FDA: disregards human health


Richard Moore

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    FDA Rules Override Warnings About Drug
    By Rick Weiss
    The Washington Post
    Sunday 04 March 2007
Cattle antibiotic moves forward despite fears of human risk.

The government is on track to approve a new antibiotic to treat a pneumonia-like
disease in cattle, despite warnings from health groups and a majority of the 
agency's own expert advisers that the decision will be dangerous for people.

The drug, called cefquinome, belongs to a class of highly potent antibiotics 
that are among medicine's last defenses against several serious human 
infections. No drug from that class has been approved in the United States for 
use in animals.

The American Medical Association and about a dozen other health groups warned 
the Food and Drug Administration that giving cefquinome to animals would 
probably speed the emergence of microbes resistant to that important class of 
antibiotics, as has happened with other drugs. Those super-microbes could then 
spread to people.

Echoing those concerns, the FDA's advisory board last fall voted to reject the 
request by InterVet Inc. of Millsboro, Del., to market the drug for cattle.

Yet by all indications, the FDA will approve cefquinome this spring. That 
outcome is all but required, officials said, by a recently implemented "guidance
document" that codifies how to weigh the threats to human health posed by 
proposed new animal drugs.

The wording of "Guidance for Industry #152" was crafted within the FDA after a 
long struggle. In the end, the agency adopted language that, for drugs like 
cefquinome, is more deferential to pharmaceutical companies than is recommended 
by the World Health Organization.

Cefquinome's seemingly inexorable march to market shows how a few words in an 
obscure regulatory document can sway the government's approach to protecting 
public health.

Industry representatives say they trust Guidance #152's calculation that 
cefquinome should be approved. "There is reasonable certainty of no harm to 
public health," Carl Johnson, InterVet's director of product development, told 
the FDA last fall.

Others say Guidance #152 makes it too difficult for the FDA to say no to some 

"The industry says that 'until you show us a direct link to human mortality from
the use of these drugs in animals, we don't think you should preclude their 
use,' " said Edward Belongia, an epidemiologist at the Marshfield Clinic 
Research Foundation in Wisconsin. "But do we really want to drive more 
resistance genes into the human population? It's easy to open the barn door, but
it's hard to close the door once it's open."

The FDA knows how hard it can be to close that door. In the mid-1990s, 
overriding the objections of public health experts from the Centers for Disease 
Control and Prevention (CDC), the drug agency approved the marketing of two 
drugs, Baytril and SaraFlox, for use in poultry. Both are fluoroquinolones, a 
class of drugs important for their ability to fight the bioterror bacterium that
causes anthrax and a food-borne bacterium called campylobacter, which causes a 
serious diarrheal disease in people.

Before long, doctors began finding fluoroquinolone-resistant strains of 
campylobacter in patients hospitalized with severe diarrhea. When studies showed
a link to poultry, the FDA sought a ban. But while Abbott Laboratories, which 
made SaraFlox, pulled its product, Baytril's manufacturer, Bayer Corp., pushed 

"They fought this tooth and nail. It took years," said Kirk Smith, an 
epidemiologist at the Minnesota Department of Health.

Finally, late in 2005, Bayer gave up, but not before fluoroquinolone resistance 
had spread even further.

    A Question of Resistance

Microbes are constantly mutating, and some of those mutations happen to confer 
immunity to one drug or another. Exacerbating the problem, bacteria constantly 
exchange bits of DNA with each other, spreading that resistance.

Given those realities, experts agree that all antibiotics should be used 

"If a drug is used less, then less resistance emerges," said Patricia Griffin, 
chief of intestinal disease epidemiology for the CDC.

Prudence is especially important for medicines of last resort, which is why the 
cefquinome application stirred such a storm.

Cefquinome is a fourth-generation cephalosporin, the most recent of several 
steadily improving versions of the cephalosporin family of antibiotics. Only one
medicine from that family has been approved in the United States - a powerful 
human drug called cefepime (brand name Maxipime), which is the only effective 
treatment for serious infections in cancer patients and a reliable lifesaver 
against several other nearly invincible infections.

InterVet developed cefquinome to treat bovine respiratory disease, the most 
common disease in cattle. Recognizing the potential public health implications 
of using a close cousin of cefepime in animals, the FDA's Center for Veterinary 
Medicine, which oversees animal drug approvals, convened its expert advisers in 

One of the first things the group learned was that more than a dozen medicines 
are already on the market for the respiratory syndrome, and all are still 

"If we have no susceptibility problem, why do we need one more new drug?" asked 
James E. Leggett Jr., a professor of medicine at Oregon Health & Science 
University, whom the FDA brought in as a consultant on the cefquinome question.

The panel also learned that the disease would be a relatively minor issue but 
for the stressful conditions under which U.S. cattle are raised, including 
high-density living spaces and routine shipment on crowded trains for hundreds 
or thousands of miles. Those "production dynamics" suppress the animals' immune 
systems, explained feedlot consultant Kelly Lechtenberg of Oakland, Neb., and 
virtually guarantee that bovine respiratory disease will be a major problem.

Yet Stephen Sundlof, head of the FDA's Veterinary Medicine Center, told the 
panel members that under agency rules they should ignore those issues and 
consider only the language in Guidance #152.

    Flaws Seen in Rules

Guidance #152 is essentially a checklist of points to consider when weighing the
potential human impact of a new animal drug.

After the Baytril debacle, the public health community embraced the idea of a 
guidance document. A formalized risk-assessment process promised to minimize the
chances of making a bad regulatory call.

But a struggle ensued when the FDA hosted meetings to spell out the criteria to 
be used for measuring risk, often with veterinarians and veterinary drug 
companies on one side and doctors and public health experts on the other.

