Last post, I described some of the features of the voluntary process that might convince veterinary drug companies to give up lucrative approvals to sell antibiotics for production purposes, like growth promotion and feed efficiency. In essence, the voluntary process laid out in Draft Guidance for Industry #213 (Guidance #213), will allow drug companies to apply for new approvals of the same drugs for therapeutic purposes, broadly defined to include disease prevention and control as well as the treatment of demonstrably ill animals. Sales under the new approvals will allow companies to make up for profits lost in giving up production claims.
From a public health point of view, new preventive uses are likely to be indistinguishable from—and just as troublesome as–the production uses they replace. Both involve large quantities of antibiotics used at low levels over long periods of time, the perfect recipe for encouraging the development of resistant bacteria.
Relabeling rather than reducing the massive uses of antibiotics would be a public health failure.
Draft Guidance #213 responds to the temptation of relabeling by imposing special criteria for new approvals for prevention claims. While at first blush these criteria appear to be reassuring, they are anything but. In effect, they offer a new path to drug approval that would circumvent and weaken current regulatory standards.
Guidance #152: A Public Health Victory for FDA
Current standards are embodied in Guidance for Industry #152 (Guidance #152), one of the genuinely bright spots in the FDA’s record of combating antibiotic resistance. Put in place in 2003, Guidance #152 established an elegant way of combining qualitative factors, for example how drugs are used in human medicine and the levels of consumption of food animals, to reach an assessment of the potential for an animal drug to cause resistant disease that matters to humans.
The standards are based on the scientifically sound principle that the overall amount of drug use is a major driver of the evolution of antibiotic resistance. Thus, Guidance #152 rates flock-wide or herd-wide uses of drugs a key factor in assessing risk, regardless of whether the uses are for preventive or production purposes.
Typically, cattle, swine and poultry are raised in very large, confined animal feeding operations (CAFOs). Resistant bacteria fill the guts of all these animals and are also found on their skin and in their manure. Exposure to antibiotics enriches the populations of resistant bacteria in guts and manure lagoons, which then make their way to humans through food, other humans and the environment. Herd- and flock-wide drug use in CAFOs help explain the continued use of massive quantities of drugs sold in the U.S.
An important factor in Guidance #152 is whether the animal drugs are (or are in classes of drugs that are) used in human medicine. If so, resistance has implications for human (and animal) medicine. Such drugs are considered “medically important.”
The good news is that adherence to Guidance #152 has brought to a virtual halt the issuance of new approvals of medically important drugs for herd-wide and flock-wide uses in major food animal species—cattle, swine, or poultry.
Although Guidance #152 needs improvement—for example, to broaden its definition of drugs critically important to humans beyond those involved in foodborne illness—the fact that the FDA has not approved medically important drugs for large-scale, indiscriminate use for the past decade is a major triumph for public health.
Draft Guidance # 213: A Way Around Guidance #152
Surprisingly, Draft Guidance #213 does not propose to apply Guidance #152 to its decisions for new approvals. Instead it offers a separate approval process “in lieu of Guidance #152” that speaks to the issues of duration and level of use and treatment of apparently healthy animals, but leaves lots of wiggle room.
For example, the new labels for prevention would have to specify a duration of use, but the guidance does not say how long that duration can be. Draft Guidance #213 encourages, but does not require, that doses for the prevention uses be higher than current production doses.
But the big loophole in Draft Guidance #213 is the FDA’s expectation that any new indications should “be available only to those animals that need the drug for the new indication, rather than the entire flock or herd when such use is not necessary.” This leaves open the possibility that routine flock- or herd-wide use can be considered when it is necessary, an option not available in Guidance#152.
In fact, considering necessity as a factor in risk assessment of animal drugs goes beyond the FDA’s statutory authority. Although it is not clear how necessity would play out in the new approval process, the concept is foreign to the Food, Drug and Cosmetic Act, which flatly requires that new animal drugs intended for use in food-producing animals be safe with regard to human health (21 C.F.R. 514.1(b)(8)). The statute does not allow for the approval of unsafe drugs because they are necessary for animal health or efficient meat production.
The conditions most likely to necessitate long term preventive uses of antibiotics in flocks or herd are endemic diseases resulting from diet or crowded, stressful conditions in CAFOs.
A Sweet Deal for Industry
We cannot know whether the FDA will walk through the doors it opened in Guidance #213. It may not. But, as we discussed last post, the voluntary process puts the agency under great pressure to satisfy the demands of the industry with regard to new approvals.
New flock- and herd-wide approvals for prevention would lock in high drug use in CAFOs and gut the victories achieved under Guidance #152. It is possible that the weaker standard in Draft Guidance #213 could eventually displace the high standard of Guidance #152 altogether.
A sweet deal for industry, a travesty for public health.