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Clinical Trials

Challenge Testing

OK, it’s time to address the topic of challenge testing against the coronavirus epidemic. Let’s define our terms: by this, I mean “deliberately exposing volunteers to infection by the virus in order to evaluate prophylactic treatments by comparison to controls”. I will say at the outset that I am not in favor of this idea, so that might save some people the time of reading this post. I’ll also say that my objections exactly overlap with those raised here at Stat, so if you’ve read that one you will probably not come across much new here, either.

This is not an unknown technique in anti-infective therapy; challenge trials are in fact run at times when targeting less dangerous viral infections. Here is a WHO guidance document on the idea, and here is a key section to quote:

It is important to note that not all diseases for which vaccines might be developed are suitable for conducting human challenge trials. In many cases, human challenge with a virulent or even an attenuated organism would not be considered ethical or safe. For example, if an organism causes a disease with a high case fatality rate (or there is a long and uncertain latency period) and there are no existing therapies to prevent or ameliorate disease and preclude death, then it would not be appropriate to consider human challenge trials with such an organism. However, a human challenge trial might be considered when the disease an organism causes has an acute onset, can be readily and objectively detected, and existing efficacious treatments (whether curative or palliative) can be administered at an appropriate juncture in disease development to prevent significant morbidity (and eliminate mortality).

There’s the rub. We do not really have effective treatments for the coronavirus, and the more we understand about its effects in humans the less sure we are about its long-term effects. There are clearly people who have much less severe and people who have far more severe acute courses of disease, and the same goes for the long-term sequelae. And while we know a few major risk factors to sort these out (age, obesity, cardiovascular conditions), we do not understand nearly enough. Children are largely protected – but some children have major complications. Healthy 30-year-olds are at far less risk than 85-year-olds, no doubt whatsoever – but some healthy 30-year-olds have had an awful time with the virus, and we don’t know why. If we could really identify a cohort of prospective patients for whom we could say “Yeah, you folks will be OK – you’re not going to get that sick, and we have something to treat you if you do”, then that would be one thing. But we don’t.

That’s one point that has to be made up front. Now we have to ask what challenge trials would be for in our situation. The idea is that they would speed up vaccine development, giving us more data more quickly in Phase II trials (which is where we really start testing to see if any given vaccine candidate can be protective). But I don’t think we need to run challenge trials at all – not under current conditions. We have areas where the coronavirus is spreading so well through the population that I don’t see the advantage. Sure, a controlled challenge would provide you with an experimental setup where the control group almost certainly gets infected and you can compare them with the vaccine recipients. But as things stand, the main difference between doing that and testing in many of the hard-hit locations is that you would just need to round up a smaller N for the challenge trial. And yeah, that’s going to be cheaper, and perhaps take a shorter amount of time. But will it? Getting a human challenge trial off the ground against the coronavirus will not be the work of a moment – there are many places that would simply not sign off on such a design. What sort of waivers will the participants need to sign? Remember, you’ve made them sick deliberately, so you’re more on the hook than ever to provide their treatment.

I realize that there is a web site where people have been volunteering for just such trials. This is going to sound tiresome, but it’s not as simple as that. Challenge trials would be conducted just like any other clinical trial: taking place at one or more medical facilities, with interviews and full medical histories and exams for all participants. Yes, the “1 Day Sooner” folks are listing >30,000 names at the moment, but only a certain section of those people would be logistically or medically suitable/available – it doesn’t mean that there’s a line of 30,000 people ready to go. To be honest, I think that if someone actually were to announce a challenge trial that rounding up enough volunteers might not be the rate-limiting step, but that’s the step that 1 Day Sooner is addressing.

Now consider who those volunteers would be – who they would have to be. Young, healthy people – who else? We’re already stepping close to the line with the whole idea, and giving it to anyone in a more at-risk population would surely step over it. But even the Phase I safety trials of the vaccines have brought in age groups that would be unacceptable in a challenge trial for Phase II, and the Phase II trials – since they’re taking place out “in the wild” can similarly enroll people who would never be in a deliberate challenge. This means that the data you would obtain from such a challenge is skewed heavily away from some of the people that you are going to want to treat first. Both efficacy and safety can (and do) vary by age, existing medical conditions and other variables that you’re going to have to make sure to not address in the challenge trial.

The FDA guidance for coronavirus vaccine trials release the other day actually does take up this idea (page 18). They have it in the break-glass-in-case-of-emergency category, if there is just no other way to demonstrate efficacy:

If it is no longer possible to demonstrate vaccine effectiveness by way of conducting clinical disease endpoint efficacy studies, the use of a controlled human infection model to obtain evidence to support vaccine efficacy may be considered. However, many issues, including logistical, human subject protection, ethical, and scientific issues, would need to be satisfactorily addressed.

Yep. In the end, despite the heroic sound of the idea, I think that such trials are (1) still ethically questionable, (2) fraught with legal complications, (3) are for those reasons and others not likely to run meaningfully faster than regular Phase II trials, and (4) will produce data that may not be able to be extrapolated to the real-world situation. I don’t see the point.

188 comments on “Challenge Testing”

  1. Simon Auclair the Great and Terrible says:

    They are insane. So stand by to see them happen. With Zn.

  2. Gabriel Durazo says:

    What if the challenge trial group were servicemen in the military? These are mostly young, healthy people who already risk their lives to protect the rest of us. It seems to me this this sort of vaccine test would be in line with that.

    1. MrRogers says:

      Nope. There’s no way to avoid coercion in that context. It would be too easy for a superior officer to explicitly or subtly “volunteer” his subordinates for such a study.

      1. Kevin says:

        This is already happening. It is not coerced, per se, but federal research institutions which conduct clinical trials do allow for service members to participate and get paid (but at a lower rate than civilians).

    2. confused says:

      This analogy is why the ethical issues don’t seem very compelling to me. From the USS Theodore Roosevelt etc., the risk of death in a young healthy population should be less than 0.1%. (The one death on the TR was age 41; if you limit the population to say 18-35 or even 18-30, it should be much lower.) Since there is some probability the vaccine will work or you wouldn’t have gotten past Phase I, the actual risk in a challenge trial should be less than that.

      So the real risk will be less than going to war. And the benefit to the US populace overall of getting a vaccine a few weeks earlier is probably larger than the (questionable) benefits we’ve gained from any conflict since WWII.’

      It’s certainly less than the risk of BASE jumping, which young people do with no benefit except enjoyment.

      I don’t see why medical ethics should be held to such a different standard than other human activities. (Yes, I know all the historical bad examples — but this is the 21st century. Culture is so utterly different than the 1920s-1950s that they’re not really relevant.)

      If challenge trials *wouldn’t* get us a vaccine “a few weeks earlier”, though — say because you can just enroll people in a Phase III trial who are likely to go do risky things in Brazil or Houston — then there’s no point to taking the risk.

      1. Thomas says:

        Would it not need to have a control arm? So only 50% would be protected?

        1. Ian Malone says:

          Absolutely. So you are doing a challenge trial in a relatively healthy population with low risk of poor outcomes? The 50% on treatment might come through okay, the 50% on placebo will be at that risk.
          Now, say it all goes to plan. Congratulations! You have demonstrated this helps people who don’t really need it.
          Next step, a population at risk of poor outcomes. Again, 50% of these are unprotected. Poor outcomes aren’t just death either, there are younger people who have apparently sustained medium term lung damage (I know one forty year old who was healthy before and is now on an inhaler for breathing difficulties).
          You may say we don’t need to test in the at-risk populations; if we show immunity then it’ll be fine for everyone. This ignores two possibilities. One: that a vaccine may improve outcomes without providing full immunity, as the macaque trials show for the Oxford vaccine. Such a benefit might not show in a healthier population or be different in the at-risk group. Two: that immunity may operate differently in the at-risk group, there is now some evidence of a T-cell response, while current vaccine efforts aim to raise antibodies to the spike protein.
          The advantage would be a slightly quicker answer as to whether it works. I think the challenge advocates have this idea that you’d dose everybody, give them the virus and within a fortnight know the answer. The logistics of trials mean it’s not going to happen that way, the vagaries of clinical data mean you’ll still need a lot of people and an observation period to know for sure, and lastly with candidate vaccines now actually being produced on an at-risk basis this is not really a limiting step anyway, making all of this borderline ethics mostly irrelevant.

          1. confused says:

            I’m not sure you’d need a placebo. If the vaccine is any good, if everyone is intentionally exposed, it should be pretty obvious that it works without a control.

            But even if so… if we’re talking something like a healthy 18-35 age group who have some degree of medical monitoring, even if 50% are placebo, I’d expect zero deaths out of 1,000 infected-on-placebo would be the most likely outcome. (Since the IFR in that group is already going to be below 0.1%, and you’ve excluded the highest-risk members of that age group.)

            Yeah something that works in young people *might* not work in older ones. But it’s risk vs benefit. The benefit of a vaccine sooner is huge enough (not just in lives saved, but also ending social disruption) that the risk becomes much less comparatively important.

          2. Ian Malone says:

            You’re arguing that it would be harmless, but also that we’d be able to tell if there was any effect without a placebo? You can’t really have both, we know very little about how unaffected people clear the infection, that’s what the placebo group are for. Unless… you give them enough virus to make sure they really do get ill. It doesn’t answer the question about imperfect immunity (again, that macaque study) or how much vaccine is needed, whether boosters are needed.
            And, again, just looking at the numbers who didn’t actually die doesn’t tell you the whole picture of possible harms https://www.hopkinsmedicine.org/health/conditions-and-diseases/coronavirus/what-coronavirus-does-to-the-lungs

            Finally, to restate my last point, on the “the benefit of a vaccine sooner is huge enough”, this doesn’t really get us the vaccine any sooner. Manufacturing is beginning on the vaccines that are furthest along, the clinical trial results are not rate limiting here. The desire for challenge trials to hurry things up comes from anxiety and impatience, not logic.

          3. confused says:

            Yes, I do mean giving enough virus to infect everybody, isn’t that what a challenge trial entails?

            I agree manufacturing is being scaled up already, but I’m talking about speeding up regulatory approval – to go from trials to mass vaccination. If you do a challenge trial with a decent sample size (say thousands), and it works — in an emergency situation like this, shouldn’t that be enough?

            China is already vaccinating certain people. If the US has to wait until 2021…

            In my opinion, this is important enough to “throw out the playbook”. I understand that all the rules and steps exist for a very good reason, but the current situation is doing all kinds of damage which goes far beyond the reported deaths and measurable economic damage. People are social animals. This kind of lifestyle just isn’t healthy.

          4. loupgarous says:

            Interesting you mention macaques being used in animal studies of their vaccine. The particular strain of macaque the Oxford team used, Rhesus monkeys, commonly carries herpes B virus without serious harm. The same virus can jump zoonotically to humans causing an infection with a grave prognosis (raw case fatality rate 80%).

            We see a similar issue with Reston ebolavirus, but reversed – it infects crab-eating macaques, causing an infection with a very high case fatality rate, but has jumped zoonotically into humans causing a mild infection with few or no symptoms and no known fatalities.

            So, do studies of the Oxford vaccine in rhesus monkeys necessarily tell us much about its safety and efficacy in humans? I’m inclined to agree with your answer, Ian – no. We’re still learning SARS_CoV2’s bag of tricks.

    3. Nesprin says:

      I’d really worry about informed consent in military settings for the same reason I would worry about do a study in a prison.

    4. Ian Malone says:

      The sensible thing, and one we’ve been trying in the UK, is to try to recruit medical personnel. They are already at higher risk of exposure and aren’t likely to try to increase that on the basis of having possibly been given a vaccine. It has the bonus of potentially protecting a crucial group, but you also don’t want them to be the first people due to the risk of side effects and other adverse events like ADE.

    5. Kevin says:

      “What if the challenge trial group were servicemen in the military? These are mostly young, healthy people who already risk their lives to protect the rest of us.”

