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FDA Rules Override Warnings About Drug

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 there."

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."

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