isn’t yet possible. The vaccine study participants are apparently living carefully.

      1. DataWatcher says:

        I’m guessing that’s going to be a consideration in all the trials. The “volunteers” are self-selecting, and it’s safe to assume that most of them are at least adequately educated and aware of the everyday risks of COVID, have been behaving accordingly, and will continue to do so. Whether that biases the selection in favor of people more likely to contract relatively mild cases (e.g., lower viral loads due to digilant masking and social distancing) is an interesting question that I haven’t seen addressed.

        1. confused says:

          How is this compatible with the idea, stated earlier on this blog, that human challenge trials wouldn’t advance the vaccine timeline meaningfully?

          (I understand that there are of course ethical issues with challenge trials…)

          This also kind of implies, IMO, poor selection of candidates — I think I’d be advertising at bars and stuff in states where those are open…

  56. DataWatcher says:

    I do find it concerning that we may be seriously underestimating the logistical complications of vaccine distribution, once a vaccine actually gets approved. The U.S. is a BIG country, and a lot of people (esp. some of the most high-risk people) live well off any “beaten track” in rural hamlets, trailer parks, remote urban locations far from any clinics or hospitals, etc. As of yet, I haven’t heard any details of a coordinated distribution plan, over and beyond Trump’s vague “We have a general working on it” promises. Anyone know any further details?

  57. FrankN says:

    The problem is that according to everybody’s calculation, including my personal “back of the envelope” one, there should have been 32 infections in the placebo group alone by October 15. However, A. Bourla has stated today that the total number of registered infections in the study is still below the 32 threshold.

    This means that everybody, possibly including BioNTech/ Pfizer and the FDA, seems to have worked with wrong assumptions. Either (i) infection rates among trial participants have remained substantially below average, possibly since the participants acted much more infection risk-aware than the majority of the population, or (ii) a good part of the now published infection rate relates to asymptomatic cases, while the trial(s) only recognise and count symptomatic ones.

    Both issues are no problems per se – to the opposite. But they seem to considerably delay the demonstration of vaccine efficacy as demanded by the FDA.

    1. Dark Day says:

      This may be a minority opinion, but speaking for myself I’m more than willing to wait a little longer (even if “a litte” means at least a few more months) for a vaccine that’s been as thoroughly vetted as possible. And I’m sure that the more thorough and conscientious the process looks to the general public, the more encouraging the uptake will be.

    2. debinski says:

      As a Pfizer trial participant, I can confirm that I am COVID-averse and taking good precautions. But I am less cautious than initially (march-may), so maybe the cases will pick up if everyone is loosening up. The study site I attend has had 0 cases out of 220 subjects, as of last week. I found that surprising. I am feeling more of an obligation to get out and about (and also having less fear since the death rates are so much lower).

      1. DataWatcher says:

        Be careful! The morbidities associated with serious infection are still very serious!

      2. Hopeful Layman says:

        . . . It’s possible, of course, that you and the majority of the people in that study site happen to have been injected with the vaccine, not the placebo — which would be excellent news, because it could mean that the vaccine actually prevents infection, not just symptoms. But then I’m “Hopeful”, which these days is probably a fool’s game . . .

        1. debinski says:

          I wish that were the case but each site has their own 50:50 placebo/active randomization. I’m almost certain I got the placebo. I do wonder if Pfizer just chose not to analyze the efficacy data yet since they have to wait a few more weeks to get the required safety data anyway.

      3. Marko says:

        ” The study site I attend has had 0 cases out of 220 subjects, as of last week. ”

        That’s kinda surprising to me. Is that site drawing from an area that has been showing particularly low infection rates in the general population ? I would’ve expected at least a couple of infections per month out of a group that size , maybe half as many if the vaccine is very effective at preventing symptomatic infection.

        1. Hopeful Layman says:

          Or again (he said “hopefully”), maybe it’s preventing infection entirely. I don’t remember what the earlier primate studies showed, or the phase I/II trials.

