It
was a small victory in a grim, relentless, and runaway catastrophe. In July,
Kent Brantly and Nancy Writebol, both American medical workers in Liberia,
became stricken with Ebola hemorrhagic fever after treating dozens suffering
from the disease, which has a mortality rate of between 50 percent and 90
percent. They were rushed doses of an experimental cocktail of Ebola antibodies
called ZMapp, flown home via a Gulfstream III on separate flights on Aug. 2 and
5, and isolated inside a special tent called an “aeromedical biological
containment system.” The U.S. State Department and the Centers for Disease
Control and Prevention (CDC) coordinated the flights, operated by Phoenix Air,
a private transport company based in Georgia. Cared for in a special ward at
Emory University in Atlanta, they recovered within the month and later met with
President Obama. It appeared a win for the White House.
Mapp
Biopharmaceutical, the San Diego company that developed ZMapp, is also in a way
a White House project. It’s supported exclusively through
federal grants and
contracts that go back to 2005. The antibody mixture hadn’t yet passed its
first phase of human clinical trials, but after the two Americans were infected
with Ebola, the Food and Drug Administration granted emergency access to ZMapp.
It’s
impossible to say whether ZMapp was vital to the Americans’ survival. There
were a limited number of doses available. Mapp ran out after having given doses
to the two Americans, a Spanish priest, and doctors in two West African
countries, although it declined to say how many. And that raised a fair
question: Why hadn’t the promising treatment gone through human clinical trials
sooner, and why were there so few doses on hand?
Since
appearing in Guinea in December, Ebola has spread to five West African countries
and infected 5,864 people, of which 2,811 have died, according to the World
Health Organization’s Sept. 22 report. This number is widely considered an
underestimate. The CDC’s worst-case model assumes that cases are “significantly
under-reported” by a factor of 2.5. With that correction, the CDC predicts
21,000 total cases in Liberia and Sierra Leone alone by Sept. 30.
A
confluence of factors has made it the biggest Ebola outbreak yet. For starters,
West Africa has never seen Ebola before; previous outbreaks have mainly
surfaced in the Democratic Republic of the Congo in Central Africa. The initial
symptoms of Ebola—fever, vomiting, muscle aches—are also similar to, and were
mistaken for, other diseases endemic to the region, such as malaria.
Then,
when officials and international workers swept into villages covered head to
toe and took away patients for isolation, some family members became convinced
that their relatives were dying because of what happened to them in the
hospitals. They avoided medical care and lied to doctors about their travel
histories. Medical staff at local hospitals became scared and quit their jobs.
Aid workers trying to set up isolation units or trace infected people’s
contacts were attacked by angry villagers. With these countries short on
resources, staff, medical equipment, and basic understanding of the disease,
Ebola took hold and spread.
In
the face of these chaotic conditions, there have been a number of admirable and
vigilant responses, from local doctors and emergency workers to nongovernmental
organizations such as Doctors Without Borders. Foreign governments have so far
pledged about a third of the $988 million the United Nations says is needed to
fight the epidemic. On Sept. 17, the Obama administration announced plans to
send 3,000 military personnel to assist with shipping and distribution of
medical equipment and supplies. The American personnel will also help build
treatment centers and train health-care providers in the region.
Could
a large stockpile of ZMapp have halted the spread of Ebola? No one can say.
What’s certain is that the U.S. government hasn’t done a good job taking the
idea behind ZMapp and turning it into a treatment. The technology for antibody
cocktails such as ZMapp has “been around for a few decades,” says Robert Garry,
a professor of microbiology at Tulane University. “This is something that,
given the emergency, the government could have moved a little faster on, quite
honestly.” He’s more right than he knows. The treatment came into the hands of
a little-known Pentagon agency in late 2010, and, Bloomberg Businessweek has
learned, ZMapp sat there dormant, waiting for a contract, for two years.
There
are, broadly speaking, two ways to spend money on biological defense: on gloves
or on drugs. A response to any attack requires a public health infrastructure,
things like gowns, boots, masks, and gloves to prevent the spread of infection,
training for doctors and nurses, and field hospitals that can be moved to the
site of an outbreak. Or a threat can be met with what the federal government
calls a “medical countermeasure,” a vaccine to prevent infection or a
therapeutic to aid in recovery.
