To control the Covid-19 pandemic, we need an effective vaccine against SARS-CoV-2, the virus that causes this highly infectious disease.
Some argue that we should speed up the development and testing of new vaccines by using human challenge trials, in which volunteers who have received a candidate vaccine are deliberately exposed to the coronavirus. We agree with this view, but question the proposed methodology of these trials.
Most or all discussions of challenge trials take it as given that a placebo, or dummy vaccine, would be given to half of the participants selected at random from the volunteer pool. The use of placebos doesn’t make sense in this particular case.
It is clear why double-blind trials with placebo control groups are often used in testing a new drug or treatment: They are a reliable way to separate what is often a weak signal from possible confounders or sources of noise, including the placebo effect.
But the use of a placebo in a challenge trial for a Covid-19 vaccine is both pointless and ethically questionable.
We’ll use a deliberately simplistic analogy to help explain why. Suppose we need to test a new type of parachute during wartime, when a better parachute happens to be urgently needed. Sooner or later it will have to be tried in a real jump. But we won’t let that happen until we are already quite sure it is going to work. And we are certainly not going to give dummy parachutes to a control group, randomly selected from a group of volunteers. We already know what will happen to them.
This comparison is more apt than it might first appear. First, with Covid-19 we are dealing with an international medical emergency. The immediate objective is not to develop the theoretically best vaccine, but to arrive at something that will shut down the pandemic as soon as possible. There will be plenty of time afterward to carry out further studies with all appropriate protocols. The goal now is to save lives.
Second, we (sadly) have by now enough information on the morbidity and mortality of Covid-19 to know that even if only young, healthy volunteers participate in challenge trials, some of those given the placebo will become sick after infection with the coronavirus, and some might die. It is pointless to put these people at risk when there is almost no useful knowledge to be gained by doing so.
In effect, the general population is all the control group we need to answer the question that needs to be answered: Is the candidate vaccine at least 50% effective? We pick this figure because it has been mandated by the Food and Drug Administration as a minimum requirement for approval. Greater effectiveness would be desirable, of course. But the point here is that the purpose of a challenge trial for a Covid-19 vaccine is not to precisely measure an incremental improvement or to isolate the exact mechanism of action, as it might be in testing a new cancer chemotherapy. It is much more like testing a parachute under wartime conditions.
As with parachutes, we are not going to do a challenge trial until we have a candidate vaccine that has already shown reasonable safety and has the capacity to induce at least some useful degree of immunity. There are already several vaccines that have gotten over this bar.
Also as with parachute testing, giving the real treatment to 100% of the volunteers removes one of the major ethical barriers to challenge trials: the high probability of harmful side effects or death to members of a control group. It is possible, of course, that the vaccine might not work perfectly and some of the volunteers who get the real vaccine might become infected or suffer side effects. But the overall risk to the volunteers as a group would, obviously, be much smaller without a placebo arm. Indeed, the risk of overall harm could be lower than in a conventional vaccine trial, which requires that a large number of people who get a placebo become infected so we can tell whether the vaccine works.
Another advantage of not using a placebo is that it would be less ethically questionable to test the vaccine on older participants or those with comorbidities, which is especially relevant for Covid-19. While such subjects would still be at elevated risk in a challenge trial, they would no longer be subject to the near-certainty of harmful outcomes if they happened to be in the control group. Thus, tests using high-risk subjects without a placebo group could generate useful knowledge in return for only a modest increase in total societal risk.
One possible objection to the no-placebo strategy is that we can’t be sure how many of the volunteers would become infected if they didn’t have a real vaccine unless a placebo control group is used. If we were testing a new medication under normal circumstances, this objection could be decisive. But with Covid-19, we are able to estimate this number from the considerable data we already possess about the unvaccinated general community.
What about the placebo effect? How can we screen that out if we don’t have a control group? That question is moot since there is no known process through which a placebo could conceivably induce immunity from a viral infection to a degree comparable to a real vaccine.
Could there be a serious but low-probability side effect identifiable only by using a placebo arm? If such an effect was peculiar to the vaccine, we would not need a placebo control group to infer that it was caused by the vaccine. If it is something such as anaphylaxis that can be triggered in several ways, we could infer that it was caused by the vaccine if its frequency was significantly greater in the volunteer group than the general population (for which such frequencies are already well-known). Placebos are useful only when we do not know what will happen if a proposed treatment is not used.
