Do Challenge Trials Make Sense for COVID-19

Continuing the discussion from 1DaySooner: Open Letter on Challenge Trials for COVID-19:

I’ve raised these objections too.

That’s one point that has to be made up front. Now we have to ask what challenge trials would be for in our situation. The idea is that they would speed up vaccine development, giving us more data more quickly in Phase II trials (which is where we really start testing to see if any given vaccine candidate can be protective). But I don’t think we need to run challenge trials at all – not under current conditions. We have areas where the coronavirus is spreading so well through the population that I don’t see the advantage.

In the end, despite the heroic sound of the idea, I think that such trials are (1) still ethically questionable, (2) fraught with legal complications, (3) are for those reasons and others not likely to run meaningfully faster than regular Phase II trials, and (4) will produce data that may not be able to be extrapolated to the real-world situation. I don’t see the point.

That last point is particularly important:

Now consider who those volunteers would be – who they would have to be. Young, healthy people – who else? We’re already stepping close to the line with the whole idea, and giving it to anyone in a more at-risk population would surely step over it. But even the Phase I safety trials of the vaccines have brought in age groups that would be unacceptable in a challenge trial for Phase II, and the Phase II trials – since they’re taking place out “in the wild” can similarly enroll people who would never be in a deliberate challenge. This means that the data you would obtain from such a challenge is skewed heavily away from some of the people that you are going to want to treat first. Both efficacy and safety can (and do) vary by age, existing medical conditions and other variables that you’re going to have to make sure to not address in the challenge trial.

For a much more thoughtful analysis, by international experts on the topic, I suggest this recent piece in PNAS:

And for those who raise the most basic ethical concerns, I suggest an honest comparison to living kidney donation. I haven’t seen anyone even attempt to explain the ethical difference between surgically removing someone’s kidney and exposing them to SARS-CoV-2. I think there’s a simple explanation. There isn’t a difference.

Challenge trials will use only young healthy volunteers. If you think this means the results will not be perfectly and completely extendable to every human population, you are correct. If you think this makes a challenge trial worthless, you are being deceived.

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I did try once:

I’m not real sure why you didn’t think this was helpful, but it certainly was an attempt :slight_smile: . Perhaps you can clarify by showing us your analysis.

Those comments were about a “kidney donation trial.” My question is simple and straightforward, and utterly unrelated to a “kidney donation trial.” I’ll copy it, again, from above. Last call.

I haven’t seen anyone even attempt to explain the ethical difference between surgically removing someone’s kidney and exposing them to SARS-CoV-2. I think there’s a simple explanation. There isn’t a difference.

My point is not that it is wrong or unreasonable to raise concerns about challenge trials. There are big questions, that should be asked and explored, and there are fundamental ethical principles at play.

My problem is the simple and unhelpful nature of the conversation, especially in this blog post that openly admits it’s not even original. Please consider reading the PNAS piece to see what a careful ethical and biomedical argument looks like. Please see how the authors refer to challenge trials and maybe look at the paper they cite (and which they co-wrote) that argues for challenge trials directly. I linked it below.

Okay, let me rephrase my answer.

In terms of potential harm to the patient, there may not be a substantial ethical difference. In this case, I might agree with your simple explanation, but that’s only part of the story.

In terms of potential benefit to others, there is a material difference that substantially changes the ethical analysis. When we remove a kidney, There is clear, quantifiable, direct, rapid, and large benefit to the recipient of the donor kidney. In contrast, there is no benefit to others in exposing someone to SARS-CoV-2 outside the context of a trial. In the context of a trial, the benefit is at best debatable right now, for reasons that I’ve laid out as have others.

So let’s grant that the potential for harm may be essentially equivalent, but there are differences in the potential benefit. That changes how we should think about the ethics of the two situations.

It is worth unpacking some of the difference in potential benefit some more, which might expose some of the ethical questions behind this.

  1. We take out the kidney for the kidney, but we expose people to SARS-CoV-2 for new knowledge. Is there a difference between harming people for knowledge versus harming people to produce tangible material? Probably not, but I wonder if respond to it differently.

