Drugs being re-purposed in hopes they will help against COVID-19 cost
little to make but may prove challenging to produce in quantities
needed for a pandemic, a drug pricing expert said.
“Any pharmaceutical company manufacturing any treatment currently in
clinical trials against coronavirus needs a clear plan to upscale
production massively,” Andrew Hill, a University of Liverpool research
fellow, told Reuters.
“Otherwise, supplies of these drugs could quickly run out.”
In a study released Friday in the Journal of Virus Eradication, Hill
and five other researchers, including Howard University chemist Joseph
Fortunak, examined the cost of manufacturing medicines in recent or
ongoing COVID-19 trials.
Using prices for active pharmaceutical ingredients to build
estimates, they said Gilead Science’s experimental drug remdesivir,
originally for Ebola, could be made for as little as $0.93 for a day’s
supply.
Gilead said the figure does not “accurately reflect” manufacturing costs at scale, but did not give those costs.
Fujifilm Holdings Corp’s flu drug Avigan runs $1.45 to make per day, the researchers said. Fujifilm did not immediately comment.
Meanwhile, decades-old malaria medicine hydroxychloroquine – touted
by President Donald Trump and others as a possible game changer despite
no scientific proof it works – costs 8 cents.
Other drugs the researchers examined included the related malaria
medicine, chloroquine, the antibiotic azithromycin, Roche’s lung drug
Esbriet and rheumatoid arthritis treatment Actemra, as well as an AbbVie
HIV drug and a Hepatitis C cocktail.
“Should repurposed drugs demonstrate efficacy against COVID-19, they
could be manufactured profitably at very low costs,” the authors wrote,
giving range of between $1 and $29 per course of treatment.
Nonetheless, demand for medicines that prove their mettle could
swiftly outstrip supply, necessitating new industry alliances, parallel
manufacturing by multiple companies, and shared intellectual property,
Hill said.
“The demands could be huge, and could lead to shortages for people normally taking these drugs for other diseases,” he added.
Roche, which received $25 million in U.S. funding for Actemra’s
COVID-19 trial, said it is ramping up output capacity for intravenous
Actemra and has boosted supplies by 50% in recent weeks. The Swiss
drugmaker added that given Actemra is not yet approved for COVID-19,
pricing discussions are premature.
For Fujifilm’s Avigan, Japan provided some $128 million to boost
supplies to treat 2 million people, as triple the dose is required for
COVID-19 than for influenza.
Gilead can produce 140,000 remdesivir treatment courses near-term, and 1 million-plus by December, it has projected.
Sanofi can make millions of hydroxychloroquine doses, but whether
that suffices may depend on if trials show it should be used for
potentially millions of mildly affected patients, or for only severe ICU
patients, Chief Executive Paul Hudson told Reuters last week.
Sanofi has boosted production of hydroxychloroquine by 50% across its
eight manufacturing sites worldwide and said Friday it would donate 100
million doses to 50 countries, while Novartis has pledged 130 million
doses and said it is hunting for more ingredients, should trials show
the medicine works.
So far, some doctors including in China say results have been inconclusive. https://www.reuters.com/article/us-health-coronavirus-production-costs/coronavirus-drug-hopefuls-are-cheap-to-make-but-may-be-in-short-supply-idUSKCN21S0WM
French pharmaceutical giant Sanofi said Friday it had decided to
donate 100 million doses of hydroxychloroquine, the decades-old
anti-malaria drug touted by some as a potential weapon against the novel
coronavirus, across 50 countries.
In a statement, the company said it increased its production capacity
by 50% across its eight hydroxychloroquine manufacturing sites
worldwide, adding it was on track to quadruple it by the summer.
“Sanofi is calling for coordination among the entire
hydroxychloroquine chain worldwide to ensure the continued supply of the
medicine if proven to be a well-tolerated and effective treatment in
COVID-19 patients”, it said. https://www.reuters.com/article/us-healt-coronavirus-sanofi-hydroxychlor/sanofi-will-donate-100-million-doses-of-hydroxychloroquine-to-50-countries-idUSKCN21S0JK
After a widely expected and sharp drop in the U.S. economy over the
next three months, a panel of top business economists sees high
joblessness persisting for more than a year in an outcome that would
douse hopes for a quick, post-pandemic return to normal.