        2. debinski says:

          Our area is not low risk (Raleigh, NC) and we’ve had some recent spikes. Our numbers of cases, hospitalization and deaths are higher now than they’ve ever been. Pfizer did not require that subjects were at high risk (essential workers, etc) but Moderna did so they may get results sooner.

          1. Marko says:

            OK , thanks.

          2. guineapig says:

            I just got the 1st shot in the Pfizer trial yesterday (sore arm, general malaise, could be I got the real stuff or maybe just be allergies). They asked how often I went out shopping and to meet other people. I didn’t ask if there was an acceptable range of answers.

  58. Dark Day says:

    Here’s an example of what I’d call irresponsible reporting. It’s GOOD news (to me) that Pfizer is adhering to solid scientific practices and holding off on its attempt to get its vaccine approvedd until all the data are in. But an article like this, with the headline “HISTORIC VACCINE RACE MEETS HARSH REALLITY,” spins that into a fear-mongering suggestion that Pfizer’s “admission Tuesday that it still doesn’t know whether its coronavirus vaccine works” represents a “failure to meet its self-imposed goal” and, hence, is “a dose of reality for the historic global vaccine race.”

    https://www.politico.com/news/2020/10/27/vaccine-race-meets-harsh-reality-432964

    If you go on to read the article, its overall tone isn’t quite that pessimistic, but between the headline and the lead paragraph, a lot of readers will go away from it with less confidence in the vaccine trial and vetting process than ever before. The writers and editors of this piece could just as easily have “spun” a more positive article saying, in effect, “Good news — science is taking its course. The eventual result will be a more reliable and effiacious vaccine.”

    The company’s failure to meet its self-imposed goal “doesn’t know wether their vaccines work

    https://www.politico.com/news/2020/10/27/vaccine-race-meets-harsh-reality-432964

  59. Dark Day says:

    Aren’t we rushing things a little bit here? According to this article, this morning Moderna announced that “they’re ready to dole out” the vaccine.

    Really?! Apparently, Moderna is close to completing their Phase III trials, and they have tens of thousands of doses ready to go. But (as far as I can tell) they haven’t submitted any data or applied for any kind of approval (so much for “transparency”) — paperwork-wise alone, I’d think that they’re at least a month or two away from being “ready”. And hasn’t the FDA insisted that an additonal two months be tacked onto the research timeline to identify additional possible adverse effects?

  60. Dark Day says:

    ANOTHER one of those misleading headlines!! Are actually TRYING to sabotage a vaccine roll-out?! This is really starting to p!ss me off . . .

    https://www.cnn.com/2020/10/30/health/covid-19-vaccine-predictions-pharmaceutical-companies/index.html

  61. Dark Day says:

    I know it seems as if I’m fixated on this issue, but without decent vaccine uptake we will have no chance of revitalizing our economy, rebuilding our cultural and social lives, and re-establishing our everyday person-to-person relationships in a normal, mentally healthy way. Even WITH widespread uptake it will be a long haul at best, but with millions of Americans apparently on the Trumpian anti-science bandwagon, the prospects look bleaker than ever:

    https://www.statnews.com/2020/11/04/public-health-recover-rebuke-at-polls/

  62. Jens says:

    Biontech made this announcement this morning:
    https://investors.biontech.de/news-releases/news-release-details/pfizer-and-biontech-announce-vaccine-candidate-against-covid-19
    Sounds very good. Let’s have a closer look to the data asap, please.

  63. debinski says:

    And all the media were wrong with their dire reporting that Pfizer didn’t have their 32 cases in October as planned and we were in for a nuclear winter. I remember reading what Pfizer actually said and it was only that they hadn’t looked at the data yet. Turns out they decided 32 wasn’t enough and kept it blinded. They have had 94 already and expect to complete with 164 in Dec:
    https://www.statnews.com/2020/11/09/covid-19-vaccine-from-pfizer-and-biontech-is-strongly-effective-early-data-from-large-trial-indicate/

  64. debinski says:

    This is curious: They started their analysis on Nov 4 (at which point they had 94 cases).

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