Should there be human challenge vaccine trials for Covid-19?

Why I didn’t — and Nir Eyal thought I should — sign the open letter calling for this

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Yesterday, 1 Day Sooner posted this Open Letter calling for human challenge vaccine trials for Covid-19. As they describe such trials:

Human challenge trials deliberately expose participants to infection, in order to study diseases and test vaccines or treatments. They have been used for influenza, malaria, typhoid, dengue fever, and cholera. Researchers are exploring whether human challenge trials could speed up the development of a vaccine for COVID-19, saving thousands or even millions of lives.

Below is an email in which I explain why I declined to sign this letter. Further below is an exchange with Nir Eyal, who is one of the initial signers of the letter, to which my email gave rise. These emails have been slightly copy-edited.

From: Otsuka,MH
Sent: 14 July 2020 14:40
To: Isaac Martinez [project manager at 1 Day Sooner]
Subject: RE: Coronavirus Vaccine Open Letter

Dear Isaac,

Thanks for your email and your invitation to sign your letter. I’ve given this a fair amount of thought but on balance have decided against signing the letter. Here’s why (though I would be happy to be persuaded otherwise):

You write the following in {…} your letter:

Decades of psychological research on highly altruistic behaviors has demonstrated that a large, and likely growing, fraction of the general population is willing to undergo meaningful risks to benefit others due to genuinely altruistic motivation rather than insensitivity to risk, psychopathology, or other ethically concerning motives.

I can see a defensible Covid-19 human challenge trial solely involving such highly altruistic individuals who are sufficiently well off that there wouldn’t be a concern about exploitation. But what your website says about what should be done to ensure that the vulnerable aren’t exploited is not reassuring. You don’t rule out payment beyond coverage of costs. You also suggest recruitment of those in high risk jobs, on account of the fact that it’s less likely that they’d be made worse off, given their baseline likelihood of infection. In the case of those in low paid, high risk jobs (e.g., bus driver, supermarket worker, hospital cleaners, carer, security guard), I’d be concerned about exploitation if they’d be provided payment beyond costs. Even if there’s no payment beyond cost, I’d also be concerned about exploitation if people enrol in order to gain access to good health care, in a place like the US, where health care provision is so poor. I realise that, as Joan Robinson once said, the only thing worse than being exploited is not being exploited. But this remains a sticking point for me, especially given the history of exploitation in vaccine trials, as described in this NYRB piece.

Best,
Mike

From: Nir Eyal
Sent: 14 July 2020 17:10
To: Otsuka,MH [and others]
Subject: Re: Coronavirus Vaccine Open Letter

{…} Of course please don’t sign if ambivalent, but in my opinion the specific worry about exploitation is a little off. Conventional efficacy trials must home in on a community with lots of ongoing infections and strife (where people are at high risk of being exposed), and, to be maximally informative, recruit also ones like to have severe outcomes should they get infected. All that correlates with health, economic, and democratic disadvantage. Challenge trials can be held wherever, and because risk minimization comes first, would recruit only young and healthy folks, with emphasis on ones educated enough to comprehend the risks reliably. They are most likely to be held near leading research centers in the US, UK, or NL (though that may change). It is true that, thinking about the interests of recruits, I suggested focusing recruitment on professions/areas/populations where there are likely to be many infections at some point in the future and before herd immunity is achieved (not necessarily in the months in which the trial is being held). But first, that’s just me and my idiosyncrasies, not a universally-shared suggestion by those rooting for challenge trials; second, many well-to-do professions/areas/populations will answer that description — e.g. many inhabitants, rich or poor, of large metropolitan hubs, many medical practitioners,…; and third, I proposed it just so that we treat study subjects nicely (it is not scientifically required) — so if you feel that minimizing incremental risk in the proposed way matters less than nonexploitation, you can simply reject my idiosyncratic proposal, while sticking with challenge trials in a different form.

I say a bit more about exploitation on pp. 4–6 of ‘Why Challenge Trials of SARS‐CoV‐2 Vaccines Could Be Ethical Despite Risk of Severe Adverse Events

Best wishes,
Nir

From: Otsuka,MH
Date: Tuesday, July 14, 2020 at 1:03 PM
To: Nir Eyal [and others]
Subject: RE: Coronavirus Vaccine Open Letter

[Responses from Nir Eyal inserted in italics with vertical bar to the left.]

Thanks, Nir.

1. You write: “Conventional efficacy trials must home in on a community with lots of ongoing infections and strife (where people are at high risk of being exposed), and, to be maximally informative, recruit also ones like to have severe outcomes should they get infected. All that correlates with health, economic, and democratic disadvantage.”

