Right now, about 7.8 billion people are intensely interested in the question of when the coronavirus problem will abate. Even those living in poor tropical countries with low rates of infection and a very young population, say Nigeria, are impacted by the huge drop in commodity prices.
While there is a great deal of promising research on vaccines, the process takes a long time. But what if there were a way to speed up the process of vaccine development through deregulation? In fact, there is such an option, although it is controversial.
When vaccines are tested, it is difficult to get statistically significant results if the infection rates are low. Thus a random group of 1000 volunteers might end up not being exposed to the virus, especially in this era of social distancing. For this reason, medical scientists often rely on “challenge studies” where participants are deliberately infected with a virus.
You can probably already see the problem—is it ethical to deliberately infect people with a dangerous virus?
On the other hand, this idea is not as wacky as it might seem:
1. We do challenge studies with flu vaccines. Yes, the coronavirus is more dangerous than the flu. But these studies would be done with young adults, for whom the risk is only modestly higher than for the flu, not dramatically higher as with a 70-year old. (I mean only slightly higher in absolute terms; I’m not sure how much higher the risk is in relative terms. But with ethical questions, it’s absolute distinctions that matter.)
2. A recent article in Nature suggests that challenge studies of Covid-19 vaccines might well be ethical, and indeed might even be beneficial for the participants themselves.
3. There are vaccines that might be available as soon as September, but also might be held back for a long period due to the inability to do challenge studies. Given how severely this pandemic is damaging the world (in terms of health, wealth and happiness), this potential roadblock is a really big deal.
I’d favor paying volunteers, but given what’s at stake it might be possible to find 1000 people to volunteer without pay. Lots of young people volunteer to fight in wars. We could give each of them a Presidential Medal after it’s over.
Some fear that providing financial incentives would “prey on the poor”:
I happen to be a bioethicist who doesn’t have huge objections to attracting study participants by offering financial incentives. But I think in this study, ensuring a high level of public trust is important, and I would advise researchers not to attract volunteers through high payments. This would have the advantage of making sure that the study doesn’t prey on the poor.
If that’s really such a problem then you could have income quotas, where the percentage of poor and non-poor participants is roughly in line with the US population. I actually think that sort of quota would be “preying on the poor”, not helping them; I’m just saying that none of the traditional objections actually hold water. If we really want to do this, we can find an ethical way of doing so.
The Nature article advocating a challenge study suggests the participants would be divided into two groups, one of which gets a placebo. But while I understand that’s standard procedure, I wonder if it is necessary in this case. Someone correct me if the following is wrong:
Don’t we already know from numerous natural experiments that a very large proportion of people exposed to the virus will become infected? And that’s in natural conditions such as passengers on the Diamond Princess or workers in a Korean call center. If the virus challenge were more direct and intentional, wouldn’t the infection rate be extremely high, so that the vaccine could be tested without a (unprotected) control group?
This is a highly contagious disease, indeed one that some scientists believe 50% of people are likely to contract at some point. Under those conditions, how dangerous is a challenge study giving a vaccine that has already provided strong hints of effectiveness (in previous studies) to a bunch of healthy young people?
Right now, these decisions involving the well being of the entire world are not being made by you or me or Xi Jinping or President Trump or the US Congress. They are not being made by free individuals making free choices. Rather, they are being made by a few medical ethicists. My hunch is that the public as a whole is more “utilitarian” than the average medical ethicist. Should a decision this important be made by the public? Shouldn’t they at least be consulted.
Notice how the media slides over this issue. Here’s a story from Business Insider:
“We may get enough data in a couple of months to see if the vaccine works, but if transmission levels drop, this could take up to six months,” the group said on Thursday.
No mention of the fact that medical ethicists might put the planet through 4 additional months of misery by banning challenge studies, and the public doesn’t even know that.