The number of jobs destroyed by the U.S. economy’s crisis-driven
sudden stop could top 4.5 million, according to the median estimate of
45 forecasters surveyed by the National Association for Business
Economics.
Fewer than 2 million of those positions will be recovered by the end
of 2021, the economists expect, pushing the unemployment rate above 6
percent for the next 21 months in a massive blow to a labor market that
had been considered among the best for workers in decades.
“Panelists believe that the U.S. economy is already in recession and
will remain in a contractionary state for the first half of 2020, as the
COVID-19 pandemic severely restricts economic activity,” said NABE
President Constance Hunter, chief economist for KPMG.
“Conditions will improve by the end of the year with support from
aggressive fiscal and monetary stimulus,” she said, with annualized
growth near 6% by year’s end.
But that will follow a devastating contraction in the second quarter
of 2020, with the median forecast expecting GDP to fall at an annualized
rate of 26.5% for the April to June period.
The prognosis is in line with other recent predictions by economists and some Fed officials.
The breadth of the responses to the NABE survey showed the
uncertainty economists have about what happens when major parts of an
economic system simply shut down, in this case as a result of efforts to
stem the spread of the coronavirus. The responses included estimates
that second-quarter GDP would fall by a full 50%.
Estimates at the other extreme saw only a 1% fall in second-quarter
GDP, and a rocket-like 20% rebound from there with millions of jobs
created and unemployment falling quickly.
The median outcome of persistent job loss, however, is sobering in
the face of the trillions of dollars in new programs the Fed, Congress
and the Trump administration have approved in recent weeks to try to
keep the economy “whole” through the pandemic and ready to restart once
the health crisis passes. https://www.reuters.com/article/us-health-coronavirus-usa-forecast/high-u-s-unemployment-2-5-million-jobs-lost-through-2021-survey-idUSKCN21S0BL
China’s Wuhan city, where the global coronavirus pandemic began, is
still testing residents regularly despite relaxing its tough two-month
lockdown, with the country wary of a rebound in cases even as it sets
its sights on normalising the economy.
Concerns remain over an influx of infected patients from overseas as
well as China’s ability to detect asymptomatic patients, and the
government in Wuhan has tried to reassure the public that it remains
vigilant.
Feng Jing, who runs a group of community workers looking after the
Tanhualin neighborhood in Wuhan, said during a government-run tour for
journalists on Friday that they would continue to carry out extensive
checks on residents.
“We carry out comprehensive heath checks everyday and keep detailed
records of their health condition,” she said, adding that there is no
likelihood of asymptomatic cases in her community.
“Currently our neighbourhood is an epidemic-free community – it’s
been 45 days so far, so we don’t have this situation,” she said.
China reported a fall in new coronavirus cases on Friday after
leaders promised to accelerate the country’s economic recovery, boost
domestic demand and put more people back to work.
The country reported 42 new cases on Thursday, down from 63 a day
earlier. Of the daily total, 38 were imported, down from 61 on
Wednesday.
China’s central government coronavirus taskforce chaired by Premier
Li Keqiang said on Thursday that they would speed up efforts to revive
the economy while at the same time introducing targeted measures aimed
at preventing infected people from crossing the country’s border.
It said China now needed to “actively create favourable conditions”
to restore normality in the economy, though it warned there was still a
risk of a rebound in cases.
In Shanghai, state media have also been deployed to dispel online
rumours that the city has now become “the most dangerous place in the
country” as thousands of people flood in from Wuhan, including many
asymptomatic and recovered patients.
With the government now promising to deploy resources to tackle
high-risk areas, much of the focus has shifted to Heilongjiang, which
reported 28 new imported cases crossing the border from Russia on
Thursday. The province has so far found 154 cases of imported
infections.
The virus, which first broke out in the Chinese city of Wuhan in late
2019, has since spread around the world infecting more than 1.4 million
people, killing more than 87,700.
