“Billions of people could be having debates … about human challenge trials.”
There’s something peculiar about this way of promoting the idea. Either human challenge trials are worth it, or they are not worth it, or “it depends” (on context, on opinion). It shouldn’t require billions of people to figure out something that basic. And if the answer is “it depends”, then it’s going to depend on medical technicalities or simply on local culture, and again, having billions debate it isn’t helpful.
Whether to have human challenge trials is ultimately a question about something that very few people are involved with, namely vaccine development methodology. To seriously address it requires knowledge of that process that few of us possess. If debates need to occur, quality matters more than quantity.
I strongly disagree with this idea that only a few vaccine experts should be debating the topic. Aside from a few basic technical concepts, the basic question here is ethical. Everyone can judge ethical questions. And if the past year has taught us anything, it’s that medical ethics questions are too important to be left to the experts.
I agree; it seems like the contrary argument assumes that experts make better decisions and take a more flexible approach on issues where there’s less direct public pressure, awareness, and debate. Instead, it seems to me they’re like to say “that seems weird, I’m busy, so why bother listening to your weird proposal.” Reminds me of Big Block of Cheese Day from the West Wing.
Having everyone talk about it builds awareness and familiarity in the population, basically ensuring that it becomes politicized, and either guaranteeing it happens next time, or ensures it does not happen, depending on which faction happens to be in power at that time.
I mean, Measles Vaccine is already “controversial” and Measles is worse than covid (in both transmissibility and cfr)
Hi Ericf, thanks for responding! Do you think that it’s possible to run a human challenge trial in the early stage of a deadly pandemic, without any known treatment for the disease, without provoking a major public debate?
If not—if debate and politicization of early-pandemic HCTs is guaranteed—then it seems to me that the right question isn’t whether to debate it, but how to debate it. And that’s only a relevant question if we have accepted the need to debate it.
I haven’t kept up on the state of debate of the trolley problem, but there should be a discussion among bio-ethisists and regulators about the ethics of infecting N people to prevent N x X infections among other people.
The current state seems to be “it is unethical to switch tracks, no matter who is on each track.” Which, for all I know, is the correct answer.
My intuition is that experts need to see public opinion change, as well as that of their colleagues, before they’ll feel comfortable running more HCTs. Without some amount of pressure, our tendency to see inaction as less blameworthy than action will prevent a serious reconsideration of how we do things.
Also, even quality expert debate is lacking, as the OP I hope makes clear.
Finally, I think that ethics are for everybody. People should have a say in the ethics of the society in which they live.
Overall, it’s not clear to me if you just disagree with the one line you picked out, or the substance of the post overall.
I disagree with that one line, mostly—the idea that having “billions” of people “debating” an issue is a meaningful or constructive goal.
Human challenge trials seem like a useful thing. Although maybe there’s some inconvenience because the infected people need to remain quarantined throughout the trial. And maybe there are other considerations that I don’t know about, intrinsic to vaccine development, that make it less useful or practical than it seems.
Those are about the extent of my thoughts on the issue. They are not especially deep.
I’m just saying that this vision of having everyone on Earth “debating” your favorite issue doesn’t make sense. I see two things to be accomplished here: clarity about whether and how human challenge trials are appropriate, and having policy and practice reflect this.
If there is actually still something to be discovered regarding the desirability and efficacy of HCTs, having “billions” debate it is not the way to do it. The vast majority of people on Earth know almost nothing about how the immune system works or the process of developing vaccines. They are not in a position to know any technical considerations that may affect the utility of HCTs.
remizidae said, “I strongly disagree with this idea that only a few vaccine experts should be debating the topic. Aside from a few basic technical concepts, the basic question here is ethical. Everyone can judge ethical questions.”
I am not saying that only vaccine experts should have a say. But I am saying that you can’t have this discussion without them! There may always be some detail, regarding how the real world works, that impacts the viability of HCTs, and which only experts know about.
But OK, let’s suppose that HCTs make technical sense in certain contexts. Then perhaps “the basic question here is ethical”, and “everyone can judge” it. If everyone can judge this appropriately, surely it doesn’t take billions of people to arrive at one of (1) yes (2) no (3) it depends?
