We may not be so lucky next time


Lenzer


It may be due to dumb
luck—not public health preparedness—that only four people died from anthrax
bioterrorism to date, according to some experts. They warn that other organisms,
such as smallpox, which are highly contagious, could cause hundreds of thousands
of deaths in a matter of weeks. Problems with the anthrax vaccine, testing for
anthrax and its treatment, seemingly hindered or misrepresented at every step by
those who stand to make a buck, cause some to believe that unless the public
health is placed ahead of profits, the public may not be able to expect adequate
protection in the case of future bioterror attacks or naturally occurring
epidemics.

Just 10 weeks
before the September 11 attacks, top government officials participated in an
exercise dubbed Dark Winter. The exercise, held at Andrews Air Force Base in
Washington, DC, created a frightening scenario that eerily presaged terrorist
attacks of and after September 11. A paragraph from the final page of the Dark
Winter script reads: “The NY Times, Washington Post, and U.S.A
Today
receive anonymous letters demanding the immediate removal (one week)
of all U.S. forces from Saudi Arabia and all war ships from the Persian Gulf.
Failure to comply will result in renewed attacks on U.S., which will include
anthrax, plague and smallpox. Each letter also contained a genetic fingerprint
of the smallpox strain matching the fingerprint of the strain causing the
current epidemic.”

Dark Winter
participants were forced to cope with a smallpox release in Oklahoma City, in
which a projected 300,000 U.S. citizens would be infected, one-third of whom
would be dead or dying within the first 3 weeks of the attack. Analysts at the
Johns Hopkins Center for Civilian Biodefense Studies commenting on the exercise
concluded: “The lack of sufficient vaccine or drugs to prevent the spread of
disease severely limited management options.” They also noted that as the
vaccine supply dwindled and the healthcare system was “overwhelmed” in the
exercise, that social unrest increased and that there was “Sporadic violence
against minorities who appear to be of Arabic descent.”

Although some
could dismiss the Dark Winter program and its analysis as an intellectual
exercise, a review of some of the problems with existing vaccine, diagnostic
tests, and treatment of anthrax, given below, provides very little reassurance
of preparedness and raises a key question that the Hopkins analysts failed to
address, notably, “Why is the U.S. unable to respond effectively to such an
attack?”

 

What
The Anthrax Saga Reveals


At first blush,
vaccination may seem to be the surest protection against anthrax. However,
scientific uncertainty and faulty production techniques have derailed widespread
use of the vaccine. BioPort Corporation, the sole-source U.S. producer of
anthrax vaccine, has been beset by safety problems since the company’s
inception. Production was halted in 1998 due to quality-control concerns
identified during FDA inspections. As a result, the Defense Department has been
able to vaccinate only 500,000 of its 2.4 million troops despite a 1997 order
requiring all military personnel to receive the vaccine. In addition, a number
of troops have faced court martial rather than take the vaccine fearing that it
is the cause of the elusive Gulf War Syndrome.


Beyond safety,
however, some scientists say the real question is “Does the vaccine work?” The
Pentagon says it does. It points to studies showing that the vaccine was 88
percent effective in monkeys after 100 weeks. Government scientists point to
other studies showing that 62 of 65 vaccinated monkeys subjected to lethal
challenges of inhaled anthrax survived while all 18 unvaccinated monkeys died.
The Defense Department further defends the vaccine by pointing to a study of
at-risk wool-mill workers showing the vaccine to be 93 percent effective.

But Dr. Meryl
Nass isn’t convinced and states, “You won’t see me getting in line for the
vaccine.” Nass, who has written extensively on the use of anthrax for
bioterrorism, stated during Congressional testimony in 1999 that claims of
effectiveness based on the monkey studies are questionable. First, although
there are numerous strains of anthrax, only one strain was used to infect the
monkeys. In addition, Nass points out, in a study of vaccinated guinea pigs,
one-half of the animals died after exposure to 27 of 33 strains of anthrax. She
also notes that what works in monkeys may not work in humans.

Even the highly
touted wool mill study has raised as many questions as it answered. Doctors from
the National Naval Medical Center and the U.S. Army, writing in the Archives
of Internal Medicine
point out that the wool-mill worker study included so
few cases of inhaled anthrax (most had the skin form of anthrax) that it was
impossible to determine whether the vaccine provided any protection against
inhaled anthrax—even though it clearly reduced the cutaneous, or skin form, of
the disease. Experience with another vaccine suggests there may be good reason
for concern. A vaccine under development for plague had to be abandoned in 1999
when it was found that, although it did reduce the skin form of the disease
transmitted by flea bites, it failed to protect against its highly lethal,
inhaled form.