When differences could not be resolved after repeated drafts and months of work,
the agency sidestepped some tough issues and adopted language that both sides 
agree can block approval of the most worrisome drugs - those such as Baytril 
that are put in animal feed or water, and so are easily overused. But public 
health experts say the wording tilts the playing field toward industry for other
kinds of drugs. They want to see it revised.

Most glaring, they say, is that the guidance makes it almost impossible to say 
no to a new animal drug unless it is likely to threaten the effectiveness of an 
antibiotic that is a critical player against food-borne illnesses. By contrast, 
the World Health Organization recommends saying no if approval would spur 
resistance to any antibiotic that is important for fighting "serious human 
disease" - not just food-borne illnesses.

Cefquinome's primary threat is that it may undermine the usefulness of the 
closely related human drug, cefepime. But as it turns out, the FDA does not 
consider cefepime a front-line drug against food-borne infections. So although 
it is a highly important drug in human medicine generally - and although the 
Infectious Diseases Society of America even recommends it against some 
food-borne bacteria - that risk does not count under the terms of Guidance #152.

A related problem is that the guidance's definition of "food-borne" is 
conservative, said Margaret Mellon of the Union of Concerned Scientists, a 
science policy advocacy group. For example, most urinary tract infections are 
caused by intestinal bacteria acquired from food, and cefepime is prescribed for
those infections. If the FDA counted those infections as food-borne, then the 
guidance's formula would call for rejecting cefquinome for cattle.

"But FDA didn't do that," Mellon said. "That restricted the analysis right 

Moreover, the guidance does not take into account that when microbes become 
resistant to fourth-generation cephalosporins, they often gain resistance to 
third-generation versions, too.

Third-generation cephalosporins are among the only effective therapies for 
serious gastrointestinal diseases in children and are the sole therapies for 
many cases of meningitis. That means the emergence of resistance to 
fourth-generation cephalosporins "could have a much more far-reaching effect" 
than is considered under the terms of Guidance #152, John H. Powers, a medical 
officer at the FDA's Center for Drug Evaluation and Research, told the agency's 
panel of experts.

    How Great a Risk?

Richard Carnevale, vice president for scientific and regulatory affairs at the 
Animal Health Institute, which represents veterinary drugmakers, said critics 
should not presume that a dozen drugs effective against bovine respiratory 
syndrome are enough.

"It's not a question of whether there is a need or not," Carnevale said. "The 
answer is, there's always a need."

The institute contends that the risk to human health posed by animal antibiotics
has been overblown.

Officials at InterVet declined several requests to be interviewed. In a 
statement, the company said it "fully supports the prudent use of antibiotics in

The statement also said that in Europe, fourth-generation cephalosporins similar
to cefquinome have been used in animals for the past decade "without 
compromising the interests of public health."

Yet recent European data indicate that resistance against this class of 
antibiotics is on the rise.

An analysis of E. coli bacteria in pigs and other animals in Spain, published in
December, found high levels of the resistance that renders fourth-generation 
cephalosporins useless. A January report from Britain documented similar 
resistance patterns emerging at 10 farms.

Microbes resistant to fourth-generation cephalosporins have also begun to pop up
in European patients. Such resistance is virtually unknown in the United States,
where fourth-generation cefepime has been used in patients since 1997. That 
suggests that the resistance emerging in Europe is a result of veterinary use, 
said Steve Roach of the Food Animal Concerns Trust, a Chicago public interest 

Roach says he is concerned that history is about to repeat itself. U.S. cattle 
were free of bacteria resistant to third-generation cephalosporins in 1997, but 
by 2003 one of every five samples was resistant. "This is exactly what should be
avoided with cefquinome," he said.

    Merely Suggestions

At the FDA advisory meeting in September, the agency's experts defied Guidance 
#152 and voted 6 to 4 against approval of cefquinome. But that day, and in 
follow-up interviews, Sundlof, the agency's veterinary chief, made it plain that
the vote was "not binding."

"I think we all agreed ... that Guidance for Industry #152 would be the criteria
against which we would base our decisions on safety," Sundlof said at the 

Concerned that the FDA is poised to approve cefquinome, Congress's only 
microbiologist recently wrote to the agency.

"Given the recent outbreaks of E. coli and other food borne illnesses across the
nation, it is hardly the time to ignore the advice of scientists, and 
potentially impair our ability to treat deadly infections," wrote Rep. Louise M.
Slaughter (D-N.Y.), who chairs the House Rules Committee.

Yet, being realists, the FDA advisers in September said more than just no. They 
told the FDA that if it approves cefquinome, then it should at least impose 
limits to minimize the potential consequences. One suggestion was to explicitly 
preclude "off label" use of the drug - that is, to tell veterinarians that it 
can be used only for bovine respiratory disease.

But Sundlof said that, under FDA rules, those decisions must be left up to 
veterinarians unless there is clear evidence that wider use is causing harm.

"We have to take a fairly legal interpretation," Sundlof said in an interview. 
"If we have no evidence of a problem, or sparse evidence, we would not be able 
to make the prohibition prior to approval."

However, raising a point that opponents do not find very reassuring, he noted: 
"As soon as we have the first glimpse of evidence that off-label use of a drug 
is causing resistance, we have the authority to prohibit off-label use."

The advisers also urged that as a condition of approval, the FDA should demand 
that InterVet provide annual reports on how much cefquinome was used and in 
which animals - data that would help scientists detect links between the drug's 
use and patterns of resistance that emerge in people.

"Without reliable, meaningful data on the quantity of use, the purpose of use, 
the type, number and location of animals treated, it will be exceedingly 
difficult to interpret fluctuations in rates of resistance," said Susan Prolman 
of the Union of Concerned Scientists.

    But Sundlof offered little hope for that outcome.

"That is information that would be useful to have," he said. But the agency does
not have the authority to demand it.

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