In
the 1990s, after revelations of the Soviet biological and chemical weapons
programs and the 1995 sarin gas attack in the Tokyo subway, the U.S. assigned
its defensive drugmaking to the Pentagon. After 2001, that budget rose from
$880 million to $1.12 billion. Since then, roughly a third of the Pentagon’s
budget for biological and chemical defense, about $3.9 billion in total, has
gone toward a list of “biological threat agents.” The list is classified, but
it now numbers 18, according to a 2014 analysis by the U.S. Government
Accountability Office. Ebola is almost certainly on this list and likely near
the top. The Soviet Union had an Ebola program, and Aum Shinrikyo, the cult
that released the sarin gas in Tokyo, sent doctors in 1993 to what is now the
Democratic Republic of the Congo on an unsuccessful mission to get an Ebola
sample.
Members
of the Security Council attend a meeting on the Ebola crisis at UN headquarters
in New York on Sept. 18Photograph by Shannon Stapleton/ReutersMembers of the
Security Council attend a meeting on the Ebola crisis at UN headquarters in New
York on Sept. 18
Then
because the 2001 anthrax attacks on the Capitol in Washington were directed at
civilians, the Department of Health and Human Services launched a parallel
track in biochemical defense. Soon, the HHS began keeping a list, too. Over the
next two years, the budget at the National Institute of Allergy and Infectious
Diseases (NIAID), part of the HHS, jumped from $2.04 billion to $3.7 billion.
Two separate arms of the federal government were becoming pharmaceutical
companies, with a total yearly budget of close to $5 billion.
By
2006, says Robert Kadlec, the White House became aware of this problem. NIAID’s
budget went to sponsor basic research at university and commercial labs, but
the agency didn’t move its ideas through the FDA approvals process. The
Pentagon’s program “never got enough money to be a pharmaceutical company,”
says Kadlec, a consultant and public health physician who held several
high-level posts in biodefense in the George W. Bush administration. “They got
enough for research and development,” he says, “but not for licensure.”
“We
identified the struggle as the advanced development,” says Senator Richard
Burr, a Republican from North Carolina. By “advanced development” he means the
challenge of getting promising treatments through trials and approvals. “We
called that area sort of ‘the valley of death’ for any product,” he says.
Kadlec helped Burr write legislation that created the Biomedical Advanced
Research and Development Authority (Barda). Unlike the Pentagon, Barda, a
civilian agency, was granted fast-track contracting authority. It would get
promising drugs out of research labs into trials and through to production.
Unfortunately,
Barda was underfunded from the start. Pharma companies generally spend about a
billion dollars to get a single drug from idea to FDA license. “Look at $100
million for Barda,” says Kadlec, referring to the agency’s annual budget.
“We’ve been operating literally on dimes when they need dollars.” In the last
months of the Bush administration, he says, he persuaded the president to
propose an appropriation of $900 million. Unlike almost every other pet project
in Washington, it didn’t make it into the 2009 stimulus bill.
The
San Diego headquarters of Mapp Biopharmaceutical, maker of the experimental
drug ZMapp, in August 2014Photograph by Frank Duenzl via NewscomThe San Diego
headquarters of Mapp Biopharmaceutical, maker of the experimental drug ZMapp,
in August 2014Around the same time, Mapp Biopharmaceutical was looking for a
sponsor. Founded in 2003, the company has nine employees (as of Aug. 9) and no
external investors. For about a decade, it’s taken an approach to Ebola that
had been largely abandoned. Rather than develop a vaccine, which triggers the
body to create its own antibodies—defenses against a virus—Mapp worked to
develop monoclonal antibodies, a ready-made supply that can be introduced into
the body as a therapy after infection. The company didn’t respond to requests
for comment.
Mapp
had been funded through grants from NIAID, the civilian agency that did only
basic research. While NIAID continued to fund Mapp until 2013, the grants were
small, generally around $1 million a year, enough to keep the lights on, but
not enough to get Mapp into clinical trials. Barda, underfunded and then
focused on influenza, did not offer a contract. The agency’s spokeswoman,
Gretchen Michael, says that “in terms of Ebola, there haven’t been products
mature enough to get Barda level of funding” up until ZMapp this year. And so,
according to a person familiar with the project who wasn’t authorized to speak,
informal communication among scientists brought the company to the Defense
Threat Reduction Agency, or DTRA, the arm of the Pentagon that would lead it
out of the valley of death.