      No, let’s not decide that the military provides an endless supply of more-readily-risked (and implicitly less-valuable-to-protect) lives, please–especially given just how punishing its structure is of noncomformity or any perception of ‘weakness’ or ‘fear’.

      These kids already volunteered to get shot at on our behalf (sometimes because it was the only way out of poverty); let’s not assume that that means that they also need to be first in line to be infected with a potentially deadly disease, or for every other risk to life and limb that might serve a socially useful purposes.

  3. Zee Bendelstein says:

    Thanks for the clear views.
    So if we (unfortunately from many other perspectives) have enough sites around the world where “natural” challenges are arising in sufficient quantity in the form of community transmission of the virus. However, if these transmissions are disproportionately happening in younger/healthier individuals, presumably we would be limited in our ability to guage the effect of the vaccine on severity, once infected. But we could still test actually RNA presence/absence which would give us a good handle on prevention of infection in the first place?

    1. RA says:

      Good point. Are we going to get a sufficient sample of older participants who are going to go out and party to get exposed to the virus? What if you give the vaccine to some number of old people and both treatment and placebo arms mostly distance and mask and stay home. How do you reject the null hypothesis for older people then?

      1. Adrian says:

        There is no way risk groups like older people would be permitted to participate in a challenge trial.

        1. RA says:

          Didn’t say that we should do challenge trials on elderly people, but that traditional studies may fail to adequately assess vaccine efficacy in the elderly, just like challenge trials in healthy people.

          Aren’t you an anti-masker? How do you reconcile opposition to both masks and challenge trials?

          In general, my observation is that you are against anything that might save American lives.

          1. Adrian says:

            You seem to be mixing what I was saying with statements from other people, challenge trials with older people would be mass murder.

            I am not participating in your culture wars.

            In the US the culture warriors on one side are claiming that masks would be necessary against COVID-19, and the culture warriors on the other side are claiming that COVID-19 is either a hoax or harmless.

            Both sides are provably wrong.

            Here in Europe there is no sizeable disagreement that COVID-19 is a problem, the only discussions are regarding how to keep it under control.

            I was myself surprised that the country where I am living managed to get new infections down to one of the lowest levels in Europe despite a pretty moderate lockdown and no mask usage. I never made mask usage part of a culture war, so accepting the evidence that they are not necessary was just a positive surprise for me.

            Cloth/scarf masks let half of the virus through, I can imagine they might even have a negative effect if people wearing them are reducing social distancing out of a false sense of security.

            Didn’t you just say that “the vast majority of transmission is driven by relatively few superspreaders”? If you want to save American lives, I would recommend you focus instead on not allowing indoor superspreader events like nightclubs.

          2. RA says:

            Hahahaha!

            Seems like your schtick includes:

            Slowing vaccine development
            Stating that anti-vaxxers are justified because of US foreign policy
            Disputing the need for masks when widespread community transmission has taken root in a country
            Generally criticizing US Democrats and US foreign policy generally
            Taking umbrage at the suggestion that Russia could ever do anything wrong
            Feigning disinterest in US culture wars while cartoonishly trying to egg them on

            So, curious what is your take on this article?

            https://www.cbsnews.com/news/anti-vax-movement-russian-trolls-fueled-anti-vaccination-debate-in-us-by-spreading-misinformation-twitter-study/

            Is it a) fake news b) true c) a source of employment d) other?

          3. Adrian says:

            d) Our whole Twitter business has been outsourced for 8 years to Comrade President of the United States of America.

            There are cloth/scarf masks that let 50% of the virus through, and there are surgical masks that let only 10% of the virus through.

            In East Asian countries all people are wearing surgical masks.
            What kind of mask are you wearing?

          4. RA says:

            Comrade Trump is your most valuable asset indeed….something on which we agree.

            Sadly, the greed in our country led to a lot of manufacturing capacity being outsourced overseas, including that of higher filtration masks. Our current leaders on both the political and medical side also failed us with mask procurement and messaging. So, we use cloth masks because of a shortage of our own doing because we don’t have enough good masks and are not distributing them well in our unequal society. It sucks. People are dying because of this. But there is zero evidence that bareface is superior to universal cloth masking in a high transmission area, which you want people to think.

          5. Adrian says:

            Evidence that cloth masks are significantly better than not wearing masks is also weak. It is likely better then bareface, assuming people are not using masks as excuse to ease on social distancing. How many people are aware that cloth masks are only halving the virus amount?

            This is not only due to outsourcing. A few months ago everyone was busy with crazy ideas how to produce ventilators, which is really hard. Surgical masks are a boring low-tech product whose production could be ramped up easily when there are buyers, they are basically a cloth mask with the right cloth.

            Last month California made masks mandatory and reopened nightclubs. Think about how stupid this is when you are arguing with superspreader events.

          6. RA says:

            Opening up bars and nightclubs is stupid. Just like bareface. The 2 are not mutually exclusive!

          7. Adrian says:

            It is stupid to put so much emphasis on cloth face masks whose benefits might be more marginal than most people assume.

            Is there a huge outcry against the governor of California for reopening nightclubs, and for not ramping up surgical mask production in California to produce enough for all citizens (like Taiwan is doing since February)?

            The strong focus on cloth masks distracts from discussing what would actually be effective.

        2. Zee Bendelstein says:

          Absolutely not advocating challenge trials – on anyone, let alone high-risk groups.
          As RA mentioned this is more making the point that our ability to measure the impact of the vaccine on disease severity in high-risk groups will be limited if high-risk groups are better at shielding themselves (e.g. through extended lockdown) such that high-risk individuals in both the vaccinated and control group have a lower base exposure to the virus.

  4. DocGuy says:

    Aside from the issue of generalizing findings from healthy volunteers to the population at large, I suppose one would need to compare lives lost/saved, i.e., the probability of death/harm to the volunteers against the probability of lives saved from introducing a vaccine earlier.

    1. Metaphysician says:

      As I understand it, that is *not* how ethical medical research is done. Harm to one experimental subject is not balanced by benefit to another, only by the probability of benefit to the subject. Or, to put it bluntly: human test subjects are not human sacrifices. It doesn’t matter how many lives can be saved via the information, you are not allowed to go intentionally killing your volunteers.

      In the context of covid 19, in order for a challenge trial to be acceptable, the hazard to the test subject must be no worse than the hazard if they never entered the trial. Even taking into account the presence of constant attentive medical care, that is a bar I don’t think we can reach.

      1. RA says:

        So are all phase 1 drug studies unethical? Participating in them involves a higher risk than not participating in the study at all.

  5. emba says:

    I am generally view ideas like challenge testing with a great deal of suspicion, since I generally think ought not to take advantage of foolish people this way. But I do wonder about the idea for studying transmission.

    Crowds are voluntarily gathering for parties, rallys etc. We have little idea as to how the virus is being transmitted in these environments. Would there be an ethical framework to study these events very very carefully (i.e., know about them before they happen, get all the testing ready, get video cameras, register participants etc.) given that they will seem to happen without incentivization?

    1. confused says:

      >>I am generally view ideas like challenge testing with a great deal of suspicion, since I generally think ought not to take advantage of foolish people this way.

      Why is volunteering even necessarily foolish?

      I’m 30. My chance of dying if I get COVID normally is maybe 0.1%, probably less. My chance of being hospitalized (looking at the USS Theodore Roosevelt) is maybe 1-2%.

      If the vaccine has been shown to produce antibodies in Phase I trials, then it probably won’t be completely useless, so my chance of death or hospitalization in a challenge trial would be less than that.

      If I think taking that risk will benefit society, it doesn’t seem irrational to take the risk. Unless, under the same standard, you’d say joining the military or doing charitable work in a war zone is inherently irrational.

  6. David Rogers says:

    Loved your use of the word “sequelae”.

  7. Steve Scott says:

    This brings into question the anticipated behavior of the test subjects in the Phase I/II/III trials. It’s hoped they will go about their daily lives as before, and come in contact with Covid-19 on their own. No ethical issue there.
    But we don’t know whether the fact that they have volunteered makes them part of a select responsible group- very cautious- avoiding crowds, wearing masks, etc. In that case they’re not likely to get infected (placebo or vaccine groups) and the trials would be a failure.
    On the other hand, some may decide to be their own “challenge testers” and intentionally try to get exposed out in public for the good of all. As long as nobody is encouraging them to do that, it would seem to be ethical.

    1. Steve Scott says:

      In my comment above, I should have said “Phase III” (only) but suppose subjects in Phase I or II studies wind up hospitalized with Covid-19. That would not be a very good sign.

    2. RA says:

      Yes.

      I think the traditional trial approach will be at a high risk of type II error.

      How many failed studies and dead people will be sufficient to “break the glass?”

      We should have broken the glass in so many ways in January…yet here we are and the bodies keep piling up.

  8. ab says:

    Two points. First, some (most) vaccines aren’t going to work. That means you’ll run the challenge trial and NOT end up with a vaccine at the end of it. I wonder how many challenge trial volunteers understand they’re likely going to be infected to trial a vaccine that ultimately won’t work? Second, safety. The upside of needing a lot of n’s to determine efficacy is that a lot of folks get the vaccine candidate, which is what you need to do anyway to determine if a vaccine is safe. I think challenge trials sound great to folks who’ve never had to actually run an experiment and haven’t seen how messy even the simplest yes/no biological questions always become.

    1. RA says:

      Good point, but how does that compare to the number of people who will ultimately get placebos and ineffective vaccines in all the trials for the bazillions of vaccines to test that all need huge sample sizes. If most vaccines won’t work, wouldn’t be to our benefit and cause harm to fewer people to chuck out the ineffective approaches ASAP by using challenge trials to winnow the field?

      1. Adrian says:

        Human trials of COVID-19 vaccines are already winnowing the field since March.

        Derek has a point that Phase II trials might not even be faster with challenge trials in the current situation, and you don’t provide any arguments why they would be faster.

    2. confused says:

      >> First, some (most) vaccines aren’t going to work

      Are we really confident of this? Given how much biotech is advancing, is past experience really a good guide to the expected failure rate in 2020?

      1. Adrian says:

        For several of the fastest progressing vaccine developments, an approval would be the first approval ever of a vaccine that works this way.

        The current state of biotech is that in some cases the companies involved have already been working for 10 or 20 years on that, without a single previous product.

        Speaking about past experience, despite its $30 billion valuation Moderna has a 100% failure rate on past developments.

  9. Rhenium says:

    Minor typo in the first paragraph, “you’re read” should likely be “you’ve read”.

  10. luysii says:

    There is a much simpler (and ethical) way to do this. Give the prophylaxis to individuals at high risk for infection (because of their work — e.g. nurses, first responders, docs, orderlies etc. etc.). I proposed this a while ago in a post arguing that infecting people with the 4 known coronaviruses known to cause the common cold might help stop the pandemic. It wouldn’t have to be blinded, but a control group would be required.

    For details please see — https://luysii.wordpress.com/2020/05/24/a-way-to-end-the-pandemic-an-update/

  11. Paul D. says:

    There is nothing stopping those getting the vaccine (or the placebo control) in trials from then exposing themselves. So I’m not sure how you avoid vaccine trials becoming de facto challenge trials.

    1. Pedwards says:

      There’s a difference between intentionally putting other people at risk (even with their consent), and people putting themselves at risk.

      You’ll never be able to engineer-out the potential for people to do stupid things.

    2. luysii says:

      Exactly something similar happened with the bicycle helmet laws. The number of accidents with bad head injuries didn’t decrease, because riskier behavior was indulged in because people thought they were safe

    3. Marko says:

      Indeed. If they only recruit patients who regularly attend Trump rallies , the trials should move along quickly. “Warp-speed” , even.

