Challenge Trials for COVID-19 Trials Beginning

Okay. Perhaps I missed what you were saying.

Rereading the letter, this is the core request they are making;

If we are going to do challenge trials, and we likely are, it seems like these are things governments should probably be doing at this time.

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The Tuskegee study lingers large in in the field of bioethics:

The challenge study here is very different from infecting people with syphilis without their knowledge or consent, but the Tuskegee study still affects how many scientists will view this challenge study. Purposefully infecting people with a virulent virus sets off a lot of alarm bells.

I do think your position holds a lot of merit, don’t get me wrong. We just have to be careful about crossing this line, and do it the right way if the study goes forward.

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I did not know that. $10,000 is not volunteering, it is a high risk job. Given the obvious social-economic disparity in how people would respond to such an inducement, I do not believe this can be ethically managed. My free enterprise bent has limits.

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I don’t think they were infected without their knowledge by the researchers. They were just diagnosed, not informed of the diagnosis, and not treated. Technically, this may not be a Challenge Study.

It’s okay. I think you just wanted to discuss different topics than the ones I do. There are legitimate hard questions about the practical aspects of the proposal (will it save time? will we learn what we need to learn?), and about the ethical details (will there be true informed consent? will there be disparities in risk distribution?). My view is these questions are not unique to the proposal. This certainly doesn’t mean they aren’t important question–they are huge. They just aren’t specifically about the proposal to do challenge trials of COVID-19 vaccines.

Then there are the big overarching ethical questions. The main one, to me, is whether we as humans should breach an ethical barrier. Specifically: should we undertake a challenge study using a pathogen, knowing that we do not have a rescue therapy that can save a participant from serious illness. Rescue therapy is the “backstop” that (as I understand it) provides ethical grounding for challenge studies. We don’t have that right now, and so participants would accept the risk of serious harm including death.

That’s the ethical question that I find so important. I think that some (I believe this is @T_aquaticus position) would judge such a study to be ethically unacceptable on principle. I respect that position and in fact I haven’t ruled it out myself. But I have presented a challenge that has been poorly addressed (if it has been addressed at all) in this conversation. This is the challenge of living kidney donation. The protestations so far are so lame that I lost my patience and suggested that you don’t even want to discuss the topic. I’d be glad to be wrong, but spare me quick unconsidered responses that ignore the challenge. I don’t see any ethical difference between a surgeon removing someone’s kidney and a doctor giving a SARS-CoV-2 dose to a healthy volunteer.

I was there when several serious smart people discussed this (the permanent loss of a loved one’s kidney, in abdominal surgery under general anesthesia). I know what the important questions are. And I don’t have patience with dodges.

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This question, I think, I would answer that this is an unusual situation, and for this reason we can cross this barrier (with all the ethical guardrails already discussed), BUT that barrier should go right back afterwards.

The ethical computation for more normal situations is different. Perhaps this might pave the way to rework these more normal cases too, but we should consider them separately. It will help to temporarily change rules if we are assured that the rule change really is temporary.

Do you agree with this?

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I would very strongly agree with this.

I think I would only add something that you surely implied, which is that we clearly explain the rationale, in the form of an ethical framework (a “calculation” to use an icky word for this) that is explicit about the risks and how they were weighed against the benefits.

This is how the process worked in the case of the new living kidney donation program. It was understood that the removal of a kidney from a healthy person required extraordinary ethical defense, by showing that the benefit was substantial and that the donor was making a fully informed decision and giving meaningful consent. In our case, my loved one was required to undergo psych evaluation. (!)

My point being: if we decide to do this, we explain why we did it and why it was such an extraordinary choice to make.

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I certainly agree that an ethical rationale is required. However, given the circumstances and the rush, can we really trust any ethical rationale here? By definition, it won’t have stood the test of time. It is entirely possible that in retrospect we’ll see the rationale as deficient, but it still might make sense to have crossed the barrier at the time.

In this case, more than the precise ethical rationale, I suspect that an ethical process is more important. There is a distinction between the two, because we can judge objectively if an ethical process is followed, consistent with ethical principles that have been well settled for decades.

It will take far longer time to judge the ethical rationale. Even if the rationale presented in our moment is weak, doesn’t mean there isn’t a stronger rationale available. Even if the rationale seems strong now, doesn’t mean it will continue to seem that way in time.

Do you see that distinction between process and rationale?

That there is risk is, in and of itself, does not automatically decide the issue in my mind. While the public generally takes risk assessment to be the chance something might happen, in engineering, risk is really the odds something will happen. When speed limits are set on a highway, the number of lives that will be lost over time given that limit are a near certainty. Acceptable industrial safety thresholds actually reference what is acceptable exposure to risk from driving and flying. People seem to confound the care they take to minimize personal risk with reducing the social incidence of risk, but in reality, there has always been a trade off between the public purse, employment, freedom of recreation, convenience, and risk. All this to say, is there a price on a human life? - Oh you bet, and that price has enthusiastic public support.

So here too is an assessment of personal risk vs. public interest. There is no pure high road. It is a fallen world. Risk can only be distributed as fairly and informed as possible.

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This is a poor argument IMO. It seems the argument seeks to erase our judgment, by pointing at… our previous judgment. Such an argument would be considered morally repugnant in other contexts, namely any context in which we seek to reform and change.

Of course. I just don’t see you making a valid argument that helps us in the current challenge. “Be cautious” is great advice almost everywhere and almost all the time, but “defend the status quo” really isn’t. I’m baffled that the death toll from a non-challenge trial, in which the placebo group is wandering in the world without vaccination and in which higher-risk populations are included, all without the rescue therapy I was just writing about, doesn’t make a big impression. And I guess the living kidney donors just don’t make an impression at all. I’m struggling to understand that.