On the other hand, if you think you already know that HCTs are useful and important and neglected, but are held back by institutional resistance, then maybe it would help to convince a lot of other people that things should change. But in that case, I would find the language of “debate” to be disingenuous.
I mean, suppose you stirred things up enough that billions of people were debating HCTs, and it turned out that for some reason, they’re no good. You would have wasted the time of the entire human race, as well as probably permanently misleading millions of people on the issue.
So you need to make a choice. Are you basically certain that HCTs urgently need to become acceptable? Then openly advocate them. Are you still unsure whether HCTs would actually make for a better world? Then try to figure out whether they would, before you set out to “guide the attention” of billions to this issue.
Let’s imagine that “billions” is two billion people, and that it takes the reading of one book for each to feel they have an adequate depth of understanding to have an informed opinion on pandemic vaccine testing alternatives. That might be 5 hours per person.
Ten billion person-hours is a little over one million person-years.
COVID-19 has killed over 1.6 million people so far. If a better approach to vaccine testing could have prevented 2⁄3 of those deaths, and each person who died lost just one QALY (which I suspect is an unrealistically conservative estimate), then that balances out with the time investment of having two billion people read a book.
Consider that over two billion people are certainly spending more than a total of five hours talking and thinking about the pandemic. Having a large part of the time they were going to spend thinking and talking about it anyway devoted to HCTs and other alternative vaccine testing approaches would be a good use of that time.
It’s also possible that humanity would make the considered decision not to enact an alternative approach because they value conventional medical ethics to that degree. I don’t have the hubris to be certain they’re wrong. But I am confident that they should consider it.
As Peter McCluskey illustrated, although I’ve thought about this issue way more than anybody else I personally know in real life, I still am nowhere close to adequately educated on the subject. So I feel confident in advocating for mass conversation on the subject, but not for mass adoption of HCTs.
I did some google-research… From wikipedia, I learned that HCTs have already been performed many times, for a variety of pathogens (I didn’t know that). So it seems like they are already part of accepted practice.
I found a reddit thread with comments from a few people who work in the medical industry, remarking e.g. that HCTs would only have come in at Phase 3 and would only have saved a little time. And a PNAS opinion piece giving what I guess is the common opinion among the bioethics establishment, that HCTs are not appropriate for Covid, and their reasons for this opinion (I have not studied their arguments; but they mention 1DaySooner).
Whatever their merit, I note that these counterarguments do not involve pure ethical reasoning about the bare idea of HCTs, they involve technological and epidemiological details that outsiders do not know.
This is why I’m against this call for “mass conversation”. So far all I’m hearing is “if we had vaccines sooner, lives would have been saved, what if HCTs would have done this?” But it turns out that HCTs have been used in the past, and that there are alleged reasons why they wouldn’t help in the specific case of Covid.
At the very least, an HCT advocate using our recent global experience as motivation, ought to now address the specifics of how the Covid vaccines were developed, and provide some plausible detailed reasons as to why and how HCTs could have accelerated that process.
I can actually expand on this a little bit for you.
HCTs have been run in the past, but only for diseases where we had an efficacious treatment. The reason COVID HCTs would only have been run in the Phase 3 stage is because early in the pandemic, we had no proven-effective treatment.
This is a choice based on ethical and political reasoning, rather than science.
As Peter McCluskey points out, the choice not to begin an immediate mass-vaccination campaign with the untested mRNA vaccines we had on January 13th is likewise based on political and ethical reasoning, rather than a scientific choice. We now know, of course, that those vaccines were extremely effective. We’d have saved a colossal number of lives if we had. If we’d paused to run HCTs early on and then distributed the vaccines, we’d have still saved the vast bulk of lives that have been lost.
It’s only because our institutional leaders have made the ethical and political choices they have on our behalf that HCTs appear to be ineffective. We could have made different choices that were equally scientific, but based on different political and ethical reasoning. Continuing with our conventional ethical/political choice cost us over a million lives. Is it worth it? Medical ethicists disagree, none of the experts are talking about it enough, and it’s time for them to step it up and for The People to have a say.
OK, let’s talk about some of the issues that would arise in this scenario.
Taking an mRNA vaccine means becoming temporarily transgenic. mRNA for Covid spike protein is injected into your muscle cells, they produce it, and this stimulates antibody production.