But not every offer to someone who is disadvantaged is exploitative. Selling such a person safe and nourishing food at cost, rather than a profit, would not be exploitative.

Since the vaccines in conventional Phase 3 efficacy trials have already undergone Phase 1 and Phase 2 trials, they’ve been screened (albeit imperfectly) for safety. So the downside risks are guarded against, and the vaccine will probably either do some good or simply be ineffective.

Moreover, in this case (unlike a human challenge trial) participation in a trial doesn’t increase one’s risk of coronavirus infection.

So a conventional efficacy trial doesn’t seem exploitative when conducted among the disadvantaged. By contrast, the human challenge trial is more like an offer to perform hazardous work, which gives rise to risks of exploitation.

{Nir Eyal:} Good point. You are by and large right about standard phase 3 being nonexploitative, but there are exceptions in which it may be exploitative, e.g.:

1. The only way to get into critical care in a surge situation (like currently in Brazil?) is to be a study participant with related privileges;

2. The only way to get DECENTLY GOOD doctors is through the trial;

3. Researchers remain very unsure about risks of the vaccine (which may actually be the case this time round, especially about risks coming from “disease severity enhancement”, for which there is no testing on humans prior to the efficacy trial);

4. Perhaps if participants believe incorrectly that 1/2/3 above is the case, and researchers exploit that incorrect view;

2. In ‘Why Challenge Trials of SARS‐CoV‐2 Vaccines Could Be Ethical Despite Risk of Severe Adverse Events’ you write:

But no one I know seriously argues that worries about beneficial, perfectly consensual research that is marred merely by an exploitative route to benefit and consent is enough to ban a study that can be expected to save an inordinate number of lives. Remember that the challenge trial design could cut several months in the wait for vaccine rollout, translating into thousands or millions of lives spared from exponential growth in direct Covid deaths.

It appears that, as against the Astrazeneca approach to Phase 3, human challenge trials would save at best one or two months’ time. And (as you mention in your paper) that has to be discounted by the probability that the vaccine will be shown to be ineffective in any event.

{Nir Eyal:}

1. How much time would be saved depends on many parameters. It could actually be longer than 2 months, e.g. if the first 5 trials all fail (either scientifically, or in the sense that the trial verifies that the vaccines are no good) and by then preparations for a challenge are completed.

2. In WIP, Pedro Rosa Dias (Imperial College development economist), Ara Darzi (Imperial College global health leader) and I estimate that even one month of expediting vaccine arrival would avert the loss of over 720k life years and over 40mn years in poverty (with the bulk of the latter in developing nations).

But even if the expected number of lives saved would justify a human challenge trial of one sort or another, it doesn’t justify an exploitative human challenge trial if a nonexploitative human trial is also available.

{Nir Eyal:} A nonexploitative phase 3 is definitely going to be “available” in the sense that scientifically it would be possible to hold one. But what if the nonexploitative trial would take 1 month longer? Then arguably considerations of nonexploitation wouldn’t be stringent enough to rule out the somewhat more exploitative design — given the numbers I cite above. Another complication would arise if the only reason a challenge could not happen in settings in which it would not have been exploitative is that the local ethics committee (or FDA, or…) wouldn’t allow it — on sound or on unsound grounds.

It appears, moreover, that it would be possible to conduct a nonexploitative human challenge trial which recruits only among relatively well-off highly altruistic individuals.

{Nir Eyal:}

1. Agree — thanks so much for coming around to seeing that you should sign a letter that supports SOME form of human challenge trials, without committing to the exact form. (-: (Not to worry — I know that you are not signing…)

2. There is an interesting general question here, about exploitation. Suppose the only way to benefit the worse off is to act exploitatively toward them. For example, in our setting, suppose that UK researchers are wondering whether to conduct a challenge trial in the UK or in a developing country, among the global poor. Let us assume that the trial must be a challenge design, in light of its expediency and earlier failures to reach statistically meaningful results in a conventional phase 3. These researchers have no way of helping the global poor short of treating them well inside a trial. Challenge trial participation would be beneficial overall in prospect, by e.g. providing exclusive access to drugs hoarded almost entirely by the US — an unrealistic prospect in a phase 3 study (because it must occur in the heart of a raging outbreak, and local communities wouldn’t let study participants have huge priority in such conditions). But assume further that the UK researchers could instead benefit the globally better off, albeit only by equal/smaller amounts, and without exploitation (e.g. by directing to UK patients the beneficial-overall package of challenge trial participation). Should the researchers then benefit the better off, no matter what? I doubt it.

Best,
Mike

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Professor, Dept. of Philosophy, Logic & Scientific Method, LSE

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