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FRIDAY, JULY 10, 2020
‘Desperation science’
slows the hunt for
coronavirus drugs
Marilynn Marchione
AP - Desperate to solve the deadly conundrum
of COVID 19, the world is clamouring for fast
answers and solutions from a research system
not built for haste.
The ironic, and perhaps tragic, result: Scien-
tiic shortcuts have slowedunderstandingof the
disease anddelayed the ability to ind out which
drugs help, hurt or have no effect at all.
As deaths from the coronavirus relentlessly
mounted into the hundreds of thousands, tens
of thousands of doctors and patients rushed to
use drugs before they could be proved safe or
effective. A slew of low-quality studies clouded
the picture even more.
"People had an epidemic in front of them
and were not prepared to wait," said Critical
Care Chief Dr Derek Angus at the University
of Pittsburgh Medical Center. "We made
traditional clinical research look so slow
and cumbersome."
It wasn't until mid-June — nearly six months
in — when the irst evidence came that a drug
could improve survival. Researchers in the
United Kingdom (UK) managed to enrol one of
every six hospitalised COVID 19 patients into a
large study that found a cheap steroid called
dexamethasone helps and that a widely used
malaria drugdoes not. The study changedprac-
ticeovernight, even though results hadnot been
published or reviewed by other scientists.
In the United States (US), one smaller but rig-
orous study found a different drug can shorten
recovery time for seriously ill patients, but many
questions remain about its best use.
Doctors are still frantically reaching for any-
thingelse thatmight ight themanyways thevirus
can do harm, experimenting with medicines for
stroke, heartburn, blood clots, gout, depression,
inlammation,AIDS, hepatitis, cancer, arthritisand
even stem cells and radiation.
"Everyone has been kind of grasping for
anything that might work. And that's not how
you develop sound medical practice," said
a Cleveland Clinic researcher and frequent
advisor to the US Food and Drug Administra-
tion (FDA) Dr Steven Nissen. "Desperation is
not a strategy. Good clinical trials represent
a solid strategy."
Fewdeinitive studies have been done in the
US, with some undermined by people getting
drugs on their own or lax methods from drug
companies sponsoring the work.
And politics magniied the problem. Tens of
thousands of people tried a malaria medicine
after US President Donald Trump relentlessly
promoted it, saying, "What have yougot to lose?"
Meanwhile, the nation's top infectious disease
expert, Dr Anthony Fauci, warned "I like to prove
things irst." For threemonths, weak studies po-
larisedviews of hydroxychloroquineuntil several
more reliable ones found it ineffective.
"The problem with 'gunslinger medicine',
or medicine that is practised where there is a
hunch ... is that it's caused society as a whole
to be late in learning things," said Johns Hop-
kins University's Dr Otis Brawley. "We don't
have good evidence because we don't ap-
preciate and respect science."
He noted that if studies had been conduct-
ed correctly in January and February, scientists
would have known by March if many of these
drugs worked.
Even researchers who value science are
taking shortcuts and bending rules to try to
get answers more rapidly. And journals are
rushing to publish results, sometimes paying
a price for their haste with retractions.
Research is still chaotic — more than 2,000
studies are testing COVID 19 treatments from
azithromycin to zinc. The volume might not
be surprising in the face of a pandemic and a
novel virus, but some experts said it is troubling
that many studies are duplicative and lack the
scientiic rigour to result in clear answers.
"Everything about this feels very strange,"
said Angus, who is leading an innovative study
using artiicial intelligence to help pick treat-
ments. "It's all being done on COVID time. It's
like this new weird clock we're running on."
Here is a look at some of the major ex-
amples of "desperation science" underway.
A MALARIA DRUG GOES VIRAL
To scientists, it was a recipe for disaster: In a
medical crisis with no known treatment and
a panicked population, an inluential public
igure pushes a drug with potentially serious
side effects, citing testimonials and a quickly
discredited report of its use in 20 patients.
Trump touted hydroxychloroquine in doz-
ens of appearances starting inmid-March. The
FDA allowed its emergency use even though
studies had not shown it safe or effective for
coronavirus patients, and the government
acquired tens of millions of doses.
Trump irst urged taking it with azithromy-
cin, an antibiotic that, like hydroxychloroquine,
can cause heart rhythm problems. After
criticism, he doubled down on giving medical
advice, urging "You should add zinc now ... I
want to throw that out there." In May, he said
he was taking the drugs himself to prevent
infection after an aide tested positive.
Many people followed his advice.
Medical Director of a California poison con-
trol centre Dr Rais Vohra told of a 52-year-old
COVID 19 patient who developed an irregular
heartbeat after three days on hydroxychloro-
quine – from the drug, not the virus.
"It seems like the cure was more dangerous
than the effects of the disease," Vohra said.
Studies suggested the drug wasn't helping,
but theywereweak. And themost inluential one,
published in the journal
Lancet
, was retracted
after major concerns arose about the data.
Craving better information, a University of
Minnesota doctor who had been turned down
for federal funding spent USD5,000 of his own
money to buy hydroxychloroquine for a rigor-
ous test using placebo pills as a comparison. In
early June, Dr David Boulware's results showed
hydroxychloroquine did not prevent COVID 19
in people closely exposed to someone with it.
A UK study found the drug ineffective for
treatment, as did other studies by the US Na-
tional Institutes of Health (NIH) and the World
Health Organization.
Boulware's colleague, Dr RahdaRajasingham,
aimed to enrol 3,000 health workers in a study
to see if hydroxychloroquine could prevent in-
fection, but recently decided to stop at 1,500.
When the study started, "there was this be-
lief that hydroxychloroquine was this wonder
drug," Rajasingham said. More than 1,200 peo-
ple signed up in just twoweeks, but that slowed
to a trickle after some negative reports.