A 2000 report by
the House’s Government Reform Committee highlighted these concerns. The
committee concluded: “At best, the vaccine provides some measure of protection
to most who receive it. Just how much protection is acquired, by whom, for how
long, and against what level of challenge are questions the [Defense Department]
answers with an excess of faith but a paucity of science.”

Despite
scientific uncertainty and technical problems, the Pentagon has poured over $126
million into its exclusive relationship with BioPort, causing Reform Committee
members to conclude that the Defense Department is “captive to old technology
and a single, untested company.”

Questions about
financial conflicts of interest have also dogged BioPort. Critics have asked why
a start-up company with no track record was given a multimillion-dollar
contract. They also wanted to know why, when BioPort nearly went belly-up, the
Pentagon doubled the sole-source contract from $25.7 million to $49.8 million
while simultaneously reducing the contracted number of vaccine doses from 7.5 to
5.3 million. A central concern is the cozy relationship between BioPort and the
Pentagon (one of BioPort’s top guns is the former chairperson of the Joint
Chiefs of Staff, Admiral William Crowe).

Dr. Barbara Hatch
Rosenberg, a biological arms-control expert with the Federation of American
Scientists, argues, “Admiral Crowe has no expertise in anthrax vaccine. His only
role is to secure a contract and that’s not a position that should go to an
insider. It appears to be a conflict of interest.”


Commenting on the
revolving door between government officials and industry that can lead to
mega-buck contracts while too often giving short-shrift to the public interest,
Jerome Hoffman, Professor of Emergency Medicine at UCLA, notes, “Although
industry routinely tries to convince us that its motives are philanthropic, its
primary agenda is, and pretty much has to be, to maximize its own profits.” Dr.
Hoffman doesn’t believe that people expect anything different. But he points out
that we do expect our government to put the public’s interest first. “But the
pharmaceutical industry is one of the leading ‘contributors’ to both political
parties, and there are a lot of indications—from the ‘industry-friendly’
directives to the FDA (Food and Drug Administration) to the blanket rejection of
price controls on medications which are far more costly here than anywhere else
in the world, to the dance between Bayer and Secretary Thompson over the price
of Cipro—that our government values corporate interests over any other.”

 

America
for Bayer, Bayer for America


Although Cipro was
initially touted as the only cure for anthrax, some doctors were puzzled by the
claim. After all, a number of drugs, including penicillin and doxycycline, are
not only effective, but also are far cheaper, and in most instances, safer than
Cipro. Further, doctors have extensive experience treating anthrax with
penicillin and doxycycline, but virtually no experience with Cipro. So, how did
Cipro come to be the drug that Tom Brokaw would hold aloft while telling
viewers, “In Cipro we trust?”

In part, the
answer has to do with initial uncertainty about the anthrax spores and whether
they had been genetically engineered to be resistant to older antibiotics.
However, according to some physicians, that concern should not have been a green
light to endorse Cipro since there was virtually no experience with the drug in
human anthrax.

Another part of
the answer rests in the ability of Bayer, Cipro’s manufacturer, to file for Food
and Drug Administration approval for use in treating anthrax. Although, doctors
can legally prescribe medications that have not won FDA approval for a specified
condition (called “off-label” prescribing), there can be significant advantages
to having FDA approval, as the anthrax scare so clearly showed. In a very savvy
move in 2000, Bayer applied for FDA approval to use Cipro to treat anthrax. What
many people didn’t realize was that while Bayer won that approval (and
penicillin and doxycycline remained unapproved), it was not because Cipro was
clinically superior to penicillin or doxycycline, but because Bayer could afford
the enormous costs associated with winning FDA approval. Smaller companies that
manufacture generic drugs, such as penicillin, may be unable to underwrite such
costs. Following the anthrax scare, the government expedited approval for
penicillin and doxycycline and the Centers for Disease Control modified its
recommendations to doctors, indicating that both of these drugs were acceptable
treatments for anthrax following initial use of Cipro.

Although it
appeared that sufficient supplies of antibiotics were available for the anthrax
scare, questions of profiteering quickly arose. Bayer president and CEO, Helge
Wehmeier argued that the company already cut their wholesale prices for Cipro
from $1.77 to 95 cents per pill. But Cipro, which raked in over $1 billion in
U.S. sales in 2000, cost U.S. patients as much as $5 per pill—while generic
versions sell in other countries for 10 cents per pill.