In having trials, one is not only testing that the Covid mRNA vaccine is effective against Covid; one is also testing whether the vaccine itself has side effects.
Are you proposing to move straight to mass vaccination, without testing for vaccine side effects? But if not, how will making the trials HCTs, save time? HCTs are only different in the way that they test efficacy against the pathogen. When it comes to testing for side effects of the vaccine itself, don’t you have to wait just as long as you do, in a non-challenge trial?
Vaccinate with safety and efficacy data (conventional trials)
Vaccinate only with efficacy data (early HCTs)
Vaccinate with no data (immediate vaccination campaign on development of a vaccine)
I’m advocating that option 2 and option 3 be considered as realistic scientific, ethical, and political possibilities during the early stage of a deadly future pandemic akin to the one we face now.
Two of the questions I still have are:
What are the worst side effects of any vaccine that’s ever been tested?
How frequently do vaccines fail in conventional trials due to safety concerns?
This paper finds that 33% of tested vaccines have made it through all 3 trial phases. One of the worst consequences of a historically approved vaccine, used as an example by the AAMC of why we can’t rush a COVID-19 vaccine, was the polio vaccine where 120,000 doses contained live virus.
This caused ten deaths. Stack that up against over 1.6 million and counting.
Once again, I’m not strictly saying the AAMC is wrong. But they are begging the question. Comparing the historical base rate of deaths due to unsafe vaccines vs. the base rate of expected deaths due to COVID-19 is, on its face, a pretty reasonable and obvious approach to evaluating what we should do.
The AAMC glosses right over this issue. They must know it’s why many of their readers are looking up the article in the first place. So they’re choosing to ignore this line of thinking. I’m asking them to stop ignoring it.
If (2) and (3) were seriously considered, then I’d think you’d particularly want to avoid using only a single vaccine.
From a civilizational point of view, the largest issue isn’t the expectation of the direct outcome—it’s that there’s a small chance you may have a bad outcome with very little variance across the population.
I’d be much less concerned about doing (2) or (3) with twenty different vaccines than with one.
Black Swan considerations definitely apply here. Although as far as I know, we haven’t had a vaccine that outright killed the majority of the people taking it, it’s not impossible. Maybe it’s just rare enough that we haven’t established a meaningful base rate. You’d also want to be concerned about the possibility of interactions from giving multiple vaccines to one person.
It might make sense to do something like vaccinating populations in the hardest-hit areas first, trying new vaccines as they become available, prioritizing the safest and most effective vaccines as data emerges.
If you want to make the case that with a different ethos, Covid-19 mortality might have been dramatically lower, it would help to exhibit a scenario in which this happens.
Much is being made of the fact that mRNA vaccines were first synthesized, very soon after the virus’s genetic sequence became available. But this just means that a particular molecular construct (a carrier for spike protein mRNA, I guess) could quickly be synthesized.
To go from that to mass vaccination, even if we skip trials for efficacy and safety, requires that you know enough about how the virus and the vaccine behave within the body, to have some idea of where and how to administer the vaccine to a patient. Also, there needs to be infrastructure to mass-produce the vaccine, and a way to distribute it.
Complications known to me, in the case of Covid mRNA vaccines, are that Covid’s interaction with the body and the immune system is intricate and was not immediately understood (this matters in deciding how to introduce a vaccine into the body), and that mRNA vaccines currently require ultracold refrigeration for their distribution, an infrastructure that doesn’t even exist in some countries.
Let’s see a concrete counterfactual scenario for rapid deployment of a Covid mRNA vaccine in 2020, that takes into account these two factors; and then we can start to estimate how many extra lives the HCT ethos might have saved.
Let’s imagine that “billions” is two billion people, and that it takes the reading of one book for each to feel they have an adequate depth of understanding to have an informed opinion on pandemic vaccine testing alternatives. That might be 5 hours per person.
I don’t think there’s a policy issue on which one billion people let alone two billion people read a book.
Even for an issue like climate change most people don’t read a book about it.
When it comes to the usefulness of a public debate it’s worth looking at two important enviromental issues. Mercury pollution is bad. CO2 pollution is bad.
Obama’s EPA managed to be very effective in fighting mercury pollution but unable to do anything about fighting CO2 pollution. A key difference between the two is that CO2 pollution was a heavily politized issue while nobody spoke about mercury pollution.