  12. Alyssa Vance says:

    If bioethicists ran the world, knives would be illegal, to stop people from cutting themselves; chair designs would have to go through a government pre-approval process, to make sure that no one could fall off; stores would always be out of baking soda, because not enough factories could meet the purity requirements; German cars couldn’t be sold in the US, because American crash testing took so long that no manufacturer bothered to do it; everyone would still use kerosene lamps for light, because electricity might shock someone; radio broadcasts would all be censored, because hate radio played a key role in the Rwandan genocide of 1994; charities would have to run every volunteer by an ethical review committee, to make sure they weren’t tricked or coerced into participating; and Forrest Fenn would be in prison, after someone died while searching for his treasure.

    1. steve says:

      Absolute and total nonsense that just illustrates your ignorance of the field. Bioethicists like Art Caplan are actually leading the charge to do these studies. So learn something first before casting charges based on complete lack of knowledge.

  13. steve says:

    It makes no ethical or scientific sense. From the ethical point of view, we still don’t know all the long-term sequelae of infection so it’s immoral to intentionally infect healthy human volunteers as it’s impossible to give informed consent. People who throw around risk numbers like case fatalities are ignoring the moribidity of the disease and the fact that we learn more and more as we go along. A couple of months ago young children were immune now we know about MIS-C. A couple of months ago we didn’t know about all the neurological effects. From a scientific point of view it makes little sense to give a virus to a population likely to clear it quickly when what we’re trying to do is protect the population at risk, especially when we have no clue why one population is more likely to develop severe COVID symptoms than another.

    1. confused says:

      >>From the ethical point of view, we still don’t know all the long-term sequelae of infection so it’s immoral to intentionally infect healthy human volunteers as it’s impossible to give informed consent.

      I’m not sure that is clearly true. We know death is a possibility, and strokes seem to be a potential complication (which can cause permanent disability, which some people might view as more frightening than death). So I don’t see how unknown risks could change the picture so radically as to invalidate informed consent.

      There are lots of things people voluntarily do that carry a pretty significant risk of death or disability (various extreme sports, for example). It’s not clear to me why that suddenly becomes unacceptable – or the standard for “informed” becomes much higher – just because a medical intervention is involved.

      1. Adrian says:

        How many percent of people with mild COVID-19 have irreversible long-term lung damage?
        According to CT images of scuba divers (n=6) lung damage is common even after mild COVID-19.
        Does such damage heal within a few years, or does it permanently disqualify from scuba diving?
        It is too early for an answer.

        What other long-term surprises might COVID-19 offer?
        We don’t know.

        1. confused says:

          How long after “recovery” were these CT scans taken, and how was “recovery” defined? No longer being infectious doesn’t necessarily mean completely recovered.

          Is the damage seen of a type that would normally be expected to be permanent, e.g. from experience with other viral pneumonias? SARS-CoV-2 is a novel virus, but that doesn’t mean all prior knowledge is irrelevant.

          Does the damage correlate with functional impairment? In my own field (air pollution) reductions in lung capacity can be measured that don’t necessarily correlate terribly well with symptoms experienced.

          (Honest questions, not arguments. I’ve seen a lot of claims about long-term sequelae, but all I’ve seen so far were either anecdotal or in really severe cases. I would be very interested to see any decent data.)

          1. Adrian says:

            This was 5-6 weeks after recovery.

            “CT scans of the patients’ lungs revealed such an extent of damage that it makes a full recovery unlikely.”

            Are you considering it functional impairment when a scuba diver is no longer fit to dive?
            Scuba diving is demanding for the lungs, what kills you under water doesn’t necessarily correlate with symptoms when breathing normally.

            More details are in various reports on the original German (non-scientific) publication like
            https://www.caymancompass.com/2020/04/24/divers-face-long-term-health-impact-from-covid-19/

            Perhaps they are lucky and the damage is not permanent.
            Perhaps there are other unknown risks a complex disease like COVID-19 might have.

          2. confused says:

            5-6 weeks after “recovery” may not mean much, depending on how “recovery” is defined. “No longer infectious” may come well before “no longer symptomatic”.

            >>Are you considering it functional impairment when a scuba diver is no longer fit to dive?

            If they actually can’t do things they could do before, absolutely that’s a functional impairment. (At least for these specific people, it might not matter for others.)

            If a doctor just told them it wasn’t safe to dive based solely on imagery… maybe not.

            >>More details are in various reports on the original German (non-scientific) publication

            Yeah, see, this is the thing. I just do not put much credence on claims about COVID from non-scientific/non-medical sources, after seeing a lot of nonsense from non-scientific news outlets (even relatively mainstream/low-politics ones).

            All the more so in this case when “permanent damage” is being claimed based on observations 6 weeks after recovery … maybe, depending on how “recovered” is being defined it could actually be much less than 6 weeks.

            I am not saying there is no permanent damage in these cases. But I think the information available is so limited/flawed/questionable that it essentially provides no evidence in support.

            Enough people have had COVID, and been recovered for 2-3 months (in New York for example) that I would also expect to see a lot better evidence than this if it were generally true.

            I am sure someone will have bad sequelae from an otherwise mild infection, since people vary. But that’s very different from saying that it is common enough to be relevant to the overall picture of how dangerous the disease is.

            Generally, having chickenpox gives you immunity against future infection. But I had it twice. But that doesn’t invalidate the general statement either.

          3. Adrian says:

            It was you who claimed that we would know all the long-term sequelae of infection.
            Reality is that we don’t.

            Regarding “If a doctor just told them it wasn’t safe to dive based solely on imagery…”:
            Pulmonary fibrosis is a contraindication for diving.

        2. confused says:

          >>It was you who claimed that we would know all the long-term sequelae of infection.
          Reality is that we don’t.

          I did not (intend to) claim that. I was claiming that any unknown effects would not be worse than the known effects of death or permanent disability (a known possible effect of strokes). So the existence of unknown effects would not make informed consent impossible.

          I only went off on the digression about lung damage because I was hoping you had a more scientific source for this than I’d seen, since I’d heard of this but not enough real detail to know if it had any validity.

        3. gippgig says:

          What other long-term surprises might COVID-19 offer? It might increase the risk of dementia. The brain damage seen in autopsies suggests that those who survive severe cases will probably have a much higher risk. Do those with mild or asymptomatic cases show a similar pattern of blood clots (i.e., in the lungs, which can be sampled in a living patient)? If COVID-19 does increase the dementia rate, how long is it likely to take to detect this? This could be as bad as AIDS.

          1. gippgig says:

            (I know COVID-19 has a higher death toll than AIDS. The insidious thing about AIDS is the long delay from infection to the disease (& its horrible course).)

          2. confused says:

            Can you really extrapolate from harm seen in *autopsies* (on the dead) to long-term effects in survivors? And I am not really talking about the more severe cases, either – it is not unexpected that people who were on the brink of death, e.g. on ventilators, would have long-term problems.

            But given that the context of this discussion is young, healthy people who are very unlikely to end up on ventilators, what’s most relevant in this context is whether long-term effects happen in *non-critical* cases.

            Is the cause of dementia even understood well enough to make plausible predictions? Sure, one can speculate any kind of long-term effect *could* happen.

            But why should COVID do this stuff when all the other tons of respiratory viruses (seasonal coronaviruses, influenza, parainfluenza, RSV, adenovirus, rhinovirus, etc.) don’t?

          3. confused says:

            Also, CDC claims that influenza is linked to strokes: https://www.cdc.gov/flu/highrisk/heartdisease.htm That implies clotting effects even for flu, doesn’t it?

            I am not saying COVID doesn’t have long-term sequelae: that would be dumb. I am questioning whether they are common enough to change the overall picture of the disease’s severity. (IE, if COVID is say 5-10x deadlier than flu, then as long as long-term sequelae are not more than 5-10x more common, then it doesn’t change the overall picture.)

          4. gippgig says:

            Do the brains of people who have died from other diseases (such as influenza) show similar damage? If not, that would suggest more severe consequences from COVID-19.
            Doing cognitive tests (should be easy) on those who have had a mild or asymptomatic case might provide a clue.

          5. confused says:

            Maybe… but I am still not sure about extrapolation from dead to survivors. Oxygen deprivation can cause brain damage, and people who die of COVID probably mostly have oxygen deprivation.

            If you specifically compared autopsies of COVID victims and flu victims and other pneumonia victims, who were treated identically (eg were ventilators used and how/when), *then* that comparison would be meaningful, I guess.

            Though there might be a lot of confounding factors — both COVID and other pneumonia tend to hit the very elderly hardest, so there may be a lot of pre-existing cognitive issues.

            Yeah, I think tests on *survivors* would be by far the most informative about effects on survivors.

            But, again, I am not saying COVID doesn’t have long-term sequelae! I am mostly asking for better data, as I’ve seen a lot said about this, but it’s basically all anecdotal.

          6. Adrian says:

            Current knowledge about the root causes of many diseases causing dementia is very poor, noone really knows what actually causes Alzheimer or Parkinson.

            Dementia caused by virus infections is due to virus passing the blood–brain barrier and entering the brain. It is similar for dementia caused by bacteria.

            Whether influenza can the pass the blood–brain barrier is disputed.

            100 years later it is still unclear whether 5 million cases of sleepy sickness were caused by the Spanish Flu.

            None of the above is caused by blood clots.

            As child I had a disease that gave me immunity, but the virus might be hiding in my body and reactivate itself 60 years later causing a different disease.

            Some viruses have a modus operandi to enter the brain and cause some specific behavior, the same virus strain might cause this in a wide range of mammals from bats to humans.

            In some cases SARS-CoV-2 has been found in the brain.
            Recently there is some suspicion that severe respiratory problems in COVID-19 might actually be caused by whatever SARS-CoV-2 does in the brain.

            Data on long-term sequelae of SARS-CoV-2 infection will only be available after a long time, after 6 months we do not even fully understand all the short-term effects.

          7. gippgig says:

            A series of microstrokes can definitely cause dementia – see multi-infarct dementia. That’s what I’m worried about. A tripling of the risk in survivors of severe COVID-19 with little change in asymptomatic cases would be bad, but near certainty in severe cases and a tripling in asymptomatic cases would (eventually) be catastrophic.

  14. Thomas Read says:

    I feel like small challenge trials with say ~30 young healthy participants could still have significant value. In a matter of weeks we could find out which vaccines are useless, and which we should immediately put huge effort into manufacturing, in parallel with regular trials to determine efficacy in the wider population. And even a vaccine that turns out to be safe but only works in young people would be useful, e.g. allowing schools and universities to return safely.

    Of course if legal complications mean such a trial would not end up starting for months then there may be no point, but we’ve already seen how pointless red tape can suddenly disappear if governments are on board.

    1. Adrian says:

      You are describing a normal Phase 1 trial, like the one Derek discussed in his previous post.
      A challenge does not bring additional value to that.

      1. Marko says:

        Of course it would bring additional value. The small sample size of a P1 trial negates the possibility of determining efficacy re : protection against infection/disease. All you can reliably evaluate is immune response by lab-based measures. With a challenge trial , the infection rate and/or disease rate difference between the control group and the vaccine group would be stark if the vaccine was effective.

        1. Adrian says:

          A Phase I trial is not intended to show protection against infection.
          The purpose of Phase I is to see safety and side effects in healthy uninfected adults, and for finding the best dose.

          A challenge trial in Phase I would be stupid since it would make it harder to observe problems of the vaccine itself.

          Efficacy is Phase II.

          1. Marko says:

            The same argument holds for P2. The point is that challenge trials would add significant value in terms of speeding up those trials. If not for the ethical considerations , any sane researcher would endorse their use for COVID-19.

          2. Adrian says:

            How would challenge trials speed up Phase II?

            Challenge trials would give you only data about the lowest-risk group being infected under laboratory conditions.

            Are your laboratory infections similar to real infections?
            How is safety in the high-risk groups (old, obese,…) you want to protect with a vaccine?
            Does the vaccine work in the groups you want to protect?
            Your challenge trial cannot answer any of these.