According to a
Wall Street Journal
report, 3 U.S. drug makers are willing to sell generic
Cipro for 40 cents per pill and note that they would still be turning a profit
at that price. For its part, Wehmeier claims, “Bayer is fully committed to
supporting America in its war on bioterrorism.”

 

Testing
For Serum Parsnip Levels


During this flu season,
hospital emergency departments have been besieged with worried patients
wondering if they have anthrax. At this writing, the Centers for Disease Control
report that they are still receiving roughly 25-50 requests for anthrax testing
per week. With the filing of a $37 million lawsuit against doctors who sent an
anthrax victim home, mistakenly thinking he had the flu, doctors are also
shaking in their boots. They ask how they can be expected to tell which of the
several hundred thousand patients with flu symptoms could actually have anthrax.

Making matters
worse, some doctors are giving advice ranging from bad to ludicrous according to
some experts. Dr. Isadore Rosenfeld writing in the November 12 issue of
Parade
magazine told readers that they should ask their doctor for Cipro or
doxycycline if  “…you find yourself surrounded by people who, suddenly and for
no apparent reason, have come down with what is seemingly the flu…”

However, such
paranoia-inducing comments fly in the face of reason, according to other
doctors. Robert Solomon, MD, vice chair of the Department of Emergency Medicine
at Ohio Valley Medical Center in Wheeling, West Virginia asks, “One wonders if
Dr. Rosenfeld would consider that this is the flu season and that might be the
reason patients have flu symptoms?”


Unfortunately,
however, since early anthrax and flu have so many similar symptoms and since
anthrax cultures can take up to several days to yield results, some doctors
heaved a sigh of relief on November 5, when the Mayo Clinic and Roche announced
in a press conference that they had jointly developed a new test that could
diagnose anthrax in just 30 minutes. The new test relies on polymerase chain
reaction (PCR) that can detect minute amounts of the anthrax bacillus in a blood
sample.

Without this
test, some emergency doctors warn that flu season will be hell this year. “This
new test should be assessed by the appropriate federal agencies and made
available ASAP,” according to Meryl Nass. “There are several [tests] that look
pretty good, including the Mayo test,” adds Nass. She believes PCR tests could
rapidly screen out the majority of hoaxes, leaving a manageable number of
specimens to be tested further, to confirm that they are truly positive.

Indeed, the
claims made by Roche and the Mayo Clinic seem impressive. Franklin R. Cockerill,
III, MD, the Mayo Clinic microbiologist who led the anthrax test development
team claims that the test is 100 percent accurate when anthrax is present.
However, his claim is based only on test tube studies, and he acknowledges that
no human studies with the Roche test have been concluded that would allow
scientists to assess the test’s accuracy in humans. Therefore, until human
studies are completed, Dr. Cockerill recommends that the PCR test be used in
conjunction with conventional culture-based testing methods.

Another problem
with the Roche PCR test is that it can’t deliver on the very thing doctors say
they want most; the ability to reassure patients who don’t have the anthrax.
That’s because even if the test can accurately identify patients with anthrax in
their blood, such identification may come too late. According to Dr. Richard
Meyer, bioterrorism laboratory director with the Centers for Disease Control,
“We don’t know enough about when anthrax appears in the bloodstream to be
certain that sample collection after the onset of symptoms will be useful.”
Since anthrax is sequestered in the lungs and surrounding lymph nodes during the
initial phases of infection, some fear that by the time anthrax appears in the
blood, it may be too late to help the patient.

Solomon questions
Roche’s claims of 100 percent accuracy noting that there is no example of
anything in medicine that is 100 percent accurate in humans. “The PCR test is
based on test tube studies, and if you have 100 percent accuracy in a test tube
study, that’s wonderful. But it tells you absolutely nothing about how it will
perform in humans. Even if the test is highly accurate—and there is much reason
to doubt it will be—it won’t always be right. If you can’t assuage a patient’s
fears in a way that’s intellectually honest then it is deceitful to hold out a
negative test result as reassurance. If we’re going to order the test knowing it
will almost always be negative, because almost no one will have anthrax anyway,
then all we’re doing is pretending the reassurance is from the test rather than
because of the extraordinarily low prevalence of the disease. If that’s all
we’re doing, then a test for parsnip poisoning will serve the purpose quite
nicely.”

