PHOTO: FRANCIS CRICK INSTITUTET
he pandemic’s shadow has Tami
Minnier questioning everything about
medical practice—including how clini-
cal trials scrutinize it. “We have all
these traditions that we haven’t really
challenged,” says Minnier, a nurse at
the University of Pittsburgh Medical Center
(UPMC) and its chief quality officer.
Like many others who operate the global
machinery of trials, which test everything
from cancer drugs to the benefits of exer-
cise, Minnier has spent years lamenting their
shortcomings, including their sluggish pace,
their shortage and lack of diversity of vol-
unteers, and that they’re often too small to
produce conclusive results. But change has
been slow. COVID-19 upended that, compel-
ling trials to adapt to new constraints, such
as limits on in-person participation. It also
led to a proliferation of sometimes creatively
designed trials testing ways to fight the virus.
Clinical trialists hope many reforms will
stick. “I’m really interested in the extent to
which the pandemic has served as a forcing
mechanism to change the conduct of trials
for the better,” says Joseph Unger, a health
services researcher and biostatistician at the
Fred Hutchinson Cancer Research Center.
“It’s like a natural experiment.”
UPMC, with hundreds of active clinical tri-
als, is one of many places around the world
where the experiment is playing out. Prepan-
demic, clinical research “could be methodical
and careful and take years,” Minnier says, but
when patients seriously ill with a new disease
flooded emergency rooms, health care pro-
viders were awash in questions. Should they
give steroids? Would flipping someone onto
their stomach improve breathing? When
should doctors resort to a ventilator? Queries
quickly became research studies. This “ques-
tioning of, ‘Why are we doing what we’re do-
ing’” in patient care was, Minnier says, “the
driving force for me personally” to start to
rethink so much across medicine.
A 10-minute walk away, at UPMC’s 600-bed
main hospital, physician Derek Angus treats
patients in the intensive care unit (ICU) and
runs clinical trials for sepsis, a bloodstream
infection. Although sepsis is the leadingcause of death in hospitals, sepsis trials have,
historically, accomplished little. Patients and
families often decline to participate because
the trials test one drug at a time, often with
a 50% chance of getting a placebo. “Mean-
while, you’re really sick, in septic shock,” says
Angus, who has tried for years to design what
he calls “smarter, more efficient trials.”
After swiveling to COVID-19, Minnier and
Angus bonded over their desire for trials that
offer quick, clear answers. Part of the solu-
tion, they believe, is to fuse clinical research
with patient care, which can both speed re-
cruitment and lighten the burden on partici-
pants. For example, if a clinical trial requires
the same blood test a patient’s doctor is seek-
ing, Angus says, it could tap into those results
rather than requiring a separate blood draw.
Once patients are enrolled, he wants trials
to feel seamless, a model he compares to the
iPhone his elderly mother operates with ease.
The phone is “designed to look effortless,” he
says, “even though the engineering is more
complicated now than it’s ever been.”
Behind the scenes, re-engineered data in-
frastructure at UPMC is smoothing the pro-
cess. In the years preceding COVID-19, Oscar
Marroquin, a cardiologist who leads the insti-
tution’s health care data and analytics activi-
ties, took steps to meld millions of electronic
medical records with ongoing or potential
trials, making it easier to flag patients who
might be eligible or track them if enrolled.
That system became more quickly integrated
into research when COVID-19 struck, and
Marroquin is now applying it beyond the
coronavirus, for example to studies of cancer
and back pain.
Minnier and Angus, who was recently
named UPMC’s chief innovation officer, are
also helping other UPMC researchers design
statistically powerful studies that yield rapid
results. One way to accomplish this is with
a pragmatic trial, which assesses the power
of interventions in patients already getting
them. Another uses Bayesian statistics, which
allow patients to be randomized in different
ways as the trial progresses, depending on
how a treatment performs.
UPMC physicians recently launched a
COVID-19 trial that combines those innova-
tions to study monoclonal antibodies, a treat-1308 10 DECEMBER 2021 • VOL 374 ISSUE 6573 science.org SCIENCE
smaller.) TOP1 is present in many animals, so
the approach should work in other species,
the team says.
That could alleviate some ethical dilem-
mas, some researchers say. “The choice is
made before the animal is born,” says Tak
Mak, a geneticist at the Princess Margaret
Cancer Centre. For his breast cancer studies,
he only uses female mice and so has had to
sacrifice all males born. This new technology
“will eliminate this unpleasant and ineffi-
cient reality,” he says.
Although Wiles expects same-sex litters
may become routine in labs, he’s not optimis-
tic about agriculture. “Sadly, it’s ‘dead in the
water’ for food production while the world
fears [genetically modified organisms].”
Sue Leary, president of the Alternatives
Research & Development Foundation, a non-
profit seeking alternatives to animals in re-
search, says she sees little benefit to the new
approach. “You can’t solve an ethical prob-
lem with another ethical problem, which is
genetic engineering,” she says. The method
is “not pragmatic” for culling farm animals,
she argues, saying researchers should adopt
alternatives to using mice.
Few seem concerned that the method will
be tried in humans anytime soon. It works
best with species that have big litters and
short gestations, Qimron says. And it requires
genetic modifications not feasible in humans.
The team is making mice capable of
producing these litters freely available to
academic scientists. Tel Aviv University
immunologist Mordechay Gerlic, whose
lab is the one that managed to produce
some all-female mice litters with CRISPR a
couple years ago, says he looks forward to
the next steps. “I was very happy to see that
they used a similar approach, and target
the same region [in the Y chromosome],”
Gerlic says. In the future, as the approach
expands to other animals, he says, “it will
be important to define other regions in the
Y chromosome.” j
These mice have been genetically modified to parent
single-sex litters.
By Jennifer Couzin-FrankelTHE NEW NORMALCOVID-19 spurred nimbler trials that demand less
of patients—and many changes may stick
How pandemic pressure is
re-engineering clinical trials
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