            Any sane researcher would not consider a challenge trial a proper replacement for Phase II.

    2. Rhenium says:

      It is “pointless red tape” until it kills a bunch of people and influences others not to seek out the best treatments. As they say in aviation “regulations are written in blood”.

      1. confused says:

        I agree in general, but there is an argument that emergency situations ought to be an exception from the usual regulations.

        1. Adrian says:

          The emergency use authorization of hydroxychloroquine for COVID-19 is a good example why not following the usual regulations is a bad idea.

          1. confused says:

            I’m not sure. A week’s faster timeline on a vaccine would do a lot more good than 5 bad drugs approved would do harm, I think. How many deaths do you think use of HCQ has caused? Current US death rates reported are something like 500-550/day, so 1 week would be something like 3500-3700 lives saved in the US alone.

          2. Adrian says:

            How much harm can a bad vaccine approved and administered to millions do?

            Both physical harm to peoples health and lives, and permanent damage to the safety reputation of vaccines in general.

            The next madness is that there might be 100 million doses of a vaccine produced before approval, and administered within a very short time after approval.

            With 100 million doses already produced there will also be an enormous pressure to not delay or even deny approval on weak indication of risks. Imagine someone insisting that another round of trials is necessary after the President of the United States has already announced that the vaccine will be available next week.

            Imagine an unexpected safety issue of a vaccine is that it kills people with a rare genetic variation that 0.1% of the population has.
            This is low enough that it might not be visible during any kind of trials.
            The vaccine might kill 100k healthy people before anyone notices, and noone would initially understand why.

          3. Thomas says:

            A bad approved drug may hamper research for something that actually works.

          4. confused says:

            >>Imagine an unexpected safety issue of a vaccine is that it kills people with a rare genetic variation that 0.1% of the population has.

            Has anything like this, or even an order of magnitude less, ever been seen in any vaccine development before modern ethics standards applied? Even the 1977 swine flu vaccine debacle was a rate of a (serious but usually non-fatal) complication (Guillain-Barre syndroms) far, far below 0.1%.

            A 0.1% death rate because of unknown genetic variants just seems completely unrealistic.

          5. Robert Clark says:

            Actually, no:

            Treatment with Hydroxychloroquine, Azithromycin, and Combination in Patients Hospitalized with COVID-19.
            According to a protocol-based treatment algorithm, among hospitalized patients, use of hydroxychloroquine alone and in combination with azithromycin was associated with a significant reduction in-hospital mortality compared to not receiving hydroxychloroquine.
            https://www.ijidonline.com/article/S1201-9712(20)30534-8/fulltext

            Robert Clark

  15. steve says:

    BTW, you don’t need challenge studies to triage vaccines. You can inject healthy human volunteers with the vaccine and measure antibody and T cell responses (e.g., Elispot). That way you don’t risk the morbidity and mortality involved in giving healthy individuals the virus, especially in the context of recent data showing that the age at which people are at risk is trending down.

  16. Kevin says:

    Hi Derek, I’m glad it seems my commenting on your previous piece spurred thoughts of challenge trials for you. I’d like to address a few points from my perspective.

    You fail to discuss the actual challenge trial methodology that would be beneficial at this point in time. You specifically focus on challenge trials testing vaccine candidates, which has tended to historically (in the last ~50 years, not in early experiments such as that for cowpox) been used to support optimization of vaccine dosing volume and schedule.

    The challenge trial that is most useful at the moment, and is inherently the most dangerous, would involve exposing volunteers to various amounts of coronavirus to determine what viral load exhibits symptoms 70-80% of the time. Why is this the most useful? Because of the unknowns involving pathogenesis. Today in the Washington Post, the coronavirus was implicated in “thousands more deaths than would have been expected from heart disease and a handful of other medical conditions”. These are being called “excess deaths”. I call them deaths from the coronavirus, and we have no idea why they’re happening. It is my opinion that a challenge trial with a primary end-goal of determining optimal viral exposure dose (for potential future challenge trials with efficacious vaccines/if rescue therapy exists) can also be used to elucidate pathogenesis uniquely. When studying natural infection (or in placebo group individuals in Phase 3 trials) the immune response to infection is only known after an uncertain latency period. Understanding the initial 1-3 days after infection are crucial for fully understanding SARS-CoV-2, and we sacrifice that data in all other settings (we only look AFTER the onset of symptoms in natural infection, and Phase 3 trial participants can’t be monitored daily).

    1. Adrian says:

      This is true only in countries like the US that failed to get COVID-19 under control.

      In countries with low case numbers and contact tracing it is common that 14 days quarantine is required for everyone who was exposed to an infected person. When you know a group of people was exposed to an infected person exactly 10 hours ago, then the same data is available.

      1. Kevin says:

        I am not talking about disease transmission dynamics. I am referring to biomolecular signaling upon cellular infection by SARS-CoV-2. Immune-response pathways are dynamic and detailed, and I’ve only seen one review article which has collected and done analysis on this specific coronavirus (https://www.tandfonline.com/doi/full/10.1080/10408363.2020.1770685).

        This article and the research it sources from do not identify the specific immune pathway signaling SEQUENCE.

        1. Adrian says:

          You were claiming that “in all other settings” the “initial 1-3 days after infection” cannot be observed otherwise.

          I explained that this is not true if you look at the right places.

          1. Kevin says:

            With a challenge trial, blood can be collected at anytime post-infection starting exactly at t=0. I should have been more specific. It cannot otherwise be obtained in such a manner.

  17. myst_05 says:

    Mr. Lowe, I believe you’re not addressing the biggest ethical question in your post. Given that we’re recording ~5k deaths per day globally (and these are just official death counts, in reality it could be as high as 10k or 15k), speeding up the vaccine by even *1 day* using a vaccine challenge trial would save far more lives than could ever be lost during a deliberate trial. A proper trial would require ~2k volunteers – 1k in the vaccine group and 1k in the placebo group. Even if *all* of them perish to the virus (which, you must admit, is exceedingly unlikely), it would still be a smaller sacrifice than the daily toll of this virus.

    That’s why the volunteers website is called “1 Day Sooner” – even a single day could make an incredible difference. Or are you saying that running human challenge trials wouldn’t save us even a single day in terms of the timeline for deploying the vaccine?

    1. Adrian says:

      “(3) are for those reasons and others not likely to run meaningfully faster than regular Phase II trials, and (4) will produce data that may not be able to be extrapolated to the real-world situation”

  18. Nicolas Tilmans says:

    Point very well taken that perhaps this isn’t even needed given how much viral transmission is going on in many places. I would love your thoughts what’s the largest (or smallest) amount of time we could save if we had an effective therapeutic in hand today. For example, you’re quite bullish on antibody therapies coming online in the near-ish term. If one of those was successful, could a small N trial where the antibody was held in the back freezer in case a patient showed a viral load via daily testing get us to an answer in two months or less?

    Again, grant that this may be unnecessary and some of the ethical issues, just curious on what levers alter the cost benefit tradeoff and how significant a change would be relevant.

  19. Len says:

    Though not a prophylactic study, if not yet performed, would it be reasonable to conduct testing with a prime inoculation soon after very recently confirmed Covid-19 patients present in a low risk age group for poor outcomes (whether or not they are in hospital) providing the test vaccine(s) in earlier disease free trials have been found to be safe & shown to establish a robust IgM (19S antibodies) response after about 5 to 7 days or so? Of course, those requiring hospitalization should be provided with appropriate standard of care. I also would suggest that it would be well to have inclusion criteria requiring serum zinc levels to be not less than the mid normal range (per gender) endeavoring to include patients who are more likely to have a healthy immune response. [If this isn’t required in initial vaccine trials, why not? And has/is testing for zinc status of all Covid-19 patients on day hospitalized been/being performed? How it relates to outcomes may be importent to know.]
    A boost 28 days later could still be included & may be beneficial for patients enduring a protracted persistence of Covid-19. And (yeah, in my dreams) if the broad outcome was found to be highly positive based upon IgM & other Igs, diminished cytokine storm, no serious complications & shortener hospital stay, would it then be worth considering trials of this nature in higher risk age groups?

    1. Len says:

      Ah, make that boost 21 days later. Apologies.

  20. cynical1 says:

    I am really on the fence so I am not trying to convince anyone one way or the other. But I am trying to distinguish what the ethical difference between a challenge trial with COVID-19 in vaccine development versus using healthy volunteers in any Phase I drug trial for any other disease? Remember there was BIA 10–2474 which wound up having some rather serious side effects and one death in a handful of volunteers.

  21. TrolleyProblematic says:

    This kind of thinking seems really inflexible. In essence, it boils down to a trolley problem, where you could either kill thousands of people or cause one volunteer a maybe permanently broken rib, while the volunteer is begging you to let him take the chance for the good of others. Doctors, soldiers take higher risks regularly anyway, not to mention the economic damage that the pandemic is wrecking worldwide.

    The claim that a challenge trial would not accelerate vaccine development seems fishy to me as well. Even a regular trial involving 10000 volunteers would probably have to run for months to get enough people infected, since the inflated variance will lower the power of the study. Marc Lipschitz, along with the other advocates of challenge trials, obviously also think that there would be some accleration. Regarding the red tape, well, there are other countries than the US.

  22. RA says:

    While we wring our hands, Alabama students are conducting their own challenge studies.

    https://www.nbcnews.com/news/us-news/alabama-officials-warn-students-holding-coronavirus-parties-intentionally-get-infected-n1232760

    We’re just not getting any data out of it.

  23. Marko says:

    Even Fauci thinks the 614G mutant may be more transmissible. Many of the so-called experts on twitter continue to reject any new evidence that contradicts their established narrative. Humility is in shorter supply than N95s nowadays :

    “…It does look like a particular mutation may make the virus more transmissible,” Fauci said.
    During a COVID-19 Q&A with JAMA Network, Fauci added not all scientists are in agreement over the development. He said more research is needed. “There’s a little dispute about it, but I think the data is showing that there is a single mutation that actually makes the virus be able to replicate better and maybe have high viral loads,” Fauci said….”

    https://www.kxnet.com/news/national-news/fauci-new-mutation-may-allow-covid-19-to-more-easily-replicate/1

    1. Adrian says:

      Humility would be not posting April news that have already been discussed here as comment to a completely unrelated post.

      1. Marko says:

        The Fauci statement is a significant development on a much-debated issue , one that most of the “experts” seem destined to be proven wrong about.

        Humility would be not declaring yourself moderator of this comment thread.

        1. Adrian says:

          The D614G topic went through the media 2 months ago, and for some reason media like the one you are linking are now calling it a “new mutation” for publishing the same story again.

          Fauci saying “more research is needed” is not not much different from what Derek wrote 2 months ago, do you have a link to the mentioned data?

  24. Taylor says:

    No, old people WILL volunteer as well (and far more than you’d expect.) And you don’t need 50,000 old people volunteering to get statistically decent results… with a truly well-designed study, we’d probably need only a few hundred to test the most promising prophylactics on the horizon.

    And yes, dozens will die. Dozens. In a country where over 120,000 are already dead. This “ethical” argument really, REALLY rubs me the wrong way. Derek, how many articles have you written over the past 6 months bemoaning the lack of quality data backing up the various proposed candidates? If we can get a confirmation (or rejection) one month sooner, thousands of lives will be saved, maybe tens of thousands.

    I haven’t checked in the past couple weeks, but is the famotidine study back yet? How about the losartan one (which looked really really promising in mice studies) ? In principle, these studies could be run in just 3 weeks with a challenge test, but instead months and months end up passing.

    This isn’t Tuskegee. This is absurd navelgazing, and insultingly paternalistic… it’s really goddamned condescending to imply that no non-scientist could ever make a truly informed decision to accept the risk, to step up and potentially make the ultimate sacrifice for the greater good.