Of course I might be wrong, and I look forward to clarification in the comment section. I have an open mind. I request, however, that you read the Nature article, and don’t just assume I’m an economist who “just doesn’t understand these issues”. Nature is a prestigious outlet, which doesn’t typically publish papers written by crackpots.
It’s also possible that the roadblock is not medical ethics, but some other problem such as our dysfunctional tort law system. However, I was already skeptical of medical ethicists, due to their frequent support for laws banning kidney markets. These laws kill tens of thousands of Americans each year.
PS. I was thinking of entitling this post “There are no deontological ethicists in a foxhole.”
READER COMMENTS
Alan Goldhammer
Apr 28 2020 at 2:07pm
Those who are interested can sign up for such studies HERE. It is my opinion having worked tangentially in this field that challenge studies are not warranted and more dangerous than doing similar studies of flu vaccine. We do not know the full spectrum of the disease and there is no a priori way to select healthy individuals who are at minimal risk (though one could limit this to females under 30 with Type O positive blood as those markers seem to present the lowest risk based on observational data from a number of databases so far).
The animal studies with both the British and Chinese vaccine showed high levels of neutralizing antibodies along with protection when the animals were challenged. this has been the traditional way of analyzing vaccine potency and should work with humans in the absence of a challenge study. The bigger barrier to vaccine development has always been safety. Trials are large so they can pick up the 1 in 10,000 adverse reactions. This was bypassed in 1976 when a massive inoculation campaign was begun against the Swine flu. There were much higher levels of Guillain-Barre syndrome with this vaccine relative to the routine flu shot.
Scott Sumner
Apr 28 2020 at 2:36pm
Agree that large safety studies make sense due to the risks involved, but I don’t follow at all your arguments against challenge studies. What specifically is incorrect regarding the arguments I made in the post?
Alan Goldhammer
Apr 28 2020 at 3:44pm
If I were on an Institutional Review Board, I would oppose such challenge studies. I don’t think they are needed to show efficacy. I’ve read a lot of literature on this over the years and don’t think they materially have contributed much. We had something of a challenge study with the AIDS vaccine trials in Africa where people were not counseled about safe sex. None of the vaccines worked, and people thinking they might have been protected got AIDS; a tragic outcome.
I’ve read more epitope identification papers in the last three weeks and believe that science is sound at this point regarding the trialed vaccines. All that needs to be done is test the antibodies from the trial participants. this is very straight forward and does not put anyone at risk. SARS-CoV-2 is not as innocuous as common influenza.
I am sure that there will be a challenge study(s) set up. My age is disqualifying but were I 50 years younger, I doubt I would enroll. I would counsel my two children not to.
Scott Sumner
Apr 28 2020 at 4:24pm
These arguments don’t address any of my concerns. The AIDS example has no bearing on this. Nor does the fact that Covid-19 is slightly risker than flu for 20-year olds. That’s not relevant. The question is whether getting a solution 4 months sooner for a gigantic problem that is killing huge numbers of people is worth a tiny extra risk, taken freely by volunteers. (And if the Nature article is correct, perhaps no extra risk.) Maybe it isn’t, but you aren’t presenting any arguments that even come close to making me change my mind.
Alan Goldhammer
Apr 28 2020 at 8:16pm
I read the Eyl paper in detail. I’ve also been reading preprints for the last six weeks of clinical results from all over the world. We have a virus with a very complicated pathology that has sickened every single age category. There is ample data now about young people having strokes and other serious illnesses. There is an incomplete understanding across all age groups.
The purpose of informed consent is to describe the risks to those enrolling in the trial. According to the regulations governing informed consent, only risks may be described for the trial as the benefit is unknown other than it is a vaccine against COVID-19. At present one can only list all of the possible vaccine related adverse events (and remember this is a brand new vaccine vector of which little is known other than some very small trials several years ago against SARS) along with the possible effects brought on by a SARS-CoV-2 infection if the vaccine is not effective.