"Thenational conversationabout this drughas
changedfromeveryonewantsthisdrugtonobody
wants anything to do with it," she said. "It sort of
has become political where people who support
the president are pro-hydroxychloroquine."
Researchers just want to know if it works.
LEARN AS YOU GO
In Pittsburgh, Angus is aiming for something
between Trump's "just try it" and Fauci's "do
the ideal study" approach.
In a pandemic, "there has to be amiddle road,
another way," Angus said. "We do not have the
luxury of time. We must try to learn while doing."
The University of Pittsburgh Medical Cen-
ter's 40 hospitals in Pennsylvania, New York,
Maryland and Ohio joined a study underway
in the UK, Australia and New Zealand that
randomly assigns patients to one of dozens
of possible treatments and uses artiicial
intelligence to adapt treatments, based on
the results. If a drug looks like a winner, the
computer assignsmore people to get it. Losers
are quickly abandoned.
The system "learns on the ly, so our physi-
cians are always betting on the winning horse,"
Angus said.
A small number of patients given usual
care serve as a comparison group for all of the
treatments being tested, so more participants
wind up getting a shot at trying something.
Mark Shannon, a 61-year-old retired bank
teller from Pittsburgh, was the irst to join.
"I knew that there was no known cure. I knew
thattheywerelearningastheywentalonginmany
cases. I just put my trust in them," he said.
Shannon, who spent 11 days on a breathing
machine, received the steroid hydrocortisone
and recovered.
Doris Kelley, a 57-year-old preschool teacher
in Ruffs Dale, southeast of Pittsburgh, joined
the study in April.
"It felt like someone was sitting on my
chest and I couldn't get any air," Kelley said
of COVID 19.
She has asthma and other health problems
and was glad to let the computer choose
among the many possible treatments. It as-
signed her to get hydroxychloroquine and she
went home a couple days later.
It's too soon to know if either patient's drug
helped or if they would have recovered on
their own.
THE BUMPY ROAD TO REMDESIVIR
When the new coronavirus was identiied,
attention swiftly turned to remdesivir, an ex-
perimental medicine administered through an
IV that showed promise against other corona-
viruses in the past by curbing their ability to
copy their genetic material.
Doctors inChina launched two studies com-
paring remdesivir to the usual care of severely
and moderately ill hospitalised patients. The
drug's maker, Gilead Sciences, also started its
own studies, but they were weak - one had no
comparison group and, in the other, patients
and doctors knew who was getting the drug,
which compromises any judgments about
whether it works.
The NIH launched the most rigorous test,
comparing remdesivir to placebo IV treat-
ments. While these studies were underway,
Gilead also gave away the drug on a case-by-
case basis to thousands of patients.
In April, Chinese researchers ended their
studies early, saying they could no longer enrol
enough patients as the outbreak ebbed there.
In a podcast with a journal editor, Fauci gave
another possible explanation: Many patients
already believed remdesivir worked and were
not willing to join a study where they might
end up in a comparison group. That may have
been especially true if they could get the drug
directly from Gilead.
In late April, Fauci revealed preliminary
results from the NIH trial showing remdesivir
shortened the time to recovery by 31 per cent
— 11 days on average versus 15 days for those
just given usual care.
Some criticised releasing those results
rather than continuing the study to see if
the drug could improve survival and to learn
more about when and how to use it, but in-
dependent monitors had advised that it was
no longer ethical to continue with a placebo
group as soon as a beneit was apparent.
Until that study, the only other big, rigor-
ous test of a coronavirus treatment was from
China. As that country rushed to build ield
hospitals to deal with the medical crisis, doc-
tors randomly assigned COVID 19 patients to
get either two HIV antiviral drugs or the usual
care and quickly published results in the
New
England Journal of Medicine
.
"These investigators were able to do it un-
der unbelievable circumstances," the journal's
top editor, Dr Eric Rubin, said on a podcast. "It's
been disappointing that the pace of research
has been quite slow since that time."
WHY SCIENCE MATTERS
By not properly testing drugs before allowing
wide use, "time and time again in medical his-
tory, people have been hurt more often than
helped," Brawley said.
For decades, lidocainewas routinely used to
prevent heart rhythm problems in people sus-
pected of having heart attacks until a study in
themid-1980s showed the drug actually caused
the problem it was meant to prevent, he said.
A University of Wisconsin lawyer and bio-
ethicist Alta Charo recalled the clamour in the
1990s to get insurers to cover bone marrow
transplants for breast cancer until a solid study
showed they "simplymade peoplemoremiser-
able and sicker" without improving survival.
Writing in the
Journal of the American Medi-
cal Association
, former FDA scientists Drs Jesse
Goodman and Luciana Borio criticised the
push to use hydroxychloroquine during this
pandemic and cited similar pressure to use an
antibody combo called ZMapp during the 2014
Ebola outbreak, whichwaned before that drug's
effectiveness could be determined. It took four
years and another outbreak to learn that ZMapp
helped less than two similar treatments.
During the 2009 2010 swine lu outbreak,
the experimental drug peramivir was widely
used without formal study, Drs Benjamin Rome
and Jerry Avorn of Brigham and Women's
Hospital in Boston noted in the
New England
Journal
. The drug later gave disappointing
results in a rigorous study and ultimately was
approved merely for less serious cases of lu
and not severely ill hospitalised patients.
Patients are best servedwhenwe stick to sci-
ence rather than "cutting corners and resorting
to appealing yet risky quick ixes," they wrote.
In this photo provided by the University of Pittsburgh Medical Center (UPMC), Chairwoman of
family medicine Dr Ruba Nicola adjusts her personal protective equipment at the hospital in
Monroeville, Pennsylvania on April 17. PHOTO: AP