Again it all seems obvious until you design the experiment. “Just expose people to the virus” does a lot of work for you but it by no means an experimental design. Please interview a scientist on how they would choose to do this experiment and your argument will be stronger. Do you put the test subject in a room with sick people? Inject it? Gas people with it? How large is the exposure? When you do it the standard way, people are exposed to “normal” levels of the virus not some standard that must first be scientifically established. Not all viral infections are the same, quantities and methods matter.
I’m all for challenge studies to get a quick read on efficacy but I don’t see that doing anything about Phase 3 studies. Vaccine Phase 3 studies are not the size they are simply because of efficacy. It’s because you need large trials to identify safety signals that are too rare to pop up in a small Phase 1 trial. Covid is bad but most people haven’t had it and the vast majority of people survive. The vaccine is going to go into *everyone on the planet* in an ideal world. The risk/benefit ratio is hugely critical for a scenario like this, and it’s very challenging to track adverse events in a non-controlled environment. To avoid Ph3 studies you would need a new way to accurately track safety in the general public.
At first I recoiled, but you convinced me on the merits. We have an all volunteer army risking their lives to protect the rest of us and that doesn't seem unethical. At sporting events we could cheer volunteers who risked their lives in challenge trials and offer our gratitude and collective sorrow at funerals for those given placebos. Seems odd, but better than the alternative of greater death.
My question: do challenge trials exist in other countries that emphasize the collective over the individual? I am sure an apples-to-apples comparison is challenging considering situations like the suspect trials of Russia’s Sputnik vaccine.
Two limitations of the challenge model that challenge trial proponents rarely if ever address.
1. What is needed is a vaccine that prevents infection from real-world exposures to the virus. A challenge trial exposes patients to the virus in a different way, everyone getting a set amount via the same type of exposure. So a challenge trial should be great for clinical proof of concept, measured efficacy in a challenge trial may differ from real-world effectiveness of the same vaccine. Expose people to not enough virus and you may overestimate real-world effectiveness; epose them to too much and you may understimate vaccine potential and even reject an effective vaccine.
2. Challenge trials would be smaller and faster, which means conserably less safety data.
Both Moderna and Pfizer vaccines essentially charged right into Phase 3 without the typically slower process of first showing some efficacy in Phase 2, helped by the government's guaranteed purchase. Either or both of these vaccines could have failed in Phase 3, as many drugs do. Challenge trials would offer the advantage of weeding out ineffective drugs quickly.
I have nothing to add here; I just want to know the most plausible way to make challenge trials happen. I think the best strategy might be persuading the government of Russia or China to do them.
Sigh. No. The main ethical reason for not doing challenge trials is that COVID-19 is a new disease whose long term effects are unknown. Back in March or April, there was essentially no effective treatment; now at least, hospitals have figured out how to reduce the fatality rate somewhat (assuming they're not overrun with patients). But this is not a disease you want to have!
Just a quick thought (PhD epidemiologist who studies ID): covid-19 is rather an unusually attractive candidate for challenge trials. You can find me musing about the use of challenge trials if you look closely enough. But it is a disease family for which vaccines had been developed (in animals but that's not nothing), for which there was a lot of research on vaccine targets because of SARS-1, and which had a relatively low fatality rate among young people.
Replace it with either smallpox or HIV and the arguments get a lot trickier.
From a cost benefit standpoint you also have to consider the manufacturing time to produce vaccines at a mass level. As far as I can tell, the longer period for a traditional phase three trial did not delay the manufacturing of either of the available vaccines. It's clear that approving either in August would not have delivered one hundred million shots in arms by the end of the year.
There is a whole separate problem of whether Operation Warp Speed was actually aggressive enough in ramping up manufacturing capacity. And the clear failure to prepare a robust enough delivery system.
Speaking as a fellow philosophy major (and one who's generally skeptical of a lot of what passes for bioethics), I'm not sure this article really engages with the ethical worry posed by challenge trials.
To be scientifically rigorous, as you acknowledge, a challenge trial would have to deliberately expose vulnerable, high-risk individuals to a virus with a substantial chance of killing them. That's different in kind from simply failing to use all means necessary to keep such people from getting infected (we never do everything possible to keep people from being infected, sometimes because of ethical constraints and sometimes because the measures would be too costly). Or to make the same point another way, people in the placebo arm of a normal vaccine trial are no worse off than non-participants in the trial; people in the placebo arm of a challenge vaccine trial will--reasonably often!--end up far worse off than had they ignored the invitation and chosen not to volunteer.
The response to this is, well, they consent to self-sacrifice. But we get a lot more dubious about consent when it comes to serious self-harm (see: hard drugs, dueling). It's really not like the medical personnel case, where there is rightly a huge amount of investment in trying to *keep* such personnel from being exposed to the virus--exactly what you can't do in a challenge trial.