I am not opposed to a challenge trial if it is appropriately controlled. I only caution that it is not risk free for those who enter. I also do not think it will markedly shorten development. Finally, I think one of the Chinese vaccines will be the first one approved.
Thomas Hutcheson
Apr 29 2020 at 11:48am
“If I were on an Institutional Review Board, I would oppose such challenge studies. I don’t think they are needed to show efficacy.”
This is a utilitarian objection to HCT’s not an “ethical” one.
Dylan
Apr 28 2020 at 5:23pm
I don’t know enough about challenge studies to have a firm opinion one way or the other. I like the idea given our circumstances, but would want to get more informed input before advocating for it.
However, this part I feel informed enough to think that this part is a bad idea. The amount of info we have on transmission is pretty limited, and the populations in those natural experiments are going to be quite different from what we would see with a group of volunteers.
Derek Lowe has a post from yesterday talking about two studies that were done on two different IL-6 agents as a treatment option, the mechanism of action is very similar for each, so we would have expected similar results, but instead we’re seeing different signals from the two trials (one seems to help, the other one looked at first like it hurt, but more likely had no effect). The whole post is good in laying out some of the problems with drug discovery, but this is the part that is relevant to your post.
Sure, the bolded part talks about small, uncontrolled trials. But, when you’re looking at challenge studies for a potential vaccine, they’re all going to be small. In some cases you can get around having a control arm, and still get useful data, but that’s not something that will speed up the process, it will likely make it longer.
Scott Sumner
Apr 28 2020 at 7:39pm
I see no reason for the coronavirus challenge study to be “small”. The government should be willing to throw billions of dollars in subsidies into the project. Second, the fact that drug discovery studies are often underpowered is not really relevant to a vaccine challenge study, where you hope for and expect a high level of success.
Dylan
Apr 28 2020 at 9:47pm
I think you misunderstood me, I’m not talking about the number of patients, I’m talking about the diversity of the patient population. With a challenge study, you’re going to be getting volunteers that are by design different than the population as a whole. And, we have some idea that the virus behaves differently among different age cohorts, not only in the seriousness of the disease, but other aspects as well. For example, younger people that have recovered from the virus are showing lower levels of antibodies, sometimes the antibodies are barely present. It’s not clear if that is enough to grant any kind of immunity at all going forward, even if in general people that have had the disease are immune to getting it again for at least some period of time. There’s also worries about people that have had a mild case, actually being more susceptible to the disease the second time around, making it more deadly. Something that we’ve seen with other viruses in the past.
If you’re looking at only a subgroup of the population in your study, one that you know has a different reaction to the virus, but one where you don’t have nearly enough data on about the extent of the differences, than any study that doesn’t have a control arm is going to be “small.”
Rajat
Apr 29 2020 at 12:39am
I had some similar thoughts. One response could be that if we’re allowing young people to choose to take a small risk, why not relax the age requirement and allow older people to choose to take a larger risk? I don’t see a major distinction from a utilitarian perspective. After all, older people face a higher risk from the virus, but they also have fewer years to lose and may value them less anyway. Maybe someone could approach Ezekiel Emanuel?
Scott Sumner
Apr 29 2020 at 1:51am
That’s right. There’s risk with the vaccine, but there’s also risk for the elderly in not taking the vaccine and getting Covid-19.
Dylan
Apr 29 2020 at 12:17pm
It’s not so much the safety risk from the vaccine itself that is the worry in a challenge study (although Alan points out that safety is very much a concern with vaccines that are going to be given to a larger population), but the risk is that you are intentionally exposing a population to the virus, and the chances are the vaccine won’t work. My understanding is that the vaccines that are the furthest along are using technological approaches that have been tried multiple times in other infectious diseases, but so far have not been successful. We’re going to have to get very lucky to have these work. Intentionally exposing healthy volunteers that are in the age group that is at the lowest overall risk seems reasonable, higher risk age groups less so.