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As has been pointed out, standard trials should include older adults (see here for example). In practice, they may not, of course, but they should. If they do, then that complicates the ethical question for me, since now you also have to weigh the risks against the benefit of faster and better controlled results that may not be applicable to the population most in need of protection. You would like to know as early as possible if a vaccine has an unacceptably high rate of adverse reactions in those over 60, say.

This might argue in favor of a simultaneous two-pronged approach, one a challenge trial in healthy younger people and one a conventional trial in a broader range of subjects. If the first prong fails, then the vaccine fails and the second prong can be aborted. If it succeeds, the second prong can continue while manufacturing starts.

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Yes, this is discussed extensively in various pieces on the topic over the past month or so. What I am struggling to understand is the apparent lack of ethical concern about a standard trial that includes older people, who are at far higher risk. As I just asked in my previous post, where will I find comments on the dead participants in that trial–the placebo participants who are infected during this huge, slow, trial? I’m genuinely curious about why a challenge trial on young people is more worrying than that. Are some corpses different from others?

That means some of those people die.

I think this is being proposed. I think the important background includes a desire to be prepared for the possibility that we’ll need many trials. There are something like a hundred vaccines under development.

Would you like to be the first person in this thread to discuss living kidney donors and how the ethics of that process relate to challenge trials?

https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(20)30438-2/fulltext

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The difference is that in a standard trial, we are not intentionally infecting these older people.

In the control arm of a standard trial, some of the older patients will get infected, but they would have been infected any ways, and they will be treated with standard of care. So the ethical concerns here are substantially reduced. The older patients in the control arm are not facing any new risks, and in fact they might be getting better health care than they might otherwise receive.

In contrast, all the patients in a Challenge Trial are exposed more than they would have been exposed on their own. That introduces risk that they would not already have face.

Now, if there starts to be strong evidence accruing that the vaccine helps, then keeping older patients in the control arm (and not giving them the vaccine) raises a different ethical question. This, however, is an ethical challenge in most randomized-control clinical studies. Often there are rules put in place, or negotiated with regulators as the trial proceeds, where the trial can be brought to end more quickly if there is a strong positive signal, at which time the control arm will get the treatment too.

Yes, but dying from a virus is different than dying from the vaccine. Dying from the vaccine should be much less likely in this case, but we won’t know till we try.

Yes, I think that is what will be done.

I thought I already discussed them…

It’s not helpful to repeat that. The challenge is to defend the claim that this matters, or that it matters so much that it’s worth a long tedious discussion with one big question repeatedly ignored.

These are tidy rationalizations. We have no rescue treatment.

You wrote some things about a “kidney donor trial.” My repeated question, which I’ll now give up on, is about the ethics of living kidney donation. The repeatedly ignored question is why/how a surgeon removing a kidney from a healthy living donor is different from a HCW giving SARS-CoV-2 to a healthy young person.

Hint: there’s no difference.

There’s no universally accepted ethical calculus, but it is often felt that causing a death by choosing to take an action is in a different ethical category than deaths that would have occurred without any intervention. So some corpses might be different than others.

As far as I can tell, these corpses (older people who die from adverse reactions in a conventional trial) are morally equivalent to deaths caused by infecting volunteers in a challenge trial. (And all of this applies to morbidity as well, of course.)

Not really, since I’ve decided that both are ethically acceptable if done with good safeguards – and since I have to get back to writing grants to fund SARS-CoV-2 sequencing. (We sequenced a bunch of genomes but whatever stray funds we’d scraped together ran out, so we had to stop sequencing.)

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It’s not obvious to me that the risk of a fatal adverse reaction in an elderly recipient of a vaccine for this virus (given its peculiar immunological age profile) is lower than the risk of death for an infected healthy young person. Both are quite small.

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I did address it before:

However, what would be the ethics of someone donating a kidney for a drug company study that then went on to earn hundreds of millions of dollars from those discoveries while also benefiting thousands or hundreds of thousands of patients? What would the ethics be if they were offering large sums of money for people to participate?

To add to that point, would you be willing to set up a foundation that sought out individuals who would be willing to donate a kidney for research? Personally, I would consider donating a kidney to an individual, but I highly doubt I would donate a kidney to a research group. However, if they offered a million bucks might I reconsider?

I would not personally be motivated to donate a kidney (as a living donor) for research, nor would I be enthusiastic about a foundation to do that. My enthusiasm for living kidney donation is completely related to the benefit to another person, weighed against the risk/cost to the donor. I happen to agree with the founders of the 1DaySooner organization, one of whom (the main person, IIRC) is a living kidney donor who is motivated by what she sees as a clear moral equivalency between living kidney donation and the challenge trial.

Your comments about the profits potentially earned by companies don’t seem relevant here, since that applies regardless of how a trial is organized.

Perhaps you mean to call concerned attention to the size of compensation of volunteers. I agree that this is a concern that should be part of ethical considerations.

Yes, the famous trolley car dilemma and its many variants. This one is actually imminent and realistic.

I would agree that there is strong commonality between the challenge trial and live kidney donation. However, like with almost everything in life, the devil is in the details. Risking your health for an individual is a bit different than risking your health for a drug company, at least it seems that way at a base human level. When there are profit and career motives in play it adds to the ethical calculus. With live kidney donation to an individual it is a clear trade of risk for the donor and life for the recipient. There isn’t someone profiting millions of dollars, or someone increasing the status within the scientific community because they have a successful scientific study.

It could be that I am seeing demons and witches where there are none, and I may be overly sensitive when it comes to this topic. If nothing else, thanks for responding and I look forward to future discussions.

It doesn’t apply in the case of live kidney donation to an individual. That’s the point I was trying to make.

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