The pandemic has wreaked havoc on the global economy as governments imposed lockdowns to rein in its spread. https://www.reuters.com/article/us-health-coronavirus-china/chinas-wuhan-to-keep-testing-residents-as-coronavirus-lockdown-eases-idUSKCN21S0FV
The Italian government is planning to extend its lockdown to contain
the country’s COVID-19 outbreak until May 3, two trade union sources
told Reuters on Thursday after meeting ministers.
The lockdown, closing most Italian businesses and preventing people
leaving their homes for all but essential needs, has been in place since
March 9 and was due to end on April 13.
After a marked reduction from previous peaks, new infections have
picked up in the past two days, frustrating hopes that the illness was
in clear retreat.
“The Prime Minister has confirmed that, as of today, the conditions
to restart the suspended activities are not yet in place,” UIL union
leader Carmelo Barbagallo said in a statement.
After the government shuttered businesses not deemed essential to the
supply chain on March 21, calls have recently been growing from
industry lobbies to reopen some activities to prevent an economic
catastrophe.
The trade union sources and an industry source said the closure of
industries may be slightly eased before the end of April, with a few
factory sites allowed to reopen if health conditions permitted.
Local branches of employers’ lobby Confindustria in the northern
regions of Lombardy, Veneto, Piedmont and Emilia Romagna have been vocal
in pleading to re-open plants, even though they are heavily affected by
the coronavirus.
The regions represent 45% of Italy’s economic output.
Google (GOOG,GOOGL) says its unemployment application portal could potentially be used in other states.
NYC’s unemployment insurance filing system has
peaked at a 1,600% increase in web traffic since the coronavirus
pandemic started, compared to a typical week.
Google’s alternative is backed by the tech giant’s cloud platform and can handle a higher volume of users.
Google is partnering with several states and
federal agencies “on a number of projects to help them better serve
citizens during the COVID-19 pandemic.”
Even as hospitals and governors raise the alarm about a shortage of ventilators,
some critical care physicians are questioning the widespread use of the
breathing machines for Covid-19 patients, saying that large numbers of
patients could instead be treated with less intensive respiratory
support.
If the iconoclasts are right, putting coronavirus patients on
ventilators could be of little benefit to many and even harmful to some.
What’s driving this reassessment is a baffling observation about
Covid-19: Many patients have blood oxygen levels so low they should be
dead. But they’re not gasping for air, their hearts aren’t racing, and
their brains show no signs of blinking off from lack of oxygen.
That is making critical care physicians suspect that blood levels of
oxygen, which for decades have driven decisions about breathing support
for patients with pneumonia and acute respiratory distress, might be
misleading them about how to care for those with Covid-19. In
particular, more and more are concerned about the use of intubation and
mechanical ventilators. They argue that more patients could receive
simpler, noninvasive respiratory support, such as the breathing masks
used in sleep apnea, at least to start with and maybe for the duration
of the illness.
“I think we may indeed be able to support a subset of these patients”
with less invasive breathing support, said Sohan Japa, an internal
medicine physician at Boston’s Brigham and Women’s Hospital. “I think we
have to be more nuanced about who we intubate.”
That would help relieve a shortage of ventilators so critical that
states are scrambling to procure them and some hospitals are taking the
unprecedented (and largely untested) step of using a single ventilator
for more than one patient. And it would mean fewer Covid-19 patients,
particularly elderly ones, would be at risk of suffering the long-term
cognitive and physical effects of sedation and intubation while being on
a ventilator.
None of this means that ventilators are not necessary in the Covid-19
crisis, or that hospitals are wrong to fear running out. But as doctors
learn more about treating Covid-19, and question old dogma about blood
oxygen and the need for ventilators, they might be able to substitute
simpler and more widely available devices.
An oxygen saturation rate below 93% (normal is 95% to 100%) has long
been taken as a sign of potential hypoxia and impending organ
damage. Before Covid-19, when the oxygen level dropped below this
threshold, physicians supported their patients’ breathing with
noninvasive devices such as continuous positive airway pressure (CPAP,
the sleep apnea device) and bilevel positive airway pressure ventilators
(BiPAP). Both work via a tube into a face mask.