I don't know the right answer to the main question here (sc. "Challenge Trials: yea or nay?"), but I have a comment about the dynamics of the debate.
I suspect that people react to the choice between challenge trials and standard Phase 3 trials as though they are facing a choice between killing and letting die.
Some people think that distinction (i.e. causing harm vs letting harms occur) is ethically irrelevant, and indeed a source of ethical confusion. (This group is not perfectly coextensive with consequentialists, but fairly close).
Other people think that it is a distinction of fundamental ethical importance, which changes actions from permissible to impermissible: there are some things that one may not do, but may allow to happen. (This group is not perfectly coextensive with deontologists, but fairly close).
I believe the research on popular belief among non-philosophers shows quite a lot of support, more than majority, for the ethical importance of the killing/letting die distinction, and the causing/allowing distinction in general.
So you start your campaign of persuasion with some hard work ahead of you. It runs counter, or at least seems to run counter, to widespread and deeply held ethical intuitions.
There are many questions about how public health officials evaluated costs and benefits to come to the decisions they mad. Why no challenge trials? is just one:
. Why no mass testing of asymptomatic people?
. Why no compensated self-isolation for asymptomatic people who test positive?
. Why the delay in approving cheap, fast screening tests?
. Why were recommendation of different kinds of social distancing, mask wearing, ventilation, traffic flow in different kinds of venues not tested to provide feedback on best/least cost practice?
. Why did officials not say for the beginning that recommendations would change as they learned more (not wearing/wearing masks, importance of hand washing/scrubbing surfaces)?
. Why the virtual silence on the point that social distancing is as much to protect others as to protect oneself. Why "Stay safe" instead of "Be safe"?
. Why was messaging not based on explicit, evolving models with recognition of how models were changing.
. If there are good answers to these questions, why have officials not supplied them?
The general impression is of total improvisation, as if the very idea of a pandemic was totally novel concept in public health.
Challenge trials are only more ethical in a very academic sense, which is why I think you're drawn to the topic. Obviously, killing people in an experiment vs people dying in an experiment are two very different things. And it's easier to talk about in the context of a low fatality disease like Covid, but what if the disease in question is overwhelmingly fatal? I guess you could get comfortable with killing people intentionally from a strictly utilitarian perspective, but I don't think that's where society's ethical code is at this point.
I'm a microbiologist by trade, and I think that it was a huge mistake to not to human challenge trials. Among other things, it's much easier to determine whether the vaccine induces sterilizing immunity, ie if people are protected from getting infected. And if they are infected, do they have infectious virus? It's also an efficient way of identifying which vaccine candidates are likely to be more or less effective. Still, human challenge trials are not enough and we'd still need phase 3 trials to detect rare events. The high fatality rate for older people makes human challenge studies that include people over 60 a harder question. (Then again, if a vaccine is >95% effective for people 18-55, it's almost certainly going to be pretty effective for people 65+.) But there are some challenges for human challenge trials:
We need to optimize infection: what is the inoculation dose, in other words, how many "live" viruses do we use? How do we infect them? Aerosols, droplets? Do we expose them to a high dose over a short period of time or a lower dose over a longer period of time? The world of immunology is full of infection models that are very reliable, ie the animal is reliably infected, but the infection method is somewhat different from how natural infection occurs, so it is only somewhat applicable to real-world infection.
This means that we'd have to spend some time optimizing the protocols before testing any vaccines. It's going to take quite a few volunteers.
If you run into trouble optimizing human challenge trials, phase 3 trials may end up being faster. But with a pandemic like this, you need to throw the kitchen sink at it.
I do think it's important to make sure that the volunteers are not pressured to take part and truly understand what they're doing. It's also important to remember that some subjects might die, and so you have to prepare the public for it.
I agree that we should do challenge trials, but this seems to almost entirely gloss over the actual hurdles to doing them:
1. Regulatory uncertainty. The FDA website says that companies need to discuss human challenge trials with the FDA before they are conducted. If that process is slow, then any potential time savings are wasted.
2. Public reaction. I think that the challenge trials are ethical, but how will the public react if someone died in a Pfizer challenge trial? Does Pfizer want to risk their reputation on that?
Another way of saying this, if your phase 3 design means you know people are going to get infected, just over time, because they took the placebo, isn't it just more of a "passive aggressive challenge trial"?
One challenges via natural infection in society at large, the other does so under supervised medical conditions. If the difference is challenge can be faster, especially for things with an IFR under, say, 2-3% where you are using what appears to be a pretty safe technology in mRNA... it seems unethical to *not* do a challenge trial.