“Billions of people could be having debates … about human challenge trials.”
There’s something peculiar about this way of promoting the idea. Either human challenge trials are worth it, or they are not worth it, or “it depends” (on context, on opinion). It shouldn’t require billions of people to figure out something that basic. And if the answer is “it depends”, then it’s going to depend on medical technicalities or simply on local culture, and again, having billions debate it isn’t helpful.
Whether to have human challenge trials is ultimately a question about something that very few people are involved with, namely vaccine development methodology. To seriously address it requires knowledge of that process that few of us possess. If debates need to occur, quality matters more than quantity.
I strongly disagree with this idea that only a few vaccine experts should be debating the topic. Aside from a few basic technical concepts, the basic question here is ethical. Everyone can judge ethical questions. And if the past year has taught us anything, it’s that medical ethics questions are too important to be left to the experts.
I agree; it seems like the contrary argument assumes that experts make better decisions and take a more flexible approach on issues where there’s less direct public pressure, awareness, and debate. Instead, it seems to me they’re like to say “that seems weird, I’m busy, so why bother listening to your weird proposal.” Reminds me of Big Block of Cheese Day from the West Wing.
Having everyone talk about it builds awareness and familiarity in the population, basically ensuring that it becomes politicized, and either guaranteeing it happens next time, or ensures it does not happen, depending on which faction happens to be in power at that time. I mean, Measles Vaccine is already “controversial” and Measles is worse than covid (in both transmissibility and cfr)
Hi Ericf, thanks for responding! Do you think that it’s possible to run a human challenge trial in the early stage of a deadly pandemic, without any known treatment for the disease, without provoking a major public debate?
If not—if debate and politicization of early-pandemic HCTs is guaranteed—then it seems to me that the right question isn’t whether to debate it, but how to debate it. And that’s only a relevant question if we have accepted the need to debate it.
I haven’t kept up on the state of debate of the trolley problem, but there should be a discussion among bio-ethisists and regulators about the ethics of infecting N people to prevent N x X infections among other people. The current state seems to be “it is unethical to switch tracks, no matter who is on each track.” Which, for all I know, is the correct answer.
I appreciate you commenting!
My intuition is that experts need to see public opinion change, as well as that of their colleagues, before they’ll feel comfortable running more HCTs. Without some amount of pressure, our tendency to see inaction as less blameworthy than action will prevent a serious reconsideration of how we do things.
Also, even quality expert debate is lacking, as the OP I hope makes clear.
Finally, I think that ethics are for everybody. People should have a say in the ethics of the society in which they live.
Overall, it’s not clear to me if you just disagree with the one line you picked out, or the substance of the post overall.
I disagree with that one line, mostly—the idea that having “billions” of people “debating” an issue is a meaningful or constructive goal.
Human challenge trials seem like a useful thing. Although maybe there’s some inconvenience because the infected people need to remain quarantined throughout the trial. And maybe there are other considerations that I don’t know about, intrinsic to vaccine development, that make it less useful or practical than it seems.
Those are about the extent of my thoughts on the issue. They are not especially deep.
I’m just saying that this vision of having everyone on Earth “debating” your favorite issue doesn’t make sense. I see two things to be accomplished here: clarity about whether and how human challenge trials are appropriate, and having policy and practice reflect this.
If there is actually still something to be discovered regarding the desirability and efficacy of HCTs, having “billions” debate it is not the way to do it. The vast majority of people on Earth know almost nothing about how the immune system works or the process of developing vaccines. They are not in a position to know any technical considerations that may affect the utility of HCTs.
remizidae said, “I strongly disagree with this idea that only a few vaccine experts should be debating the topic. Aside from a few basic technical concepts, the basic question here is ethical. Everyone can judge ethical questions.”
I am not saying that only vaccine experts should have a say. But I am saying that you can’t have this discussion without them! There may always be some detail, regarding how the real world works, that impacts the viability of HCTs, and which only experts know about.
But OK, let’s suppose that HCTs make technical sense in certain contexts. Then perhaps “the basic question here is ethical”, and “everyone can judge” it. If everyone can judge this appropriately, surely it doesn’t take billions of people to arrive at one of (1) yes (2) no (3) it depends?