In general, I’m OK with letting volunteers make the choice for themselves, as long as there is adequate disclosure of the risks, but we shouldn’t expect to get an accurate sample of the population when we ask for volunteers. Which is why you want a control arm.
Mark Z
Apr 28 2020 at 8:44pm
“This would have the advantage of making sure that the study doesn’t prey on the poor.”
Oy vey. I find this argument extremely frustrating, and I’ve heard it a lot from bioethicists and the scientists who follow their thinking. I’ve heard it asked on numerous occasions, “at what point does paying someone a certain amount of money to participate in a trial become coercive.” Taking for granted that paying a person enough to get them to do something is inherently ‘coercive.’ That makes no sense though. If it’s coercive because it will induce uninformed people to do something against their interest because they underestimate the risk or undervalue their lives, payment makes no difference: they’ll still underestimate the risk or undervalue their lives if they agree to do it for free. There’s no reason people who do this for altruistic or other non-pecuniary motives won’t suffer from the same cognitive biases or lack of information. If it’s exploitative to pay people to do it, then it’s exploitative to let volunteers do it for free.
And I am certain that some of the ethicists would, without appreciating the contradiction, object to income quota because the study would disproportionately benefit rich people or would bias the outcome in favor of a vaccine that primarily benefits demographic groups correlated with wealth (in theory, vaccine efficacy could vary with genetic factors associated with ethnicity, though I don’t know how often this actually happens). I’ve heard this reason given by scientists (who’s ethics views tend to be largely determined by the received wisdom of upstream bioethicists) for flat out opposing the use of CRISPR technology ever: because it will, at first, disproportionately benefit rich people.
Maintstream bioethics, as a discipline (I would say it often more resembles a religion), seems intent on becoming one of the biggest unnecessary impediments to medical progress, and it’s unfortunate we’re starting to see that with this pandemic.
Phil H
Apr 29 2020 at 3:54am
“at what point does paying someone a certain amount of money to participate in a trial become coercive.”
There is a very simple answer to this, and it’s something that anyone who hangs around on an economics website should readily appreciate: a price is both a cost and a signal.
In this case, the signal says “this is an approved economic activity,” which according to the lived experience of every single American (and Brit) means that steps have been taken to make it as safe as possible. You can in concert provide a “warning” about potential risks, but that warning cannot ultimately undo the message sent by the attaching of a price to trial participation. At best, trial participants will be left with mixed messages.
More generally, I think Scott’s completely wrong on this. There is no evidence at all (beyond some striking but ultimately non-data anecdotes) that ethics rules are actually slowing medical progress on anything, including covid. This is a problem that exists only in the minds of libertarians.
Scott Sumner
Apr 29 2020 at 7:12pm
I linked to a Nature study that provides evidence. You may disagree with the study, but simply waving your hand and saying “no evidence” is a pretty weak response.
Are you also going to argue that there’s no evidence that medical ethicists contribute to the kidney shortage?
Phil H
Apr 29 2020 at 9:34pm
Scott, the Nature article says nothing like “medical ethicists are preventing the fast development of a vaccine.” It says the exact opposite! It is literally written by a bioethicist who supports the idea of a challenge trial. It’s published in one of the world’s two most influential science journals.
Kidneys – I’m far from convinced that “medical ethicists” are a powerful enough group to sway the argument either way. To the extent that the non-existence of a kidney market is due to ethical concerns (and I’m not yet convinced of this), I suspect they are “folk ethics” in the minds of legislators.
P Burgos
Apr 28 2020 at 10:59pm
Are they doing challenge studies in China? I haven’t heard anything about it, and I doubt that the ethics of a challenge study mean much to the CCPs leadership.
I would suspect that the case that challenge studies speed up vaccine development is a bit overstated. My guess is that Mr. Goldhammer is right, that the real bottleneck is testing for safety, not testing for efficacy, and that the animal models or in vitro studies are largely good enough to show efficacy.