We believe that having a placebo control group in a SARS-CoV-2 vaccine challenge trial is senseless. Not only does it virtually guarantee a deleterious outcome for an appreciable percentage of those in the control group, it generates little or no useful knowledge bearing on the only question that is really relevant right now: Is the new vaccine decisively effective? There will be plenty of time later to pursue incremental improvements in coronavirus vaccines, and for those sorts of studies conventional trials with placebos may well be entirely appropriate.
We agree with an anonymous volunteer quoted on 1DaySooner, an organization created to advocate on behalf of challenge volunteers: “Given the possible death toll, I think unprecedented approaches to vaccine testing are warranted.”
Kent A. Peacock is a professor of philosophy at the University of Lethbridge. John R. Vokey is a professor of psychology at the University of Lethbridge.
I think you meant “serious” not “serous” in the 3rd to last paragraph.
It’s just not safe not to have the gold standard test or scientific.
I agree with the authors as far as a direct challenge with a placebo arm. That would be jumping out of the plane with no parachute.
I was going to sign up for a trial which would give me a 50/50 chance to get an early vaccine. But after realizing that a good part of the trial involved the data for
next two years and that I would probably be ineligible for a “true” vaccine as that would change the data. I never looked into it further since my goal was the vaccine.
They give you a lot of forms and information when you volunteer and they make it very clear that you can opt out at any time.
To be honest I think it’s not a well designed trial, at least not the one I’m in. You will almost certainly be able to deduce what you were given based on a variety of indicators.
I fully concur. There is already a very large historical control population with well-documented statistics on attack rate, morbidity and mortality. It is minimally inferior science and vastly superior wisdom and morality.
How about using 10 pairs of counties in various states which have had parallel responses. This would normalize the state regs and other variables. One (randomly chosen) county would be vaccinated an the other would be “business as usual.” With a daily incident rate of 2-5% it would not take long to resolve…if you could get about 50% participation.
The same arguments apply to using Hydroxychloroquine regimes early in the infection process. If the argument against its use is based on lack of a double blind placebo controlled test, then the same arguments applies to vaccine trials.
I totally disagree with the authors,
We need placebos to prove efficacy, most medical interventions are not parachutes
We still do not know if these investigational vaccines are safe or not, and even phase III studies are not enough to establish that, we need good post marketing surveillance studies to assess that.
Rushing a vaccine will do more harm than good
I’ve volunteered for this. I signed up with 1DaySooner & registered in the NIH central COVID trial volunteer site.
I did it knowing about the placebo possibility. I’d participate tomorrow if this gets the green light.
People, kids of only 18 volunteer to go to war, and war carries a far, far greater risk than unprotected exposure to SARS-COV-2. Yet people volunteer.
I’m 34, I’m not overweight, my blood pressure is perfect. With full blown exposure & only the placebo, there’s a 99.5% (at least) chance I’ll be fine. May feel like crap for a while, may not. I’ll gladly take that risk to potentially save tens of thousands of lives, when every month counts. These trials would save people, not only from the literal virus, but from the catastrophic mental health & economic consequences that in the long run, may prove more deadly than the bug itself.
We should have held these trials months ago, as soon as we had candidates we know are reasonably safe. I can’t imagine what we’re waiting for?
The authors are missing a central point about the control group here, while making many valid but peripheral points. They say:
“ In effect, the general population is all the control group we need to answer the question that needs to be answered: Is the candidate vaccine at least 50% effective?“ – and suggest it’s unethical to withhold a probably useful vaccine from this group.
What do they miss?:
The control group is in fact a sample of the general population, but simply an identifiable and observable group, and one that’s had the same screening as the test group.
As to ethical propriety, you may as well say we should skip the trial and work to just give it to everyone and see what happens, since by waiting for a trial we are “withholding” it from some who might have gotten the maybe effective vaccine.
I do see the point of eliminating the placebo group when a blood test can measure immunity, my concern would be intentionally giving someone the COViD19 virus when there’s is No approved treatment/cure. I have read that challenge trials are used for vaccines, they are generally used when the infection rate is low and there is treatment/cure for the infection. Once one vaccine is approved perhaps that one can be used as a control.
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