A recent CDC
report lends weight to Dr. Solomon’s concerns. In comparing a commercial PCR
test made by Idaho technologies, when six environmental samples grew anthrax on
culture, a PCR assay was only able to correctly identify anthrax in two of the
instances. On the other hand, of eight samples identified as positive by PCR,
only two were positive by culture. Several possible explanations for the test’s
inaccuracy were given including possible contamination, splitting of samples and
errors in methods of sample collection and preparation. In addition, it was
noted that PCR could identify spores that were killed or non-viable, showing a
positive result, while cultures would be negative.


Given such
problems with anthrax prevention and testing, some doctors have suggested that
patients get the flu shot. A microbiologist—not a physician—interviewed for a
PBS show on bioterrorism weighed in with the idea that the “patriotic” thing to
do is for all citizens of the U.S. to get the flu vaccine this year so doctors
could tell who had the flu and who didn’t. However, Solomon scoffs at the notion
that such an approach is useful for reassuring patients noting, “The flu shot is
only 70 percent effective in preventing influenza. This would leave a large
group of people more, not less, worried that they have anthrax when they develop
flu symptoms.” Others recommend testing for the flu when patients develop
symptoms. But Solomon dismisses this strategy as well stating, “Of all the
patients who present with flu symptoms, only half will actually have influenza.
Of those patients, many will not test positive for it in the lab. So most
patients with flu symptoms will not have a positive test for influenza. This
will leave another group of people panic-stricken.”

Roche has
announced that for its “contribution” to the war against bioterrorism, they are
donating free tests to a number of labs. But some see this as a cynical way to
promote a questionable test. The tests will sell for $50 to $60 a piece and can
only be run on Roche’s LightCycler machine that lists at $57,000.

 


Industry Response To Bioterror


The 19 percent profit
margin enjoyed by the pharmaceutical industry is the highest of any industry,
eclipsing the 5 percent median profits of all Fortune 500 firms. Hoffman
remarks, “When a drug company can make a product that is both profitable and
life-saving, it’s a win-win situation for everybody. But any time it comes to a
choice between the public health or profits, drug companies can and must
sacrifice the former for the latter, because like all corporations they see
their ultimate responsibility as being to their stockholders.

“The recent dance
between Bayer and the government over Cipro shows this quite clearly. Both
sides—and a mostly uncritical media—pushed the image of Tommy Thompson
heroically twisting Bayer’s arm to get a great price, and Bayer going along,
albeit just a bit reluctantly, as a ‘good corporate citizen.’ But while this was
all happening, Thompson’s Department of Health and Human Services was trying to
hush up the fact that its ‘discount’ price was more than twice as much as it was
paying the same company for the same pill in another government program. Of
course all these prices are far greater than what it would cost for a generic
version of ciprofloxacin, and even more compared to what it costs to produce the
drug—providing Bayer with a huge profit to go along with its public relations
success. When the next public health crisis arises, why should we expect
industry—or our government—to behave any differently?”

Although many
believe that profit incentives fuel medical innovation and scientific
excellence, critics believe that science itself may be deformed by financial
conflicts of interest. Hoffman comments, “Unfortunately, since so much money is
riding on the interpretation of scientific studies there is an enormous tendency
to inflate both the level of evidence, and its significance. That may be why we
seem to discover a great new cure for some terrible disease almost every
day—only to find out, over and over again, that very little has changed.

“When scientists
are funded by industry, the results tend to favor their sponsor
disproportionately,” states Hoffman. “While it is impossible to do perfect
science, the more that a researcher brings conflicts of interest to the work,
the more likely it is that the research itself will be tainted. If we really
want to put the public health first, we shouldn’t tolerate a system whereby the
majority of work on medicines is paid for directly by the pharmaceutical
industry, to whom the researchers are beholden.”

What can be done?
Hoffman states, “There are many possible alternatives to having a drug company
fund the grant, supervise the project, and own the data. I won’t even raise the
question of whether we would be better served by a national health care system,
for drug manufacturers as well as for physicians. But why not at least require,
for example, that a proportion of sales revenues—no more than they currently
spend—be placed in a central pot, to be administered to scientists by the
National Institutes of Health, without any direct tie to the companies?”

What does Hoffman
think it would take to make needed changes? “It is up to us—the citizenry, not
just physicians—to demand that government look out for the public interest and
not the corporate bottom line. We may have lucked out this time, because anthrax
is hard to spread, but we’d better think hard about fundamental changes if we
don’t want to be so dependent on luck in the future.”                      Z



 

Jeanne
Lenzer is a freelance journalist.