Scott Sumner
Apr 29 2020 at 1:53am
Actually, the vaccine being developed in Oxford has already passed the safety test, so I don’t think that’s the issue.
Alan Goldhammer
Apr 29 2020 at 7:55am
Scott – I hope you are not inferring the Oxford vaccine is safe; we do not know that as it has only passed a preliminary safety test. The vaccine and pharmaceutical industry is rife with lots of example of drugs passing Phase 1 safety tests and causing lots of adverse events when given to the broad population. Some have to be withdrawn for the market or their use restricted.
Vaccines present a special problem as they are given to healthy people and in many cases to infants and children. You do NOT want a vaccine given to those people if safety issues have not been fully addressed. This is the reason for large vaccine trials.
It may be for a pandemic vaccine, society will tolerate greater safety uncertainty and perhaps that is the approach that needs to be taken. In such a case, everyone has to be aware of the safety uncertainty. The government may want to set up a vaccine compensation fund the same way this was addressed for childhood immunizations.
Scott Sumner
Apr 29 2020 at 7:13pm
Again, I’m all for “large” trials.
Dylan
Apr 29 2020 at 8:06am
Unfortunately, I don’t think this is true regarding efficacy and animal models. I don’t have much knowledge of vaccine development, but I can certainly tell you that animal models for most therapeutics are close to useless in terms of efficacy. They’re better in safety, at least giving you a pretty good indication that the drug candidate isn’t going to kill the person straight away.
The most advanced vaccine is entering Phase II trials in China now, and this is to get efficacy data, although I’ve not seen enough information on the design of the trial. Apparently, for Ph I, they made everyone stay in a central facility, but for Ph II they will be tested at home over the course of 6 months. Certainly doesn’t sound like a challenge trial.
Lorenzo from Oz
Apr 28 2020 at 11:42pm
Let’s apply the Australian principle of social analysis (in the race of life, back self-interest, it is the only horse that’s trying). Do medical ethicists get more significance by having veto power? Does that not give them an incentive to wield that veto power? At the margin, is that choice going to be driven by moral considerations, or significance-protecting considerations? (Remembering that we are VERY good at morally self-deluding ourselves.)
Scott Sumner
Apr 29 2020 at 1:53am
Good point.
john hare
Apr 29 2020 at 5:33am
I may be missing the point in any of several directions as I see the argument as a simple matter of numbers and ethics.
If 20,000 people a month are dying from this virus that could be saved by a vaccine, then 80,000 people could be saved if the vaccine is in use four months earlier. The relevant question being, “how many corners can be cut and how much risk is justified to save those four months?”
If 10,000 people are put at a 1% chance of dying in the trial if the vaccine being tested doesn’t work, then there might be as many as 100 people killed for the chance of saving 80,000. 100 dead if the vaccine doesn’t work down to 0 if it does. The raw numbers seem simple to me even if the ethics are not.
Mark Bahner
Apr 29 2020 at 9:10pm
I would be shocked if the opportunity to be a participant in a challenge trial was given to all the members of the NATO armed forces, if 10,000 volunteers could not be found in under 24 hours.
Swimmy
May 1 2020 at 3:48pm
Placebo controls are probably still needed, for multiple reasons.
You want to know not only whether a vaccine prevents COVID completely, but also if it makes the infection less severe. Hard to compare against the general population, which is not randomly infected.
You also want to know whether it shortens duration. Tricky to compare against the general population, again because they’re not randomly infected.
You want to control the dose that you infect people with. Different exposures to the virus mean different severity of infection–see Hanson’s posts on variolation. You can give all your study participants the same ‘dose’ of the virus.
You want to rule out the effect of other mitigating treatments that people in the general public might be using (e.g. zinc lozenges).
I’m 100% in favor of human challenge studies and my partner signed up for it. But I think you lose too much information when you give up the control group. If a vaccine makes infection less severe but doesn’t prevent it, I still want it.
Comments are closed.