  2. The kidney helps a relatively small number of people, but the new knowledge we get might help far more per participant in a study if the study is successful, or no one if it isn’t successful. It might be an uncertain chance high reward. At the same time, this knowledge we would still get by other means with a standard trial during the pandemic, so that significantly dampens the reward. It might actually be an uncertain chance at low reward. This sort of uncertainty is not part of the kidney benefit analysis.

  3. We have to take out kidneys on an ongoing basis, but these challenge trials would come to an end very quickly once the first few vaccines are approved (probably in less than 12 months now). So the ethical dilemma of challenge trials sunsets very quickly, but we will still be taking kidneys out.

  4. Kidney donations are helpful even if even one person donates a kidney. Exposing SARS-CoV-2 to patients only produces a benefit of there are thousands of them willing to sign up at the same time. People are not exactly lining up to donate kidneys. So, in this case, would it be ethical to to start a trial without ensuring first that all participants are screened and consented?

Those are all differences. I know you don’t want me to talk about trials, but the ethical analysis has to include an analysis of the benefits, and I’m not sure of any benefits outside of a clinical trial for exposing people to the virus. That is the only reason it is coming up here.

Certainly, I will read this closely.

However, people do seem to be lining up to do a COVID challenge trial.

I wonder if that means something important. What if, after we have a vaccine on the market, we go back to those lines of people lining up for a challenge trial to make them an offer? We could tell them:

A challenge trial is equally risky as donating a kidney, and you signed up for a challenge trial but were not able to participate. You can still do a lot of good by donating a kidney. Why not consider this?

I wonder, with that proposition, we might suddenly get a larger number of kidney donors. That would be important and exciting.

It’s zero at best.

I provided no “simple explanation.” I sought to address one big false objection, raised in the previous thread, about the difference between actively harming/risking a patient vs. passively doing so (by sending thousands of people, including vulnerable populations, into the world after giving them a placebo). That “ethical concern” is invalidated by living kidney donation, and so are other “objections” raised about consent, etc. Advocates for prepping for challenge trials draw the explicit comparison with kidney donation, a process that requires intensive ethical approval EVERY TIME IT HAPPENS.

I am frustrated by the inaccurate impression that you give readers when you write things like this: “would it be ethical to to start a trial without ensuring first that all participants are screened and consented?” This ignores everything that has been written about the idea.

The rest of what you wrote is about your perceptions of how to quantify and calculate benefit. All true, but unconvincing as objections to the design of potential challenge trials.

I’d like to see acknowledgment of the work already done on the proposals, and a bit more respect for the people who have done it. It has not gone well so far.

Well I agree with you there. The potential to harm participants alone is not a valid reason to object to challenge trials. Kidney donors are a good test case showing that we regularly submit patients to a similar level of risk. So there isn’t a new level of risk being considered here.

If that was your point, I agree with you. :slight_smile:

There certainly are people who have done a lot more work on this. I trust the system to work this particular question out. Nothing I’ve written should be construed as a public statement against others who are experts in this and are hashing this out publicly in papers and discussion with the FDA, or even open letters.

As I’ve said, I think we likely will do Challenge Trials in the end. I’m not objecting, just thinking about it. :slight_smile:

Well, I don’t want to give the impression that the answer must be “no.” I was just thinking about it. I agree also that the process does require intensive ethical approval. In this case, I really do trust the system to work. I’m not making an objection to challenge trials, but just thinking about it. Is that okay?

Your readers might believe that it is reasonable to ask “would it be ethical to to start a trial without ensuring first that all participants are screened and consented?” That was disappointing. “Thinking about it” has to mean addressing it as it is, and showing that you have read and understood what our friends and colleagues have worked so hard to propose.

Others can take it from here.

Well then, let me be clear.

In this case, there is good reason to trust the IRB boards that are governing these trials. If they determine it is ethical to start a trial, it likely is and I would not second guess them. There are times when ethical skepticism is warranted, but this is not one of those cases.

Well, I was hard on you and I don’t intend to discourage discussion or thought or dissent. Challenge trials would be unprecedented. They entail some ethical situations that are unique compared to other kinds of clinical trials. They require somewhat extraordinary scrutiny and defense.

It would be a mistake to agree to challenge trials as though they are no different from military service or are trivially justifiable using standard ethical norms. It is also a mistake to claim or imply that the proposals (and that’s all they are) regarding challenge trials have failed to consider these and other questions and concerns.

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