Again it all seems obvious until you design the experiment. “Just expose people to the virus” does a lot of work for you but it by no means an experimental design. Please interview a scientist on how they would choose to do this experiment and your argument will be stronger. Do you put the test subject in a room with sick people? Inject it? Gas people with it? How large is the exposure? When you do it the standard way, people are exposed to “normal” levels of the virus not some standard that must first be scientifically established. Not all viral infections are the same, quantities and methods matter.
I’m all for challenge studies to get a quick read on efficacy but I don’t see that doing anything about Phase 3 studies. Vaccine Phase 3 studies are not the size they are simply because of efficacy. It’s because you need large trials to identify safety signals that are too rare to pop up in a small Phase 1 trial. Covid is bad but most people haven’t had it and the vast majority of people survive. The vaccine is going to go into *everyone on the planet* in an ideal world. The risk/benefit ratio is hugely critical for a scenario like this, and it’s very challenging to track adverse events in a non-controlled environment. To avoid Ph3 studies you would need a new way to accurately track safety in the general public.
At first I recoiled, but you convinced me on the merits. We have an all volunteer army risking their lives to protect the rest of us and that doesn't seem unethical. At sporting events we could cheer volunteers who risked their lives in challenge trials and offer our gratitude and collective sorrow at funerals for those given placebos. Seems odd, but better than the alternative of greater death.
It’s the trolley problem!
My question: do challenge trials exist in other countries that emphasize the collective over the individual? I am sure an apples-to-apples comparison is challenging considering situations like the suspect trials of Russia’s Sputnik vaccine.
Two limitations of the challenge model that challenge trial proponents rarely if ever address.
1. What is needed is a vaccine that prevents infection from real-world exposures to the virus. A challenge trial exposes patients to the virus in a different way, everyone getting a set amount via the same type of exposure. So a challenge trial should be great for clinical proof of concept, measured efficacy in a challenge trial may differ from real-world effectiveness of the same vaccine. Expose people to not enough virus and you may overestimate real-world effectiveness; epose them to too much and you may understimate vaccine potential and even reject an effective vaccine.
2. Challenge trials would be smaller and faster, which means conserably less safety data.
Both Moderna and Pfizer vaccines essentially charged right into Phase 3 without the typically slower process of first showing some efficacy in Phase 2, helped by the government's guaranteed purchase. Either or both of these vaccines could have failed in Phase 3, as many drugs do. Challenge trials would offer the advantage of weeding out ineffective drugs quickly.
I have nothing to add here; I just want to know the most plausible way to make challenge trials happen. I think the best strategy might be persuading the government of Russia or China to do them.
Sigh. No. The main ethical reason for not doing challenge trials is that COVID-19 is a new disease whose long term effects are unknown. Back in March or April, there was essentially no effective treatment; now at least, hospitals have figured out how to reduce the fatality rate somewhat (assuming they're not overrun with patients). But this is not a disease you want to have!
Rather than rant for several paragraphs, I'll defer to this Derek Lowe post, who has laid it out far more clearly than I ever could: https://blogs.sciencemag.org/pipeline/archives/2020/07/02/challenge-testing
Just a quick thought (PhD epidemiologist who studies ID): covid-19 is rather an unusually attractive candidate for challenge trials. You can find me musing about the use of challenge trials if you look closely enough. But it is a disease family for which vaccines had been developed (in animals but that's not nothing), for which there was a lot of research on vaccine targets because of SARS-1, and which had a relatively low fatality rate among young people.
Replace it with either smallpox or HIV and the arguments get a lot trickier.
From a cost benefit standpoint you also have to consider the manufacturing time to produce vaccines at a mass level. As far as I can tell, the longer period for a traditional phase three trial did not delay the manufacturing of either of the available vaccines. It's clear that approving either in August would not have delivered one hundred million shots in arms by the end of the year.
There is a whole separate problem of whether Operation Warp Speed was actually aggressive enough in ramping up manufacturing capacity. And the clear failure to prepare a robust enough delivery system.
Speaking as a fellow philosophy major (and one who's generally skeptical of a lot of what passes for bioethics), I'm not sure this article really engages with the ethical worry posed by challenge trials.
To be scientifically rigorous, as you acknowledge, a challenge trial would have to deliberately expose vulnerable, high-risk individuals to a virus with a substantial chance of killing them. That's different in kind from simply failing to use all means necessary to keep such people from getting infected (we never do everything possible to keep people from being infected, sometimes because of ethical constraints and sometimes because the measures would be too costly). Or to make the same point another way, people in the placebo arm of a normal vaccine trial are no worse off than non-participants in the trial; people in the placebo arm of a challenge vaccine trial will--reasonably often!--end up far worse off than had they ignored the invitation and chosen not to volunteer.