  25. wubbles says:

    If you, an American and joined the bomber force in WWII your chances of survival were one in three. Today you’re asking whether or not the men who did that would be willing to take one more risk, not for their country, but for the lives of billions around the world. My brother risked his life for a lost war in Afghanistan, and we’re concerned about the ethics of risking lives for a far better cause.

    Challenge studies would have far faster readouts. Rather then wait months with thousands of participants for enough infections to take place for the difference in rates to be significant, within weeks enough infections would have happened to know. The question of extrapolation can be solved by ensuring the participants are well mixed. Right now we’re on track for everyone to be infected: a challenge trial conducted well would hopefully give us a vaccine candidate that could be administered and halt the plague in its tracks. Wouldn’t you want to know sooner that a vaccine worked?

    1. RA says:

      If only the coronavirus had a turban instead of a spiky head, we might get our “leaders” to take seriously a situation where there is a 9/11 level death toll every few days.

  26. RA says:

    Nobody talks about this (wonder why…haha), but in a paper published in a source no less than Science magazine, a group of authors including Dr. Fauci wrote this:

    “It is likely that a SARS-CoV-2 challenge strain will, by design, cause mild illness in most volunteers and thus may not recapitulate the pulmonary pathophysiology seen in some patients.”

    https://science.sciencemag.org/content/368/6494/948

    Got that? A concern about challenge trials is THEY WON’T MAKE PATIENTS SICK ENOUGH.

    So, it’s worth asking, are our “ethical” leaders opposing challenge trials because they are too dangerous or because they are NOT DANGEROUS ENOUGH?!?!?

    Meanwhile, the pandemic rages, bodies pile up, and our “ethical” leaders cheer the widespread transmission that will lead to lotsa great research opportunities! Awesome!

    1. confused says:

      Well, there is a valid point here. If the data is useless then even a small risk is not justified.

      I’ve come across on this comment thread as arguing for challenge trials. But I’m not necessarily. There are two big questions:

      1) would they help? (Give us an effective/safe vaccine sooner)
      2) if they would help, would they be ethical?

      I’m talking only about 2), since I don’t have the knowledge to evaluate 1).

      If challenge trials would not speed up the timeline/would not provide useful effectiveness data,then I wouldn’t be in favor of them. That’s what this statement sounds like (data would not be useful to prove effectiveness in the people who are really at risk).

      But if they *would* work, I don’t think an ethical argument against them really holds up. This isn’t 1950 – non-medical people have enough access to information that I think the participants in trials can really be participants rather than passive subjects, so the ethical position isn’t equivalent to the researchers simply imposing risks on the subjects.

      1. Taylor says:

        They absolutely would help. You only have to look at Derek’s history of (rightfully) bitching over the past 5 months over the poor data behind all of these wunderdrugs that have been presented. It’s really really hard to rule out all of the confounding factors.

        Assuming we had the infrastructure and the policies and the motivated leaders (and we probably don’t, but assuming we did), a challenge study could be conducted in as little as three weeks on any vaccine or drug and it would provide MUCH more convincing statistics than simply crossing your fingers and waiting to see who shows up at the ER over an extended period of time (and oh by the way during that time hospital standard of care policies will inevitably shift, further clouding the issue.)

        It’s actually rather astonishing Derek can’t see the obvious connection between the crappy data / bad statistics he so rightfully complains about, the months of waiting around for confirmation on HCQ, losartan, famotidine, (as hundreds of thousands die) and the lack of challenge studies.

        The “unethical” argument is, as you note, completely ridiculous and extremely condescending. 120,000 people are dead. The amount of dead in challenge studies would be in the dozens or hundreds, and they all would’ve chosen to risk their lives. It’s an utterly absurd display of misguided paternalism to suggest we should prevent them from risking their lives to save thousands.

        Let them learn and decide for themselves (exaggerate the risks if need be. You’ll still get enough volunteers.) Build bronze statues of the ones that don’t make it and take care of their families, sure. But to suggest it’s ethically better to sacrifice tens of thousands more as unwilling victims is lunacy. This has nothing whatsoever to do with Tuskegee.

        1. RA says:

          This! You are completely right.

          I like your bronze statues idea. Word on the street is that a whole lot of statue space is newly available!

          I actually doubt that many people will die in a challenge trial. A milder strain will be used. The people who undergo challenge trials will /should get the best most timely medical care possible. Risk is nonzero, but not as high as people are thinking. Might not need that many bronze statues.

          So…why is Pharma and the government so opposed to challenge trials?

          Do they not realize the potential benefit? Nah, I don’t think they are that dumb.

          I hope I am wrong, but I can’t shake this feeling that they don’t want to do challenge trials because they don’t want an early up/down verdict on any of their preferred early horses – adenoviral, mRNA mostly – which THEY THINK are not likely to be super effective, but they need to keep American hope springing eternal, a ruse that would be deprived by a quick challenge trial. Under this depressing theory, the race to get the first effective vaccine is already lost, and the winner will be China. China has a near monopoly on inactivated virus vaccines in development (which importance of tcell responses would suggest is a good horse to bet on) but are pursuing all the other mechanisms too. They would probably have no qualms about doing challenge trials…maybe they already have. They are giving vaccines to their military and their citizens traveling abroad. Wonder if they just finished a challenge trial and they know they likely have an effective vaccine or maybe more than one and are confirming with larger studies and working out safety issues.

          1. Adrian says:

            Ignoring some other things that don’t make sense, I am puzzled about your “A milder strain will be used.”

            I am not aware that any SARS-CoV-2 variants would be known to differ in disease severity.

          2. Derek Lowe says:

            *What milder strain*? This is bizarre.

          3. RA says:

            Scroll up and read the whole thread, dude.

          4. RA says:

            “It is likely that a SARS-CoV-2 challenge strain will, by design, cause mild illness in most volunteers and thus may not recapitulate the pulmonary pathophysiology seen in some patients.”

            https://science.sciencemag.org/content/368/6494/948

          5. Derek Lowe says:

            My question stands: no such strain exists now. If I understand your argument, you believe that challenge trials will speed up the process and save lives. And as for my contention that this could still be ethically unacceptable, you say not to worry, it’ll be done with a milder strain of the virus. But finding and validating one will take extra time, which will not speed anything up at all. (And as the article you link to notes, there would still be questions about whether it would provide useful information anyway).

          6. RA says:

            First, thank you for this blog and the opportunity to comment here.

            I am not a virologist, but seems like there is a number to choose from:

            https://www.dailymail.co.uk/health/article-8237849/Coronavirus-mutated-Strains-evolved-far-deadlier-spread-Europe-New-York.html

            Maybe the one that hit Seattle first? Don’t you all have some way of engineering/attenuating them to make them milder? There is a process for making live attenuated vaccines, right?

            In any case, these are Dr. Fauci’s words, not mine!

          7. Adrian says:

            Daily Fail from April reporting on the same paper Derek discussed in detail here in the blog at the same time.

            And contrary from what you are claiming it does not mention Dr. Fauci.

          8. Some idiot says:

            Er, just a quick comment here… Firstly, in my opinion, quoting the Daily Mail is a bit similar to quoting any paper found in a Christmas cracker: may be entertaining to read, but don’t depend on the truth of the statements…!

            As regards “just” making an attenuated strain (plus making sure that it is attenuated, will stay attenuated, and that every dose you give will be exactly the same amount of exactly the same strain, plus doing all the GMP qualifications for it, and all the animal studies to back up the data before using it in humans; I am sure that the Mammalian Scaleup Person would be far more qualified to talk about that than I am), well, it sounds like a classic case of “nothing is impossible for the person who doesn’t have to do it…”

            I should also say that I am not a virologist… I am a scale-up chemist, developing manufacturing methods for new (small-molecule) medicines. However, some of the issues/challenges/frustrations are similar at least… And I would hate to be the one trying to scale up a production of a homogeneous virus strain under pretty high bio security conditions, with a very short deadline (assuming the facilities were available). “Just” in order that one could do a vaccine challenge. Because if everyone didn’t get precisely the same strain, then you can more or less throw the results out the window…

          9. RA says:

            No, the words I am talking about are these: ““It is likely that a SARS-CoV-2 challenge strain will, by design, cause mild illness in most volunteers and thus may not recapitulate the pulmonary pathophysiology seen in some patients.”

            Those are in an article in Science magazine that is co-authored by Dr. Fauci.

            I think it is fair question to ask, based on those words, whether challenge studies are as dangerous and unethical as some may suggest.

            The utility of information gained from them is a separate question and also worthy of vigorous debate, much of which has been done in the comments on this post.

          10. RA says:

            Dr. Fauci’s words seems to imply that use of such a strain is possible. If that is in error, then I would defer to the authors and the publication that published those words.

          11. Some idiot says:

            Ok, I haven’t read the article, but I will give you my take on the quote:

            “It is likely that a SARS-CoV-2 challenge strain will, by design, cause mild illness in most volunteers and thus may not recapitulate the pulmonary pathophysiology seen in some patients.”

            My interpretation is, well, just my interpretation, but I read that sentence to mean something completely different… I will re-phrase it to try and emphasise the other meaning:

            By design, a SARS-CoV-2 challenge on vaccinated people will cause only mild illness in most volunteers, because the vaccine will protect to some extent.

            In other words, he is not saying that the virus strain would be designed to give milder symptoms, but rather that by design, a vaccine should make symptoms of an infection milder…

            My interpretation…! I would be interested to hear your thoughts… (-:

          12. Adrian says:

            Regarding the article in Science, you are misreading what you quoted.
            It is not talking about different strains of the virus, it is discussing the disadvantages that having only young healthy individuals limits the usefulness of the data resulting from the trial.

            When reading the context it is clear that it means the following, I have [] inserted the relevant part from the preceeding sentence:
            “It is likely that a SARS-CoV-2 challenge strain will, by design [due to selecting only young healthy individuals], cause mild illness in most volunteers and thus may not recapitulate the pulmonary pathophysiology seen in some patients.”

          13. RA says:

            We are getting into some heavy duty linguistic parsing here!!!

            I interpreted the words “by design” to be referring to the word “strain” immediately preceding it.

            Still think that is a reasonable interpretation.

            But if it isn’t, you still gotta deal with the rest of the sentence “…cause mild illness in most volunteers and thus may not recapitulate the pulmonary pathophysiology seen in some patients.”

            Ok, so I am asking this. How does one reconcile the following 2 things:

            1) the argument that challenge trials are dangerous and unethical
            2) That whatever strain is used they will “cause mild illness in most volunteers and thus may not recapitulate the pulmonary pathophysiology seen in some patients.”

            I see a disconnect between the argument in 1 and the words in 2.

            How is that wrong?

            The

          14. Some idiot says:

            “ We are getting into some heavy duty linguistic parsing here!!!”

            Agree completely…! But if the worst outcome of that is that we agree that we disagree on the interpretation of someone else’s text, then I take that as a good sign…! 😉

            You say that you interpreted “by design” to refer to “strain” just previously. I take your point, but I disagree. Partially due to the fact that “by design” is between commas, but I’ll come back to that later. I feel that if he wanted to say what you are interpreting him to say, then he would have said something like “the challenge strain would be designed to cause milder symptoms” (paraphrasing, again).

            However, I think a more reasonable interpretation of his meaning is “ok, a vaccine should have a protective effect. So if a vaccinated person is challenged with the virus, then they should get milder symptoms (ie the vaccine has an effect). Which in turn means that you would not see the severe pulmonary effects seen with people who really get hit hit over the head with it (without a vaccine).

            Or, put another way, a person who has been vaccinated and then challenged should, by design, have milder symptoms and thus not show pulmonary symptoms (and if this is not the case, then the vaccine doesn’t bleeding well work properly).

            Your thoughts on that interpretation?
            🙂

          15. Adrian says:

            You are making the mistake of taking one sentence out of context, and then parsing it in a way that does not make sense with context.