In the summer of 2011, right as Mapp was
looking for a new sponsor, DTRA was taking a hard look at what it was doing.
Created in 1998 largely to counter all weapons of mass destruction, DTRA had taken
on the task of developing drugs for the Pentagon, because there was no one else
to do it. The agency’s leadership toured labs, talked to researchers, and
brought in advisers from pharmaceutical companies and academia. The conclusions
from that review, laid out in a presentation this reporter has seen, weren’t
encouraging.
The
presentation describes the agency’s work as it was in 2011. Too much effort was
wasted on “knowledge products,” or basic science. Unpromising projects weren’t
killed and continued to waste money. Drug development was managed around yearly
budgets rather than end goals. Efficacy studies, which determine whether drugs
work on animals, weren’t complete. Nor were safety studies, which test whether
a drug is OK for human use. One slide lays out problems with 10 of the agency’s
programs. In one, samples of Ebola were found in a freezer in a containment lab
without patient histories, control samples, or even validation that they
contained the virus. The samples were safe but useless for drug development.
Overall,
the 2011 presentation concluded, the agency lacked “translational S&T
project management discipline,” which is a bureaucratic way of saying that
there was no way to take ideas and move them down the long path toward a drug
that has been approved by the FDA for production or technology ready for the
Pentagon to deploy.
Ebola
timeline
One
year later, in a second report, an external Ph.D. researcher looked at DTRA’s
projects on technology to detect chemical and biological attacks. He found “a
lack of solid technical oversight for a period of years” and “a near absence of
strategic vision, complicated by much programmatic incoherency.” One project
suffered from an “egregious lack of coordination.” Another is described as “an
unmitigated disgrace, divorced from any sense of reality.”
According
to two people familiar with the project who were not authorized to speak, Mapp
received a commitment from DTRA in February 2011 for MB-003, ZMapp’s predecessor.
This means that the antibody had been deemed a worthy idea but needed to go
through a review process before any actual money could be disbursed to develop
it. And that’s when the ZMapp program left the valley of death and entered
purgatory. Unlike Barda, DTRA doesn’t have fast-track contracting authority.
Rather, it uses the Pentagon-wide contracting standards. This is slow anywhere
in the Department of Defense. At DTRA, it can be agony.
“It
was one of the most frustrating places I ever worked,” says Riva Meade. “I
lasted 13 months.” Meade, now retired, worked in Pentagon contracting her
entire career, much of it at the Defense Advanced Research Projects Agency
(Darpa). Around the same time as the 2011 review, she was brought in to DTRA as
the chief of the agency’s business division.
Meade
describes two problems. First, DTRA’s contracting officers added unnecessary
hurdles into an already cumbersome process. They aimed to be what Meade calls
“super clean”—no audits, no reviews. This is difficult for research and
development, when the government is frequently buying something it’s never
bought before and doesn’t know how to buy it. “They just had a policy where
they wanted never to be called out for making mistakes,” says Meade. “If you
want to run a shop like that, it’s going to take a long time. I’m not sure it’s
a good policy when you’re working in R&D and you need to get things done
that the country needs done.” The contracts department also refused to use
expertise from other agencies to assess highly technical programs.
Meade’s
time as the business chief at DTRA also coincided with a culture clash within
the agency, one confirmed by three other people familiar with the agency who
declined to speak on the record. DTRA had hired several people with experience
at private pharmaceutical companies, who were used to killing programs and
spending money on the ones that remained.
The
new arrivals wanted to work like a drug company, and drive products through early
clinical trials. Older employees wanted to focus on research. “When you work
with a group of scientists who believe that the best thing that they can do is
have a published paper, you’re not going to get a lot of productivity when it
comes to pharmaceuticals,” says Meade. “Published papers are important in that
line of work, but that seemed to be more important to them than anything else.”
The
people with pharma experience, she says, in turn failed to show the patience
necessary to work in any government agency. “Frequently, what [government
contracting officers] were requesting was ridiculous,” she says, “but you know
what, you just do it.” One trick to federal contracting, she explains, is to
know when not to fight.
Kadlec,
the former Bush administration official who was still working in biodefense
medicine, was well aware of both the delay with ZMapp and the more general
problems at DTRA. He says other private companies working with the agency
encountered similar hold-ups. “It was like, can we do any better than this?” he
says.