In severe pneumonia or acute respiratory distress unrelated to
Covid-19, or if the noninvasive devices don’t boost oxygen levels
enough, critical care doctors turn to mechanical ventilators that push
oxygen into the lungs at a preset rate and force: A physician threads a
10-inch plastic tube down a patient’s throat and into the lungs,
attaches it to the ventilator, and administers heavy and long-lasting
sedation so the patient can’t fight the sensation of being unable to
breathe on his own.
But because in some patients with Covid-19, blood-oxygen levels fall
to hardly-ever-seen levels, into the 70s and even lower, physicians are
intubating them sooner. “Data from China suggested that early intubation
would keep Covid-19 patients’ heart, liver, and kidneys from failing
due to hypoxia,” said a veteran emergency medicine physician. “This has
been the whole thing driving decisions about breathing support: Knock
them out and put them on a ventilator.”
To be sure, many physicians are starting simple. “Most hospitals,
including ours, are using simpler, noninvasive strategies first,”
including the apnea devices and even nasal cannulas, said Greg Martin, a
critical care physician at Emory University School of Medicine and
president-elect of the Society of Critical Care Medicine. (Nasal
cannulas are tubes whose two prongs, held beneath the nostrils by
elastic, deliver air to the nose.) “It doesn’t require sedation and the
patient [remains conscious and] can participate in his care. But if the
oxygen saturation gets too low you can achieve more oxygen delivery with
a mechanical ventilator.”
The question is whether ICU physicians are moving patients to
mechanical ventilators too quickly. “Almost the entire decision tree is
driven by oxygen saturation levels,” said the emergency medicine
physician, who asked not to be named so as not to appear to be
criticizing colleagues.
That’s not unreasonable. In patients who are on ventilators due to
non-Covid-19 pneumonia or acute respiratory distress, a blood oxygen
level in the 80s can mean impending death, with no room to give
noninvasive breathing support more time to work. Physicians are using
their experience with ventilators in those situations to guide their
care for Covid-19 patients. The problem, critical care physician Cameron
Kyle-Sidell told Medscape
this week, is that because U.S. physicians had never seen Covid-19
before February, they are basing clinical decisions on conditions that
may not be good guides.
“It’s hard to switch tracks when the train is going a million miles
an hour,” said Kyle-Sidell, who works at a New York City hospital. “This
may be an entirely new disease,” making ventilator protocols developed
for other conditions less than ideal.
As doctors learn more about the disease, however, both frontline
experience and a few small studies are leading him and others to
question how, and how often, mechanical ventilators are used for
Covid-19.
The first batch of evidence relates to how often the machines fail to
help. “Contrary to the impression that if extremely ill patients with
Covid-19 are treated with ventilators they will live and if they are
not, they will die, the reality is far different,” said geriatric and
palliative care physician Muriel Gillick of Harvard Medical School.
Researchers in Wuhan, for instance, reported that, of 37 critically ill Covid-19 patients who were put on mechanical ventilators, 30 died within a month. In a U.S. study
of patients in Seattle, only one of the seven patients older than 70
who were put on a ventilator survived; just 36% of those younger than 70
did. And in a study
published by JAMA on Monday, physicians in Italy reported that nearly
90% of 1,300 critically ill patients with Covid-19 were intubated and
put on a ventilator; only 11% received noninvasive ventilation.
One-quarter died in the ICU; 58% were still in the ICU, and 16% had been
discharged.
Older patients who do survive risk permanent cognitive and
respiratory damage from being on heavy sedation for many days if not
weeks and from the intubation, Gillick said.
To be sure, the mere need for ventilators in Covid-19 patients
suggests many in the studies were so critically ill their chances of
survival were poor no matter what care they received.
But one of the most severe consequences of Covid-19 suggests another
reason the ventilators aren’t more beneficial. In acute respiratory
distress syndrome, which results from immune cells ravaging the lungs
and kills many Covid-19 patients, the air sacs of the lungs become
filled with a gummy yellow fluid. “That limits oxygen transfer from the
lungs to the blood even when a machine pumps in oxygen,” Gillick said.
As patients go downhill, protocols developed for other respiratory
conditions call for increasing the force with which a ventilator
delivers oxygen, the amount of oxygen, or the rate of delivery, she
explained. But if oxygen can’t cross into the blood from the lungs in
the first place, those measures, especially greater force, may prove
harmful. High levels of oxygen impair the lung’s air sacs, while high
pressure to force in more oxygen damages the lungs.
