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<h1 id="link-22923e83" class="css-19rw7kf e1h9rw200">NYT:<br>
</h1>
<h1 id="link-22923e83" class="css-19rw7kf e1h9rw200">These
Coronavirus Trials Don’t Answer the One Question We Need to Know</h1>
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<p id="article-summary" class="css-1smgwul e1wiw3jv0">We may not
find out whether the vaccines prevent moderate or severe cases of
Covid-19.</p>
<div class="css-vp77d3 epjyd6m0">
<div class="css-1baulvz">
<p class="css-1nuro5j e1jsehar1">By <span class="css-1baulvz">Peter
Doshi</span> and <span class="css-1baulvz last-byline">Eric
Topol</span></p>
<div class="css-8atqhb">
<p class="css-qckjh9 e1wtpvyy0">Dr. Doshi is an associate
professor at the University of Maryland School of Pharmacy<em
class="css-18i2nvy">. </em>Dr. Topol is a professor of
molecular medicine at Scripps Research.</p>
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<ul class="css-1u1psjv epjyd6m3">
<li class="css-ccw2r3 epjyd6m1"><time class="css-129k401
e16638kd0" datetime="2020-09-22T13:05:44-04:00">Sept. 22, 2020</time></li>
</ul>
<br>
<p class="css-158dogj evys1bk0">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?</p>
<p class="css-158dogj evys1bk0">The answer is obvious. You would
want to protect against the worst cases.</p>
<p class="css-158dogj evys1bk0">But that’s not how the companies
testing three of the leading coronavirus vaccine candidates,
Moderna, <a class="css-1g7m0tk" title=""
href="https://www.nytimes.com/2020/09/17/health/covid-moderna-vaccine.html"
rel="nofollow noopener" target="_blank">Pfizer</a> and <a
class="css-1g7m0tk" title=""
href="https://www.nytimes.com/2020/09/19/health/astrazeneca-vaccine-safety-blueprints.html"
rel="nofollow noopener" target="_blank">AstraZeneca</a>, whose
U.S. trial is on hold, are approaching the problem.</p>
<p class="css-158dogj evys1bk0">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.</p>
<p class="css-158dogj evys1bk0">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.<br>
<br>
</p>
<p class="css-158dogj evys1bk0">The <a class="css-1g7m0tk" title=""
href="https://www.modernatx.com/sites/default/files/mRNA-1273-P301-Protocol.pdf"
target="_blank" rel="nofollow noopener">Moderna</a> and <a
class="css-1g7m0tk" title=""
href="https://s3.amazonaws.com/ctr-med-7111/D8110C00001/52bec400-80f6-4c1b-8791-0483923d0867/c8070a4e-6a9d-46f9-8c32-cece903592b9/D8110C00001_CSP-v2.pdf"
target="_blank" rel="nofollow noopener">AstraZeneca</a> studies
will involve about 30,000 participants each; <a
class="css-1g7m0tk" title=""
href="https://pfe-pfizercom-d8-prod.s3.amazonaws.com/2020-09/C4591001_Clinical_Protocol.pdf"
target="_blank" rel="nofollow noopener">Pfizer’s</a> 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.</p>
<p class="css-158dogj evys1bk0">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.<br>
<br>
</p>
<p class="css-158dogj evys1bk0">There are several reasons this is a
problem.</p>
<p class="css-158dogj evys1bk0">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.</p>
<p class="css-158dogj evys1bk0">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.<br>
<br>
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 <a class="css-1g7m0tk" title=""
href="https://doi.org/10.1001/archinte.165.3.265"
target="_blank" rel="nofollow noopener">have not been associated</a>
with reductions in deaths.<br>
<br>
</p>
<p class="css-158dogj evys1bk0">Second, Moderna and Pfizer
acknowledge their vaccines appear to induce side effects that are
similar to the symptoms of mild Covid-19. In <a
class="css-1g7m0tk" title=""
href="https://doi.org/10.1101/2020.08.17.20176651"
target="_blank" rel="nofollow noopener">Pfizer’s early phase
trial</a>, more than half of the vaccinated participants
experienced headache, muscle pain and chills.</p>
<p class="css-158dogj evys1bk0">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.</p>
<p class="css-158dogj evys1bk0">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.<br>
<br>
</p>
<p class="css-158dogj evys1bk0">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.</p>
<p class="css-158dogj evys1bk0">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.</p>
<p class="css-158dogj evys1bk0">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.<br>
<br>
</p>
<p class="css-158dogj evys1bk0">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.</p>
<p class="css-pncxxs etfikam0"><a class="css-1g7m0tk" title=""
href="https://faculty.rx.umaryland.edu/pdoshi/" target="_blank"
rel="nofollow noopener">Peter Doshi</a> is an associate
professor of pharmaceutical health services research at the
University of Maryland School of Pharmacy and an associate editor
of <a class="css-1g7m0tk" title="" href="https://www.bmj.com/"
target="_blank" rel="nofollow noopener">The BMJ</a>, a medical
journal. <a class="css-1g7m0tk" title=""
href="https://www.scripps.edu/faculty/topol/" target="_blank"
rel="nofollow noopener">Eric Topol</a> is a professor of
molecular medicine at Scripps Research, where he founded and
directs the <a class="css-1g7m0tk" title=""
href="https://www.scripps.edu/science-and-medicine/translational-institute/"
target="_blank" rel="nofollow noopener">Translational Institute</a>,
which is focused on individualized medicine.</p>
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