Boots
drying out at sun after being washed with Chlorine at the MSF field hospital in
Kailahun, Sierra LeonePhotograph by Samuel ArandaBoots drying out at sun after
being washed with Chlorine at the MSF field hospital in Kailahun, Sierra Leone
In
late 2012, Kadlec wrote a report for the Center for Biosecurity at the
University of Pittsburgh Medical Center on the potential benefits of monoclonal
antibodies, the Mapp approach. The report, he says, was in part designed to
nudge DTRA toward completing Mapp’s contract. In it, he suggests that the
Pentagon fast-track a few sample projects, including one for “prophylaxis against
a fast-moving virus.” Kadlec does lay some blame on the Pentagon’s contracting
process, an encumbrance that civilian agencies don’t have to worry about. “You
have to do this like you’re buying an F-35,” he says. “As you well know, a
vaccine is not an airplane.”
In
February 2013, Alan Rudolph, whose name appears on several presentations urging
more streamlined decision-making at the agency, left DTRA. “I think that was a
huge divide,” says Meade. “The pharma guys lost.” Rudolph’s departure happened
to come the same month the agency finally wrote its first check to Mapp
Biopharmaceutical.
According
to one person familiar with DTRA, without the contract delays, Mapp could have
completed its human safety and animal efficacy trials by now to earn an FDA Emergency
Use Authorization, the step necessary for either the CDC or the Pentagon to
stockpile the drug. There’s no guarantee that, with this extra time, there
might now be doses of ZMapp in a warehouse. There’s still no guarantee that it
works. (It’s impossible to know from the handful of people who’ve taken it.)
But we’d have a better idea if it hadn’t been stuck in the federal bureaucracy
for four years. The drug’s path through the research labs of the
Washington-Baltimore corridor show that no part of the federal government is
set up to work as a pharmaceutical company. Barda is underfunded. DTRA can’t
move quickly. And the federal government, until now, hasn’t made Ebola a
priority. “That’s why we don’t have an Ebola countermeasure,” says Kadlec. “We
failed to invest enough dollars to have it mature.”
Even the seemingly straightforward stuff can
be hard. This summer, when Barack Obama decided that the U.S. was going to
bring home Americans stricken with Ebola, the White House had to deal with
pushback. According to two people familiar with the matter who weren’t
authorized to speak on the record, the State Department first asked the U.S.
Air Force, whose Transportation Command flies C-17 Globemasters outfitted with
biological containment systems for sick patients. But the Air Force demurred.
Its C-17s fly servicemen. The State Department didn’t respond to a late request
for comment on why the government used a private carrier. The Air Force
referred questions to the National Security Council. Edward Price, spokesman
for the NSC, says that “we did not request U.S. military transport,” by which
he means the White House.
A
shipment of supplies and equipment arrives in Liberia, the first since
President Obama’s speech at the CDC on Sept. 16Photograph courtesy U.S.
Embassy, MonroviaA shipment of supplies and equipment arrives in Liberia, the
first since President Obama’s speech at the CDC on Sept. 16
Biological
hazards are difficult to plan for. Any pathogen can pose a threat to troops
deployed abroad or citizens at home. It can spread as a weapon or on its own as
a natural outbreak. Any plan spends money on something that hasn’t happened
yet, something difficult for any president to do. And it forces different
federal agencies to work well together, something no U.S. president has yet
done. According to Kadlec, Bill Clinton became alarmed about bioterror toward
the end of his administration. George W. Bush fired his predecessor’s bioterror
adviser, then rehired him after Sept. 11. Dick Cheney was consumed by
bioterror. Barack Obama is now. And he’s handling a situation none of his
predecessors planned for: a natural foreign outbreak that may destabilize
countries and become a national security risk.
Barda
now has given Mapp Biopharmaceutical a $25 million contract to start clinical
trials with ZMapp. This is promising, but it hasn’t fixed the problem. The
Pentagon and the HHS have a list of threats, and no real way to work down the
list, to get treatments for these threats through the FDA’s approval process.
Every outbreak will make every administration look feckless and incompetent.
But the U.S., at the very least, needs to admit to itself that one of its
functions is to be a pharmaceutical company—and get better at it. “As long as
there’s not sufficient money to address every one of the targeted diseases,”
says Senator Burr, “it’s going to force the system to make a decision based on
what’s the greatest threat today.” He’s talking about his valley of death
problem. A lot of money for ZMapp hasn’t fixed it.
Bloomberg
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