            Read the whole article, not only the one sentence.

            Nothing in this whole section in the article is talking about different virus strains.

            It first states “However, this approach has shortcomings with respect to pathophysiology and safety.” and then elaborates on that. What you quoted are the authors explaining one shortcoming with respect to pathophysiology of challenging young healthy volunteers.

            The sentence you are quoting is saying the same as Derek who wrote “This means that the data you would obtain from such a challenge is skewed heavily away from some of the people that you are going to want to treat first.”

          16. RA says:

            Thanks for your interpretation! But, yeah, I don’t agree with your parsing. It seems to presuppose that they already know the vaccine is effective and likely to lead to the challenge of having mild symptoms before doing the challenge trial itself. (as a tangent, my “conspiracy theory” is the exact opposite…that they already think based on Monkeys that these mRNA and adenoviral vaccines won’t be that good and a challenge trial would pull back the curtain on the Wonderful Wizards of mRNA and Adenoviral vectors)

            Nothing any of you have said takes away from the fact that Fauci’s group has in print that a LIMITATION of a challenge study is that it is UNLIKELY TO CAUSE VERY SEVERE DISEASE. SO, debate the merits of challenge trial scientific utility till the cows come home and the quarterly earnings reports are due, but I remain unconvinced that there is much of an ethical/safety issue here based on this. Maybe a PR issue. Maybe a public perception issue. Maybe more sinister financial corruption. But c’mon, Fauci himself said these challenge studies are likely to cause mild disease so on that basis I will choose to disagree with those who think that the status quo is the ethically superior course of action for our country.

          17. Adrian says:

            No, what the article you are citing actually says is that a limitation of a challenge study is that the resulting data is inferior to the data obtained in a normal trial.

            You simply cannot learn anything about side effects and protection in the high-risk groups the actually need protection like morbid obesity or old age when they are excluded from the trial.

          18. RA says:

            Challenge trials and traditional trials are not mutually exclusive. In fact, they could synergistic.

  27. Robert Clark says:

    The problem with making a blanket statement you will cover no more reports on a particular medication is that it puts you in a bad position when positive reports come out.

    The RECOVERY trial had some serious problems with it as the retracted Lancet report did. The use of near toxic levels of hydroxychloroquine in the RECOVERY trial IS a major big deal. This was twice the levels used in the Brazilian study that led to premature deaths and had to be stopped early.

    The RECOVERY trial leads assert it did not cause any extra deaths, but now it’s been four weeks since their announcement on HCQ and they still have not released their data. In contrast when they made their announcement on dexamethasone, they released their data in only one week.

    The Henry Ford Health system showing beneficial HCQ effects has released their data so they have opened it up to critical public review. The RECOVERY trial leads do not get to protect their reputations at the cost of human lives. They actively encouraged doctors not to use a medication that can save lives according to the Henry Ford Health system report. The RECOVERY trial data MUST be released now ASAP to see if this was a valid recommendation.

    The longer they delay the more lives that can cost. This will be far more damaging to their reputations than simply releasing their data and it is found that the data itself leaves room for doubt about their conclusions.

    Robert Clark

    1. Tom says:

      It’s been a while since you came on here again touting HCQ… one small problem, the article you linked to in an earlier reply post is a retrospective study. While there may be something in it that could lead to further investigation, it doesn’t really add much more to what has already been done at this stage and certainly doesn’t constitute touting HCQ as an effective treatment. As the authors themselves note:

      “However, our results should be interpreted with some caution and should not be applied to patients treated outside of hospital settings. Our results also require further confirmation in prospective, randomized controlled trials that rigorously evaluate the safety, and efficacy of hydroxychloroquine therapy for COVID-19 in hospitalized patients. Considered in the context of current studies on the use of hydroxychloroquine for COVID-19, our results suggest that hydroxychloroquine may have an important role to play in reducing COVID-19 mortality.”

      I’m all for them conducting a full randomized trial if they wish, just to end the debate once and for all. I’m not convinced, nor are many others nowadays (the WHO etc.), but hey, this is just me leaving my critical public review…

      1. Robert Clark says:

        The problem is the RECOVERY trial still has not released their data. So it is no better than a retrospective study. In fact, it is arguably worse since in the retrospective study you can examine their data to draw conclusions on their validity.

        The longer the RECOVERY trial team delays the release of their data the more suspicious it becomes that there is a problem with it, especially considering they released the dexamethasone data after only one week.

        If they continue to withhold the data after this Henry Ford Health system positive study then it begins to look more and more like Lancet retracted paper case, who also refused to release their data.

        Remember the RECOVERY trial leads went beyond simply saying they found no effect. They actively told doctors not to use it and even told patients if they were offered it not to take it.

        IF it turns out the Henry Ford Health system conclusions are correct, then that means they actively caused more patients to die than needed.

        That might be forgivable if they honestly believed that then. It is not forgiveable if they are now hiding the data because it will show that conclusion was not justified.

        Robert Clark

        1. Tom says:

          I agree that any study that presents findings should soon follow that up with their actual data to support so, you won’t find me disagreeing with you there.

          However: https://www.sciencemag.org/news/2020/06/three-big-studies-dim-hopes-hydroxychloroquine-can-treat-or-prevent-covid-19

          Even if you ignore the RECOVERY trial data being missing, two studies mentioned there for PEP did not find benefit for HCQ. You advocate it as an early treatment… they were trying to use it as a prophylaxis and it did not work. If you combine this with the Solidarity Trial results through the WHO (admittedly I cannot find their data myself so that doesn’t help the case much), which led to the cancellation of their HCQ trial based on their findings, the odds are still stacked against HCQ in general.

          1. theasdgamer says:

            The Boulware study actually showed significant prophylaxis for HC, but you had to combine the raw data from days 1-3 yourself to see it. It’s astounding that the authors missed it.

          2. Joseph Psotka says:

            WHO has restarted the trial.

          3. Robert Clark says:

            One of the studies mentioned in the Science article, from the Univ. of Minn., has its conclusions now in question because for the great majority of subjects they didn’t actually do testing. They relied on the subjects own self-report of symptoms to determine whether or not they had it. But it is known such self-reports can be 80% inaccurate, either by false positives or false negatives.

            There was also a study from Spain mentioned in that Science article that didn’t find an effect. I hope for this study they did actually do testing. That study recently concluded so hopefully they will release their data soon.

            Note though, that Indian studies have shown HCQ effective for prophylaxis.

            Robert Clark

          4. theasdgamer says:

            It’s too early to come up with a definite decision about hydroxychloroquine effectiveness as regards science’s interests. There’s a lot of politics in science and we need to give it time to sort those things out.

            There are now three recent positive studies of hydroxychloroquine–two hospital studies (Rahimian & Ford Hospital) and a groundbreaking outpatient study (Zelenko). We need eyes to look at those and sift out the bathwater.

    2. Some idiot says:

      “when positive results come out”

      “If” would be a better word. You certainly haven’t delivered any.

      Yes, I am also interested in seeing the RECOVERY data. But you spouting the old disinformation suggesting that the study is flawed is just plain disappointing, particularly since your points have been refuted numerous times before. Yet you keep repeating them. Pure misinformation.

      Go away and troll other places. Or, if you come back, please bring real data with you (i.e. RCTs).

      1. Robert Clark says:

        The problem is NO ONE has ever used dosages that high with hydroxychloroquine. The one case where they did use anything close to that was the Brazil trial, which only used half that amount, had to be stopped because of the higher number of deaths caused by it.

        If the RECOVERY trial wants to be believed that dosage didn’t cause additional negative effects they have to release the data.

        Robert Clark

        1. Tom says:

          ” The first day loading dose in RECOVERY (1.86g base) is twice the first day loading dose for treating malaria. This dose has been selected based on the available data of the IC50 for SARS-CoV-2. The objective is to reach plasma concentrations that are inhibitory to the virus as soon as safely possible. The plasma concentrations that will result are at the higher end of those encountered during steady state treatment of rheumatoid arthritis. Given the significant mortality in patients hospitalised with COVID-19, this dose is felt to be justified. This is the schedule that has been adopted by the World Health Organisation in their SOLIDARITY trial. ” – https://www.recoverytrial.net/files/recovery-intervention-sheet-hydroxychloroquine-v3-0-final-190420-13-33.pdf

          They themselves acknowledge the higher than normal dose, and justify it… I would argue that anything that needs such a high does to have an affect (i.e. the IC50 is clearly not great if that is the case) is already on the back foot in terms of having a therapeutic effect. Secondly, the fact that expected plasma concentrations would be at the higher end of those encountered during treatment of rheumatoid arthritis still suggests that the amount of drug used is not outside of clinicians understanding of the drug in the body.

          If HCQ didn’t work sufficiently at such a high dose that is required based on the IC50, it is very much unlikely to work at the lose dose you expect it to either… ergo it will not be an effective treatment at any dose, drugs need to bind at the right concentrations to actually work!

        2. Some idiot says:

          Listen, they used that _initial_ dosage in order to get the pharmacokinetics to run usefully for an acute dosage. As has been explained before, numerous times.

          There was no difference in side effects between HCQ and placebo, meaning toxicity was not a problem. As has been explained before, numerous times.

          If HCQ was going to work with lower doses, then the positive effects should have been seen with the higher acute doses here. But they weren’t. As has been explained before, numerous times.

          So could you get real, and stop spreading the same tiresome disinformation. If you want to persuade us, show us some RCTs that show positive results.

          1. Robert Clark says:

            Someone can give an excuse for doing something. That does not mean the excuse is reasonable. The Brazilian dosage that caused unnecessary deaths was already known about, at only half that of the RECOVERY trial. One of the RECOVERY leads, Martin Landry, to justify the dosage, was quoted as citing a maximal dose of HCQ allowable in the UK that was actually multiple times higher than the known LETHAL dose.

            Studies that claim that HCQ worked were at far less levels than the RECOVERY trial. It is that hypothesis that was to be tested.

            If they claim there were no additional deaths under their high dose levels, release the data. The longer they keep it hidden the greater are the chances we have a situation like the retracted Lancet paper where the authors knew it wouldn’t hold up to close scrutiny.

            IF they are keeping it hidden for this reason, then a legitimate argument can be made they are guilty of malfeasance.

            Robert Clark

          2. Some idiot says:

            Oh good grief… Top tip: by trying to smear the RECOVERY trial with the name of the garbage Lancet article, you are showing yourself to be someone who si spreading deliberate misinformation. But the only person you are fooling is yourself…!

            Yes, I am looking forward to seeing the RECOVERY data. We all are. But the reported results show NO SIGN OF TOXICITY PROBLEMS. Try to get that into your head!!!

            And by the way, if you want to argue that a lower dose would have given a better result, then you would need a damn good reason for it. Dose/effect curves go one way. And please don’t parrot the BS that it is “because it is toxic”, because we have been through that many times now and there is not a shred of evidence that your contention has so much the slightest fact to back it up with. No, instead try to come up with a proper scientific argument, instead of the usual word salad you throw in the air.

            And quit with the continual smearing and disinformation. You aren’t fooling anyone but yourself.

          3. theasdgamer says:

            “Dose/effect curves go one way.”

            So giving 100,000 units of heparin will produce a better outcome than 5,000 units?

            There is a joke in medicine: “I became a doctor so that I could cut and poison people.” Medicines given in sufficiently large quantities become poisonous.

          4. Some idiot says:

            As usual, a very simplistic reply, but I’ll bite… Yes, dose/effect curves go one way… I’m actually not sure whether or not you know what you are talking about, but let’s take the example you mention. The more heparin you give a patient, the larger clot-clearing effect you will see. Of course, if you add too much, the negative effects of this would start to be seen (loss of clotting function, plus other side effects that are not related to clotting).

