Challenge Trials for COVID-19 Trials Beginning

It relies on a level of intellectual and emotional intelligence that is unevenly distributed in the US. In many parts of the US, including the place I live, it has been very effective.

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Some clarifying comments.

The challenge trials are not Phase I trials AFAIK and are not about safety.

I think that this points to a strong ethical consideration in favor of the challenge trial. It is meant to assess effectiveness, quickly, in a population that is not at high risk. Because it is ensuring exposure/infection of all participants, it does not look at high risk populations. I don’t know if you are proposing a large-scale trial that does include such people, but I suspect that this would be rejected ethically, right off the bat.

In other words, inclusion of at-risk populations in a trial of a vaccine is not something that distinguishes the challenge trial from the standard ones.

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From the article in the OP:

What happened to Phase II???

Nonetheless, safety is a focus of all phases of human trials, but admittedly less so in later trials.

One aspect to consider is if the vaccine is protective in at risk populations. Some herd immunity would be helpful, but if we are going to choose between vaccines then we would want to use the vaccine that protects all groups. Will a study group of healthy young people provide us that data? I don’t know.

It’s a really tough balancing act between the quality of data we get and the risk involved in the study.

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I agree but I’m afraid I don’t see how the challenge trial is different. The standard trial lets people catch the virus somehow in the world. The challenge trial takes control of that. That’s the difference. That’s the only difference. And the only purpose is to get meaningful results faster.

I think the ethical conversation needs to be about the active infection of healthy people, thereby exposing them (actively is the key word, perhaps the only key word) to a pathogen. IMO the most relevant and informative comparison is to living kidney donors. Almost none of the comments in this thread so far are relevant to the question of whether to introduce challenge trials in place of standard trials.

As it happens, I was part of the process in which a loved one participated in the founding of a living kidney donor program, by being the first person (at that hospital) to volunteer to donate a kidney to a stranger. I will never forget what the surgeon said to my loved one: “This surgery will do you no good. It is my job to ensure that it does you no harm.” We all know that the surgeon could not promise that, and that my loved one was being exposed to significant potential harm.

I think we’re probably done here, but if we want to explore the ethical questions surrounding challenge trials, and the ethical weighting that they require, I will be interested in the conversation. I will expect that the conversation acknowledge the already-existing medical situations represented by living kidney donors, and that those who comment on SARS-CoV-2 challenge trials be willing to explain how living kidney donation is different.

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It’s a bit like a trial for a cancer drug where you give people cancer instead of waiting until they are older and naturally develop cancer.

That’s a very good comparison, but there are some nuances worth considering. First, people are donating their kidneys to another person. It is a person to person transaction that benefits a person’s life. A drug trial is for the benefit of scientific research and will ultimately result in profits for a company. I have no problem with drug companies making a profit off of medicines (although we could certainly discuss the ethics of how large a profit they should earn). 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?

Ethics are really murky at times.

Please feel free to disagree with me wherever you see fit. Again, I fully admit my biases here and it is good to hear from other people on this topic. If nothing else, I can supply the viewpoints of someone who is biased against these types of studies.

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A standard trial would also include older patients, and those patients specifically excluded in the challenge trials discussed here. This means a challenge trial would not tell us directly how well the vaccine worked in the populations most at risk for serious complications. This is a significant disadvantage, especially because the populations most at risk are also those who will be first to receive the vaccine.

No one is suggesting we replace standard trials with challenge trials. Rather, standard trials and challenge trials would proceed alongside one another. Right?

There are many differences, and I’ve noted a few here.

  1. In clinical studies, the population used has a dramatic effect on results. Challenge trials have a different population than standard trials, which makes them less translatable to practice. In contrast, the kidney donation studies would be using the exact same population of donors in the intended practice.

  2. It isn’t possible to imagine a kidney donation trial without kidney donors. It is, in contrast, easy to envision standard trials that would produce the same (perhaps better) information, but just at a slower rate (maybe).

  3. Kidney trials match very closely the intended treatment the intend test. Exposure in challenge trials is controlled (which increases statistical power) but we can’t expect them to mimic exposure the virus “in the wild,” which again reduces their translatability.

These are substantial differences from a kidney donor trial. Challenge trials vs. standard trials there is a trade off between the hope of increasing speed and the certainty of reduced translatability. This tradeoff is not part of the kidney donor example, and it may be importnat.

Agreed. I couldn’t see how your comments about drug trials were relevant to the ethical distinction between a challenge trial and a standard one. I don’t think anyone wants to actually discuss that so I’ll get back to work.

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I doubt most of that is even accurate, but I also note with frustration that it’s not about the ethical questions that I mistakenly thought we were going to address.

Who cares?

You just listed practical matter of dubious relevance and you are talking about a “kidney donor trial” when I was talking about a program in which people have a kidney removed forever from their body.

I see a pattern of failure or refusal to discuss the ethics.

This is now bordering on a propagandistic crusade against challenge trials. “Hope of”??? “Certainty of reduced translatability”? I guess we’re not going to actually talk about the real ethical questions. Which is good because it’s a busy day.

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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