November 15, 2000


 FDA hastening withdrawal of fluoroquinolone approvals for poultry

Posted Nov. 1, 2000

The FDA-CVM plans to withdraw approval for fluoroquinolone use in poultry, an action the AVMA believes would "sidestep the process" the agency created for assessing the public health risk of animal drugs with some degree of antimicrobial resistance.

According to industry sources, in October the agency asked the manufacturers, Bayer Corporation and Abbott Laboratories, to voluntarily withdraw their fluoroquinolone products labeled for use in chickens and turkeys from the market because of concerns over fluoroquinolone-resistant Campylobacter. If the companies do not agree to voluntarily withdraw the drugs, enrofloxacin and sarafloxacin, the FDA is expected to issue a Notice for Opportunity of Hearing.

Taking that action would short-circuit the FDA's evaluation process of the Framework document by skipping the public meeting where acceptable risk and setting of the monitoring and resistance thresholds will be discussed.

FDA-CVM director, Dr. Stephen F. Sundlof said that, until the end of October, he could neither confirm nor deny that the agency is moving toward withdrawal. "It's a regulatory issue that has to go through a specific process, and during that process, even until we've reached a final decision, we're not allowed to comment on it."

As to whether the FDA would follow its Framework document, Dr. Sundlof would say only, "While we're trying to develop policy—which is what the Framework document is all about—if we thought that the public health was in jeopardy, even though we may have not come to a final policy on how we're going to regulate these products, we would be compelled to move to prevent any further risk to the public health."

The AVMA, the Animal Health Institute, and the Coalition for Animal Health have each written to Secretary of Health and Human Services Donna E. Shalala expressing concern with the CVM's anticipated actions. In its Oct 11 letter the AVMA objected to the planned action to remove the fluoroquinolone approvals before the resistance threshold is established.

AVMA executive vice president, Dr. Bruce W. Little, signer of the letter, also pointed out that the FDA has not published its final risk assessment on the human health impact of Campylobacter resistance to fluoroquinolones associated with use in chickens.

The AVMA wants to review the final risk assessment to determine whether the aggressive efforts instituted by the Association and the poultry industry to reduce the risk of resistant organisms or genetic material developing in animals have had the desired effect. Those efforts include AVMA promoting judicious veterinary use of antimicrobials—including fluoroquinolones, and developing educational materials with the AASP, AAAP, and AABP through an FDA grant. The AVMA is also funding a pilot project to initiate an animal pathogen-resistance monitoring program and is helping support a Veterinary Antimicrobial Decision Support System.

Currently available data would point to the need for more thorough review of data before further FDA action is taken. FoodNet reported a 19 percent decrease in the incidence of human Campylobacter foodborne infections between 1998 and 1999, for example. Reportedly the proportion of resistant Campylobacter on chickens at slaughter remained constant or slightly declined during that time. For this reason the AVMA anticipates that the final FDA risk assessment should report a decrease in the human health impact related to the presence of fluoroquinolone-resistant Campylobacter on chickens.

Another piece of data that creates doubt over the alleged link between poultry and human isolates is that the percentage of human Campylobacter isolates increased from 13.3 percent in 1998 to 17.6 percent in 1999, while the percentage remained level or slightly declined in the presumed major source of resistant Campylobacter—chicken.

Also, at a CDC Emerging Disease Conference this past July, preliminary analysis of a 1998 CDC case control study was presented. Questions arise when one reads the printed abstracts. As indicated by odds ratios, the associations with human Campylobacter infections, in order of importance from greatest to least, were as follows: foreign travel, drinking raw milk, eating chicken or poultry meat cooked outside the home, eating nonpoultry meat cooked outside the home, having contact with farm animals, living on or visiting a farm, having contact with puppies, eating undercooked poultry, and eating raw seafood.

The AVMA called for an interdepartmental agency approach whereby not only the FDA but also the USDA would develop a risk assessment management policy associated with antimicrobial use in animal agriculture.

The Animal Health Institute's Oct 9 letter to Secretary Shalala, signed by Alexander Mathews, president and CEO, contends: "The risk assessment contemplates only the single action of product removal and provides no opportunity to predict or measure the success of that action in safeguarding human health." That conclusion was reached by a risk assessor the AHI retained-the same expert the CVM itself had consulted when it initially started development of its risk model.

"We believe that it is imperative that CVM complete its risk assessment on the use of fluoroquinolones in poultry only after the current modeling effort is reviewed by additional risk assessment experts," the AHI stated. "An outside review by risk assessment experts or by the GAO will reveal whether the CVM model can provide an analysis of public policy alternatives, including suspension of the use of an approved product."

The Coalition for Animal Health, of which the AVMA is a member, wrote to Secretary Shalala on Oct 11 that its members are "extremely dismayed" at the CVM's approach toward regulating fluoroquinolone use in food-producing animals. "This is the FDA/CVM's first effort to withdraw an approval based on resistance concerns since it published its draft antibiotic resistance 'framework' in December 1998, so this action will establish the precedent for all future regulatory activity," the Coalition stated. "It strikes us as manifestly unfair that CVM would begin a regulatory activity without allowing the regulated manufacturers to see the case on which the action is based."

The Coalition expressed deep concern over recent public statements by high-level CVM officials indicating that public opinion now carries equal weight with sound science in determining policy. "US regulatory agencies simply cannot follow the example of European agencies in allowing the 'precautionary principle' to override science in setting regulatory policy."

The Coalition calls for Secretary Shalala's personal intervention and strongly suggests that she (1) suspend any regulatory actions based on the current risk assessment, (2) convene a group of risk assessment experts to review the CVM model, (3) have the Interagency Task Force on Antimicrobial Resistance conduct an in-depth review of the CVM Framework document and risk assessment, and (4) identify the impact of recent USDA and industry successes in reducing the prevalence of pathogens in meat and poultry on potential resistance.

Late development

As the JAVMA went to press, the FDA-CVM announced it does propose to withdraw approval of the new animal drug application for use of the fluoroquinolone antimicrobial enrofloxacin in poultry. As grounds, the agency cites new evidence that the product has not been shown to be safe.

The CVM has issued a notice of opportunity for a hearing on its proposal, scheduled to be published in the Oct 31, 2000 Federal Register. It is also available through the FDA's Dockets Management Branch at

Individuals or companies covered by the notice must submit a request for a hearing within 30 days of the notice's publication in the Federal Register.