[D66] These Coronavirus Trials Don’t Answer the One Question We Need to Know

[R.O.]

  NYT:


  These Coronavirus Trials Don’t Answer the One Question We Need to Know

We may not find out whether the vaccines prevent moderate or severe 
cases of Covid-19.

By Peter Doshi and Eric Topol

Dr. Doshi is an associate professor at the University of Maryland School 
of Pharmacy/. /Dr. Topol is a professor of molecular medicine at Scripps 
Research.

  * Sept. 22, 2020


If you were to approve a coronavirus vaccine, would you approve one that 
you only knew protected people only from the most mild form of Covid-19, 
or one that would prevent its serious complications?

The answer is obvious. You would want to protect against the worst cases.

But that’s not how the companies testing three of the leading 
coronavirus vaccine candidates, Moderna, Pfizer 
<https://www.nytimes.com/2020/09/17/health/covid-moderna-vaccine.html> 
and AstraZeneca 
<https://www.nytimes.com/2020/09/19/health/astrazeneca-vaccine-safety-blueprints.html>, 
whose U.S. trial is on hold, are approaching the problem.

According to the protocols for their studies, which they released late 
last week, a vaccine could meet the companies’ benchmark for success if 
it lowered the risk of mild Covid-19, but was never shown to reduce 
moderate or severe forms of the disease, or the risk of hospitalization, 
admissions to the intensive care unit or death.

To say a vaccine works should mean that most people no longer run the 
risk of getting seriously sick. That’s not what these trials will determine.

The Moderna 
<https://www.modernatx.com/sites/default/files/mRNA-1273-P301-Protocol.pdf> 
and AstraZeneca 
<https://s3.amazonaws.com/ctr-med-7111/D8110C00001/52bec400-80f6-4c1b-8791-0483923d0867/c8070a4e-6a9d-46f9-8c32-cece903592b9/D8110C00001_CSP-v2.pdf> 
studies will involve about 30,000 participants each; Pfizer’s 
<https://pfe-pfizercom-d8-prod.s3.amazonaws.com/2020-09/C4591001_Clinical_Protocol.pdf> 
will have 44,000. Half the participants will receive two doses of 
vaccines separated by three or four weeks, and the other half will 
receive saltwater placebo shots. The final determination of efficacy 
will occur after 150 to 160 participants develop Covid-19. But that is 
only if the trials are allowed to run long enough. Pfizer will look at 
the accumulating data four times, Moderna twice and AstraZeneca once to 
determine if efficacy has been established, potentially leading to an 
early end to the trials.

Knowing how a clinical trial defines its primary endpoint — the measure 
used to determine a vaccine’s efficacy — is critical to understanding 
the knowledge it is built to discover. In the Moderna and Pfizer trials, 
even a mild case of Covid-19 — for instance, a cough plus a positive lab 
test — would qualify and muddy the results. AstraZeneca is slightly more 
stringent but would still count mild symptoms like a cough plus fever as 
a case. Only moderate or severe cases should be counted.

There are several reasons this is a problem.

First, mild Covid-19 is far more common than severe Covid-19, so most of 
the efficacy data is likely to pertain to mild disease. But there is no 
guarantee that reducing the risk of mild Covid-19 will also reduce the 
risk of moderate or severe Covid-19.

The reason is that the vaccine may not work equally well in frail and 
other at-risk populations. Healthy adults, who could form a majority of 
trial participants, might be less likely to get mild Covid-19, but 
adults over 65 — particularly those with significant frailty — might 
still get sick.

This is the case with influenza vaccines, which reduce the risk of mild 
disease in healthy adults. But there is no solid evidence they reduce 
the number of deaths, which occur largely among older people. In fact, 
significant increases in vaccination rates over the past decades have 
not been associated <https://doi.org/10.1001/archinte.165.3.265> with 
reductions in deaths.

Second, Moderna and Pfizer acknowledge their vaccines appear to induce 
side effects that are similar to the symptoms of mild Covid-19. In 
Pfizer’s early phase trial 
<https://doi.org/10.1101/2020.08.17.20176651>, more than half of the 
vaccinated participants experienced headache, muscle pain and chills.

If the vaccines ultimately provide no benefit beyond a reduced risk of 
mild Covid-19, they could end up causing more discomfort than they prevent.

Third, even if the studies are allowed to run past their interim 
analyses, stopping a trial of 30,000 or 44,000 people after just 150 or 
so Covid-19 cases may make statistical sense, but it defies common 
sense. Giving a vaccine to hundreds of millions of healthy people based 
on such limited data requires a real leap of faith.

Declaring a winner without adequate evidence would also undermine the 
studies of other vaccines, as participants in those studies drop out to 
receive the newly approved vaccine. There may well be insufficient data 
to address the aged and underrepresented minorities. There will be no 
data for children, adolescents and pregnant women since they have been 
excluded. Vaccines must be thoroughly tested in all populations in which 
they will be used.

None of this is to say that these vaccines can’t reduce the risk of 
serious complications of Covid-19. But unless the trials are allowed to 
run long enough to address that question, we won’t know the answer.

The trials need to focus on the right clinical outcome — whether the 
vaccines protect against moderate and severe forms of Covid-19 — and be 
fully completed. It is not too late for the companies to do this, and 
the Food and Drug Administration, which reviewed the protocols, could 
still suggest modifications.

These are some of the most important clinical trials in history, 
affecting a vast majority of the planet’s population. It’s hard to 
imagine how much higher the stakes can be to get this right. Cutting 
corners should not be an option.

Peter Doshi <https://faculty.rx.umaryland.edu/pdoshi/> is an associate 
professor of pharmaceutical health services research at the University 
of Maryland School of Pharmacy and an associate editor of The BMJ 
<https://www.bmj.com/>, a medical journal. Eric Topol 
<https://www.scripps.edu/faculty/topol/> is a professor of molecular 
medicine at Scripps Research, where he founded and directs the 
Translational Institute 
<https://www.scripps.edu/science-and-medicine/translational-institute/>, 
which is focused on individualized medicine.

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