On the other hand, if you think you already know that HCTs are useful and important and neglected, but are held back by institutional resistance, then maybe it would help to convince a lot of other people that things should change. But in that case, I would find the language of “debate” to be disingenuous.
I mean, suppose you stirred things up enough that billions of people were debating HCTs, and it turned out that for some reason, they’re no good. You would have wasted the time of the entire human race, as well as probably permanently misleading millions of people on the issue.
So you need to make a choice. Are you basically certain that HCTs urgently need to become acceptable? Then openly advocate them. Are you still unsure whether HCTs would actually make for a better world? Then try to figure out whether they would, before you set out to “guide the attention” of billions to this issue.
Let’s imagine that “billions” is two billion people, and that it takes the reading of one book for each to feel they have an adequate depth of understanding to have an informed opinion on pandemic vaccine testing alternatives. That might be 5 hours per person.
Ten billion person-hours is a little over one million person-years.
COVID-19 has killed over 1.6 million people so far. If a better approach to vaccine testing could have prevented 2⁄3 of those deaths, and each person who died lost just one QALY (which I suspect is an unrealistically conservative estimate), then that balances out with the time investment of having two billion people read a book.
Consider that over two billion people are certainly spending more than a total of five hours talking and thinking about the pandemic. Having a large part of the time they were going to spend thinking and talking about it anyway devoted to HCTs and other alternative vaccine testing approaches would be a good use of that time.
It’s also possible that humanity would make the considered decision not to enact an alternative approach because they value conventional medical ethics to that degree. I don’t have the hubris to be certain they’re wrong. But I am confident that they should consider it.
As Peter McCluskey illustrated, although I’ve thought about this issue way more than anybody else I personally know in real life, I still am nowhere close to adequately educated on the subject. So I feel confident in advocating for mass conversation on the subject, but not for mass adoption of HCTs.
I did some google-research… From wikipedia, I learned that HCTs have already been performed many times, for a variety of pathogens (I didn’t know that). So it seems like they are already part of accepted practice.
I found a reddit thread with comments from a few people who work in the medical industry, remarking e.g. that HCTs would only have come in at Phase 3 and would only have saved a little time. And a PNAS opinion piece giving what I guess is the common opinion among the bioethics establishment, that HCTs are not appropriate for Covid, and their reasons for this opinion (I have not studied their arguments; but they mention 1DaySooner).
Whatever their merit, I note that these counterarguments do not involve pure ethical reasoning about the bare idea of HCTs, they involve technological and epidemiological details that outsiders do not know.
This is why I’m against this call for “mass conversation”. So far all I’m hearing is “if we had vaccines sooner, lives would have been saved, what if HCTs would have done this?” But it turns out that HCTs have been used in the past, and that there are alleged reasons why they wouldn’t help in the specific case of Covid.
At the very least, an HCT advocate using our recent global experience as motivation, ought to now address the specifics of how the Covid vaccines were developed, and provide some plausible detailed reasons as to why and how HCTs could have accelerated that process.
I can actually expand on this a little bit for you.
HCTs have been run in the past, but only for diseases where we had an efficacious treatment. The reason COVID HCTs would only have been run in the Phase 3 stage is because early in the pandemic, we had no proven-effective treatment.
This is a choice based on ethical and political reasoning, rather than science.
As Peter McCluskey points out, the choice not to begin an immediate mass-vaccination campaign with the untested mRNA vaccines we had on January 13th is likewise based on political and ethical reasoning, rather than a scientific choice. We now know, of course, that those vaccines were extremely effective. We’d have saved a colossal number of lives if we had. If we’d paused to run HCTs early on and then distributed the vaccines, we’d have still saved the vast bulk of lives that have been lost.
It’s only because our institutional leaders have made the ethical and political choices they have on our behalf that HCTs appear to be ineffective. We could have made different choices that were equally scientific, but based on different political and ethical reasoning. Continuing with our conventional ethical/political choice cost us over a million lives. Is it worth it? Medical ethicists disagree, none of the experts are talking about it enough, and it’s time for them to step it up and for The People to have a say.
OK, let’s talk about some of the issues that would arise in this scenario.
Taking an mRNA vaccine means becoming temporarily transgenic. mRNA for Covid spike protein is injected into your muscle cells, they produce it, and this stimulates antibody production.