The response to this is, well, they consent to self-sacrifice. But we get a lot more dubious about consent when it comes to serious self-harm (see: hard drugs, dueling). It's really not like the medical personnel case, where there is rightly a huge amount of investment in trying to *keep* such personnel from being exposed to the virus--exactly what you can't do in a challenge trial.
I don't know the right answer to the main question here (sc. "Challenge Trials: yea or nay?"), but I have a comment about the dynamics of the debate.
I suspect that people react to the choice between challenge trials and standard Phase 3 trials as though they are facing a choice between killing and letting die.
Some people think that distinction (i.e. causing harm vs letting harms occur) is ethically irrelevant, and indeed a source of ethical confusion. (This group is not perfectly coextensive with consequentialists, but fairly close).
Other people think that it is a distinction of fundamental ethical importance, which changes actions from permissible to impermissible: there are some things that one may not do, but may allow to happen. (This group is not perfectly coextensive with deontologists, but fairly close).
I believe the research on popular belief among non-philosophers shows quite a lot of support, more than majority, for the ethical importance of the killing/letting die distinction, and the causing/allowing distinction in general.
So you start your campaign of persuasion with some hard work ahead of you. It runs counter, or at least seems to run counter, to widespread and deeply held ethical intuitions.
There are many questions about how public health officials evaluated costs and benefits to come to the decisions they mad. Why no challenge trials? is just one:
. Why no mass testing of asymptomatic people?
. Why no compensated self-isolation for asymptomatic people who test positive?
. Why the delay in approving cheap, fast screening tests?
. Why were recommendation of different kinds of social distancing, mask wearing, ventilation, traffic flow in different kinds of venues not tested to provide feedback on best/least cost practice?
. Why did officials not say for the beginning that recommendations would change as they learned more (not wearing/wearing masks, importance of hand washing/scrubbing surfaces)?
. Why the virtual silence on the point that social distancing is as much to protect others as to protect oneself. Why "Stay safe" instead of "Be safe"?
. Why was messaging not based on explicit, evolving models with recognition of how models were changing.
. If there are good answers to these questions, why have officials not supplied them?
The general impression is of total improvisation, as if the very idea of a pandemic was totally novel concept in public health.
.
Challenge trials are only more ethical in a very academic sense, which is why I think you're drawn to the topic. Obviously, killing people in an experiment vs people dying in an experiment are two very different things. And it's easier to talk about in the context of a low fatality disease like Covid, but what if the disease in question is overwhelmingly fatal? I guess you could get comfortable with killing people intentionally from a strictly utilitarian perspective, but I don't think that's where society's ethical code is at this point.
I'm a microbiologist by trade, and I think that it was a huge mistake to not to human challenge trials. Among other things, it's much easier to determine whether the vaccine induces sterilizing immunity, ie if people are protected from getting infected. And if they are infected, do they have infectious virus? It's also an efficient way of identifying which vaccine candidates are likely to be more or less effective. Still, human challenge trials are not enough and we'd still need phase 3 trials to detect rare events. The high fatality rate for older people makes human challenge studies that include people over 60 a harder question. (Then again, if a vaccine is >95% effective for people 18-55, it's almost certainly going to be pretty effective for people 65+.) But there are some challenges for human challenge trials:
We need to optimize infection: what is the inoculation dose, in other words, how many "live" viruses do we use? How do we infect them? Aerosols, droplets? Do we expose them to a high dose over a short period of time or a lower dose over a longer period of time? The world of immunology is full of infection models that are very reliable, ie the animal is reliably infected, but the infection method is somewhat different from how natural infection occurs, so it is only somewhat applicable to real-world infection.
This means that we'd have to spend some time optimizing the protocols before testing any vaccines. It's going to take quite a few volunteers.
If you run into trouble optimizing human challenge trials, phase 3 trials may end up being faster. But with a pandemic like this, you need to throw the kitchen sink at it.
I do think it's important to make sure that the volunteers are not pressured to take part and truly understand what they're doing. It's also important to remember that some subjects might die, and so you have to prepare the public for it.
I agree that we should do challenge trials, but this seems to almost entirely gloss over the actual hurdles to doing them:
1. Regulatory uncertainty. The FDA website says that companies need to discuss human challenge trials with the FDA before they are conducted. If that process is slow, then any potential time savings are wasted.
2. Public reaction. I think that the challenge trials are ethical, but how will the public react if someone died in a Pfizer challenge trial? Does Pfizer want to risk their reputation on that?
Another way of saying this, if your phase 3 design means you know people are going to get infected, just over time, because they took the placebo, isn't it just more of a "passive aggressive challenge trial"?
One challenges via natural infection in society at large, the other does so under supervised medical conditions. If the difference is challenge can be faster, especially for things with an IFR under, say, 2-3% where you are using what appears to be a pretty safe technology in mRNA... it seems unethical to *not* do a challenge trial.