What will COVID vaccine trials look like?
There are over 100 potential vaccines being developed, and several are already in preliminary testing in humans. There are three steps to testing a vaccine: showing that it doesn’t have any common, nasty side effects; showing that it raises antibodies; showing that vaccinated people don’t get COVID-19.
The last step is the big one, especially if you want it fast. I knew that in principle, but I was prompted to run the numbers by hearing (from Hilda Bastian) of a Danish trial in 6000 people looking at whether wearing masks reduces infection risk. With 3000 people in each group, and with the no-mask people having a 2% infection rate over two months, and with masks halving the infection rate, the trial would still have more than a 1 in 10 chance of missing the effect. Reality is less favorable: 2% infections is more than 10 times the population percentage of confirmed cases so far in Denmark (more than 50 times the NZ rate), and halving the infection rate seems unreasonably optimistic.
That’s what we’re looking at for a vaccine. We don’t expect perfection, and if a vaccine truly reduces the infection rate by 50% it would be a serious mistake to discard it as useless. But if the control-group infection rate over a couple of months is a high-but-maybe-plausible 0.2% that means 600,000 people in the trial — one of the largest clinical trials in history.
How can that be reduced? If the trial was done somewhere with out-of-control disease transmission, the rate of infection in controls might be 5% and a moderately large trial would be sufficient. But doing a randomised trial in setting like that is hard — and ethically dubious if it’s a developing-world population that won’t be getting a successful vaccine any time soon. If the trial took a couple of years, rather than a couple of months, the infection rate could be 3-4 times lower — but we can’t afford to wait a couple of years.
The other possibility is deliberate infection. If you deliberately exposed trial participants to the coronavirus, you could run a trial with only hundreds of participants, and no more COVID deaths, in total, than a larger trial. But signing people up for deliberate exposure to a potentially deadly infection when half of them are getting placebo is something you don’t want to do without very careful consideration and widespread consultation. I’m fairly far out on the ‘individual consent over paternalism’ end of the bioethics spectrum, and even I’d be a bit worried that consenting to coronavirus infection could be a sign that you weren’t giving free, informed, consent.
Thomas Lumley (@tslumley) is Professor of Biostatistics at the University of Auckland. His research interests include semiparametric models, survey sampling, statistical computing, foundations of statistics, and whatever methodological problems his medical collaborators come up with. He also blogs at Biased and Inefficient See all posts by Thomas Lumley »
It depends on the alternatives – most of the world are not living our luxury first world lives.
If all you are asking for is “free informed individual consent”, the inhuman cruelties of first world immigration and asylum laws create plenty of opportunities where deliberate COVID-19 infection is better than any other option.
For a healthy adult in the 20s a deliberate COVID-19 infection has a lower mortality than paying a smuggler to put him on a shaky boat over a sea hoping to get asylum elsewhere.
If you offer free plane tickets and permanent residency in New Zealand for the volunteer and his family in exchange for his participation in the trial, that’s better than anything he would have imagined in his dreams.
Even if death would be certain, you would still find more volunteers than you need who would give free informed individual consent to death in exchange for permanent residency for their family in New Zealand.
I am not saying anything like that would be ethical, just that “free informed individual consent” can be an incredibly low bar.
4 years ago
That sort of thing is also frowned on by medical (and non-medical) ethicists, though on somewhat different grounds. I wouldn’t feel any obligation not to use a vaccine tested that way, but it still makes me uncomfortable. And, yes, I realise ‘makes me feel uncomfortable’ is not an ethical argument that should have any force for anyone else.
It’s arguable more ethical than conducting trials in developing countries for treatments that are primarily aimed at Western nations. Which happens regularly.
Once you agree to the argument though, it isn’t limited to vaccine trials, though. You might well be able to get ‘free informed consent’ to kill someone and harvest their organs for transplant if you gave residency to their families. Or if you aren’t a government, but you paid enough money.
There’s a literature on whether endorsing organ-buying and voluntary indentured servitude and such like would improve the world. And maybe I’d feel different about it if I was born in Chad.
From a practical view, however, NZ hasn’t even managed to approve a system where residents can voluntarily agree to support extra refugees, so I think this is a non-starter for political reasons independent of one’s ethical view.
4 years ago
All clinical trials must follow ICH-GCP. These are the guidelines which dictate informed consent. No ethics committee in the world would approve a study which offered the sort of exchange suggested. It’s one of the reasons we don’t test investigational drugs in prisons, for example
4 years ago
It’s very far from all trials that follow ICH-GCP, though nearly all trials intended to support new drug approvals do.
In this case, though, I think the ethical question is worth considering separately from the regulatory one. There are stronger arguments against it than “not in accordance with ICH-GCP”
4 years ago
In a strictly personal capacity, let me say that I agree with Thomas that this is hard. In general, we do not permit coercion in trials for extremely good reasons, and it is clear that a huge payout would be problematic. On the other hand, a lot of people are going to die without a vaccine and we accept people taking extraordinary risks in a crisis (Firefighters enter burning buildings, police arrest armed criminals — ideally without inuring them).
I do think the context of a “challenge trial” totally swaps ideas like Robin Hanson’s just infect you and healthy people. In fact it is the only way I can conceive of it being possible to argue for it.
So if we go this way, I think there is a hard discussion about how to balance overall mortality and to make sure that individual rights are respected. I think it goes without saying that any test group would be sitting next to the nest respiratory ICU money can buy (without any patient charges).
At chernobyl they send in 3 heroes to the flooded basement to keep the reactor from blowing. That scene, in the miniseries, made me feel creepy as a scientist. You could feel the pressure. It turns out all three lived:
https://www.businessinsider.com/chernobyl-volunteers-divers-nuclear-mission-2016-4
and it is hard to argue that it wasn’t a good thing that the reactor did not further explode.
So a very challenging area and I am POSITIVE that a) there are no easy answers, b) should it be done some careful thinking has to take place, and c) I don’t want to be involved with it as I like sleeping at night.
4 years ago