            In other words (as with other drugs) the positive effect rises with dose, and at some point the negative effects start to rise and become problematic as well. This defines the therapeutic window.

            However, even at the higher doses, which bring on side-effects, you will still see a strong positive response from the desired effect. That does _not_ decline.

            In a similar manner, in the case of HCQ, if HCQ has an antiviral effect at the doses you are talking about, then HCQ would have at least as large an antiviral effect with a higher dose. However, in this study, no antiviral effect was observed. Neither were there observed greater side effects than with placebo.

          5. Marko says:

            It’s entirely possible that the dose-response curve for hydroxychloroquine is non-monotonic , especially if its primary benefit is immunomodulatory ( as it is for lupus and RA) , and the the desired “response” is prevention of cytokine storm without disrupting an effective immune response. The same applies for dexamethasone.

            And dose–response curves are NOT always one way. Non-monotonic curves are common for steroid hormones , for example.

          6. Some idiot says:

            Point taken, but given that the hypothesis has always been that it is acting as an antiviral, and not as an immunomodulatory agent (the former backed up by in-vitro studies), plus the fact that it has always been claimed that it must be “administered early in order to clear out the virus” suggest that the usual dose-response curves for infection are the ones that would be relevant here.

          7. Marko says:

            Yes , I think the proponents of hydroxychloroquine may have shot themselves in the foot by not emphasizing the likely immune-modulating effect from the outset. I would have pitched the antiviral effect , if any , as a bonus. Same with the zinc add-on. It would have helped if Trump had kept his trap shut too , of course.

            When I first heard about it , and found that it was used for lupus and RA , it immediately struck be as being a plausible candidate , given that we knew early on that cytokine storm / dysregulated immune response were responsible for many of the worst effects of COVID-19.

            I still suspect it might help some if given at the right time and at the right dose , but I don’t think it’s a game-changer by any means. Unfortunately , with the way the issue has been politicized , we may never know for sure.

          8. theasdgamer says:

            There are several explanations out there for HC’s multimodal action. Here’s one I found:

            1. zinc ionophore
            2. anti-thrombotic (especially important to protect capillaries and small blood vessels around the alveoli and heart; covid seems to increase clotting)
            3. alkalinizer (of endosomes I presume)
            4. immunosuppressant for cytokine storm
            5. anti-inflammatory agent
            6. suppresses auto-immune antibodies

            So there are two postulated antiviral modes.

            Somehow HC gets into endosomes. Maybe it acts as an ionophore in that specific case. And maybe a virus also penetrates the same endosome. And the virus also penetrates some other endosomes that also have HC / zinc. And when the virus is able to escape the endosome, the zinc also is able to diffuse out near the nucleus and the zinc is able to interfere with the viral RNA replication.

            Maybe in some endosomes there is too much HC for the virus to be able to escape the endosome and the virus ends up being consumed by the lysozome.

            https://www.facebook.com/drericberg/videos/650983608792889

    3. RA says:

      What’s your opinion on challenge trials in those taking hydroxychloroquine?

      Perhaps we have a potential source of both agreement and way to make this thread more germane to the post!

  28. Greemram@science.com says:

    You continue to struggle in explaining the most basic precepts of mainstream
    virology. As always, consult the consensus. The ring vaccination program for EVD did not require such a thing as challenge testing. It’s called RING VACCINATION. Why do we keep bringing up these outdated protocols. Simply because it might get trump re-elected, that’s why.

    1. drsnowboard says:

      And your comment is even less intelligible. I’m assuming you mean challenge studies are irrelevant because you are in favour of ring vaccination as a control measure. Does that not require contact tracing, isolation, and community engagement and god forbid, common sense and an infrastructure to support it? Let alone no large gatherings of cult devotees.

  29. ghyu says:

    If challenge trials aren’t better than traditional trial designs, why do we only do challenge trials on animals? The risk of severe disease in a healthy 18-30 year old under medical observation is almost zero. You wouldn’t even need 50% placebo. If a vaccine works well, you should get sterilizing immunity and none of the vaccinated group should be positive for viral RNA and almost all of the placebo group would have at least some viral replication. How ethical is it to give some people in the wild a placebo when you could easily give almost all of them the vaccine in a challenge trial?

    1. RA says:

      Nail hit on head.

      I think they don’t want us to know how mediocre are their new-fangled, Pharma-favored mRNA and adenoviral vaccines that are the furthest along.

      The public has no idea that sterilizing immunity, a vaccine that could stop the spread is a pipe dream at the moment. The bar is going to be super low…a vaccine that might prevent a statistically significant number of people, but not all, from progressing to the worst complications of COVID-19, but still able to get infected and still able to spread to vulnerable hosts, who will be everywhere for a long time. The current vaccines, while hopefully will be a step in the right direction, are no “Get out of Mask Free” card, but I don’t think the powers that be want to emphasize that to a weary, angry public nor their shareholders.

      Meanwhile, China is laughing at us as they aggressively pursue both tried and true and new fangled.

    2. Taylor says:

      Placebo testing isn’t necessarily needed in the case of vaccines… you can simply compare to a similar group of unvaccinated people. (The risk in doing this is actually that you’ll see adverse events reported that *aren’t* actually real, but if those adverse events aren’t scary then it’s not an issue.)

      That said, I think Derek gets a little myopic about his field and the limitations they’ve been working with for the past few decades. Of COURSE challenge trials are better. They can give you much faster results (likely ultimately resulting in literally thousands of lives saved), and you can study the body’s immune reaction on a day by day basis so you can get a much clearer picture of how the vaccine performs in homo sapiens. And because it happens so quickly and all at once, you can rule out the confounding effects in hospitals’ standard of care changing.

      The downside is that some people will die. A rather small number of brave, informed volunteers would die and in exchange, thousands of unwilling victims of COVID-19 would be saved.

      1. David says:

        @Taylor: “Placebo testing isn’t necessarily needed in the case of vaccines… you can simply compare to a similar group of unvaccinated people. ”

        You would have to be very certain that the unvaccinated comparison group is actually similar. Almost by definition, they aren’t, as they didn’t take the decision to volunteer for the study (implying a behavioral difference). Even seemingly minor differences between groups can lead to a spurious result.

        A placebo-controlled study ensures that the active and comparison groups are drawn from the same population (not “similar” – same) and randomization, over a sufficiently large sample, balances risk factors including those not recognized.

        1. RA says:

          To this point, I wonder about how effective placebo control will be in these studies given that the vaccine candidates produce quite a lot of constitutional symptoms. While those who get the vaccine know it and behave accordingly, while those who don’t get the vaccine also know it and behave accordingly? If they did, then I think that would bias the trials towards the null hypothesis. Yet another potential reason for Type II error in these trials. I hope the trials will at least measure whether participants think they got the vaccine or placebo to control for this.

          1. David says:

            @RA: To mask the treatment allocation to subjects, the placebo group could be given a standard influenza vaccine, which also can produce similar systemic symptoms (injection site reaction, mild fever, etc).

        2. Taylor says:

          @David: Well, you could draw your observational group from the same applicant pool. But I’m not arguing against placebo testing of vaccines; I’m just pointing out it *might* not be strictly necessary. Depends on what your goal/concern is.

          I brought it up mainly out of habit, I think, because some anti-vaxxers like to harp on the fact that certain childhood vaccines never went through placebo testing. Their insinuation is that this means there could be hidden dangers, which is absurd… adverse reactions would be detectable regardless (you just wouldn’t be able to rule out the “nocebo” effect.)

  30. Joseph Psotka says:

    Can you please give us a perspective on alpha1-AT as a preventative drug for covid-19. Several studies now suggest it is effective. It could be used in the placebo group as a comparison of which is more effective. However, I think this whole business of challenge trials is a test of moral clarity.

  31. Steve Scott says:

    I can see some similarities between challenge testing and Phase III clinical studies. In the Phase III, you want participants to put themselves in contact with Covid-19. The riskier their behavior, or the riskier the circumstances they are in unavoidably, the better it is for the researchers.
    As I suggested earlier, if everyone in the study follows the health warnings, and doesn’t come in contact with Covid-19, the study fails. So I would suggest that Phase III is a sort of “soft challenge” test. The researchers could speed up the results by intentionally selecting candidates based on their personal risk factors or behaviors, and they can’t be blamed if any of them becomes sick or dies.

  32. Bill says:

    I’m not understanding the ethics of vaccine trials. Once Phase I trials are successfully completed, the candidate vaccine has demonstrated safety. We’re currently losing 20,000 people a month to the virus. That may soon double. Why wouldn’t it be more ethical to vaccinate people with a safe candidate that hasn’t yet been proven effective vs letting them simply die waiting for a vaccine?

    1. Adrian says:

      Phase I only shows safety in a very small group of healthy young people. People at risk of dying from COVID-19 won’t be in a Phase I trial.

      General safety is demonstrated after Phase III.

      And how do you imagine billions of doses of a brand-new vaccine candidate would suddenly appear?
      Speculative setup and start of vaccine production before approval is already happening.

    2. Some idiot says:

      I understand your question, but it is a bit complex…

      The short version is that when you say “Phase 1 has demonstrated safety”, well, that requires modification. Certainly, if the trial lead to a death or other serious adverse effects, then yeah, it’s in the dustbin. However, remember that you are looking at vaccination with a very small group of very low risk individuals, with a very high level of medical supervision as well (and the goal of Phase 1, for a vaccination, is to see whether or not you develop antibodies, and not kill people in the process).

      Let’s say you have tested 20-30 people in this very low risk population (no way in the world would you test high-risk groups). For the purposes of argument, let’s say that the rate of severe adverse effects/death is 1 in 50. There is a decent chance you would not be aware of this in Phase 1. Let’s say that death rate from COVID-19 is about 1%. That means that the death rate would be lower if you did not vaccinate. But you wouldn’t know that just after Phase 1. Plus, the general population is going to be less healthy, and (on average) have access to a far lower level of medical care than those in the trial.

      Two side points here…

      (A) more generally, this shows why the safety of vaccines has to be _very_ high… with a normal medicine, you are treating an existing condition, so some level of side effect is more or less accepted, as long as it is not as severe as the disease. However, with a vaccine, the goal is probably to give it to almost the entire population, the vast majority of whom are symptom free, so it has to be _extremely_ safe in order to justify use.

      (B) I know this point can be pretty politically touchy, but I am not meaning to be political, but… Especially with that level of fatality/illness, everyone following simple precautions mean that the rate of spread will fall dramatically. Not necessarily fun, but effective none the less. A lot of different countries have shown this. It just requires the willpower of the leaders, and cooperation from the citizens. But you need both.

      1. RA says:

        So, regarding point B, I am curious about how you might explain this:

        1) The US, with a bad outbreak, it is considered dangerous to speed up vaccine deployment.
        2) In China, where the outbreak is controlled due to authoritarianism and culture, they are already deploying a vaccine in their military and citizens to have to travel abroad.

        So, is the US vaccine policy more rationally aligned with US interests, or is the Chinese vaccine policy more aligned with Chinese interests?

        1. Some idiot says:

          In my opinion: both. They are not mutually exclusive.

  33. Bill says:

    I would think you would limit early use to a highly select group. Surely scientists can characterize which people in which locals are at the most extreme risk. Early protection of the critical 1% might reduce fatalities by greatly more than 1%.

    Of course there’s risk. But avoiding all such risk will condemn tens, perhaps hundreds of thousands to needless death. I don’t see how you can be rock-solid on protocol to minimize risk and not consider the total result of such “safety”.

    1. Adrian says:

      Risk of infection or risk of dying if infected?

      1% greatest risk of infection is the “young and stupid” age group around high school graduation.

      1% greatest risk of dying if infected is the age group 90+.

  34. David says:

    @Bill –

    Phase 1 trials might demonstrate safety in small groups of healthy volunteers. But larger trials are needed to understand safety well enough to dose millions of people. The Dengue Fever vaccine caused deaths in certain susceptible recipients. In “vaccine enhancement” in which a seemingly safe vaccine actually ends up making the disease worse not better. Large, well-controlled studies are still required.