In having trials, one is not only testing that the Covid mRNA vaccine is effective against Covid; one is also testing whether the vaccine itself has side effects.
Are you proposing to move straight to mass vaccination, without testing for vaccine side effects? But if not, how will making the trials HCTs, save time? HCTs are only different in the way that they test efficacy against the pathogen. When it comes to testing for side effects of the vaccine itself, don’t you have to wait just as long as you do, in a non-challenge trial?
Yes, I think there are basically three options:
Vaccinate with safety and efficacy data (conventional trials)
Vaccinate only with efficacy data (early HCTs)
Vaccinate with no data (immediate vaccination campaign on development of a vaccine)
I’m advocating that option 2 and option 3 be considered as realistic scientific, ethical, and political possibilities during the early stage of a deadly future pandemic akin to the one we face now.
Two of the questions I still have are:
What are the worst side effects of any vaccine that’s ever been tested?
How frequently do vaccines fail in conventional trials due to safety concerns?
This paper finds that 33% of tested vaccines have made it through all 3 trial phases. One of the worst consequences of a historically approved vaccine, used as an example by the AAMC of why we can’t rush a COVID-19 vaccine, was the polio vaccine where 120,000 doses contained live virus.
This caused ten deaths. Stack that up against over 1.6 million and counting.
Once again, I’m not strictly saying the AAMC is wrong. But they are begging the question. Comparing the historical base rate of deaths due to unsafe vaccines vs. the base rate of expected deaths due to COVID-19 is, on its face, a pretty reasonable and obvious approach to evaluating what we should do.
The AAMC glosses right over this issue. They must know it’s why many of their readers are looking up the article in the first place. So they’re choosing to ignore this line of thinking. I’m asking them to stop ignoring it.
If (2) and (3) were seriously considered, then I’d think you’d particularly want to avoid using only a single vaccine. From a civilizational point of view, the largest issue isn’t the expectation of the direct outcome—it’s that there’s a small chance you may have a bad outcome with very little variance across the population.
I’d be much less concerned about doing (2) or (3) with twenty different vaccines than with one.
Black Swan considerations definitely apply here. Although as far as I know, we haven’t had a vaccine that outright killed the majority of the people taking it, it’s not impossible. Maybe it’s just rare enough that we haven’t established a meaningful base rate. You’d also want to be concerned about the possibility of interactions from giving multiple vaccines to one person.
It might make sense to do something like vaccinating populations in the hardest-hit areas first, trying new vaccines as they become available, prioritizing the safest and most effective vaccines as data emerges.
If you want to make the case that with a different ethos, Covid-19 mortality might have been dramatically lower, it would help to exhibit a scenario in which this happens.
Much is being made of the fact that mRNA vaccines were first synthesized, very soon after the virus’s genetic sequence became available. But this just means that a particular molecular construct (a carrier for spike protein mRNA, I guess) could quickly be synthesized.
To go from that to mass vaccination, even if we skip trials for efficacy and safety, requires that you know enough about how the virus and the vaccine behave within the body, to have some idea of where and how to administer the vaccine to a patient. Also, there needs to be infrastructure to mass-produce the vaccine, and a way to distribute it.
Complications known to me, in the case of Covid mRNA vaccines, are that Covid’s interaction with the body and the immune system is intricate and was not immediately understood (this matters in deciding how to introduce a vaccine into the body), and that mRNA vaccines currently require ultracold refrigeration for their distribution, an infrastructure that doesn’t even exist in some countries.
Let’s see a concrete counterfactual scenario for rapid deployment of a Covid mRNA vaccine in 2020, that takes into account these two factors; and then we can start to estimate how many extra lives the HCT ethos might have saved.
I don’t think there’s a policy issue on which one billion people let alone two billion people read a book.
Even for an issue like climate change most people don’t read a book about it.
When it comes to the usefulness of a public debate it’s worth looking at two important enviromental issues. Mercury pollution is bad. CO2 pollution is bad.
Obama’s EPA managed to be very effective in fighting mercury pollution but unable to do anything about fighting CO2 pollution. A key difference between the two is that CO2 pollution was a heavily politized issue while nobody spoke about mercury pollution.
How do those thoughts influence your response to the broader argument?