In a letter
last week in the American Journal of Respiratory and Critical Care
Medicine, researchers in Germany and Italy said their Covid-19 patients
were unlike any others with acute respiratory distress. Their lungs are
relatively elastic (“compliant”), a sign of health “in sharp contrast to
expectations for severe ARDS.” Their low blood oxygen might result from
things that ventilators don’t fix. Such patients need “the lowest
possible [air pressure] and gentle ventilation,” they said, arguing
against increasing the pressure even if blood oxygen levels remain low.
“We need to be patient.”
“We need to ask, are we using ventilators in a way that makes sense
for other diseases but not for this one?” Gillick said. “Instead of
asking how do we ration a scarce resource, we should be asking how do we
best treat this disease?”
Researchers and clinicians on the front lines are trying. In a small study
last week in Annals of Intensive Care, physicians who treated Covid-19
patients at two hospitals in China found that the majority of patients
needed no more than a nasal cannula. Among the 41% who needed more
intense breathing support, none was put on a ventilator right away.
Instead, they were given noninvasive devices such as BiPAP; their blood
oxygen levels “significantly improved” after an hour or two. (Eventually
two of seven needed to be intubated.) The researchers concluded that
the more comfortable nasal cannula is just as good as BiPAP and that a
middle ground is as safe for Covid-19 patients as quicker use of a
ventilator.
“Anecdotal experience from Italy [also suggests] that they were able
to support a number of folks using these [non-invasive] methods,” Japa
said.
To be “more nuanced about who we intubate,” as she suggests, starts
with questioning the significance of oxygen saturation levels. Those
levels often “look beyond awful,” said Scott Weingart, a critical care
physician in New York and host of the “EMCrit” podcast. But many can
speak in full sentences, don’t report shortness of breath, and have no
signs of the heart or other organ abnormalities that hypoxia can cause.
“The patients in front of me are unlike any I’ve ever seen,”
Kyle-Sidell told Medscape about those he cared for in a hard-hit
Brooklyn hospital. “They looked a lot more like they had altitude
sickness than pneumonia.”
Because U.S. data on treating Covid-19 patients are nearly
nonexistent, health care workers are flying blind when it comes to
caring for such confounding patients. But anecdotally, Weingart said,
“we’ve had a number of people who improved and got off CPAP or high flow
[nasal cannulas] who would have been tubed 100 out of 100 times in the
past.” What he calls “this knee-jerk response” of putting people on
ventilators if their blood oxygen levels remain low with noninvasive
devices “is really bad. … I think these patients do much, much worse on
the ventilator.”
That could be because the ones who get intubated are the sickest, he
said, “but that has not been my experience: It makes things worse as a
direct result of the intubation.” High levels of force and oxygen
levels, both in quest of restoring oxygen saturation levels to normal,
can injure the lungs. “I would do everything in my power to avoid
intubating patients,” Weingart said.
One reason Covid-19 patients can have near-hypoxic levels of blood
oxygen without the usual gasping and other signs of impairment is that
their blood levels of carbon dioxide, which diffuses into air in the
lungs and is then exhaled, remain low. That suggests the lungs are still
accomplishing the critical job of removing carbon dioxide even if
they’re struggling to absorb oxygen. That, too, is reminiscent of
altitude sickness more than pneumonia.
The noninvasive devices “can provide some amount of support for
breathing and oxygenation, without needing a ventilator,” said ICU
physician and pulmonologist Lakshman Swamy of Boston Medical Center.
One problem, though, is that CPAP and other positive-pressure
machines pose a risk to health care workers, he said. The devices push
aerosolized virus particles into the air, where anyone entering the
patient’s room can inhale them. The intubation required for mechanical
ventilators can also aerosolize virus particles, but the machine is a
contained system after that.
“If we had unlimited supply of protective equipment and if we had a
better understanding of what this virus actually does in terms of
aerosolizing, and if we had more negative pressure rooms, then we would
be able to use more” of the noninvasive breathing support devices, Swamy
said.