    Finally, once a vaccine is licensed, it will create a slowdown in development of other vaccines. The first one to get approved may not be the best. So we’ve got to get this right.

    1. Bill says:

      It’s like an assay balance. Taking the time to get everything “right” is on one side.

      20,000 per month (and that’s just USA) on the other side.

      I hope someone is doing the math.

      1. Adrian says:

        That is a reason for administering a vaccine that will likely either not work or not be safe?
        After Phase I there is a 90% chance that the vaccine candidate might never get approved due to that.

        And which vaccine candidate specifically are you talking about?
        With around 20 vaccine candidates already in human trials and more than 100 other under development there is a fair chance that one of them might get approved in the end.
        Which one this might be noone knows for sure.

      2. RA says:

        Different segments of our society will view this differently based on their own self-interests.

        If you are well-heeled, educated on how to prevent infection, equipped to do so, for YOU the daily death toll of the less fortunate is rationally less of a concern than insuring that any vaccine that you have to take down the road is as perfect as possible and letting others bear the burden of making sure that when you roll up your sleeve (literally, decidedly not figuratively) that this vaccine is as safe and effective as possible. Really no rush, no need to break any glass..after all, breaking glass is dangerous. One might cut one’s hand, after all.

        However, if you are not as fortunate, educated, and/or you work in higher-risk settings, etc there is more of a sense of urgency for you because the likelihood of serious illness and death is much higher and the risk/benefit equation changes. And the response of our society boils down to “Sucks to be you…and whatever happens to you is basically your fault.”

        1. Adrian says:

          In most areas of engineering it is common that the engineers know what the fastest realistic schedule is, and when management pushes for a more aggressive schedule everyone knows that disaster is inevitable.

          Your “breaking glass” talk sounds familiar to people who have heard the motivational talks from bad managers who are pushing so far that the project is destined to fail.

          1. RA says:

            Except that the country’s “managers” are the ones saying no to challenge trials.

        2. Derek Lowe says:

          Not the first time I’ve been called a murderer by proxy. But it’s not something one learns to enjoy. I realize that you’re probably deliberately looking to provoke people, but you might consider that it’s not a good look for your point of view, either.

          1. RA says:

            I don’t think you are a murderer! Please don’t think I am implying that at all. I actually love your blog and learn a ton from the discussion here, and unlike a lot of other commentators here, consider it rude to insult you or impugn your personal motivations as our esteemed host. I think you are a doing an incredible service translating complex concepts to a broad audience. I agree with a lot of what you have to say. We will agree to disagree about challenge trials.

            I do have deep suspicions about the motivations of those who are leading the country’s response to this pandemic, however. And I am trying to stand up for those who are suffering greatly. Please don’t take that personally.

            From my point of view, this isn’t about you or me or what sort of look I have or whether people feel provoked.

            So, again, thank you very much for this blog and the incredible service you deliver.

          2. Derek Lowe says:

            Sorry about that! I think we both came across too strongly, which is a common problem in text. You’re welcome to comment, of course – this situation brings out rather high emotions in everyone.

          3. RA says:

            Totally! We’re all taking this day by day!

          4. Adrian says:

            Regarding your “trying to stand up for those who are suffering greatly”: The road to hell is paved with good intentions.

            People who believe COVID-19 is just a hoax to allow Bill Gates to microchip everyone have the same kind of conviction and belief in bad government/companies/… as you have on the other side of the aisle.

            Evidence-based people evaluate the arguments and evidence available, and are always willing to accept that what they assumed to be true might not be.

            The section in the article co-authored by Dr. Fauci where you misparsed a sentence out of context above to make it fit your option is a response to challenge trial suggestions, explaining why they might not be helpful.

            And it is not only in the US that challenge trials are not requested by people who are actually involved. They are at best considered an inferior option if testing on people exposed to COVID-19 naturally is no longer possible.

            Vaccine development is already progressing as fast as is possible. Usually the joke goes “A manager is someone who thinks that 9 pregnant women can create a baby in 1 month”. This sounds completely absurd, but it also nicely summarizes countless project failures in companies.

            Testing of a vaccine takes time.
            Starting production of a vaccine takes time.
            And any possible ways to achieve speedup is already being done.
            At that point one has to accept that things cannot be accelerated even further.

  35. Adrian says:

    One thing that is not discussed in this post from Derek, and that is worth mentioning explicitly:

    What timeline do people have in mind when they are desperately trying to find ways to cut the time until vaccine approval by weeks or even days?

    I have the impression many people here are relying on timelines where the President of the United States will announce the approval of the first vaccine before the US elections in 4 months, and “faster” would mean September instead of October.
    That’s, well, very optimistic in any case.
    And no, I cannot imagine any kind of “pointless red tape” that would prevent an approval before the US elections if any vaccine is available that could get approved.

    A hypothetical “1 day earlier” would more likely be one day earlier in 2021 or 2022.

    1. RA says:

      The earlier the better, but even challenge trial advocates are missing some of the benefits.

      Let’s for the sake of argument say that there would be zero days sooner (which I don’t believe). There is still reason to do them.

      Instead of “1 day fewer” let’s call it “100 mediocre vaccines fewer.”

      Use challenges to chuck out all the least effective approaches and then unify our efforts and marshall our resources to test a some fewer number of more likely winners. Less phase 3 studies with bigger sample sizes –> more likely to give accurate efficacy and safety results. In this scenario, challenge trials don’t undermine safety but enhance it in the long run.

      Biology will determine the winners, not corrupt human beings. Let the best vaccine(s) win.

  36. exGlaxoid says:

    Just test the vaccine in areas of high virus spread, which is 40 of 50 states according to the media. Give it to people who appear to be doing lots of dumb things, medical workers, church goers, and Republican delegrates. Once a vaccine is approved, it seems like treating health care workers (especially people at senior living facilities), teachers, minsters, and others who see many people a day or older people who be prudent. Given that older people often have poor immunity from vacccines, treating their caregivers might do more to protect them that treating the elderly themselves. (both residents and staff is best.)

    I do find it encouraging that while diagnosed cases are going up, the deaths are dropping, both in the US, but also in some other countries like Sweden, where they are now very low. We are seeing both more young cases as well as the effects of better treatments, some drug routines that appear to work better, and just a better understanding of the course and treatment of the disease.

    if we can get antibodies into even a decent production by the fall, that may provide a temporary way to help the elderly and others that do catch Covid, thus continuing to drop the death rate. At the rate Covid is spreading, we may well have a slowdown due to limited herd immunity by then as well. The number of people with antibodies was 8-10% in NC in late June accoording to the Wake Forest study of 5000 people, up from 1-2% in April, so the spread was going up at about 4-5% per month then, and might be higher now.

  37. Kaleberg says:

    Ignoring the ethical issues, I don’t see how a challenge trial is going to speed things up. If COVID-19 doesn’t just magically disappear, there will be lots of opportunities for exposure from ordinary activities. Unlike AIDS which was often spread by needle sticks, COVID-19 is rarely spread by injection or blood contact. A challenge gets ONE data point right up front, but knowing that the vaccine provides immunity on day 21 or day 30 is of limited use. We also need to know about days 60, 90, 120 and so on. Sixty days of immunity might be useful, but only if a booster can extend it.

    I know some people are arguing that even a one day speed up would help, but I don’t see how one can test duration of immunity without letting time pass. Materials scientists do shorter tests and extrapolate, but that’s hard to do in biological systems.

    As long as COVID-19 is a problem, we can pick a trial length and endpoints to get meaningful results without an artificial challenge. Maybe a three month 50% effective vaccine is worth it, especially if immunity can be extended. Unless we get COVID-19 under control without using a vaccine, there are going to be lots of people at higher risk, especially as restrictions are lifted. Meat cutters, choir leaders and bartenders come to mind, and I am sure there are others who would love to be in a Phase III trial.

    1. Taylor says:

      At the risk of sounding impolite, there’s literally no ethical issue at all for anyone with the emotional maturity above a toddler level, with the exception of some people living inside the bubble here. The fire chief doesn’t say “wait, is there an ethical issue here?” before sending men into a burning building to save people. What we have here are simply the reflexive responses of navel-gazing bureaucrats who don’t understand what the lessons of Tuskegee actually were. The overwhelming majority of people are in favor of letting a few dozen (or even a few hundred) *fully informed* volunteers die to save many thousands more. Yes, that includes high-risk volunteers and yes, there will be sufficient numbers of them.

      I’m repeating myself a bit here but i really think that this hand-wavey “ethical issues” objection needs to be very firmly pushed back on. Go out and ask people outside of the medical community bubble. There are no ethical issues here whatsoever. Literally everyone I’ve talked to, smart or not-so-smart, empathic or callous, is in favor of challenge testing.

      And any insinuation that a challenge component wouldn’t significantly speed up results, *and* remove some confounding factors (changing standards of care in hospitals), *and* allow us to study the immune response from day 0, is just plain wrong.

      And yes, that speedup certainly includes studying duration of immunity, if that really is a concern.

      This is all so obviously self-evident I’m not sure what to say. Waiting around for people to catch the virus “naturally” takes a significant amount of time (and introduces biases). Immediately giving them the virus a set amount of time after the vaccine removes that wait period.

  38. theasdgamer says:

    Dr. Lowe, will you be addressing the new Zelenko outpatient preprint of his protocol?

  39. Eugene says:

    Challenge trials brings to mind Jenner’s Cowpox innoculation test on a young boy (n=1!) followed by Smallpox innoculation, would that protocol pass muster before a review board today? Medical science has certainly made progress since then, I would hope.

    1. Taylor says:

      I would’ve hope that allegedly rational and intelligent scientists were capable of a little more nuance and critical thinking than that. That’s Trump-level argumentation right there.

      In this case, you would be able to find tens of thousands of intelligent, fully informed volunteers if only you had the clear thinking and courage and humanity to ask.

  40. theasdgamer says:

    Some of you may still be interested in hydroxychloroquine studies. Here’s a link to a site that links more than 32 studies about HC.

    I find in unsurprising but a little disappointing that some people have decided that the weight of HC studies are negative when the literature shows that not to be the case. And it’s also disappointing that some people have decided that some negative HC studies of hospitalized patients bears weight on HC studies of outpatients despite the fact that those self-same negative studies clearly say that they have nothing to say about outpatient treatment.

  41. bacillus says:

    Not sure if this has already been covered, but if you are going to perform human challenge trials for a virus with no therapeutic, then you are going to have to hopitalize or otherwise isolate these people for at least a week to monitor for adverse effects. This is hardly a normal environment. You’re crazy if you think you’re just going to get challenged with virulent virus then simply walk away from the clinic.

  42. Linda Klavinskis says:

    The International Society for Vaccines (ISV) held a very insightful panel discussion – debating the issue of whether Human challenge studies acceptable in developing a COVID-19 vaccine? with panelists Dr Stanley Plotkin (VaxConsult), Dr Peter Openshaw (Imperial College London) and Dr Stanley Perlman (Univ of Iowa), moderated by Dr David Weiner (Wistar Inst) – recording can be found on You Tube https://www.youtube.com/watch?v=_pg6dDRdxXQ

  43. Marko says:

    Coronavirus vaccine: Oxford team aim to start lab-controlled human trials

    Jenner Institute at Oxford looks to recruit healthy volunteers for controversial ‘challenge trial’

    https://www.theguardian.com/science/2020/jul/16/coronavirus-vaccine-oxford-team-volunteers-lab-controlled-human-challenge-trial

  44. An Old Chemist says:

    Nobel laureates call for ‘challenge trials’ to speed up vaccine process

    https://www.cnn.com/2020/07/16/health/vaccine-open-letter-challenge-trials-intl-gbr/index.html

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